Veterinary Psychopharmacology Veterinary Psychopharmacology

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Second Edition

Sharon L. Crowell‐Davis, DVM, PhD, DACVB Professor of Behavioral Medicine Department of Veterinary Biosciences and Diagnostic Imaging College of Veterinary Medicine University of Georgia Athens, USA

Thomas F. Murray, PhD Provost Creighton University Department of Pharmacology Omaha, USA

Leticia Mattos de Souza Dantas, DVM, MS, PhD, DACVB Clinical Assistant Professor of Behavioral Medicine University of Georgia Veterinary Teaching Hospital Department of Veterinary Biosciences and Diagnostic Imaging College of Veterinary Medicine University of Georgia Athens, USA This edition first published 2019 © 2019 John Wiley & Sons, Inc.

Edition History John Wiley & Sons (1e, 2005)

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Library of Congress Cataloging‐in‐Publication Data Names: Crowell-Davis, Sharon L., author. | Murray, Thomas, 1946– author. | Dantas, Leticia Mattos de Souza, author. Title: Veterinary psychopharmacology / Sharon L. Crowell-Davis, Thomas F. Murray, Leticia Mattos de Souza Dantas. Description: Second edition. | Hoboken, NJ : Wiley-Blackwell, 2019. | Includes bibliographical references and index. | Identifiers: LCCN 2018040372 (print) | LCCN 2018040803 (ebook) | ISBN 9781119226246 (Adobe PDF) | ISBN 9781119226239 (ePub) | ISBN 9781119226222 (hardback) Subjects: | MESH: Veterinary Medicine–methods | Psychopharmacology–methods | Veterinary Drugs | Psychotropic Drugs Classification: LCC SF756.84 (ebook) | LCC SF756.84 (print) | NLM SF 756.84 | DDC 636.089/578–dc23 LC record available at https://lccn.loc.gov/2018040372 Cover Design: Wiley Cover Images: © Leticia Mattos de Souza Dantas, © Thomas F. Murray, © Sharon L. Crowell-Davis

Set in 10/12pt Warnock by SPi Global, Pondicherry, India

10 9 8 7 6 5 4 3 2 1 For my children, James Michael and Kristina Ruth, who have been a source of invaluable support through a rough few years. For my husband, Bill, who loved being married to a scientist, and who supported my work in so many ways I couldn’t list them all. For my new co‐author, Leticia Dantas, friend and colleague beyond compare. For my parents, Ruth and Wallace Davis, who have passed on to another world, but who are also with me every day. Thank you for everything you taught me. For all the furred and feathered beings who have taught me so much over the years. For Rhiannon, who understands. – Sharon L. Crowell‐Davis

This is dedicated to my wife Cristina P. Murray, daughter Lia L. Murray and family Maltipoo, Sport. – Thomas F. Murray

To all my patients and beloved pets who have driven me to relentlessly seek more knowledge, more experience, and never accept defeat even when inevitable as sometimes it is in medicine. To my Tiger (a.k.a. Tatá), a very special cat whose sweetness and intelligence have brought such joy to my life and taught me, my family, and many staff members and students at UGA so much. You might never know, but you will always guide and inspire me. To my son, best friend and light of my life, John‐Eduardo Dantas Divers (a.k.a. Dado), whose birth has awakened a larger than life quest to always be the best version of myself. To my beloved husband, Steve Divers, my loving cheerleader and supporter. To my friend, Sharon Crowell‐Davis, who is an example of strength, kindness and resilience. It has been such a privilege to share this extraordinary project with you. – Leticia Mattos de Souza Dantas vii

Contents

Contributors xxi Preface xxiii Acknowledgments xxv

Part I Principles of Veterinary Psychopharmacology 1

1 General Principles of Psychopharmacology 3 Thomas F. Murray Drug Action 3 Dose Dependence of Drug Interaction with Receptors 4 Structural Features of the Central Nervous System (CNS) and Neurotransmission 5 Biogenic Amine Neurotransmitters and Affective Disorders 8

2 Amino Acid Neurotransmitters: Glutamate, GABA, and the Pharmacology of Benzodiazepines 11 Thomas F. Murray Introduction 11 Glutamatergic Synapses 11 Pharmacology of Ketamine and Tiletamine 14 GABAergic Synapses 15

3 Biogenic Amine Neurotransmitters: Serotonin 21 Thomas F. Murray Introduction 21 The Biogenic Amines 21 Serotonin 22

4 Biogenic Amine Transmitters: Acetylcholine, Norepinephrine, and Dopamine 29 Thomas F. Murray Acetylcholine 29 Norepinephrine 32 Dopamine 37

5 Neuropeptides: Opioids and Oxytocin 43 Thomas F. Murray Introduction 43 Endogenous Opioid Peptides 43 Oxytocin 47 viii Contents

Part II Practice of Veterinary Psychopharmacology 51

6 Introduction to Clinical Psychopharmacology for Veterinary Medicine 53 Sharon L. Crowell‐Davis and Leticia Mattos de Souza Dantas Introduction 53 Prescribing in the United States: The Animal Medicinal Drug Use Clarification Act (AMDUCA 1994) 54 Cost 55 Drug Selection 56 Medicating the Patient 57 Competition Animals 58 Taking the Behavioral History 58 The Behavioral Exam 63 Duration of Treatment 63 Limitations 64

7 Benzodiazepines 67 Leticia Mattos de Souza Dantas and Sharon L. Crowell-Davis Action 67 Overview of Indications 67 Contraindications, Side Effects, and Adverse Events 69 Overdose 69 Clinical Guidelines 69 Specific Medications 71 I. Alprazolam 71 Clinical Pharmacology 71 Uses in Humans 72 Contraindications 72 Side Effects 72 Overdose 72 Doses in Nonhuman Animals 72 Discontinuation 72 Other Information 72 Effects Documented in Nonhuman Animals 73 II. Chlordiazepoxide HC1 73 Clinical Pharmacology 73 Uses in Humans 74 Contraindications 74 Side Effects 74 Overdose 75 Doses in Nonhuman Animals 75 Discontinuation 75 Other Information 75 Effects Documented in Nonhuman Animals 75 III. Clonazepam 76 Clinical Pharmacology 76 Uses in Humans 76 Contents ix

Contraindications 76 Side Effects 77 Drug Interactions 77 Overdose 77 Doses in Nonhuman Animals 77 Discontinuation 77 Other Information 77 Effects Documented in Nonhuman Animals 77 IV. Clorazepate Dipotassium 78 Clinical Pharmacology 78 Uses in Humans 79 Contraindications 79 Side Effects 79 Dependence 79 Overdose 79 Doses in Nonhuman Animals 79 Effects Documented in Nonhuman Animals 79 V. Diazepam 80 Clinical Pharmacology 80 Uses in Humans 82 Contraindications 82 Side Effects 82 Overdose 83 Doses in Nonhuman Animals 83 Discontinuation 83 Other 83 Effects Documented in Nonhuman Animals 84 VI. Flurazepam Hydrochloride 86 Clinical Pharmacology 86 Uses in Humans 87 Contraindications 87 Side Effects 87 Overdose 87 Doses in Nonhuman Animals 87 Effects Documented in Nonhuman Animals 87 VII. Lorazepam 87 Clinical Pharmacology 87 Uses in Humans 88 Contraindications 88 Side Effects 89 Overdose 89 Doses in Nonhuman Animals 89 Discontinuation 89 Effects Documented in Nonhuman Animals 89 VIII. Oxazepam 89 Clinical Pharmacology 89 Uses in Humans 90 Contraindications 90 x Contents

Side Effects 90 Overdose 90 Doses in Nonhuman Animals 90 Discontinuation 91 Other Information 91 Effects Documented in Nonhuman Animals 91 IX. Triazolam 91 Clinical Pharmacology 91 Uses in Humans 91 Contraindications 91 Side Effects 91 Overdose 92 Doses in Nonhuman Animals 92 Effects Documented in Nonhuman Animals 92 Important Information for Owners of Pets Being Placed on Any Benzodiazepine 92

8 Selective Serotonin Reuptake Inhibitors 103 Niwako Ogata, Leticia Mattos de Souza Dantas, and Sharon L. Crowell‐Davis Action 103 Overview of Indications 103 Contraindications, Side Effects, and Adverse Events 104 Adverse Drug Interactions 104 Overdose 105 Clinical Guidelines 105 Specific Medications 106 I. Citalopram Hydrobromide 106 Clinical Pharmacology 106 Uses in Humans 106 Contraindications 106 Side Effects 106 Overdose 107 Other Information 107 Effects Documented in Nonhuman Animals 107 II. Fluoxetine Hydrochloride 108 Clinical Pharmacology 108 Uses in Humans 108 Contraindications 108 Side Effects 109 Overdose 110 Doses in Nonhuman Animals 110 Discontinuation of Fluoxetine 110 Other Information 110 Effects Documented in Nonhuman Animals 110 III. Fluvoxamine 115 Clinical Pharmacology 115 Uses in Humans 115 Contraindications 115 Side Effects 116 Contents xi

Overdose 116 Other Information 116 Effects Documented in Nonhuman Animals 116 IV. Paroxetine Hydrochloride 117 Clinical Pharmacology 117 Uses in Humans 117 Contraindications 117 Side Effects 118 Overdose 119 Discontinuation of Paroxetine 119 Other Information 119 Effects Documented in Nonhuman Animals 119 V. Sertraline Hydrochloride 119 Clinical Pharmacology 119 Uses in Humans 120 Contraindications 120 Side Effects 120 Other Information 121 Effects Documented in Nonhuman Animals 121 VI. Escitalopram Oxalate 122 Clinical Pharmacology 122 Uses in Humans 122 Contraindications 122 Side Effects 123 Overdose 123 Other Information 123 Effects Documented in Nonhuman Animals 123 Important Information for Owners of Pets Being Placed on Any SSRI 124

9 Miscellaneous Serotonergic Agents 129 Leticia Mattos de Souza Dantas and Sharon L. Crowell‐Davis Introduction 129 Azapirones 129 Action 129 Overview of Indications 129 Contraindications, Side Effects, and Adverse Events 129 Adverse Drug Interactions 129 Overdose 129 Clinical Guidelines 129 Specific Medications 130 I. Buspirone 130 Clinical Pharmacology 130 Uses in Humans 131 Contraindications 131 Side Effects 131 Overdose 131 Other Information 131 Effects Documented in Nonhuman Animals 132 xii Contents

Serotonin Antagonist/Reuptake Inhibitors (SARIs) 135 Action 135 Overview of Indications 135 Contraindications, Side Effects, and Adverse Events 135 Adverse Drug Interactions 135 Overdose 135 Clinical Guidelines 135 Specific Medications 135 I. Trazodone Hydrochloride 135 Clinical Pharmacology 135 Uses in Humans 137 Contraindications 137 Side Effects 137 Overdose 137 Other Information 138 Effects Documented in Nonhuman Animals 138

10 Anticonvulsants and Mood Stabilizers 147 Sharon L. Crowell‐Davis, Mami Irimajiri, and Leticia Mattos de Souza Dantas Action 147 Overview of Indications 148 Clinical Guidelines 148 Specific Medications 148 I. Carbamazepine 148 Clinical Pharmacology 149 Side Effects 149 Effects in Non‐human Animals 149 II. Gabapentin 149 Clinical Pharmacology 149 Uses in Humans 150 Contraindications 150 Side Effects 150 Overdose 150 Doses in Nonhuman Animals 150 Other Information 150 Effects Documented in Non‐human Animals 151 Cattle 151 III. Pregabalin 152 Clinical Pharmacology 152 Uses in Humans 153 Side Effects 153 Effects Documented in Nonhuman Animals 153

11 Sympatholytic Agents 157 Niwako Ogata and Leticia Mattos de Souza Dantas Action 157 Overview of Indications 157 Contraindications, Side Effects, and Adverse Events 158 Contents xiii

Overdose 159 Clinical Guidelines 159 Specific Medications 160 I. Clonidine 160 Clinical Pharmacology 160 Uses in Humans 160 Contraindications 160 Side Effects 161 Other Information 161 Effects Documented in Nonhuman Animals 161 II. Detomidine 161 Clinical Pharmacology 161 Use in Humans 162 Contraindications 162 Side Effects 162 Other Information 162 Effects Documented in Nonhuman Animals 162 III. Dexmedetomidine 163 Clinical Pharmacology 163 Use in Humans 163 Contraindications 163 Side Effects 164 Effects Documented in Nonhuman Animals 164 IV. Propranolol 165 Clinical Pharmacology 165 Use in Humans 165 Contraindications 165 Side Effects 165 Effects Documented in Nonhuman Animals 166

12 N‐Methyl‐D‐Aspartate (NMDA) Receptor Antagonists 171 Niwako Ogata and Leticia Mattos de Souza Dantas Action 171 Overview of Indications 172 Contraindications/Side Effects, and Adverse Events 172 Clinical Guidelines 173 Specific Medications 173 I. Dextromethorphan 173 Clinical Pharmacology 174 Contraindications and Side Effects 174 Other Information 174 Effects Documented in Nonhuman Animals 174 Horses 175 II. Amantadine 175 Clinical Pharmacology 175 Use in Humans 175 Contraindications 175 xiv Contents

Side Effects 175 Overdose 176 Effects Documented in Nonhuman Animals 176 III. Memantine 176 Clinical Pharmacology 176 Use in Humans 177 Side Effects 177 Other Information 177 Effects Documented in Nonhuman Animals 178 IV. Huperzine A 179 Clinical Pharmacology 179 Use in Humans 179 Overdose and Side Effects 179 Effects Documented in Nonhuman Animals 179

13 Monoamine Oxidase Inhibitors 185 Leticia Mattos de Souza Dantas and Sharon L. Crowell‐Davis Action 185 Overview of Indications 186 Specific Medications 186 I. Selegiline Hydrochloride 186 Clinical Pharmacology 186 Uses in Humans 187 Contraindications 187 Side Effects 188 Overdose 188 Discontinuation 188 Other Information 188 Effects Documented in Nonhuman Animals 190

14 Antipsychotics 201 Lynne Seibert and Sharon Crowell‐Davis Introduction 201 Action 201 Overview of Indications 202 General Pharmacokinetics 203 Contraindications, Side Effects, and Adverse Events 203 Overdose 203 Clinical Guidelines 204 Specific Medications 204 I. Acepromazine Maleate 204 Clinical Pharmacology 204 Indications 204 Contraindications 204 Side Effects 204 Adverse Drug Interactions 205 Overdose 205 Doses in Nonhuman Animals 205 Effects Documented in Nonhuman Animals 205 Contents xv

II. Azaperone 206 Clinical Pharmacology 206 Indications 206 Doses in Nonhuman Animals 206 III. Chlorpromazine 206 Clinical Pharmacology 206 Uses in Humans 207 Indications in Veterinary Medicine 207 Contraindications 207 Side Effects 207 Effects Documented in Nonhuman Animals 207 IV. Clozapine 207 Clinical Pharmacology 207 Uses in Humans 207 Contraindications 207 Side Effects 207 Doses in Nonhuman Animals 208 Effects Documented in Nonhuman Animals 208 V. Fluphenazine 208 Clinical Pharmacology 208 Contraindications and Side Effects 208 Effects Documented in Nonhuman Animals 208 VI. Haloperidol 209 Clinical Pharmacology 209 Uses in Humans 209 Contraindications 209 Side Effects 209 Overdose 209 Doses in Nonhuman Animals 209 Effects Documented in Nonhuman Animals 209 VII. Pimozide 210 Clinical Pharmacology 210 Uses in Humans 210 Contraindications 210 Side Effects 211 Doses in Nonhuman Animals 211 Effects Documented in Nonhuman Animals 211 VIII. Promazine 211 Clinical Pharmacology 211 Indications 211 Contraindications 211 Side Effects 211 IX. Sulpiride 211 Clinical Pharmacology 211 Uses in Humans 212 Contraindications 212 Side Effects 212 Doses in Nonhuman Animals 212 Effects Documented in Nonhuman Animals 212 xvi Contents

X. Thioridazine 212 Clinical Pharmacology 212 Uses in Humans 213 Contraindications 213 Side Effects 213 Doses in Nonhuman Animals 213 Effects Documented in Nonhuman Animals 213 Important Information for Owners of Pets Being Placed on an Antipsychotic 213

15 CNS Stimulants 217 Sharon L. Crowell‐Davis Action 217 Overview of Indications 217 Contraindications, Side Effects, and Adverse Events 217 Adverse Drug Interactions 217 Overdose 217 Clinical Guidelines 218 Specific Medications 219 I. Amphetamine 219 Clinical Pharmacology 219 Uses in Humans 220 Contraindications 220 Side Effects 220 Overdose 220 Discontinuation 220 Other Information 220 Effects Documented in Nonhuman Animals 220 Other Species 221 II. Atomoxetine HCl 221 Clinical Pharmacology 221 Uses in Humans 222 Contraindications 222 Side Effects 222 Overdose 222 Discontinuation 222 Other Information 223 Effects Documented in Nonhuman Animals 223 III. Methylphenidate Hydrochloride 223 Clinical Pharmacology 223 Uses in Humans 224 Contraindications 224 Side Effects 224 Overdose 225 Doses in Nonhuman Animals 225 Discontinuation 226 Other Information 226 Effects Documented in Nonhuman Animals 226 Contents xvii

Important Information for Owners of Pets Being Placed on CNS Stimulants 226 Clinical Examples 227 Case 1 227 Signalment 227 Presenting Complaint 227 History 227 Diagnosis 227 Treatment Plan 227 Follow‐Up 227

16 Tricyclic Antidepressants 231 Sharon L. Crowell‐Davis Action 231 Overview of Indications 231 Contraindications, Side Effects, and Adverse Events 232 Adverse Drug Interactions 232 Overdose 232 Discontinuation 233 Clinical Guidelines 233 Specific Medications 233 I. Amitriptyline 233 Clinical Pharmacology 234 Uses in Humans 234 Contraindications 234 Side Effects 234 Overdose 235 Discontinuation 235 Other Information 235 Effects Documented in Nonhuman Animals 235 II. Clomipramine Hydrochloride 236 Clinical Pharmacology 236 Uses in Humans 237 Contraindications 237 Side Effects 238 Overdose 238 Discontinuation 238 Effects Documented in Nonhuman Animals 238 III. Desipramine 243 Clinical Pharmacology 243 Uses in Humans 243 Contraindications 243 Side Effects 243 Overdose 244 Effects Documented in Nonhuman Animals 244 IV. Doxepin 244 Clinical Pharmacology 244 Uses in Humans 245 xviii Contents

Contraindications 245 Side Effects 245 Overdose 245 Effects Documented in Nonhuman Animals 245 V. Imipramine 246 Clinical Pharmacology 246 Uses in Humans 246 Contraindications 246 Side Effects 246 Overdose 247 Effects Documented in Nonhuman Animals 247 VI. Nortriptyline 248 Clinical Pharmacology 248 Uses in Humans 248 Contraindications 248 Side Effects 248 Overdose 248 Effects Documented in Nonhuman Animals 248 Important Information for Owners of Pets Being Placed on any TCA 248

17 Opioids and Opioid Antagonists 257 Leticia Mattos de Souza Dantas and Sharon L. Crowell‐Davis Action 257 Overview of Indications 257 Contraindications, Side Effects, and Adverse Events 258 Clinical Guidelines 258 Specific Medications 258 I. Nalmefene 258 Clinical Pharmacology 258 Uses in Humans 259 Contraindications 259 Side Effects 259 Other Information 259 Effects Documented in Nonhuman Animals 259 II. Naloxone HCl 260 Clinical Pharmacology 260 Uses in Humans 260 Contraindications 260 Side Effects 260 Overdose 260 Doses in Nonhuman Animals 261 Discontinuation 261 Effects Documented in Nonhuman Animals 261 III. Naltrexone Hydrochloride 261 Clinical Pharmacology 261 Uses in Humans 262 Contraindications 262 Contents xix

Side Effects 262 Overdose 262 Discontinuation 262 Other Information 262 Uses Documented in Nonhuman Animals 262 IV. Pentazocine 264 Clinical Pharmacology 264 Uses in Humans 264 Contraindications 264 Side Effects 265 Overdose 265 Discontinuation 265 Other Information 265 Effects Documented in Nonhuman Animals 265

18 Hormones 269 Sharon L. Crowell‐Davis Introduction 269 Oxytocin 270 Clinical Pharmacology 270 Indications 270 Side Effects 270 Doses in Nonhuman Animals 270 Effects Documented in Nonhuman Animals 270 Progestins 270 Action 270 Overview of Indications 271 Contraindications, Side Effects, and Adverse Events 271 Overdose 271 Clinical Guidelines 272 Specific Medications 272 I. Medroxyprogesterone Acetate (MPA) 272 Clinical Pharmacology 272 Uses in Humans 272 Contraindications 272 Side Effects 272 Adverse Drug Interactions 272 Effects Documented in Nonhuman Animals 272 II. Megestrol Acetate 273 Clinical Pharmacology 273 Uses in Humans 273 Contraindications 273 Adverse Drug Interactions 273 Side Effects 273 Overdose 274 Effects Documented in Nonhuman Animals 274 xx Contents

19 Combinations 281 Leticia Mattos de Souza Dantas, Sharon L. Crowell‐Davis, and Niwako Ogata Introduction 281 Overview of Drug Augmentation 281 Potentially Beneficial Combinations 282 Adverse Interactions and Contraindications 283 Changing and Weaning Patients off Medications 285 Cytochrome P450 (CYP) 285 Interactions That Can Affect Dosing 285 Algorithms: Possible Future Direction 286 Conclusion 288

Index 291 xxi

Contributors

Sharon L. Crowell-Davis, DVM, PhD, DACVB Thomas F. Murray, PhD Professor of Behavioral Medicine Provost, Department of Veterinary Biosciences and Creighton University Diagnostic Imaging Department of Pharmacology College of Veterinary Medicine Omaha, NE, USA University of Georgia Athens, GA, USA Niwako Ogata BVSc, PhD, DACVB Associate Professor of Veterinary Behavior Leticia Mattos de Souza Dantas DVM, MS, PhD, Medicine Purdue University DACVB College of Veterinary Medicine Clinical Assistant Professor of Behavioral West Lafayette, IN, USA Medicine University of Georgia Veterinary Teaching Lynne Seibert DVM, MS, PhD, DACVB Hospital Department of Veterinary Biosciences and Veterinary Behavior Consultants Diagnostic Imaging Roswell, College of Veterinary Medicine GA, USA University of Georgia, Athens, GA, USA

Mami Irimajiri BVSc, PhD, DACVB Synergy General Animal Hospital Animal Behavior Service Saitama, Japan Adjunct Professor Kitasato University College of Veterinary Medicine Towada, Aomori, Japan xxiii

Preface

The first edition of this book grew out of a As this edition goes to print, we are already series of phone calls that Dr. Crowell‐Davis planning for the third as new information received over the years from various veteri- and protocols in veterinary mental health narians wanting information about their care keep being tested and developed. patients’ behavior problems and the psycho- Information on the effects of various active medications that might help them. psychoactive drugs in dogs, cats, and other What were appropriate drugs for given prob- veterinary patients comes from two major lems? What were appropriate doses? What sources. First, animals were often used to side effects should be watched for? The first test and study the actions of various drugs answer to this steadily accumulating set of during their initial development. Thus, the questions was a continuing education course reader who peruses the references will in psychopharmacology specifically organ- find papers published as early as the 1950s, ized for veterinarians. The course was first when major breakthroughs in psychophar- presented at the University of Georgia in macology were being made to much newer November of 2001 and is now part of UGA’s publications in human and veterinary neu- Outpatient Medicine annual Continuing roscience. With the establishment of the Education, as Behavioral Medicine has American College of Veterinary Behaviorists become integrated with all other specialties in 1993 and the overall rapid development of of our teaching hospital. From the original the field of Clinical Behavioral Medicine, courses, taught by Dr. Murray and Dr. there has been increasing research on Crowell‐Davis and the assistance from the the efficacy of various medications on the clinical residents at the time (Dr. Lynne treatment of various mental health and Seibert and Dr. Terry Curtis), the next logical behavioral/psychiatry disorders of compan- step was a textbook so that practicing veteri- ion animals, zoo animals, and other nonhuman narians would have a resource to turn to for animals. the answers to their various questions. Years There are often huge gaps in our knowl- later, Dr. Crowell‐Davis and Dr. Dantas felt edge, and the reader may note them through- an urgent need to update the book and add out the book. While we can glean bits and several new drugs that more recently are pieces of pharmacokinetic and other data used by diplomates of the American College from studies done on dogs and cats during of Veterinary Behaviorists, so this knowledge early drug development, the quality and could be available to general practitioners. quantity of the information are highly varia- Where studies were available, we tried to ble. Studies of teratology and carcinogenicity make this edition purely evidence‐based and are typically done on rats, mice, and rabbits, avoided including personal communications while comprehensive studies of all aspects and short publications as much as possible. of pharmacological activity in the body are xxiv Preface

done only in humans, the species that has Leticia Mattos de Souza Dantas, DVM, MS, historically been of interest. It is hoped PhD, DACVB that, as interest in this field continues Clinical Assistant Professor to evolve, more comprehensive data will of Behavioral Medicine become available; new data will be supplied University of Georgia Veterinary in future editions. Teaching Hospital Department of Veterinary Biosciences Sharon L. Crowell‐Davis, DVM, and Diagnostic Imaging PhD, DACVB College of Veterinary Medicine Professor of Behavioral Medicine University of Georgia Department of Veterinary Biosciences Athens, GA, USA and Diagnostic Imaging College of Veterinary Medicine University of Georgia Athens, GA, USA xxv

Acknowledgments

There is so much to be thankful for on this the didactic program at the University of second edition of Veterinary Psychopharma- Georgia to this date without the continuing cology. From all the veterinarians who request support of various administrators over the consults and always ask questions about years. In the first edition, Dr. Royce Roberts, psychoactive medications; reminding us of Dr. Crowell‐Davis’ department head of many how important this resource is, to all of the years was acknowledged. On this edition, we students who push us to be updated, creative would like to thank Dr. Stephen Holladay for and enthusiastic about practicing and teach- all his encouragement and support to both ing. We dream of a time where mental health of us. Dr. David Anderson, Dr. Keith Prasse, and psychiatry care will be fully integrated Dr. Bob Lewis, and Dr. Jack Munnell have into the standard of care in veterinary medi- also facilitated Dr. Crowell‐Davis’ con tinuing cine across the globe and part of the curricu- work in this field previously. In the past lum of every veterinary medicine school. To 10 years, our service has had major support all of you that are eager to learn and provide from our hospital director, Dr. Gary Baxter, the best care for your patients, we thank you. to whom Dr. Dantas is incredibly grateful You are leading the way in our profession and as he has supported and allowed for the this book is for you. service’s revitalization, allowing for a more We wanted to keep the acknowledgments competitive and business‐oriented approach from the first edition to the many people to her practice. who, besides the authors, contributed to the Finally, this book is for all animals who co‐ work involved in bringing together the exist with humankind, providing us with so information presented at that time. Of par- much affection, companionship and even ticular assistance were Linda Tumlin, Wendy health benefits, but who have to adapt to our Simmons, and Lucy Rowland. In their capac- lifestyle and often undergo significant mental ity as librarians and reference librarians they suffering that can remain ignored, undiag- were invaluable in locating and obtaining nosed, and untreated. Our mission is to heal much of the information provided in our and to improve the quality of life of all patients first edition. we have the privilege to treat; and increase We also could not have developed and the awareness in our society that the mental run the Behavioral Medicine Service and and emotional suffering of animals matters. 1

Part I

Principles of Veterinary Psychopharmacology 3

General Principles of Psychopharmacology Thomas F. Murray

Creighton University, Omaha, NE, USA

Drug Action psychopharmacology, the largest group of receptors are proteins. These include recep Pharmacology is the science of drug action, tors for endogenous hormones, growth and a drug is defined as any agent (chemical, factors, and neurotransmitters; metabolic hormone, peptide, antibody, etc.) that, enzymes or signaling pathways; transporters because of its chemical properties, alters and pumps; and structural proteins. Usually the structure and/or function of a biological the drug effect is measured at a much more system. Psychopharmacology is a sub‐disci complex level than a cellular response, such pline of pharmacology focused on the study as the organism level (e.g. sedation or change of the use of drugs (medications) in treating in behavior). mental disorders. Most drugs used in ani Drugs often act at receptors for endoge mals are relatively selective. However, selec nous (physiologic) hormones and neuro tivity of drugs is not absolute inasmuch as transmitters, and these receptors have they may be highly selective but never com evolved to recognize their cognate signaling pletely specific. Thus, most drugs exert a molecules. Drugs that mimic physiologic multiplicity of effects. signaling molecules at receptors are agonists, Drug action is typically defined as the initial that is, they activate these receptors. Partial change in a biological system that results agonist drugs produce less than maximal from interaction with a drug molecule. This activation of activation of receptors, while change occurs at the molecular level through a drug that binds to the receptor without drug interaction with molecular target in the capacity to activate the receptor may the biologic system (e.g. tissue, organ). The function as a receptor antagonist. Antagonists molecular target for a drug typically is a mac that bind to the receptor at the same site romolecular component of a cell (e.g. protein, as agonists are able to reduce the ability DNA). These cellular macromolecules that of agonists to activate the receptor. This serve as drug targets are often described as mutually exclusive binding of agonists and drug receptors, and drug binding to these antagonists at a receptor is the basis for receptors mediates the initial cellular competitive antagonism as a mechanism of response. Drug binding to receptors either drug action. One additional class of drugs enhances or inhibits a biological process or acting at physiologic receptors are inverse signaling system. Of relevance to the field of agonists. At physiologic receptors that

Veterinary Psychopharmacology, Second Edition. Sharon L. Crowell-Davis, Thomas F. Murray, and Leticia Mattos de Souza Dantas. © 2019 John Wiley & Sons, Inc. Published 2019 by John Wiley & Sons, Inc. 4 General Principles of Psychopharmacology

250 curves describe in vitro drug action where 200 the actual concentration of the drug interact ing with a receptor is known. Inspection of 150 dose–response relationships reveals that for any drug, there is a threshold dose below 100 which no effect is observed, and at the oppo site end of the curve there is typically a ceil 50 Effect (arbitrary units) ing response beyond which higher doses do 0 not further increase the response. As shown –10 –9 –8 –7 –6 –5 –4 in Figure 1.2, these dose‐ or concentration‐ Log [drug] M response curves are typically plotted as a function of the log of the drug dose or con Agonist Antagonist centration. This produces an S‐shaped curve Partial agonist Inverse agonist that pulls the curve away from the ordinate Figure 1.1 Theoretical logarithmic concentration‐ and allows comparison of drugs over a wide response relationships for agonist, partial agonist, range of doses or concentrations. antagonist, and inverse agonist drugs acting at a A drug‐receptor interaction is typically common receptor. In this theoretical set of reversible and governed by the affinity of the concentration‐response curves, the agonist drug for the receptor. The affinity essentially produces a maximum response while the partial agonist is only capable of evoking a partial response. describes the tightness of the binding of the The antagonist binds to the receptor but is not drug to the receptor. The position of the capable of activating the receptor and therefore theoretical S‐shaped concentration‐response does not produce a response. Inverse agonists bind curves depicted in Figure 1.2 reveals the to an inactive form of the receptor and produce an potency of these drugs. The potency of a effect which is in the inverse direction of that produced by the agonist. drug is a function of its affinity for a receptor, the number of receptors, and the fraction of receptors that must be occupied to produce exhibit constitutive activity in the absence of a maximum response in a given tissue. In activation by an endogenous agonist, inverse Figure 1.2, Drug A is the most potent and agonists stabilize an inactive conformation Drug C is least potent. The efficacy of all and therefore reduce the activation of the three drugs in Figure 1.2, however, is identical receptor. Thus, inverse agonists produce in that they all act as full agonists and produce responses that are the inverse of the response to an agonist at a given receptor. Theoretical log concentration‐response curves for 110 these four classes of drugs are depicted in 100 Drug A 90 Figure 1.1. 80 Drug B 70 Drug C 60 Dose Dependence of Drug 50 40 Interaction with Receptors 30

% Maximum effect 20 10 Receptor occupancy theory assumes that drug 0 action is dependent on concentration (dose) –10 –9 –8 –7 –6 –5 –4 and the attendant quantitative relationships Log [drug] M are plotted as dose‐ or concentration‐ Figure 1.2 Theoretical logarithmic concentration‐ response curves. Dose–response analysis is response relationships for three agonists which typically reserved to describe whole animal differ in relative potency. Drug A is more potent than drug effects, whereas concentration‐response Drug B, which in turn is more potent than Drug C. Srcua Faue o h eta Nros Syste (CNS) and Neurotransmissio 5

100% of the maximal effect. As a general Structural Features principle in medicine, for drugs with similar of the Central Nervous margins of safety, we care more about efficacy System (CNS) than potency. The comparison of potencies and Neurotransmission of agonists is accomplished by determining the concentration (or dose) that produces 50% of the maximum response (Effective The cellular organization of the mammalian brain is more complex than any other biologic Concentration, 50% = EC50). In Figure 1.2, the −8 −7 −6 tissue or organ. To illustrate this complexity, EC50 values are 10 , 10 , and 10 M, respec consider that the human brain contains tively, for Drugs A, B and C; hence, the rank 12 13 15 order of potency is Drug A > Drug B > Drug C, 10 neurons, 10 glia, and 10 synapses. with Drug A being the most potent since its Understanding how this complex informa tion processor represents mental content and EC50 value is the lowest. Figure 1.3 depicts three additional theoretical concentration‐ directs behavior remains a daunting biomed response curves for drugs with identical ical mystery. Recent reconstruction of a potencies but different efficacies. In this volume of the rat neocortex found at least example, Drug A is a full agonist, producing a 55 distinct morphological types of neurons maximum response, whereas Drugs B and C (Makram et al. 2015). The excitatory to are partial agonists, producing responses, inhibitory neuron ratio was estimated to be respectively, of 50% and 25% of the maxi 87:13, with each cortical neuron innervating mum. Similar to receptor antagonist drugs, 255 other neurons, forming on average more partial agonists can compete with a full ago than 1100 synapses per neuron. This remark nist for binding to the receptor. Increasing able connectivity reveals the complexity of concentrations of a partial agonist will inhibit microcircuits within even a small volume of the full agonist response to a level equivalent cerebral cortex. to its efficacy, whereas a competitive antago Most neuron‐to‐neuron communication nist will completely eliminate the response in the CNS involves chemical neurotrans of the full agonist. mission at up to a quadrillion of synapses. The amino acid and biogenic amine neuro transmitters must be synthesized in the 110 presynaptic terminal, taken up, and stored 100 in synaptic vesicles, and then released by 90 Drug A exocytosis, when an action potential invades 80 Drug B 70 the terminal to trigger calcium influx. Once 60 Drug C released into the synaptic cleft, transmitters 50 can diffuse to postsynaptic sites where they 40 are able to bind their receptors and trigger 30

% Maximum effect 20 signal transduction to alter the physiology of 10 the postsynaptic neuron. Just as exocytotic 0 release of neurotransmitters is the on‐switch –10 –9 –8 –7 –6 –5 –4 for cell‐to‐cell communication in the CNS, Log [drug] M the off‐switch is typically a transport pump Figure 1.3 Theoretical logarithmic concentration‐ that mediates the reuptake of the transmitter response relationships for three agonists with similar into the presynaptic terminal or uptake into potency but different efficacies. Drug A is an agonist glia surrounding the synapse. A schematic of that produces a maximum response while Drugs B and C are partial agonists only capable of evoking a a presynaptic terminal depicted in Figure 1.4 partial response. Drug A is therefore more illustrates the molecular sites that regulate efficacious than Drug B, which in turn is more neurotransmission. Once synthesized or efficacious than Drug C. provided by reuptake, the neurotransmitter 6 General Principles of Psychopharmacology

the extracellular concentration of transmitters PRESYNAPTIC Action and therefore a mechanism for termination TERMINAL potential of their respective synaptic actions. The mono amine transporters (dopamine, norepi nephrine, and 5‐hydroxytryptamine) are the pharmacological targets for antidepressants Vesicle and psychostimulants. Presynaptic terminals also express neuro pH transmitter autoreceptors that function as local circuit negative feedback inhibitor Autoreceptor mechanisms to inhibit further exocytotic release of the transmitter when its synaptic concentration is elevated. Figure 1.5 illustrates the comparison of Transporter presynaptic terminals for the biogenic amine neurons: dopamine, norepinephrine, and 5‐hydroxytryptamine (serotonin). The Figure 1.4 Presynaptic terminal of monoaminergic neuron, depicting sites of vesicular release, reuptake biosynthesis of each biogenic amine trans transport, and vesicular transport and storage. mitter is indicated with uptake and storage in Monoamine transmitters are synthesized in the synaptic vesicles. The vesicular uptake of all cytoplasm or vesicle. Transport from the cytoplasm three biogenic amines depicted is mediated to the vesicular compartment is mediated by the by a common transporter, vesicular mono reserpine sensitive vesicular membrane transporter (VMAT2). Release into the synapse occurs by amine transporter 2 (VMAT2). VMAT2 is exocytosis triggered by an action of potential the vesicular monoamine transporter that invasion of the terminal. Neurotransmitters are transports dopamine, norepinephrine, and rapidly transported from the synaptic cleft back into 5‐hydroxytryptamine into neuronal synaptic the cytoplasm of neuron by a process termed vesicles. VMAT2 is an H+‐ATPase antiporter, reuptake, which involves a selective, high‐affinity, Na+‐dependent plasma membrane transporter. which uses the vesicular electrochemical gradient to drive the transport of biogenic amines into the vesicle (Lohr et al. 2017). is transported into the synaptic vesicle for In contrast to VMAT2 being expressed in subsequent exocytosis. The pH gradient all three biogenic amine neurons, each across the vesicular membrane is established neurotransmitter neuron expresses a distinct by the vacuolar H+‐ATPase, which uses ATP plasma membrane transporter. These trans hydrolysis to generate the energy required to porters are members of the SLC6 symporter move H+ ions into the vesicle (Lohr et al. family that actively translocate amino acids 2017). This movement of H+ ions creates the or amine neurotransmitters into cells against vesicular proton gradient and establishes an their concentration gradient using, as a driv acidic environment inside the vesicle (pH ing force, the energetically favorable coupled of ~5.5). Specific reuptake transporters are movement of ions down their transmem localized on the plasma membrane where brane electrochemical gradients. The dopa they recognize transmitters and transport mine transporter (DAT), the norepinephrine them from the synaptic cleft into the transporter (NET), and the serotonin trans cytoplasm of the terminal (Torres et al. 2003). porter (SERT) are all uniquely expressed in These transporters have evolved to recognize their respective neurotransmitter neurons specific transmitters such as dopamine, and couple the active transport of biogenic serotonin, norepinephrine, glutamate, and amines with the movement of one Cl− and gamma‐aminobutyric acid (GABA). In all two Na+ ions along their concentration gra cases, these presynaptic transporters re gulate dient. The ionic concentration gradient is DOPAMINE NEURON NOREPINEPHRINE NEURON 5-HYDROXYTRYPTAMINE NEURON

Tyrosine Tyrosine Tyrosine

L-DOPA L-DOPA 5-Hydroxytryptamine Fluoxetine Modafinil Nisoxetine paroxetine DA Vanoxerine DA Reboxetine 5-HT sertraline

DA DA 5-HT DA NE Adrenergic autoreceptors 5-HT autoreceptors DAT NET autoreceptors SERT

DA receptors Adrenergic receptors 5-HT receptors

Figure 1.5 Schematic comparison of dopamine, norepinephrine, and 5‐hydroxytryptamine (serotonin) synapses. Each neuron expresses a monoamine transporter selective for its neurotransmitter. These transporters function as reuptake pumps that terminate the synaptic actions of the transmitters and promote uptake and eventual storage of the transmitter in vesicles. Selective drug inhibitors of each monoamine transporter are shown. Abbreviations: DA, dopamine; DAT, dopamine transporter; NE, norepinephrine; NET, norepinephrine transporter; 5‐HT, 5‐hydroxytryptamine; SERT, serotonin transporter. 8 General Principles of Psychopharmacology

created by the plasma membrane Na+/K+ being used as an antihypertensive. Some ATPase and serves as the driving force for patients treated with reserpine developed transmitter uptake. Examples of drugs that depressive symptoms severe enough in act as selective inhibitors for all three bio some cases to produce suicide ideation. genic transporters are listed. The three mon Animals given reserpine also developed oamine transporters, DAT, NET, and SERT, depression‐like symptoms consisting of represent important pharmacological targets marked sedation. Reserpine was shown to for many behavioral disorders including deplete the CNS of DA, NE, and 5‐HT by depressive, compulsive and appetite‐related virtue of its ability to block the vesicular behavioral problems. The three neurotrans uptake of these monoamines. Blocking the mitter terminals also express unique presyn vesicular uptake of monoamines leads to a aptic autoreceptors that regulate exocytotic depletion of the transmitters due to degrada release. tion by the mitochondrial enzyme MAO. Therefore, vesicular storage of monoamines is not only a prerequisite for exocytosis but Biogenic Amine also a means of preventing degradation of the transmitters in the cytosolic compartment. Neurotransmitters One other observation in the 1950s was and Affective Disorders that imipramine, developed initially as an antipsychotic drug candidate, elevated mood The role of biogenic amines in affective dis in a subpopulation of schizophrenic patients orders has a long history, beginning in with comorbid depressive illness. Preclinical the 1950s. The biogenic amine theory research revealed that imipramine, and other for affective disorders emerged as pharma tricyclic antidepressants, were able to block cologists and psychiatrists began to explore monoamine transport into presynaptic ter the biologic basis for mental disorders. minals. This action would therefore produce Initially, insights were gained from better an elevation of synaptic levels of biogenic understanding of the cellular actions of drugs amines. All these observations with iproni and correlation of this knowledge of drug azid, reserpine, and imipramine were there action with the therapeutic and behavioral fore consistent with the original formulation responses to the same drugs in the clinic. In of the biogenic amine hypothesis for affective its original formulation, the biogenic amine disorders. theory for affective disorders stated that Although today we continue to recognize depression was due to a deficiency of bio the role of biogenic amines in depression, genic amines in the brain, while mania was several discrepancies in the original due to an excess of these transmitters. In the hypothesis are appreciated. As an example, 1950s, iproniazid was used in the treatment some clinically effective antidepressants do of tuberculosis, and it was observed that in not block the presynaptic transport of some patients with depressive symptoms, monoamines and are not MAO inhibitors. their mood improved over the course of However, importantly for a hypothesis that a chronic regimen with iproniazid. attempts to correlate synaptic levels of Concurrently, preclinical research showed monoamines with mood, while synaptic that iproniazid was an inhibitor of the levels of monoamines are elevated within a enzyme monoamine oxidase (MAO). MAO time domain of a few hours after antidepres catalyzes the degradation of dopamine (DA), sant administration, the symptoms of depres norepinephrine (NE), and serotonin (5‐HT), sion do not resolve until several weeks of and inhibition of MAO was found to elevate chronic therapy with antidepressant drugs. the levels of these transmitters in animal Contemporary hypotheses to explain the brains. Also, in the 1950s, reserpine was mechanism of action of antidepressant drugs References 9 therefore seek an appropriate temporal synaptic levels of biogenic amines, contem correlation between neurochemical drug porary views of the mechanism of action of action and the mitigation of the symptoms antidepressants are focused on the regula of depression. Rather than a focus on the tion of receptor signaling.

References

Lohr, K.M., Masoud, S.T., Salahpour, A., and neocortical microcircuitry. Cell 163: Miller, G.W. (2017). Membrane transporters 456–492. as mediators of synaptic dopamine Torres, G.E., Gainetdinov, R.R., and Caron, dynamics: implications for disease. European M.G. (2003). Plasma membrane monoamine Journal of Neuroscience 45 (1): 20–33. transporters: structure, regulation and Makram, H., Muller, E., Ramaswamy, S. et al. function. Nature Reviews Neuroscience 4 (1): (2015). Reconstruction and stimulation of 13–25. 11

Amino Acid Neurotransmitters Glutamate, GABA, and the Pharmacology of Benzodiazepines Thomas F. Murray

Creighton University, Omaha, NE, USA

Introduction Glutamatergic Synapses

In addition to their role in intermediary Glutamate and aspartate produce powerful metabolism, certain amino acids function excitation in neural preparations and as small molecule neurotransmitters in the glutamate is generally accepted as the most central and peripheral nervous systems. prominent neurotransmitter and major excit- These specific amino acids are classified atory transmitter in the brain. The establish- as excitatory or inhibitory, based on the ment of glutamate as a neurotransmitter in characteristic responses evoked in neural the brain was historically difficult due to its preparations. Application of excitatory role in general intermediary metabolism. amino acids such as glutamic acid and aspar- Glutamate is also involved in the synthesis tic acid typically depolarize mammalian neu- of proteins and peptides, and also serves rons, while inhibitory amino acids such as as the immediate precursor for GABA in gamma aminobutyric acid (GABA) and gly- GABAergic neurons. The enzyme glutamic cine characteristically hyperpolarize neu- acid decarboxylase (GAD) converts glutamate rons. Glutamate, aspartate, and GABA all to GABA in these GABAergic neurons. In represent amino acids that occur in high contrast to GABA, the glutamate content of concentrations in the brain. The brain levels brain outside of glutamatergic neurons is of these amino acid transmitters are high high as a consequence of its role in interme- (μmol g−1) relative to biogenic amine trans- diary metabolism and protein synthesis. An mitters (nanomol g−1) such as dopamine, array of neurochemical methods accordingly serotonin, norepinephrine, and acetylcho- has demonstrated that all cells contain some line. In mammals, GABA is found in high glutamate, and in the brain all neurons con- concentrations in the brain and spinal cord, tain measurable amounts of glutamate. but is present in only trace amounts in In neurons, glutamate is primarily synthe- peripheral nerve tissue, liver, spleen, or heart sized from glucose through the pyruvate→ (Cooper et al. 2003). These observations acetyl‐CoA → 2‐oxoglutarate pathway, and reveal the enrichment of this amino acid in from glutamine that is synthesized in glial the brain and suggest an important functional cells, transported into nerve terminals, role in the central nervous system (CNS). and converted by neuronal glutaminase into

glutamate. In terminals of glutamatergic other three EAAT subtypes being localized neurons, glutamate is stored in synaptic to neurons. The two glial glutamate vesicles from which Ca2+‐dependent release transporters have been shown to be the in response to depolarization occurs. This primary regulators of extracellular glutamate synaptically released glutamate is taken up, in the CNS (Amara and Fontana 2002). in part, by glial cells and converted to glu- EAATs accomplish glutamate influx driven tamine by the enzyme glutamine synthetase. by the cotransport of 3 Na+ and 1 H+ ions This glutamine is then transported back to with the countertransport of 1 K+ ion. EAAT‐ neurons where glutamate is regenerated mediated glutamate uptake is therefore through the action of glutaminase (Figure 2.1). electrogenic and dependent on the Na+ Extracellular glutamate concentrations are gradient. The 3:1 ratio of Na+ to glutamate maintained within physiological levels by a molecules transported causes a significant family of transmembrane proteins known as Na+ influx into the glial cells when the excitatory amino acid transporters (EAATs). glutamate uptake is stimulated (Kirischuk At least five EAATs have been identified with et al. 2016). This elevation of intracellular individual subtypes, differing with respect to Na+ can trigger a reverse mode of action of their pharmacology and distribution within the Na+/Ca2+ exchanger (NCX), leading to a the CNS. Two of these EAATs are localized stimulation of Ca2+ signaling pathways in glia primarily on glial cells in the CNS with the or neurons.

Glutamatergic synapse

Gln Glu Glutamine synthetase Glial cell mGluR release modulating autoreceptor

Phosphate-activated glutaminase

Glu Gln Presynaptic neuron Postsynaptic neuron

Glu Glu

Postsynaptic receptor Vesicular transporter

Plasma membrane transporter

Figure 2.1 Schematic representation of a glutamatergic synapse. Glutamine (Gln) is converted to glutamate (Glu) by mitochondrial glutaminase in glutamatergic neurons. Glutamate is released into the synaptic cleft where it may activate both pre‐ and postsynaptic receptors. Glutamate in the synaptic cleft is recaptured by neuronal and glial plasma membrane transporters that terminate the synaptic actions of the excitatory transmitter. Glial glutamate is converted to glutamine by the enzyme glutamine synthetase. This glutamine is then shuttled back to glutamatergic neurons to replenish the glutamate. Glutamate receptors include both G‐protein coupled (mGluRs) and ligand‐gated ion channel (AMPA, NMDA and kainite) receptors. Gltmtri Synapse 13

There is some evidence that neuronal of inward currents carried by Na+ and Ca2+ EAATs are localized predominantly outside ions. The voltage dependence of the inward the synapse where they control extrasynaptic, ionic current through the NMDA receptor rather than synaptic, glutamate concentra- arises from Mg2+ blockade of this channel at tion. This extrasynaptic glutamate may normal resting membrane potentials. This function to activate pre‐ and postsynaptic channel‐blocking action of extracellular Mg2+ metabotropic glutamate receptors (mGluRs). is relieved when the cell is depolarized. Thus, Presynaptic mGluRs are involved in the feed- the NMDA receptor signaling requires depo- back regulation of synaptic glutamate release. larization of the cell through the excitatory In the normal brain, the prominent gluta- actions of non‐NMDA receptors before this matergic pathways are: (i) the cortico‐cortical ligand‐gated ion channel can produce an pathways; (ii) the pathways between the thal- inward current. This property of NMDA amus and the cortex; and (iii) the extrapy- receptors has led to the channel being termed ramidal pathway (the projections between a coincident detector due to the requirement the cortex and striatum). Other glutamate for simultaneous activation of NMDA recep- projections exist between the cortex, the tors and excitatory input to a cell as a precon- substantia nigra, the subthalmic nucleus, and dition for the passage of ionic current through the pallidum. Glutamate‐containing neu- NMDA receptor ion channels. ronal terminals are ubiquitous in the CNS A molecular classification of glutamate and their importance in brain function and receptors has confirmed the subdivision neurotransmission is therefore considerable. based on pharmacological profiles of recep- Estimates of the fraction of neurons in the tor subtypes. Molecular cloning techniques brain that use glutamate as a neurotransmit- have identified gene families corresponding ter range from 70% to 85%. to each functional subtype of glutamate Glutamate receptors are categorized into receptor. NMDA receptors are formed by two main classes, namely, ionotropic gluta- assemblies of three gene families including mate receptors (iGluRs) and metabotropic NR1, NR2A‐D, and NR3A/3B (Mayer and receptors (mGluRs). The iGluRs were Armstrong 2004). Functional NMDA recep- originally classified using a pharmacologic tors exist as heteromers containing two NR1 approach that led to identification of three and two NR2 subunits (Erreger et al. 2004). subtypes bearing the names of selective NMDA receptors can also contain NR3A agonists: (i) the AMPA; (ii) kainate; and subunits that modulate the channel function. (iii) NMDA receptors. These glutamate AMPA receptors are comprised of assem- receptor subtypes are often described as blies from the GluR1–GluR4 gene family, being either NMDA (N‐methyl‐D‐asparate) whereas kainate receptors are assemblies of or non‐NMDA (AMPA and kainate) recep- GluR5–GluR7 and KA1 and KA2 subunits. tors based on their sensitivity to the synthetic In addition to the iGluRs, there are aspartate analog NMDA. All of these iGluRs metabotropic glutamate receptors (mGluRs) represent ligand‐gated cation channels per- that are members of the large family of G‐ meable to Na+ and K+ with differing permea- protein coupled receptors. These mGluRs bilities to Ca2+. Activation of these receptors are therefore not ligand‐gated ion channels, by glutamate or selective agonists at normal but, rather, change cell physiology through membrane potentials allows Na+ to enter the an interaction with G‐proteins that in turn cell with attendant membrane depolarization; regulate the activity of enzymes and/or ion this is the underlying mechanism for the channels involved in cell signaling cascades. rapid excitatory response of most neurons to These mGluRs are widely distributed in the glutamate. In addition to Na+ permeability brain where they mediate a variety of effects NMDA receptors also have a high permeabil- including the modulation of glutamate ity to Ca2+ and display a voltage‐dependence release from glutamatergic neurons. These 14 Amino Acid Neurotransmitters

presynaptic mGluRs therefore function as Ketamine and the newer dissociative autoreceptors. anesthetic tiletamine act as noncompetitive Inasmuch as glutamate receptors mediate antagonists of NMDA receptors in the CNS most of the excitatory transmission in the (Figure 2.2). The discovery by Lodge et al. brain, they represent important potential (1983) of the ability of ketamine and related targets for therapeutic intervention in a arylcyclohexylamines to antagonize specifi- number of behavioral disorders. cally the neuronal excitation mediated by the synthetic aspartate analog, NMDA, provided a pivotal advance in our understanding of the mechanism of action of dissociative anes- Pharmacology of Ketamine thetics. Based on the earlier observation that and Tiletamine ketamine selectively reduced polysynaptic reflexes in which excitatory amino acids were Ketamine is an anesthetic agent that was first the transmitter, Lodge and coworkers investi- introduced in clinical trials in the 1960s. It gated the action of ketamine on the excitation is a dissociative anesthetic, which is a term of cat dorsal horn interneurons by amino originally introduced by Domino and col- acids used in the classification of excitatory laborators to describe the unique state of amino acid receptors, namely, NMDA, quis- anesthesia produced by ketamine in which the qualate, and KA (Lodge and Mercier 2015). subject is profoundly analgesic while appear- The microionotophoretic or intravenous ing disconnected from the surrounding administration of ketamine selectively environment (Miyasaka and Domino 1968). reduced the increased firing rate of dorsal Domino’s laboratory attributed this unique horn neurons evoked by focal application anesthetic state to a drug‐induced dissocia- of NMDA. The excitatory responses elicited tion of the EEG activity between the by quisqualate and KA remained little thalamocortical and limbic systems. It was affected. The selective NMDA‐blocking demonstrated that the cataleptic anesthetic effect was not restricted to ketamine inas- state induced by intravenous ketamine much as the dissociative anesthetics, phency- (4 mg kg−1) in cats was associated with an clidine (PCP) and tiletamine, had similar alternating pattern of hypersynchronous δ actions that paralleled their relative anes- wave bursts and low voltage, fast wave thetic potencies. The primary molecular activity in the neocortex and thalamus. target for ketamine‐induced analgesia and Subcortically, the δ wave bursts were anesthesia therefore appears to be brain observed prominently in the thalamus and NMDA receptors. The inhibitory concentra- caudate nucleus, and the EEG patterns of tion for ketamine antagonism of NMDA thalamic nuclei were closely related phasi- responses in rat cortical preparations range cally to the δ waves of the neocortex. In from 6 μM to 12 μM. These values are com- contrast to the marked δ wave bursts in the parable to the plasma concentration (20– neocortex, thalamus, and caudate nucleus, 40 μM) obtained in rats following intravenous prominent δ waves were not observed in the anesthetic doses. It therefore appears likely cat hippocampus, hypothalamus, or mid- that a large fractional occupancy of NMDA brain reticular formation. The hippocampus receptors may be required for ketamine showed θ “arousal” waves in spite of the induction of anesthesia (Murray 1994). appearance of high voltage, hypersynchro- Subanesthetic doses of ketamine produce a nous δ wave bursts in the thalamus and neo- spectrum of psychoactive actions in humans cortex. Thus, ketamine was demonstrated including mood elevation, distortions in to produce a functional dissociation of the body image, hallucinations, delusions, and EEG activity between the hippocampus and paranoid ideation. These effects resemble thalamocortical systems. those of PCP (phencyclidine) and are GABegc Synapse 15

NMDA receptor

Competitive antagonist Glutamate NMDA

Na+ – Ca2+ + Glycine

Ketamine Tiletamine

Mg2+

Figure 2.2 Schematic of the NMDA subtype of glutamate receptors. NMDA receptors possess binding sites for the transmitter glutamate and the co‐agonist, glycine. Competitive antagonists bind to the glutamate site, whereas noncompetitive antagonists such as ketamine and tiletamine bind to a site in the ion channel domain. Mg++ exerts a voltage‐dependent block of the ion channel. responsible for the illicit use of ketamine. resulting in a desuppression of BDNF transla- The availability of ketamine in veterinary tion (Kavalali and Monteggia 2015). A key medicine has resulted in numerous case role for BDNF in mediating antidepressant reports of ketamine abuse by veterinarians. efficacy has previously been established Similar to the anesthetic and analgesic actions (Bjorkholm and Monteggia 2016). of ketamine, the psychoactive properties appear to be related to the noncompetitive antagonism of NMDA receptors. GABAergic Synapses Great interest in ketamine as an antidepressant has emerged due to human clinical data Of all the putative neurotransmitters in the that has demonstrated the rapid and sustained brain, γ‐aminobutyric acid (GABA) is antidepressant effects of ketamine (Murrough perhaps the one whose candidacy rests on et al. 2017). Ketamine has therefore been the longest history of investigation. Glutamic repurposed as a rapidly acting antidepressant, acid decarboxylase (GAD), the enzyme that triggering great interest in glutamate signaling catalyzes the formation of GABA, appears to mechanisms underlying depressive disorders. be largely restricted to GABAergic neurons Ketamine, its metabolites, and other NMDA and therefore affords a suitable marker for receptor antagonists produce rapid antide- this population of neurons. In brain regions pressant‐like effects in mouse behavioral such as the hippocampus, histochemical models that are dependent on rapid protein studies have demonstrated that GAD is dis- synthesis of brain‐derived neurotrophic factor tributed in the neuropil with highest concen- (BDNF). Experiments in animal models show trations between cell bodies reflecting the that ketamine‐mediated blockade of NMDA presence of GABAergic neuron terminals. receptors at rest deactivates eEF2 kinase, The abundance of GABAergic interneurons 16 Amino Acid Neurotransmitters

and projection neurons in the brain has been high intracellular Cl− concentrations, the typi- estimated to represent 17–20% of the neu- cal response of an activated GABAA receptor rons in the brain (Somogyi et al. 1998). Upon in the mature CNS is hyperpolarization medi- − activation, these GABAergic neurons release ated by Cl influx. Functional GABAA recep- GABA from presynaptic terminals into the tors are pentameric ligand‐gated ion channels synaptic cleft. The concentration of GABA in assembled from members of seven different the synaptic cleft is controlled by the high subunit classes, some of which have multiple affinity uptake into presynaptic terminals isoforms: α (1–6), β (1–3), γ (1–3), δ, Е, θ, and and glial cells. In contrast to glutamate which π. A pentameric assembly could theoretically is predominantly taken up by astrocytes, be composed of over 50 distinct combinations GABA represents the primary inhibitory of these subunits; however, GABAA receptor neurotransmitter in the mammalian brain subunits appear to form preferred assemblies and is removed from the synaptic cleft resulting in possibly dozens of distinct recep- mainly by the neuronal GABA transporter tor complexes in the brain. Most GABAA (GAT) subtype GAT1. Because of the high receptor subtypes are presumed to be com- capacity and abundance of synaptic GAT1, posed of α‐, β‐, γ‐subunits. Molecular studies GABA rarely escapes the synapse (Kirischuk have demonstrated that distinct GABAA et al. 2016). receptor assemblies often have different phys- GABA represents the major inhibitory iologic and pharmacologic profiles, suggesting transmitter in the brain and this inhibition is that subunit composition is an important mediated by GABA binding to postsynaptic determinant of pharmacological diversity in receptors. GABAergic systems serve impor- GABAA receptor populations. Deficits in tant regulatory functions in the brain such as GABAAR function have been demonstrated vigilance, anxiety, muscle tension, epilepto- in a range of behavioral and CNS disorders, genic activity, and memory. In brain areas, including anxiety, psychosis, and epilepsy. such as the cerebral cortex and the hip- GABAA receptors represent the molecular pocampus, GABAergic neurons are predom- target for all of the characteristic pharmaco- inantly interneurons that function as primary logical actions of benzodiazepines, including regulators of the activity of the projecting sedation, muscle relaxation, seizure suppres- glutamatergic pyramidal neurons. The activity sion, and anxiety reduction (anxiolysis). of these GABAergic interneurons is largely Benzodiazepines allosterically enhance the driven by glutamatergic afferents arising GABAA receptor opening frequency, pro- from either projecting afferents or recurrent ducing a potentiation of the GABA‐induced glutamatergic collaterals (Figure 2.3). inhibitory response (Rudolph et al. 1999). It is now generally recognized that The benzodiazepine binding site is believed GABAergic‐mediated inhibition results from to be located at the interface between the GABA activation of GABAA receptors α‐ and γ2‐subunits of a pentameric GABAA (GABAARs). GABAARs are heteropentameric receptor complex. There are six types of α − Cl ‐selective ligand‐gated ion channels that subunit, α1–α6, and GABAA receptors con- mediate fast inhibition within the CNS. When taining the α1‐, α2‐, α3‐, or α5‐subunits in activated by GABA, these GABAARs promote combination with any β‐subunit and the γ2‐ the diffusion of this ion according to its con- subunit are sensitive to benzodiazepines, centration gradient. Thus, GABAA‐receptor such as diazepam, alprazolam, and clonaze- activation may depolarize or hyperpolarize pam (Möhler et al. 2002). GABAA receptors membranes depending on the difference in containing these four α‐subunits are most Cl− concentration of the postsynaptic neuron abundant in the brain and the most prevalent and extracellular milieu (Figure 2.4). Although receptor complex is comprised of α1β2γ2 excitatory responses to GABA have been subunits. GABAA receptors that do not described in embryonic cells that maintain respond to benzodiazepines such as GABegc Synapse 17

GABAergic synapse Glial cell Gln Glu Glutamine GABA-T synthetase GABA GAT Presynaptic GABAB receptor

Glutaminase

Gln GAD Presynaptic neuron Glu Postsynaptic neuron

Vesicular transporter GABA GABA Postsynaptic Plasma membrane receptor transporter GAT

Figure 2.3 Schematic representation of a GABAergic synapse. Glutamate is the immediate precursor of GABA in these neurons where it is metabolized by the enzyme glutamic acid decarboxylase (GAD). The GABA is stored in and released from vesicles into the synaptic cleft. Synaptic GABA activates both pre‐ and postsynaptic receptors. The latter are primarily ligand‐gated ion channels (GABAA receptors), whereas presynaptic GABAB receptors are G‐protein coupled receptors involved in the regulation of neurotransmitter release. GABA in the synaptic cleft is recaptured by an active transporter (GAT) in the plasma membrane of both neurons and glia. GABA is metabolized by the mitochondrial enzyme GABA‐transaminase (GABA‐T) to succinic semialdehyde which in turn is converted to succinic acid by the enzyme succinic semialdehyde dehydrogenase. Succinic acid exerts a negative feedback inhibition on GAD. Succinic semialdehyde dehydrogenase is inhibited by the anticonvulsant sodium valproate.

Figure 2.4 Schematic structure of the GABAA receptor pentamer GABAA receptor pentamer composed of two α‐subunits, two β‐subunits and one γ‐ subunit. The neurotransmitter GABA binds to a site at the interface − between the α‐ and β‐subunits (●) causing the Cl channel to open. Benzodiazepines such as clonazepam and diazepam bind to a site at γα the interface of the α‐ and γ‐subunits and act as positive allosteric modulators to augment the actions of GABA. Cl– ββ

GABA binding site Benzodiazepine (clonazepam) binding site 18 Amino Acid Neurotransmitters

diazepam and clonazepam are less abundant (Möhler et al. 2001). The α2‐GABAA receptor in the brain and are characterized by the expressing neurons in the cerebral cortex and presence of the α4‐ and α 6‐subunits (Möhler the hippocampus are therefore specific tar- et al. 2002). The use of transgenic mice with gets for the future development of selective mutated GABAA receptors has recently dem- anxiolytic drugs. The sedative actions of ben- onstrated that it may be possible to develop zodiazepines, in contrast, appear to be medi- benzodiazepine‐like drugs that are anxiose- ated by α1‐subunit containing GABAA lective, meaning that they may reduce anxi- receptors. Changes in sleep pattern and EEG ety in the absence of sedation and muscle frequency associated with classical benzodi- relaxation (leading to incoordination). The azepines are attributable to most GABAARs anxiolytic action of diazepam is selectively (other than α1‐containing receptors), with α2 mediated by potentiation of GABAergic receptors having the most profound influ- inhibition in a population of neurons ence. These studies indicate that future drug expressing α2‐subunit containing GABAA development of more subunit‐specific ben- receptors, which constitute only 15% of zodiazepine ligands may have more selective all diazepam‐sensitive GABAA receptors pharmacologic profiles.

References

Amara, S.G. and Fontana, A.C.K. (2002). Arylcyclohexylamines: Present and Future Excitatory amino acid transporters: keeping Applications (ed. J.‐M. Kamenka, E.F. up with glutamate. Neurochemistry Domino and P. Geneste). Ann Arbor, MI: International 41: 313–318. NPP Brooks. Bjorkholm, C. and Monteggia, L.M. (2016). Lodge, D. and Mercier, M.S. (2015). Ketamine BDNF – a key transducer of antidepressant and phencyclidine: the good, bad and the effects. Neuropharmacology 102: 72–79. unexpected. British Journal of Pharmacology Cooper, J.R., Bloom, F.E., and Roth, R.H. 172: 4254–4276. (2003). The Biochemical Basis of Mayer, M.L. and Armstrong, N. (2004). Neuropharmacology, 7e. New York: Oxford Structure and function of glutamate University Press. receptor ion channels. Annual Review of Erreger, E., Chen, P.E., Wyllie, D.J.A., and Physiology 66: 161–181. Traynelis, S.F. (2004). Glutamate receptor Miyasaka, M. and Domino, E.F. (1968). Neural gating. Critical Reviews in Neurobiology 16: mechanisms of ketamine‐induced 187–224. anesthesia. International Journal of Kavalali, E.T. and Monteggia, L.M. (2015). Neuropharmacology 7: 557–573. How does ketamine elicit a rapid Möhler, H., Crestani, F., and Rudolph, U. antidepressant response? Current Opinion (2001). GABAA‐receptor subtypes: a new in Pharmacology 20: 35–39. pharmacology. Current Opinion in Kirischuk, S., Héja, L., Kardos, J., and Billups, B. Pharmacology 1: 22–25. (2016). Astrocyte sodium signaling and the Möhler, H., Fritschy, J.M., and Rudolph, U. regulation of neurotransmission. Glia 64: (2002). A new benzodiazepine 1655–1656. pharmacology. The Journal of Lodge, D., Anis, N.A., Berry, S.C., and Burton, Pharmacology and Experimental N.R. (1983). Arylcyclohexylamines Therapeutics 300: 2–8. selectively reduce excitation of mammalian Murray, T.F. (1994). Basic pharmacology of neurons by aspartate like amino acids. In: ketamine. In: The Pharmacologic Basis of Phencyclidine and Related Anesthesiology (ed. T.A. Bowdle, A. Horita References 19

and E.D. Karasch), 337–355. New York: specific γ‐aminobutyric acidA receptor Churchill Livingstone. subtypes. Nature 401: 796–800. Murrough, J.W., Abdallah, C.G., and Mathew, Somogyi, P., Tamas, G., Lujan, R., and S.J. (2017). Targeting glutamate signaling in Buhl, E.H. (1998). Salient features of depression: progress and prospects. Nature synaptic organisation in the cerebral Reviews Drug Discovery 16: 472–486. cortex. Brain Research Reviews 26 (2–3): Rudolph, U., Crestani, F., Benke, D. et al. 113–135. (1999). Benzodiazepine actions mediated by 21

Biogenic Amine Neurotransmitters Serotonin Thomas F. Murray

Creighton University, Omaha, NE, USA

Introduction other hallucinogens to the antipsychotics and antidepressants, as well as other centrally Psychopharmacology had its beginnings in acting agents, such as medetomidine, clomi the early 1950s and has steadily grown into pramine, and l‐deprenyl, are now associated one of the major areas of pharmacology with biogenic amine mechanisms. and psychiatry. Before the advent of these psychoactive drugs, various central nervous system (CNS) agents, such as the narcotics, The Biogenic Amines barbiturates, and stimulants were known, but none of these represented important The term “biogenic amines,” as used in psychop psychotherapeutic agents, and psychiatrists harmacology, includes the two catecholamines had an extremely limited chemotherapeutic dopamine (DA) and norepinephrine (NE), armamentarium. The initial breakthrough and the indoleamine, 5‐hydroxytryptamine came when the drugs, chlorpromazine and (5‐HT, serotonin), the structures of which reserpine, proved to be effective antipsychotic are indicated in Figure 3.1. Norepinephrine and anti‐schizophrenic agents. has been known for many years as the Soon after the development of the anti transmitter in peripheral sympathetic psychotic (or neuroleptic) drugs, the antide neurons, and much is now known regard pressant action of iproniazid was discovered, ing its biosynthesis, storage, uptake, release, and this therapeutic effect became correlated and degradation mechanisms. Serotonin has with the inhibition of monoamine oxidase also been extensively investigated; and while (MAO) and a consequent rise in brain biogenic its distribution is less ubiquitous, it also reg amines (serotonin, dopamine, and norepi ulates critical functions in the CNS. nephrine). A great deal of research has been Dopamine, which until the early 1960s, was carried out on a diverse array of psychoactive considered primarily as a precursor of NE, is drugs in attempts to more fully understand now established as a CNS transmitter in its their mechanism of action. From all of this own right. Its presence in the neostriatum research one striking common denominator and limbic system in high concentrations emerges, namely, that many of these agents initially led to speculation of its possible appear to modify in some way biogenic role in CNS function. These observations amines found in the CNS. Almost all of the and other related studies have demonstrated psychoactive drugs, ranging from LSD and that degeneration of DA neurons of the

OH Figure 3.1 Structures of biogenic amine (catecholamine and indolamine) HO CH2CH2NH2 HO CH CH NH 2 2 2 neurotransmitters dopamine, norepinephrine, and serotonin. HO HO DOPAMINE NOREPINEPHRINE

HO CH2CH2NH2

N H 5-HYDROXYTRYPTAMINE (SEROTONIN)

nigro‐striatal track is involved in Parkinson’s investigations which have led to our current disease. In fact, the use of its precursor, understanding of serotonin as a central 1‐dopa, in the treatment of this disease was neurotransmitter. historically based on this concept. The devel Early interest in serotonin functions in the opment of histochemical fluorescence tech brain intensified with the recognition that niques for the visualization of the biogenic many hallucinogenic drugs (e.g. LSD) were amines within the nerve cell bodies and structurally related to the serotonin molecule. terminals has permitted the mapping of the Because these hallucinogens act like serotonin, biogenic amine pathways throughout the it was postulated that the hallucinogenic various parts of the CNS. From such investi activity of LSD is related to its serotonergic gations it is now known that NE and 5‐HT agonist activity. Thus, the compound neurons, whose cell bodies are found largely bufotenin, or N,N‐dimethylserotonin, a very in the locus coeruleus and midbrain raphe close analog of serotonin, is a potent hallucino nuclei, respectively, terminate more or less in gen when administered centrally. Several other the same regions of the CNS. DA cell bodies compounds, such as the substances psilocybin originate largely in the substantia nigra, the and psilocin, the indoleamines found in the ventral tegmental area, and in the arcuate “magic” mushrooms of Mexico, and other nucleus of the hypothalamus, and their neu drugs of abuse, such as the dimethyl‐ and die rons terminate in the neostriatum; limbic thyl‐analogs of tryptamine, have the basic structures; and the median eminence and indole ethylamine structure. Hallucinogens pituitary, respectively. are now known to mediate many of their psy choactive effects by activating serotonin 2A receptors (5‐HT2AR). The 5‐HT2AR is highly Serotonin expressed on pyramidal neurons in the frontal cortex and has been implicated in several Serotonin was first chemically identified in mental and behavioral disorders, including the 1940s, although its existence in the schizophrenia, anxiety, and depression (Schmid gastrointestinal tract was previously known. and Bohn 2010). Its presence in blood serum and platelets, Inasmuch as serotonin is found in many and the fact that it exerted vasoconstrictor cells outside of the central nervous system activity led to the derivation of the name that are not neurons, only about 1–2% of the “serotonin.” It was, however, only its discov whole body serotonin content is found in the ery in mammalian brain that initiated the brain. Serotonergic neurons synthesize this extensive neurochemical and pharmacologic transmitter, beginning with the conversion of Serotoni 23 dietary tryptophan to 5‐hydroxytryptophan. is an interaction between a monoamine Plasma tryptophan varies as a function of oxidase inhibitor and a selective serotonin diet and elimination of dietary tryptophan reuptake inhibitor. The accidental ingestion can dramatically lower levels of serotonin of 5‐hydroxytryptophan by dogs, however, in the brain. Following the production of has been documented to result in a life‐ 5‐hydroxytryptophan by hydroxylation of threatening syndrome resembling a seroto tryptophan in serotonergic neurons, the 5‐ nin syndrome (Gwaltney‐Brant et al. 2000). hydroxytryptophan is rapidly decarboxylated A review of 21 cases of accidental 5‐hydroxy to produce serotonin (5‐hydroxytryptamine). tryptophan by dogs indicated that ingestion The serotonin precursor, 5‐hydroxytrypto phan of a single 500 mg capsule of these dietary is sold as an over‐the‐counter dietary sup supplements would be sufficient to produce plement (sometimes termed Griffonia seed adverse sequelae in dogs. extract) for its claimed ability to treat condi In the mammalian brain, serotonergic tions such as depression, headaches, obesity, neurons are localized to clusters of cell and insomnia in humans (and animals). The bodies of the pons and brain stem termed oral administration of 5‐hydroxytryptophan the raphe nuclei (Figure 3.2). These groups results in rapid absorption from the gastroin of 5‐HT neurons project in both ascending testinal tract and in turn readily crosses the and descending pathways to the forebrain blood–brain barrier (Gwaltney‐Brant et al. and spinal cord, respectively. Forebrain 2000). This 5‐hydroxytryptophan can be structures receiving 5‐HT innervation rapidly converted to serotonin in the brain include the cerebral cortex, the striatum, and the spinal cord. Excessive stimulation and the hippocampus. These ascending of serotonin receptors due to dramatic ele projections to the cerebral cortex and lim vations of 5‐HT causes a “serotonin syn bic regions emanate from rostral raphe drome” that may be associated with muscle nuclei axons, while the caudal raphe nuclei rigidity, myoclonus, salivation, agitation, in the brainstem give rise to the descending and hyperthermia in animals and humans. projections terminating in the medulla and The most common cause of this syndrome spinal cord.

Cerebral cortex

Hippocampus CB Striatum Thalamus OB

SN/VTA Raphe Hypothalamus nuclei

Spinal cord

Figure 3.2 Schematic diagram of the serotonergic pathways in animal brain. Serotonergic cell bodies are localized to clusters of cells in the pons and rostral brain stem referred to as the raphe nuclei. 24 Biogenic Amine Neurotransmitters

Serotonergic terminals are the sites of synaptic actions of 5‐HT, they have been an vesicular release of the transmitter at syn important target for drug development. As a apses in the projection field (e.g. the cerebral consequence, a number of selective serotonin cortex, limbic structures). Following the reuptake inhibitors (SSRIs) have been devel release of 5‐HT in the synapse, the action of oped, such as fluoxetine, sertraline, and par the transmitter is terminated through a oxetine for use in the treatment of depression, high‐affinity reuptake into the presynaptic anxiety, panic attack, and obsessive–compulsive terminal. This reuptake is mediated by spe disorder in humans. Both fluoxetine and cific transporter proteins that have evolved clomipramine (a tryciclic antidepressant with to recognize and transport serotonin. These some selectivity for the serotonin trans serotonin transporters (SERTs) are members porter) have been approved for the treatment of a gene family of Na+ and Cl−‐dependent of separation anxiety in dogs. These reuptake transport proteins. The serotonin transport inhibitors act as indirect serotoninmimetics ers are expressed in the brain in presynaptic by increasing the half‐life of serotonin in the and somatodendritic membranes of seroto synapse, resulting in prolonged activation of nin neurons. These 5‐HT transporters also multiple serotonin receptor subtypes. The exist in other tissues, such as platelets, pla localization of the serotonin transporter on centa, and the lung. Given the critical role of the presynaptic terminal of serotonergic neurons serotonin transporters in the regulation of the is depicted in Figure 3.3.

Serotonergic synapse Glial cell

5-HT1A MAO release modulating autoreceptor

Tryp 5-HTP 5-HT Postsynaptic TrypOHase L-AADC neuron Presynaptic 5-HT neuron

Vesicular transporter

Plasma membrane Postsynaptic receptor serotonin transporter (SERT) 5-HT1A 5-HT3 5-HT1D 5-HT4 5-HT2A 5-HT6 5-HT2C 5-HT7

Figure 3.3 Schematic representation of a serotonergic synapse. Tryptophan is the dietary precursor for serotonin (5‐HT) synthesis and is converted to 5‐hydroxytryptophan (5‐HTP) by the enzyme tryptophan hydroxylase (TrypOHase). 5‐HTP is converted to 5‐HT by the enzyme l‐aromatic amino acid decarboxylase (L‐AADC). 5‐HT is stored in and released from vesicles, and synaptic 5‐HT activates both pre‐ and postsynaptic receptors. Synaptic 5‐HT action is terminated by the reuptake of the transmitter into the presynaptic terminal. This reuptake is mediated by the plasma membrane serotonin transporter (SERT). Cytoplasmic 5‐HT can be degraded by the mitochondrial enzyme monoamine oxidase (MAO). Serotoni 25

The function of serotonin is exerted upon the release of serotonin via reverse transport its interaction with specific receptors. There through SERT. Fenfluramine is also a direct are 15 distinct 5‐HT receptor genes in the acting agonist at 5‐HT2B receptors. Until the human genome, and they may be expressed late 1990s, it was used in human medicine as either pre‐ or postsynaptically in various an anorectic agent in combination with brain areas. All 5‐HT receptor subtypes phenteramine (Fen‐Phen). An association (except the 5‐HT3 receptor) are G‐protein between fenfluramine use and valvular heart coupled receptors. These serotonin recep disease and pulmonary hypertension, how tor genes characterized to date include the ever, led to the removal of this preparation 5‐HT1, 5‐HT2, 5‐HT3, 5‐HT4, 5‐HT5, 5‐HT6, from the market. The 5‐HT2B receptor is and 5‐HT7 subtypes. Within the 5‐HT1 enriched in human cardiac valves and appears group, there are subtypes, 5‐HT1A, 5‐HT1B, to be the target for a fenfluramine metabolite‐ 5‐HT1D, 5‐HT1E, and 5‐HT1F. There are induced cardiac valve abnormalities. three 5‐HT2 subtypes, 5‐HT2A, 5‐HT2B, and Serotonergic neurons possess two func 5‐HT2C as well as two 5‐HT5 subtypes, 5‐ tional types of autoreceptors. One autorecep HT5A and 5‐HT5B. These receptors are tor is the 5‐HT1B receptor that is expressed coupled to G‐proteins that affect the activi primarily on serotonergic neuron terminals, ties of enzymes such as adenylate cyclase and functions as a regulator of 5‐HT release. and phospholipase C, or ion channels such as Activation of the 5‐HT1B receptor inhibits potassium channels. The 5‐HT3 class of serotonin release from the axon terminals receptors are unique in that they represent and therefore functions as a local negative ligand‐gated ion channels that mediate rapid feedback regulator of serotonin levels in the excitatory signaling events. The 5‐HT2A synapse. These 5‐HT1B autoreceptors have receptors mediate platelet aggregation and been suggested to play a role in depression, smooth muscle contractions. Serotonin, 5‐ anxiety states, aggression, migraine, and loco hydroxy‐l‐tryptophan, and hallucinogenic motor activity. Serotonergic involvement in drugs induce a head‐twitch response in mice aggression was indicated in studies with that is a behavioral proxy for brain 5‐HT2AR transgenic mice lacking the 5‐HT1B receptor; activation (Schmid and Bohn 2010). The 5‐ these 5‐HT1B knockout mice are more HT2C receptors are suspected in the control aggressive than the normal 5‐HT1B receptor‐ of food intake as mice lacking this gene expressing mice (Sari 2004). A second become obese from increased food intake functional autoreceptor is the 5‐HT1A recep and are also subject to lethal seizures. The tor that is found on serotonergic cell bodies 5‐HT3 receptors are present in the gastroin and dendrites (somatodendritic) in raphe testinal tract and chemoreceptor trigger nuclei serotonin neurons as well as on post zone in the area postrema and their activa synaptic neurons receiving input from 5‐HT tion can trigger vomiting. Also present in pathways (Figure 3.4). Activation of 5‐HT1A the gastrointestinal tract are 5‐HT4 recep somatodendritic autoreceptors inhibits 5‐ tors that function in secretion and peristalsis. HT neuron firing, 5‐HT synthesis and 5‐HT The 5‐HT6 and 5‐HT7 receptors are distrib release from axon terminals. Direct applica uted throughout the limbic system in the tion of 5‐HT onto 5‐HT neurons in the dorsal brain and 5‐HT6 receptors are unique in that raphe produces an inhibitory effect on the they display high affinity for both typical serotonergic neuron firing activity through (chlorpromazine) and atypical (clozapine) the activation of a hyperpolarizing potassium antipsychotic drugs. conductance. The 5‐HT1A autoreceptors on Serotonergic drugs such as fenfluramine the cell bodies of serotonergic neurons in have a different mechanism of action than the raphe nuclei presumably respond to the the reuptake inhibitors; fenfluramine inter extracellular 5‐HT released from the soma acts with the 5‐HT transporter to promote and dendrites of these neurons. These 5‐HT Normal 5-HT neuron Postsynaptic neuron

5-HTT 5-HT neurotransmitter Postsynaptic 5-HT 5-HT1AR receptors

5-HT1AR

5-HTT 5-HT1BR

(–) 5-HT1AR

Acute SSRI treatment 5-HT neuron Postsynaptic neuron 5-HT neurotransmitter S 5-HT1AR S Postsynaptic 5-HT S receptors

S S 5-HTT S 5-HT1AR S 5-HTT 5-HT1BR S S

(–) S S 5-HT1AR S SSRI S

After chronic SSRI treatment 5-HT neuron Postsynaptic neuron 5-HT 5-HTT neurotransmitter S

Postsynaptic 5-HT S S receptors

S S S 5-HT1AR

S 5-HTT 5-HT1BR S

S S

S SSRI S

Figure 3.4 Diagram depicting the regulation of the firing activity of 5‐HT neurons by 5‐HT1A autoreceptors localized on soma and dendrites (somatodendritic). Normal: Endogenous 5‐HT released from dendrites of serotonergic neurons activates 5‐HT1A autoreceptors and decreases neuronal firing activity. Acute: Acute administration of selective 5‐HT reuptake inhibitor (SSRI) potentiates 5‐HT induced decrease in neuronal firing leading to reduced release of 5‐HT in forebrain structures. Chronic: After chronic treatment with a SSRI, the 5‐HT1A autoreceptors desensitize and firing activity is restored or enhanced in the presence of the SSRI, leading to increased release of 5‐HT in forebrain structures. This adaptive change in 5‐HT neuronal control may be obligatory for an antidepressant response to manifest. Serotoni 27 autoreceptors function in the feedback inhi polymorphism was associated with SERT bition of raphe neurons to maintain a regular functional differences and increased amyg firing pattern of serotonin neurons. dala response to fearful stimuli (Hariri et al. It is well established that acute SSRI 2002). The link between serotonergic neuro administration leads to a rapid (within one transmission and affective disorders was to two hours) inhibition of SERT in the CNS; further established through studies of gene– however, the antidepressant effects in environment interaction. Individuals with a humans and animals take weeks to fully particular allele of the 5‐HT transporter gene manifest. One of the primary postulated appeared to be more vulnerable to stressful mechanisms of action of SSRIs is the desen events in that they were more likely to sitization of somatodendritic 5‐HT1A auto become clinically depressed (Caspi et al. receptors after chronic administration. As 2003). These important studies indicate that depicted in Figure 3.4, the potential increase rather than cause disease, genes may interact in 5‐HT transmission in forebrain areas, with the environment to control susceptibility which should result from preventing the to affective disorders such as depression. reuptake of 5‐HT in presynaptic terminals, is Serotonin pathways have also been shown prevented by a decrease in the firing rate of to be involved in obsessive–compulsive 5‐HT neurons because 5‐HT reuptake is also disorder (OCD). Clomipramine was first inhibited in raphe nuclei serotonin neuron shown to have efficacy in the treatment of cell bodies. This was first demonstrated by OCD in 1980. In the 1990s, this clinical examining the effects of an SSRI in the rat effectiveness was extended to SSRIs such as brain (Blier and de Montigny 1983). The fluoxetine, sertraline, and paroxetine. The receptor mediating this initial decrease of the therapeutic response of clomipramine and firing of 5‐HT neurons was subsequently SSRIs in treating OCD in humans and acral identified as a 5‐HT1A receptor on the 5‐HT lick dermatitis in dogs may be mediated by neurons themselves (autoreceptor) (Blier increased activation of 5‐HT2C receptors 2010). This 5‐HT1A autoreceptor desensitizes through elevated synaptic levels of serotonin over the course of chronic (two to three weeks) in forebrain structures, such as the orbito SSRI administration, allowing a recovery to frontal cerebral cortex. The efficacy of SSRIs normal of the firing of 5‐HT neurons in the in treating OCD to some extent generalizes presence of reuptake inhibition. This to 5‐HT1A receptor agonists; these direct increased firing rate results in a marked activators of a serotonin receptor represent a increase in 5‐HT transmission in projecting group of structurally related compounds, the areas because 5‐HT release is highly depend azapirones, best exemplified by buspirone. ent on firing. The desensitization of the 5‐ The azapirones possess significant affinity HT1A autoreceptor is therefore temporally and selectivity for 5‐HT1A receptors where correlated with the onset of the therapeutic they exert partial agonist activity. Acute treat action of SSRIs in depression. Studies in ment with buspirone produces a transient animals have shown that the somatoden reduction in the firing rate of 5‐HT neurons, dritic 5‐HT1A receptor desensitization may similar to that seen initially with SSRIs. This be related to the ability of SSRIs to trigger the response is presumed to reflect the conse internalization of these receptors into cyto quences of direct activation of 5‐HT1A soma plasmic compartments (Riad et al. 2004). todendritic autoreceptors by buspirone. A role for limbic serotonergic neurotrans Chronic administration with azapirones mission involvement in anxiety‐related does, however, lead to a gradual increase in behavioral traits has recently emerged from 5‐HT neuron firing due to the progressive human studies of genetic differences in sero desensitization of 5‐HT1A autoreceptors. In tonin transporter function. These studies addition to the activation of 5‐HT1A autore demonstrated that 5‐HT transporter gene ceptors, buspirone acts as a partial agonist at 28 Biogenic Amine Neurotransmitters

the postsynaptic 5‐HT1A receptors in fore azapirone agonists are also used in the treat brain structures. This pharmacologic profile ment of generalized anxiety disorder where for azapirones differs from that of SSRIs, they produce less sedation, less psychomotor tricyclic antidepressants, and monoamine disruption, and less cognitive impairment oxidase inhibitors (MAOI) in that these lat than benzodiazepines. Although in clinical ter drug classes produce an indiscriminate trials buspirone is typically shown to be effi activation of all serotonin receptor subtypes. cacious in treating anxiety, patients’ response This generalized activation of multiple 5‐HT is more delayed than with benzodiazepines; receptor subtypes is consequently associ this most likely reflects the requirement for ated with a number of adverse effects of 5‐HT1A autoreceptor desensitization to SSRIs, MAOIs, and tricyclics, such as nau achieve the therapeutic response. The aza sea, vomiting, sleep disturbance, and sexual pirones are therefore an alternative to either dysfunction. The most common side effects SSRIs or benzodiazepines for the treatment of azapirones are limited to headache, diz of specific behavioral disorders in companion ziness, and nausea. Buspirone and other animals.

References

Blier, P. (2010). Altered function of the Journal of the American Veterinary serotonin 1A autoreceptor and the Association 216: 1937–1940. antidepressant response. Neuron 65: 1–2. Hariri, A.R., Mattay, V.S., Tessitore, A. et al. Blier, P. and de Montiginy, C.J. (1983). (2002). Serotonin transporter genetic Electrophysiological investigations on the variation and the response of the human effect of repeated zimelidine amygdala. Science 297: 400–403. administration on serotonergic Riad, M., Zimmer, L., Rbah, L. et al. (2004). neurotransmission in the rat. Journal of Journal of Neuroscience 24 (23): 5420–5426. Neuroscience 3: 1270–1278. Sari, Y. (2004). Serotonin1B receptors: from Caspi, A., Sugden, K., Moffitt, T.E. et al. protein to physiological function and (2003). Influence of life stress on depression: behavior. Neuroscience and Biobehavioral moderation by a polymorphism in the Reviews 28: 565–582. 5‐HTT gene. Science 301: 291–293. Schmid, C.L. and Bohn, L. (2010). Serotonin, 386–389. but not N‐methyltryptamines, activates the Gwaltney‐Brant, S.M., Albretson, J.C., and serotonin 2A receptor via a β‐Arrestin2/Src/ Khan, S.A. (2000). 5‐Hydroxytryptophan Akt signaling complex in vivo. Journal of toxicosis in dogs: 21 cases (1989–1999). Neuroscience 30 (40): 13513–13524. 29

Biogenic Amine Transmitters Acetylcholine, Norepinephrine, and Dopamine Thomas F. Murray

Creighton University, Omaha, NE, USA

Acetylcholine bound enzyme, acetylcholinesterase (ACHE), which represents the mechanism for termi Acetylcholine was the first compound to be nation of the signal in cholinergic neuro identified as a neurotransmitter in the peri transmission. ACHE has one of the highest pheral nervous system; however, knowledge catalytic powers ever reported for an enzyme concerning the anatomical organization of and is therefore capable of a rapid clearance cholinergic neurons lagged behind other of ACh from the synaptic cleft. This distin transmitter substances due to the lack of guishes cholinergic neurons from those of suitable techniques for mapping cholinergic other biogenic amines where the synaptic pathways. Many of these technical obstacles signal is terminated by the high‐affinity have been surmounted in recent years. reuptake of the transmitter. Acetylcholine is Acetylcholine is synthesized in cholinergic the neurotransmitter of all autonomic ganglia, neurons by a reaction catalyzed by the cyto postganglionic parasympathetic synapses, solic enzyme choline acetyltransferase (CAT). the neuromuscular junction, and cholinergic This linkage of choline and an acetate group neurons in the central nervous system. provided by acetyl‐CoA is not, however, the Cholinergic pathways in the brain have rate‐limiting step in the biosynthesis of now been identified by histochemical and acetylcholine (ACh); rather, the high‐affinity neurochemical methods (Figure 4.2). The transport of choline from the extracellular majority of cholinergic neurons in the mam medium by a specific transporter protein malian brain are found in four regions. These represents the rate‐limiting step. ACh is include: (i) the brainstem pedunculo‐pontine stored in vesicles in cholinergic terminals and lateral dorsal tegmental nuclei; (ii) a sub and released into the synaptic cleft by exocy set of the thalamic nuclei; (iii) the striatum, tosis (Figure 4.1). The proteins involved in where cholinergic neurons serve as local this exocytotic release of ACh are the targets interneurons; and (iv) the basal forebrain for botulinum toxin; the therapeutic actions nuclei, which collectively serve as the major of Botox in the treatment of neuromuscular sources of cholinergic projection neurons to disorders derive from the ability of this the cerebral cortex, hippocampus, and amyg toxin to block the release of ACh from cho dala (Ballinger et al. 2016). The cholinergic linergic neuron terminals (Coffield 2003). neurons originating in the nucleus basalis Acetylcholine released from neurons into the of Meynert, substantia innominata, and the synaptic cleft is hydrolyzed by the membrane diagonal band (basal forebrain) project to

Cholinergic synapse Glial cell

AChE

AChE Ac-CoA Presynaptic Postsynaptic neuron neuron ACh Choline Vesicular acetyltransferase transporter

ACh Choline transporter AChE

AChE Postsynaptic receptor (muscarinic or nicotinic) Choline

Acetic acid

Figure 4.1 Schematic representation of a cholinergic synapse in the central nervous system. The precursor for acetylcholine (ACh) synthesis is choline. ACh is synthesized from choline and acetyl CoA by the enzyme choline acetyltransferase. The ACh is stored in and released from vesicles. Synaptic ACh activates postsynaptic receptors comprised of both muscarinic and nicotinic subtypes. The synaptic action of ACh is terminated by the enzyme acetyl cholinesterase (AChE) through hydrolysis to acetate and choline. The choline is salvaged by a high affinity transporter for reutilization in the syntheses of ACh.

Cerebral cortex Hippocampus Tectum Habenula Striatal inter- D.raphe neurons Olfactory Thalamus CB bulb Amygdala

BMSI Hypo- S. nigra thalamus Interpeduncular nucleus

Figure 4.2 Schematic diagram of the cholinergic pathways in animal brain. Central cholinergic neurons exist as both local circuit interneurons and projection neurons. Abbreviation: BMSI = Basal Nucleus of Meynert/ Substantia Inominata. Acetylcholin 31 virtually all cerebral cortical areas and layers in the cerebral cortex and hippocampus. (Sarter et al. 2016). These projections termi High doses of either drug can also produce nating throughout the cerebral cortex degen delirium, hyperactivity, visual hallucina erate in senile dementia and Alzheimer’s tions, and disorientation. disease and this cholinergic neuron loss has The M2 muscarinic receptor predomi been correlated with the degree of cognitive nates in hindbrain regions while the M1 decline. The ACh content of the brain in receptor is expressed at high levels in the Alzheimer’s patients at postmortem is pro cerebral cortex and hippocampus which are foundly reduced. These observations have brain regions involved with memory and led to the cholinergic hypothesis of cognitive cognition. The M1 muscarinic receptor has decline in senile dementia that has served as accordingly generated considerable recent the basis for pharmacological attempts to interest as a target for drug discovery of ameliorate learning and memory deficits by agents that might facilitate learning and restoration of cholinergic neurotransmission. memory. In animal models, M1 muscarinic One pharmacologic strategy for augmenting receptor agonists restore cognitive impair cholinergic transmission has been the use of ment associated with damage to cholinergic inhibitors of ACHE. Inhibition of this enzyme pathways and may exert additional disease‐ prolongs the half‐life of ACh in the synapse modifying effects beneficial to Alzheimer’s and therefore enhances cholinergic trans disease (Fisher et al. 2003). mission. Drugs such as tacrine, donepezil The other class of cholinergic receptors (Aricept®) and rivastigmine (Exelon®) are that exist in the central nervous system are ACHE inhibitors (ACHEI) that have been nicotinic receptors. These ACh receptors are used in the treatment of cognitive dysfunc members of the ligand‐gated ion channel tion associated with Alzheimer’s disease. superfamily and are composed of multiple These drugs produce modest beneficial homologous subunits oriented around a cen effects for periods of approximately one year, tral cation channel. Twelve different types of but do not prevent the progressive deteriora nicotinic receptor subunits have been identi tion of mental function in Alzheimer’s fied in the brain (α2–10 and β2–β4) and each patients. Inhibition of ACHE has moreover nicotinic cholinergic receptor is composed of a high propensity for adverse effects and a five of these subunits. The combination of significant fraction of patients withdraw these subunits into a pentameric structure from treatment due to side effects. determines its electrophysiological and phar Cholinergic receptors that mediate the syn macological properties. It takes the binding of aptic actions of ACh are either muscarinic or two molecules of ACh to open the cation nicotinic cholinergic receptors. The muscarinic channel and allow the Na+ influx and depo receptors are members of the G‐protein cou larization of neuronal membranes. The most pled receptor family and five subtypes of common nAChR subtypes in the brain are muscarinic cholinergic receptors (M1–M5) α4β2 and α7 receptors. have been characterized. Muscarinic receptor In addition to responding to ACh, these activation therefore trigger their signaling receptors, as their name implies, are also through activation of heterotrimeric G pro activated by the alkaloid nicotine found in teins that in turn affect the opening, closing, tobacco leaves. Nicotine shares with other and kinetics of K+, Ca2+, and non‐selective drugs of abuse the ability to activate the mes cation channels. The alkaloids, atropine and ocortical limbic dopaminergic pathways that scopolamine, act as nonselective, competitive represent the reward circuitry of mammalian antagonists of these muscarinic receptors. brain. The interaction with nicotinic cholin Both atropine and scopolamine are capable of ergic receptors in this pathway underlies the disrupting working memory in humans and rewarding and dependence‐related actions of animals through their antimuscarinic actions nicotine. In addition to the adverse addictive 32 Biogenic Amine Transmitters

properties of nicotine, this naturally occur The biosynthesis of norepinephrine in ring product increases mental alertness and central neurons begins with the precursor improves memory in humans and animals. tyrosine. Tyrosine is converted to l‐dopa by Chronic transdermal nicotine has indeed the soluble enzyme tyrosine hydroxylase been found to improve attentional perfor (Figure 4.3). Tyrosine hydroxylase is the mance in Alzheimer’s disease patients and in rate‐limiting step in the biosynthesis of nor individuals with the precursor age‐associated epinephrine and the activity of this enzyme is memory impairment syndrome (White and closely coupled to the neuronal firing rate. Levin 2004). There is therefore a great deal of The l‐dopa is in turn converted to dopamine interest in the pharmaceutical industry by the enzyme l‐dopa decarboxylase. In directed toward the development of synthetic noradrenergic, but not dopaminergic, neurons nicotinic receptor agonists for the treatment the dopamine is converted into norepineph of memory deficits and cognitive dysfunction. rine by dopamine‐β‐hydroxylase and stored There are currently several nicotine analogs in in vesicles for release. Once the norepineph various stages of preclinical and clinical rine is released into the synaptic cleft, the development for use in neurodegenerative signaling action of this transmitter is termi and Alzheimer’s disease to mitigate the cog nated by the selective, high affinity of reuptake nitive effects of the disease and delay clinical of norepinephrine by a distinct transporter cognitive manifestations. expressed on noradrenergic neurons (NET). Amphetamine and related psychostimulants exert their sympathomimetic and central Norepinephrine stimulant properties through the inhibition of norepinephrine reuptake and the facilitation The neurotransmitter norepinephrine is of the transmitter release. distributed throughout the brain. The rela Norepinephrine interacts with both alpha tively low concentration of norepinephrine and beta adrenergic receptors expressed in in the brain, however, initially led physiolo the brain. There are eight subtypes of adr gists to question its functional importance. energic receptors expressed in the brain Application of a fluorescent histochemical including alpha‐1A, 1B, 1D, alpha‐2A, 2B, 2C, technique subsequently permitted the visu beta‐1 and beta‐2 adrenergic. All adrenergic alization of norepinephrine containing neu receptors are G‐protein coupled receptors. rons and pathways in both the central and While the release of all neurotransmitters is peripheral nervous system. Norepinephrine, regulated by presynaptic autoreceptors that dopamine, and epinephrine are catechola respond to the released transmitter, this was mines. The microanatomy of catechola first demonstrated in noradrenergic neurons. mine‐containing neurons in the central The noradrenergic neuron autoreceptors are nervous system is distinct from amino acid members of the alpha‐2 adrenergic receptor and cholinergic fibers in that they possess class. Agonists for alpha‐2 adrenergic recep varicosities along the axons in terminal fields. tors, such as clonidine, produce an inhibition These varicosities contain all the machinery of norepinephrine release, while alpha‐2 for neurotransmitter synthesis, storage, and antagonists, such as yohimbine, increase the release and are therefore the points of amount of norepinephrine released from synaptic contact with target neurons. This presynaptic terminals. Given the existence of unique microanatomy therefore allows a three subtypes of alpha‐2 adrenergic recep single catecholamine neuron with long tors, the identity of the subtypes representing terminal branches to possess thousands of presynaptic autoreceptors was addressed varicosities. One catecholamine neuron using gene knockout strategies in mice. This consequently can influence the activity of approach has shown that both alpha‐2A and thousands of target neurons. alpha‐2C‐adrenergic receptors are involved Norepinephrin 33

Noradrenergic synapse

Glial cell

Release- MAO modulating autoreceptor

Tyr L-DOPA DA NE Postsynaptic TH L-AADC DBH neuron NE Presynaptic neuron NE

Postsynaptic receptor (alpha or beta) Plasma membrane transporter (NET) NE Vesicular transporter

Figure 4.3 Schematic representation of a noradrenergic synapse. The amino acid precursor tyrosine is converted to l‐dopa by the enzyme tyrosine hydroxylose (TH) in noradrenergic neurons. The l‐dopa is the converted to dopamine by l‐aromatic amino acid decarboxylase (L‐AADC), and the dopamine is in turn converted to norepinephrine (NE) by dopamine‐β‐hydroxylase (DBH). The NE is stored in and released from vesicles, and synaptic NE activates a complement of pre‐ and postsynaptic receptors. Synaptic NE action is terminated by the reuptake of the transmitter into the presynaptic terminal. This reuptake is mediated by the plasma membrane NE transporter (NET). Cytoplasmic NE can be degraded by the mitochondrial enzyme monoamine oxidase (MAO). Presynaptic release modulating autoreceptors are the α2‐adrenergic subtype. in the presynaptic control of transmitter release ceruleus. Collectively, this noradrenergic sys in noradrenergic neurons (Hein et al. 1999). tem plays a critical role in the regulation of Noradrenergic neurons in the brain emanate arousal, attention, mood, and cardiovascular from cell bodies in the pons (Figure 4.4). function. An additional group of noradrenergic The primary nuclear complex from which neurons lies outside the locus ceruleus where noradrenergic neurons arise in the mammalian they are sparsely distributed throughout the brain is the locus ceruleus. Norepinephrine lateral ventral tegmental area of the pons neurons belonging to this nuclear complex (Cooper et al. 2003). branch widely in their terminal fields, allow Selective alpha‐2 (α2) receptor agonists, ing, for example, a single norepinephrine such as clonidine, xylazine, and medetomi axon to innervate a large fraction of the cer dine produce sedation, analgesia, and muscle ebral cortex. Locus ceruleus noradrenergic relaxation in animals. As a class, α2‐agonists efferents innervate target cells in cerebral are widely used as analgesic and sedative drugs cortical, subcortical, and spinomedullary in veterinary medicine. Clonidine, which is a fields. The sole source of norepinephrine partial agonist with high selectivity for α2A input to the cerebral cortex and hippocam versus α1 adrenergic receptors, has served pus, brain regions critical for cognitive and as the prototype drug for this class and rep affective processes, is derived from the locus resents one of the most widely investigated 34 Biogenic Amine Transmitters

Hippocampus Cerebral cortex

Thalamus Olfactory bulb

Locus ceruleus

Hypothalamus

Figure 4.4 Schematic diagram of the noradrenergic pathways in animal brain. Noradrenergic cell bodies are localized to the caudal pons in the locus ceruleus and also distributed more diffusely in the ventral tegmentum.

drugs in anesthesia and pain therapy receptors are most likely postsynaptic recep (Giovannoni et al. 2009). The sedative effects tors on dendrites of target neurons receiving of these drugs are mediated by the activation input from noradrenergic neurons (Glass of α2 receptors on the locus ceruleus noradr et al. 2001). The more variable effects of energic neurons. By selectively targeting medetomidine on the blood pressure of dogs α2A adrenergic receptors, dexmedetomidine and cats is produced by a combination of alters the level of arousal by reducing the stimulation of central α2A sites and periph firing rate of locus ceruleus neurons, and eral postsynaptic α2A receptors in vascular norepinephrine release (Song et al. 2017). smooth muscle. Similarly, the sedative actions of medetomi Although throughout the 1990s the emer dine (Domitor®) in dogs is most likely medi gence of SSRIs as the primary treatment of ated by the α2A adrenergic receptor subtype, depressive illness focused attention on ser inasmuch as this receptor was the only α2 otonergic mechanisms, traditional antide subtype recently shown to be expressed in pressants such as the tricyclic antidepressants canine brainstem (Schwartz et al. 1999). The (TCAs) and monoamine oxidase inhibitors actions of medetomidine may be reversed (MAOIs) increase synaptic concentrations of through the administration of atipamezole both norepinephrine and serotonin. Simi (Antisedan®) due to the α2 adrenergic recep larly, newer drugs such as venlafaxine that tor competitive antagonist properties of the block the reuptake of both serotonin and latter compound. Medetomidine also affects norepinephrine (SNRIs) are effective antide the cardiovascular system of dogs and cats, pressants (Hardy et al. 2002). When coupled producing marked bradycardia. The medeto with the recent introduction of the selective midine‐induced bradycardia is produced by a norepinephrine reuptake inhibitor (NRI) central action where activation of α2A adren reboxetine as an antidepressant, there has ergic receptors in the nucleus tractus solitarius been a resurgence of interest in the role of reduces sympathetic outflow (Cullen 1996). noradrenergic mechanisms in depression These nucleus tractus solitarius α2A adrenergic and affective disorders in general. Norepinephrin 35

The renewed attention on noradrenergic the norepinephrine (NET) and serotonin pathways is consistent with the original for transporters (SERT) in vitro have been well mulation of the biogenic amine theory of characterized, and indicate that several of affective disorders which posited that depres these antidepressants are relatively selective sive symptoms arose from a deficiency of inhibitors of norepinephrine reuptake. As biogenic amines such as norepinephrine indicated in Table 4.1, the TCAs desipramine (Schildkraut 1965). This hypothesis arose and nortriptyline have selectivity for the nor from the observations in the 1950s that ipro epinephrine transporter, while amitriptyline niazid, an MAOI, elevated mood in depressed and imipramine display little selectivity. patients being treated for tuberculosis, and In contrast. the SSRIs fluoxetine, sertraline, that imipramine, developed as an antipsy and paroxetine preferentially inhibit the chotic, elevated mood in patients with serotonin transporter. depressive illness. Imipramine was subse Although technically a tricyclic compound, quently shown to inhibit the reuptake of the the structurally unique drug reboxetine is biogenic amines norepinephrine and seroto very selective as an inhibitor of norepineph nin. The demonstration of the effectiveness rine reuptake. The human literature indi of imipramine as an antidepressant led to the cates that there is no significant difference development of an array of TCAs that remain between the antidepressant efficacies of nor in use in human and veterinary medicine. epinephrine‐ and serotonin‐selective antide The TCAs that remain in clinical use are the pressant drugs (Brunello et al. 2002). These tertiary amines amitriptyline, clomipramine, data suggest that both noradrenergic and doxepin, and imipramine; and the secondary serotonergic mechanisms are involved in amines desipramine and nortriptyline. While depressive symptomatology and, as a conse the tertiary amines were originally proposed quence, chronic inhibition of either NET‐ or to have some selectivity for inhibiting the SERT‐mediated reuptake leads to improve serotonin transporter in vitro, their secondary ment in the symptoms of clinical depression. amine metabolites generated in vivo prefer An interesting observation from a preclinical entially inhibit the norepinephrine trans investigation recently indicated that the porter. The differential affinities of TCAs for behavioral effects of the SSRIs fluoxetine,

Table 4.1 Interaction of antidepressants with the norepinephrine (NET) and serotonin (SERT) transporters in vitro.

NET Selectivity Drug KI (nM) NET KI (nM) SERT (ratio SERT/NET)

Desipramine 0.77 288 374 Reboxetine 8 1070 130 Nortriptyline 4.34 190 44 Doxepin 40 355 9 Amitriptyline 27 107 4 Imipramine 28 37.2 1.3 Fluoxetine 1235 17.7 0.014 Sertraline 220 3.4 0.015 Paroxetine 161 0.033 0.0002

Note: The antidepressants are listed in decreasing order of NET selectivity. Source: Brunello et al. (2002); Rothman and Baumann (2003). 36 Biogenic Amine Transmitters

sertraline, and paroxetine were either absent receptors. Newer antidepressants such as the or severely attenuated in transgenic mice SSRIs and NSRIs have negligible affinities for incapable of producing norepinephrine these neurotransmitter receptors and therefore (Cryan et al. 2004). These results indicate possess a much more favorable side effect that norepinephrine may play an important profile (Kent 2000). First‐generation TCAs role in mediating the acute behavioral and commonly produce constipation, urinary neurochemical effects of many antidepres retention, dry mouth, sedation, and postural sants including some widely used SSRIs. hypotension, and are highly toxic on overdose. An important concept that is germane to The latter side effects of sedation and postural our current understanding of the mechanism hypotension are well correlated with affinity for of action of antidepressants is that the alpha‐1‐adrenergic receptors, whereas the original biogenic amine theory of affective other autonomic responses are correlated with disorders is an over‐simplification. A critical their respective affinities for muscarinic cholin discrepancy in the view that mental depres ergic receptors. TCAs also exhibit cardiac sion is simply due to a deficiency in synaptic toxicities such as enhancing or slowing of levels of biogenic amines is that TCAs, cardiac conduction, and arrhythmias that are MAOIs, SSRIs, and NSRIs all act to increase potentially lethal on overdose or in vulnera the levels of biogenic amines in the synapse ble populations. within hours whereas the therapeutic response As depicted in Table 4.2, the SSRIs and does not manifest until two to three weeks of NSRI have much lower affinities for mus chronic drug administration. Newer theo carinic and alpha‐1‐adrenergic receptors and ries of the mechanism of therapeutic action are accordingly nonsedating and do not pro of antidepressant drugs have accordingly duce hypotension, dry mouth, constipation, focused on adaptive changes in receptor or other side effects typical of TCAs. MAOIs sensitivities with temporal patterns that share with TCAs the property that they can be agree with those of the clinical therapeutic lethal on overdose, and in addition have the response. Thus chronic, but not acute, added risk of potentially severe hypertensive administration of antidepressants produces crisis due to pressor effects of dietary tyramine changes in both noradrenergic and sero or the interaction with several over‐the‐counter tonergic receptor systems. These adaptive changes provoked by chronic antidepressant drug administration include the down‐regu Table 4.2 Antidepressant affinities for H1‐histamine, β muscarinic cholinergic, and alpha1 and alpha2 lation of ‐adrenergic, alpha‐1‐adrenergic, adrenergic receptors. alpha‐2‐adrenergic, 5‐HT2 serotonergic, and 5‐HT1A serotonergic receptors in various Receptor affinity (nM) brain regions (Brunello et al. 2002). These adaptive changes in receptor sensitivity Antidepressant H1 M Alpha1 Alpha2 typically require 14–21 days of chronic anti depressant drug treatment which mimics the Doxepin 0.17 23 23 1270 time course for the therapeutic response. Amitriptyline 0.95 9.6 24 690 Although the TCAs, MAOIs, SSRIs, and NSRIs do not appear to differ significantly Nortriptyline 6.3 37 55 2030 with respect to the temporal pattern for onset Desipramine 60 66 100 5500 of therapeutic response or for clinical efficacy, Fluoxetine 1000 1300 5900 >10 000 they do differ with respect to side effect pro Sertraline >10 000 500 300 5000 files. The adverse effects of TCAs are manifold Paroxetine 1000 89 >10 000 >10 000 and are a function of the affinities of these com Reboxetine 1400 3900 >10 000 >10 000 pounds for alpha‐1‐adrenergic, alpha‐2‐adren ergic, H1 histamine, and muscarinic‐cholinergic Source: Kent (2000); Brunello et al. (2002). Dopamin 37 and prescription drugs. The newer SSRI and important neurotransmitter in the brain NSRI antidepressants therefore have a much‐ that accounts for approximately 50% of the improved therapeutic index and tolerability as catecholaminergic neurons in the CNS. compared to TCAs and MAOIs. These dopaminergic neurons exist in discrete pathways that are distinct from the distribu tion of noradrenergic neurons. Dopamine Similar to synthesis of norepinephrine in the CNS, dopamine is formed from the Dopamine is a catecholamine neurotrans precursor tyrosine. Tyrosine is converted mitter originally believed to function only into l‐dopa by tyrosine hydroxylase and the as a precursor for norepinephrine and epi l‐dopa is metabolized to dopamine by the nephrine biosynthesis. It is, however, now enzyme l‐aromatic amino acid decarboxy established that dopamine functions as an lase (Figure 4.5). Dopaminergic neurons are,

Nerve impulse

Ca2+

Synthesis Release Tyrosine modulating modulating autoreceptor Ca2+ (–) autoreceptor DOPA DA

DA DA

DAT DA DA

DA DA DA

Postsynaptic dopamine receptor

Figure 4.5 Schematic representation of a dopaminergic synapse. As in NE neurons, tyrosine is converted to l‐dopa and then to dopamine (DA) in dopaminergic neurons. These neurons lack the enzyme dopamine‐β‐ hydroxylase and DA therefore functions as the neurotransmitter in these cells. The DA is stored in and released from vesicles, and synaptic DA activates both pre‐ and postsynaptic receptors. Synaptic DA action is terminated by the reuptake of the transmitter into the presynaptic terminal. This reuptake is mediated by the plasma membrane DA transporter (DAT). Cytoplasmic DA can be degraded by the mitochondrial enzyme monoamine oxidase (MAO). The presynaptic DA autoreceptors are primarily D2 dopamine receptors. 38 Biogenic Amine Transmitters

however, distinct from noradrenergic neurons Other dopaminergic projections in the in that they do not express dopamine β brain include those of the arcuate nucleus in hydroxylase, and hence do not convert dopa the hypothalamus with axons terminating in mine into norepinephrine. the intermediate lobe of the pituitary, where Two important nuclei containing dopamin dopamine acts as an inhibitory regulator of ergic cell bodies are located in the mesen prolactin release. Collectively these dopa cephalon. One of these nuclei is the substantia mine pathways therefore have many roles in nigra with long axon projections to the stria normal brain function (Figure 4.6). In the tum. This nigrostriatal dopamine pathway cerebral cortex, dopamine is important for contains the majority of total brain dopamine executive functions such as attention and and is the pathway that degenerates in working memory; in the basal ganglia, it is Parkinson’s disease. Parkinsonian patients necessary for motivational salience, reward, with only mild symptoms are thought to have and fluent motor function; and in the hypo as much as a 70–80% reduction in striatal thalamus it regulates prolactin release (Nutt dopamine content, whereas patients with et al. 2015). severe symptoms have more than 90% loss of Within dopaminergic presynaptic termi nigrostriatal dopaminergic neurons. The nals the mitochondrial enzyme MAO can other major mesencephalic nucleus contain degrade free dopamine. At these axon termi ing dopaminergic cell bodies is the ventral nals dopamine is released by action potential‐ tegmental area (VTA); this nucleus lies driven exocytosis from vesicles into the medial to the substantia nigra in the mesen synaptic cleft. The synaptic action of dopa cephalon. The VTA projects to limbic struc mine is terminated by the high‐affinity reup tures, such as the nucleus accumbens, and to take of dopamine mediated by the dopamine the cerebral cortex (prefrontal cortex). These transporter (DAT) expressed on the presyn dopaminergic pathways are therefore termed aptic terminal. The use of dopamine trans respectively the mesolimbic and mesocorti porter knockout mice has indicated that the cal dopamine systems. Due to the fundamen absence of this transporter produces a 300‐ tal involvement of the VTA dopaminergic fold increase in the amount of time required projection to the nucleus accumbens in to clear dopamine from the synapse the regulation of reward‐related behavior, (Gainetdinov et al. 2001). Inasmuch as the this system has been characterized as the dopamine transporter protein is the molecu neuroanatomical reward center in the lar target for psychostimulant drugs such as brain (Spanagel and Weiss 1999). Synaptic cocaine, methylphenidate, modafinil, and dopaminergic transmission in the nucleus amphetamine; the actions of these drugs are accumbens is increased in response to natu blunted in mice lacking the transporter. ral rewards such as food, water, and sex; and Dopamine in the synapse interacts with a also by drugs of abuse such as ampheta family of dopamine receptors (D1, D2, D3, D4, mine, cocaine, opioids, and nicotine. The and D5) that are localized to either presynap dopamine theory of reward and addiction tic or postsynaptic membranes. These five that began to emerge in the 1970s states that dopamine receptor subtypes are all G‐protein dopamine release mediates reward and thus coupled receptors whose cell‐signaling leads to addiction. More recent refinement of actions are mediated by stimulation or this theory suggests that dopamine clearly inhibition of adenylyl cyclase, activation of has a central role in addiction to stimulant phospholipase C or regulation of K+ channel drugs, which act directly on dopamine syn conductance. Dopamine D2 receptors are apses, but that it has a less important role, if expressed as both pre‐ or postsynaptic receptors. any, in mediating reward and addiction to As autoreceptors at the cell body, they decrease other drugs such as opiates, nicotine, and the firing rate of dopaminergic neurons, cannabis (Nutt et al. 2015). and as autoreceptors on axon terminals, Dopamin 39

Prefrontal cortex

Striatum

N. accumbens VTA Hypothalamus Substantia nigra Olfactory Amygdala tubercle Median eminence Pituitary

Figure 4.6 Schematic diagram of the dopaminergic pathways in animal brain. Dopaminergic cell bodies are localized to midbrain structures including the ventral tegmental area (VTA) and substantia nigra. Additional DA cell bodies are in the arcuate and periventricular nuclei projecting to the median eminence and intermediate lobe of the pituitary. The mesolimbic DA pathway from the VTA to the nucleus accumbens represents a component of the reward circuitry of the brain.

the D2 receptors regulate the release of dopa (Haldol®), as well as second‐generation drugs, mine (Schmitz et al. 2002). such as clozapine (Clozaril®) and risperidone The dopamine hypothesis of schizophrenia (Risperdol®). Therapeutic doses of most antip was originally formulated in the late 1960s sychotic drugs produce levels of D2 receptor by Van Rossum (1966). He suggested that occupancy in the striatum of 60–80%, while the pathophysiology of schizophrenia might atypical antipsychotics such as clozapine involve an over‐stimulation of dopamine produce lower levels of striatal D2 receptor receptors. Key elements of this hypothesis occupancy ranging from 10 to 66% (Lidow were that drugs used to treat schizophrenia et al. 1998; Seeman and Kapur 2000). Recent acted as dopamine receptor antagonists, and PET studies in human patients with schizo indirect acting dopaminergic agonists such phrenia have demonstrated an increased as amphetamine could produce features of occupancy of striatal D2 receptors by endog a psychosis in normal humans or exacerbate enous dopamine (Abi‐Dargham et al. 2000). certain symptoms in schizophrenics. The This observation supports the dopaminergic dopamine hypothesis of schizophrenia has hyperactivity hypothesis of schizophrenia. also derived support from the observation While much attention has been focused on that the clinical potency of antipsychotic striatal D2 dopamine receptors in schizo drugs is well correlated with their affinities phrenia, these receptors are unlikely to be for D2 dopamine receptors. These antipsy the primary target for the therapeutic action chotic drugs include first‐generation com of antipsychotic drugs to mitigate the thought pounds such as chlorpromazine (Thorazine®), disorder of schizophrenic patients. Striatal trifluoperazine (Stelazine®) and haloperidol D2 dopamine receptors certainly are the 40 Biogenic Amine Transmitters

target for the Parkinson‐like extrapyramidal cells these enzymes are responsible for the side effects of typical antipsychotic drugs. oxidative deamination of monoamines. Antipsychotic drugs such as fluphenazine In the late 1980s, deprenyl was shown to have been reported to cause extrapyramidal delay the onset of disability, and hence the symptoms in horses when this drug is used need for l‐dopa therapy, associated with to produce sedation (Kauffman et al. 1989; early, untreated cases of Parkinson’s disease Brewer et al. 1990). In horses, the extrapy (Parkinson Study Group 1989). This obser ramidal symptoms manifest as akathisia and vation suggested that deprenyl may exert a repetitive pawing. neuroprotective action to ameliorate an The D2 receptor representing the target underlying disease process in Parkinson’s for the therapeutic effects of antipsychotic disease. Neuroprotection in this context drugs are likely to be those expressed in the refers to an intervention that protects or cerebral cortex (Lidow et al. 1998). The cer rescues vulnerable neurons and slows the ebral cortex possesses higher densities of D1 progression of the neurodegenerative disease. than D2 dopamine receptors and these D1 MAO activity could contribute to neural receptors are downregulated after chronic degeneration by producing hydrogen perox antipsychotic drug treatment (Lidow et al. ide which, although normally detoxified by 1998). These D1 dopamine receptors may be glutathione, can react with ferrous iron to linked to some of the negative symptoms of generate the highly reactive and cytotoxic · schizophrenia such as chronic apathy and hydroxyl (OH ) radical. Thus, by inhibiting cognitive deficits such as memory impair MAO‐B, deprenyl may exert a neuroprotect ment. The activation of prefrontal cortical ant action through the reduction in the gen D1 receptors in a narrow occupancy range eration of free radicals. Environmental has been shown to enhance signaling in pre chemicals may also contribute to the devel frontal cortex neurons engaged in working opment of neurodegenerative disorders such memory in nonhuman primates (Lidow as Parkinson’s disease, and chemicals struc et al. 1998). This observation points to an turally related to the designer drug precursor essential role of the D1 dopamine receptor MPTP (1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahy function in the prefrontal cortex during dropyridine) may require metabolism by working memory. MAO to produce active neurotoxins. In this Germane to the function of dopaminergic case, MAO inhibitors such as deprenyl would pathways in the brain is the introduction of be neuroprotective due to the inhibition of l‐deprenyl (or selegiline) (Anipryl®) to con the formation of neurotoxic metabolites. trol canine cognitive dysfunction syndrome. Postmortem studies have consistently impli Deprenyl is a selective irreversible inhibitor cated oxidative damage in Parkinson’s dis of the enzyme MAO‐B. Monoamine oxidase ease and the source of reactive oxygen species exists in two forms termed MAO‐A and may also derive from the dysfunction of the MAO‐B. MAO is a mitochondrial enzyme mitochondria caused by either environmen that is widely expressed in tissues, including tal or genetic mechanisms (Greenamyre and the gastrointestinal tract, the liver, platelets, Hastings 2004). smooth muscle, and the brain. In the brain, the The ability of deprenyl to act as a neuro preferred substrates for MAO‐A are norepi protectant may therefore be involved in its nephrine and serotonin whereas the preferred therapeutic actions in canine cognitive dys substrate for MAO‐B is phenylethylamine. function. Chronic deprenyl treatment dra Dopamine and tyramine are metabolized at matically elevates brain levels of the trace equivalent rates by the two forms of MAO. amine β‐phenylethylamine and also produces MAO enzymes are localized to the outer modest increases in striatal dopamine con membranes of mitochondria in both neu tent (Youdim and Weinstock 2004). The ronal and non‐neuronal cells. In neuronal elevation of β‐phenylethylamine may also References 41 contribute to the pharmacological actions Chronic administration of deprenyl to elderly of deprenyl inasmuch as this compound pro dogs improves decrements in hearing, activity, motes the release of dopamine and inhibits attention, and ability to navigate stairs (Ruehl dopamine reuptake. The administration of et al. 1995). The combined neuroprotectant l‐deprenyl leads to the appearance of l‐meth and indirect actions to facilitate dopaminergic amphetamine as a major metabolite in animals neurotransmission may account for its effects and this compound may contribute to the clin on behavior and cognitive function in elderly ical benefits of this drug (Engberg et al. 1991). dogs (Milgram et al. 1993).

References

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Neuropeptides Opioids and Oxytocin Thomas F. Murray

Creighton University, Omaha, NE, USA

Introduction The existence of specific receptors for opiates in mammalian tissues had been sus- Endogenous neuropeptide signaling systems pected since the 1950s based on strict have been shown to have a role in a wide structure–activity requirements, including array of behavioral functions ranging from sterospecificity, for opiate drugs. In the early promoting social attachment behavior 1970s, methods developed for the direct between mating partners in certain species, biochemical detection of receptors were to regulation of vigilance and modulation of applied to the search for specific opiate pain perception, to name a few. Neuropeptides receptors in brain tissue. Using a radioligand have major roles in regulating the activity of binding method, Snyder and colleagues neuronal signaling between brain regions, identified an opiate receptor in brain and and expression of neuropeptides and their intestinal tissue in 1973 (Snyder 2004). The receptors has served as an important genetic identified receptor was pharmacologically substrate on which evolutionary forces have relevant in that an extensive series of opiate optimized behaviors (McGrath 2017). drugs bound with affinities closely matching their analgesic potencies. These opiate receptors were found to be enriched in areas Endogenous Opioid Peptides of animal brain known to be involved in the processing of sensory and pain signals such Opiates are drugs derived from opium and as the periaqueductal gray, medial thalamus include morphine, codeine (both alkaloids), and the substantia gelatinosa of the spinal and a variety of semisynthetic analogs derived cord and brainstem. A very high density of from them or from thebaine, which is another opiate receptors was also found in the locus component of opium (Pasternak and Pan coeruleus where opioids exert a regulatory 2013). Opium preparations extracted from influence on noradrenergic pathways (Snyder poppy seeds have been used for thousands of 2004). The discovery of these specific years to treat pain, cough, diarrhea, and to receptors for opiates immediately suggested produce euphoria. The term opioid is more the presence of endogenous opiate‐like general and is used to describe all drugs, irre- substances that normally target these spective of structure, with a morphine‐like receptors. The first description of such activity, including endogenous peptides. endogenous substances was in 1975 with the

characterization of substances from porcine opioid peptides and their respective precur- brain that had opiate agonist properties sors are listed in Table 5.1. (Hughes et al. 1975). These substances The Pro‐enkephalin precursor encodes for consisted of two enkephalin pentapeptides: multiple copies of [Met]enkephalin as well as [Met]enkephalin (Tyr‐Gly‐Gly‐Phe‐Met) one copy of [Leu]enkephalin. Similarly, Pro‐ and [Leu]enkephalin (Tyr‐Gly‐Gly‐Phe‐Leu). dynorphin encodes for three opioid peptides Subsequent to the identification of these of distinct lengths including dynorphin A, two enkephalin pentapeptides, other inves- dynorphin B, and the neoendorphins. tigators characterized several additional The POMC‐derived peptides have a endorphins (endogenous opioids) from por- limited distribution in the central nervous cine hypothalamus‐neurohypophysis. The system (CNS) with high levels found in the endorphins all contain the N‐terminal Tyr‐ arcuate nucleus and pituitary. The pro‐ Gly‐Gly‐Phe (Met or Leu) sequence followed dynorphin and pro‐enkephalin peptides have by varied C‐terminal extensions yielding a wider distribution in the CNS and are peptides from 5 to 31 amino acids in length frequently found in the same pathways. The (Akil et al. 1998). Two important members of pro‐enkephalin peptides are present in areas the endorphin family are β‐endorphin, an of the CNS that are involved with the extremely potent endogenous opioid and perception of pain such as laminae I and II of dynorphin A, a 17‐amino acid peptide with a the spinal cord, the spinal trigeminal nucleus, distinctive neuroanatomical distribution and and the periaqueductal gray. These peptides physiology. In mammals, the endogenous are also found in limbic structures regulating opioid peptides are derived from four affective behavior and reward, such as the precursors: pro‐opiomelanocortin (POMC), amygdala, the nucleus accumbens, the pro‐enkephalin, pro‐dynorphin, and pro‐ hippocampus, the locus ceruleus, and the nociceptin/orphanin FQ. The characteriza- cerebral cortex. Although there are a few tion of the POMC gene revealed that it codes long axon enkephalinergic tracts in the brain, for the stress hormone ACTH and the opioid these peptides are typically expressed in peptide β‐endorphin. The endogenous interneurons. One group of long axon

Table 5.1 Mammalian endogenous opioids.

Precursor Endogenous opioid Amino acid sequence

Pro‐opiomelanocortin β‐endorphin Tyr‐Gly‐Gly‐Phe‐Met‐Thr‐Ser‐Glu‐Lys‐Ser‐ Gln‐Thr‐Pro‐Leu‐Val‐Thr‐Leu‐Phe‐Lys‐Asn‐ Ala‐Ile‐Ile‐Lys‐Asn‐Ala‐Tyr‐Lys‐Lys‐Gly‐Glu Pro‐enkephalin [Met]enkephalin Tyr‐Gly‐Gly‐Phe‐Met [Leu]enkephalin Tyr‐Gly‐Gly‐Phe‐Leu Pro‐dynorphin Dynorphin A Tyr‐Gly‐Gly‐Phe‐Leu‐Arg‐Arg‐Ile‐Arg‐Pro‐ Lys‐Leu‐Lys‐Trp‐Asp‐Asn‐Gln

Dynorphin A (1–8) Tyr‐Gly‐Gly‐Phe‐Leu‐Arg‐Arg‐Ile Dynorphin B Tyn‐Gly‐Gly‐Phe‐Leu‐Arg‐Arg‐Gln‐Phe‐Lys‐ Val‐Val‐Thr α‐neoendorphin Tyr‐Gly‐Gly‐Phe‐Leu‐Arg‐Lys‐Pro‐Lys

β‐neoendorphin Tyr‐Gly‐Gly‐Phe‐Leu‐Arg‐Lys‐Pro Pro‐nociceptin/OFQ Nociceptin Phe‐Gly‐Gly‐Phe‐Thr‐Gly‐Ala‐Arg‐Lys‐Ser‐ Ala‐Arg‐Lys‐Leu‐Ala‐Asn‐Gln Edgnu Opioi Peptide 45 pro‐dynorphin and pro‐enkephalin gene by successful isolation of cDNA clones for the product‐containing pathways comprise part mu and kappa receptors. The cloning and of the output neurons of the striatum and sequencing of all three opioid receptors from accumbens (Akil et al. 1998). In the dorsal a variety of species verified that these recep- striatum, the striatonigial neurons contain tors belonged to the G‐protein coupled family pro‐dynorphin products, substance P and of receptors. GABA; whereas the striatopallidal neurons Opioids modulate neuronal activity and contain enkephalin and GABA. As a result of the three opioid receptor subtypes mediate the limited distribution of β‐endorphin in the this neuromodulation by activating multiple brain, the enkephalins and dynorphins are signaling pathways. Signaling through the considered to be the predominant central cognate mu opioid receptor and the Gi opioid peptide neurotransmitters. protein, for example, reduces neuronal It is now well established that these endog- excitability through physical interactions enous opioids interact with an opioid recep- with the potassium and calcium channels. tor family composed of three subtypes. Opioid‐induced decreases in Ca2+ influx into Pharmacological studies using opioid pep- presynaptic neurons inhibit neurotransmitter tides, alkaloids, and synthetic derivatives of release. Opioid receptors also activate or opiates indicated multiple subtypes of opioid reduce the activity of multiple kinases, receptors. This classification of multiple including those of the G‐protein receptor opioid receptors was originally based on the kinase family (GRK), the mitogen activated production of distinct syndromes in dogs by protein kinase family (MAPK), and the derivatives of morphine (Martin et al. 1976). protein kinases A and C (PKA and PKC). The three drugs used in these early studies These kinases not only play an important were morphine as the prototype for the mu role in turning off opioid receptor signaling (μ) opioid receptor, ketocyclazocine for the (desensitization), but also function to shape kappa (κ) opioid receptor and SKF‐10,047 (N‐ cellular function on short‐ and long‐term allylnormetazocine) for a sigma receptor. The timescales through protein phosphorylation morphine syndrome (mu μ) in the dog was and gene transcription. characterized by miosis, bradycardia, The affinity of endogenous opioid peptides hypothermia, a general depression of the for μ‐, δ‐ and κ‐receptors varies, but none of nociceptive responses, and indifference to the peptides bind exclusively to only one environmental stimuli. Ketocyclazocine receptor. β‐endorphin has similar affinities (kappa κ) constricted pupils, depressed the for μ‐ and δ‐opioid receptors but has very flexor reflex, and produced sedation but did low affinity for κ‐receptors. [Met] and [Leu] not markedly alter pulse rate or the skin enkephalins have high affinity for δ‐opioid twitch reflex. SKF‐10047 (sigma σ), in con- receptors and have approximately 10‐fold trast to morphine and ketocyclazocine, lower affinity for μ‐opioid receptors; these caused mydriasis, tachypnea, tachycardia, endogenous enkephalins possess negligible and mania (Martin et al. 1976). The sigma site affinity for κ‐receptors. Of the three subtypes was subsequently demonstrated not to repre- of opioid receptors, the subtype with the sent an opioid receptor inasmuch as the greatest selectivity for endogenous peptides actions of SKF‐10047 were not blocked by is unquestionably the κ‐opioid receptor. The prototypic opioid antagonists such as nalox- κ‐receptor displays sub‐nanomolar (nM) one and naltrexone. Investigations with both affinities for the dynorphins, while its affinity nonpeptide and peptide derivatives led to the for [Leu] enkephalin is 100 nM; a potency demonstration of the delta (δ) opioid receptor difference of 1000‐fold (Akil et al. 1998). The as the third subtype. In fact, the first opioid endogenous ligands for κ‐opioid receptors receptor to be cloned was the delta receptor are the dynorphins. With the exception of (Kieffer et al. 1992) and this was soon followed the dynorphins, most endogenous opioid 46 Neuropeptides

peptides have a higher affinity for δ‐ rather subtype while exerting an antagonist action than μ‐receptors. Notwithstanding this at a different opioid receptor subtype. pharmacological signature of endogenous As indicated in Table 5.2, compounds such opioids, the μ‐receptor clearly mediates the as morphine and etorphine exhibit a prefer- analgesic and euphorigenic actions of opioid ence for μ‐opioid receptors but also activate drugs. The δ‐opioid receptor is much less δ‐ and κ‐receptors with lower affinity. involved in the analgesic and rewarding Similarly, the opioid receptor antagonists, effects of opioid drugs, while κ‐opioid naloxone, naltrexone, and diprenorphine are receptors mediate spinal analgesia and promiscuous in the sense that they do not dysphoria. The use of transgenic mice that discriminate well between opioid receptor lack μ‐opioid receptors has revealed that subtypes. morphine‐induced analgesia, reward, Veterinary pharmacology of opioids is respiratory depression, and constipation are characterized, and complicated, by the dra- virtually absent in these mice (Keiffer 1999). matic species differences that exist with A summary of the receptor selectivities regard to drug‐induced responses. As with and efficacies of opioid drugs is given in humans, morphine activation of μ‐opioid Table 5.2. Similar to other drugs, these receptors produces CNS depression in the opioids exert either an agonist, partial‐ dog and monkey, whereas excitation is agonist, or antagonist action at a given observed in the cat, horse, goat, sheep, pig, receptor. The term mixed agonist/antagonist, mouse, and cow. The excitatory effects of although confusing, is sometimes used to opioids such as fentanyl have indeed been describe the pharmacology of specific used illegally in racehorses. The physiologi- opioids such as buprenorphine. This term cal basis for these species differences in implies that a given drug may exert agonist or response to opioids is poorly understood, but partial agonist activity at one opioid receptor is likely a function of the distinct distribution and/or density of opioid receptors in the neurocircuitry of the limbic system. The Table 5.2 Actions and selectivity of opioids at “morphine mania” that is characteristic in opioid receptor subtypes (μ, δ, and κ). cats is avoided by either repeated administration of small doses or concurrent administra- Receptor tion of an antipsychotic (neuroleptic) or sedative. In all species, however, morphine Drug μ δ κ and related opioids are capable of relieving intense pain associated with injury or Morphine +++ + + surgery. Methadone +++ + The chronic administration of opioids such Etorphine +++ +++ +++ as morphine to laboratory rodents produces a Fentanyl +++ + sensitization to the locomotor‐enhancing Sufentanil +++ + + effects of these drugs. This sensitization, or reverse tolerance, also develops to the oral Butorphanol p.a. ++ gnawing stereotypy observed in rats Buprenorphine p.a. ant. (Kornetsky 2004). This sensitization in Pentazocine p.a. ++ response to chronic exposure to an opioid Nalbuphine ant. + indicates that a long‐lasting change in opioid Diprenorphine ant. ant. ant. receptor signaling mechanisms develops that Naloxone ant. ant. ant. is distinct from those mechanisms subserving tolerance development to particular pharma- Naltrexone ant. ant. ant. cologic actions of opioids. A hyperactive Note: + = agonist; p.a. = partial agonist; ant. = antagonist. endogenous opioid neurotransmission caused Oxytoci 47 by opioid receptor sensitization may be drug. Dextromethorphan has been demon- involved in the expression of animal behavio- strated to reduce stereotypic cribbing in ral stereotypies. This may have relevance to horses and self‐directed mutilation stereotyp- the effectiveness of opioid antagonists in ste- ies in dogs (Dodman et al. 2004; Rendon et al. reotypic self‐licking and self‐mutilation 2000). This pharmacologic effect of dex- behavior in dogs and horses (Dodman et al. tromethorphan may be presumed to derive 1987, 1988). The effectiveness of opioid antag- from its ability to antagonize glutamate acti- onists such as naltrexone, naloxone, and vation of NMDA receptors in the CNS. diprenorphine may therefore be related to their ability to reverse or attenuate a sensitization that develops to endogenous opioid pep- Oxytocin tide activation of opioid receptors. Antagonists such as naltrexone, naloxone, and diprenor- The neurohypophyseal hormone oxytocin phine are nonselective and also interact with (OT) regulates biological functions in both kappa‐opioid receptors (KOR). KORs are peripheral tissues and the CNS. OT is a expressed in the brain, spinal cord, and critical mediator for two of the fundamental peripheral tissues in structures related to pain defining reproductive characteristics in circuits such as dorsal root ganglia (Hall et al. mammals, namely, placental birth and 2016). KOR agonists have antinociceptive lactation. OT has also been shown to be effects without the characteristic adverse critical in the formation and maintenance of effect profile associated with μ‐opioid recep- mother–infant bonds in mammals and in the tor activation (Hall et al. 2016). KOR agonists regulation of social behavior beyond the do, however, have the potential to induce maternal context, including social dysphoria in animals. attachments among adults, social cognition, In the context of the treatment of self‐ and aggression (French et al. 2016). OT mutilation stereotypies, one other aspect of signaling impacts forebrain structures that the pharmacology of compounds structurally are important in the regulation of attachment, related to opioids that deserves discussion is parental care, reward, emotional and social the effectiveness of dextromethorphan. memory. This compound is the stereoisomer of lev- In mammals, the nonapeptide OT structure omethorphan, a potent morphine‐like analge- is highly conserved with leucine in the 8th sic. As described earlier in this chapter, opioid position (Leu8‐OT). However, in marmosets drugs display pronounced stereospecificity (Callithrix), a nonsynonymous nucleotide with respect to their ability to bind to opioid substitution in the gene codes for proline receptors. Thus, the levorotatory isomer of in the 8th residue position (Pro8‐OT) morphine, l‐ or (−) morphine, is pharmaco- (French et al. 2016). OT binds to its cognate logically active while the dextrorotatory iso- G protein‐coupled receptor (OTR) and mer, d‐ or (+) morphine, is essentially inactive. exerts diverse effects, including stimulation Similarly, the levorotatory isomer levometho- of cAMP production (Gs), inhibition of ade- rphan substitutes for morphine whereas its nylyl cyclase (Gi/o), inhibition or stimulation dextrorotatory isomer dextromethorphan is of potassium channel currents (Gi), and acti- over 1000‐fold less active at opioid receptors. vation of phospholipase C (Gq) (Stoop 2012). The inactivity of dextromethorphan at opioid In the brain, OT neuron cell bodies are receptors does not, however, generalize to the located exclusively in the hypothalamus with NMDA subtype of glutamate receptor where projections to both cortical and subcortical this compound acts as a potent noncompeti- structures, including the limbic system tive antagonist (Franklin and Murray 1992). (Charlet and Grinevich 2017). In this regard, Dextromethorphan is widely used in human OT and dopamine neurons project to similar medicine as an over‐the‐counter antitussive forebrain regions including the prefrontal 48 Neuropeptides

cortex, the nucleus accumbens, and striatum, ing currents through a pertussis‐sensitive where they control social and affiliative Gi/o protein. In addition, OT can activate behaviors, such as sexual behavior and pair adenylate cyclase via coupling to Gs protein bonding (Charlet and Grinevich 2017). The and increase cAMP production, which distribution of OT and the closely related directly leads, without PKA activation, to a nonapeptide arginine vasopressin (AVP) sodium‐dependent TTX‐resistant sustained neurons and receptors (for OT, the OTR and, inward current (Stoop 2012). Considered for AVP, the V1aR, V1bR, and V2R) have together both OT and AVP can exert either been well characterized in rodents. OTRs in inhibitory or excitatory effects in the CNS the rodent brain have most prominently been depending on the brain region being studied. found in the accessory olfactory bulb, the These neuropeptides act as neuromodula- anterior olfactory nucleus islands of Calleja, tors, unlike conventional neurotransmitters, the central and extended amygdala, the CA1 in that they do not simply excite or inhibit an of hippocampus, the ventral medial hypo- electrically excitable cell, but rather alter the thalamus, the nucleus accumbens, the brain effects of other ongoing events occurring at stem, and the spinal cord (Stoop 2012). This the cell. distribution includes substantial overlap with In domesticated animals, such as the dog, the social behavior network. The social visual contact with humans has been found behavior network includes forebrain and to be sufficient to increase OT compared to midbrain nuclei and has extensive connectiv- isolation in dogs, suggesting that there is a ity with the mesolimbic reward system positive feedback loop between OT and gaz- (French et al. 2016). ing (i.e. visual contact) in dogs interacting The OTR can be linked to different G pro- with humans (Rault et al. 2017). Additional teins leading to different functional effects. physical contact increases OT for a longer OTR coupling to the pertussis‐insensitive duration, and more frequent interactions ini- heterotrimeric Gq/11 protein activates the tiated toward humans correlate with higher phospholipase Cβ pathway, which accumu- OT increase in CSF. Although the OT litera- lates phosphoinositide and mobilizes intra- ture is full of such positive responses, there is cellular Ca2+. This pathway underlies uterus contrasting evidence that negative situations smooth muscle cell contraction, and, in also mobilize OT. It has accordingly been neurons, can inhibit inward rectifying proposed that OT may be evolutionarily conductances (Stoop 2012). In neurons, linked to social coping strategies (Rault et al. however, OT can also activate inward rectify- 2017).

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and scratching behavior in dogs. Journal of and sensitization: implications for abuse. American Veterinary Medical Association Neuroscience and Biobehavioral Reviews 27: 193 (7): 815–819. 777–786. Franklin, P.H. and Murray, T.F. (1992). High Martin, W.R., Eades, C.G., Thompson, J.A. affinity [3H]dextrorphan binding in rat brain et al. (1976). The effects of morphine‐ and is localized to a noncompetitive antagonist nalorphine‐like drugs in the nondependent site of the activated N‐methyl‐D‐aspartate and morphine‐dependent chronic spinal receptor‐cation channel. Molecular dog. Journal of Pharmacology and Pharmacology 41 (1): 134–146. Experimental Therapeutics 197 (3): French, J.A., Taylor, J.H., Mustoe, A.C., and 517–532. Cavanaugh, J. (2016). Neuropeptide McGrath, P.T. (2017). A genetic cause of diversity and the regulation of social age‐related decline. Nature 551: 179–180. behavior in New World primates. Frontiers Pasternak, G.W. and Pan, Y.X. (2013). Mu in Neuroendocrinology 42: 18–39. opioids and their receptors: evolution of a Hall, S.M., Lee, Y.S., and Hruby, V.J. (2016). concept. Pharmacology Reviews 65: Dynorphin A analogs for the treatment of 1257–1317. chronic neuropathic pain. Future Medicinal Rault, J.L., van den Munkhof, M., and Chemistry 8 (2): 165–167. Buisman‐Pijlman, F.T.A. (2017). Oxytocin as Hughes, J., Smith, T.W., Kosterlitz, H.W. et al. an indicator of psychological and social (1975). Identification of two related well‐being in domesticated animals: a pentapeptides from the brain with potent critical review. Frontiers in Psychology 8 opiate agonist activity. Nature 258: 577–580. (1521): 1–10. Kieffer, B.L. (1999). Opioids: first lessons from Rendon, R.A., Shuster, L., and Dodman, N.H. knockout mice. Trends in Pharmacological (2000). The effect of NMDA receptor Science 20: 19–26. blocker, dextromethorphan, on cribbing in Kieffer, B.L., Befort, K., Gaveriaux‐Ruff, C., horses. Pharmacology Biochemistry and and Hirth, C.G. (1992). The δ‐opioid Behavior 68: 49–51. receptor: isolation of a cDNA by expression Snyder, S.H. (2004). Opiate receptors and cloning and pharmacological beyond: 30 years of neural signaling characterization. Proceedings of the National research. Neuropharmacology 47: 274–285. Academy of Science 89: 12048–12052. Stoop, R. (2012). Neuromodulation by Kornetsky, C. (2004). Brain‐stimulation oxytocin and vasopressin. Neuron 76: reward, morphine‐induced oral stereotypy, 142–159. 51

Part II

Practice of Veterinary Psychopharmacology 53

Introduction to Clinical Psychopharmacology for Veterinary Medicine Sharon L. Crowell‐Davis and Leticia Mattos de Souza Dantas

University of Georgia, Athens, GA, USA

Introduction being made via in vitro growth of neurons derived from psychiatric patients with spe- The term psychopharmacology derives from cific diagnoses (Burke 2004; Vadodaria et al. three Greek words. Psyche means soul or 2018). The serotonin production, serotoner- mind; pharmacon means drug. Finally, the gic receptor activity, serotonin transporter term logos means to study. Thus, activity, and other specific chemical activity psychopharmacology, in a basic sense, is the can then be studied from these in vitro cells study of drugs that affect the soul or mind. derived from known phenotypes (Vadodaria We are interested in such drugs because et al. 2018). psychoactive medications affect the brain’s While we can never truly understand the physiology and endocrinology, consequently animal mind, we can measure changes in causing changes in behavior and motivation. animal behavior that occur as a consequence Therefore, these drugs can be beneficial for of the administration of various drugs that animals with mental health and behavior enter the brain. We can also place those problems. They have been used with varying changes within the context of species‐typical results in human psychiatry for several dec- social organization and communication to ades, and their efficacy has improved over interpret what is likely happening in terms of time as we have come to better understand changes in the emotional and motivational the complex interrelationships between brain state of the animal. The use of psychoactive chemistry, emotional states, and overt behav- medications has rapidly been integrated into ior. We are also developing an improved the practice of veterinary clinical behavioral understanding of the genetics and neuroanat- medicine because they can often be of omy of various major behavior problems such tremendous assistance in the treatment of as aggression, major depressive disorder, the serious behavioral and mental health and bipolar disorder (e.g. Krishnan 1999; problems that are routinely encountered in Vadodaria et al. 2018). Nevertheless, much this field. remains to be discovered. Psychoactive medications can be extremely While a great deal is understood about what useful in the treatment of mental health happens on cell surfaces, the exact mecha- conditions and behavior problems in animals, nism by which receptors and the molecules but it is rare for medication alone to provide that interact with them affect mood and a cure. In most cases, treatment is most effec- behavior is poorly understood. Progress is tive if medication is used in combination with

environmental management and behavior psychoactive medication for the treatment therapy, such as desensitization and counter- of behavior problems in animals are conditioning interventions. The most com- Clomicalm (clomipramine) for separation mon protocols for behavior therapy are anxiety disorder in dogs, Anipryl (L‐depre- defined and discussed briefly in this chapter nyl) for cognitive dysfunction in elderly but are not the focus of this book. dogs, Sileo (dexmedetomidine) for noise While data on the effect of psychoactive aversions in dogs and Reconcile (fluoxe- medications on brain pathologies observed in tine) for dogs with separation anxiety dis- the pet population are increasing yearly, order. Extra‐label use means that the much of the available data on actual efficacy medication has not been approved by the for specific problems is derived from human Food and Drug Administration (FDA) for psychiatric use and extrapolated to use in vet- the specific problem and the specific spe- erinary clinical behavioral medicine. When cies for which it is being prescribed. Thus, using a medication with little historical use in use of Clomicalm for separation anxiety pets, it must be remembered that sometimes disorder in cats or storm phobia in dogs medications have different efficacy and dif- would be extra‐label use. Use of all other ferent side effect profiles in different species. psychoactive medications for any behavior A medication that works well in humans may problem on any species constitutes extra‐ work better or worse in a cat or dog, and label use. those species may exhibit side effects never This does not mean that use of medica- observed in humans. Some drugs, such as tri- tions other than clomipramine, L‐deprenyl, cyclic antidepressants, are safer in cats and fluoxetine or dexmeditomidine is con- dogs than in humans. Wherever possible, traindicated for behavioral problems in data from studies on the use of a given medi- animals or that the extra‐label use of clomi- cation in domestic species are provided. pramine, L‐deprenyl, fluoxetine or dexmedi- Beyond this, drugs that are commonly used tomidine is contraindicated. In veterinary by specialists in veterinary clinical behavioral clinical behavioral medicine, the off‐label medicine, but about which there is little pub- status of most drugs means that the substan- lished data, are discussed with reference to tial safety and efficacy trials required by the use in humans. Some medications have been FDA for on‐label use have not been con- used little or not at all in the pet population, ducted. In many cases, for economic rea- but based on their use in humans, might reasons, such trials will never be conducted, sonably be tried in pets that have been refrac- despite substantial scientific evidence that a tory to better‐tested treatments when the given drug has a real usefulness, with mini- owner is willing to take the chance that their mal side effects, for a particular problem in a species of pet will have a side effect that has particular species. not been observed in humans. In all cases, the There are specific requirements for extra‐ species from which particular information on label use of any medication, psychoactive, or clinical use of a medication has been derived otherwise. First and foremost, there must be a will be identified. valid veterinarian‐client‐patient relationship. The veterinarian must have personally exam- Prescribing in the United States: ined the patient and, based on their own knowledge of the patient’s physical and The Animal Medicinal Drug Use behavioral status, determined that extra‐label Clarification Act (AMDUCA 1994) use of medication is appropriate and may be beneficial. To come to this determination, the As this book goes to press, the use of most veterinarian must conduct a physical exam psychoactive medications in veterinary med- and take both a medical and behavioral icine is extra‐label. The only label uses of history. While some behaviors cannot be Cos 55 observed in the examination room, objective When prescribing psychoactive medica- information about the patient’s behavioral tions, one should keep in mind that some history can be gathered by interviewing the have the potential for human abuse. For owner and other persons who have personally example, diazepam, which can be very helpful witnessed the problem. for a variety of phobias, is a Schedule IV drug Because of widespread use and some degree that has a rapid onset of effect and is addic- of knowledge of psychoactive medications in tive. Methylphenidate, used in dogs with true society at large, it is not uncommon for per- hyperkinesis, is a Schedule II drug that is sold sons who are not qualified or licensed to make illegally. It is essential that detailed records be decisions regarding medications to attempt to kept of the exact prescription and that the do so. Dog trainers, behaviorists who are not patient be monitored closely for response. veterinarians, and others, may attempt to con- Also, the practitioner must follow specific vince a pet’s owner and/or the pet’s veterinar- state laws regarding prescribing such medica- ian to use a particular drug that the veterinarian tions. For example, in Georgia, as of 2003, does not feel is appropriate. Likewise, news U.S. Drug Enforcement Administration shows that mention use of a particular drug in (DEA) Class II medications must be pre- a pet may result in many calls to veterinarians scribed in writing only. Telephone prescrip- in the area requesting that the drug be pre- tions can be done on an emergency basis, but scribed. In all cases, it must be remembered there must be a written follow‐up within one that the decision regarding which drug to use week. DEA Class III–IV drugs can have five for a given problem in a given pet is the veteri- refills or up to six months’ prescription writ- narian’s responsibility and therefore the vet- ten. Laws covering these details will vary erinarian’s decision. It is likewise the from state to state and country to country. veterinarian’s responsibility to remain current Some of the drugs discussed in this book can- in her or his understanding of the use of psy- not be used legally in certain countries. In all choactive drugs. When a prescription is writ- cases, it is the veterinarian’s responsibility to ten for a given medication, the veterinarian be aware of both national and local laws that must have a specific rationale for the use of apply to the individual’s practice. that medication in that patient, and its use Because of the nature of behavioral and must be accepted under current standards of mental health problems in pets, it is often not evidence‐based clinical behavioral medicine. advisable to provide prescriptions for long Because some psychoactive medications are periods without rechecking the patient in used very commonly and to good effect for person. Since progress, behavior therapy behavior problems, it can be easy to slip into techniques, environmental management, habits of treating such medications as if their and physical health must be monitored, all use was on‐label. In all cases of extra‐label use patients on psychoactive medication should of medication, however, clients should be come in for outpatient rechecks regularly for informed of the extra‐label status of the drug a prescription to be continued. At this time, and of what the term extra‐label means. progress and prognosis are assessed and the Clients should be informed of known side medication may be changed, the dose effects and the risk of novel side effects occur- increased or decreased, or the medication be ring in their pet. An informed consent state- continued as during the previous months. ment that describes the extra‐label status of the drug, explains why the medication is being prescribed, lists known side effects, and states Cost the risk of novel side effects can be provided to the client. One copy can be provided to the Unlike human medicine, where cost issues client to take home for reference and a signed are often of low priority when making a copy kept in the patient’s medical records. decision as to which medication to use, cost 56 Introduction to Clinical Psychopharmacology for Veterinary Medicine

is often a significant issue in all areas of new clinical trials are completed and studies veterinary medicine, including clinical are published. Thus, some statements made behavioral medicine. Large chain pharmacies in this book will become outdated as a result can often offer significantly lower prices than of new research findings. It is important for small, individually operated and owned the practitioner to keep up to date with pharmacies. However, the latter are research publications. sometimes the only viable source of special Each patient is a unique individual. At this compounding that may be needed for time, we can only choose what to use based particular patients. The cost of a daily dose first on the species, the diagnosis, and the can also vary with how much medication is health status of the individual patient in a purchased at one time, especially if combination of evidence regarding the compounding is required. Often, medication efficacy of various medications for the is less expensive if bought in bulk, for example particular problem being treated. However, if a 90‐day supply as opposed to a 30‐day the first medication used is not effective or supply. For cats and parrots, many generates unacceptable side effects, it is not medications must routinely be compounded. necessarily the case that no medication will For cats and small dogs, if tablets are work. Sometimes a different medication in available, they can be reasonably split into the same class of drugs will work well, even if smaller doses than allowed by the scoring the first medication was ineffective. with the use of a pill cutter. Sometimes a medication from a totally For some patients that can be pilled but different class is required. Sometimes that refuse to consume flavored liquids, and combinations or augmentation are required. will even spit them out, compounding into Using combinations in particular requires small capsules will be necessary. While initial that the clinician understand exactly how purchases should be small in order to allow each medication works in the brain so that time to determine if the pet does not exhibit overdosing and adverse drug interactions do serious side effects and does respond not occur. Details of using combinations of positively to the medication, clients may drugs are discussed in Chapter 19, as well as obtain considerable savings over the long throughout the discussion of specific term if a bulk purchase is made once long‐ medications. term use is expected. Because some When choosing a drug, selectivity of mech- psychoactive medications can be expensive, anism is an issue that has at times been con- it is recommended that the practitioner is sidered advantageous in human psychiatry. aware of the relative costliness of these However, the topic is controversial and will medications at pharmacies in their area and not be discussed in depth in this book. In gen- via legitimate mail order pharmacies and that eral, a potential advantage to multiple mecha- clients contact multiple pharmacies to get nisms of action in a single drug, for example, price quotes for their specific prescription. norepinephrine reuptake inhibition and serotonin reuptake inhibition, is possible increased robustness of efficacy. This presup- Drug Selection poses that both or all of the multiple mechanisms of action in some way benefit the Specific information on drug selection will particular patient’s problem. A potential be given in the chapters on various classes of problem is a greater possibility of multiple drugs; however, there are certain general side effects. Better decision‐making protocols considerations that will be discussed here. on this issue will be more feasible when very First, it is important to remember that our exact relationships are discovered between understanding of drug selection for specific specific behaviors or behavior problems in a behavior problems is changing rapidly as given species and a particular molecular Mdctn the Patien 57 action in the brain. The following should with a highly palatable food. If the owner and always be considered when choosing a dog do not already have such a routine, it can medication: be initiated by first offering a highly palatable, small, semifirm amount of food. This can be What are the species and signalment? a piece of hot dog, cheese, canned dog food What is the diagnosis? that is not too moist or one of the various pill Is the drug being considered indicated for pockets that are on the market. It should be that species, signalment, and diagnosis? offered in whatever fashion works best for How experienced is the veterinarian with the the patient. Tossing works well for some drug or drug combination? dogs, who will catch the treat and gulp it. Are there any studies published on the actual Other dogs will respond best if they are efficacy for this diagnosis? If so, what is the hand‐fed or if the treat is offered on a small actual efficacy? plate. Once the dog consumes the treat What is the side effect profile? rapidly and without pausing to chew, a pill or What is the health status of the patient? Does capsule can be hidden in it. Pilling should the patient have any conditions that are always be followed by the reward of a highly contraindicated with this drug? palatable treat. How much is cost an issue of concern for the For the cat that cannot be pilled at all, it client? How expensive is the drug? may be necessary to hide the medication in What other drugs have been tried, and how palatable food. First, identify a food that the did the patient respond? cat finds very desirable, such as tuna fish, a How can the patient be medicated? If special particular brand of canned food, or shredded forms of dosing are required, can the drug chicken. Begin offering the cat a small be provided in those forms, for example, a amount of the food on a regular routine. palatable liquid to be hidden in food? Have the medication compounded as a liquid that is compatible in flavor with the treat, for example, tuna juice. Then begin mixing the Medicating the Patient medication in with the treat. If the cat rejects a full dose, it may be necessary to initially Often there are issues of the patient being mix in a partial dose. The dose can then be resistant to taking medication. This is gradually increased over several days until particularly problematic if the medication the cat is eating the complete dose. has an unpleasant taste, which is the case Transdermal medication of cats that are with undisguised tricyclic antidepressants. difficult to medicate would be desirable if it Also, many medications must be given daily was effective. However, research to date on for a long period of time. For the patient that azapirones, selective serotonin reuptake is fearful and/or aggressive, which are inhibitors (SSRIs), and tricyclic antidepres- common problems, the difficulties are sants has invariably identified this method of compounded. Owners may not be able to medication to be ineffective. Blood levels of handle the pet without frightening it, and drugs administered transdermally are sub- they may also run the risk of being bitten if stantially lower than blood levels of drugs they attempt to force‐pill the patient. administered orally (Ciribassi et al. 2003; Different approaches are helpful for dogs and Mealey et al. 2004). Raising the level of drug cats, but in general developing some routine in the transdermal medication to levels that of food intake prior to beginning medication produce comparable blood levels might result can be useful. in dermatitis. Many dogs gulp highly palatable foods Because of the difficulty in medicating without pausing to taste. This is especially veterinary patients, slow‐release forms of the case if a routine has been established various medications are desirable so that a 58 Introduction to Clinical Psychopharmacology for Veterinary Medicine

single action of medicating the patient can after which it might be legally returned to result in the long action of the drug. Slow‐ competition once all traces of medication release forms of several medications have have been metabolized and cleared from its been developed for humans. However, in all system. cases remember that the medications have The existence of serious behavioral been designed for the human digestive tract, problems in animals owned for competition which is substantially different physiologi- of any sort also begs the question of breeding cally from that of the carnivorous cat and dog that animal. Animals with significant and the herbivorous rabbit and horse. Thus, behavioral problems should probably not be rates of absorption are likely to vary substan- bred. This issue should be discussed with the tially in these species from the rates that owner if they are likely to breed an animal occur in humans. with a behavior problem.

Competition Animals Taking the Behavioral History Treating nonhuman animals that are shown in conformation or performance classes or As discussed above, a diagnosis must be arrived that are raced presents special ethical and at before a decision is made on which drug or legal issues. Many organizations that oversee drugs to use. Coming to a diagnosis requires the racing, conformation competition, and that a detailed behavioral history be taken. This performance competition of purebred applies to cases that are entirely behavioral or animals specifically prohibit the use of psychological in nature as well as cases that psychoactive medications, at least during involve an interaction between behavior competition. It is because of the problem of problems and medical problems or behavior illegally doping racehorses with psychoactive problems and physical injury. An example of medications during racing that we have data the latter might be a traumatic injury that the on the pharmacokinetics of several drugs in patient licks at and mutilates even when the the horse. Other organizations, especially original injury has healed entirely. small, breed‐specific organizations that Behavioral histories can be collected in two foster interest in a breed or activity in which main ways. First, a standardized form can be there are not large amounts of money at provided for the client to fill out. This tech- stake, allow medication, at least under certain nique can be particularly useful in the case of situations. Such situations might include the a client who brings up a behavior problem treatment of a behavior problem diagnosed during a routine exam for which 10 or 15 min- by a veterinarian and with notification of the utes of the veterinarian’s time have been judge that the animal is on medication for the scheduled. This will not be adequate time to diagnosed problem. When treating purebred address a serious problem. However, the animals that are placed in any form of moment can be used to verify that the client’s competition, it is important to communicate pet has a problem that requires a longer openly with the owner and, as appropriate, appointment with the veterinarian in order to the organization sponsoring the competition, address. The client can be given the history as to whether or not certain medications are form and instructed to make an appointment allowed. The owner may have to make a to return for a behavioral evaluation or a choice between continuing to enter their referral to a specialist can be discussed. animal in competitions or using medication. Ideally, the client should mail the form back Sometimes it is legal and desirable to remove in advance so that the veterinarian has the the patient from competition for a period of time to review it before the client and patient a few months while the problem is treated, return. The other way that information can Takn the Behaviora Histor 59 be collected is by a direct interview. The 1) My dog lowers his head and tucks his tail direct interview has the disadvantage that between his legs whenever I get near some clients will digress at length, requiring while he’s eating. Then he’ll just cringe skillful interviewing techniques to tactfully and stare at the floor so long as I’m near. If bring them back to the problem at hand. The I stay for long, he may start growling. advantage is that information can often be 2) My dog stops eating whenever anyone obtained that is not likely to come out on the gets near him. If I stand by his food bowl, written form. he’ll walk away. A blended technique involves using both 3) Once I put the food bowl down, I leave means of collecting history. Have the client fill the kitchen. If I don’t leave fast enough, out the written form in advance and either my dog will chase after me, barking, and mail it to you or turn it in upon arrival for the growling. I’ve been bitten twice when I appointment. Read the written answers before didn’t leave fast enough. Everyone knows entering the room with the client. From those to stay out of the kitchen while he’s responses, develop a list of questions that eating. build on the information you have obtained from the initial document. The history needs These three dogs clearly have three very dif- to include the following seven areas: signal- ferent problems. However, owners may use ment, problem behaviors, current environ- the same subjective language in interpreting ment, early history, any types of interventions those problems. Since the veterinarian needs or training methods attempted, miscellaneous to make a diagnosis based on facts and clini- behaviors, and medical history. cal indicators, not opinions and interpreta- The signalment gives information about tions, it is essential to get descriptions of probabilities of certain diagnoses with given what the patient is doing that is a problem. A chief complaints. If the complaint is phrase that can be helpful in leading the cli- elimination of urine in the house, cognitive ent into this is: “Can you describe what (your dysfunction is more likely in a 12‐year‐old pet) does that makes you say he/she is angry than in a 7‐year‐old dog, while it does not (or sad, jealous, spiteful, depressed, etc.)? occur in a 2‐year‐old. If the complaint is What is his/her body language like?” Most owner‐directed aggression in a cat, play people will understand what is needed once aggression is more likely in a 2‐year‐old than this question has been posed two or three in a 12‐year‐old. times and will begin giving objective descrip- A great deal needs to be learned about the tions. A few will say things like “Oh, you main problem behavior or chief complaint. know. He just acts jealous.” At this point, it First, it is necessary to get a good description may be helpful to ask the client to pretend of what behavior it is that the owner perceives that they were a neutral observer, totally as a problem. Owners often initially give uninvolved in the situation, or to pretend their subjective interpretation of the that they witnessed the pet’s behavior on TV. behavior, rather than describing what the pet Again, from this point of view, ask them to is actually doing and what its body language describe what the problem pet and other looks like. It is necessary to get a specific involved people and animals actually did. It description of exactly what is happening, may require the description of multiple spe- with objective indicators of intensity, cific incidents for any underlying patterns to frequency, duration, and recovery time. For become clear. In the case of aggression, get example, the owner may say that their dog complete, detailed descriptions of every inci- “gets angry” whenever they go near the food dent of aggression that the client can recall. It bowl while it is eating. In the author’s may be necessary to get information from experience, the following diversity of scenar- multiple people, because the client may not ios may lead to the use of this phrase. have personally witnessed some of the 60 Introduction to Clinical Psychopharmacology for Veterinary Medicine

important incidents. For this reason, it is Changes in the frequency or form of the often desirable to have the entire family, or at problem that have happened over time also least multiple family members, present for need to be identified. Changes generally the interview. happen for a reason; understanding why the Beyond a good description of what is actu- change has occurred will lead to a better ally occurring, several specific pieces of understanding of the problem and, hence, information are needed. When did the identification of a specific treatment. problem begin? As a general rule, problems It is important to know what has been done of long duration are more difficult to resolve so far to attempt to correct the problem. than problems of recent onset but that Clients may have read books, found informa- depends on the etiology or neurophysiology tion on the Internet or taken advice from that is behind the behavior. However, unqualified professionals. Again, find out duration of the problem can affect the exactly what they actually did, and do not rely prognosis. Problems of long duration are on client familiarity with behavioral jargon. likely to have undergone progressive changes The author has frequently had clients tell her in behavior and brain remodeling. For that they had already tried “desensitization,” example, a feline elimination behavior only to learn that, in fact, they had not done problem that began as avoidance of the dirty so. Either the technique had been incorrectly litter and/or separation anxiety disorder described to them, or they had not under- when the owners were absent on vacation stood the technique, or they had not adapted may have evolved into a location preference the technique to their pet’s specific needs. In for the carpet under the dining room table contrast, if they have been trying something and, most recently, into a generalized carpet that seems to be working and that is appro- preference. Changes over time in priate, instruct them to continue. Sometimes manifestation of the problem and in probable a technique has been working, but has causes of the problem need to be examined stopped working because the pet has reached carefully throughout the history‐taking a stage at which it needs a modification of the procedure. technique in order for progress to resume. The examining veterinarian also needs to Find out the specific dosages and dosing know the frequency of the problem behavior schedules that have been prescribed by other and the circumstances in which the problem veterinarians. Find out exactly what the client occurs. The frequency is needed in order to did, as well, because they may have modified have baseline information from which to the original instructions for various reasons. evaluate response to treatment. Spraying It is not uncommon to find that a suitable three times a week can be good or bad, medication has been previously prescribed, depending on whether the patient was spray- but at only the lowest dose, and the client dis- ing two times a month or 10 times a week at continued the medication when it didn’t work the beginning of treatment. Information at that dose. Alternatively, the client may have about the circumstances in which the prob- given the medication more or less frequently lem behavior occurs can lead to improved or at a lower or higher dose than prescribed understanding of the motivation for the without telling the veterinarian who origi- behavior and, possibly, to identification of cir- nally prescribed the drug. The author has cumstances that the owner needs to avoid found it to be important, as a matter of rou- with environmental management. For exam- tine, to ask referring veterinarians exactly ple, if an aggressive cat is particularly prone to what dosage schedule they prescribed and to attacking a woman when she is wearing a also ask the client the exact schedule by which broomstick skirt, it may be necessary for her they medicated their pet. to discontinue wearing broomstick skirts Client education about what to expect from when at home, at least temporarily. psychoactive medications and how to dose is Takn the Behaviora Histor 61 critical. For example, SSRIs may not take addressed at once simply because even the effect for four to six weeks with daily dosing. most dedicated client has a finite amount of However, many of my clients have been giv- time they can spend helping their pet. On the ing them only on an as‐needed basis and other hand, in some cases, different prob- decided from that schedule that the medicine lems can be caused by the same etiology or doesn’t work. Also verify exactly what side brain pathology. This is commonly the case effects the patient has experienced with a par- with generalized anxiety disorder, which can ticular medication. This information may tell cause several secondary phobias. Often, the you that the medication is contraindicated frequency, duration, and severity of the epi- with this particular patient or that the client sodes will decrease once the patient is treated needs further education about the medica- for the main condition. tion. For example, some pets experience The patient’s current environment has transient, mild sedation of a few days’ dura- many facets, any, or all, of which can affect tion when first put on a SSRI. Usually, they behavior. Main categories are: (i) the humans recover from this in one to two weeks and in the environment; (ii) other animals in the return to normal levels of activity. Clients environment; and (iii) the physical who have not been warned of this potential environment, which includes all aspects of side effect may have taken their pet off medi- housing and management. cation or decreased the dose too early in the Regarding the human environment, it is treatment and done so without telling their important to know who lives with the pet or veterinarian. is a frequent visitor. This will include all A different area for discussion is the ques- family members who live in the home, but tion of whether there are other behavior may also include housekeepers, babysitters, problems besides the chief complaint that gardeners, and other domestic personnel. caused them to bring their pet to you in the Identify when individuals are typically at the first place. While some clients will state that house and how they interact with the patient the pet is “perfect” except for that one or are involved with the patient’s care. Also problem, others will have a short or long list ask if there have been any significant of other dysfunctional behaviors they do not departures, especially around the time the like or perceive as a problem. In some cases, problem began. Examples would include the other problems will be even more serious older children leaving for college and spouses than the presenting complaint. The client who have departed due to separation or may have brought the pet in for the original divorce. complaint because they heard through some Also find out what other animals, typically means that this problem was treatable. The but not necessarily household pets, interact client may have assumed that the other prob- with the pet. The species, gender, age, and lems were untreatable and would not have behavioral relationship with the patient brought them up except for your specifically should be identified for all household pets. asking. Sometimes the client will not have An example of non‐pet animals that may be mentioned other problems because he or she of importance would include neighborhood considers them minor. If it turns out that the cats or dogs that frequently visit the yard or pet has multiple problems, it is good to make even house. This is of potential significance a problem list and have the client prioritize with urine marking and any stress‐induced them as to which he or she most wants to behavior problem. A different example would have treated first. Sometimes it is not possi- be a large number of squirrels living outside ble to treat two particular problems at once that cause frequent arousal in a patient that because there is some degree of conflict in has arousal‐induced aggression. the treatment techniques for the two prob- The degree and type of detailed information lems. More often, the problems cannot all be about the environment that will be needed 62 Introduction to Clinical Psychopharmacology for Veterinary Medicine

will necessarily vary somewhat with species techniques. Impressed by advertising and the and chief complaint. The following basic charisma of the trainer or simply due to information should always be obtained: (i) a ignorance or despair to resolve their pet’s description of the housing the patient lives problem, they may leave the pet with the in, for example, the size of the house and trainer or do things to the pet under the what areas of the house the patient has access trainer’s directions that make them to and, in the case of dogs, whether or not the uncomfortable, make their pet afraid or even backyard is fenced; (ii) information about hurt them. In taking the history, first get a diet and feeding schedules; and (iii) the entire good description of exactly what has been daily routine for handling and caring for the done to the patient. If there are problems, patient. In the case of cats, identify how explain objectively why they are problems. In many litter boxes there are in the house, cases of clear abuse, the trainer should be whether or not they are hooded, what type of reported to the state veterinarian’s office. litter is in them, where they are located in the Often, owners feel guilty about what has house, and how often they are cleaned. Much happened to the pet. This is especially likely of this will be important background to be the case if they stood by while the pet information that you will need in designing was mistreated and the mistreatment has your total treatment program. now resulted in a major behavior problem, Learning the early history is not always typically fear of people or fear‐induced useful in coming to a diagnosis or designing a aggression. Some owners will become treatment program (although it is important defensive, both of their own actions and of for prognosis evaluation). However, their trainer. In this case, calmly conducted sometimes quality information is identified client education about appropriate animal that may help the owners better understand training techniques is essential. their pet. If there is a background of Often, operant conditioning‐based abandonment, owners are likely to be more techniques are involved in a treatment sympathetic to their pet’s current difficulty program’s behavior therapy interventions. with being left alone. Information to obtain Understanding a pet’s response to various includes the source of the pet, the age when learning situations will be important. For obtained, and any information that is example, the author once worked with an available about previous owners, including aggressive dog that was often tense during the pet’s possible experiences with them, interactions with the family. However, the such as abuse, and their reports about the command “Gimme five,” which meant to pet’s early behavior. raise the paw to be touched by the palm of a Learning about training and other struc- human family member, consistently resulted tured learning experiences the patient has in relaxation and an amicable interaction. had is important with all species, but espe- The command “Gimme five,” accompanied cially with species that typically undergo by a treat, was an important part of the initial extensive formal training, such as the dog phase of treatment. and the horse. The veterinarian needs to be Miscellaneous other behaviors that need to familiar not only with ethical and appropriate be touched on briefly or in depth, depending training techniques, but also with commonly on the chief complaint, include sexual used abusive training techniques and devices. behaviors, maternal behaviors, and While there are many ethical and competent grooming. In particular, grooming, in all of animal trainers, there are also, unfortunately, its aspects of bathing, brushing the coat and plenty of unethical and abusive animal teeth, clipping the nails, and cleaning the trainers. Owners sometimes take their pet, in ears can be a source of historical problems good faith, to a trainer whom they do not that the family has simply accepted. However, realize is using abusive and inappropriate identifying what parts of grooming result in Takn the Behaviora Histor 63 behaviors of escape, fear, or aggression can its general demeanor, for example, hiding be essential to understanding the patient. It is under a chair, curiously investigating the important to ask about the patient’s behaviors exam room and visiting people, or climbing of self‐grooming, as well. Early cases of into the owner’s lap and soliciting attention. obsessive‐compulsive disorders, discussed If there are serious concerns about possible below, may manifest as simple increased biting incidents, the patient should be amounts of grooming with lesions just wearing an appropriately fitted basket beginning to develop, which the clients will muzzle. It is essential that a basket muzzle be not have thought to mention. used so that the patient can pant and drink If you have been the patient’s veterinarian water. Most patients can be taught to calmly its entire life, you will know its medical accept the basket muzzle, or even voluntarily history. Often, though, you will treat patients place their muzzles into it, by pairing wearing who have been previously cared for by one or of the basket muzzle with receipt of delicious more other veterinarians. If at all possible, food treats. obtain copies of the medical records from all In the case of other pets such as cats, previous veterinarians. Medical issues of parrots, and rabbits, again, much can be particular relevance include: (i) illness, learned by direct observation of the patient. injuries, or elective surgery that occurred Unless it is not safe to do so, allow the patient around the time the problem began; (ii) to move freely around the exam room while chronic medical problems; and (iii) previous you interview the client. or current medication for the behavior or Sometimes it is desirable to do a specific, other problems. direct exam of the behavioral responses of the patient to specific stimuli. Before doing The Behavioral Exam this, carefully consider what you have learned from the owner and from direct observation While you are taking the history, even if it is of the pet’s spontaneous behavior and what is a brief history to supplement a written safe to do. history given to you by the owner, you will be Finally, it is important to discuss with the able to conduct your initial direct behavioral owners what their specific goals are for their exam of the animal. For horses and other pet. Discuss whether or not the goals are large animals, it is ideal that this initial realistic and potentially attainable and give interview be conducted in a location where an initial estimate of how long it is likely to you can comfortably observe the patient as take to achieve their goals. While we may you talk with the client. You may be able to think, based on prior discussion, that we observe the actual problem, for example, understand the owner’s goals, we may not. cribbing or head shaking, but also discern such important information as whether or Duration of Treatment not the horse is constantly alert and never relaxes, avoids people, rushes people with its Once a patient’s problem has been diagnosed ears pinned back, approaches people and and a treatment plan devised, a common solicits attention, etc. Likewise, with dogs, question is how long the treatment will take. which will usually be observed in the exam Many owners are concerned that their pet room, note what signaling the patient sends will have to be on medication for the rest of to the human family members, yourself, and its life. The exact duration will vary not only your staff. If there are any concerns about with the treatment, the species, and the prob- aggression to you or your staff, the patient lem, but with the individual patient. Also, the should be kept on a leash at all times. family’s ability to follow through with man- Otherwise, allow the patient to wander freely agement changes and behavior therapy inter- around the exam room so that you can note ventions will affect the duration of treatment. 64 Introduction to Clinical Psychopharmacology for Veterinary Medicine

Nevertheless, behavior problems and anxiety orders, there is not always a good analogy as disorders are not cured in a week or 10 days. neurophysiology, neuroendocrinology, and The goal is remission of clinical signs when- neuroanatomy can significantly differ among ever possible. Commonly, several months are species. Looking at the literature on human required and so are maintenance therapy and obsessive‐compulsive disorder, patients who management. Severe or refractory cases may are persistent hand washers may seem useful take years or never completely resolve or go in investigating possible best treatments for into remission. When treatment is initiated, dogs that persistently lick their paws. In the the authors instruct the owner that our goal long run, it may or may not turn out that is, first, to identify and conduct treatments treatment of human obsessive‐compulsive that entirely resolve the problem. After that, disorder is a good model for treatment of treatment should be continued for several canine compulsive disorders as these condi- months after the problem appears to be tions are not even considered to be a single resolved. A gradual weaning process can be entity in the same species. It is probably a discussed but, depending on the original further stretch to look to treatments diagnosis, the client needs to be informed approved for social phobia in humans and that the patient might relapse clinically. Some assume that this is necessarily a good model anxiety disorders do require lifelong medical for excessively shy cats. As stated above, the management. underlying neurochemistry and learning processes may well be different so keeping up with evidence‐based neuroscience is para- Limitations mount. Nevertheless, until more trials are conducted comparing the efficacy of various Information on FDA‐approved and unique drug treatments on specific populations, we uses of medications in humans is given must rely on the vast literature of human because, sometimes, this can be a valuable psychiatry as a starting point. reference tool when considering what to Not all drugs commercially available in a attempt with a nonhuman patient. However, given class are covered in this book, and not some cautions are in order. First, it is all classes of psychiatric drugs are covered. important to understand that the fact that Selection of specific drugs to be discussed is Drug A and not Drug B is listed as approved based on a combination of the authors’ for disorder X does not necessarily mean that experience with the medication, published Drug B is not useful for disorder X, or even reports on the medication, and current avail- that Drug A is better. It means that the ability of the medication. Some of the newest company that owns the patent on Drug A has drugs that have been developed for human invested the money in the trials mandated by psychiatric disorders may have great poten- the FDA to prove that Drug A is better than tial for veterinary patients but are not covered placebo. It might be the case that Drug B is in this edition because of a lack of experience better for disorder X, but the company or safety/clinical studies in veterinary popu- owning the patent for Drug B does not lations. Future editions will doubtless include consider it economical to seek to obtain a further expanded drug list, just as this sec- approval for disorder X. Or Drug B might be ond edition includes drugs that were not in available generically, and there is no company the first edition. willing to invest the large amounts of money Likewise, while there is some discussion of necessary for FDA approval. effects on mice and rats, the extensive and Additionally, while human psychiatric detailed information available in the litera- disorders and the research on their treatment ture on the various metabolic effects and can sometimes be considered to be models behavioral changes that occur in laboratory for animal behavioral and mental health dis- testing are not covered comprehensively, References 65 because such coverage would double the size is directed to the care of privately owned of this book without greatly increasing its domesticated or exotic animals rather than usefulness to the veterinarian whose practice laboratory populations.

References

Burke, W.J. (2004). Selective versus multi‐ Mealey, K.L., Peck, K.E., Bennett, B.S. et al. transmitter antidepressants: are two (2004). Systemic absorption of mechanisms better than one? Journal of amitriptyline and buspirone after oral and Clinical Psychiatry 65 (suppl 4): 37–45. transdermal administration to healthy cats. Ciribassi, J., Luescher, A., Pasloske, K.S. et al. Journal of Veterinary Internal Medicine 18 (2003). Comparative bioavailability of (1): 43–46. fluoxetine after transdermal and oral Vadodaria, K.C., Stern, S., Marchetto, M.C., administration to healthy cats. American and Gage, F.H. (2018). Serotonin in Journal of Veterinary Research 64 (8): 994–998. psychiatry: in vitro disease modeling using Krishnan, K.R. (1999). Brain imaging correlates. patient‐derived neurons. Cell and Tissue Journal of Clinical Psychiatry 60 (suppl 15): 50–54. Research 371: 161–170. 67

Benzodiazepines Leticia Mattos de Souza Dantas and Sharon L. Crowell‐Davis

University of Georgia, Athens, GA, USA

Action the clinical studies of their effect on humans, few clinical studies or even case reports of The benzodiazepines work by facilitating their effect on nonhuman animals have been GABA in the central nervous system (CNS). published. Fortunately, there are a few, and They do this specifically by binding to some of the laboratory studies conducted on GABAA receptors. The behavioral effects are animals provide useful information on such due to action on the hypothalamus and the topics as toxicity, half‐life and dose–response limbic system. relationships. Of the commercially available benzodiazepines, only alprazolam, chlordiazepoxide, Overview of Indications clonazepam, clorazepate dipotassium, diazepam, flurazepam, lorazepam, oxazepam, and Benzodiazepines are anxiolytic medications triazolam will be discussed in this chapter. with a rapid onset of action that lasts for a Benzodiazepines are potentially useful for few to several hours, depending on the any problems involving anxiety, fear, or pho- specific drug and the species. There are bia in which a rapid onset of action is desired. specific binding sites in the brain for Their immediate and discrete efficacy makes benzodiazepines, with the highest density them particularly useful for fears that are being in the central cortex, the cerebellum, induced by specific stimuli that can be pre- and the limbic system (Braestrup and Squires dicted in advance. Examples of appropriate 1977; Möhler and Okada 1977; Danneberg use include fear-based urination, urine and Weber 1983). There are benzodiazepine marking, or specific phobias such as storm receptors elsewhere in the body, for example, phobia or separation anxiety with panic, and on bovine adrenal chromaffin cells (Brennan fear of people (without aggression) in dogs; and Littleton 1991). Thousands of benzodiaz- feather‐picking and fear of people in birds; epine molecules have been synthesized, foal rejection due to fear in mares; urine although only a small segment of these are marking, storm phobia, separation anxiety, available commercially (Sternbach 1973). and fear/anxiety in cats. In humans, benzo- While thousands of papers have been pub- diazepines reduce somatic symptoms of lished on laboratory studies of the effects of generalized anxiety disorder, but do not benzodiazepines on nonhuman animals and reduce cognitive symptoms, that is, chronic

worry (Gorman 2003). Thus, they are proba- Stein 1968). This results in modern textbooks bly not an ideal drug of choice for veterinary of veterinary behavior being ambivalent on patients that exhibit chronic anxiety inde- the subject of the use of benzodiazepines pendent of external stimuli. Benzodiazepines in the treatment of nonhuman aggression. with active metabolites, especially diazepam, For example, Landsberg et al. (2003) state: should be used with caution in cats because “Benzodiazepines can be considered for the of the rare possibility of medication‐induced treatment of any condition that may have a hepatic necrosis. fear or anxiety component, including fear The use of benzodiazepines in cases aggression …,” but later in the same paragraph involving aggression is controversial. When they point out that benzodiazepine’s chlordiazepoxide and diazepam were first “disinhibition could lead to an increase in released in the early 1960s for use in aggression.” In more recent publications, psychiatry, they were considered to have caution is still advised (Horwitz and Neilson great potential in the treatment of aggression 2007; Landsberg et al. 2013). Clinically, just in humans because in various studies of as alcohol or benzodiazepines can result in laboratory animals it was noted that they had loss of inhibitions and consequent atypical an effect of calming and taming “wild” or behavior, including aggression, in humans, “vicious” animals (DiMascio 1973). However, so can the use of benzodiazepines result in the potential initially believed to be present loss of normal inhibitions and consequent did not turn out to be either consistent or atypical behavior in animals. The challenge reliable. Effect on aggression varies between is distinguishing between inhibited and un‐ species and between individuals and depends inhibited behaviors, since an animal that on the type of aggression being measured is already showing aggression, in theory, is and how it is provoked, the specific benzo- not inhibited. However, that does not mean diazepine, the specific dose, and whether or that the aggressive behavior could not fur- not the benzodiazepine is given as a single, ther escalate. In addition, benzodiazepines, acute dose or whether it is given repeatedly particularly diazepam, appear to increase over a period of days (see Randall 1960, impulsivity (Thiébot et al. 1985), which is a 1961; Boyle and Tobin 1961; Heise and Boff component that, when present in aggressive 1961; Heuschele 1961; Horowitz et al. 1963; behavior, is a poor prognostic indicator for Scheckel and Boff 1966; Valzelli et al. 1967; nonhuman patients. Generally, lacking good Boissier et al. 1968; Fox and Snyder 1969; clinical guidelines as to the specific aggres- Hoffmeister and Wuttke 1969; Sofia 1969; sion situations in which benzodiazepines Bauen and Possanza 1970; Christmas and might be helpful or risky, they should be Maxwell 1970; Cole and Wolf 1970; Fox et al. avoided or used with extreme caution in 1970; Guaitani et al. 1971; Langfeldt and cases involving aggressive animals. It is Ursin 1971; Miczek 1974; Salzman et al. essential that companion animal owners are 1974; Kochansky et al. 1975; Miczek and educated about the potential risks. O’Donnell 1980; Rodgers and Waters 1985; The benzodiazepines may result in Mos et al. 1987; Mos and Olivier 1989; Olivier increases in affiliative behavior. For example, et al. 1991; Gao and Cutler 1993; Miczek rhesus monkeys (Macaca mulatta) treated et al. 1995; Tornatzky and Miczek 1995 with chloridazepoxide, diazepam, or loraze- for some examples of research on humans pam exhibit increased social grooming, and animals that repeatedly identify these social approach, and social contact (Kumar discrepancies). While benzodiazepines some- et al. 1999). times decrease aggressiveness, their use All benzodiazepines are metabolized in sometimes results in increased aggression. the liver and excreted through the kidneys. Relief from anxiety can result in the loss Therefore, premedication blood work to assess of inhibition of behavior (e.g. Margules and the function of these organs is recommended. Ciia Guideline 69

Contraindications, Side aggressiveness, and paresis. In cats, the 10 Effects, and Adverse Events most common signs were prostration, ataxia, muscle tremors, agitation, coma, mydriasis, Side effects include sedation, ataxia, muscle polypnea, decubitus, bradypnea, and vomit- relaxation, increased appetite, paradoxical ing (Bertini et al. 1995). Several publications excitation, increased friendliness, anxiety, that are more recent have pointed out that the hallucinations, muscle spasticity, insomnia, accidental ingestion of an owner’s benzodiaz- and idiopathic hepatic necrosis in cats. The epines is common, and highlights the need latter has specifically been reported as a of veterinarians to discuss safety measures response to diazepam. with clients (Campbell and Chapman 2000; Gusson et al. 2002; Wismer 2002; Cope et al. 2006; Cortinovis et al. 2015). Overdose Clinical Guidelines Treatment of overdose is primarily supportive. Activated charcoal can be used to adsorb Benzodiazepines are DEA Schedule IV drugs. benzodiazepines within the gastrointestinal While they are available by prescription, there tract. In cats, vomiting can be induced with is potential for human abuse due to both 0.05 mg kg−1 of apomorphine subcutaneously psychological and physical dependency. (SC) or 1 mg kg−1 xylazine SC. Flumazenil Benzodiazepines are excreted through (Mazicon), a benzodiazepine receptor antag- the milk and pass through the placenta. They onist, can be given to partially or fully reverse therefore should be used with caution and the effects. Typically administered intrave- generally avoided in pregnant or lactating nously in veterinary medicine, a study with females. dogs as an animal model for children showed While benzodiazepines are good anxiolyt- that the intralingual and submucosal routes ics, they can have an amnesic effect and can be viable alternatives for reversing benzo- sometimes interfere with learning. Thus, they diazepine sedation (Unkel et al. 2006). That may be more useful in situations in which the warrants further investigation in companion control of intense fear is more important than animals as these options could be practical ongoing learning. Nevertheless, the fact that for hypotensive and hypovolemic patients. they can have an amnesic effect does not Three hours after ingestion, gastric lavage or mean that they always do, and research on the induction of vomiting is not recommended, ability to learn while under the influence of because benzodiazepines are rapidly absorbed benzodiazepines exhibits as much variation from the gastrointestinal tract. By this time, as research on the effect of benzodiazepines gastric lavage or induction of vomiting is on aggression (e.g. Iwasaki et al. 1976; Vachon not useful and sedation or convulsions will et al. 1984; Hodges and Green 1987). The make these procedures counterproductive. authors have had numerous cases in which Hypothermic patients should be kept in a learning that was subsequently retained long warm environment. Intravenous fluids can term clearly occurred while the patient was help increase the rate of excretion of the given a benzodiazepine. benzodiazepine. The potential deleterious effects of benzo- In a study of benzodiazepine poisoning in diazepines for human patients with cognitive companion animals, specifically dogs and impairment and dementia disorders (such as cats, the 10 most common signs observed in Alzheimer’s disease) have been under inves- dogs were, in order of prevalence, ataxia, tigation. Accelerated cognitive deterioration prostration, agitation, vomiting, hyperesthe- has been reported (Billioti de Gage et al. sia, muscle tremors, coma, hypersalivation, 2012; Billioti de Gage et al. 2015; Defranchesco 70 Benzodiazepines

et al. 2015; Pariente et al. 2016). Such studies for decreasing medication will vary with the raise a concern regarding the prescription patient, a general rule is to decrease no faster and long‐term treatment of senior and than 25–33% per week. Many patients will elderly veterinary patients, even though sim- require that the decrease occur more slowly. ilar investigations have not been carried out In addition to the above considerations, in veterinary medicine yet. Benzodiazepines all benzodiazepines have the potential to have also been associated with falls in elderly produce physical addiction. Generally, ben- people (Pariente et al. 2008; Ballokova et al. zodiazepine dependency in human medicine 2014) and increased mortality with long‐ is associated with high dosage drug regi- term use (Charlson et al. 2009). The use of mens, use of benzodiazepines of higher benzodiazepines for sedation of patients potency and short duration of action, and with post‐traumatic stress disorder has been with long duration of treatment (Riss et al. associated with greater post‐intensive care 2008; Brett and Murnion 2015). However, symptoms (Parker et al. 2015). investigation of these factors is lacking in There is wide variation in the optimum veterinary medicine and ignores the role dose for a given patient. It is best to have the of genetics and other physiological factors client give the pet a test dose in the low range in physiological tolerance. Different benzo- of the dosage schedule at a time when they diazepines produce different kinds of physical will be home to watch the pet for several dependence. In studies of flumazenil‐ hours. It is also necessary to give clients induced abstinence in dogs that had been safety instructions due to the potential of treated chronically with diazepam, nordiaz- benzodiazepines causing ataxia and incoordi- epam, flunitrazepam, alprazolam, oxazepam, nation (e.g. blocking access to stairs and halazepam, and lorazepam, it was found that balconies), among other concerns such as oxazepam and lorazepam resulted in a less‐ hyperphagia. In this way they can observe intense physical dependence than did the whether their pet has such side effects as other benzodiazepines (Martin et al. 1990). paradoxical excitement or sedation at that Therefore, if it is anticipated that a dog dose. Paradoxical excitement generally occurs will need to be regularly medicated with a at a specific window of dosage. Therefore, benzodiazepine for an extended period of if paradoxical excitement occurs, the dose time, oxazepam or lorazepam may be a bet- should be increased, while if sedation occurs, ter choice than the other benzodiazepines. the dose should be decreased. If the patient Dogs made dependent on diazepam by pro- exhibits no side effects, the medication can longed administration of 60 mg kg−1 day−1 then be tried at that dose in the situation and acutely withdrawn by administration of that induces fear. If the low dose used at the flumazenil exhibit tremor, rigidity, decreased beginning is insufficient to alleviate the fear, food intake, and tonic, clonic convulsions steadily increase the dose until fear is allevi- (McNicholas et al. 1983). ated or side effects are encountered. Tolerance is a phenomenon that also Withdrawal of patients that have been occurs with these medications; that is, when frequently dosed with benzodiazepines over a patient is on a benzodiazepine for an a period of several weeks should be gradual. extended period, steadily greater doses may This allows the identification of a specific be required to achieve the same behavioral dose that may still be required to control the effect (Danneberg and Weber 1983). problem behavior. Also, sudden termination Benzodiazepines can safely be used with a in a patient that has been continuously on a variety of other psychoactive medications. benzodiazepine for several weeks can result Details of these combinations are discussed in rebound, that is, a resumption of symptoms further in Chapter 19. that may be more intense than they were The doses of the various benzodiazepines before treatment. While specific schedules are shown in Tables 7.1 and 7.2. Seii Medication 71

Table 7.1 Doses of various benzodiazepines for dogs and cats.

Medication Dogs Cats

Alprazolam (Xanax) 0.02–0.1 mg kg−1 q4h 0.0125–0.25 mg kg−1 q8h Chlordiazepoxide (Librium) 2.0–6.5 mg kg−1 q8h 0.2–1.0 mg kg−1 q12h Clonazepam (Klonopin) 0.1–0.5 mg kg−1 q8–12h 0.015–0.2 mg kg−1 q8h Clorazepate dipotassium (Tranxene) 0.5–2.0 mg kg−1 q4h 0.5–2.0 mg kg−1 q12h Diazepam (Valium) 0.5–2.0 mg kg−1 q4h 0.1–1.0 mg kg−1 q4h Flurazepam (Dalmane) 0.1–0.5 mg kg−1 q12h 0.1–0.4 mg kg−1 q12h Lorazepam (Ativan) 0.02–0.5 mg kg−1 q8–12h 0.03–0.08 mg kg−1 q12h Oxazepam (Serax) 0.04–0.5 mg kg−1 q6h 0.2–1.0 mg kg−1 q12–24h

Note: All doses given are orally and are given as needed until the desired effect is reached. The hourly schedules are the maximum frequency at which the medication should be given. As a general rule, start at the lowest dose and titrate upward if needed. See text for further explanation. Source: Scherkl et al. (1985), Dodman and Shuster (1994), Simpson and Simpson (1996), Overall (1994b, 1997, 2004), Simpson (2002), Crowell‐Davis et al. (2003), Landsberg et al. (2003).

Table 7.2 Dose of diazepam for parrots, horses, elimination half‐life in healthy humans and rabbits. is about 11.2 hours. However, in humans, changes in absorption, distribution, metab- Parrot Horse Rabbit olism, and excretion occur in various disease states; for example, impaired hepatic Two drops of 5 mg ml−1 10–30 mg 0.1–0.6 mg kg−1 solution per ounce of q8h or renal function. This is no doubt also the drinking water case in nonhuman animals. Doses should be decreased in old or obese veterinary Source: Ryan (1985), Crowell‐Davis (1986). patients and in those with impaired liver or renal function (Pharmacia and Upjohn 2001). Specific Medications The two most common metabolites are α‐hydroxy‐alprazolam and a benzophe- I. Alprazolam none. The benzophenone is inactive, but α‐hydroxy‐alprazolam has about half the Chemical Compound: 8‐Chloro‐1‐ activity of alprazolam. Metabolism is initi- methyl‐6‐phenyl‐4H‐s‐triazolo [4,3‐α] [1,4] ated by hydroxylation that is catalyzed by benzodiazepine cytochrome P450 3A. Therefore, any drugs DEA Classification: DEA Schedule IV drug that inhibit the activity of this metabolic Preparations: Generally available as 0.25‐, pathway are likely to result in decreased 0.5‐, 1.0‐, and 2.0‐mg tablets. Also available clearance of alprazolam (Pharmacia and as a 1 mg ml−1 oral solution. The extended Upjohn 2001). release form comes in 0.5‐, 1‐, 2‐, and In humans, extended‐release tablets are 3‐mg tablets. absorbed more slowly than non‐extended‐ release tablets, resulting in steady‐state con- Clinical Pharmacology centration that is maintained for 5–11 hours Alprazolam is readily absorbed following after dosing. Time of day, consumption of a oral administration. In humans, peak con- meal, and type of meal affect the absorption centrations occur in the plasma at one rate (Pharmacia and Upjohn 2001). Since the to two hours, and the plasma levels are pro- digestive physiology and typical diet of vet- portionate to the dose given. Mean plasma erinary patients differ significantly from the 72 Benzodiazepines

digestive physiology and diet of humans, it is Overdose likely that there is substantial variation from the human data. Clinical signs reported in dogs that had In African green monkeys, the mean elimina- consumed overdoses of up to 5.55 mg kg−1 tion half‐life is 5.7 hours (Friedman et al. 1991). alprazolam included ataxia, disorientation, depression, hyperactivity, vomiting, weakness, Uses in Humans tremors, vocalization, tachycardia, tachypnea, In humans, alprazolam is approved for use hypothermia, diarrhea, and increased saliva- in generalized anxiety disorder, anxiety with tion. In 38% of the cases, clinical signs devel- depression, and panic disorder with or with- oped within 30 minutes of ingestion. Ataxia out agoraphobia. Effective treatment of typically resolved within 9 hours, but some panic disorder requires several months, and dogs were ataxic for up to 24 hours. Depression withdrawal must be very gradual, taking at lasted 10–31 hours. There was no correlation least eight weeks, in order to avoid rebound between the dose consumed and paradoxical (Pecknold et al. 1988). excitement (Wismer 2002). Treat an overdose with gastric lavage and sup- Contraindications portive treatment, including fluids. Flumazenil Alprazolam is contraindicated in patients may be given for complete or partial reversal; with known hypersensitivity to benzodiaz- however, administration of flumazenil to a epines, glaucoma, or severe liver or kidney patient that has received alprazolam daily for disease. It is also contraindicated in pregnant several weeks may result in convulsions. or lactating females. It should not be given with medications that significantly impair Doses in Nonhuman Animals the oxidative metabolism of cytochrome Initiate treatment at the lowest dose. If no P450 3A, such as the antifungal agents keto- undesirable side effects occur, titrate dose up conazole or itraconazole (Pharmacia and to the desired effect. Upjohn 2001). Discontinuation Side Effects If a patient has been receiving alprazolam Side effects typical of the benzodiazepines, daily for several weeks, discontinuation including sedation, ataxia, muscle relaxation, should be gradual, and conducted over a increased appetite, paradoxical excitation, period of at least one month. and increased friendliness, may occur. Rats treated with 3–30 mg kg−1 day−1 of Other Information alprazolam over a two‐year period showed While liver failure has not been reported a dose‐related tendency to develop cata- in cats or other veterinary patients given racts in females and corneal vascularization alprazolam for behavior problems, it has in males. Lesions appeared after at least occurred in humans. While it is a rare event 11 months of treatment. Rats given doses of even in humans, liver failure should always alprazolam up to 30 mg kg−1 day−1 and mice be considered as a possible sequela to medi- given doses up to 10 mg kg−1 day−1 for a cation with alprazolam. period of two years showed no evidence of Dogs given alprazolam at an escalating increased cancer. Alprazolam has not been dose over 18–26 days until a dose of shown to be mutagenic in rats. In rats given 12 mg kg−1 four times a day (q.i.d.) is attained, alprazolam at doses up to 5 mg kg−1 day−1, then maintained on that dose for about fertility was unimpaired. The LD50 (the dose three weeks, become physically addicted, as that kills half of the animals tested) in the demonstrated by flumazenil‐precipitated rat is 331–2171 mg kg−1 (Pharmacia and abstinence (Sloan et al. 1990). These doses Upjohn 2001). are much higher than would be given for the Clinical Pharmacology 73 clinical treatment of anxiety disorders. Acute of rain or strong winds. To do this, owners withdrawal of an addicted dog may result of storm‐phobic pets must monitor weather in seizures. Other sequelae to withdrawal conditions closely. As a general rule for patients reported in humans include insomnia, with severe signs of this phobia, medication abnormal involuntary movement, head- should be given if there is any likelihood that aches, muscle twitching, and anxiety. Dogs weather conditions that induce fear responses addicted to alprazolam that underwent will occur. If, however, the fear‐inducing acute withdrawal due to administration of stimuli have already begun and the patient is flumazenil exhibited wild running, barking, showing fear when the owner realizes there and lunging at nonexistent objects, and will be a problem, alprazolam should still uncontrolled splaying, rigidity, and jerking be administered. For alprazolam‐responsive of the limbs (Martin et al. 1990). As with patients, fear is likely to be somewhat abated, humans, veterinary patients that have been although a higher dose may be required for on alprazolam daily for several weeks should full relief from signs of fear. have their dose gradually decreased. In a case report published by Duxbury (2006), As with other benzodiazepines, alprazolam alprazolam was used as an adjunctive medica- is particularly noted for its rapid action. tion to a treatment protocol with clomi- For example, in the treatment of humans with pramine to control anxiety signs during the panic disorder, patients treated with alpra- owner’s absence in a dog diagnosed with sepa- zolam respond within the first week of treat- ration anxiety disorder. Alprazolam was admin- ment, while patients treated with imipramine, istered orally one hour before departures. a tricyclic antidepressant, respond, but not Dogs chronically dosed with increasing until the fourth week of treatment (Charney quantities of alprazolam until they began et al. 1986). This rapid response has been losing weight did so at doses of 48 mg kg−1 by observed clinically in veterinary patients, day 18–28 of the increasing regimen (Martin making alprazolam a good choice for dogs et al. 1990). that exhibit panic behaviors to the degree that rapid improvement is essential. II. Chlordiazepoxide HC1

Effects Documented in Nonhuman Animals Chemical Compound: 7‐Chloro‐2‐(methyl‐ Cats amino)‐5‐phenyl‐3H‐1,4‐benzodiazepine While the use of alprazolam to treat behavior 4‐oxide hydrochloride problems in cats is mentioned in several text- DEA Classification: DEA Schedule IV drug books, the authors are unaware of any papers Preparations: Generally available in 5‐, 10‐, presenting results of clinical use in this species and 25‐mg capsules. with the exception of a report on humane handling of cats in the veterinary hospital. Anseeuw et al. (2006) suggested using alprazolam to Clinical Pharmacology decrease arousal in cats returning home from medical visits, especially if their housemates Chlordiazepoxide HCl acts on the limbic become reactive upon the reunion. system of the brain, modifying emotional res ponses. It has antianxiety, appetite‐stimulating, Dogs and sedative effects. It is also a weak analge- Crowell‐Davis et al. (2003) used alprazolam sic. It does not have an autonomic blocking as part of a treatment protocol for dogs with effect, so moderate doses do not affect blood storm phobia. Alprazolam is most likely to be pressure or heart rate (Randall et al. 1960). effective if it is given 30–60 minutes before It crosses the blood–brain barrier, is highly the occurrence of the earliest stimuli that bound to plasma proteins, and is metabo- elicit fear responses, for example, the sound lized by the liver. Metabolites generated in 74 Benzodiazepines

the liver include desmethyldiazepam (nor- daily dose of 5 mg kg−1 PO for nine weeks is diazepam), demoxepam, desmethylchlordi- ultimately excreted in the urine as oxazepam, azepoxide, and oxazepam (Schwartz and while an additional 1.3% is excreted in Postma 1966; Kaplan et al. 1970; ICN the feces on either regimen (Kimmel and Pharmaceuticals 1996). These metabolites Walkenstein 1967). are active and typically have long half‐lives. Electroencephalographic studies in the In humans, peak blood levels are not cat have shown that the peak drug effect reached until several hours after taking for chlordiazepoxide, when given at the medication. Chlordiazepoxide has a half‐ 1.25 mg kg−1 intraperitoneally (IP), occurs life in humans of 24–48 hours, and plasma within 90 minutes (Fairchild et al. 1980). −1 levels decline slowly over several days. The LD50 in mice is 123 ± 12 mg kg IV and Chlordiazepoxide is excreted in the urine, 366 ± 7 mg kg−1 intramuscularly (IM). In rats, −1 with only 1–2% in unchanged form (ICN the LD50 is 120 ± 7 mg kg IV and more than Pharmaceuticals 1996). 160 mg kg−1 IM (ICN Pharmaceuticals 1996). −1 In dogs, plasma levels peak around 7–8 hours The oral dose LD50 is 590 mg kg in rabbits, after a single dose of 4 mg kg−1 or 20 mg kg−1 of 1315 mg kg−1 in rats, and 620 mg kg−1 in mice chlordiazepoxide. Plasma levels are about half (Randall et al. 1965). In cats, a dose of the peak value after 24 hours and chlordiaze- 200 mg kg−1 PO was fatal in five days (Randall poxide is still being excreted in the urine and Kappell 1973). 96 hours after administration. This dose causes mild sedation with high plasma levels Uses in Humans for 24 hours in this species. When dogs are Chlordiazepoxide is used in the treatment of redosed daily, there is no cumulative effect on various anxiety disorders, for short‐term blood levels or sedation. Dogs given doses of relief of symptoms of anxiety, for example, 50 mg kg−1 by mouth (PO) for six months have preoperatively, and for relief from symptoms shown no adverse effects (Randall 1961). of alcoholism. Doses of 10–40 mg kg−1 may produce ataxia, while doses of 80 mg kg−1 produce sleep when Contraindications dogs are not stimulated (Randall et al. 1960). Chlordiazepoxide is contraindicated in Doses of 2.5–20 mg kg−1 have an appetite‐ patients with known sensitivity to this or stimulating effect (Randall et al. 1960). other benzodiazepines. Avoid or use with When dogs are given a single dose of 0.5– extreme caution in patients with a history of 0.8 mg kg−1 PO, peak plasma levels occur ear- aggression, because chlordiazepoxide, like all lier, just two to five hours after dosing, and benzodiazepines, may cause loss of learned the half‐life is likewise shorter, 12–20 hours inhibitions. (Koechlin and D’Arconte 1963). Seven days Reduced doses should be used in geriatric after administration of a single dose of patients and patients with mild to moderate 4 mg kg−1, 44% of the dose is recovered through liver or kidney disease. the urine, while five days after the same dose Chlordiazepoxide crosses the placental an additional 44% is recovered in the feces. barrier and enters the milk. There is an Urinary excretion rate peaks at 10 hours after increased risk of congenital malformations oral administration (Koechlin et al. 1965). when chlordiazepoxide is given during the In the dog, demoxepam, one of the metabolites first trimester of pregnancy. Therefore, its of chlordiazepoxide, has a half‐life of 10–20 hours, use should be avoided in pregnant as well as with substantial individual variation. Some lactating females. of the demoxepam is subsequently converted to oxazepam (Schwartz et al. 1971). Side Effects Slightly over 1% (1.1%) of chlordiazepoxide Various side effects, including sedation, given as a single 26 mg kg−1 dose PO or as a ataxia, paradoxical excitation, and rage may Clinical Pharmacology 75 occur. In humans, there have been isolated several weeks, discontinuation should be reports of effects on blood coagulation in gradual and conducted over at least a one‐ patients receiving chlordiazepoxide at the month period of time. same time that they are given anticoagulants. Blood dyscrasias, jaundice, and hepatic dys- Other Information function occasionally occur in humans (ICN Chlordiazepoxide has been shown to cause Pharmaceuticals 1996). Any veterinary patient delayed reversal learning and failure to that is maintained on chlordiazepoxide for an accomplish successive discrimination learn- extended period of time should have complete ing in the rat, although it does not disrupt blood counts and blood chemistries conducted simultaneous discrimination (Iwahara and regularly. Tolerance may develop, particularly Sugimura 1970; Iwasaki et al. 1976). to the sedative effects (Goldberg et al. 1967). Two out of six dogs given chlordiazepoxide Effects Documented in Nonhuman Animals at 127 mg kg−1 died with evidence of Taming effects have been noted in multiple circulatory collapse, as did six out of six given species, including monkeys, rats, tigers, 200 mg kg−1 day−1. Dogs given 80 mg kg−1 lions, dingos, and squirrels at doses that did exhibited nonspecific toxic changes (Wyeth not induce sedation (e.g. Harris 1960; Heise Laboratories Inc. 1999b). and Boff 1961; Scheckel and Boff 1966). Rat pups of mothers given 10, 20, and 80 mg kg−1 during conception and pregnancy Cats had normal growth and showed no congenital Laboratory cats given chlordiazepoxide intra- anomalies. Lactation of the mothers was unaf- peritoneally at doses ranging from 1.25 to fected. When rats were given 100 mg kg−1, 5 mg kg−1 exhibited dose‐related stimulation there was a significant decrease in fertilization and decreased sleep. They were also observed rate. There was also a decrease in the viability to be playful or mildly aggressive on this med- and body weight of the pups. These problems ication, although what form of aggression was were attributed to the sedation induced at this exhibited is not specifically described dose, which resulted in less mating activity (Fairchild et al. 1980). At 10 mg kg−1 PO, cats and decreased maternal care. Some of the exhibit muscle relaxation when suspended by offspring also exhibited skeletal defects at this the scruff of the neck (Randall 1961). dose (ICN Pharmaceuticals 1996). Dogs Overdose Angel et al. (1982) treated a strain of nervous In case of overdose, conduct gastric lavage pointer dogs with chlordiazepoxide or immediately, then provide general supportive placebo at 3.5 mg kg−1 in the morning for therapy. Administer intravenous fluids and seven consecutive days. The dogs’ avoidance maintain an adequate airway. If excitation of humans was significantly attenuated with occurs, do not use barbiturates. Flumazenil is the chlordiazepoxide treatment, but not the indicated for the complete or partial reversal placebo. The dogs’ behavior returned to of the sedative effects of chlordiazepoxide. baseline four days after discontinuation of medication (Angel et al. 1982). Doses in Nonhuman Animals Five of eight laboratory beagle dogs with Initiate treatment at the lowest dose. If no abnormal withdrawn and depressed behav- undesirable side effects occur, titrate dose up ior exhibited improvement when given to the desired effect. 5 mg kg−1 daily of chlordiazepoxide, while the behavior of all three of three beagles with Discontinuation the same symptoms, given 2.5 mg kg−1 daily As with other benzodiazepines, if the patient of chlordiazepoxide, was resolved (Iorio has been receiving chlordiazepoxide daily for et al. 1983). 76 Benzodiazepines

Chlordiazepoxide has an appetite stimula- Preparations: Generally available as 0.5‐, tion effect in dogs, with a single low dose 1.0‐, and 2.0‐mg tablets. increasing food intake of fasted dogs. Chronic treatment with chlordiazepoxide for 90 days Clinical Pharmacology results in weight gain (Randall et al. 1960). Clonazepam is completely and rapidly absorbed following oral dosing. In humans, Monkeys maximum plasma concentrations are Chlordiazepoxide has been used to tame reached in one to four hours, with an elimi- monkeys at a dose of 1 mg kg−1 (Zbinden and nation half‐life of 30–40 hours. Dogs given Randall 1967). 0.2 mg kg−1 IV exhibit an elimination half‐life In social colonies of rhesus monkeys, of 1.4 ± 0.3 hours. Most clonazepam is metab- chlordiazepoxide (2.5–5.0 mg kg−1 PO daily) olized to various inactive metabolites. In produces dose‐dependent increases in social humans, less than 2% is excreted in the urine grooming, approach, contact, self‐grooming, in an unchanged form. Because extensive feeding, and resting with the eyes open. metabolism occurs in the liver, hepatic dis- There is also decreased vigilance and aggres- ease may result in impaired elimination. sion (Kumar et al. 1999). Thus, clonazepam is not the best choice for patients with liver disease. Pharmacokinetics Zoo Animals are dose‐dependent throughout the dose A number of zoo animals changed from being range (Al‐Tahan et al. 1984, Roche aggressive or intensely frightened to being calm, Laboratories 2001). nonaggressive, and even friendly when given Cats given 1000 mg kg−1 clonazepam PO chlordiazepoxide. These include a male European survived. In contrast, cats given bromazepam lynx (Lynx lynx; 6 mg kg−1 PO), a female dingo died at a dose of 1000 mg kg−1, while several (Canis familiaris dingo; 3–7 mg kg−1 PO), a benzodiazepines proved fatal in cats at much female Guinea baboon (Papio papio; 13 mg kg−1 lower doses (Randall and Kappell 1973). PO), a male California sea lion (Zalophus califor- In dogs given 0.5 mg kg−1 of clonazepam nianus; 7 mg kg−1 PO), a male Burmese macaque every 12 hours (q12h) for a period of three (Macaca nemestrina andamensis; 5 mg kg−1 IM), weeks, the elimination half‐life of clonazepam a female red kangaroo (Macropus rufus; increases with each passing week. In week 11 mg kg−1 PO), a female mule deer (Odocoileus one, the average half‐life is about two hours, hemionus; 2.2 mg kg−1 IV), a male white‐bearded while by week three it is almost eight hours. gnu (Connochaetes taurinus; 4 mg kg−1 IM), a Acute withdrawal from clonazepam after female gerenuk (Litocranius walleri; 5 mg kg−1 three or more weeks of treatment has been IM), and three golden marmosets (Leontocebus shown to result in anorexia, hyperthermia, rosalia; 15 mg kg−1 PO) (Heuschele 1961). and weight loss (Scherkl et al. 1985). Plasma Animals that did not respond as desired to concentrations in the range considered to be chlordiazepoxide included a male klipspringer therapeutic in humans can be maintained in (Oreotragus oreotragus saltatrixoides), a dogs by dosing 0.5 mg kg−1 two times a day female South American tapir (Tapirus ter- (b.i.d.) or three times a day (t.i.d.) (Al‐Tahan restris), and a Hensel’s cat (Felis pardinoides) et al. 1984). (Heuschele 1961). Uses in Humans III. Clonazepam Clonazepam is used to treat a variety of seizure disorders and panic disorder. Chemical Compound: 5‐(2‐Chlorophenyl)‐ 1,3‐dihydro‐7‐nitro‐2H‐1,4‐benzodiaz- Contraindications epin‐2‐one Clonazepam is contraindicated in patients DEA Classification: DEA Schedule IV with a history of sensitivity to benzodiaz- controlled substance epines, severe liver or kidney disease, or Clinical Pharmacology 77

glaucoma. Clonazepam should not be given should be combined cautiously with clonaze- to pregnant or lactating females. pam, because concurrent use may result in Low doses should be used in patients with clonazepam overdose due to insufficient mild to moderate kidney or liver disease, metabolism (Roche Laboratories 2001). because their ability to metabolize and excrete clonazepam will be compromised. Overdose Symptoms of overdose that are characteristic Side Effects of CNS depressants may occur, including As with all benzodiazepines, clonazepam sedation, confusion, diminished reflexes, and may result in sedation, ataxia, muscle coma. Gastric lavage should be initiated as relaxation, increased appetite, paradoxical soon as possible, followed by appropriate excitation, increased friendliness, anxiety, supportive treatment and monitoring of and hallucinations. respiration, pulse, and blood pressure. Carcinogenicity of clonazepam has not Flumazenil, a benzodiazepine‐receptor been studied. Genotoxic studies are antagonist, can be used to partially or com- insufficient to conclude if clonazepam has pletely reverse the effects, but should be any genotoxic potential. In rats given avoided in patients that have been treated 10–100 mg kg−1 day−1 over two generations, with clonazepam daily for an extended period there was a decrease in the number of of time because seizures may be induced. pregnancies and the number of offspring that survived until weaning. With administration Doses in Nonhuman Animals of clonazepam to pregnant rabbits during the Initiate treatment at the lowest dose. If no period of organogenesis at doses ranging undesirable side effects occur, titrate dose up from 0.2 to 10.0 mg kg−1 day−1, various to the desired effect. malformations, including cleft palate, open eyelids, fused sternebrae, and defects of the Discontinuation limbs occurred at a low, non‐dose‐related As with all benzodiazepines, clonazepam rate. Pregnant rabbits given 5 mg kg−1 day−1 should be reduced gradually in patients that or higher doses exhibited reductions in have been receiving it on a daily basis for maternal weight gain, while reductions in several weeks. embryo‐fetal growth occurred at doses of 10 mg kg−1 day−1. However, no adverse effects Other Information were observed on the mothers, embryos, or Clonazepam is not useful in the treatment of fetuses when mice and rats were given doses myoclonus caused by serotonin syndrome. up to 15 and 40 mg kg−1 day−1, respectively (Roche Laboratories 2001). Effects Documented in Nonhuman Animals Elimination of clonazepam from both Cats plasma and the cerebral cortex becomes In laboratory studies, clonazepam is substan- slower with age (Barnhill et al. 1990). tially less toxic to cats than chlordiazepoxide, diazepam, or flurazepam (Table 7.3). Drug Interactions Ranitidine and propantheline, which decrease Dogs stomach acidity, and fluoxetine, an SSRI, have In a case report, Carter (2011) used little to no effect on the metabolism of clonazepam to treat noise phobias in a dog clonazepam. Cytochrome P‐450 inducers, diagnosed with hyperactivity. This dog was including phenytoin, carbamazepine, and treated initially with fluoxetine (which phenobarbital, facilitate clonazepam metabo- helped control the hyperactivity signs) but lism, resulting in a 30% decrease in clonaze- the patient still presented with noise phobias. pam levels in humans. Strong P‐450 3A The dog was less reactive to noises within a inhibitors, such as oral antifungal agents, week of initiation of treatment. 78 Benzodiazepines

Table 7.3 Dose at which muscle relaxation is achieved and lethal dose of some benzodiazepines when given orally to cats.

Benzodiazepine Muscle relaxation mg kg−1 PO Lethal dose mg kg−1 PO

Chlordiazepoxide hydrochloride 2 200 Clonazepam 0.05 >1000 Diazepam 0.2 500 Flurazepam 2 400

Note: The lethal dose for clonazepam is listed as >1000 mg kg−1 because this dose was not fatal, and higher doses were not given. The data are based on only two cats per benzodiazepine, and individual variation in metabolism would be expected to produce a wider range of doses than given in this table. However, the data show the relative differences between drugs in these effects. Source: Randall and Kappell (1973).

Other After administration of a 50‐mg dose of Clonazepam has been shown to have a tam- clorazepate to humans, 62–67% of the radio- ing effect on aggressive primates, with activity was excreted in the urine and 15–19% concurrent muscle weakness and hypnosis. was excreted in the feces within 10 days (Abbott Laboratories 2004). IV. Clorazepate Dipotassium As with other benzodiazepines, dogs metabolize clorazepate more rapidly than do Chemical Compound: Potassium 7‐chloro‐ humans. After administrations of oral 2,3,‐dihydro‐2‐oxo‐5‐phenyl‐1H‐1,4 clorazepate, humans have been reported to benzodiazepine‐3‐carboxylate have a half‐life elimination of nordiazepam of DEA Classification: DEA Class IV non‐nar- 40.8 ± 10.0 hours (Wilensky et al. 1978) or cotic agent over 80 hours (Boxenbaum 1980). In contrast, Preparations: Generally available as 3.75‐, the half‐life of nordiazepam in dogs is about 7.5‐, 11.25‐, 15‐, 22.5‐mg tablets and 3.75‐, nine hours (Brown and Forrester 1991). 7.5‐, 15‐mg capsules. In humans, Tranxene SD (sustained delivery) has longer efficacy than does the Clinical Pharmacology regular‐release product, Tranxene. In dogs, Clorazepate is metabolized in the liver and there is no difference in either time of peak excreted in the urine. In the acidity of the plasma concentration or serum concentra- digestive tract, it is rapidly decarboxylated to tions two hours after administration. form nordiazepam, also called desmethyldiaz- However, 12 hours after administration of a epam, which is the active metabolite (Troupin single 2.5–3.8 mg kg−1‐dose serum concen- et al. 1979; Greenblatt et al. 1988). Plasma lev- tration of regular release was 24 ± 77.9 ng ml−1 els of nordiazepam will be proportionate to of nordiazepam, while serum concentration clorazepate dose. Nordiazepam is further of nordiazepam with sustained delivery was metabolized by hydroxylation to conjugated 215 ± 66.1 ng ml−1 (Brown and Forrester oxazepam (3‐hydroxynordiazepam) and p‐ 1991). There was no gender effect on disposi- hydroxynordiazepam (Abbott Laboratories tion of the drug, although this study only 2004). involved four males and three females and so Nordiazepam is also an active metabolite cannot be considered conclusive on this of diazepam. Clorazepate provides higher issue. Peak nordiazepam concentrations concentrations of nordiazepam over a longer were 372–1140 ng ml−1 with the regular period of time than does diazepam and has release. Peak nordiazepam concentrations less sedative effect (Lane and Bunch 1990). were 450–1150 ng ml−1 with sustained Clinical Pharmacology 79

delivery. Overall, the bioavailabilities of the paradoxical excitation, increased friendliness, two products were not different. anxiety, and a variety of other side effects In healthy adult dogs given a single dose of may occur. Transient sedation and ataxia clorazepate orally at a dose of 2 mg kg−1 were observed in one of eight healthy adult maximum nordiazepam concentrations at dogs given a single dose of 2 mg kg−1 of 59–180 minutes after administration range clorazepate (Forrester et al. 1990). from 446 to 1542 ng ml−1. After multiple such Potential mutagenic effects of clorazepate doses given q12h, maximum nordiazepam have not been studied sufficiently to come to concentration is reached at 153 ± 58 minutes any conclusions. However, other minor tran- and ranges from 927 to 1460 ng ml−1. The quilizers, for example, diazepam, have been mean elimination half‐life after a single dose associated with an increased risk of fetal is 284 minutes, while the mean elimination abnormalities if given during the first trimes- half‐life after multiple doses is 355 minutes. ter of pregnancy. Nordiazepam is excreted in After multiple doses of clorazepate, there are milk. Therefore, use of clorazepate in preg- significant decreases in serum chemical val- nant and nursing females should be avoided. ues of albumin, total protein, and calcium, while there are significantly increased con- Dependence centrations of urea nitrogen and glucose. As with all benzodiazepines, continuous There are also significant increases in total administrations of clorazepate can result in white blood cell count, segmented neutro- dependence. In humans, the severity of with- phils, lymphocytes, and eosinophils. Urine drawal symptoms has been shown to be related pH decreases significantly. Also, serum to the dose that has been taken. Dogs and rab- alkaline phosphatase activity increases while bits have exhibited seizures when clorazepate alanine transaminase (ALT) values decrease. was abruptly withdrawn after dependence was Despite these changes, all values remain established (Abbott Laboratories 2004). In all within normal reference ranges after 21 days cases, it is recommended that if a patient has on 2 mg kg−1 b.i.d. (Forrester et al. 1990). received clorazepate regularly over a period of Concurrent administration of clorazepate several weeks, the dose be decreased gradually. and phenobarbital in dogs results in significantly lower concentrations of nordiazepam, Overdose necessitating higher doses in dogs that are on In case of overdose, immediate gastric lavage phenobarbital because of epilepsy (Forrester and supportive measures should be con- et al. 1993). ducted. Administer intravenous fluids and maintain an open airway. Flumazenil, a ben- Uses in Humans zodiazepine receptor antagonist, can be used Clorazepate is used for management of anxi- to completely or partially reverse the effects ety disorders and short‐term relief of anxiety. of an overdose. Treatment with flumazenil may result in seizures, especially in patients Contraindications that have frequently been given clorazepate Clorazepate is contraindicated in patients for a long period of time. with a history of adverse reactions to clorazepate and in patients with acute narrow‐angle Doses in Nonhuman Animals glaucoma. Since clorazepate has depressant For nonhuman animals, initiate treatment at effects on the CNS, avoid concurrent use with the lowest dose. If no undesirable side effects other CNS depressants. occur, titrate the dose up to the desired effect.

Side Effects Effects Documented in Nonhuman Animals As with all benzodiazepines, sedation, Clorazepate is used in dogs when a long ataxia, muscle relaxation, increased appetite, duration of action is desired, for example, in 80 Benzodiazepines

cases of separation anxiety in which a Clinical Pharmacology serotonin reuptake inhibitor has not had Diazepam has a CNS depressant effect, time to take effect and the shorter‐acting specifically on the limbic system, thalamus, anxiolytics are not sufficient to keep the dog and hypothalamus, which results in calm while the owner is gone for a full day. anxiolytic, calming, sedative, skeletal muscle Irimajiri and Crowell‐Davis (2014) used relaxation, and anticonvulsant effects. It does clorazepate in a dog diagnosed with not have any peripheral autonomic blocking separation anxiety disorder for 30 days, action or produce extra‐pyramidal side 30–60 minutes before the owner’s departures, effects. It acts by activation of the γ‐ while waiting for clomipramine to take full aminobutyric acid system at the GABAA effect. The drug was discontinued as the dog receptor complex. This results in decreased showed consistent improvement, with no neural transmission throughout the CNS problems. (Roche Laboratories 2000). Pineda et al. (2014) investigated the effec- Following oral administration, the usual tiveness of clorazepate used in combination route in treating behavior cases, diazepam is with fluoxetine and behavior modification rapidly absorbed, with peak plasma levels for the treatment of anxiety disorders in occurring 0.5–2 hours after administration in dogs. Thirty‐six dogs diagnosed with anxiety humans and one hour after administration to disorders (with and without aggressive rats (Schwartz et al. 1965). Diazepam readily behavior) completed the trial. Clorazepate crosses the blood–brain barrier, is highly dipotassium was administered orally at bound to plasma proteins, is highly lipid‐ 1.0 mg kg−1 every 24 hours for 4 weeks and soluble, and is widely distributed through the fluoxetine at 1.0 mg kg−1 every 24 hours for body. Blood concentrations are proportional 10 weeks. Improvement was reported in 25 to the dose given. In horses, 87% of diazepam dogs. This study did not observe increase in is bound to plasma protein when the serum −1 aggression during treatment with cloraze- concentration is 75 ng ml . This is a lower pate. The majority of dogs in both groups percentage than for humans (Plumb 2002). (anxious patients with and without aggres- The half‐lives of diazepam and its two pri- sion) showed improvement over time. mary metabolites are shown in Table 7.4. Greater improvement in clinical signs was Diazepam undergoes extensive first‐pass observed for anxious non‐aggressive dogs. hepatic metabolism when given orally. In the The authors suggested that benzodiazepines liver, diazepam is changed into multiple might not be an ideal choice for the treat- metabolites, including desmethyldiazepam ment of fear aggression, in agreement with (nordiazepam), temazepam, and oxazepam. Crowell‐Davis (2008). In dogs given an intravenous injection of 1 mg kg−1 of diazepam, about 61% of it is V. Diazepam excreted in the urine while about 34% is

Chemical Compound: 7‐Chloro‐1,3‐dihydro‐1‐ Table 7.4 Half‐life of diazepam, in hours, and some methyl‐5‐phenyl‐2H‐1,4‐benzodiazepin‐ of its metabolites in the dog, cat, and horse. 2‐one DEA Classification: DEA Class IV non‐ Benzodiazepine Dog Cat Horse narcotic agent Preparations: Generally available as 2‐, 5‐, Diazepam 2.5–3.2 5.5 7–22 and 10‐mg tablets. Also available as a 1 Nordiazepam 3.6–10 21.3 12 and 5 mg ml−1 suspension for oral administration and a 5 mg ml−1 injectable solution. Oxazepam 3.5–5.7 18–28 Rectal gels are available in 2.5‐, 5‐, 10‐, 15‐, Source: Löscher and Frey (1981), Norman et al. (1997), and 20‐mg sizes. Shini et al. (1997), Plumb (2002). Clinical Pharmacology 81 excreted in the feces, either as diazepam or, and Nauss 2011). When dogs were given predominantly, as a metabolite. In humans, 25 mg kg−1 of diazepam per day for 10 days, no only about 10% of diazepam is excreted in the diazepam was subsequently found in urine feces, again predominantly as a metabolite. In extracts. In these dogs, the main pathway of contrast to dogs and humans, diazepam given metabolism of diazepam was N‐demethylation to rats is excreted predominantly through the and hydroxylation, followed by excretion as feces, whether it is given intraperitoneally or oxazepam glucuronide. While oxazepam can orally (Schwartz et al. 1965). Thus, the exact be conjugated with glucuronic acid, diazepam metabolism of diazepam varies between spe- has first to be hydroxylated in order to pro- cies. This variation happens at many levels duce a compound that can subsequently be and may account for much of the variation in excreted as a glucuronide (Ruelius et al. 1965). clinical response. Dogs chronically administered doses of 0.56, In the cat, the half‐life of diazepam is 4.5, 9, or 36 mg kg−1 daily of diazepam exhibit approximately 5.5 hours, and the half‐life of a linear relationship between total plasma nordiazepam is 21.3 hours (Plumb 2002). levels and brain levels of diazepam, nordiaz- There is an initial rapid increase in levels of epam, and oxazepam, and the chronic dose of nordiazepam for two hours after intravenous diazepam. At higher doses, there is more free injection of diazepam, with about 54% of nordiazepam and oxazepam, and less free diazepam being biotransformed to nordiaz- diazepam in the plasma, cerebrospinal fluid, epam (Cotler and Gustafson 1978; Cotler and brain (Wala et al. 1995). et al. 1984). After this, nordiazepam levels The half‐life of diazepam is 7–22 hours in are maintained within 50% of peak nordiaz- the horse. The half‐life of nordiazepam is epam levels for 24–48 hours. Approximately 18–28 hours while the half‐life of oxazepam, 70% of diazepam given by intravenous injec- another active metabolite, is 12 hours tion is excreted in the urine, 50% as known (Norman et al. 1997; Shini et al. 1997; Plumb metabolites. Approximately 20% is excreted 2002). Peak levels of diazepam occur in the in the feces, 50% of that as nordiazepam serum 40 minutes after an intramuscular (Cotler and Gustafson 1978). Diazepam is injection of a dose of 10 mg per horse. fatal to cats within one day when given at a Diazepam is not detected in horse serum dose of 500 mg kg−1 PO (Randall and Kappell more than six hours after administration. 1973) but hepatic failure is also documented Nordiazepam levels in the serum peak three in therapeutic doses (Park 2011; Beusekom hours after administration of diazepam. The et al. 2015). A study by Beusekom et al. (2015) metabolites oxazepam and temazepam can shed light on how hepatic CYP450‐mediated be found in the urine up to 121 and 79 hours, biotransformation of diazepam differs respectively, after injection of diazepam, but between cats and dogs. Cats have a limited are not found in the serum after administra- capacity to glucuronidate diazepam hydroxyl tion by assays that do not detect levels below metabolites. 1.1 ng ml−1. Overall, diazepam is excreted in Diazepam is rapidly metabolized in dogs, the urine mainly as oxazepam (37%), temaz- with a half‐life of 2.5–3.2 hours while the half‐ epam (33%), and nordiazepam (29%), with life of nordiazepam is 3.6–10 hours (Vree <0.2% being excreted as diazepam (Marland et al. 1979; Löscher and Frey 1981). The et al. 1999). More recent studies by Hayami metabolite oxazepam reaches maximal et al. (2013) and Nakayama et al. (2016) show plasma concentration in about two hours, temazepam as the major metabolite pro- then declines with a half‐life of about duced from microsomial reactions in the 3–5.7 hours (Vree et al. 1979; Löscher and liver. CYP3A seems to be the main enzyme Frey 1981). Greyhounds seem to metabolize responsible for the metabolism of diazepam diazepam and its metabolites in a slower fash- (Nakayama et al. 2016). Measurements ion, but further studies are required (Kukanich of various cardiopulmonary parameters in 82 Benzodiazepines

horses given clinically usual doses of diaze- Lower doses should be used in patients pam intravenously have identified few with compromised liver or renal function significant changes. Doses greater than and in geriatric or debilitated patients. 0.2 mg kg−1 IV are likely to induce recum- Diazepam may cause loss of inhibitions and bency in this species due to muscle relaxant result in increased aggression in aggressive properties (Muir et al. 1982; Matthews et al. patients. Its use should be avoided in working 1991; Kerr et al. 1996). animals, for example, drug detection dogs, In rabbits, there are multiple metabolites because their ability to perform their working with the primary metabolite being oxazepam tasks may be compromised. Extreme caution (Jommi et al. 1964; Sawada et al. 1976). should be used in giving riding and driving Comparison of research on guinea pigs, rats, horses diazepam since the muscle rabbits, and mice demonstrates the existence fasciculations, ataxia, and sedative properties of substantial interspecies variation in metab- may be dangerous. olism. Rat liver predominantly hydroxylates The use of diazepam in cats should be diazepam in the C3 position and only slightly avoided as hepatic failure has been causes N‐demethylation; mouse liver predom- documented even in therapeutic doses (Park inantly N‐demethylates, but does hydroxylate, 2011; Beusekom et al. 2015). Longer‐acting whereas in the guinea pig only N‐demethyla- benzodiazepines without active metabolites tion occurs. Rabbits, like mice, predominantly (clonazepam, lorazepam, and oxazepam) are demethylate but hydroxylate to some degree. a safer option for this species (author’s note). The major metabolite of diazepam in blood, Diazepam crosses the placental barrier and brain, and adipose tissue of guinea pigs is N‐ enters the milk. There is an increased risk of demethyldiazepam. Oxazepam is not a signifi- congenital malformations when diazepam is cant metabolite in this species, but it is in the given during the first trimester of pregnancy. mouse (Jommi et al. 1964; Marcucci et al. 1969; Therefore, its use should be avoided in Marcucci et al. 1970a, 1970b; Marcucci et al. pregnant and lactating females (Roche 1971; Mussini et al. 1971). Laboratories 2000). Bergamottin, a furanocoumarin that occurs in grapefruit juice, reduces the activity Side Effects of the P450 enzymes CYP3A12 and CYP1A1/2, Side effects include ataxia, sedation, concurrently causing an increase in plasma increased appetite, paradoxical excitation, levels of diazepam in dogs, but not in Wistar transient cardiovascular depression, muscle rats (Sahi et al. 2002). relaxation, increased friendliness, anxiety, apparent hallucinations, muscle spasticity, Uses in Humans insomnia, and idiopathic hepatic necrosis in Diazepam is used in humans for the relief of cats. Idiopathic hepatic necrosis in cats is symptoms of anxiety and management of discussed further below. There have been anxiety disorders. It is also used in the treat- occasional reports of neutropenia and ment of convulsive disorders, for relief of jaundice in humans. Muscle fasciculations skeletal muscle spasms, and for symptomatic may occur in horses given diazepam. relief of acute alcohol withdrawal. The rate of metabolism may be decreased if diazepam is given concurrently with other Contraindications medications that compete with it for the Diazepam is contraindicated when there is a P450 isoenzyme system by which it is known hypersensitivity of the patient to the metabolized, including the selective seroto- drug, in patients with glaucoma, and in cats nin reuptake inhibitors. that have been exposed to the insecticide Reproduction studies on rats given 1, 10, chlorpyrifos, because diazepam may potenti- 80, and 100 mg kg−1 daily of diazepam during ate organophosphate toxicity (Plumb 2002). pregnancy resulted in lowered pregnancy Clinical Pharmacology 83 rates and surviving offspring in rats given camera should be positioned to evaluate 100 mg kg−1. There were no teratological whether or not this dose of medication is effects, lowered pregnancy rates, or reduced effective in treating the behavioral signs. As survival of offspring given up to 80 mg kg−1 stated before, making sure that the house is (Beall 1972). In humans, however, research proofed against potential accidents (such as has suggested a risk of congenital malforma- blocking the animal’s access to stairs, coun- tions when diazepam is used during the first tertops, balconies, etc.) should be highlighted. trimester. Because diazepam crosses the If the dose is insufficient, the dose can gradu- placenta and enters the milk, its use should be ally be increased over a period of days until a avoided in pregnant and lactating females of clinically effective dose is identified or unde- all species. sirable side effects occur. If the anxiety is −1 The oral LD50 in rats is 1240 mg kg and in effectively controlled before significant side mice is 720 mg kg−1 (Roche Laboratories effects occur, the dose that accomplishes this −1 2000). The oral LD50 in rabbits is 328 mg kg result can then be used. If significant side (Randall et al. 1965). effects occur before effective treatment is accomplished, then the use of this particular Overdose medication in the patient must be Immediate gastric lavage and supportive reevaluated. measures should be conducted. Administer intravenous fluids and maintain an open air- Discontinuation way. Flumazenil, a benzodiazepine receptor Patients that have been treated with diaze- antagonist, can be used to completely or par- pam on a daily basis for several weeks should tially reverse the effects of an overdose. be gradually withdrawn. Diazepam is more Treatment with flumazenil may result in addicting than some of the other benzodiaz- seizures, especially in patients that have fre- epines, such as lorazepam and oxazepam. quently been given diazepam for a long period of time. Other Diazepam appears to interfere with the Doses in Nonhuman Animals acquisition of new learning, but not with the Initiate treatment for nonhuman animals at recall of material already learned (e.g. the lowest dose. If no undesirable side effects Ghoneim et al. 1984). occur, titrate dose up to the desired effect. Diazepam is commonly used in the There is a wide range of clinically effective treatment of seizure disorders in various doses for diazepam in veterinary populations. species. A detailed discussion of this use is As discussed above under clinical guidelines beyond the subject of this book. for benzodiazepines, an initial test dose of the Protein malnutrition has been shown to lowest usual dose for the species should be induce alterations in the GABAergic neuro- given when the owners will be home to transmitter system and produce hyper‐ observe the pet for sensitivity to the medica- reactivity to the effects of diazepam in male tion. This guideline is mentioned because Wistar rats used as model of anxiety (Françolin‐ diazepam is often used to treat anxiety prob- Silva et al. 2007). It is well established that lems for which symptoms may be exhibited malnutrition imposed early in life produces primarily or entirely when the owners are morphological, neurochemical, neurophysio- absent. If the pet does not exhibit untoward logical, and functional alterations in the brain side effects, this dose can then be used in the of rats (Morgane et al. 1993; Tonkiss et al. 1993; context of the situation for which the medica- Almeida et al. 1996a, 1996b, 1996c). tion is being used, for example, storms or Considering the significant population of dogs being alone. If humans will not be present, as and cats adopted at shelters and animal control is the case with separation anxiety, a video facilities that have been in a situation of neglect 84 Benzodiazepines

in the first weeks or months of life, studies that Eleven of the cats had previously been treated investigate what a less than ideal upbringing with synthetic progestins. All of those cats causes in the brain of companion animals responded to diazepam. However, 75% of the (prone to need psychoactive medication to cats that had responded well relapsed at a treat behavior and brain pathologies) are later date. Side effects observed by Marder shockingly lacking. were increased affection, lethargy, increased appetite, and ataxia. Cooper and Hart (1992) also evaluated the Effects Documented in Nonhuman Animals effect of diazepam on spraying. Their Cats subjects were 14 castrated males and 6 A single oral dose of diazepam has no promi- spayed females. Diazepam was given at nent behavioral effects at a dose of 0.2 mg kg−1. 1–2 mg/cat q12h for two weeks. If spraying A mixture of ataxia, muscle relaxation, was eliminated or reduced to the client’s increased playfulness, and exploratory satisfaction, this dose was continued for an behavior occurs at a single oral dose of additional six to eight weeks. If the cat still 1 mg kg−1. Interestingly, the higher of these sprayed, however, the dose was increased two doses produces increased wakefulness 50% for an additional two weeks. If the cat and decreased REM sleep during the one‐ to responded favorably at the higher dose, four‐hour period after administration, while treatment was continued for another six to the lower dose produces no change in wake- eight weeks. If the cat still sprayed at the fulness when compared with placebo higher dose, it was weaned off medication (Hashimoto et al. 1992). over a two‐week period. For the cats that Captive feral cats injected with 1 mg kg−1 of responded to the 1‐ or 2‐mg q12h doses, diazepam exhibit decreased defensive aggres- treatment continued for 8 to 12 weeks, after sion but have no change in flight behavior which the cat was weaned off medication. If, (Langfeldt and Ursin 1971). during weaning, a cat resumed spraying, Spraying urine is a common behavior dosage was increased back to the previously problem in cats, affecting about 10% of pre- effective dose. Some cats were treated for pubertally castrated males and about 5% of four years. Eleven out of 20 cats responded prepubertally neutered females (Hart and by complete cessation or decrease to a level Cooper 1984). While the causes and function that was acceptable to the owner. However, of spraying are poorly understood, the behav- 10 of those 11 resumed spraying when ior often decreases or ceases if an anxiolytic treatment was discontinued. Eleven of the is administered. Marder (1991) gave 19 cas- initial 20 cats had previously been trated male cats and 4 spayed female cats treated ineffectively with progestins. Five of with problems of spraying behavior 1 mg these responded to diazepam. Side effects q12h. If spraying did not cease after three observed in this study included sedation, days, the dose was increased to 2 mg q12h. ataxia, increased appetite, weight gain, Treatment was continued for one month, reduced aggression, and a calmer and more at which point the dose was halved. affectionate temperament. Treatment with Subsequently medication was gradually buspirone has subsequently been found reduced at weekly intervals until the cats to result in a lower recidivism rate than treat- were off medication one month after begin- ment with diazepam. See the discussion of ning to decrease the dose. Success was buspirone in Chapter 9. defined as at least a 75% reduction and owner Overall (1994a) treated a spraying cat with satisfaction at a 1‐ to 10‐month follow‐up. diazepam 1 mg q12h PO with initial success. Sixteen out of the 19 castrated males exhib- However, the cat could not be weaned off of ited reduced spraying, while one out of the medication without recurrence of the prob- four females exhibited reduced spraying. lem, and the spraying gradually recurred over Clinical Pharmacology 85 a one‐year period. An increase to 2 mg q12h Dogs was likewise initially successful, for three Dogs medicated with increasing doses of months, but was again followed by relapse. diazepam until they started losing weight did −1 −1 This cat was later treated with buspirone with so at doses of 20–36 mg kg day after greater success, although the cat could not be 11–29 days on the increasing dose regimen weaned off of medication (Overall 1994a). (Martin et al. 1990; Sloan et al. 1991). Acute In the cat, about 50% of diazepam is trans- withdrawal of these dogs, precipitated by formed into nordiazepam. Several clinicians administering flumazenil, results in tremors, have documented acute onset of hepatic twitches, jerks, and seizures (Martin et al. necrosis in cats given diazepam (Levy 1994; 1990; Sloan et al. 1991). Dogs given 0.05625, −1 −1 Levy et al. 1994; Center et al. 1996; Hughes 0.225, 0.5625, 4.5, 9, or 36 mg kg day of et al. 1996). Onset was usually eight to nine diazepam exhibited dose‐dependent varia- days after daily medication with diazepam tion in both the quantity and quality of symp- was initiated. Initial signs include anorexia, toms that occurred when acute withdrawal vomiting, dehydration, lethargy, hypothermia, was precipitated by administration of fluma- jaundice, and coma (Center et al. 1996). Most zenil. At the two lowest doses, only minimal affected cats have died, usually within signs were precipitated. Seizure activity 24 hours, even with vigorous supportive ther- occurs only with dogs at the two highest −1 apy, but some have survived (Levy et al. 1994). doses of 9 and 36 mg kg day, both of which The exact cause is unknown. Speculations are well above routinely used clinical doses have included: (i) a toxic intermediate metab- (Sloan et al. 1993). olite produced by some cats; and (ii) a toxic All four of four laboratory beagles treated substance incorporated into the pill during for abnormal withdrawn and depressed −1 manufacture. The latter hypothesis is ques- behavior resolved on 2.5 mg kg of diazepam tionable due to the hepatic necrosis having (Iorio et al. 1983). occurred with multiple different brands of Diazepam has been reported to be more diazepam (Center et al. 1996). Hughes et al. effective than chlorpromazine in reducing (1996) reviewed the premedication health sta- signs of fear in dogs (Hart 1985). tus of six cats that developed hepatic necrosis In a study that investigated developing and subsequent to medication with diazepam. In validating a laboratory model of noise‐ all cases, the cat had prior cardiac, pancreatic, induced fear and anxiety in dogs using open‐ or renal disease. Current recommendations field and thunderstorm tests, diazepam for the use of diazepam in cats are to do a decreased inactivity (freezing‐like behavior) baseline physical exam, complete blood count duration in both test naïve and experienced (CBC), and blood chemistries to confirm that subjects (Araujo et al. 2013). the cat is in good health. Repeat the blood Ibáñez and Anzola (2009) evaluated the use chemistries at three to five days. If there is of fluoxetine, diazepam and behavior modifi- elevated ALT or aspartate transferase (AST), cation for the treatment of various anxiety discontinue the medication (Center et al. disorders in dogs (with and without aggres- 1996). While hepatic necrosis in response to sive behavior). Diazepam was administered −1 treatment with diazepam is usually fatal, the orally at a dosage of 0.3 mg kg once a day for problem itself is rare. Some clients who have 4 weeks and fluoxetine was administered −1 cats for which diazepam is otherwise a good orally at a dosage of 1.0 mg kg once a day for choice, and for whom cost is a significant 10 weeks. Thirty‐four dogs completed the issue, may wish to try diazepam without mon- study and clinical improvement was reported itoring of liver function. In all cases, however, in 76% of them. Increased aggression was not the client should be informed of the rare, but reported in any of the subjects, including present, potential for a fatal consequence with those with aggression as part of the initial this drug. clinical presentation. 86 Benzodiazepines

In a cross‐sectional study of 37 dogs with Other Species behavior pathologies and their owners, Diazepam decreases fear in the marmoset Herron et al. (2008) investigated the effects (Callithrix penicillata) when exposed to a −1 and adverse effects of diazepam and the own- potential predator. Doses of 1 mg kg IM er’s perception of treatment. Diazepam was produce only a small reduction in behaviors considered as very (24%) or somewhat (43%) considered indicative of fear. Doses of −1 effective by most owners. Reasons reported 2 mg kg IM produce a much stronger for discontinuation of treatment included anxiolytic effect without a significant sedative −1 adverse effects (58%) and lack of efficacy effect. Doses of 3 mg kg IM produce a (53%). Adverse effects reported were sedation, sufficient sedative effect that overall activity increased appetite, ataxia, agitation, increased levels are compromised (Barros et al. 2000). activity, vomiting, diarrhea, and aggression. Diazepam has been used to tame monkeys at a dose of 1 mg kg−1 (Zbinden and Randall Horses 1967). Within social colonies of rhesus −1 Sexual behavior in stallions can be inhibited monkeys, diazepam (2.5–5 mg kg by mouth both by a novel environment and by classical daily) produces dose‐dependent increases in conditioning. Sexual behavior has been shown social grooming, approach, contact, self‐ to be normalized by slow intravenous injec- grooming, feeding, and resting with the eyes tion of 0.05 mg kg−1 of diazepam (McDonnell open. There is also decreased vigilance and et al. 1986, 1987; McDonnell 1999). aggression (Kumar et al. 1999). Performance horses are sometimes given In an experiment that investigated the diazepam as an anxiolytic and muscle relaxant, behavioral consequences of exposing male a practice which is generally illegal (Jaussaud Wistar rats to a live cat (using the elevated and Courtot 1990). Medication of a horse with T‐maze test of anxiety), administration of −1 diazepam can be detected at least 38 days later diazepam at 2 mg kg decreased the using gas chromatography‐high resolution immediate avoidance response to the cat and mass spectrometry (Jouvel et al. 2000). the neophobic reaction to a dummy cat used as a control stimulus (Bulos et al. 2015). Parrots Diazepam (1 mg kg−1) increased feeding Diazepam has been suggested as a treatment behaviors and movement in a group of wild‐ for feather‐picking at a starting dose of two caught Hemignatus virens during a short drops of the 5 mg ml−1 solution per ounce of period in captivity (Gaskins et al. 2008). drinking water, with subsequent increases in dose until feather‐picking discontinues or the VI. Flurazepam Hydrochloride bird becomes excessively sedated. However, no data on results are presented (Galvin 1983) Chemical Compound: 7‐Chloro‐1‐[2‐(diethyl- and it has been discussed that diazepam’s amino)ethyl]‐5‐(o‐fluorophenyl)‐1,3‐ sedative effects may be detrimental to such dihydro‐2 H‐1,4‐benzodiazepin‐2‐one‐ patients, suggesting that it is probably more dihydrochloride appropriate to suppress acute self‐mutilation DEA Classification: DEA Schedule IV drug episodes and not indicated for chronic treat- Preparations: Generally available as 15‐ and ment (Johnson 1987). 30‐mg capsules.

Rabbits Clinical Pharmacology Diazepam given to rabbits at a dose of 0.05– Flurazepam is rapidly absorbed from the 0.1 mg kg−1 decreases behavioral arousal as gastrointestinal (GI) tract, rapidly measured by electroencephalogram (Goldberg metabolized, and excreted primarily through et al. 1974). When given at doses of the urine. In humans, peak flurazepam 0.6 mg kg−1 day−1 PO for 30 days, it has no effect plasma concentrations occur 30–60 minutes on blood sugar levels (Dixit et al. 2001). after a single oral dose. The half‐life in Clinical Pharmacology 87 humans is 2.3 hours. In humans, its major to treatment with flurazepam have been metabolite is N1–desalkyl‐flurazepam with a reported in humans (Fang et al. 1978; half‐life of 47–100 hours. The long half‐life of Reynolds et al. 1981). Blurred vision has been this metabolite may be responsible for the reported in humans (Roche Laboratories clinical observation that flurazepam is 1994). While subtle changes in vision are increasingly effective on the second and third difficult to detect in nonhuman patients, this nights of consecutive use and that efficacy should be kept in mind if significant difficulty continues for one to two nights after discon- navigating the environment occurs after tinuation (Roche Laboratories 1994). administration of flurazepam. In humans, older men have a longer Rebound insomnia can occur with discon- elimination half‐life of desalkyl‐flurazepam tinuation. However, it is less likely to occur than younger men, after both single dose and than with shorter‐acting benzodiazepines multiple dose treatment. There is no such as triazolam (Rickels 1983). difference between older women and younger women (Roche Laboratories 1994). Overdose Whether this age/gender interaction exists in In case of overdose, conduct gastric lavage nonhuman patients has not been tested. and provide supportive measures, including When dogs are given 14C‐labeled fluraze- intravenous fluids. Flumazenil, a benzodiaze- pam at a dose of 2 mg kg−1 PO or IV, fecal pine receptor antagonist, is indicated for the excretion predominates, and over 80% is complete or partial reversal of flurazepam eliminated by either route within nine days toxicity. (Schwartz and Postma 1970). Flurazepam is fatal to cats within one hour Doses in Nonhuman Animals when given at a dose of 400 mg kg−1 PO Initiate treatment at the lowest dose. If no (Randall and Kappell 1973). undesirable side effects occur, titrate the dose up to the desired effect. Uses in Humans Flurazepam is used to treat insomnia. Effects Documented in Nonhuman Animals Flurazepam may be a preferred benzodiaze- Contraindications pine for pets that wake during the night due Flurazepam is contraindicated in patients to its long half‐life (Landsberg et al. 2003). with known hypersensitivity to this drug or There are no reports of clinical studies on the other benzodiazepines. use of flurazepam in the treatment of pets. Flurazepam crosses the placenta and also enters milk. Its use should therefore be VII. Lorazepam avoided in pregnant and lactating females. Chemical Compound: 7‐Chloro‐5‐(o‐ Side Effects chlorophenyl)‐1,3‐dihydro‐3‐hydroxy‐ Side effects are similar to those reported for 2H‐1,4‐benzodiazepine‐2‐one other benzodiazepines and include sedation DEA Classification: DEA Schedule IV drug and ataxia. Flurazepam has not been as Preparations: Generally available in 0.5‐, 1‐, extensively used in nonhuman patients as and 2‐mg tablets and 2 mg ml−1 oral solution. some of the other benzodiazepines. Therefore, it is likely that some probable side Clinical Pharmacology effects have not yet been reported. Lorazepam is identical to oxazepam except Rare cases of leucopenia, granulocytope- that it has a chlorine atom on the phenyl ring nia, elevated AST/ALT, elevated total/direct (Elliott 1976). Absorption of lorazepam is bilirubin, elevated alkaline phosphatase, and fairly rapid, except in the cat (Ruelius 1978). skin rashes have been reported in humans. In humans, peak concentrations in the Two cases of cholestatic jaundice secondary plasma occur in approximately two hours. 88 Benzodiazepines

The time to peak plasma levels of lorazepam and cats excrete it roughly equally in urine and in the cat, dog, pig, and rat is given in Table 7.5. feces (Ruelius 1978). Six days after a single In humans, the mean half‐life for lorazepam is dose of 1 mg kg−1 lorazepam PO, cats will have about 12 hours, while the half‐life for its major excreted about 47% in the urine and about metabolite, lorazepam glucuronide, is about 54% in the feces (Schillings et al. 1975). In a 18 hours. In African green monkeys, the mean species, no gender effect has been identified in half‐life of lorazepam is 1.7 hours (Friedman the qualitative urinary excretion pattern et al. 1991; Wyeth Laboratories Inc. 1999b). (Schillings et al. 1971; Schillings et al. 1975). Lorazepam glucuronidate is the primary No changes in urinary excretion patterns have metabolite in the dog, cat, human, and pig, been identified in dogs, pigs, rats, and humans but not in the rat (Schillings et al. 1971). treated with lorazepam for periods of five to Lorazepam glucuronidate has no significant eight weeks (Schillings et al. 1971). CNS activity (Gluckman and Stein 1978). Peak In rats, about three times as much loraze- plasma levels of unchanged lorazepam are pam occurs in the brain as in plasma for about almost identical in humans and dogs when 0.5–12 hours after dosing (Ruelius 1978). dogs are given a dose about 30 times higher Both lorazepam and lorazepam glucuron- than a human on a per kilogram basis. This is ide are transferred by the placenta (Wyeth because formation of lorazepam glucuronide Laboratories Inc. 1999b). is much faster in dogs than in humans (Ruelius There is good separation between anxiety‐ 1978). Cats do glucuronidate lorazepam, but reducing doses and sedative‐hypnotic doses not as rapidly or extensively as dogs. However, (Gluckman and Stein 1978). the finding that cats form the glucuronide is unexpected, because they often conjugate Uses in Humans exogenous molecules with glucuronic acid Lorazepam is used for the short‐term relief poorly or not at all (Ruelius 1978). of symptoms of anxiety and for management When cats are given a single dose of 1 mg kg−1 of anxiety disorders in humans. PO, plasma levels of unconjugated lorazepam peak at 12 hours and then begin declining, Contraindications with a half‐life of 17 hours. Plasma levels of Lorazepam is contraindicated in patients conjugated lorazepam run at about one‐third with a history of sensitivity to lorazepam or to one‐half the levels of unconjugated loraze- other benzodiazepines and in patients with pam in this species (Schillings et al. 1975). acute narrow angle glaucoma. It should be Dogs and pigs excrete lorazepam primarily used with extreme caution in aggressive in the urine, rats predominantly in the feces, animals because it may cause disinhibition

Table 7.5 Peak plasma levels and percentage of lorazepam eliminated in the urine and feces of cats, dogs, rats, and pigs.

Time to peak Peak plasma Eliminated plasma concentration in the urine Eliminated in Species Dose concentration (ng ml−1) (%) the feces (%)

Cat 20 mg kg−1 PO 12 9310 47.3 54 Dog 1 mg kg−1 PO 0.5 28 66.4 22 Pig 0.04 mg kg−1 PO 3 1.2 87.8 7.9 Rat 1 mg kg−1 IG 0.5 108 21.7 68.9

Source: Ruelius (1978). Clinical Pharmacology 89 and in pregnant or nursing females because it at 16 days of treatment, and subsequently for may cause fetal malformations and loss, and another 52 days, did not lose weight but did is probably transmitted through the milk. become physically addicted to lorazepam. However, in dogs, physical dependence on Side Effects lorazepam was found to be less intense than As with all benzodiazepines, sedation, ataxia, was physical dependence on some other muscle relaxation, increased appetite, para- benzodiazepines such as diazepam (Martin doxical excitation, increased friendliness, anx- et al. 1990). iety, and a variety of other side effects may occur. When they occur, side effects are usu- Primates ally observed early in therapy and disappear Lorazepam reduces anxiety and conflict with continued treatment or a decreased dose. behavior in squirrel monkeys (Stein and No evidence of carcinogenesis has been Berger 1971; Gluckman and Stein 1978). identified. In rabbits used to study effects on In social colonies of rhesus monkeys, loraz- reproduction, random anomalies of various epam (0.5–1.0 mg kg−1 PO daily) produces sorts occurred at all doses. At doses of dose‐dependent increases in social groom- 40 mg kg−1 fetal resorption and increased ing, approach, contact, self‐grooming, feed- fetal loss occur in rabbits (Wyeth Laboratories ing, and resting with the eyes open. There is Inc. 1999b). also decreased vigilance and aggression (Kumar et al. 1999). Overdose If an overdose occurs, induce vomiting and/or Rats and Mice conduct gastric lavage. Provide supportive ther- Lorazepam reduces conflict behavior in apy as needed. Flumazenil may be used to par- rats. In mice, it suppresses foot shock‐ tially or fully reverse the effect of lorazepam. induced fighting behavior (Gluckman and Stein 1978). Rats treated with lorazepam at Doses in Nonhuman Animals 1.25 mg kg−1 day−1 for over a year have Initiate treatment at the lowest dose. If no shown no adverse effects. However, rats undesirable side effects occur, titrate dose up treated at 6 mg kg−1 day−1 for the same to effect. While variation between individu- period of time developed esophageal als and species makes exact comparison dilation. The esophageal dilation reversed if impossible, 1 mg kg−1 of lorazepam is medication was withdrawn within two about equivalent to 5 mg kg−1 of diazepam months of detection. (Gluckman and Stein 1978). VIII. Oxazepam Discontinuation As with all the benzodiazepines, withdrawal of Chemical Compound: 7‐Chloro‐1,3‐dihydro‐3‐ a patient that has been on lorazepam should be hydroxy‐5‐phenyl‐2H‐1,4‐benzodiazepin‐2‐ accomplished gradually. Dogs that have been one addicted to lorazepam by chronic administra- DEA Classification: DEA Schedule IV con- tion of 100 mg kg−1 day−1 and acutely with- trolled substance drawn by administration of flumazenil exhibit Preparations: Generally available as 10‐, tremor, rigidity, and decreased food intake 15‐, and 30‐mg capsules and as 15‐ and 30‐ (McNicholas et al. 1983). mg tablets.

Effects Documented in Nonhuman Animals Clinical Pharmacology Dogs Oxazepam has no active intermediate Dogs given an increasing dose of lorazepam metabolites and therefore may be safer for until they reached a dose of 140 mg kg−1 day−1 patients with liver disease, obese patients, 90 Benzodiazepines

and geriatric patients than some of the other The acute oral LD50 in mice is more than benzodiazepines. An inactive glucuronide 5000 mg kg−1. conjugation of oxazepam is the primary metabolite, accounting for over 95% of uri- Uses in Humans nary metabolites in pigs and humans and Oxazepam is used for the management of anxi- likewise being the primary metabolite in ety disorders and for the short‐term ameliora- rabbits (Sisenwine et al. 1972; Sawada et al. tion of anxiety symptoms that occur with or 1976). There are at least six other minor without depression. It is considered to be espe- metabolites that account for <5% of the uri- cially useful in the treatment of anxiety, tension, nary metabolites in these species. In the rat, agitation, and irritability in geriatric patients. conjugated oxazepam is a minor metabolite, and conversion to inactive metabolites that Contraindications are minor in humans and pigs is conversely Oxazepam is contraindicated in patients with greater (Sisenwine et al. 1972). a history of hypersensitivity to this or other In human studies, absorption has been benzodiazepines. Because it crosses the pla- identified as equivalent when oxazepam is cental barrier and enters the milk, it should given as a tablet, capsule, or suspension. not be used in pregnant or lactating females. Mean elimination half‐life is approximately 8.2 hours, while peak plasma levels occur at Side Effects about 3 hours after oral dosing in humans As with all benzodiazepines, sedation, ataxia, (Wyeth Laboratories Inc. 1999a). and temperament changes due to loss of In dogs given 5–10 mg kg−1 PO of C14‐ inhibition may occur. labeled oxazepam, peak plasma levels Rarely, leucopenia and hepatic dysfunction occur in 4–6 hours, with some drug, or a have been reported in humans treated with metabolite, remaining in the system for at oxazepam. Fetal abnormalities have not been least 120 hours. Twenty‐four hours after observed in rats subjected to breeding stud- administration, about three‐quarters of the ies of oxazepam. total dose are excreted. At 96 hours (four Rats given oxazepam as 0.5% of their diet days) after administration, urinary excre- for six weeks exhibit fatty metamorphosis of tion has accounted for about 68% of the the liver without necrosis or fibrosis. C14, while fecal excretion has accounted for Mice given 35 or 100 times the human dose about 35% of the C14 (Walkenstein et al. of oxazepam for nine months exhibit dose‐ 1964). related increases in liver adenomas (Fox and Oxazepam exerts an anticonvulsant effect Lahcen 1974). Rats given 30 times the human in 50% of mice given a dose of 0.6 mg kg−1 maximum dose over two years showed an orally, while ataxia is observed in 50% of mice increase in benign thyroid follicular cell given a dose of 5 mg kg−1 orally. Thus, there is tumors, testicular interstitial cell adenomas, a wide separation of effective doses and doses and prostatic adenomas. There is no evidence that induce side effects. There is also a that clinical use of oxazepam is carcinogenic. significant dose separation between effective antianxiety levels in rats subjected to shock Overdose and the doses required to produce motor In case of an overdose, induce vomiting and/ incoordination. or conduct gastric lavage. Provide supportive Oxazepam has a larger spread than either treatment. Flumazenil can be used to par- chlordiazepoxide or diazepam between the tially or fully reverse the effect of oxazepam. minimal effective dose and the dose that causes side effects. It causes better anxiolytic Doses in Nonhuman Animals effects with less depressant effects as well Initiate treatment at the lowest dose for (Gluckman 1965). nonhuman animals. If no undesirable side Clinical Pharmacology 91 effects occur, titrate the dose up to the Clinical Pharmacology desired effect. Triazolam has a short plasma half‐life, 1.5– 5.5 hours in humans. The initial step in Discontinuation metabolism is hydroxylation, which is cata- As with all benzodiazepines, dose reduction lyzed by cytochrome P450 3A (CYP 34A). should be done gradually for patients that have The primary metabolites are conjugated glu- been medicated daily for several weeks. curonides, which are presumably inactive. However, oxazepam is less addicting than some Both triazolam and its metabolites are other benzodiazepines, such as diazepam. excreted primarily in the urine (Pharmacia and Upjohn 1999). Other Information When triazolam is administered orally to Some research in humans has suggested that pregnant mice, it is uniformly distributed in oxazepam may be more effective than the fetus. The fetal brain develops chlordiazepoxide in treating aggression approximately the same concentration in the (Gardos et al. 1968; Kochansky et al. 1975). brain as does the mother (Pharmacia and Upjohn 1999). Effects Documented in Nonhuman Animals Initially, triazolam decreases latency to Cats sleep and number of nocturnal awakenings Oxazepam is used as an appetite stimulant in and increases the duration of sleep. However, cats, with a longer duration of action than after two weeks of consecutive nightly doses, diazepam (Landsberg et al. 2003). its efficacy decreases. On the first and/or second night after discontinuation from two Dogs weeks of continuous use, a rebound effect Dogs given increasing doses of oxazepam to occurs, with the total time asleep becoming 270 mg kg−1 by day 72 of treatment, and less than at baseline (Pharmacia and Upjohn subsequently given this dose for an additional 1999). 30 days, did not lose weight. While chronic administration of oxazepam at such a high Uses in Humans dose did produce physical dependence, the Triazolam is used for the short‐term dependence was not as intense as with some (7–10 days) treatment of insomnia in humans. other benzodiazepines such as diazepam (Martin et al. 1990). Contraindications Dogs given 480 mg kg−1 daily for four weeks Triazolam is contraindicated in any patient showed no specific changes. Two of eight with a history of sensitivity to this or other dogs given 960 mg kg−1 died with evidence of benzodiazepines. Triazolam should not be circulatory collapse. In chronic toxicity given concurrently with any medications that studies, dogs given 120 mg kg−1 day−1 for substantially impair metabolism mediated by 52 weeks exhibited no toxic effects. Thus, cytochrome P450 3A, including ketoconazole, there is a wide margin of safety. itraconazole, and nefazodone (Pharmacia and Upjohn 1999). IX. Triazolam Side Effects Chemical Compound: 8‐Chloro‐6‐(o‐chlo- Interdose withdrawal sometimes produces rophenyl)‐1‐methyl‐4H‐s‐tria‐zolo‐[4,3‐α] daytime anxiety in human patients after as [1,4] benzodiazepine little as 10 days’ treatment with triazolam DEA Classification: DEA Schedule IV con- (Pharmacia and Upjohn 1999). Increased trolled drug anxiety should be considered as a potential Preparations: Generally available as 0.125‐, side effect in nonhuman patients for which 0.25‐, and 0.5‐mg tablet. this short‐acting benzodiazepine is being 92 Benzodiazepines

used to treat night‐time restlessness or cases, significantly increases non‐REM sleep anxiety. (except that at 0.01 mg kg−1 PO it significantly Otherwise, side effects common to the increases REM, rather than non‐REM, sleep) benzodiazepines, including sedation, ataxia, (Scherschlicht and Marias 1983). and temperament changes due to loss of inhibition, may occur. In a 24‐month study of carcinogenesis that Important Information for was conducted on mice given up to 4000 Owners of Pets Being Placed times the recommended human dose, no evi- on Any Benzodiazepine dence of carcinogenesis was identified (Pharmacia and Upjohn 1999). The following should be considered when Overdose placing an animal on a benzodiazepine. Triazolam is a very potent benzodiazepine. 1) Benzodiazepines are fast‐acting, but only Therefore, signs of overdosage may occur at last a few hours. moderate overdoses, for example, four times 2) Some pets become unsteady, sleepy, or the maximum recommended therapeutic excited when on a benzodiazepine. The dose in humans. first dose should be given when the owner In case of overdose, conduct immediate is home and can observe the pet. gastric lavage and provide supportive 3) There is wide variation between individu- treatment. Flumazenil can be used for the als regarding the optimal dose to use to complete or partial reversal of triazolam. treat a particular problem. Also, some pets respond well to one benzodiazepine Doses in Nonhuman Animals but not to another. Pet owners should Initiate treatment at the lowest dose. If no work closely with their veterinarian until undesirable side effects occur, titrate the the best drug and dose for their pet is dose up to the desired effect. identified. 4) If the owner’s pet is medicated with a ben- Effects Documented in Nonhuman Animals zodiazepine for several weeks, withdrawal Rabbits needs to be gradual. Triazolam, at doses of 0.01 or 0.1 mg kg−1 IV 5) Benzodiazepines are DEA Schedule IV or PO given to rabbits, reduces wakefulness drugs. Therefore, special restrictions during the subsequent six hours and, in most apply to their prescription and use.

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Selective Serotonin Reuptake Inhibitors Niwako Ogata1, Leticia Mattos de Souza Dantas2, and Sharon L. Crowell‐Davis2

1 Purdue University, West Lafayette, IN, USA 2 University of Georgia, Athens, GA, USA

Action be informed of this so that they do not have unrealistic expectations. While some The selective serotonin reuptake inhibitors response may be observed within a few days (SSRIs) are a class of antidepressants that of initiation of treatment, improvement inhibit the reuptake of serotonin. This results commonly does not occur for three to four in an increase in serotonergic neuro‐trans weeks, or even longer. Thus, if an SSRI is mission by allowing serotonin molecules to act recommended, caution the client that the for extended periods of time. With prolonged pet’s response to the medication will not be use, there is also down‐regulation of seroto evaluated until it has been on medication nin receptors. Currently the Food and Drug daily for at least one month. SSRIs should Administration (FDA) has approved six of never be given on an “as‐needed” basis, them in human medicine to treat depression: because they will generally be ineffective if citalopram (Celexa), escitalopram (Lexapro), used this way. They can be used in cases of fluoxetine (Prozac), paroxetine (Paxil, Pexeva), specific phobias (such as agoraphobia or and sertraline (Zoloft). Fluoxetine is also avail storm phobia) and are particularly useful in able as an FDA‐approved veterinary product cases of anxiety that occurs pervasively and named Reconcile®. frequently, as in the case of generalized anxi ety disorder (e.g. Gorman 2002). Animals with generalized anxiety disorder exhibit an Overview of Indications almost constant state of low‐level anxiety, regardless of their current environment, and The SSRIs are classified as antidepressants; are hyperreactive to a variety of fear‐induc however, they have anxiolytic, anticompul ing environmental stimuli. sive, and some antiaggressive effects (e.g. Fluoxetine has been used in the treatment of Charney et al. 1990; Coccaro et al. 1990; behavior problems in domestic animals more Kavoussi et al. 1994; Sanchez and Hyttel commonly than any other SSRI. As a conse 1994; Stein and Stahl 2000; Walsh and Dinan quence, there is more information about safety, 2001). It is primarily for these reasons that side effects, and efficacy in various species for they are used in veterinary medicine. The this medication than any other. Following onset of all effects is usually slow, and clients fluoxetine, paroxetine and sertraline have been who have pets on treatment with SSRIs must used the most and are mentioned in various

textbooks, even though there is a lack of clini aggression, mania, decreased libido, hypona cal trials on their use for mental health treat tremia, and seizures. Mild sedation and ment in veterinary medicine. decreased appetite are the most common Common uses for behaviour problems in side effects observed by the authors in dogs. domestic animals include anxiety disorders, Both are typically transient. If the appetite affective aggression, obsessive compulsive decrease is sufficient to cause concern about disorders, and urine marking. They can adequate food intake, temporarily increasing potentially be used for offensive and preda the palatability of the diet and/or hand feed tory aggression (Carrillo et al. 2009). However, ing is usually sufficient to induce adequate medication should never be considered a sub food consumption until this phase passes. stitute for adequate restraint and safety meas Serotonin syndrome is a phenomenon ures for patients with this or any other type of reported in humans. It is a consequence of aggressive behavior. As discussed in Chapter 1, taking excessive quantities of medications that serotonin is involved in the control of aggres increase serotonin levels and/or taking certain sion. Reisner et al. (1996) measured cerebro medications that are incompatible with SSRIs spinal fluid (CSF) levels of 5‐hydroxyindole concomitantly. Signs and symptoms can be acetic acid (5‐HIAA) in 21 dogs with a diagno grossly grouped into mental changes, neuro sis of “dominance” aggression and 19 control muscular changes and autonomic changes. dogs. The dogs with “dominance” aggression Treatment should include decontamination, had significantly lower concentrations of CSF anticonvulsants, thermoregulation, and fluid 5‐HIAA than did the 19 controls (Reisner therapy (Mills 1995; Brown et al. 1996; Martin et al. 1996). When used in the treatment of 1996). This phenomenon is discussed in compulsive disorders, response to serotonin further detail in Chapter 19 (Combinations). reuptake inhibitors (SSRIs) varies with the When mothers are given various SSRIs specific signs of the disorder and the duration (fluoxetine, sertraline, paroxetine, or one of of the problem (Irimajiri et al. 2009). the previous with clonazepam), the neona All SSRIs are metabolized in the liver and tal acute pain response is decreased and excreted through the kidneys. Therefore, pre parasympathetic cardiac modulation during medication blood work to assess the function the recovery period is increased (Oberlander of these organs is recommended. It is also et al. 2002). worth noting that SSRIs can cause urinary incontinence or retention through predomi nant serotonin receptor subtypes at the site Adverse Drug Interactions of action. The excitatory effects on the bladder sphincter seem to be medicated by 5‐HT2 SSRIs are competitive inhibitors of a number receptors, whereas the inhibitory effects on the of cytochrome P450 liver enzymes. Therefor e, bladder seem to be mediated by 5‐HT1 recep if a patient is placed on an SSRI and another tors (Espey et al. 1998; Lowenstein et al. 2007). medication that is metabolized by the P450 There is an indication that the effect might liver enzymes, elevated plasma levels may be various among species (Thor et al. 2002). develop in the medications, potentially result ing in toxic side effects (Albers et al. 2002). To date, there is minimal data on variation Contraindications, Side between breeds and species in the P450 Effects, and Adverse Events enzymes as it relates to the metabolism of var ious psychoactive drugs. Therefore, findings Side effects observed in various species in humans must be substantially relied upon include sedation, tremor, constipation, diar for the time being. Since there is substantial rhea, nausea, anxiety, irritability, agitation, variation, even within the human population, insomnia, decreased appetite, anorexia, it is expected that further studies will also Ciia Guideline 105 reveal substantial variation in veterinary Overdose populations (DeVane 1994). All of the SSRIs can increase levels of In case of overdose, conduct gastric lavage, warfarin due to P450 interactions and due to give activated charcoal, give anticonvulsants competition for plasma protein binding sites. as needed, and provide supportive therapy. Fluoxetine and fluvoxamine are the strong est inhibitors of CYP1A2 and CYP2C9, P450 (both enzymes that metabolize warfarin) Clinical Guidelines (Albers et al. 2002). Fluoxetine, fluvoxamine, sertraline, and SSRIs should generally be given once a day. paroxetine cause significant inhibition of If large doses are required for efficacy, the CYP2D6, which metabolizes amitriptyline, total daily dose can be divided to minimize amphetamine, clomipramine, desipramine, side effects. SSRIs should not be given on a haloperidol, imipramine, and nortriptyline sporadic, as‐needed basis. Efficacy of a given (Crewe et al. 1992; Albers et al. 2002). SSRI on a given patient should not be Fluvoxamine causes the greatest degree evaluated until the patient has been on of inhibition of CYP3A4, which metabo medication daily for at least a month. If, at lizes alprazolam, buspirone, clomipramine, one month, some degree of improvement is clonazepam, and imipramine (Albers et al. observed, the medication should be 2002). continued at the same dose, or at a higher Fluoxetine and fluvoxamine cause the great dose if improvement has been only slight. est degree of inhibition of CYP2C19, which SSRIs may alter blood glucose levels. metabolizes amitriptyline, clomipramine, diaz Therefore, while they can be used with epam, imipramine, and propranolol (Albers diabetic patients, they should be used with et al. 2002). caution, and blood glucose levels should be Fluvoxamine causes the greatest degree of monitored closely. Decreased doses should inhibition of CYP1A2, which metabolizes be used in patients with mild dysfunction of amitriptyline, caffeine, clomipramine, clozap the liver or kidneys. SSRIs should not be used ine, haloperidol, imipramine, and olanzapine, at all in patients with severe dysfunction of in addition to warfarin (Brøsen et al. 1993; the liver or kidneys. There is no relationship Albers et al. 2002). between plasma levels of SSRIs and clinical In addition, SSRIs should not be given with response. Therefore, measuring plasma levels monoamine oxidase inhibitors (MAOIs), is not useful (Albers et al. 2002). Animal because fatal drug interactions can occur. doses are given in Table 8.1.

Table 8.1 Doses of various SSRIs for dogs, cats, horses, and parrots.

SSRI Dog Cat Parrot Horse

Citalopram 0.5–1.0 mg kg−1 Fluoxetine 1.0–2.0 mg kg−1 0.5–1.5 mg kg−1 2.0–5.0 mg kg−1 0.25–0.5 mg kg−1 Fluvoxamine 1–2 mg kg−1 0.25–0.5 mg kg−1 Paroxetine 1.0–1.5 mg kg−1 0.5–1.5 mg kg−1 2.0 mg kg−1 q12h 0.5 mg kg−1 Sertraline 0.5–4.0 mg kg−1 0.5–1.5 mg kg−1

Note: All doses given are orally, once daily, unless otherwise specified. Do not evaluate efficacy until the patient has received the medication daily for at least one full month. 106 Selective Serotonin Reuptake Inhibitors

Specific Medications humans is about 1.5 days, while the half‐life of demethylcitalopram is 2 days and of I. Citalopram Hydrobromide DDCT, 4 days (Pollock 2001). Citalopram is metabolized by CYP2C19, Chemical Compound: (±)‐1‐(3‐Dimethyl CYP3A4, and CYP2D6 (Pollock 2001; Forest aminopropyl)‐1‐(4‐fluorophenyl)‐1,3 Laboratories, Inc. 2002). Since citalopram is dihydroisobenzofuran‐5‐carbonitrile metabolized by multiple enzyme systems, it DEA Classification: Not a controlled is not expected that concurrent medication substance with drugs that affect only one of these sys Preparations: Generally available as 10‐, tems would cause clinically significant effects. 20‐, and 40‐mg tablets and as a 2‐mg ml−1 In geriatric populations and individuals peppermint‐flavored oral solution. with reduced hepatic or renal function citalopram clearance time is slower than for younger populations without reduced Clinical Pharmacology hepatic or renal function. Citalopram doses Citalopram is a strong inhibitor of serotonin should be reduced in these populations reuptake and has little effect on reuptake (Forest Laboratories, Inc. 2002). of dopamine or norepinephrine. Of the currently available SSRIs, it appears to be Uses in Humans the most selective inhibitor of 5‐hydroxy Citalopram is used to treat depression. It has tryptamine (5‐HT) uptake (Pollock 2001). also been shown to be significantly more It has very little to no effect on the 5‐HT1A, effective than placebo in treating impulsive 5‐HT2A, dopamine D1 and D2, α 1, α 2 and β‐ aggressive behavior in humans (Reist et al. adrenergic, histamine H1, γ‐aminobutyric 2003). acid (GABA), muscarinic cholinergic, and benzodiazepine receptors. Contraindications Citalopram is metabolized to desmethyl Citalopram is contraindicated in patients tak citalopram (DCT), di‐desmethylcitalopram ing monoamine oxidase inhibitors (MAOIs). (DDCT), citalopram‐N‐oxide, and a deami MAOIs should be discontinued for at least nated propionic acid. At steady state, while two weeks before beginning treatment with the parent compound, citalopram, is the citalopram. Likewise, citalopram should be predominant component, DCT and DDCT discontinued for at least two weeks before occur in significant amounts. Citalopram is beginning an MAOI. more effective than its metabolites in pre venting serotonin reuptake. Dogs appear to Side Effects convert more citalopram to metabolites than In a small number of patients, treatment with do humans. Specifically, in dogs, peak DDCT citalopram can result in anxiety, changes concentrations are approximately equal to in appetite, vomiting, diarrhea, changes in peak citalopram concentrations, whereas in urinary frequency, insomnia, sedation, humans, steady‐state peak DDCT plasma excitement, seizures, hyponatremia, abnor concentrations are less than 10% of citalo mal bleeding, mydriasis, and various other pram concentrations (Forest Laboratories, side effects unique to individuals, including Inc. 2002). anaphylaxis. In humans, when a single oral dose is given, In studies of carcinogenesis, mice were peak blood levels are reached in two to given up to 240 mg kg−1 day−1 of citalopram four hours (Pollock 2001). When it is given for 18 months, and rats were given up daily, steady‐state plasma concentrations to 24 mg kg−1 day−1 for 24 months. No are reached in about seven days (Forest increased carcinogenesis occurred in the Laboratories, Inc. 2002). The half‐life in mice. Rats exhibited an increased incidence Seii Medication 107 of small intestine carcinoma. Albino rats and 31 after initiation of treatment. Some given 80 mg kg−1 day−1 for two years exhib data suggest that dogs convert citalopram to ited degeneration and atrophy of the its metabolites more than do humans. The retinas. Retinal degeneration did not occur phenomenon of sudden death was not in rats given 24 mg kg−1 day−1, mice treated observed in rats given up to 120 mg kg−1 day−1, at doses of up to 240 mg kg−1 day−1 for which produced plasma levels of citalopram 18 months, or dogs treated for a year with and its metabolites similar to those observed doses of up to 20 mg kg−1 day−1. These doses in dogs on 8 mg kg−1 day−1. Subsequent are greater than what would be used thera intravenous studies showed that DDCT peutically in mice and rats. The implication produced prolonged QT intervals. Combined of these findings for other domestic species with the fact that dogs metabolize more is not known. citalopram to DDCT than do other species Citalopram has been mutagenic in some studied, this medication should not be bacterial assays. It has not been found to be considered a first‐choice SSRI to use in this mutagenic in mammalian assays, however species (Forest Laboratories, Inc. 2002). (Forest Laboratories, Inc. 2002). Citalopram at doses of 16–72 mg kg−1 day−1 Overdose decreased mating behavior in both male and Gastric lavage may be useful if conducted female rats and decreased fertility at doses soon after ingestion. Induction of emesis is ≤32 mg kg−1 day−1. In rat embryo/fetal not recommended. Give activated charcoal development studies, pregnant rats were and provide supportive therapy. There is no given citalopram at doses of 32, 56, or specific antidote. 112 mg kg−1 day−1. This resulted in decreased embryo/fetal growth and survival and an Other Information increased rate of abnormalities at the high While the peppermint‐flavored solution may dose of 112 mg kg−1 day−1. Toxicity, with clin seem an obvious choice for use in very small ical signs, occurred in the pregnant females animals, taste aversion could be a problem at this dose. There were no harmful effects with various species and individuals. Other on the fetuses at 56 mg kg−1 day−1 or lower. In SSRIs may be better choices for animals rabbit embryo/fetal development studies, under 10 kg. pregnant females were given 15 mg kg−1 day−1 In humans, citalopram has not been shown with no adverse consequences (Forest to significantly affect the metabolism of Laboratories, Inc. 2002). digoxin, warfarin, theophylline, or triazolam Citalopram is excreted in milk. In humans, (Forest Laboratories, Inc. 2002). sedation, decreased feeding, and weight loss have been recorded in the infants of mothers Effects Documented in Nonhuman Animals being treated with citalopram. When con Dogs sidering giving citalopram to a pregnant or Citalopram has been effectively used to treat nursing female, the potential benefits must canine acral lick dermatitis (ALD) in dogs be weighed against the potential risks to when given at a dose of 0.5–1.0 mg kg−1 daily. the embryo, fetus, or young animal (Forest Specifically, six of nine dogs responded, with Laboratories, Inc. 2002). the average time to achieving a status of Citalopram has a longer half‐life in geri “much improved” or better being 2.6 weeks. atric patients than in younger patients. It is Side effects that were observed in this recommended that the lower range of the population included sedation, anorexia, and dose be given in geriatric patients (Forest constipation. Long‐term follow‐up of more Laboratories, Inc. 2002). than one year was available on three dogs. Five of 10 beagles given citalopram at a One was continued on a dose of 0.5 mg kg−1 dose of 8 mg kg−1 day−1 died between days 17 and remained lesion‐free. One relapsed on 108 Selective Serotonin Reuptake Inhibitors

two occasions when medication was reuptake (Altamura et al. 1994; Eli Lilly discontinued, but recovered when 2004). In the dog fluoxetine is well absorbed medication was resumed at a maintenance (up to 72%) after oral administration and it dose of 0.33 mg kg−1; a third relapsed when is largely metabolized in the liver. After a medication was discontinued. This dog was single dose with approximately 2 mg/kg body changed to fluoxetine for economic reasons weight, peak plasma concentrations occur and responded to that agent, on which it was around 1.8 hours (fluoxetine) and around likewise maintained for more than one year 12.8 hours (norfluoxetine) while elimination (Stein et al. 1998). half-life ranged from 3 to 12.9 hours (fluoxe tine) and from 33 to 64 hours (norfluoxetine) II. Fluoxetine Hydrochloride (Elanco Animal Health 2007). The elimination half‐life of fluoxetine is substantially delayed in patients with liver Chemical Compound: (+)‐N‐methyl‐3‐ disease as compared to patients without liver phenyl‐3‐(α α α ‐trifluoro‐ρ ‐tolyl) disease. In contrast, human patients on dial oxypropylamine hydrochloride ysis had steady‐state fluoxetine and nor DEA Classification: Not a controlled fluoxetine concentrations similar to those of substance patients with normal kidneys. Thus, while Preparations: Generally available as 10‐ and the presence of liver disease should always be 20‐mg tablets, 10‐, 20‐, and 40‐mg considered cause for reducing the dose, capsules, a slow release 90‐mg tablet, and a patients with renal disease may be able to tol mint‐flavored solution of 20 mg/5 ml. erate a normal dose. Elderly patients have not Reconcile is available in 8‐, 16‐, 32‐ and been observed to have a higher incidence of 64 mg chewable tablets. adverse events than young adult patients (Eli Lilly 2004). Clinical Pharmacology The median lethal dose in rats is 452 mg kg−1 Fluoxetine is a strong inhibitor of serotonin PO. The median lethal dose in mice is reuptake and a very weak inhibitor of 248 mg kg−1. Phospholipids have been shown norepinephrine reuptake. Fluoxetine also has to increase in the tissues of dogs, mice, and very little binding to muscarinic, rats chronically medicated with fluoxetine histaminergic, and α 1‐adrenergic receptors (Eli Lilly 2004). compared with other antidepressants such as the tricyclic antidepressants. Uses in Humans Fluoxetine is well absorbed after oral Fluoxetine hydrochloride is used to treat administration, although food may delay its depression, premenstrual dysphoric disorder, absorption by one to two hours. Metabolism obsessive‐compulsive disorder (OCD), and is not proportional to dose; that is, when bulimia in humans. fluoxetine is given repeatedly, it is metabolized more slowly than if it is given as Contraindications a single dose. In humans, peak plasma The combination of fluoxetine and MAOIs concentrations of a single oral dose occur in can result in serious and sometimes fatal six to eight hours, while the elimination half‐ drug interactions. The two medications life is one to six days (Altamura et al. 1994; Eli should never be given together. Because of Lilly 2004). It is extensively metabolized in the long half‐life of fluoxetine, treatment the liver to norfluoxetine, its principal with a MAOI should not be initiated until metabolite, which is a less‐potent SSRI, but five weeks have passed since the has an elimination half‐life of 4–16 days. In discontinuation of fluoxetine. Conversely, animal models, S‐norfluoxetine has been fluoxetine treatment should not be initiated found to be comparable to the parent until two weeks have passed since the compound in inhibition of serotonin discontinuation of an MAOI. Thioridazine Seii Medication 109 should also not be given with fluoxetine or withdrawal from fluoxetine. However, in until at least five weeks have passed since humans, fluoxetine is effectively used to treat discontinuation of fluoxetine, because depression in diabetic patients (Lustman fluoxetine may result in elevated levels of et al. 2000). In diabetic patients, insulin doses thioridazine. Rarely, various allergic events may need to be modified when initiating and may occur in response to fluoxetine, discontinuing treatment with fluoxetine. including anaphylactoid reactions. Fluoxetine is tightly bound to plasma Fluoxetine inhibits the liver enzymes protein. Therefore, concomitant adminis cytochrome CYP2C9, CYP2D6, CYP2C19, tration with drugs that are also tightly bound and CYP3A4. Therefore, elevated levels of to plasma protein (e.g. digitoxin) can pro medications that are metabolized by any of duce plasma levels of either (or both) drugs these enzymes may occur when given concur that are high compared with what they are if rently, for example, tricyclic antidepressants, given alone, resulting in adverse side effects. benzodiazepines, carbamazepine, and halop Fluoxetine can alter anticoagulant effects eridol. Low doses should be used when these and cause increased bleeding in patients are combined with fluoxetine. concurrently given warfarin. Co‐administration of fluoxetine and tryp Fluoxetine has not been found to be carci tophan may lead to adverse events. Because nogenic, mutagenic, or impair fertility. tryptophan is available over the counter, cli However, in rats given 7.5 mg kg−1 daily or ents should be cautioned to not supplement 12 mg kg−1 daily of fluoxetine during preg their pet with tryptophan when it is being nancy, there was increased postpartum pup medicated with fluoxetine or any other sero death. Rats given 5 mg kg−1 daily did not have tonin reuptake inhibitor. increased pup mortality. Also, when ewes in Co‐administration with warfarin can result late gestation are given a 70 mg IV bolus of in increased bleeding. fluoxetine over a two‐minute period, tran sient decreases in uterine artery blood flow, Side Effects fetal PO2, and oxygen saturation occur In a small number of patients, treatment within the first 15 minutes. These values do with fluoxetine can result in anxiety, changes not return to normal after the passage of in appetite, vomiting, diarrhea, changes in 24 hours. In addition, fetal pH decreases and urinary frequency, insomnia, sedation, fetal PCO2 increases during the first 4 hours excitement, seizures, hyponatremia, abnormal and then they return to normal within bleeding, and decreased sexual motivation. 24 hours. There are no differences in uterine Decreased sexual motivation has been docu artery blood flow, blood gas status, or cardi mented to occur in nonhuman animals, as well ovascular measures between fluoxetine‐ as humans (Matuszcyk et al. 1998). While this treated ewes and control ewes (Morrison side effect makes fluoxetine undesirable for et al. 2002). use in breeding animals, it makes it potentially Because of potential risks to the fetus, useful for treatment of problems of undesira fluoxetine should not be given to pregnant ble sexual behavior in neutered animals and is females unless the potential benefits clearly irrelevant for animals with behavior problems outweigh the potential risks to the fetus. that are not intended for breeding. Veterinary Likewise, because fluoxetine is excreted in patients that exhibit increased anxiety with milk, it is recommended that it not be given administration of fluoxetine may improve and to nursing females unless either a clear need be subsequently maintained on this medica outweighs the fact that the offspring are also tion if the dose is decreased. being medicated or the offspring are fed a Fluoxetine may alter the metabolism of milk substitute. While caution is indicated, blood glucose. In particular, hyperglycemia children of women who took fluoxetine may develop during treatment with fluoxe throughout pregnancy did not show any tine, while hypoglycemia may develop upon decrement in birth weight, preschool IQ, 110 Selective Serotonin Reuptake Inhibitors

language development, or behavior (Nulman problem. Once it is confirmed that the prob et al. 2001). lem has achieved long‐term remediation with During toxicity testing, rats were given up medication, fluoxetine is decreased at a rate to 12 mg kg−1 daily of fluoxetine for two years not to exceed 25% of the maintenance dose without any evidence of carcinogenicity. per week. Some patients experience relapses at given decreases. If this happens, go back up Overdose to the lowest effective dose and continue for There are no specific antidotes for overdose another one to three months, and then with fluoxetine. In 87 cases in which humans attempt to decrease the dose again. ingested an acute overdose of fluoxetine without concurrent ingestion of other drugs, Other Information the most common symptoms were tachycar Fluoxetine has been more extensively used dia, drowsiness, tremor, vomiting, or nausea. in the treatment of behavior problems in Thirty of the patients (47%) did not develop any domestic animals than any other SSRI. Cats symptoms. Asymptomatic patients ingested exhibit a strong distaste for the mint‐flavored a mean dose of 341 mg and a maximum dose solution designed for humans. Rather than of 1200 mg (Borys et al. 1992). Gastric lavage attempt to give this orally, it is recommended may be helpful if done soon after the overdose. that a compounding pharmacist prepare a Induction of emesis is not recommended. solution in a tuna‐ or chicken‐flavored liquid Give activated charcoal and supportive therapy. or that tablets are dispensed. Give diazepam for seizures. While fluoxetine is not approved for use in the treatment of aggression in humans, Doses in Nonhuman Animals several small studies have supported the Doses reported for dogs generally range from hypothesis that it is effective in treating 1.0–2.0 mg kg−1day−1, while doses reported aggression (e.g. impulsive aggression, self‐ for cats run a bit lower, generally ranging injurious behavior) in some patients (see, e.g. from 0.5–1.5 mg kg−1 day−1. Smaller animals Charney et al. 1990; Coccaro et al. 1990; and/or species with faster metabolism, such Cornelius et al. 1991; Markowitz 1992; as birds, will need higher doses to obtain Kavoussi et al. 1994). In addition, a meta‐ clinical efficacy. Doses reported for birds analysis of 3992 patients treated with fluoxe range from 2.0 to 5 mg kg−1 day−1. Conversely, tine or placebo during clinical trials revealed larger animals are likely to need smaller that aggressive events were four times less doses on a per kilogram basis. While there likely to occur in fluoxetine‐treated patients are no clinical reports of the treatment of than in placebo‐treated patients (Heiligenstein rats, mice, or rabbits with fluoxetine, these et al. 1993). Fluoxetine has been shown to species have tolerated very high doses in suppress aggression in various laboratory laboratory studies of toxicity. Horses may be animal species, for example, golden hamsters effectively treated with 100–200 mg daily, or (Mesocricetus auratus) and lizards (Anolis approximately 0.25–0.50 mg kg−1. carolinensis) (Deckel 1996; Deckel and Jevitts 1997; Ferris et al. 1997). Discontinuation of Fluoxetine For patients that have been on fluoxetine for Effects Documented in Nonhuman Animals several weeks or months, it is recommended Administration of fluoxetine to dogs and cats that discontinuation be done gradually rather is quite common in small animal practice in than abruptly. In practice, if fluoxetine is North America. One survey study using 127 effective in the treatment of the target behav veterinary professional participants in North ior or anxiety‐related problem, continue America showed 83% of clinician prescribed medication for another one to three months, it to their feline and canine patients for depending on the severity of the primary an array of behavior problems. These were Seii Medication 111 anxiety disorders, aggressive behavior, com rical, self‐induced alopecia on the forelimbs. pulsive disorders, phobias/fear and other The cat was also a nervous and hyperactive problem behaviors, with anxieties being more pet. There were no cutaneous lesions other common in dogs. While in cats, elimination than the hair loss, and the cat had no fleas or behaviors, anxiety disorders, aggression, der flea manure. Treatment with methylpredni matologic/grooming, compulsive disorders solone, phenobarbital, a commercial lamb and others, elimination behaviors being most and rice diet, and finally, megestrol acetate, common (Kaur et al. 2016). all failed to resolve the problem. In fact, dur ing these treatments, the hair loss became Cats more extensive and eventually involved the Fluoxetine in a 15% pluronic lecithin organo abdomen, flanks, and thighs in a symmetrical gel (PLO gel) formulation can be absorbed pattern. Finally, treatment with fluoxetine, through the skin of cats into the systemic 0.66 mg kg−1 (2 mg daily) was attempted. The circulation. However, bioavailability of cat discontinued the excessive licking and transdermally administered fluoxetine is after five months had grown a full hair coat. only 10% that of the oral route although it The owner also reported that the cat was was administered in a single dose. When more relaxed and a more pleasant pet. concentrations are increased to achieve The second case described by Romatowski clinically effective levels, dermatitis results. involved two five‐year‐old, spayed female, Thus, transdermal administration of fluoxe domestic shorthair littermates. The two cats tine is not recommended (Ciribassi et al. had gotten along well until they were moved 2003). Eichstadt et al. (2017) made a com to a new home approximately one year prior parison of serum concentration between to presentation. Before the move, the cats daily administration of transdermal had been entirely indoors. After the move, (5 mg kg−1) with the proprietary transdermal they were allowed access to the backyard. base (PCCA Lipoderm) and oral (1 mg kg−1) One cat began rejecting the other, hissing fluoxetine in cats. The drug administration whenever she approached. The rejected cat for both routes was daily for 60 days. The began intermittently urinating in various blood concentrations or fluoxetine and nor places in the house on a variety of substrates, fluoxetine were seemingly accumulated by for example, countertops, plastic or paper time and the concentrations between the bags, the sleeping place of the cat that was two routes were significantly different at the rejecting her, and the owner’s clothes. 30‐day point. Oral administration was much Urinalysis of the cat with the elimination higher for both concentrations. Since this behavior problem was unremarkable. study did not evaluate the clinical effects, Treatment with buspirone, 5 mg two times a the author did not conclude if the given day (b.i.d) for 30 days, was ineffective, as was transdermal dose was clinically sufficient. treatment with diazepam, 1 mg b.i.d. Both Hartmann (1995), in a letter to the cats were then placed on 2 mg fluoxetine American Journal of Psychiatry, reported on a daily. This treatment resulted in a cat with ALD that had not responded to more discontinuation of the hissing behavior. The conventional treatments, including hypoaller cats resumed sleeping together and grooming genic diets, diphenhydramine, and diazepam, each other, behavior that had not occurred but the condition resolved when given fluox since the move. Inappropriate elimination etine at 0.25–0.38 mg kg−1 daily. The only side was decreased by 50%. effect observed was mild sedation. Pryor et al. (2001) treated 17 neutered Romatowski (1998) described two clinical urine‐spraying cats, all over one year of age, cases of cats that responded to fluoxetine. with fluoxetine or a fish‐flavored liquid One was a 16‐month‐old, 3‐kg, spayed female placebo in a randomized, double‐blind, Siamese cat that was presented with symmet placebo‐controlled trial. The initial dose was 112 Selective Serotonin Reuptake Inhibitors

1 mg kg−1 PO given once daily. If the patient considered clinically significant. Vomiting did not achieve a 70% reduction in urine occurred in one cat on treatment and two spraying by the fifth week, the dose was cats on placebo. Lethargy occurred in three increased to 1.5 mg kg−1. To maintain blind cats on treatment and two cats on placebo. ing, any cat that did not show improvements, After medication was discontinued, two of including those on placebo, were given a the nine cats that had been treated did not 50% increased dose of their compounded resume spraying. However, the other seven medication. Treatment was carried out for cats resumed some degree of marking. There eight weeks, followed by an additional four was a linear correlation between the rate of weeks of monitoring the cats after they had marking during baseline and the rate of discontinued medication. marking four weeks after treatment. Because Standardized environmental management of this finding, it is recommended that most was as follows: (i) the owners were provided cats, particularly those with higher rates of with an enzymatic cleaner that they were to urine marking prior to treatment, that is, use on all soiled areas; (ii) the owners were four or more marks per week, should be instructed to provide as many litter boxes as treated for a period longer than eight weeks. cats in the household, plus one more; (iii) the owners were instructed to clean all feces and Dogs urine from the litter boxes once a day and to Six laboratory dogs overdosed with fluoxetine completely change the litter material and given orally developed grand mal seizures wash the litter boxes once per week; and (iv) that were controlled with intravenous the owners were instructed to refrain from boluses of diazepam. In another study, the physically or verbally punishing the cats. electrocardiogram (ECGs) of dogs given high Cats on the treatment showed a significant doses of fluoxetine were evaluated. decrease in spraying behavior, compared Tachycardia and increased blood pressure with baseline premedication measures after occurred. However, no changes occurred in two weeks of treatment. Their spraying rate the PR, QRS, or QT intervals (Eli Lilly 2004). continued to decrease throughout treatment. Overall (1995) described a case of a dog In contrast, the mean weekly spraying rate of with “dominance‐related” interdog aggres cats on placebo decreased slightly during the sion, “dominance aggression” to the dog’s first week and did not decrease further owner, fear of strangers, and stereotypic cir thereafter. This slight decrease was probably cling. Initial treatment with behavior modifi a response to the environmental management cation alone resulted in resolution of the and increased regular supervision that was aggression toward the owner, but did not necessarily occurring because of the research. resolve the interdog aggression or fear of By the end of the trial, all cats on treatment strangers. Therefore, medication treatment had demonstrated a 90% reduction in the was initiated. After an initial period of number of urine marks each week. Total treatment with fluoxetine alone, then cessation of spraying occurred in 66% of the buspirone, then buspirone with fluoxetine, cats on treatment by the eighth week. For and finally fluoxetine alone, the dog was weeks two through eight, there was a signifi maintained on fluoxetine at a dose of cant difference in response for the cats on 0.54 mg kg−1 daily for a period of 28 months. placebo versus the cats on treatment. The During this time, there was only one incident most common side effect reported was of interdog aggression, and there was no decreased food intake; however, this was owner‐directed aggression. Side effects reported in four of the nine cats on treatment included constant mydriasis after the and three of the seven cats on placebo. The initiation of treatment with fluoxetine. Renal decreased food intake was never to such a and hepatic function were not compromised degree that it was cause for concern or while on the long‐term fluoxetine treatment. Seii Medication 113

In a later study, Dodman et al. (1996) combined across both orders. Dogs on conducted a single‐blind crossover trial of fluoxetine exhibited, on average, a 39% the treatment of owner‐directed “dominance” decrease from baseline scores. By five weeks, aggression in nine dogs. Diagnosis was improvement on fluoxetine was significantly based entirely on context and frequency of greater than improvement on fenfluramine, aggression and did not include signaling which was slight. Concurrent studies were behavior. Therefore, patients with what the carried out on an additional 13 dogs that author considers to be other forms of were treated with clomipramine or affective aggression may have been included desipramine and another 10 dogs that were in this study’s population. Patients were treated with sertraline or placebo in a similar treated with fluoxetine at a dose of 1 mg kg−1 crossover trial. Comparisons in response PO q24h, and one week of a placebo. The across trials showed that fluoxetine was more fluoxetine and placebo were placed into effective than desipramine, fenfluramine, gelatin capsules so that they were visually and sertraline in reducing licking. Four of the indistinguishable. While owners were not 14 dogs treated with fluoxetine showed leth told which week their dog would be getting argy, 1 showed loss of appetite, and 1 showed the placebo, all dogs received the placebo hyperactivity. Two of the dogs treated with during the first week of the trial to avoid a fluoxetine showed complete remission of carryover effect from the fluoxetine, since it excessive licking, while four showed a 50% has a long half‐life. No behavior modification reduction in licking. or training was carried out during the five‐ Stein et al. (1992) likewise used fluoxetine, week study. 1–2 mg kg−1 daily for an eight‐week open A significant reduction in owner‐directed trial on five dogs with ALD. One dog almost incidents of aggression was observed by the entirely discontinued self‐injurious behavior, end of treatment. While on medication, some but developed polyuria and polydipsia. Two dogs exhibited changes in level of activity, others showed substantial improvement with changes in food or water intake, increased no side effects. One dog was removed from alertness, shaking, barking, and reclusion. the study at two weeks when there was no While it is not recommended that medication response, while another was removed from be used alone in the treatment of canine the study because it exhibited sedation. affective aggression, it is clear from this Subsequent use of fluoxetine in cases of OCD report that SSRI medications such as manifested as canine acral lick have been fluoxetine can be useful adjuncts to treatment reported as having about a 50% success rate with behavior modification. Fluoxetine has (Karel 1994). In the author’s experience, also been used to treat additional cases of improvement may not be exhibited for four inter‐dog aggression (at 1.1 mg kg−1 PO daily, weeks or more. Sedation, when it occurs, is in combination with behavior modification) often transient, and dogs usually return to (Dodman 2000). normal levels of activity after a couple of Rapoport et al. (1992) compared fluoxetine weeks. to fenfluramine in 14 dogs with ALD in an Wynchank and Berk (1998) subsequently 11‐weeks crossover treatment trial. Dogs conducted a double‐blind, randomized, were treated for five weeks with up to placebo‐controlled trial of the use of 0.96 ± 0.29 mg kg−1 daily of fluoxetine and fluoxetine in the treatment of ALD in dogs. for another five weeks with up to All dogs on treatment were dosed at 0.92 ± 0.24 mg kg−1 daily of fenfluramine. 20 mg day−1, regardless of size, for six weeks. Owners used a 10‐point scale to rate their The smallest dog was 5 kg. Thus, this dog was dogs’ licking with 0 being no licking at all and dosed at 4 mg kg−1. For a dog to qualify for 10 being the worst licking ever observed. the study, a veterinarian must have diagnosed There was no order effect, so ratings were the dog with ALD at least six months before 114 Selective Serotonin Reuptake Inhibitors

the beginning of the trial. Other causes of medication for the treatment of separation licking behavior must have been ruled out, anxiety in dogs, but only in conjunction with as well. behavior modification. Sherman-Simpson Fifty‐eight dogs, ranging in age from 1 to et al. (2007) conducted a multiple-center, 13 years, completed the trial. For dogs that placebo-controlled, double-blind, parallel- were on the treatment, owner rating of the arm study to investigate the clinical efficacy licking behavior and appearance of the lesion and safety of Reconcile (1–2 mg kg−1 daily), in decreased significantly over the course of conjunction with behavior management for treatment. The placebo group did not exhibit the treatment of separation anxiety in dogs. a significant decline. There was a significant A total of 242 client-owned dogs were rand difference between treatment and placebo omized into the study for 8-week treatment. groups in both change in appearance of the They found about 42% of dogs treated with lesion and general condition of the dog by the Reconcile improved within 1 week of treat end of the study. Veterinarians who were ment, which was significantly greater than blinded as to whether or not the photographs the 17% of dogs with placebo. Although dogs were before or after treatment evaluated pho in both groups continued to improve over tographs of the lesions. Changes in the scores the course of the 8-week treatment period, for lesion severity were significantly better for dogs in reconcile group demonstrated a the treatment group than for the placebo significant improvement compared to the group. No adverse events were reported. placebo group (72% improvement vs. 50% Irimajiri et al. (2009) reported the efficacy respectively). Later, another multi-center, of fluoxetine for compulsive disorders in placebo-controlled, double-blind rand dogs by randomized, controlled clinical trial. omized parallel-arm study on 208 client- Sixty-three dogs with compulsive disorders owned dogs diagnosed with separation were randomly assigned to treatment with anxiety conducted without behavior modifi fluoxetine (1–2 mg kg−1 daily) or a placebo cation training (Landsberg et al., 2008). In without any behavior or environmental mod this study Reconcile (1–2 mg kg−1 daily ) or ification during 42 day study. The owners placebo was given for 6 weeks. Without kept daily diary of the severity of episodes behavior modification the dogs showed 58% and the researchers collected the informa improvement in overall separation anxiety tion through telephone interviews every severity scores comparing to its pre- 2 weeks. It was found that the severity of the treatment score, however, the there was no condition was more likely to decrease (odds significant difference when it was compared ratio, 8.7) in the fluoxetine group compared to the placebo group. Based on the outcome to the placebo group. However, mean num between two studies, the authors of the study ber and duration of compulsive episodes, as recommended that pharmacotherapy should determined from daily diary entries, did not have the conjunction with behavior modifi differ significantly between groups. They cation to get the optimal outcome. also reported that the most common adverse effects were decreased appetite and mild Parrots lethargy. When fluoxetine was used to treat Mertens (1997) reported that 12 of 14 birds anxiety, Reisner (2003) reported forty dogs treated with fluoxetine for feather‐picking treated for generalized anxiety disorder with (2.3 mg kg−1 daily for at least four weeks) fluoxetine at 0.37–1.2 mg kg−1, 27 (67%) exhibited initial improvement but subse improved, 9 showed no significant behavior quently relapsed. An increased dose up to as change, and 4 got worse while on this treat high as 3 mg kg−1 b.i.d. again resulted in ment (Reisner 2003). improvement with a subsequent relapse. Side Reconcile, a chewable tablet form of fluox effects observed included frequent sneezing etine, is the another FDA approved veterinary (two birds) one week after initiation of Seii Medication 115 treatment, temporary ataxia, and lethargy Absorption is not affected by food intake. In about one hour after medication (two birds). humans, steady‐state plasma concentrations Additionally, one bird that had an extensive are achieved in about 10 days. Once people vocabulary, including songs and poems, for have achieved steady state, peak plasma con got word sequences and exhibited a reduced centrations occur in three to eight hours. The vocabulary. All problems disappeared after pharmacokinetics of fluvoxamine are nonlin treatment was discontinued. All birds were ear. Specifically, higher doses of fluvoxamine kept in good housing conditions, with provi produce proportionally higher concentra sion of intra‐ and interspecific social contact, tions in the plasma than do lower doses. good dietary management, and exercise. Fluvoxamine is metabolized by the liver, Seibert (2004) treated a 3.5‐year‐old white primarily via oxidative demethylation and female cockatiel (Nymphicus hollandicus) deamination. Nine metabolites have been (1 mg kg−1 of fluoxetine PO, q24h) with a identified. The major human metabolites are compulsive disorder that was specifically fluvoxamine acid, the N‐acetyl analog of manifested as chewing the third digit of the fluvoxamine acid, and fluvoxethanol, all of right foot. The bird responded two weeks which have little to no serotonin reuptake after initiation of treatment. After three prevention activity. Humans excrete only months of treatment, the dosage was about 2% of fluvoxamine as the parent decreased. By five months treatment was compound. The remaining 98% is excreted as successfully discontinued. various metabolites (Solvay Pharmaceuticals 2002). Primates Excretion occurs primarily via the kidneys. Vervet monkeys with various stereotypic In healthy humans, an average of 94% of the behaviors, for example, saluting, somersault medication is excreted in the urine within ing, weaving, and head tossing, were treated 71 hours of dosing. Geriatric patients clear with fluoxetine (1 mg kg−1 daily for six weeks) fluvoxamine more slowly than young adults. or placebo. Results of assessment by a rater Patients with liver disease clear fluvoxamine blind to treatment status identified a signifi more slowly than do healthy patients. cant difference between fluoxetine‐treated However, patients with renal disease have and placebo‐treated monkeys by the end of not been found to clear fluvoxamine any the trial (Hugo et al. 2003). more slowly than do persons without renal disease (Solvay Pharmaceuticals 2002).

III. Fluvoxamine Uses in Humans Fluvoxamine is used to treat OCD in humans. Chemical Compound: 5‐Methoxy‐4′‐ (trifluoromethyl)valerophenone‐(E)‐O‐ Contraindications (2‐aminoethyl)oxime maleate Fluvoxamine should not be administered DEA Classification: Not a controlled with terfenadine or cisapride. These are substance metabolized by the P450 isozyme 3A4. While Preparations: Generally available as 25‐, there is no definitive proof that fluvoxamine 50‐, and 100‐mg tablets. is a 3A4 inhibitor, there is strong evidence that it is. Thus, co‐administration could Clinical Pharmacology result in elevated terfenadine or cisapride Fluvoxamine specifically inhibits reuptake of levels, which could result in QT prolongation, serotonin in both blood platelets and brain ventricular tachycardia, and other cardiac synaptosomes (Claassen et al. 1977). It has a symptoms (Solvay Pharmaceuticals 2002). weak affinity for histaminergic, α‐ or β‐adren Fluvoxamine should not be administered ergic, muscarinic, or dopaminergic receptors. at the same time as MAOIs. It should not be 116 Selective Serotonin Reuptake Inhibitors

used in patients that have previously received 40 mg kg−1 day−1 PO, there were no fetal an MAOI until the patient has been off the malformations. In other studies, in which MAOI for at least two weeks. Conversely, pregnant rats were dosed through weaning MAOIs should not be given until a patient with 5, 20, 80, and 160 mg kg−1 day−1 PO there has stopped fluvoxamine for at least two was an increase in pup mortality at birth in weeks. rats that were dosed at 80 mg kg−1 and The metabolism of benzodiazepines by higher, decreased neonatal pup weights at hepatic oxidation, including alprazolam, 160 mg kg−1, and decreased long‐term midazolam, and triazolam (see Chapter 3) survival of the pups at all doses. Results of a can be reduced by combined use with cross‐fostering study suggested that some of fluvoxamine. Benzodiazepines metabolized the postnatal deficits in survival were due to by glucuronidation, including lorazepam, maternal toxicity; that is, the mothers being oxazepam, and temazepam, are not likely to chronically medicated at such high doses be affected by co‐administration with were not as competent mothers as were fluvoxamine (Solvay Pharmaceuticals 2002). unmedicated rats. However, there may have Fluvoxamine can alter the efficacy and been some direct drug effect on the offspring. activity of warfarin, propanaolol, tricyclic Fluvoxamine is excreted in the milk. In antidepressants, and theophylline, as well as deciding whether to medicate pregnant or other drugs metabolized by the P450 enzyme lactating females, potential risks to the system. Tryptophan may increase the offspring must be weighed against the serotonergic activity of fluvoxamine and potential benefits to the mother (Solvay should be used in combination with caution Pharmaceuticals 2002). (Solvay Pharmaceuticals 2002). In human studies, the side‐effect profile for pediatric patients has been found to be Side Effects similar to the side‐effect profile for adult In a small number of patients, treatment patients (Solvay Pharmaceuticals 2002). with fluvoxamine can result in anxiety, changes in appetite, vomiting, diarrhea, Overdose changes in urinary frequency, insomnia, Gastric lavage may be useful if it is conducted sedation, excitement, seizures, hyponatremia, soon after ingestion of an overdose. Give abnormal bleeding, mydriasis, decreased activated charcoal and provide supportive libido, and various other side effects unique therapy. There is no specific antidote. to individuals, including anaphylaxis. Studies of the potential for carcinogenicity, Other Information mutagenicity, and impairment of fertility by Comparisons of humans treated with either fluvoxamine have not revealed any such placebo or fluvoxamine showed no signifi effects. Rats were treated with doses of up cant effect of fluvoxamine on various vital to 240 mg kg−1 day−1 for 30 months, and sign indicators, serum chemistries, hematol hamsters were treated with doses of up to ogy, urinalysis, or ECG changes. Fluvoxamine 240 mg kg−1 day−1 for up to 20 months, with has not been found to significantly affect no carcinogenic effect. In fertility studies, the pharmacokinetics of digoxin (Solvay male and female rats were given up to Pharmaceuticals 2002). 80 mg kg−1 day−1 PO of fluvoxamine, with no deleterious effects on mating, duration of ges Effects Documented in Nonhuman Animals tation, or pregnancy (Solvay Pharmaceuticals Fluvoxamine has a specific antiaggressive 2002). effect on maternal aggression, because it In teratology studies in which pregnant results in decreased aggression at doses rats were given up to 80 mg kg−1 day−1 PO that do not cause concurrent nonspecific and pregnant rabbits were given up to decreases in activity (Olivier and Mos 1992). Seii Medication 117

IV. Paroxetine Hydrochloride The presence of renal or hepatic disease produces increased concentrations of par Chemical Compound: (−)‐Trans‐4R‐(4′‐ oxetine in the plasma. Therefore, patients fluorophenyl)‐3S‐[(3′, 4′‐methylene‐ with mild renal or hepatic impairment dioxyphenoxyl)methyl]piperidine should be started on a very low dose and the hydrochloride hemihydrate dose titrated upward over time. Plasma lev DEA Classification: Not a controlled els in older patients are also elevated. substance Therefore, the starting dose should be low Preparations: Generally available as 10‐, in all geriatric patients and subsequently 20‐, 30‐, and 40‐mg tablets and a 2‐mg ml−1 titrated upward as necessary (SmithKline orange‐flavored suspension. Controlled‐ Beecham Pharmaceuticals 2004). release tablets are available in 12.5‐, 25‐, Paxil CR tablets are formulated so that and 37.5‐mg sizes. dissolution occurs gradually over a period of several hours. There is also an enteric coat that prevents release of the active Clinical Pharmacology ingredient until after the tablet has left the Paroxetine has weak effects on neuronal stomach. The consumption of food does not reuptake of norepinephrine and dopamine, significantly affect release or absorption. For but is primarily a highly selective inhibitor of the slower release to occur, the tablet cannot serotonin reuptake. It has little affinity for be cut, broken, or chewed (SmithKline muscarinic, α1‐, α2‐, β‐adrenergic, dopamine Beecham Pharmaceuticals 2004). This limits (D2)‐, 5‐HT1‐, 5‐HT2‐, or histamine (H1) its potential usefulness in animals weighing receptors. Thus, there are fewer anticholin less than approximately 10 kg. Even in ani ergic, sedative, and cardiovascular side mals large enough to theoretically be given effects than some other serotonin reuptake the controlled release tablets, it is important inhibitors, such as amitriptyline, that also to remember that these tablets are designed have substantial effects on muscarinic, his for the human digestive system and dissolve taminergic and α1‐adrenergic receptors. and are absorbed at substantially slower or Paroxetine has multiple metabolites, each faster rates in various other species. about 1/50th as potent as the parent com pound. Thus, clinical efficacy of paroxetine Uses in Humans is essentially from the parent compound, Paroxetine is used to treat depression, OCD, and there are no significant contributions panic disorder, social anxiety disorder, gener from metabolites (SmithKline Beecham alized anxiety disorder, and posttraumatic Pharmaceuticals 2004). stress disorder (PTSD). Paroxetine is completely absorbed when given orally and can be given with or without Contraindications food. In humans, the half‐life is about 10 days, Do not use paroxetine in combination with with 64% being excreted in the urine, 2% as any MAOI or with thioridazine, because paroxetine, and the remainder as metabolites serious and sometimes fatal drug interactions of paroxetine. The remaining 36% is excreted can result. Patients should not be given in the feces, < 1% as paroxetine, and the paroxetine for at least two weeks before remainder as metabolites. With chronic daily initiating medication with either of these dosing, steady‐state plasma concentrations drugs. Patients should not have been given are achieved in about 10 days. Paroxetine is MAOIs for at least two weeks before distributed throughout the body, including initiation of paroxetine (SmithKline Beecham the central nervous system, with about 95% Pharmaceuticals 2004). being bound to plasma protein (SmithKline Paroxetine inhibits the liver enzyme Beecham Pharmaceuticals 2004). CYP2D6 but otherwise causes less inhibition 118 Selective Serotonin Reuptake Inhibitors

of liver enzymes than do other SSRIs such as Carcinogenicity studies were conducted in fluoxetine and fluvoxamine. Nevertheless, mice and rats on paroxetine for two years. there are a large number of medications that Mice were given 1, 5, or 25 mg kg−1 daily, and are metabolized by this enzyme, including rats were given 1, 5, or 20 mg kg−1 daily. The amitriptyline, clomipramine, dextromethor male rats in the high‐dose group had phan, imipramine, propranolol, and thiori significantly more sarcomas than did the dazine. Thus, lower doses should be used in male rats in the low‐ or medium‐dose group patients concurrently receiving any drug that or on placebo. There was no carcinogenic is metabolized by this enzyme (SmithKline effect identified in mice or female rats. The Beecham Pharmaceuticals 2004). implications of these findings for other Do not use in patients with narrow angle domestic animals are unknown (SmithKline glaucoma. Beecham Pharmaceuticals 2004). Since the Concurrent use of paroxetine and trypto dose that induced cancer in male rats was phan can result in adverse events. Because greater than what would be used as a thera tryptophan is available over the counter, cli peutic dose for the treatment of behavior ents should be advised of this (SmithKline problems in pet rats, the findings are probably Beecham Pharmaceuticals 2004). not of concern in treating this group. Paroxetine may interact with warfarin, Nevertheless, owners should be cautioned. altering its effect on bleeding. Paroxetine is Studies of potential mutagenicity of parox strongly bound to plasma protein, resulting etine have not identified any mutagenic in a greater plasma concentration of any drug effects of this medication. administered concurrently that is likewise Female rats experienced a reduced strongly bound to plasma protein (SmithKline pregnancy rate when given 15 mg kg−1 daily Beecham Pharmaceuticals 2004). of paroxetine. Male rats given 25 mg kg−1 daily had atrophic changes in the seminiferous Side Effects tubules and aspermatogenesis. Male rats In a small number of patients, treatment with given 50 mg kg−1 day−1 had vacuolation of the paroxetine can result in anxiety, changes in epididymal tubular epithelium (SmithKline appetite, vomiting, diarrhea, changes in uri Beecham Pharmaceuticals 2004). nary frequency, insomnia, sedation, excite In studies of teratogenic effects, pregnant ment, seizures, hyponatremia, abnormal rabbits were given 6 mg kg−1 daily, and bleeding, mydriasis, decreased libido, and pregnant rats were given 50 mg kg−1 daily various other side effects unique to individu during organogenesis. There were no tera als, including anaphylaxis (SmithKline togenic effects in either species and no Beecham Pharmaceuticals 2004). Studies increased postnatal pup deaths in rabbits. conducted in humans have shown that the However, in rats there was increased pup incidence of many side effects is dose‐ mortality when paroxetine was continued dependent, that is, the higher the dose, the during the last trimester and lactation. The more likely it is that side effects will occur. cause of this mortality has not been identi Withdrawal reactions occur at a higher rate fied. The implications of these findings for for paroxetine than for fluoxetine, fluvoxam other domestic animals are not known. ine, or sertraline in the human population However, because of these findings and the (Price et al. 1996). In case of decreased libido, fact that paroxetine is secreted in milk, it while this side effect makes paroxetine unde should be used in pregnant and lactating sirable for use in breeding animals, it makes females only when the potential benefits it potentially useful for treatment of animals clearly outweigh the risks (SmithKline with undesirable sexual behavior. In cats, Beecham Pharmaceuticals 2004). constipation is a potential side effect of par Geriatric patients have decreased clear oxetine (Frank and Dehasse 2003). ance time as compared with younger patients. Seii Medication 119

Therefore, lower dosing is recommended in Effects Documented in Nonhuman Animals geriatric patients (SmithKline Beecham Cats Pharmaceuticals 2004). Paroxetine has been used to treat cats for urine marking and aggression toward Overdose humans and cats (Frank and Dehasse 2003; Gastric lavage may be useful if conducted Pryor 2003; Pachel 2014). soon after ingestion. Induction of emesis is not recommended. Give activated charcoal, Dogs and provide supportive therapy. There is no Of 12 dogs treated with paroxetine (0.96– −1 specific antidote. 1.75 mg kg PO q24h), for generalized anxi ety disorder, 6 (50%) showed improvement, 4 Discontinuation of Paroxetine showed no change, and 1 dog got worse For patients that have been on paroxetine (Reisner 2003). The response of the twelfth for several weeks, it is recommended that dog is not reported. discontinuation be done gradually rather than abruptly. While abrupt discontinua Horses tion of a variety of SSRI treatments can A mare with a five‐year history of weaving cause withdrawal symptoms, this phenom exhibited a 95% decrease in this behavior −1 enon has been most frequently reported when given 0.5 mg kg daily PO. Even when with paroxetine in the human literature stressed, the mare exhibited a 57% improve (Price et al. 1996; Michelson et al. 1998). In ment over baseline. Specifically, the frequency practice, if paroxetine is effective in the of weaving changed from 43.5 per minute treatment of the target behavior problem, with kicking to less than 1 per minute. When continue medication for another one to the mare was stressed, weaving increased to three months, depending on the severity of 18.75 per minute (Nurnberg et al. 1997). the primary problem. Once it is confirmed that the problem has achieved long‐term V. Sertraline Hydrochloride remediation with medication, paroxetine is decreased at a rate not exceeding 25% of the Chemical Compound: (1S‐cis)‐4‐(3, 4‐dichlo maintenance dose per week. Some patients rophenyl)‐(1, 2, 3, 4‐tetrahydro‐N‐methyl‐ experience relapses at given decreases. If 1‐naphthalenamine hydrochloride this happens, go back up to the lowest effec DEA Classification: Not a controlled tive dose and continue for another one to substance three months, then attempt to decrease the Preparations: Generally available as 25‐, dose again. −1 50‐, and 100‐mg tablets and a 20‐mg ml Other Information liquid. In double‐blind placebo‐controlled trials conducted on humans, paroxetine was not Clinical Pharmacology found to produce any significant changes in Sertraline is a selective inhibitor of neuronal ECGs, heart rate, blood pressure, or liver serotonin reuptake. It has very weak effects enzymes. on reuptake of norepinephrine and Paroxetine has an insignificant effect on dopamine. Sertraline has no substantial the liver enzyme CYP2C19. Therefore, there affinity for adrenergic (α1, α 2, and β), is no need for lower doses of benzodiaz cholinergic, GABA, dopaminergic, epines, which are metabolized by this histaminergic, serotonergic (5‐HT1A, 5‐ enzyme, as is the case with fluoxetine HT1B, 5‐HT2), or benzodiazepine receptors. and fluvoxamine (SmithKline Beecham Therefore, the anticholinergic, sedative and Pharmaceuticals 2004). cardiovascular effects seen with some other 120 Selective Serotonin Reuptake Inhibitors

psychoactive drugs, such as the tricyclic The minimum lethal doses are 350 mg kg−1 antidepressants, are minimal. Chronic PO in male mice, 300 mg kg−1 PO in female administration of sertraline also down‐ mice, 1000 mg kg−1 in male rats, and regulates brain norepinephrine receptors. 750 mg kg−1 in female rats. Death occurs after The half‐life in humans is about 26 hours. one to two days (Pfizer Inc. 2004). Blood levels reach a steady state after approximately one week of daily dosing in a Uses in Humans healthy adult. More time is required to Sertraline is used to treat depression, OCD, achieve steady state in older patients. PTSD, panic disorder, and premenstrual Sertraline can be given with or without food dysphoric disorder in humans. (Pfizer Inc. 2004). Sertraline is metabolized extensively dur Contraindications ing its first pass through the liver, primarily to Do not use sertraline in combination with N‐desmethylsertraline, which has a plasma any MAOI, because serious and sometimes elimination half‐life of 62–104 hours. N‐des fatal drug interactions can result. Patients methylsertraline is a less potent serotonin should not be given sertraline for at least two reuptake inhibitor than is the parent com weeks before initiating medication with an pound. In human subjects given a single radi MAOI. Patients should not have been given olabeled dose of sertraline, 40–45% of the monoamine oxidase inhibitors for at least radioactivity was recovered via the urine two weeks prior to initiation of paroxetine within nine days. Another 40–45% was recov (Pfizer Inc. 2004). ered in the feces. The urine contained only metabolites of sertraline, while the feces con Side Effects tained 12–14% of the original sertraline in an In a small number of patients, treatment unchanged form, the remainder being metab with sertraline can result in anxiety, changes olites produced by oxidative deamination and in appetite, vomiting, diarrhea, changes in subsequent reduction, hydroxylation, and urinary frequency, insomnia, sedation, glucuronide conjugation (Pfizer Inc. 2004). excitement, seizures, hyponatremia, In human pediatric studies, it was found abnormal bleeding, mydriasis, decreased that children and teenagers (6–17 years of libido, and various other side effects unique age) metabolized sertraline more efficiently to individuals, including anaphylaxis. Rarely, than did adults. There was no difference patients on sertraline may have altered between males and females. In contrast, platelet function and abnormal bleeding geriatric patients clear sertraline more slowly (Pfizer Inc. 2004). than adults (Pfizer Inc. 2004). Sertraline has some effect of inhibiting the Patients with chronic mild liver impair biochemical activity of the liver enzyme ment clear sertraline more slowly than do CYP2D6. While its effect is not as substantial age‐matched patients with normal liver func as paroxetine or fluoxetine (Albers et al. tion. This is not a surprising finding given the 2002), it should be used with caution with significant metabolism of the drug in the liver drugs that are metabolized by this enzyme, in normal patients. As discussed above, clear such as the tricyclic antidepressants ance of unchanged sertraline in the urine is a dextromethorphan and propranolol. minor mode of elimination of the parent Lifetime carcinogenicity studies have been compound, and almost half of the metabolites conducted on mice and rats given up to are eliminated in the feces. In patients with 40 mg kg−1 day−1 of sertraline. Male mice mild to severe renal impairment the phar experienced a dose‐related increase in liver macokinetics of sertraline metabolism and adenomas. Female mice did not experience excretion are not significantly different from this increase. Female rats experienced an healthy controls (Pfizer Inc. 2004). increase in the rate of follicular adenomas of Seii Medication 121 the thyroid gland at 40 mg kg−1 day−1. This daily PO. Lymphoid depletion may occur in change was not accompanied by thyroid dogs given 15–160 mg kg−1 for a short period hyperplasia. There was an increase in uter of time, but has not been observed in dogs ine adenocarcinomas in female rats given treated chronically (Davies and Kluwe 1998). 10–40 mg kg−1 day−1 compared with placebo It is unknown whether sertraline is (Davies and Kluwe 1998; Pfizer Inc. 2004). excreted in milk. As with the other SSRIs, In tests of mutagenicity, no mutagenic medicating pregnant or lactating females activity has been identified. Doses of with sertraline should be done cautiously, 80 mg kg−1 day−1 result in decreased fertility with the potential benefits to the female in rats (Davies and Kluwe 1998; Pfizer Inc. being weighed against the risks to the fetus 2004). and neonate (Pfizer Inc. 2004). Pregnant rats have been given sertraline up to 80 mg kg−1 day−1, while pregnant rab Other Information bits have been given sertraline up to While sertraline is not labeled for use in the 40 mg kg−1 day−1. Sertraline was not terato treatment of aggression in humans, beneficial genic at these doses. When the pregnant rats effects for patients with borderline personality and rabbits were medicated during the disorder with impulsive aggression have been period of organogenesis, delayed ossification observed (e.g. Kavoussi et al. 1994). occurred in the fetuses when their mothers were on doses of 10 mg kg−1 day−1 in rats and Effects Documented in Nonhuman Animals 40 mg kg−1 day−1 in rabbits. At a dose of Dogs 20 mg kg−1 day−1 given to rats during the last Rapoport et al. (1992) studied the effects of third of gestation and lactation, there was sertraline versus placebo on dogs with ALD decreased body weight gain in the pups and in an 11‐week crossover treatment trial, increased early postnatal mortality. There was with five weeks each on placebo and on ser no effect at 10 mg kg−1 day−1. The increased traline. Sertraline was dosed at up to pup mortality was due to the in utero expo 3.42 ± 0.52 mg kg−1 daily. Sertraline was sure to sertraline at the higher doses (Davies significantly better than placebo, producing a and Kluwe 1998; Pfizer Inc. 2004). 21% decrease in licking behavior at five weeks Dogs given ≥40 mg kg−1 PO of sertraline as compared with baseline. However, daily orally for two weeks exhibit mydriasis, sertraline was less effective than fluoxetine, hindlimb weakness, hyperactivity, and ano which was being studied in a similar crossover rexia. Alkaline phosphatase (Alk Ph) activity trial with fenfluramine. Fluoxetine produced is increased in dogs given 80 mg kg−1 day−1 for a 39% decrease by five weeks when compared two weeks, while serum transaminase activity to baseline. No side effects were reported (ALT) is increased in dogs receiving for dogs on sertraline. However, only one 160 mg kg−1 for this period of time. Dogs dog showed clinically significant (50%) given ≥10 mg kg−1 daily PO for three months improvement in licking behavior. or longer exhibit mydriasis. In addition, dogs given ≥ 30 mg kg−1 daily PO for up to Reptiles 12 months exhibit transient hyperactivity Male A. carolinensis given sertraline at a dose and restlessness with anorexia and body of 10 mg kg−1 exhibit decreased weight loss or decreased body weight loss. aggressiveness. In addition, if sertraline is Convulsions may occur at 90 mg kg−1. Dogs given only to the “dominant” male of a pair treated with sertraline for one year exhibit that has established their hierarchical increased Alk Ph activity when dosed at relationship prior to treatment, the rank ≥10 mg kg−1 daily PO, increased relative liver order often reverses. In addition, non‐ weight when dosed at ≥ 30 mg kg−1 daily PO, aggressive associative behavior increases and increased ALT when dosed at 90 mg kg−1 (Larson and Summers 2001). 122 Selective Serotonin Reuptake Inhibitors

VI. Escitalopram Oxalate affected by food. At steady state, the extent of accumulation of escitalopram in plasma in Chemical Compound: 5‐[5‐(3,4‐dimethoxy young healthy subjects was 2.2–2.5 times the phenyl)‐3‐(2‐fluorophenyl)‐3,4‐dihydro plasma concentrations observed after a pyrazol‐2‐yl]‐5‐oxopentanoic acid single dose. The tablet and the oral solution DEA Classification: Not a controlled dosage forms of escitalopram oxalate are substance bioequivalent. Preparations: Generally available as 5‐, 10‐, Escitalopram pharmacokinetics in subjects and 20‐mg tablets. The 10‐ and 20‐mg 65 years of age were compared to younger tablets are scored. Although escitalopram subjects in a single dose and a multiple‐dose oxalate equivalent to 1 mg ml−1 escitalopram study. Escitalopram AUC and half‐life were base oral solution is also available, it con increased by approximately 50% in elderly tains the following inactive ingredients: subjects, and Cmax was unchanged. There sorbitol, purified water, citric acid, sodium −1 fore, 10 mg day is the recommended dose citrate, malic acid, glycerin, propylene for elderly patients (Forest Pharmaceuticals, glycol, methylparaben, propylparaben, Inc. 2004). and natural peppermint flavor. Clinically significant interaction has been observed between low dosages of escitalopram (5 mg day−1) and clonidine, with an increase of Clinical Pharmacology central effects of clonidine such as hypother Escitalopram is S‐enantiomer of the racemic mia and sedation in humans. The molecular citalopram with antidepressant activity and is mechanisms underlying this interaction are the newest marketed SSRI. Escitalopram has presently unknown (Nikolic et al. 2009). no significant affinity for adrenergic (alpha‐1, alpha‐2, beta), cholinergic, GABA, dopamin Uses in Humans ergic, histaminergic, serotonergic (5HT1A, Escitalopram is used to treat major 5HT1B, 5HT2), or benzodiazepine receptors. depression and generalized anxiety disorder. Although it shares the same mechanistic tar get, the serotonin transporter (SERT) with Contraindications other SSRIs, it is further classified as an allos Although the same caution, as being teric SSRI. The additional interaction of esci suggested in other SSRIs, to avoid serotonin talopram with an allosteric binding site on the syndrome is advised, escitalopram is SERT modulates the affinity of escitalopram metabolized by at least CYP3A4 and at the primary (orthosteric) site. This unique CYP2C19 and to a lesser extent by CYP2D6. pharmacological characteristic of excitalo In vitro studies did not reveal an inhibitory pram leads it to be more efficacious than effect of escitalopram on CYP2D6. However, other SSRIs (Sanchez et al. 2013). Additionally, there are limited in vivo data suggesting a in the human medicine literature, when effi modest CYP2D6 inhibitory effect for cacy and tolerability are compared, the over escitalopram, i.e., co‐administration of all evidence supports that escitalopram could escitalopram (20 mg day−1 for 21 days) with be the first choice before paroxetine, sertra the tricyclic antidepressant desipramine line and citalopram (Sanchez et al. 2013). (single dose of 50 mg), a substrate for In humans when taken orally, escitalopram CYP2D6, resulted in a 40% increase in Cmax reaches Tmax in five hours, is 56% protein and a 100% increase in AUC of desipramine. bound, and reaches steady‐state The clinical significance of this finding is concentration in the blood within one to two unknown. Nevertheless, caution is indicated weeks (Spina et al. 2012). The half‐life in in the co‐administration of escitalopram and humans is about 27–33 hours (Sanchez et al. drugs metabolized by CYP2D6 (Forest 2013). Absorption of escitalopram is not Pharmaceuticals, Inc. 2004). Seii Medication 123

Overall, comparing to other SSRIs such as Slightly increased offspring mortality was paroxetine and sertraline, escitalopram has seen at 24 mg kg−1 day−1. The no‐effect dose little inhibitory action against other CYP was 12 mg kg−1 day−1 which is approximately enzymes or P‐glycoprotein and it has a low 6 times the MRHD on a mg/m2 basis. potential for drug–drug interactions There are no adequate and well‐controlled (Sanchez et al. 2013). studies in pregnant women; therefore, escitalopram should be used during Side Effects pregnancy only if the potential benefit According to a meta‐analysis reviewing 117 justifies the potential risk to the fetus (Forest randomized controlled trials involving 25 928 Pharmaceuticals Inc. 2004). participants with all 6 SSRIs as well as 6 new‐ generation antidepressants, escitalopram and Overdose sertraline were the SSRIs that showed a high Gastric lavage may be useful if it is conducted est tolerability (Cipriani et al. 2009). When soon after ingestion of an overdose. Give side effects are observed in the treatment of activated charcoal, and provide supportive major depression with either 10 mg day−1, or therapy. There is no specific antidote. 20 mg per day of escitalopram, they usually include insomnia, diarrhea, dry mouth, som Other Information nolence, dizziness, sweating increased, con Paroxetine, sertraline and escitalopram have stipation, fatigue, and indigestion. The high affinity at the SERT while paroxetine incidence rate was dose‐dependent (Forest has the highest affinity at the SERT, whereas Pharmaceuticals Inc. 2004). escitalopram has the highest degree of In a rat embryo/fetal development study, selectivity (i.e. >1000‐fold relative to a large oral administration of escitalopram (56, 112, number of receptors and neurotransmitter or 150 mg kg−1 day−1) to pregnant animals transporters) as compared with paroxetine during the period of organogenesis resulted (>200‐fold) and sertraline (>60‐fold) in decreased fetal body weight and associ (Sanchez et al. 2013). ated delays in ossification at the two higher doses (approximately 56 times the maximum Effects Documented in Nonhuman Animals recommended human dose [MRHD] of Dogs 20 mg−1 day−1 on a body surface area [mg/ One study using five clinically healthy beagles m2] basis). Maternal toxicity (clinical signs (4 male, 1 female, age 5 ± 2 years, weight and decreased body weight gain and food 12 ± 4 kg) to determine the optimal dosing consumption), mild at 56 mg−1 kg−1 day−1, regimen and the relationship between the was present at all dose levels. The develop dose and the SERT‐occupancy has been mental no‐effect dose of 56 mg kg−1 day−1 is published (Taylor et al. 2017). It reported approximately 28 times the MRHD on a mg/ that the elimination half‐life of escitalopram m2 basis. No teratogenicity was observed at in these beagle dogs was 6.7 hours, therefore, any of the doses tested (as high as 75 times three times a day (t.i.d.) is recommended. the MRHD on a mg/m2 basis). When female According to the PET scan study, to occupy rats were treated with escitalopram (6, 12, 80% of the SERT‐sites in the basal ganglia 24, or 48 mg kg−1 day−1) during pregnancy and to elicit a therapeutic effect, the minimal and through weaning, slightly increased off dose requirement in the dogs was of spring mortality and growth retardation 1.85 mg kg−1 day−1 divided over three adminis were noted at 48 mg kg−1 day−1 which is trations. It was also observed that this dose approximately 24 times the MRHD on a mg/ regimen resulted in an occupancy at 81% in the m2 basis. Slight maternal toxicity (clinical hippocampus, 78% in both the colliculi and signs and decreased body weight gain and thalamus, and 77% in the brainstem region food consumption) was seen at this dose. containing the raphe nuclei (Taylor et al. 2017). 124 Selective Serotonin Reuptake Inhibitors

The main plasma metabolite of escitalopram some of these may interact with the in dogs is didesmethylmetabolite of escitalo medication. pram (S‐DDCT). As mentioned under citalo 2) While their pet may respond within a few pram, the QT interval on an EEG can be days, it may be a month before their pet affected by DDCT when the concentrations begins responding. They must be patient. were more than 300 ng ml−1 in beagle dogs that 3) If their pet exhibits mild sedation in the is a known risk factor of sudden deaths (Le beginning, it will probably return to nor Bloc’h et al. 2003). Taylor et al. (2017) men mal levels of activity in two or three weeks tioned that the S‐DDCT concentrations from as its body adjusts to the medication. their suggested dose of 1.85 mg kg−1 day−1 4) If their pet should experience any adverse divided over three administrations was equal events such as vomiting, diarrhea, or to 290 ng ml−1, however, for long‐term therapy seizures, they should contact their vet with escitalopram with this dose in dogs, regu erinarian immediately. lar cardiac screening is recommended. Due to 5) All use of the medication being given is its highest selectivity on the receptors and extra‐label use. This does not mean that transporters as well as little CYP 450 inhibi the drug is not indicated for the problem. tion, these data provided potential options of In fact, there may be an extensive body of using escitalopram in dogs. scientific and clinical evidence support ing the use of this drug for their pet’s problem. It means that the extensive test Important Information for Owners ing required by the FDA for on‐label of Pets Being Placed on Any SSRI usage of the drug for their particular species of pet and their particular pet’s problem has not been conducted or, if The following should be considered when in progress, has not been completed. placing an animal on an SSRI. Exceptions to this may occur after the 1) It is essential that owners inform their publication of this book if the FDA subse veterinarian of all other medication, quently approves any of the SSRIs for herbal supplements, and nutritional sup treatment of various behavior problems plements they are giving their pet, because in domestic animals.

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Miscellaneous Serotonergic Agents Leticia Mattos de Souza Dantas and Sharon L. Crowell‐Davis

University of Georgia, Athens, GA, USA

Introduction Contraindications, Side Effects, and Adverse Events

The psychotropic medications discussed in Buspirone is the only azapirone that is com this chapter have different classifications mercially available in the United States. See the and different modes of action. They are detailed discussion under buspirone below. grouped together due to having in common serotoninergic properties and being the only drugs in their class to be currently used in Adverse Drug Interactions veterinary behavioral medicine. Azapirones should not be given in combina tion with monoamine oxidase inhibitors Azapirones (MAOIs).

Action Overdose

Azapirones are serotonin 1A agonists. See information under buspirone below.

Overview of Indications Clinical Guidelines

Azapirones can be used for a variety of anxi Buspirone is anxioselective with no substan ety disorders and behaviors that may be tial sedative effect. While there may be a affected by chronic anxiety and fear, includ rapid response, it may require one to four ing generalized anxiety disorder, urine mark weeks to take effect. The patient should be ing, separation anxiety disorder, and anxious medicated daily, rather than on an as‐needed cats that are the regular recipients of aggres basis. Doses for dogs, cats, and rabbits are sion. Azapirones may be helpful in certain given in Table 9.1. cases of aggression that are triggered by stress Azapirones are commonly combined and fear signs by one animal, but should be with selective serotonin reuptake inhibitors used cautiously for this problem. (SSRIs) or tricyclic antidepressants (TCAs) in

Table 9.1 Dose of buspirone given orally for various In humans, buspirone has extensive first‐ species. pass metabolism. Food slightly decreases the extent of presystemic clearance of buspirone, Species Dose Example but this effect is not known to have any

−1 clinical significance. Buspirone is given with Dog 0.5–2.0 mg kg q8–24h 20‐kg dog or without food (Bristol‐Myers Squibb Co. 30‐mg, #30 Give 1/2 q12h 2000). It reaches maximum concentrations in about one hour in humans, with a Cat 2.5–7.5 mg/cat q12h 5‐kg cat or 5 mg, #30 subsequent elimination half‐life of about 0.5–1.0 mg kg−1 q12h Give 1/2 q12h 2.5 hours. Rabbit 0.25–1.0 mg kg−1 q12h Buspirone is primarily metabolized by oxidation by the P450 liver enzyme CYP3A4. It has one pharmacologically active patients that do not respond to either of those metabolite, 1‐pyrimidinylpiperazine (1‐PP), two drugs alone. This topic is discussed in and several inactive metabolites. In animal further detail in Chapter 19 (Combinations). tests, there has been found to be about 20 times as much 1‐PP as the parent compound in the plasma, but 1‐PP is about one‐fourth Specific Medications as active (Bristol‐Myers Squibb Co. 2000). Urinary excretion of unchanged buspirone I. Buspirone accounts for about 0.1% of the initial dose. Thus, it is eliminated almost entirely in a Chemical Compound: 8‐[4‐[4‐(2‐pyrimidi biotransformed state (Caccia et al. 1986). nyl)‐1‐piperazinyl]butyl]‐8‐azaspiro[4,5] Buspirone has nonlinear pharmacokinetics decane‐7, 9‐dione monohydrochloride so that repeated dosing results in higher DEA Classification: Not a controlled blood levels than would be predicted from substance studies of blood levels after a single dose is Preparations: Generally available as 5‐, 10‐, given (Bristol‐Myers Squibb Co. 2000). 15‐, and 30‐mg tablets. The 15‐ and 30‐mg Buspirone does not displace highly protein‐ tablets are scored so that they can readily bound medications such as phenytoin, be split into two or three pieces. warfarin, and propranolol. Thus, concurrent medication with buspirone does not generate Clinical Pharmacology the risk of inducing higher plasma levels of Buspirone is a serotonin 1A partial agonist that such drugs (Bristol‐Myers Squibb Co. 2000). has been available in the United States since No significant difference has been found 1987. It is believed to exert its action by block between geriatric and younger adult subjects ing presynaptic and postsynaptic serotonin‐ in the pharmacokinetics of buspirone. Both 1A (5‐HT1A) receptors. It fully antagonizes liver and kidney disease result in decreased presynaptic receptors, but only partially antag clearance and higher levels of buspirone onizes postsynaptic 5‐HT1A receptors. It also (Bristol‐Myers Squibb Co. 2000). Buspirone down‐regulates 5‐HT2 receptors (Eison 1989; appears to have no significant effect on blood Cole and Yonkers 2004). It has moderate affin sugar levels (Dixit et al. 2001). In contrast to ity for D2‐dopamine receptors in the brain benzodiazepines, it stimulates rather than (Peroutka 1985). It does not have anticonvul depresses respiration (Garner et al. 1989). sant, muscle relaxant, or sedative effects and is Buspirone does not appear to have therefore often referred to as anxioselective. cardiovascular effects at clinical anxiolytic The anxiolytic effect appears to be due, at least doses (Hanson et al. 1986). in part, to action on neurons in the dorsal In horses, buspirone and three major raphe (Trulson and Trulson 1986). metabolite classes can be detected in the Spcfc Medication 131 urine 1 to 12 hours after administration This may have been a behavioral response to (Stanley 2000). increased anxiety, analogous to the nervous ness reported in some human patients. Mania Uses in Humans has also occasionally been reported in Buspirone is used to treat generalized anxiety humans (Liegghio and Yeragani 1988; Price disorder in humans. In humans with general and Bielefeld 1989; McDaniel et al. 1990). As ized anxiety disorder, buspirone is more with all medications, some individuals may effective than placebo and similar in efficacy have unique, adverse reactions to buspirone. to diazepam and clorazepate, although with a Unlike the benzodiazepine anxiolytics, slightly slower onset of action (Goldberg buspirone does not produce dependence, and Finnerty 1979; Rickels et al. 1982, 1988). even after several months of treatment The benefit of buspirone over the benzodi (Robinson 1985). azepines includes avoidance of excessive In rats and mice given high doses of bus sedation and physical dependence. Use of pirone for 24 and 18 months, respectively, buspirone likewise avoids the sedation and there was no evidence of carcinogenicity. anticholinergic side effects of TCAs, which Studies of mutagenicity have also revealed are also used in generalized anxiety disorder. no such effect (Bristol‐Myers Squibb Co. It is also more effective than placebo in the 2000). treatment of major depression with moderate In studies of rats and rabbits given high anxiety (Fabre 1990; Rickels et al. 1990). doses of buspirone during pregnancy, there was no impairment of fertility or damage to Contraindications the fetuses (Bristol‐Myers Squibb Company Buspirone should be used cautiously with 2000). MAOIs (Cole and Yonkers 2004). In humans, Buspirone is excreted in milk (Bristol‐ co‐administration of buspirone and erythro Myers Squibb Co. 2000). mycin results in substantial increases in The LD50 given orally in dogs is approxi plasma levels of buspirone with concurrent mately 300 mg kg−1. Death results from increases in side effects. The implications of compromised respiratory function (Kadota this finding in nonhuman animals are et al. 1990). unknown. Nevertheless, if a patient being chronically medicated with buspirone must Overdose be given erythromycin, the dose of buspirone Conduct gastric lavage and provide support should be decreased. Ideally, other antibiotics ive treatment if an overdose is given. There is that do not exhibit this interaction should be no specific antidote (Bristol‐Myers Squibb selected. Co‐administration with itracona Co. 2000). zole also results in substantial increases in Dogs given 3 or 10 mg kg−1 may exhibit plasma levels of buspirone (Bristol‐Myers emesis. The 10 mg kg−1 dose produces Squibb Co. 2000). significantly increased urinary volume and electrolyte excretion (Hanson et al. 1986). Side Effects Side effects are uncommon, which is one advantage to the use of buspirone. Sedation Other Information does not occur in humans, but has been Buspirone causes decreased territorial and reported in nonhuman animals (e.g., see Hart maternal aggression in rats concurrently with et al. 1993). In humans, the more common a substantial decrease in social activity and side effects are dizziness, insomnia, nervous interest, suggesting that the decreased aggres ness, nausea, headache, and fatigue. One cat sion is nonspecific (Olivier and Mos 1992). placed on buspirone by one of the authors On the other hand, it causes no significant (Crowell‐Davis) began hiding in the closet. changes in social or solitary behavior patterns 132 Miscellaneous Serotonergic Agents

of rhesus monkeys (Macaca mulatta) when of buspirone administration. This study, given at a dose of 5–10 mg kg−1 daily PO. This however, did not evaluate the blood levels of is an interesting example of species differ buspirone during treatment so it remains ences in response because it contrasts with unclear if the transdermal treatment actually the increased social interaction noted clini achieved therapeutic doses. cally in the domestic cat. At a dose of 5 mg kg−1 PO buspirone causes Buspirone has also been observed to increased wakefulness and decreased REM decrease territorial aggression in rats but not sleep in cats (Hashimoto et al. 1992). in mice (Mos et al. 1992; Gao and Cutler 1993). Buspirone, at an average dose of 0.46 mg kg−1, Many cats on buspirone begin behaving in blocks motion sickness in cats (Lucot and ways that their owners often summarize as Crampton 1987). Pet cats susceptible to car “more affectionate.” Specifically, they will sickness and other forms of motion sickness stay near the owner more, rub the owner’s may benefit from a dose of approximately limbs more, climb in the owner’s lap more, 1.0 mg kg−1 prior to trips since this will allevi and remain in the owner’s lap for longer peri ate vomiting and may help with anxiety, ods of time than before. The end point of this although the latter effect may only occur with effect appears to be related to the baseline. multiple doses. Thus, cats that were already affectionate Hart et al. (1993) conducted an open trial become intensely affectionate, whereas cats of the effectiveness of buspirone on spraying that were previously not very sociable begin and urine marking in cats. The subjects were exhibiting some degree of social behavior. 47 castrated males and 15 spayed females. While the cat is on medication, it is capable Forty‐two of the males were from multiple of learning, and the social dynamic between cat households while only five were from cat and owner changes so that many cats single cat households. Thirteen of the females retain increased levels of social behavior were from multiple cat households while even after the medication is discontinued, only two were from single cat households. although it may decrease from peak levels Cats were initially medicated with 2.5 mg/cat that occur while on buspirone. q12h PO. If this dose resulted in cessation or substantial reduction by the second week, it was maintained for eight weeks. If the initial Effects Documented in Nonhuman Animals dose was not sufficiently effective, the Cats dose was increased to 5 mg/cat q12h PO Absorption of buspirone is poor when admin for an additional two weeks. If the spraying istered transdermally as opposed to orally. or marking was substantially decreased or Therefore, until such time as a transdermal ceased at this higher dose, the cats were administration technique is developed that is maintained on buspirone at this dose for proven to be effective, it is recommended that eight weeks. Cats that initially stopped buspirone always be given orally (Mealey spraying on the 5‐mg dose, but subsequently et al. 2004). Cháveza et al. (2015) did not see a resumed spraying during the eight weeks, significant difference in the reduction of were increased to 7.5 mg/cat q12h. urine marking between cats that received After the completion of eight weeks of either oral (1 mg kg−1 SID for five weeks) or −1 treatment, the dose of buspirone was transdermal (4 mg kg SID applied inside gradually decreased over a two‐week period. of the ear for five weeks) buspirone. Two If the cat continued to not spray, medication patients on the transdermal treatment group was discontinued entirely. If the cat resumed (2/19) left the study due to presenting allergic spraying at a given lower dose, the cat was reactions to the medication (itching, skin dry then treated for 6–12 months at the lowest ness, and erythema of the ear). A significant effective dose. reduction in marking frequency was observed Thirty‐two of the 62 cats treated with bus following treatment (p < 0.05) for both forms pirone responded favorably. Thus, about Spcfc Medication 133 one‐half of the cats had a positive response. spraying when treatment is discontinued, The majority of cats (81%) were given the while over 90% of cats that respond to 5‐mg dose and 12 cats were given the 7.5‐mg diazepam relapse when treatment is dose. Twenty‐one of the responders exhibited discontinued (Cooper and Hart 1992). Given complete cessation of spraying, whereas the the lower incidence of serious side effects remaining 11 responders exhibited a decrease and lower rate of recidivism, buspirone is of 75% or more. There was a clear effect of clearly a better choice than diazepam for the household type. Thirty‐two of the 55 cats treatment of urine spraying and urine from multiple cat households responded, marking in cats, especially considering the whereas none of the 7 cats from single risks of using diazepam in cats (see Chapter 7 cat households responded. There was no for a detailed discussion). significant effect of sex, although propor Overall (1994) used buspirone at 2.5 mg tionately more females than males responded q12h PO to successfully treat spraying in a favorably. Further studies with larger num cat that had previously responded to bers of cats would be required to determine if diazepam, but had stopped responding. The this trend would become significant with an patient had also been socially isolated by its adequate sample size. own volition from other cats in the household. Of the responders, contact was maintained While on buspirone, the cat not only stopped with the owners of 30 cats after treatment. spraying, but began venturing into other When treatment was discontinued, half of parts of the house. The cat could not be these resumed spraying and half did not weaned off buspirone without resumption of resume spraying. When the relapsing cats the spraying. At the time of publication, the were placed back on buspirone, 2 failed cat had been on buspirone for 16 months to respond to the second treatment, while 13 with no adverse effects. responded. Sawyer et al. (1999) reported on four cats Owners of 4 of the 62 cats reported with psychogenic alopecia that were treated sedation. Nine of the cats exhibited increased with buspirone at 5 mg/cat q12h PO. While aggression toward other cats. In at least in the frequency of grooming decreased in one some of these cases, the cats that became cat, the problem resumed when treatment more aggressive had previously been was discontinued. The problem stopped withdrawn and timid, particularly in their again when treatment with buspirone was relationship with other cats. While on resumed at a dose of 2.5 mg kg−1 q12h PO. buspirone, they became more assertive in While the cat was on treatment for a second their social interactions. Five of the cats time, the owner moved to a new home. When became agitated. Twelve owners reported medication was discontinued for a second increased friendliness toward humans. time, the problem remained resolved. This Forty of the cats had been previously result begs the question of whether the sec treated with progesterone. Of these, 30 were ond treatment cured the problem or whether nonresponders to progesterone. Fourteen of the problem was caused by environmental the 30 that had not responded to progester stresses at the original home. The other three one responded to buspirone. Seventeen cats cats treated with buspirone did not respond had been previously treated with diazepam, at all. While these poor results suggest that eight of these being nonresponders. Of the buspirone may not be a good treatment for diazepam nonresponders, only two responded psychogenic alopecia, the sample size is too to buspirone. small to come to any conclusions other than While buspirone has approximately the that buspirone may be effective in some same initial efficacy as diazepam in the cases. treatment of spraying, there is a lower Ogata (2013) treated a 2.5‐year‐old cas recidivism rate. Specifically, only about 50% trated male domestic shorthair presenting of the cats responding to buspirone resume chronic fear‐induced behavior responses to 134 Miscellaneous Serotonergic Agents

sudden and loud noises, sudden movements, Rabbits and people. Buspirone was administered at a The rabbit cerebral cortex has 5‐HT1A dose of 1 mg kg−1, PO, q12h. During the sec receptors, and the binding rate of buspirone ond week of administration, the behavior of is similar to the binding rate of buspirone in the cat improved and no adverse effects were rats and humans (Weber et al. 1997). Rabbits −1 −1 observed. After three months of treatment, treated with buspirone at 0.05 mg kg day the medication was discontinued for one PO for one month do not exhibit any changes week and the cat noise phobia relapsed. One in blood sugar (Dixit et al. 2001). week after buspirone administration was In a study aiming to investigate the role resumed, the cat was playful and the clinical of 5‐HT and its receptors in mediating signs had again improved. novelty‐elicited head‐bob behavior in rabbits, pretreatment with buspirone Dogs significantly attenuated novelty‐elicited Overall (1995) reported on one case of a dog head bobs (Aloyo and Dave 2007). with multiple behavior problems, including Buspirone may be a useful treatment for fear of approaches by strangers. As part of timid, anxious rabbits. the overall treatment program, buspirone was used (10 mg q24h PO, 23‐kg dog; Parrots 0.4 mg kg−1 daily) for the fear of strangers. Juarbe‐Díaz (2000) used buspirone (0.2 mg, The dog became less fearful and made a PO, q12h) as an adjunct agent in a treatment clear transition to friendly behavior, jump with clomipramine (3.6 mg, PO, q12h) and ing up and licking faces, and playing with environmental modification for a Congo toys with strangers. This response is similar African Gray parrot with feather‐picking and to the increased friendliness to humans self‐injurious behavior. Buspirone was added seen in cats. to treat paradoxical anxiety caused by an Marder (1991) has used buspirone in increase in the dose of clomipramine. Six combination with acepromazine or diaze weeks after addition of buspirone to the pam in intense fear‐inducing situations, such treatment regimen, the owner reported as thunderstorms, with no serious side that intensity of the feather‐picking and self‐ effects, although she does not state the effec injurious behavior was greatly decreased and tiveness of the combination. Acepromazine new feather growth was seen. was also used at a lowered dose. Marder (1991) has also used buspirone in dogs with Other Species mild separation anxiety. Buspirone was used in an experiment that aimed to validate the marmoset (Callithrix Horses penicillata) as a model of fear and anxiety. Because buspirone does not have sedative Seven subjects were first subjected to seven or muscle‐relaxant side effects, it is a better 30‐min maze habituation trials in the absence drug for treating anxiety in horses than the of a taxidermized wild oncilla cat (Felis tig- benzodiazepines. Dodman (personal com rina). Subsequently, the subjects were ran munication, 1996) has treated horses with domly assigned to five treatment trials in the buspirone at up to 250 mg day−1 per horse presence of the “predator” (three buspirone −1 with no adverse side effects. Although it sessions at 0.1, 0.5 and 1.0 mg kg , saline and may be useful in the treatment of anxiety sham injection controls). Buspirone signifi disorders, it must not be used in perfor cantly decreased the frequency of scent mark mance horses pre paring for competition. A ing, while increasing the time spent in 50‐mg dose can be detected in the urine proximity to the predator stimulus (Barros (Stanley 2000). et al. 2001). Spcfc Medication 135

Serotonin Antagonist/ Table 9.2 Dose of trazodone given orally for dogs Reuptake Inhibitors (SARIs) and cats.

Species Dose range Action

−1 −1 a Serotonin antagonist/reuptake inhibitors Dog 1.7–19.5 mg kg day PO (daily or PRN) or block serotonin 2A and 2C receptors and −1 b 1.7–9.5 mg kg PO q8–24h serotonin reuptake. Cat 50–100 mg/cat PO PRNc or Overview of Indications 10.6–33.3 mg kg−1 PO PRNc

a SARIs, more specifically trazodone, can be Gruen and Sherman (2008). b Overall (2013). used for a plethora of situations where fear c Orlando et al. (2015). and anxiety need to be controlled in compan ion animals (such as in surgery recovery and visits or to control behavior after surgery). It veterinary visits) and to treat anxiety disor can be used as needed (PRN) for situational ders. It can be used as a single agent or as an fear and anxiety (i.e. specific phobias), or adjunct drug to enhance another pharmaco daily for long‐term treatment of anxiety dis logical treatment. It has also been used in the orders. Trazodone can also be used with treatment of neuralgia and other painful caution as an adjunct drug to treatments conditions. The prescription of nefazodone, with SSRIs and TCAs and in other polyphar another SARI, is uncommon due to its poten maceutical treatments. tial liver toxicity documented in human Doses for dogs and cats are given in medicine. Table 9.2.

Contraindications, Side Effects, and Adverse Events Specific Medications

Trazodone is the only widely used SARI. I. Trazodone Hydrochloride See the detailed discussion below. Chemical Compound: 2‐[3‐[4‐(3‐chlorophe Adverse Drug Interactions nyl)‐1‐piperazinyl]propyl]‐1,2,4‐ triazolo[4,3‐ a]pyridin‐3(2H)‐one hydrochloride SARIs should not be given in combination DEA Classification: Not a controlled with MAOIs. substance Preparations: Available as 50‐, 100‐, 150‐, Overdose and 300‐mg (scored) tablets and extended release 150‐ and 300‐mg tablets. See information under trazodone below. Clinical Pharmacology Clinical Guidelines Trazodone is a triazolopyridine antidepres sant agent. The action of 5HT2A/AC antago Trazodone has antidepressant effects when nism with inhibition of the serotonin used in moderate to high doses. In lower transporter (SERT or 5‐HTT) occurs on doses, it is useful to treat insomnia and moderate to high doses. In low doses, besides in situations where sedation or activity effective 5HT2A antagonism, trazodone also restriction is desirable and appropriate acts as a H1 histaminic and α1 adrenergic (i.e. to decrease panic during veterinary receptor antagonist. This mode of action 136 Miscellaneous Serotonergic Agents

causes a hypnotic effect. When trazodone effects at serotonin 1 receptors, is active at reaches the antidepressant action via SERT serotonin 2C receptors and may account for inhibition and raising serotonin levels, the some of the adverse effects reported in the concomitant 5HT2A/AC antagonism avoids literature (i.e. nausea, headache) (Odagaki some of the side effects seen in treatments et al. 2005). Excretion is mostly via renal with SSRIs and TCAs, such as sexual dys mechanisms and only a very small amount function, insomnia, and anxiety (Stahl 2009). (0.13%) is excreted unchanged in the urine. This combination of 5HT2A/AC antagonism About 21% is excreted in the feces. additionally enhances the neurotransmission Elimination half‐life of the parent compound of neropinephine and dopamine in the is approximately 7 hours for the immediate‐ prefrontal cortex (Balsara et al. 2005; Stahl release tablets and 10 hours for the extended 2009). Trazodone may also increase seroto release tablets. nin concentrations by attenuating the Peak blood concentrations occur approxi inhibitory tone of γ‐aminobutyric acid mately one hour after oral administration in neurotransmitters in the cerebral cortex fasted human subjects, versus two hours (Luparini et al. 2004). Its dose‐dependent when taken with food (Al‐Yassiri et al. 1981). antinociceptive effects seem to be mainly The plasma concentration‐time curve is influenced by the μ1‐ and μ2‐opioid receptor increased when trazodone is taken with a subtypes combined with the serotoninergic meal. Oral availability is approximately 65% receptor (Schreiber et al. 2000). (immediate‐release tablets) (Bryant and The immediate release formulations of tra Ereshefsky 1992). Approximately 90–95% is zodone have rapid onset and short duration bound to plasma proteins. Trazodone has a of action, so when used to treat evening biphasic elimination pattern with a fast phase symptoms (insomnia, phobias with onset at of three to five hours followed by a slower night) one dose before bedtime is usually suf phase lasting six to nine hours (Stahl 2011). ficient. However, for daily treatment of anxi In dogs given 8 mg kg−1 IV, volume of distri ety disorders, trazodone commonly needs to bution was 2.53 ml kg−1 (mean), elimination be administered twice to three times a day, half‐life 169 minutes, and plasma total body which can lead to undesired sedation (Stahl clearance was 11.15 ml min−1 kg−1. After the 2009). It has fewer anticholinergic effects same dose PO, bioavailability was 85% and than TCAs (Haria et al. 1994). In a study in elimination half‐life was 166 minutes. Peak anesthetized dogs, trazodone had little effect plasma levels occurred at 445 minutes (mean) on cardiac function when compared to imi but there was a great inter‐subject variation. pramine. There was no evidence of heart IV administration was associated with tachy block or sign of rhythm disturbances other cardia in all dogs in this study, and aggression than slowing in normal sinus rhythm (Gomoll in half of the subjects (Jay et al. 2013). et al. 1979). When studied in rats, trazodone Trazodone is a substrate of the was found to have the lower cardiac toxicity cytochrome P450 3A4 (CYP3A4) enzyme compared to etoperidone and imipramine and its metabolism can be inhibited by (Lisciani et al. 1978). Trazodone is among the CYP3A4 inhibitors such as ketocona the antidepressants with lower seizure risk zole (Plumb 2015). (Pisani et al. 2002). Carbamazepine induces CYP3A4. Fol In humans, trazodone is extensively lowing co‐administration of carbamazepine metabolized in the liver, with < 1% being 400 mg day−1 with trazodone 100–300 mg excreted unchanged in the urine (Al‐Yassiri daily in humans, carbamazepine reduced et al. 1981). The most important metabolite, plasma concentrations of trazodone (as well m‐chlorophenylpiperazine (m‐CPP) is gen as m‐CPP) by 76% and 60%, respectively, erated by CYP3A4 metabolism and is bro compared to pre‐carbamazepine values ken down by CYP2D6. M‐CPP has agonistic (Otani et al. 1996). Spcfc Medication 137

Uses in Humans Side Effects Trazodone is mainly used to treat depression, Nausea, vomiting, diarrhea, edema, drowsi insomnia, anxiety, and neuralgia (Papakostas ness, dizziness, incoordination, sedation, leth and Fava 2007; Stahl 2011). argy, blurred vision, changes in weight, headache, muscle pain, dry mouth, bad taste in Contraindications the mouth, stuffy nose, constipation, or change Trazodone should not be used in conjunction in sexual interest/ability are reported in human with MAOIs (Stahl 2011) or in patients that medicine. Additionally, tremors, seizures, are hypertensive (Plumb 2015). A minimum mania, priapism, allergic reactions (rare), sui two to three weeks washout period is advisa cidal behavior, QT prolongation, arrhythmias, ble before or after MAOI administration hypotension, syncope, and sinus bradycardia (Virga 2010). It should be used with caution have also been reported in humans. Low levels in patients with severe cardiac disease, of potassium or magnesium in the blood can hepatic and/or renal disease, and glaucoma. increase the risk of QT prolongation, so condi In humans, co‐administration of trazodone tions that cause severe sweating, diarrhea, or and SSRIs such as fluoxetine may raise trazo vomiting and diuretics used together with tra done plasma levels. The implications of this zodone may increase the risk (Al‐Yassiri et al. finding in nonhuman animals is unknown 1981; Tarantino et al. 2005). but caution when combining more than In a study in 56 dogs (Gruen and Sherman one serotoninergic pharmaceutical is always 2008) vomiting (1 subject), gagging (1), colitis warranted due to the increased risk for (1), increased excitement (2), sedation (2), serotonin syndrome (Pilgrim et al. 2010). increased appetite (2) and perceived behavio Co‐administration with azole antifungals, ral disinhibition (2) were the side effects macrolide antibiotics, and phenothiazides reported. Further details on this study are may increase plasma levels of trazodone. outlined in the species‐specific section below. Trazodone may block the hypotensive effects Tolerance is not associated with trazo of some hypotensive drugs and might inter done use in the immediate release form. fere with the antihypertensive effects of The extended release form causes less day clonidine (Al‐Yassiri et al. 1981). time sedation than the immediate release There are reports of increased and form in humans, allowing for higher dos decreased prothrombin time in humans ages that reach antidepressant effects (Stahl taking warfarin and trazodone. Priapism 2009). A comparison between the two forms is reported in human medicine. Trazodone of trazodone has not been done in compan is considered to be an antidepressant with a ion animals so far. low seizure risk compared to other classes of Trazodone passes into breast milk. Its antidepressant drugs, but it should still be safety during pregnancy and lactation has used with caution in patients with a history not been studied in companion animals and of seizures. Tramadol increases the risk of the Food and Drug A (FDA)classifies it as a seizures in patients taking antidepressants category C drug for use during pregnancy. −1 and metoclopramide may increase the risk The oral LD50 of the drug is 610 mg kg of serotonin syndrome. Concurrent use of in mice, 486 mg kg−1 in rats, and 560 mg kg−1 trazodone with aspirin or non‐steroidal in rabbits. anti‐inflammatory drugs (NSAIDs) may Trazodone is non‐habit‐forming but increase the risk of gastrointestinal (GI) should be tapered off gradually to avoid bleeding. The use of central nervous sys withdrawal effects (Stahl 2011). tem (CNS) depressants with trazodone may cause addictive effects and trazodone Overdose may increase digoxin or phenytonin concen There is no specific antidote for trazodone. trations (Plumb 2015). The most severe reactions reported to have 138 Miscellaneous Serotonergic Agents

occurred with overdose of trazodone in Effects Documented in Nonhuman Animals humans have been priapism, respiratory Cats arrest, seizures, and electrocardiogram Orlando et al. (2015) conducted a study, the changes. Treatment should be symptomatic aim of which was to evaluate the safety and and supportive in the case of hypotension or efficacy of oral trazodone as a single dose excessive sedation and gastric lavage is agent for sedation in cats. The objective of recommended. Forced diuresis may be useful the study was to test if trazodone can be a in facilitating elimination of the drug. useful drug to decrease fear and anxiety prior to veterinary visits. Other Information Six male neutered laboratory cats were Veasey et al. (1999) evaluated the use of given single 50, 75 and 100 mg doses of trazodone with L‐tryptophan on sleep‐ trazodone and placebo PO. The cats’ disordered breathing in the English bulldog. weight ranged from 3.0 to 4.7 kg. Each cat Based on the hypothesis that in obstructive served as its own control and received the sleep apnea hypopnea syndrome (OSAHS) four treatments over a four‐week period −1 reduced serotoninergic drive plays a role (doses were respectively 10.6–16.7 mg kg , −1 −1 in upper airway collapse, the authors per 16.0–25 mg kg and 21.3–33.3 mg kg ). formed multitrials/dose, multidose, rand There was a washout period of four to omized sleep studies testing the effectiveness seven days between treatment days. Pre‐ of a combination of trazodone, and L‐tryp and post‐study laboratory values of com tophan, in an animal model of OSAHS plete blood count, chemistry panel, and (English bulldog). Trazodone/L‐tryptophan urinalysis and physical examinations were caused dose‐dependent reductions in res compared; during each four hours period piratory events in non‐rapid‐eye‐movement post‐treatment, sedation was measured via sleep (NREMS) and rapid‐eye‐movement accelerometers and video observations sleep (REMS). Trazodone/L‐tryptophan scored by an observer blinded to treat dose‐dependently reduced sleep fragmenta ment. Behavioral responses and stress tion, increased sleep efficiency, enhanced measurements were scored and examina slow‐wave sleep, and minimized sleep‐ tions were performed on the cats 90 min related suppression of upper airway dilator utes after treatment. Six behaviors were activity. The study concluded that trazodone scored to measure behavioral responses to with L‐tryptophan can effectively treat examinations (vocalization, struggling, sleep‐disordered breathing (SDB) in this aggression, hypersalivation, immobility, canine model of OSAHS and that the effec and open mouth breathing). Stress was tiveness of this therapy may be related to measured using McCune’s cat stress assess increased upper airway dilator activity in ment scale pre‐examination, during the sleep and/or enhanced slow‐wave sleep. exam and post‐examination. Potential serotoninergic mechanisms for Accelerometer data showed trazodone 50 mg, reducing SDB include direct 5‐HT excita 75 mg, and 100 mg caused sedation as meas tory effects at upper airway motoneurons ured by activity reduction (83%, 46%, and through increased production of 5‐HT after 66%, respectively), which contrasted with a administering L‐tryptophan, or through 14% activity increase after placebo. There direct excitation by trazodone’s metabolite, was a significant reduction in video observa m‐CPP and excitation of respiratory‐related tion scores when cats were given trazo done premotor neurons through similar mecha 100 mg compared with placebo. Mean nisms. The dose range of trazodone used latency to peak sedation for trazodone was 3.3–13.3 mg kg−1 and of L‐tryptophan 100 mg occurred at two hours. Scores was 44.3–174.3 mg kg−1. No adverse effects for behavioral response to examination, per were reported. formed at 90 minutes post‐treatment, were Spcfc Medication 139 not significantly different between cats study to exam trazodone’s efficacy for receiving trazodone 100 mg and placebo. behavior pathologies in companion dogs, as This study did not report any adverse well as treatment protocol, dose range, effects, changes in physical examinations or concurrent drug use, adverse events, and laboratory values after trazodone adminis therapeutic response in patients unresponsive tration. The authors concluded that trazo to other pharmacologic agents. done was well tolerated and caused sedation The study was a retrospective case series at all doses. with 56 privately owned dogs with anxiety This study used a small sample of cats and disorders treated at a referral veterinary not all doses were randomized, but it pioneers behavior clinic between 1995 and 2007. the documentation of the use of trazodone in Medical records of dogs with anxiety disor feline patients. More studies are warranted ders adjunctively treated with trazodone were to evaluate trazodone’s safety and efficacy in retrospectively evaluated with respect to sig different behavioral pathologies in cats. nalment, primary and secondary behavioral Stevens et al. (2016) designed a study that diagnoses, physical examination results, aimed at evaluating the efficacy of a single hematologic data (complete blood count and dose of trazodone for reducing anxiety in cats serum biochemical panel), pharmacologic during transport to a veterinary hospital and management, and outcome. The dogs facilitating medical handling. Ten client‐ included were given a primary or secondary owned cats with a history of anxiety during diagnosis of an anxiety or phobic disorder, transport or examination were included. Each had been treated with trazodone, and had cat was randomly assigned to receive 50 mg of subsequent follow‐up for at least one month. trazodone or a placebo 1–1.5 hours prior to Anxiety or phobic disorders diagnosed being put in their carriers and driven to the included generalized anxiety, separation anx hospital (dose ranged from 7.7 to 15.2 mg kg−1). iety, travel anxiety, storm phobia, noise pho Owners were blinded to treatment and scored bia, and combinations thereof. signs of anxiety in their cats (using three dif All dogs were treated with individually tai ferent scoring systems) before and during lored behavior therapy in conjunction with transport, at the clinic’s waiting room, during medication. The general pharmacologic and immediately after examination. The treatment protocol consisted of a baseline attending veterinarian also scored the cats dose of a TCA (clomipramine, amitriptyline, during their physical exam. After a one to or imipramine) or an SSRI (fluoxetine, three‐week wash‐out period, each cat sertraline, or citalopram), that at the time received the opposite treatment and the pro were providing insufficient relief of clinical tocol was repeated. Trazodone resulted in a signs of anxiety prior to the addition of significant improvement in the cats’ signs of trazodone. anxiety during transport compared to pla Trazodone administration was given at an cebo. Veterinarian and owner scores for ease initiation dose (half of the initial target dose of handling also improved with trazodone. administered for three days) to identify No significant differences were identified potential adverse effects. This strategy was between treatments in heart rate or other implemented because according to the physiological variables measured by the authors, in a preliminary trial, a small per participant clinicians. The only side effect centage of dogs that initially received the full reported was sleepiness in one cat. target dose developed sedation or adverse effects (transient soft feces or diarrhea) pre Dogs sumptively attributed to trazodone. After Gruen and Sherman (2008) explored the use the initiation dose, the target dose was estab of trazodone as an adjunctive treatment for lished as the lowest effective dose needed anxiety disorders in dogs. This was the first for behavioral calming. Additional dose 140 Miscellaneous Serotonergic Agents

increments were made empirically as administration. Several dogs were anesthe needed. The number of dose adjustments tized without complications for elective made varied by individual, severity of clini surgeries during their course of trazodone cal signs, and duration of trazodone treatment. administration. Three administration schedules were used The dogs in the study were 26 spayed in combination with an SSRI or TCA: 14 dogs females, 29 neutered males, and 1 sexually received trazodone as a daily medication, intact male that was neutered during the 20 received trazodone as needed for anxiety, course of treatment. All dogs were medi and 22 received trazodone both daily and as cally screened via physical examination, needed. In general, dogs with generalized complete blood count, serum biochemical forms of anxiety disorders were treated daily profile, and thyroid panel prior to pharma with trazodone, whereas dogs with anxiety cotherapy. All dogs had follow‐up for at that appeared more episodic or had recog least one month following initiation of nized triggers were treated as needed. Seven trazodone administration. dogs with storm phobia received daily and Thirty‐seven (66%) dogs were followed up as‐needed administration during the storm for at least one year following initiation of season (April through September). The high trazodone treatment. Of the remaining 19 est dosage (19.5 mg kg−1 [8.86 mg lb−1]) repre dogs, 3 were in their first year of trazodone sented dogs in which trazodone was given treatment at the time of the study, 12 were both daily and as needed (at the maximum lost to follow‐up prior to 1 year of treatment, dose allowed as needed). No dog received an and 4 received trazodone for < 1 year. Those individual dose of trazodone > 300 mg. The four dogs included three in which trazodone maximum daily dose was 600 mg, which administration was discontinued because of represented a combined twice‐daily and adverse effects and one that was euthanatized as‐needed dose in a dog that weighed 36 kg for unrelated health reasons. (79.2 lb). For as‐needed doses, most clients Concomitant psychoactive medications observed that behavioral effects occurred included TCAs (clomipramine, amitripty within one to two hours of trazodone admin line, and imipramine) in 31 dogs, SSRIs istration. See a comprehensive list of the (fluoxetine, sertraline, and citalopram) in 21 adverse effects observed in the dogs in this dogs, benzodiazepines (alprazolam, loraze study in the section on Side Effects. In gen pam, and clorazepate) in 18 dogs, the eral, adverse effects were mild, with only azaspirone buspirone in 12 dogs, the antipsy three dogs requiring discontinuation of chotic reserpine in 2 dogs, and a nutraceuti the drug. cal (melatonin) in 1 dog. Twenty‐one dogs Most clients for whom a direct comment received more than two psychoactive was recorded in the clinical record (n = 40) medications concomitantly, including 12 stated that their dog was either very (29 dogs treated with an SSRI or TCA in combi [73%]) or somewhat (5 [13%]) improved as a nation with a benzodiazepine. Concurrent result of use of trazodone as an adjunctive nonpsychoactive medications prescribed by agent. Three (8%) clients reported no effect the referring veterinarian included antimi of trazodone on their dog’s anxiety, and 3 crobials, heartworm‐preventative products (8%) reported adverse effects that led to (oral and topical administration), flea‐ discontinuation of treatment. For 16 (29%) preventative products, antihistamines, non dogs, no direct comment was made in the steroidal anti‐inflammatory medication, and record regarding the specific effect of the thyroid hormone supplementation. No ami medication. Using continuation of treatment traz products were coadministered. One dog for > 3 months as a measure of treatment was also receiving potassium bromide for satisfaction, trazodone administration was seizures that existed prior to trazodone useful in the treatment of anxiety for 46 Spcfc Medication 141

(82%) dogs. Duration of treatment with In a proceeding’s abstract, Virga (2004) trazodone for those dogs ranged from 3 to shared the outcome of 18 dogs diagnosed 95 months (almost eight years), with a mean with a variety of anxiety‐based behaviors of 24.8 months. and anxiety disorders that were previously Another important observation of this refractory to treatment with SSRIs (either study is that even though trazodone was not fluoxetine, paroxetine, sertraline or citalo used as a treatment for aggression, several pram). Trazodone was added as an augment dogs had some aggression as part of their ing pharmaceutical in doses ranging from spectrum of signs and no increase of 1.41 to 5.14 mg kg−1 PO b.i.d. Client‐based aggression was reported. Aggression was global assessment of patient responses was also not reported as an adverse event in any scored on a five‐point scale (0 = no improve of the dogs that were part of this study. ment; 5 = complete resolution of clinical Gruen et al. (2014) investigated the safety signs); global assessment scores were and efficacy of oral administration of trazo reported as no or minimal improvement done to facilitate confinement and calming with SSRI mono‐therapy. After trazodone after orthopedic surgery in dogs. This study was titrated to a clinically effective dose for a was a prospective open‐label clinical trial period of four weeks, global assessment and 36 client‐owned dogs were included. scores recorded marked improvement to On the day after surgery, the dogs were admin complete resolution of clinical signs in seven istered trazodone (approximately 3.5 mg kg−1 patients. Follow‐up at three and six months [1.6 mg lb−1], PO, q12h) with tramadol demonstrated sustained clinical response (4–6 mg kg−1 [1.8–2.7 mg lb−1], PO, q8 to 12h) for all seven patients. for pain management purposes. After Three case reports on the clinical use of three days, administration of tramadol was trazodone for behavioral pathologies have discontinued, and the trazodone dosage been published after Gruen and Sherman’s was increased (approximately 7 mg kg−1 (2008) study. Gruen and Sherman (2012) [3.2 mg lb−1], PO, q12h) and maintained for at treated a four‐year‐old castrated male golden least four weeks. When needed, trazodone retriever diagnosed with stormphobia with dosage was increased (7–10 mg kg−1 [3.2– behavior therapy, trazodone (5 mg kg−1 PO 4.5 mg lb−1], PO q8h). The clients completed one hour prior to storms or at the first sign of an electronic survey rating their dogs’ confine storm‐related anxiety behaviors) and a collar ment tolerance, calmness or hyperactivity impregnated with a chemical marketed as level, and responses to specific provocative being calming to dogs.1 Five weeks later, the situations prior to surgery and 1, 2, 3, and clients reported that the dog was tolerating 4 weeks after surgery and at the post‐surgery the medication well with no side effects, and evaluation (at 8–12 weeks). Most (32/36 [89%]) that the clinical signs decreased in intensity. of owners reported that their dogs, when given The most concerning clinical sign to the trazodone during the 8–12 weeks following clients (destruction) was no longer seen after orthopedic surgery, improved moderately or 10 weeks of treatment. extremely with regard to confinement toler Bennett (2013) treated an 11‐month‐old ance and calmness, as compared to their toler neutered male Great Dane diagnosed with ance prior to the initiation of trazodone separation anxiety disorder with behavior treatment. Trazodone was well tolerated even therapy, environmental enrichment, fluoxe when combination with NSAIDs, antimicrobi tine (1.8 mg kg−1 PO q24h), and clonazepam als, and other medications. No dogs were (0.085–0.128 mg kg−1 PO) one to two hours withdrawn from the study due to adverse reac prior to owner departure. Due to side effects, tions. Owner‐reported median onset of action the clonazepam dose was decreased to of trazodone was 31–45 minutes, and median 0.085 mg kg−1 and trazodone (1.6 mg kg−1 PO duration of action was ≥ 4 hours. q12h initially and increased to 3.2 mg kg−1 142 Miscellaneous Serotonergic Agents

within a week) was added to the treatment Gilbert‐Gregory et al. (2016) evaluated the regimen. After the patient received the first effects of treatment with trazodone on stress trazodone dose, it became lethargic, anorexic, signs of hospitalized dogs. Sixty dogs were and developed diarrhea. A physical examina observed for signs or behaviors indicative of tion did not find another cause of the reported stress ≤ 45 (time 1) and 90 minutes (time 2) clinical signs, so trazodone was discontinued after the administration of trazodone. A sec and the dog was prescribed a bland diet, ond group of 60 dogs was enrolled to control which resolved the clinical signs. The clients for environmental factors and did not receive did not allow for any laboratory testing and the drug. Trazodone administration was ini diagnosis that could have ruled out other tiated at 4 mg kg−1 every 12 hours with the causes for gastroenteritis or colitis. dose increased to 10–12 mg kg−1 or the fre Moesta (2014) treated a nine‐year‐old quency to every eight hours when needed for spayed female mixed breed dog presented for desired calming and anxiolytic effects. The stereotypical motor behavior (spinning) as a amount given did not exceed 300 mg dose−1 clinical sign of separation anxiety disorder, or 600 mg 24 hours−1. For dogs that were besides other more common signs of this receiving tramadol, trazodone was started at mental illness (anxiety signs related to owner 3.5 mg kg−1 every 12 hours. Signs or behav departure and destruction when left alone). iors (scored as present or absent by an Treatment consisted of behavior therapy, the observer) were assessed individually and adoption of a consistent and predictable grouped into behavioral summation catego schedule, exercise, environmental enrich ries (frenetic: lip licking, pacing, panting, ment, fluoxetine (1.1 mg kg−1 PO q24h), and spinning, trembling, etc.; freeze: averting clonazepam (0.11–0.44 mg kg−1 PO one hour gaze, pinning back ears and showing whale before owner departures). Clonazepam was eyes; fractious: growling, lunging, showing decreased to 0.33 mg kg−1 (0.44 mg kg−1 teeth, snapping). Results were compared caused ataxia) and fluoxetine was switched to within the treatment group and between paroxetine (0.3 mg kg−1 PO q24h initially, treatment and environmentally matched ani titrated up to 1.5 mg kg−1 PO q24h) due to mals. Lip licking, panting, and whining were anorexia. Six months after the initial appoint reduced (present at time 1 and absent at time ment, the spinning behavior had completely 2) in the treatment group and not in the con ceased. However, it started reoccurring when trol group. The median number of stress‐ the dog was left alone. Paroxetine was related behaviors of frenetic and freeze switched to clomipramine (titrated up to behaviors was significantly lower at time 2 3 mg kg−1 PO q12h), which decreased the compared to time 1 in the treatment group. spinning. At the nine‐month recheck appoint No significant changes were identified ment, the spinning seemed to be recurring, between time points for these summary vari possibly due to the development of tolerance ables for environmentally matched dogs. to clonazepam. Trazodone (5.5 mg kg−1 PO as One dog presented aggression following needed, before leaving the dog alone) was administration of trazodone twice and treat added to the treatment program. The dog ment was discontinued. No other adverse seemed to be moderately sedate one to two events were reported. The results support hours after trazodone administration but the use of trazodone to alleviate stress in hos spinning no longer occurred. pitalized dogs.

Note

1 DAP, CEVA Animal Health, Libourne, France. Reference 143

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Anticonvulsants and Mood Stabilizers Sharon L. Crowell‐Davis1, Mami Irimajiri2, and Leticia Mattos de Souza Dantas1

1 University of Georgia, Athens, GA, USA 2 Kitasato University, Aomori, Japan

Action with seizures. It increases neuronal respon siveness to GABA and decreases Ca inflow in Anticonvulsants or antiepileptic medications neurons. are used primarily for the treatment of Phenobarbital may affect behavior in some epilepsy. However, it has been recognized in animals because it can reduce anxiety. This human medicine that antiepileptic drugs effect is reported in mice, rats, monkeys, and may be effective for psychiatric conditions baboons (Patel and Migler 1982; Kilfroil et al. such as bipolar depression and anxiety 1989; Griffiths et al. 1991; Bertoglio and disorders (Stahl 2008). Some of these drugs Carobrez 2002). However, phenobarbital and have also been proven to be effective in other GABA‐A‐stimulating drugs such as the treatment of painful conditions, such as benzodiazepines can increase agitation and neuropathic pain (Backonja et al. 1998). anxiety in dogs (Siracusa 2016). Anticonvulsants have a variety of mecha Gabapentin and pregabalin selectively bind nisms and actions on neurotransmitter to and have high affinity to the α2 delta site of receptors, so it is not surprising that these voltage‐sensitive calcium channels (VSCCs) medications can be useful in mental health (Stahl 2008). They seem to have little or no care (Piedad et al. 2012). Some anticonvul effect as mood stabilizers in humans but are sants can change and modulate neuronal used for various pain conditions from membrane polarity, neurotransmitter activ neuropathic pain to fibromyalgia, and for ity, and neuronal firing, affecting signal various anxiety disorders (Stahl 2008). transduction (Stahl 2008; Piedad et al. 2012). Carbamazepine binds to the alpha subunit Anticonvulsants act principally by reducing of VSCCs and could act on the calcium and glutaminergic excitation, gamma‐aminobutyric potassium ion channels. This mechanism of acid (GABA)‐A stimulation for GABA‐ergic action may enhance the inhibitory actions activation, and blocking voltage‐gated Na+ or for GABA. Carbamazepine is used to treat Ca+ channel (Table 10.1). manic phases of bipolar disorder in humans, Psychiatric or mental health disorders are and it is also found to be effective in often treated effectively with antidepressants controlling aggressive behavior in bipolar and/or anxiolytics. However, these medica depression or dementia in humans (Tariot tions can interact with anticonvulsant drugs. et al. 1998; Stahl 2008). Carbamazepine has Phenobarbital is commonly used for dogs been used to treat aggression and agitation in

Table 10.1 Activity profiles on selected anticonvulsants. includes consideration of the strength of the evidence for each medicine, along with other Voltage‐gated ion variables such as the medication’s safety and Anticonvulsant channel blockade tolerability profile, its pharmacokinetic properties, formulations, and expense Carbamazepine Inhibit Na↑ (Glauser et al. 2006). Gabapentin Inhibit Ca2↑ (L‐type)a b The treatment of epilepsy in pregnancy is Inhibit α2δ subunit particularly challenging in that the fetal and ↑ Pregabalin Inhibit Ca2 maternal risks associated with maternal Inhibit α2δ subunit seizures need to be balanced against the Source: Piedad et al. (2012). potential teratogenic effects of antiepileptic a L type = voltage gated calcium channel subtypes with drugs (AEDs). No systematic information is varying levels of threshold activation. b α2δ subunit = a constituent subunit within different available on the pharmacokinetics of the channel subtypes. newer AEDs (e.g. gabapentin, pregabalin, tiagabine, topiramate, or zonisamide) dur psychotic and bipolar affective disorders ing pregnancy (Tomson and Buttino 2007). in humans. Carbamazepine has also been In an open prospective clinical study, used to control aggression in dogs and cats plasma clearance of phenytoin, phenobar (Schwartz 1994; Galliccio and Notali 2010). bitone, and carbamazepine was assessed in 14 epileptic patients during and after preg nancy. Plasma clearance showed a marked Overview of Indications increase during pregnancy, reached a maxi mum just before or after delivery, and then Anticonvulsant drugs were primarily devel decreased to early pregnancy values (Dam oped for the treatment of epilepsy, a neuro et al. 1979). logical condition that affects approximately In veterinary clinical behavioral medicine, 50 million people worldwide (Mackey 2010). when stereotypic/compulsive behaviors such They reduce seizure frequency by sup as tail‐chasing, self‐licking or self‐injurious pressing neuronal excitability via various behaviors are observed, these clinical molecular targets in the synapse, including signs have traditionally been diagnosed as voltage‐gated ion channels, voltage‐gated compulsive or obsessive‐compulsive disor sodium channels, GABAA (γ‐aminobutyric ders. However, some of these cases are multi acid type A) receptors, and glutamate recep factorial and other medical problems such tors (Piedad et al. 2012). as psychomotor seizure activity and pain In the veterinary literature, indications for can coexist, and polypharmacy might be the anticonvulsants (besides treating disorders that most effective approach. cause seizures) include stereotypic behavior and obsessive‐compulsive disorders, including tail‐chasing, fly‐snapping, or excessive self‐ Specific Medications licking in dogs and cats (Bain 2012). Some of these conditions have been proven to be caused I. Carbamazepine by seizure activity as opposed to anxiety, so the actual reason for efficacy of treatment can vary. Chemical Compound: C15H12N2O 5H‐ dibenz[b,f]azepine‐5‐carboxamide DEA Classification: Not a controlled Clinical Guidelines substance Preparation: Available as chewable 100‐ or The ultimate choice of anticonvulsants for an 200‐mg tablets, as 100‐, 200‐ and 400‐mg individual patient with recently diagnosed or XR tablets, and as a suspension of untreated epilepsy in humans usually 100 mg/5 ml (teaspoon). Seii Medication 149

Clinical Pharmacology the dog was euthanized, aggression toward Carbamazepine is one of the oldest anticon the owner was under control while increas vulsant drugs available. In spite of this, its ing the carbamazepine dosage as needed mechanism of action has still not definitively (Galliccio and Notali 2010). been established. It apparently decreases In 126 epileptic dogs with spontaneously postsynaptic response and blocks post‐ recurring generalized tonic–clonic (grand tetanic activation. It is metabolized in the mal) seizures, epidemiological aspects and liver by CYP3A4. It has one active metabolite, the efficacy of chronic oral treatment with carbamazepine‐10,11‐epoxide. Its half‐life in common antiepileptic drugs were studied. humans is highly variable, ranging from 25 to Furthermore, the pharmacokinetics of antie 65 hours. Excretion is 72% in the urine and pileptic drugs in dogs was compared with the 28% in the feces (PDR Staff (2017). values known for humans. Comparison of Carbamazepine is still extensively used the pharmacokinetics of antiepileptic drugs for treatment of epilepsy in children. showed that some drugs were suited for Oral bioavailability of carbamazepine in maintenance therapy in dogs (primidone, children is about 75–85%, and it is approxi phenobarbital, ethosuximide, trimethadi mately 75–85% bound to plasma proteins. one) whereas others appeared not to be ide Pharmacokinetics of carbamazepine in chil ally suited because of their short half‐lives dren is dependent on age and body weight (phenytoin, carbamazepine, valproic acid, and is highly variable due to the influence of diazepam, clonazepam, nitrazepam) the dosing regimen and any co‐medication. (Loscher et al. 1985). Currently, this is not a The importance of human leukocyte antigen common medication for use in veterinary (HLA) typing for prediction of adverse drug medicine. reactions to carbamazepine in children was confirmed (Djordjevic et al. 2017). For safe Cats and effective use of carbamazepine in this Schwartz (1994) reported successful treat population, physicians are asked to adjust the ment of two cats with owner‐directed aggres dosing regimen according to existing patterns sion using carbamazepine at 25 mg q12h. of genetic and environmental influences (Djordjevic et al. 2017). II. Gabapentin This medication can be effective in the manic phase of bipolar disorder treatment Chemical Compound: C9H17NO2 (Stahl 2008). It is also effective for the DEA Classification: The status of gabapen treatment of neuropathic pain (Stahl 2008). tin as a controlled substance is changing, as some individual states are now changing Side Effects its classification within that state, while the Carbamazepine has suppressant effects on DEA does not yet list it as a controlled the bone marrow, requiring blood cell counts substance to be monitored. It can cause fetal toxicity, Preparations: Veterinary approved product: such as neural tube deficit (Stahl 2008). none. Available as: 100‐, 300‐, 400‐mg oral capsules and as 600‐ and 800‐mg tablets, Effects in Non‐human Animals and as a 50‐mg ml−1 pint bottle. Dogs In one report, a dog with unpredictable Clinical Pharmacology aggression to people was examined and an Gabapentin is a GABA analogue. It binds MRI found an arachnoid cyst in the with high affinity to α2‐delta subunits of retrocerebellar location. The dog was treated voltage‐activated Ca2+ channels. Its half‐life with dexamethasone but showed avoidance in humans is five to seven hours. It is behaviors to the owner, so carbamazepine eliminated, unchanged, in the urine (PDR −1 (10 mg kg Q12h) was prescribed. Until Staff (2017). 150 Anticonvulsants and Mood Stabilizers

Uses in Humans gabapentin overdose can cause drowsiness, Gabapentin can be an effective adjunctive ataxia, dizziness, nausea/vomiting, tachy treatment for patients with refractory partial cardia, and hypotension (Klein‐Schwartz epilepsy. It is usually well tolerated and et al. 2003). Large overdoses can cause it appears to have a favorable efficacy‐to‐ fatality (Middleton 2011). toxicity ratio in human study (UK Gabapentin Study Group 1990). Gabapentin Doses in Nonhuman Animals also provides analgesic activity for patients For patients that have been on higher doses with neuropathic pain and has the advantage and/or medicated for a long period of time, a of a low side effect profile and drug toxicity gradual decrease in dose, rather than an (Rosner et al. 1996). One study showed that abrupt discontinuation, is recommended. gabapentin is effective for pain in post‐ Abrupt discontinuation can lead to herpetic neuralgia syndrome without side seizures. effects (Rowbotham et al. 1998). It can also be effective for pain from peripheral neuropathy in diabetes mellitus (Backonja Other Information et al. 1998). Preliminary clinical studies suggested that gabapentin might produce analgesia and Contraindications reduce the need for opioids in postoperative patients. Gabapentin in a total dose of Allergy to gabapentin or any of the inactive 3000 mg, administered before and during ingredients in the medication. Severe liver or the first 24 hours after abdominal hysterec kidney disease. tomy, reduced morphine consumption by 32%, without significant effects on pain Side Effects scores. No significant differences in side Of 462 dogs reported to the ASPCA’s APCC effects were observed between study‐groups (Animal Poison Control Center), for (Dierking et al. 2004). Gabapentin was tested gabapentin overdose between 2009 and 2013, to see if it reduces pain scores, analgesia the primary symptoms were ataxia, lethargy, consumption, and/or analgesia‐related side and vomiting. Of 103 cats reported during effects in the first 24 hours following surgery. the same time period, the main side effects Eight placebo‐controlled, randomized con were lethargy, sedation, and ataxia (Plumb trolled trials and meta‐analyses were per 2015). formed using the primary outcomes of pain Seven epileptic children who received scores, total analgesia consumption, and gabapentin (GBP) 10–50 mg kg−1 day−1 (mean −1 side effects over a 24‐hours period. Patients dose, 26.7 mg kg daily) as adjunctive medi who received gabapentin preoperatively cation subsequently developed behavioral reported significantly lower pain scores side effects, including tantrums, aggression and opioid consumption with no difference directed toward others, hyperactivity, and in the incidence of side effects (Seib and defiance. All behavioral changes were revers Paul 2006). ible and were managed by dose reduction or A 2.1‐T magnetic resonance imager‐ discontinuation of gabapentin. All children spectrometer and an 8‐cm surface coil in this report had baseline attention deficit technology were used to measure a 13.5‐cm3 hyperactivity disorder and developmental volume in the occipital cortex in humans. delays (Khurana et al. 1996; Lee et al. 1996). GABA was elevated in patients taking gabapentin compared with 14 complex Overdose partial epilepsy patients, matched for antie Treatment of overdose in animals should pileptic drug treatment. Brain GABA levels be supportive (Plumb 2015). In humans, appeared to be higher in patients taking Seii Medication 151 high‐dose gabapentin (3300–3600 mg day−1) Table 10.2 Dose range for gabapentin in cats and dogs. than in those taking standard doses (1200– 2400 mg day−1). Gabapentin appears to increase GABA levels in the brain (Petroff Cats Dogs et al. 1996). Daily 3–10 mg kg−1 q8h 2–20 mg kg−1 q8h Effects Documented in Non‐human Animals medication −1 −1 Cats Situational 5–20 mg kg 10–20 mg kg medicationa When gabapentin is given to cats orally, its distribution is best described by a Source: Overall (2013), Plumb (2015). a one‐compartment model, whereas the Situational medication refers to using the medication for particular stressful events, such as visits to the distribution is best described by a three‐ veterinary office. compartment model when gabapentin is The low dose is a recommended starting point. given intra‐venously (IV). Cats exhibit high The dose can be titrated up, as needed. variation in absorption with peak levels being around 100 minutes, and the half‐life being about 2.8 hours (Siao et al. 2010). −1 There is no information regarding safety in combination with 1 mg kg of meloxican and efficacy of chronic use of gabapentin in were followed for seven days, including cats but oral doses of 5–10 mg kg−1 every measures of milk concentration as well as 8–12 hours are used (Deway 2006) plasma concentration. When the gabapentin −1 (Table 10.2). One report by Inkpen (2015) dose was 20 mg kg , the maximum levels for discussed the multimodal approach of anal both blood and plasma were almost double −1 gesic medicine in cats to control pain. For what they were at 10 mg kg . The milk to chronic progressive polyarthritis in cats, on plasma ratio of gabapentin levels was top of predonisolone and cyclosporine, 0.23 + 0.06, suggesting that treated cows will buprenorphine (0.01 mg kg−1 BW, PO, q8h) have low levels of gabapentin in their milk and also gabapentin (compounded) once plasma levels have dropped below the −1 5 mg kg−1 BW, PO, q24h were used for addi clinically effective level of 2 μg ml (Malreddy tional pain management with success et al. 2012). (Inkpen 2015). Dogs Cattle According to the pharmacokinetic study Oral gabapentin, with or without meloxicam, done with several species (mice, rat, dog, may be useful for the treatment of neuropathic monkey), the dog was the only animal stud pain in cattle. Beef calves given gabapentin ied that metabolized gabapentin to N‐meth only at 10 mg kg−1 achieved peak blood levels ylgabapentin (~34% of dose) while in the of 2.97 μg ml−1 at 9.33 ± 2.73 hours and had a mouse, rat, and monkey this was minimal. half‐life of 11.02 ± 3.68 hours. When they The principal route of excretion was via urine were given 15 mg kg−1 of gabapentin with (Radulovic et al. 1995). KuKanich and Cohen 0.5 mg kg−1 of meloxicam, peak blood levels (2011) administered clinically relevant dos −1 of gabapentin were 2.11 ± 0.19 μg ml−1, which age (10–20 mg kg ) to six greyhounds to were achieved at 11.67 ± 3.44 hours. The half‐ assess the pharmacokinetics of gabapentin in life gabapentin given in this combination was dogs. The half‐life of 10 and 20 mg in dogs 20.47 ± 9.22 hours. Plasma concentrations of were 1.3 and 1.5 hours. Terminal half‐lives −1 >2 μg ml−1 lasted for up to 15 hours (Coetzee are 5.54 and 13.22 μg kg . Gabapentin was et al. 2011). rapidly absorbed and eliminated in dogs. Six Holstein‐Friesian cows given a single Thus, frequent dosing might be needed oral dose of 10 or 20 mg kg−1 of gabapentin (KuKanich and Cohen 2011). A sustained‐release 152 Anticonvulsants and Mood Stabilizers

tablet formulation of gabapentin did not both IV and PO. There were no significant produce substantially different pharmacoki differences in terminal half‐life from PO or netic results from an immediate release IV. Oral administration yielded much lower formulation when given to six beagle dogs plasma concentrations because of low bioa (Rhee et al. 2008). vailability (Terry et al. 2010). Long‐term toxicity trials for gabapentin Gabapentin has been used to treat painful have not been reported in dogs but it seems conditions such as laminitis or post‐colic to be well tolerated with few to no side effects surgery (Sanchez and Robertson 2014). A (Deway 2006). pregnant Belgian draft horse with femoral Platt et al. (2006) reported that 11 dogs neuropathy and severe pain after colic sur diagnosed with refractory idiopathic epilepsy gery was treated with gabapentin (2.5 mg kg−1 were treated orally with gabapentin for a PO Q 12 hours) for six days with success. minimum of three months at an initial dose No side effects on mare and foal were of 10 mg kg−1 every eight hours. A minimum reported (Davis et al. 2007). 50% reduction in the number of seizures per week was interpreted as a positive response Zoo Animals to gabapentin, and six of the dogs showed a Six healthy great horned owls (Bubo virgin- positive response. After the addition of ianus) were given an oral dose of a gabapentin gabapentin, both the number of seizures per suspension at 11 mg kg−1. Peak concentration week (p = 0.005) and the number of days with occurred at 51.43 + 5.66 minutes (about any seizures in a one‐week period (p = 0.03) one hour). The half‐life was 264.6 + 69.35 min were significantly reduced. Mild side effects utes (about 2½ hours). Plasma gabapentin of ataxia and sedation were observed in five was maintained at >2 μg ml−1 for almost of the dogs (Platt et al. 2006). nine hours. This is the level considered effec One clinical report from Bain (2012) used tive in treating epilepsy and neuropathic pain gabapentin an as adjunct drug to fluoxetine in humans. Thus, treating great horned owls to treat tail‐chasing in a male bull terrier q8h is probably the appropriate dose interval (12 kg), who had presented the behavior since for this bird (Yaw et al. 2015). four months old. Initially, the dog was treated with fluoxetine alone. However, for a sedative III. Pregabalin effect, acepromazine was prescribed and gabapentin (100 mg Q24h) was prescribed Chemical Compound: C8H17NO2 (s)‐3‐ for treatment for potential neuropathic pain aminomethyl‐5‐methylhexanoic acid and underlying seizure activity. Gabapentin DEA Classification: C‐V controlled substance was discontinued after one week and Preparations: Available as 25‐, 50‐, 75‐, 100‐, acepromazine was discontinued after 150‐, 200‐, 225‐, and 300‐mg capsules. Also one month. The tail‐chasing behavior was as a 20‐mg ml−1 oral solution. better after one month (Bain 2012). Clinical Pharmacology Horses Pregabalin is similar in mode of action to The pharmacokinetic profile, pharmacody gabapentin. It is structurally related to GABA namics, cardiovascular and behavioral effects but inactive at GABA receptors and does not have been reported in the horse (Dirikolu appear to mimic GABA physiologically. It et al. 2008; Terry et al. 2010). When given as a works by binding to the α2 delta subunits of single oral dose of 5 mg kg−1, gabapentin the voltage‐dependent calcium channels exhibits a peak level at about 1.4 hours. It has present in presynaptic neurons (Arain 2009). a half‐life of 3.4 hours (Dirikolu et al. 2008). This decreases the calcium influx via reduced Gabapentin caused a significant increase in release in glutamate and substance P at the sedation after IV (20 mg kg−1) compared to synapse (Salzar et al. 2009). The mode of action orally (PO) (20 mg kg−1). Horses tolerated is the same as gabapentin (Plumb 2015). Reference 153

Uses in Humans Dogs Pregabalin is a neuroactive compound The half‐life of pregabalin in dogs is 6.9 hours. currently used for several conditions Oral dosing should start at 2 mg kg−1 q12h. including partial onset focal seizure disor Then titrate up in 1 mg kg−1 increments per ders (Dewey et al. 2009; Salzar et al. 2009), week up to a maximum of 8 mg kg−1 q8h neuropathic pain (Baron et al. 2008), post‐ (Plumb 2015). operative pain in arthroplasty (Dong et al. Pregabalin is reported to be promising as a 2016), and anxiety disorders (Frampton safe and effective adjunct anticonvulsant 2014; Buoli et al. 2017). medicine for dogs who are poorly controlled This medication is approved for use in with standard drugs. Dewey et al. (2009) human for the treatment of peripheral neu reported on dogs treated with 3–4 mg kg−1 ropathic pain and in epilepsy in the European PO q8h for three months. Adverse effects Union (EU). In the US, it is approved for were mild sedation and ataxia. One owner in treating neuropathic pain from post‐herpetic the study reported several episodes of dizzi neuralgia, diabetic neuropathy, and adjunc ness and weakness in their dogs when the tive treatment for partial‐onset (focal) sei drug was administered at 4 mg kg−1 (Dewey zures (Salzar et al. 2009). et al. 2009).

Side Effects Horses For six weeks 600 mg day−1 pregabalin were Pharmacokinetics of pregabalin in five given to patients with diabetic neuropathy. healthy mares were tested. A regimen of Dizziness was the most common side effect. −1 4 mg kg was administered via nasogastric These study results showed it to be safe and tube and IV. Signs of mild transient colic or effective in reducing the pain and other asso behavior abnormality were seen in all ciated symptoms of painful diabetic neurop horses after IV. After intragastric adminis athy (Richter et al. 2005). tration, half‐life was about eight hours. It Most frequent adverse reactions are of a was concluded that with an intragastric neuropsychiatric nature and include fatigue, −1 dosage of 4 mg kg every eight hours, the dizziness, sedation, somnolence, and ataxia; median pregabalin steady‐state plasma peripheral edema and weight gain are also concentration occurred. Therapeutic con frequently described. Pharmacokinetic inter centrations and safety of this dosage have actions are scarce; however, pharmacody not been established in horses (Mullen namic interactions have been described et al. 2013). in association with drugs with depressant effects on the central nervous system (Calandre et al. 2016). Others At this time, the price of pregabalin makes it Effects Documented in Nonhuman Animals cost‐prohibitive (which probably explains Cats the small number of publications in its use on The half‐life of pregabalin in cats is 10.4 hours. domestic species so far) with a one‐month The recommended dose is 1–2 mg kg−1 q12h supply costing 20–30 times as much as medi (Plumb 2015). cation with gabapentin.

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Sympatholytic Agents Niwako Ogata1 and Leticia Mattos de Souza Dantas2

1Purdue University, West Lafayette, IN, USA 2 University of Georgia, Athens, GA, USA

Action anxiolytic effects that vary depending on acute or chronic stress (Goddard et al. 2010; Sympatholytic medications work by blocking Carlson 2013). LC firing is caused by the noradrenaline (NA) in the central nervous meaning of stimuli as well as their intensity, system (CNS). Excess noradrenalin results especially acute stress and fear‐related stimuli from acute and repeated traumatic stress. activate LC to release NA. They are antagonists or adrenergic agonists The adrenergic receptors where noradrena- binding primarily on the presynaptic line binds are divided into two major types: receptors. The behavioral effects are due to alpha and beta adrenoreceptors. Alpha‐1, the response of the limbic system and locus beta‐1, beta‐2 and beta‐3 receptors are post- coeruleus. synaptic while alpha‐2 is pre‐ and postsynaptic. Additionally, there is an NA transporter that reuptakes extracellular NA. Rapid increase in Overview of Indications NA is likely to contribute to the organism’s ability to respond effectively in dangerous situa- Sympatholytics (antiadrenergics) target alter- tions and then return to normal through ations in noradrenergic neurotransmission. negative feedback loops by the restoration of The central noradrenaline (NA) system is a the autoreceptor function. However, prolonged modulator of the mammalian response to repeated and uncontrollable stress increases stress. The noradrenergic system originates the responsivity of LC neurons, which exagger- in a relatively small number of cells located in ate NA reactivity. Therefore, pharmacologic the locus coeruleus (LC) and in other cell agents specifically target NA hyper‐reactivity groups in the medulla and pons. The axons of through these adrenergic receptors. these neurons project from the olfactory bulb In humans, alpha‐1 antagonists (e.g. prazo- to the spinal cord, including the prefrontal sin), alpha‐2 agonists (e.g. clonidine, guanfa- cortex, the amygdala, the hippocampus, the cine), and beta blockers (e.g. propranolol) are hypothalamus, the periaqueductal gray mat- the most studied (Strawn and Geracioti 2008). ter, and the thalamus. As a result, NA activity Historically, in small animals, it was not until influences a wide range of psychobiologic the late 1900s that medetomidine was licensed functions including decision‐making, atten- for intramuscular (IM) and intravenous (IV) tion, and stress response with anxiogenic or use only in dogs for sedation and analgesia in

Canada and the United States, while other There is a ceiling effect for sedation, however countries approved its use in cats as well. (Kuusela et al. 2000, Messenger et al. 2016) Later, dextomedetomidine (the active isomer and the level of sedation actually decreased of the medetomidine formulation) was when the blood concentration reached approved by the Food and Drug Administration beyond a certain level in a few studies (Vainio (FDA) for use in dogs and cats for sedation, for et al. 1986; Ansah et al. 2000). analgesia as well as preanesthetic in dogs. While oral transmucosal (OTM) detomi- Dexmedetomidine induces similar effects to dine has been available for horses as an FDA‐ medetomidine by using half‐dose (Savola and approved medication, there was no such Virtanen 1991). Atipamezole is an antagonist FDA‐licensed product for small animals until so alpha‐2 agonists can be reliably and safely Sileo (OTM dexmedetomidine) was released reversed. Atipamezole is 200–300 times more in 2016. Some authors reported using either specific for the alpha2 adrenoreceptor than injectable dexmedetomidine or medetomi- traditional antagonists, such as yohimbine dine orally as a less invasive and less painful (Lamont et al. 2001). procedure compared to IM injection, to assess Alpha‐2 adrenergic receptors are known to its effects of sedation in cats and dogs (Ansah have four subtypes, alpha‐2A, 2B, 2C, and 2D. et al. 1998; Cohen and Bennett 2015). Both Their diversity, density, and locations among spraying onto the buccal mucous membrane species appear to be different. For example, beneath the tongue or into the mouth have alpha‐2A receptors predominate in the central been attempted with mixed outcomes. Oral nervous system in dogs (Schwartz et al. 1999). dosing caused excessive salivation (particu- The effects of the alpha‐2 agonist in the indi- larly in cats) and a substantial amount of med- vidual is affected by these receptors’ distribu- ication was lost in that case (Ansah et al. 1998). tion as well as the choice of the drug, as each Other studies reported the use of non‐ medication has a different selectivity and affin- injectable forms of alpha‐2 agonists or beta ity between alpha-1 and alpha‐2 receptors. blockers to reduce fear and anxiety in dogs. The respective alpha‐2/alpha‐1 selectivity These studies used clonidine (oral tablet) in different sympatholytics is: dexmedetomi- (Ogata and Dodman 2011), detomidine dine and medetomidine (1620 : 1), detomi- (OTM gel) (Hopfensperger et al. 2013), and dine (260 : 1), clonidine (220 : 1), and xylazine propranolol (Walker et al. 1997). (160 : 1), based on the study in rats (Scheinin et al. 1989). The more selective a drug is, the more potent its effect. It is suggested that the Contraindications, Side removal of the l‐isomer from racemic Effects, and Adverse Events medetomidine may provide dexmedetomidine with a therapeutic advantage (Granholm Regardless of the administration route, a et al. 2006). Dexmedetomidine seems to be decrease has been commonly observed in the slightly more potent as its analgesic effect heart rate, in the respiratory rate, and in the lasts longer than the same dose of medetomi- rectal temperature, induced by alpha‐2 dine (Kuusela et al. 2000). Several papers have agonists. The degree of effect is varied among reported that the potential effects of sedation, alpha‐2 agonists as well as depending on the analgesia, muscle relaxation, and physiologi- dose used (Sinclair 2003). For example, mean cal responses, such as bradycardia, and heart rate (n = 6) with OTM form of hypothermia induced by alpha‐2 agonist are detomidine dropped less than 60 bpm with dose‐dependent. Due to its effect on the second degree atrioventricular (AV) block antidiuretic hormone (ADH) and the renin‐ observed in one dog (Hopfensperger et al. angiotensin system, alpha‐2 agonists lead to 2013), while the mean heart rate decrease low specific gravity urine when animals are (n = 27) with OTM form of dexmedetomi- recovering from sedation (Sinclair 2003). dine was mild (e.g. 98 bpm) (Zoetis 2016). Clinical Guidelines 159

The biphasic response of arterial blood idazoxan. Each antagonist has a different pressure after alpha‐2 agonist administration selectivity and affinity for the alpha‐2 and is reported although one study did not alpha‐1 receptors. The stronger alpha‐2 observe an increase but a decrease of blood reversal specificity is atipamezole’s following pressure after administration (Lamont et al. idazoxan, yohimbine, and tolazoline (Sinclair 2001). In humans, sudden withdrawal of 2003). In the treatment of behavioral and clonidine after long‐term administration for mental conditions in animals, alpha‐2 ago- treatment of hypertension has been nists are mostly administered by non‐injectable associated with rebound hypertension, which route (i.e. OTM or oral), which limits the may occur up to 20 hours after cessation of potential for overdosing. However, individu- the drug. Additionally, emesis is typically als that are hypersensitive to alpha‐2 agonists induced by alpha‐2 agonists due to or with severe cardiovascular, respiratory, stimulation of the chemoreceptor trigger liver or kidney disease can be potentially zone (Hikasa et al. 1989; Thawley and overdosed. Common signs of overdosing are Drobatz 2015; Willey et al. 2016). Occurrence sedation, decrease in heart rate, blood pres- of emesis is more common in cats than dogs sure, and body temperature. Supportive treat- with xylaxine (50% of dogs, 90% of cats) and ment should be provided along with the medetomidine (8–20% of dogs, up to 90% of administration of an antagonist. cats) (Vainio et al. 1986; Sinclair 2003). Individual sensitivity to each alpha‐2 mediation also seems to exist (Lucot and Clinical Guidelines (Table 11.1) Crampton 1986, Willey et al. 2016). Although overall adverse effects with an oral or OTM It is possible that preexisting stress, fear, and dose of alpha‐2 agonists are mostly mild, excitement leading to increased endogenous caution should be taken, particularly in catecholamine levels can interfere with the animals with cardiovascular disease, in effect of alpha‐2 agonists (Sinclair 2003). shock, or under extreme weather conditions. Some studies showed that the arousal at the onset of sedation delayed the effect of medetomidine IM when dogs were in a noisy Overdose environment (Clarke and England 1989). Therefore, providing an appropriate In veterinary medicine, treatment of over- environment (e.g. a quiet room) when dose is reversed by the alpha‐2 antagonists administering the medication is important so yohimbine, tolazoline, atipamezole, and the alpha‐2 can be efficacious. That can be

Table 11.1 Doses of various sympatholytics for dogs, cats, and horses for the treatment of fear and anxiety disorders.

Sympatholytic Dog Cat Horse

Alpha2 agonist Clonidine (oral) 0.01–0.05 mg kg−1, PRN Detomidine 0.35 mg m−2 0.04 mg kg−1, PRN (OTM) (=0.012–0.016 mg kg−1) PRN Dexmedetomidine 0.125 mg m–2 PRN (OTM) Beta blocker Propranolol 0.25–3 mg kg−1 BID 0.2–1 mg kg−1 TID

Source: Ogata and Dodman (2011), Zoetis (2013, 2016), Hopfensperger et al. (2013), Lansberg et al. (2013). 160 Sympatholytic Agents

interpreted clinically as the importance of agonist activity, though guanfacine is known provision of the adequate level of triggers to be more selective for alpha‐2 receptors. even though the medication is used in the Clonidine binds to alph‐2A, alpha‐2B, and behavior treatment context. It is reported alpha‐2C receptors as well as imidazoline that after reaching a ceiling effect, higher receptors, which are partially related to doses did not increase the depth of sedation sedation and hypotension. The analgesic but only the duration of sedation in dogs and effects of epidural clonidine in domestic cats (Vainio et al. 1986). Although alpha‐2 species have been studied (Plumb 2015). agonists have been used in small animal Clonidine is also useful as a diagnostic agent medicine for a long time, the approval label to determine growth hormone deficiency in by the FDA was only given for injectable dogs (Frank 2005) and as an adjunctive treat- forms recently. Only in 2016 did the FDA ment for refractory inflammatory bowel dis- approve OTM dextomedetomidine gel for ease in dogs and cats (Plumb 2015). the treatment of noise aversion in dogs Clonidine has an inhibitory action and (Zoetis 2016). All other uses described in this reduces the firing of presynaptic neurons chapter are “off‐label.” that release noradrenaline into the prefron- The advantage of OTM administration tal cortex, thereby reducing fear or anxiety over oral administration is that it can avoid in rodents and primates (Soderpalm and hepatic first‐pass metabolism, therefore, it Engel 1988) and improves the impulsive and takes full effect faster than oral administra- hyperactive behavior seen in attention defi- tion (Ansah et al. 1998; Hopfensperger et al. cit hyperactivity disorder (ADHD) in 2013). Due to the lower bioavailability of humans (Nguyen et al. 2014). Studies in OTM administration (compared to IM children comparing the effects between clo- administration), it causes less sedation and nidine and midazolam to decrease preopera- physiological effects. When the OTM form is tive anxiety to ensure smooth induction administered, impermeable gloves should be found that the anti‐anxiety effects of cloni- worn to protect skin contact. dine are similar or better than midazolam. Clonidine has a slower onset of action (e.g. 60 minutes) than midazolam (e.g. 30 min- Specific Medications utes), however (Fazi et al. 2001; McCann and Kain 2001; Cao et al. 2009). A similar slow I. Clonidine onset effect (90–120 minutes) was observed in dogs when clonidine was used to treat Chemical Compound: N‐(2,6‐Dichlorophenyl)‐ fear‐based behavior problems (Ogata and 4,5‐dihydro‐1H‐Imidazol‐2‐amine Dodman 2011). hydrochloride DEA Classification: Not a controlled substance Uses in Humans Preparations: Generally available as 0.1‐, In human medicine, clonidine has historically 0.2‐, and 0.3‐mg tablets. Also available as been used in the treatment of hypertension. 0.1‐, 0.2‐, and 0.3‐mg transdermal patches. As an extra label use, clonidine is also used for The extended release (12‐hour) form a variety of conditions including treatment of comes in 0.1‐, and 0.2‐mg tablets. substance abuse, ADHD, and as sedative and Clonidine HCl injection for epidural use is −1 analgesic agent. In perioperative patients or available as 0.1 mg ml and 0.5 mg/pre- patients in intensive care, clonidine is also servative‐free in 10 ml vials. used to reduce their anxiety (Cao et al. 2009).

Clinical Pharmacology Contraindications Clonidine is sometimes called a selective Do not give clonidine to patients with a his- alpha‐2 adrenergic agonist with some alpha‐1 tory of sensitivity to clonidine or any alpha‐2 Seii Medication 161 agonists. Patients with severe cardiovascu- related problems but aggressive dogs, and in 11 lar, respiratory, liver or kidney disease can out of 12 fear‐related aggressive dogs). be potentially overdosed, so caution is rec- Clonidine is used as an antidiarrheal agent ommended. In combination with amitripty- for inflammatory bowel disease in dogs and line, clonidine hydrochloride administration cats at 0.005–0.01 mg kg−1 BID‐TID SC or led to the development of corneal lesions in PO (Plumb 2015). rats within five days. The significance of this finding for dogs, cats, and horses is Cattle (extra‐label) unknown. Epidural analgesia, 0.002–0.003 mg kg−1 of clonidine in cattle provided bilateral perineal Side Effects analgesia/anesthesia with a dose‐dependent In Ogata and Dodman’s (2011) study, one onset and duration of action (DeRossi et al. owner reported increased sound sensitivity in 2003). a noise‐phobic dog with the use of oral clonidine administration (1 in 22 dogs). In humans, II. Detomidine the most frequent side effects (which appear to be dose‐related) are dry mouth (40%); Chemical Compound: 4‐(2,3‐Dimethylbenzyl)‐ drowsiness (33%); dizziness (16%); constipa- 1H‐imidazole hydrochloride tion, and sedation (10% each) (Boehringer DEA Classification: Not a controlled Ingelheim International GmbH 2011). substance Preparations: Available as injection form Other Information 10 mg ml−1 in 5 ml, and 20 ml vials and as In humans, tolerance to the antihypertensive 7.8 mg ml−1 in 3 ml graduated dosing syringes. effect is reported in some cases. Sudden cessation of clonidine treatment has resulted Clinical Pharmacology in symptoms such as nervousness, agitation, Detomidine is approved for sedation and headache, and tremor, accompanied or restraint primarily in equine medicine. From followed by a rapid rise in blood pressure and a clinical standpoint for sedation and analge- elevated catecholamine concentrations in sic effects, detomidine is the most potent of the plasma in humans (Boehringer Ingelheim these alpha‐2 adrenergic agonists, if com- International GmbH 2011; Nguyen et al. pared to xylazine and romifidine (Hamm 2014). Therefore, clonidine dose should be et al. 1995; Moens et al. 2003). Target‐animal tapered off gradually to avoid withdrawal safety studies showed that dosages of symptomatology (Boehringer Ingelheim 0.2 mg kg−1 (ten times the approved low dos- International GmbH 2011). age and five times the high dosage) given IV on three consecutive days were well tolerated Effects Documented in Nonhuman Animals in healthy, mature horses (Welker 2009). Dogs Detomidine can be also used for anesthesia Ogata and Dodman (2011) studied the use of and analgesia in sheep, goats, camelids, and clonidine for situational use with other anti‐ birds (Plumb 2015). anxiety medications as a treatment for fear‐ In horses, detomidine gel following OTM based behavior problems and anxiety disorders, (sublingual) administration has an elimination such as noise phobia, separation anxiety, or half‐life of approximately 1.5 hours, and bioa- fear/territorial aggression. According to own- vailability of approximately 22% (Kaukinen ers’ reports, with the dose of 0.01–0.05 mg kg−1 et al. 2010; Knych and Stanley 2011). oral administration, the reduction of fear‐based Pharmacokinetic studies in dogs with the behavior was observed 1.5–2 hours after detomidine OTM form reported that time to administration of clonidine and the effect maximum concentration and bioavailability waned after 4–6 hours (in 7 out of 10 fear‐ for detomidine gel was one hour and 34.52%, 162 Sympatholytic Agents

respectively. Harmonic mean elimination half‐ Other Information life was 0.63 hours (Messenger et al. 2016). Atipamezole may be a useful antagonist but only partially reverses detomidine sedation Use in Humans in horses (Hubbell and Muir 2006). In com- Detomidine has not been used in humans. parison, intravenous administration of yohimbine effectively and rapidly reversed Contraindications detomidine‐induced sedation, bradycardia, Do not give detomidine to patients with a his- atrioventricular heart block, and hyperglyce- tory of severe cardiovascular conditions such mia (Knych and Stanley 2011). as atrioventricular (AV) block or sinoauricu- lar (SA) block sensitivity to detomidine or any Effects Documented in Nonhuman Animals alpha‐2 agonists. Other contraindications are Horses similar to other alpha‐2 agonists. When using a FDA-approved sublingual gel, Concomitant use with phenothiazines (e.g. for the best results, allow adequate time (a acepromazine) can result in severe hypotension. minimum of 40 minutes) between the admin- Possible drug interactions have been istration of the sublingual gel and the begin- reported concurrently with sulfonamides, ning of a procedure. In general, horses show and potentiated sulfonamides as fatal dys- sedative effects lasting approximately rhythmias may occur (Plumb 2015). 90–180 minutes. When using an injection, for the best Side Effects results, allow adequate time (2–5 minutes) According to a field study with 202 horses, between administration of 0.02– −1 the most frequent side effects (which appear 0.04 mg kg IV (only for analgesia) or IM to be dose‐related) are sweating (10%), penile and beginning the procedure. A lower dose relaxation (6%), bradycardia, (5%), second‐ will generally provide 30–90 minutes of degree AV block, and frequent urination (4% sedation and 30–45 minutes of analgesia. each) (Zoetis 2013). The higher dose will generally provide Detomidine gel is reported to cause transient 90–120 minutes of sedation and 45–75 min- bradycardia in five out of six dogs and intermit- utes of analgesia. For sedation, chemical tent second‐degree AV block in one out of six restraint, analgesia in horses (extra-label): dogs in a study (Hopfensperger et al. 2013). Table 11.2.

Table 11.2 Detomidine doses for sedation, chemical restraint, and analgesia in horses (extra-label).

Use Dose Effect

Premedicant 0.005–0.03 mg kg−1 IV Caudal epidural analgesia 0.06 mg kg−1, given between S4‐S5 Duration of analgesia is 2–3 hours 0.03 mg kg−1 with morphine 0.2 mg kg−1, Duration of analgesia given between S1‐L6 is >6 hours Constant rate infusion Guaifenesin‐Ketamine‐Detomidine (GKD) CRI rate is (CRI) for total intravenous triple‐drip protocol: 10 mg of detomidine, 1.2–1.6 ml kg−1 hour−1 anesthesia (TIVA) 500–1000 mg of ketamine to 500 ml of 5% guaifenesin CRI for sedation 0.022 mg kg−1 hour−1 Partial intravenous 0.013–0.038 mg kg−1 hour−1 anesthesia (PIVA)

Source: Plumb (2015). Seii Medication 163

Table 11.3 Detomidine doses to produce standing sedation with a low incidence of recumbency in cattle (extra‐label).

IV IM

Tractable cattle 0.002–0.005 mg kg−1 0.006–0.01 mg kg−1 Anxious cattle 0.005–0.0075 mg kg−1 0.01–0.015 mg kg−1 Extremely anxious or unruly cattle 0.01–0.015 mg kg−1 0.0015–0.02 mg kg−1 Analgesia 0.01 mg kg−1

Source: Plumb (2015).

Dogs Clinical Pharmacology Hopfensperger et al. (2013) studied the use of Dexmedetomidine is FDA‐approved for seda- equine oromucosal gel administered via the tion and analgesia in dogs and cats. OTM route on six laboratory dogs. The dose Dexmedetomidine is also indicated for use as was 0.35 mg m−2 (= 0.012–0.016 mg kg−1) and a preanesthetic to general anesthesia in dogs sedation was observed (four out of six dogs) and cats. Oromucosal (OTM) gel form is for 45 minutes after administration of deto- FDA‐approved for the treatment of noise midine OTM and the duration of maximum aversion in dogs. Time to maximum concen- sedation effect was 30 minutes. tration and bioavailability for dexmedetomidine OTM gel (Sileo®) were 0.6 hour, and 28%, Cattle respectively and elimination half‐life was For standing sedation, see Table 11.3. 0.5–3 hours. Sheep, Goats Target‐animal safety studies showed a sat- −1 isfactory margin of safety when administered For anesthesia: detomidine at 0.01 mg kg IM, −1 IV or IM at doses as high as five times the followed by propofol at 3–5 mg kg IV. For −1 recommended dose in healthy, mature dogs analgesia: 0.005–0.05 mg kg IV or IM and cats (Orion Corporation 2006). q3–6 hours.

Llamas, Alpacas Use in Humans For analgesia: 0.005–0.05 mg kg−1 IV or IM In humans, dexmedetomidine is approved q3–6 hours. as an adjunct to anesthesia and as an agent for sedation in the intensive care unit Birds patients. Administration routes are IV, IM For sedation/analgesia: 0.3 mg kg−1 IM. transdermal, and via the oral mucosa. Dexmedetomidine administered transmu- cosally via the buccal mucosa has the bioa- III. Dexmedetomidine vailability of approximately 82% (Anttila Chemical Compound: 5‐[(1S)‐1‐(2,3‐dimeth- et al. 2003). ylphenyl)ethyl]‐1H imidazole hydrochloride DEA Classification: Not a controlled Contraindications substance Do not give dexmedetomidine to patients Preparations: Generally available as injec- with a history of sensitivity to dexmedetomi- tion form 0.1, and 0.5 mg ml−1 in 10 ml dine or other alpha‐2 agonists. Patients with vials (dogs and cats). Also available as severe cardiovascular, respiratory, liver, or 0.1 mg ml−1 in 3 ml prefilled multidose oral kidney disease can be potentially overdosed syringe (dogs). so caution is warranted. 164 Sympatholytic Agents

Sileo (dexmedetomidine OTM form) is may be given. During one noise event, up to contraindicated in dogs with shock, severe five doses with minimum of two hours debilitation and stress due to extreme heat, interval can be administered. cold, or fatigue. The response of Sileo has not According to the randomized, double‐ been investigated in dogs younger than blind, placebo‐controlled study to assess the 16 weeks of age, in ones that have dental or effect of dexmedetomidine OTM gel for gingival diseases, are used for breeding, are noise‐associated acute anxiety and fear, a pregnant or lactating. total of 182 privately owned dogs with a history of acute anxiety and fear associated Side Effects with noises were assessed, with 89 dogs In dexmedetomidine OTM form in dogs, the receiving 0.1 mg ml−1 dexmedetomidine most common adverse reaction was sedation, OTM gel at a dose of 125 mcg m−2 and 93 which occurred in 2 out of 12 dogs in the dogs receiving placebo (Korpivaara et al. 125 mcg m−2 dose group and in 4 out of 12 2017). For the New Year’s Eve fireworks, the dogs in the 250 mcg m−2 dose group (2 times owners were instructed to apply the gel above the standard clinical dose) in a pilot (either dexmedetomidine OTM or placebo) study where dogs between 2 and 11 years of on the buccal mucosa without allowing the age and weighing between 4 and 52 kg were dog to swallow the gel. The dose application included. All dogs were healthy and had a was decided by each owner. Thus, the dosing history of noise aversion (Orion Corporation was done one hour before the anticipated 2015). start of fireworks, or immediately after the In another study on dogs with the history first fireworks, or when the dog’s anxiety or of fear of fireworks, dexmedetomidine fearful signs were first noticed, as needed. OTM form of 125 mcg m−2 dose was used in Re‐dosing was also allowed up to five times 89 dogs that ranged between 2 and 17 years when the dog started to show anxiety or and whose body weight ranged between 4 fearful signs again with a minimum of a two‐ and 67 kg. The most common adverse reac- hour interval between the administration. tion in this study was emesis, which No dogs received any other anti‐anxiety occurred in 4 out of 89 dogs in the dexme- treatments including behavioral or detomidine OTM group, while in 1 out of 93 environmental management. The effect of dogs in the control group. When repeated the treatment was assessed by the owners, administration was given to the dogs, it was and an excellent or good effect was reported up to five times during one noise event with in 72% of dexmedetomidine dogs while in a minimum interval of two hours between only 37% in the placebo dogs. The dogs with doses. the treatment showed significantly fewer anxiety or fearful signs than the dogs with Effects Documented in Nonhuman Animals placebo when compared with each baseline. Dogs The most common adverse effect was emesis Dexmedetomidine OTM gel should be that was observed in 4 out of 89 dogs with the administered on the oral mucosa between treatment and 1 out of 93 dogs with placebo. the dog’s cheek and gum at the dose of None of them were serious and no local 125 mcg m−2. The first dose should be irritation of oral mucosa was reported. administered approximately 30–60 minutes Transient local paleness of the oral mucosa before the aversive stimulus (e.g. loud noise) was observed in 13.3–16.9% in the treatment or immediately after the dog shows early or dogs and 2.1–6.6% until two hours after the mild signs of anxiety or fear related to the third dose. auditory stimulus. If the stimulus lasts longer Injection (FDA‐approved): for sedation and than two to three hours and the dog’s signs of analgesia, 375 mcg m−2 IV, and 500 mcg m−2 fear and/or anxiety reappear, another dose IM; preanesthesia, 125 or 375 mcg m−2 IM. Seii Medication 165

Cats nerves, or stage fright. Recently, propranolol Injection (FDA‐approved) for sedation, has been used for the amnesic effect on −1 analgesia, and preanesthesia, 40 mcg kg IM. retrieved fear memory. According to the research, it has been shown that noradrener- IV. Propranolol gic transmission is not required for the consolidation of auditory fear conditioning, Chemical Compound: 1‐naphthalen‐1‐ but once a memory is reactivated, noradren- yloxy‐3‐(propan‐2‐ylamino) propan‐2‐ol ergic signaling plays a critical role in the DEA Classification: Not a controlled reconsolidation of retrieved memory in substance knockout mice. It was shown that the −1 Preparations: Available as 1 mg ml injec- disruptive effects of the beta adrenergic −1 tion form; as 4 and 8 mg ml in 500 ml oral antagonist on reconsolidation produce long‐ solution; as 10‐, 20‐, 40‐, 60‐, 80‐mg oral lasting changes in the retrieval of the mem- tablets; and as 60‐, 80‐, 120‐, 160‐mg cap- ory in rats (Dȩbiec and Ledoux 2004). sules extended release. Several studies and trials in humans followed these psychopharmacological effects of pro- Clinical Pharmacology pranolol, yet they have never been system- Propranolol is a beta blocker that competes atically reviewed until recently. Steenen primarily at beta1 and beta2 receptors. It is et al. (2016) conducted a systematic review used for hypertension, coronary artery and meta‐analysis by using four studies con- disease and tachyarrhythmias in human cerning panic disorder with or without ago- medicine. In veterinary medicine, it is raphobia (total n = 130), two studies with used primarily for acute treatment of cardio- specific phobia (total n = 37), a study with vascular conditions, such as atrial premature social phobia (n = 16), and a study with post- complexes, ventricular premature com- traumatic stress disorder (PTSD) (n = 19). plexes, supraventricular premature com- These meta‐analyses found no statistically plexes, and tachyarrhythmias. Propranolol significant differences between the efficacy can be also used for hypertrophic cardiomy- of propranolol and benzodiazepines regard- opathy in ferrets and ventricular tachycardia ing the short‐term treatment of panic disor- in horses. der with or without agoraphobia. Also, no Although in humans, propranolol is well evidence was found for the effects of pro- absorbed from the gastrointestinal tract, in pranolol on PTSD symptom severity through dogs, oral bioavailability is not good in com- inhibition of memory reconsolidation. The parison. One study reported approximately conclusion of this review was that the qual- 8% of bioavailability (Lo et al. 1982), so other ity of evidence for the efficacy of propranolol beta blockers have been alternatively used. was insufficient to support the routine use of propranolol in the treatment of any of the Use in Humans anxiety disorders. In addition to the traditional use to target peripheral sites of the noradrenergic system, Contraindications in psychiatry, propranolol has attracted Do not give propranolol to patients with a attention since 1960s. Its effect is to compete history of sensitivity to it or other beta blockers. the beta adrenoreceptor with catechola- Patients with severe cardiovascular, respira- mine, thus, blocking orthosympathetic tory, liver, or kidney disease can be poten- effects, and it was used to treat several psy- tially overdosed, therefore use with caution. chiatric conditions, such as anxiety, autism, or aggression. It has also been commonly Side Effects used to attenuate stressful conditions such Like other sympatholytics, bradycardia, AV as performance anxiety in musicians, exam block, hypotension, and peripheral vasocon- 166 Sympatholytic Agents

striction can occur. Propranolol may exacer- easier for some owners to comply. Duration bate preexisting renal impairment. After of treatment would be from a minimum of long‐term usage, the dose should be tapered three months up to six months and infre- off gradually to avoid withdrawal symptoms. quent triggers such as thunderstorms tended to take longer for the treatment. When the Effects Documented in Nonhuman Animals dog responded the treatment positively, Dogs both medications were tapered off. Notari Few studies have reported on the use of (2005) reported on treating dogs for thun- propranolol in dogs. Walker et al. (1997) derstorm and fireworks phobia with sele- published case reports in the treatment of giline (0.5 mg kg−1 day−1) in addition to phobias in dogs. According to this publica- propranolol (2.5 mg kg−1) and alprazolam tion, in all cases, phenobarbital and pro- (0.05 mg kg−1) as given situationally in con- pranolol were used together and in junction with behavior modification. All conjunction with behavior modification. cases improved within three to six months of The dose used for phenobarbital was treatment. 2–3 mg kg−1 BID while propranolol was 5 mg or more TID in small dogs, 10–20 mg TID or Cats 2–4 mg kg−1 day−1 (divided into TID) in large Walker et al. (1997) stated that 5 mg of pro- dogs. For example, a propranolol dose of a pranolol BID combined with 7.5 mg of phe- dog weighing 30 kg will be 40 mg TID. They nobarbital BID were an effective dose for also reported that propranolol given cats. No other details were mentioned about 2–3 mg kg−1 BID with phenobarbital cat cases. 2–3 mg kg−1 BID was effective if that was

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N‐Methyl‐D‐Aspartate (NMDA) Receptor Antagonists Niwako Ogata1 and Leticia Mattos de Souza Dantas2

1 Purdue University, West Lafayette, IN, USA 2 University of Georgia, Athens, GA, USA

Action Parkinson’s disease and multiple sclerosis, neuropathic pain, and glaucoma are caused Glutamate (or glutamic acid) is an excitatory by neuronal cell injury or death that is due to amino acid that works as the major neuro- the overstimulation of NMDA receptors transmitter in the central nervous system. It (Lipton 2006). Acute disorders of stroke, cen- triggers the long‐term potentiation (LTP) of tral nervous system trauma, seizures as well neuronal firing and synaptic plasticity. The as hyperalgesia in pain syndromes are also led N‐Methyl‐D‐aspartate (NMDA) receptor, by the excitotoxicity of glutamate. Therefore, which is located not only within the synapse it is considered that NMDA receptor antago- but also at extrasynaptic sites, is one of the nists can be beneficial in a number of neuro- three classes of glutamate‐gated ionotropic logical disorders. channels and is well known with the other Additionally, NMDA receptor‐mediated two receptors, the α‐amino‐3‐hydroxy‐5‐ glutamate neurotransmission has been methyl‐4‐isoxazolepropionic acid (AMPA) considered to be involved in human receptors and the kainate receptors. NMDA depression for over 20 years (Vale et al. 1971). receptors are ionotropic, ligand‐gated, gluta- Reports in rodents as animal models of mate‐sensitive neurotransmitter receptors. depression and humans from postmortem Each NMDA receptor is a tetraheteromeric tissue have shown alterations in central complex formed through the assembly of two NMDA receptor after periods of chronic GluN1 and two GluN2 protein subunits. The stress (Newport et al. 2015). Even though the NMDA receptor is the most permeable to effects of combating the excitotoxicity of Ca2+, therefore, excessive activation of the glutamate and neuroprotective efforts were NMDA receptor leads to increased intracel- of interest, severe side effects from inhibiting lular Ca2+. Although glutamate binds with the excitotoxicity of glutamate were one of these sites on the receptor, a molecular challenging when in the clinical applications of glycine (an inhibitory neurotransmitter) of NMDA receptor antagonists. This was must be attached to the glycine binding site more pronounced with competitive NMDA that is located on the outside of the NMDA receptor antagonists where the antagonists receptor to open the calcium channel simply compete with glutamate or glycine at (Carlson 2013). Several neurodegenerative the agonist‐binding sites to block normal diseases such as Alzheimer’s disease, functions, causing severe side effects such as

drowsiness, hallucinations, and even coma In the veterinary literature, the indication (Kemp and McKernan 2002). After several of NMDA receptor antagonists (such as investigations, researchers have shifted to ketamine and amantadine) is primarily for using NMDA receptor antagonists that block adjunctive analgesia to minimize the partially to avoid unwanted side effects. sensitization of the dorsal horn neurons These medications are called noncompetitive/ (Lamont 2008). For example, it was reported uncompetitive antagonists. Examples are that dogs that received ketamine infusions amantadine, memantine (uncompetitive), before, during, and after surgery had and ketamine. significantly lower pain scores after surgery It is hypothesized that chronic treatment and were significantly more active or had with conventional antidepressants results in improved feeding behavior during the same functional endpoint as the postoperative observation compared to administration of NMDA receptor control dogs (Wagner et al. 2002; Sarrau et al. antagonists (Skolnick 1999). However, a 2007). In both studies, opioid requirements systematic review and meta‐analysis of used concomitantly were not significantly ketamine and other NMDA receptor different between groups (Lamont 2008). antagonists in the treatment of major Amantadine was originally used as an depression concluded the antidepressant antiviral drug and to treat Parkinson’s disease efficacy was only observed in ketamine. in human medicine. Recently in both human Because ketamine also has a potential for and veterinary medicine, it has also been abuse and neurotoxicity as well as its used to treat chronic pain. Lascelles et al. potential therapeutic benefit, clinical use has (2008) conducted a randomized, blind, started in humans but warrants caution placebo‐controlled study to evaluate its (Newport et al. 2015). A recent paper analgesic effects as an adjunct to an analgesic discussed the possibility of developing a regimen in dogs with naturally occurring better and safer antidepressant medication osteoarthritis. They reported that the than ketamine (Zanos et al. 2016). addition of amantadine improved the dog’s physical activity and that it might be a useful adjunct therapy for dogs with osteoarthritic Overview of Indications pain. In veterinary behavioral medicine, Of the three excitatory amino acid receptor published information regarding NMDA subtypes, the NMDA receptor seems more receptor antagonists include the treatment of specifically linked to long‐term changes in stereotypic behaviors, obsessive‐compulsive neurons that play an important role in both disorders, and putative complex partial inflammation and nerve injury‐induced seizures. The drugs used in these studies central sensitization (De Kock and were dextromethorphan (Rendon et al. 2001; Lavand’homme 2007). Therefore, NMDA Dodman et al. 2004), memantine (Schneider receptor antagonists have been implicated in et al. 2009b) and Huperzine‐A (Schneider postoperative and neuropathic pain et al. 2009a), which is a herbal medication. management in humans (Collins et al. 2010). A systematic review in the human literature was not conclusive on its efficacy on Contraindications/Side neuropathic pain. The authors recommended Effects, and Adverse Events that additional randomized control trials in homogeneous groups of pain patients are According to the literature, except for keta- necessary for further conclusions (Collins mine, noncompetitive or uncompetitive et al. 2010). NMDA receptor antagonists in general are Seii Medication 173 well‐tolerated drugs with no serious adverse However, in the early 2000s, ketamine, a non- effects reported, when used in instructed competitive NMDA receptor antagonist, spe- doses in humans, for example, an open trial of cifically received attention for its rapid and amantadine in depressed patients (bipolar or robust antidepressant effects in major depres- major depression) with Borna disease virus sion (Zarate et al. 2006). Its action is not fully (BDV) infection, where 100–300 mg day−1 of understood but recent results from studies in amantadine were administered for a mean of rodents suggested that ketamine activated the 11 weeks. Major unwanted effects were mammalian target of rapamycin pathway and observed in only one out of 25 patients that subsequent synaptogenesis in the prefrontal led to a drop‐out from the study. The signs cortex as well as glycogen synthase kinase‐r beta reported were restlessness and blurring of (GK‐3β) inactivation (Scheuing et al. 2015). vision but the rest of patients tolerated the Although ketamine is generally used for anes- amantadine therapy till the end of the study thesia, at low doses, it also works as an antide- (Dietrich et al. 2000). Another study with pressant. When the dose is increased, it evokes memantine reported that in a randomized, psychotomimetic actions (Miller et al. 2016) pilot clinical trial for neuropathic pain follow- that challenge its clinical applications. In veteri- ing surgery, evaluating 5–20 mg day−1 of nary behavioral medicine, using ketamine in the memantine for four weeks, no adverse effects treatment of behavior problems or mental were observed (Morel et al. 2016). When health disorders has not yet been reported. NMDA receptor antagonists are used for out- Another psychiatric disorder where imbal- patient oral treatment in dogs, cats, and ances in glutamatergic neurotransmission horses, relatively few side effects have been might be involved is obsessive‐compulsive dis- reported so far. Dodman et al. (2004) order (OCD) or compulsive disorder. The conducted a randomized, double‐blind, nature of glutamate perturbation in OCD crossover‐designed study for 14 dogs with remains poorly understood. Research in this chronic allergic dermatitis for two weeks with area has been largely experimental with off‐label dextromethorphan (2 mg kg−1 b.i.d.). use of available medications (Pittenger 2015). Vomiting, retching, diarrhea, and lethargy were reported. A dog with lethargy and a dog Specific Medications with diarrhea withdrew from the study. All recovered once the treatment was discontin- I. Dextromethorphan ued. Schneider et al. (2009b) treated 11 dogs for compulsive disorder with memantine −1 Chemical Compound: Morphinan, 3‐methoxy‐ 0.3–1 mg kg twice a day. One client reported 17‐methyl‐, (9α, 13α, 14α)‐, hydrobromide a possible side effect from the drug on their monohydrate dogs (increased frequency of urination). DEA Classification: Not a controlled Since use of NMDA receptor antagonists is substance not yet widespread and research has been Preparations: Available in pills, gel caps, scarce, the presence or absence and the lozenges, liquids and syrups, either alone clinical significance of side effects should be or in combination with analgesics interpreted prudently. (acetaminophen), antihistamines (brom- pheniramine, chlorpheniramine, and diphenhydramine), decongestants (pseu- Clinical Guidelines doephedrine) and/or expectorants (guaifenesin). Dextromethorphan is also available in For decades, most of the research on human bulk powder from internet sites. Dose for mood disorders, especially major depression, antitussive use: 1–2 mg kg−1 q6–8h PO in cat has been based on monoaminergic systems. and dog (Kuehn 2015). 174 N‐Methyl‐D‐Aspartate (NMDA) Receptor Antagonists

Clinical Pharmacology Vomiting, retching, diarrhea, and lethargy Dextromethorphan (DXM) is a noncompeti- were reported in dogs with oral DXM tive NMDA receptor antagonist, available for (2 mg kg−1 b.i.d.) (Dodman et al. 2004). A dog use in many prescription products, as well as with lethargy and a dog with diarrhea in its most common form as over‐the‐counter withdrew from the study reported above. All (OTC) products for the treatment of cough. patients recovered once the treatment was The typical antitussive adult human dose is discontinued. 15 or 30 mg TID to QID. The antitussive effects of DXM persist for five to six hours Other Information after oral administration. When taken as According to the pharmacokinetics study of directed, side effects are rarely observed dextromethorphan after intravenous and (Drug Enforcement Administration 2014). oral administration in six healthy beagles Dextromethorphan is the dextro isomer of (KuKanich and Papich 2004), the drug had a levomethorphan, a semisynthetic morphine short half‐life, and had poor bioavailability, derivative. Although structurally similar to such as 11% in oral administration. The other narcotics, DXM does not act as a mu‐ authors concluded that its potential use with receptor opioid (e.g. morphine, heroin). The chronic oral administration is limited. antitussive activity of DXM is based on its Therefore, its effectiveness and long‐term σ action on ‐opioid receptors and DXM also has safety need to be further studied (Moriello analgesic and CNS depressant effects. DXM 2005; Saridomichelakis and Olivry 2016). and its metabolite, dextrorphan, act as potent Recently pharmacology studies in mice blockers of the NMDA receptor. At high doses showed antidepressant‐like effects of DXM used by those who abuse it, DXM causes dis- through forced swim and tail suspension sociative effects, similar to the controlled sub- tests (Nguyen and Matsumoto 2015). stances phencyclidine (PCP) and ketamine, According to the study, it is speculated that and inhibition of catecholamine reuptake. DXM may modulate the glutamatergic Approximately 5–10% of Caucasians are poor function through an NMDA blockade that DXM metabolizers, which increases their risk indirectly activates AMPA receptors. It is for overdose and death (Chyka et al. 2007). considered that AMPA receptors may In the veterinary field, it is used as an anti- contribute to the efficacy of antidepressant tussive and few side effects have been medications, including that of ketamine reported when given clinically relevant (Sanacora et al. 2008). doses. In the veterinary behavior field, IV administration of DXM is used for cribbing horses (Rendon et al. 2001) and oral DXM is Effects Documented in Nonhuman Animals used for dogs with repetitive behavior Dogs problems (Dodman et al. 2004). Dodman et al. (2004) conducted a randomized, double‐blind, crossover designed Contraindications and Side Effects study to test the efficacy of oral DXM DXM has been available as an OTC (2 mg kg−1 b.i.d. for two weeks) on 14 dogs antitussive medication for over 50 years and with repetitive behavior problems (e.g. self‐ has been considered to have a high margin of licking, self‐chewing, and self‐biting associ- safety with a clinical relevant dose. ated with chronic allergic dermatitis). Based Since DXM binds to serotonergic receptors, on a dermatology score and the owners’ daily the human literature states that it might not observations, it was concluded that DXM be safe to administer DXM with antidepres- induced a mild to moderate improvement in sants due to the risk of inducing a life‐ clinical signs (i.e. reduced the percentage of threatening serotonergic syndrome (Chyka time that allergic dogs spent in repetitive et al. 2007). behaviors). Saridomichelakis and Olivry Seii Medication 175

(2016) recommended further studies to fully results (Taira 1998; Kleinböhl et al. 2006). appreciate the effectiveness and long‐term Lascelles et al. (2008) published a randomized, safety of DXM in atopic dermatitis. blind, and placebo‐controlled study on the use Maurer and Dodman (2007) published one of oral amantadine in addition to meloxicam case report of the treatment for compulsive (a nonsteroidal anti‐inflammatory drug) on disorder in a dog using dextromethorphan as refractory osteoarthritis pain in 31 client‐ an alternative medication to memantine due owned dogs. In the study, physical activity in to its cost. Details are given in the memantine dogs was improved per client‐specific out- section of this chapter. come measures with the addition of amantadine (3–5 mg kg−1 orally every 24 hours) to Horses meloxicam treatment (0.1 mg kg−1 adminis- Rendon et al. (2001) reported DXM effects tered orally every 24 hours after a 0.2 mg kg−1 on cribbing horses. Jugular injection of DXM oral loading dose) within three weeks of the (1 mg kg−1) was administered to nine cribbing treatment. No abnormalities were reported horses and eight horses responded with on the patients’ laboratory work or adverse mean of 48% decrease in frequency compared effects during the study. to baseline, and its effect lasted 35–60 minutes following injection in almost half of the Use in Humans horses. Although no major side effects were Based on the oral administration of a single reported, one horse in the study showed amantadine 100 mg dose in 24 healthy adult higher rate of cribbing rate after the injection. humans, the time to peak concentration was 3.3 ± 1.5 hours (range: 1.5–8.0 hours). The II. Amantadine half‐life was 17 ± 4 hours (range: 10–25 hours). Amantadine is primarily excreted unchanged Chemical Compound: Adamantan‐1‐amine in the urine by glomerular filtration and hydrochloride tubular secretion. Therefore, compared with DEA Classification: Not a controlled otherwise healthy adult individuals, the substance clearance of amantadine is significantly Preparations: Available in 100‐mg capsules, reduced in adult patients with renal tablets or 50 mg/5 ml oral solution. insufficiency. The apparent oral plasma clearance of amantadine is reduced and the Clinical Pharmacology plasma half‐life and plasma concentrations Amantadine is a weak, noncompetitive are increased in healthy elderly individuals NMDA receptor antagonist. It has been used age 60 and older (Endo Pharmaceuticals Inc. treat Parkinson’s disease, drug‐induced 2009). Vale et al. (1971) reported on the extrapyramidal reactions, and virus infec- antidepression effects of amantadine. tions. Although its mechanism of action for each condition is not clearly understood, it Contraindications appears to exert its antiviral effect by prevent- Careful observation is required when ing penetration of the virus into the host cell, amantadine is administered concurrently and it is also known to prevent virus assembly with central nervous system stimulants. during virus replication (Endo Pharmaceuticals Agents with anticholinergic properties Inc. 2009). Amantadine is considered to have may potentiate the anticholinergic‐like side direct or indirect effects on dopamine neurons effects of amantadine. and oftentimes is prescribed with L‐Dopa for the management of L‐Dopa‐induced dyskine- Side Effects sia in Parkinson’s disease (Oertel and Schulz Although amantadine has not been shown 2016). Analgesic effects in orally administered to possess direct anticholinergic activity amantadine in humans had inconsistent in animal studies, clinically, it exhibits 176 N‐Methyl‐D‐Aspartate (NMDA) Receptor Antagonists

anticholinergic‐like side effects such as dry toxicity (Novartis New Zealand Limited mouth, urinary retention, and constipation 2011). Norkus et al. (2015) discussed the re‐ as well as nausea, dizziness, and insomnia evaluation of the dosing interval in the veteri- in humans (Endo Pharmaceuticals Inc. nary literature (3–5 mg kg−1 P.O. q24h 2009; Collins et al. 2010). [Lamont 2008]) as the majority of the drug was metabolized or eliminated within Overdose 24 hours (Bleidner et al. 1965). KuKanich Deaths have been reported from overdose (2013) recommended every 12 hours dosing with amantadine. The lowest reported acute due to the short half‐life for both dogs and lethal dose in humans was 1 g. Acute toxicity cats. may be attributable to the anticholinergic effects of amantadine. Drug overdose has Cats resulted in cardiac, respiratory, renal, or Amantadine is clinically used as an analgesic central nervous system toxicity. Cardiac adjunct in cats, usually in combination with dysfunction includes arrhythmia, low doses of opioids. In six cats in the phar- tachycardia, and hypertension. macokinetics study, it showed high oral bioa- The toxic dose reported for cats is vailability and the terminal half‐life 5.8 hours 30 mg kg−1 and behavioral effects may be after IV administration and 5.4 hours after noted at 15 mg kg−1 in dogs and cats. oral administration, while half‐life in humans is 9–15 hours (Siao et al. 2011). Effects Documented in Nonhuman Animals Dogs III. Memantine The pharmacokinetics of amantadine have been incompletely described in dogs. Based Chemical Compound: 3,5‐dimethylada- on urinary excretion studies in two beagle mantan‐1‐amine hydrochloride dogs, amantadine seems to be well absorbed DEA Classification: Not a controlled in dogs, about 10% is metabolized to N‐meth- substance ylamantadine, and the half‐life of amantadine Preparations: Available in 10‐, 20‐mg ta blets was short: 5 hours after a single oral dose of and oral solution: 2 mg ml−1. An extended 30 mg kg−1. No reports are available assessing release capsule is also available in 7‐, 14‐, the activity or lack thereof for the metabolite. 21‐mg, and 28‐ mg doses. Dogs administered amantadine 50 mg kg−1 every 24 hours by mouth for 30 days had neg- Clinical Pharmacology ligible amounts of drug in tissue samples Memantine is a low to moderate affinity, collected 24 hours after the last dose with the uncompetitive NMDA receptor antagonist investigators concluding that a dose of aman- with strong voltage dependency and rapid tadine is eliminated within 24 hours (Bleidner blocking/unblocking kinetics (Forest et al. 1965). Laboratories Inc. 2003). It has been used to Norkus et al. (2015) reported a single oral safely treat patients with moderate to severe dose of 100 mg amantadine (mean dose Alzheimer’s disease for more than two dec- 2.8 mg kg−1 as amantadine hydrochloride) was ades. Memantine is a derivative of amanta- given to five healthy greyhound dogs for phar- dine. Originally due to its effect in Parkinson’s macokinetics study. The terminal half‐life in disease, it was believed that memantine was a greyhound was similar (5.9 hours) to the dopaminergic or anticholinergic drug. aforementioned study in the two beagle dogs. However, in the early 1990s it was found to be Dogs appear to tolerate higher doses of neither dopaminergic nor anticholinergic at amantadine than humans. Safety data in dogs its clinically useful dosage, but rather an administered 80 mg kg−1 a day for a period up NMDA receptor antagonist (Lipton 2006). It to two years did not report any specific was also reported that memantine does not Seii Medication 177 affect the release of serotonin, nor does it Memantine has been also studied to treat alter monoamine oxidase (MAO‐A or B) or obsessive‐compulsive disorder (OCD) as an adenylate cyclase activity. In humans, augmentative regimen and several case series memantine is 100% bioavailable after an oral or open label studies have been published dose, undergoes minimal metabolism, and (Stewart et al. 2010; Wu et al. 2012). exhibits a terminal elimination half‐life of According to a double‐blind, placebo‐ 60–80 hours (75% or greater of the dose is controlled trial, 38 patients were administered eliminated intact in the urine). It rapidly either memantine (10 mg day−1 for the first crosses the blood–brain barrier with a CSF/ week, and 20 mg day−1 for the rest of the trial) serum ratio of 0.52. Memantine also showed or placebo plus fluvoxamine for eight weeks. −1 antagonistic effects at the 5HT3 receptor with All patients received fluvoxamine100 mg day a potency similar to that of the NMDA recep- for the first four weeks of the trial followed tor and blocked nicotinic acetylcholine recep- by 200 mg day−1 for the rest of the study. At tors with one‐sixth to one‐tenth the potency the end of the trial 89% of patients in the (Forest Laboratories Inc. 2003). In humans, memantine group compared with 32% in the co‐administration of memantine with acetyl- placebo group had achieved remission. The cholinesterase inhibitors (AChEI) such as authors considered that the positive outcome donepezil HCl did not affect the pharmacoki- might be partially due to the effect of netics of either compound and they are fluvoxamine, however, the overall outcome commonly used together (Gauthier and rate of this study was still higher than Molinuevo 2013). fluvoxamine monotherapy (Ghaleiha et al. It is demonstrated that memantine 2013). Another study conducted with 11 improves hippocampal long‐term potentia- patients, had treatment groups of either tion (LTP), working memory‐based learning memantine (5–10 mg day−1) or placebo in rats (Zajaczkowski et al. 1997; Ma et al. combined with either selective serotonin 2015) and functional, global, and cognitive reuptake inhibitors or clomipramine for efficacy in moderate to severe Alzheimer’s 12 weeks. One week before starting the study disease patients (Reisberg et al. 2006). It is and throughout the study, patients were generally considered that the effect of treated with a standard SSRI or clomipramine memantine to slow cognitive decline in at therapeutic dosages for at least 12 Alzheimer’s disease patients is based on its consecutive weeks. There was a positive neuroprotective action. effect in the memantine group seen after However, there is yet no general agreement 8–12 weeks. The authors concluded that a on how NMDA receptor channels are minimum of 12 weeks of treatment may be blocked by memantine (Povysheva and necessary for marked improvement. Johnson 2016). Side Effects Use in Humans Most common adverse reactions reported in After the antidepressant effect of ketamine the human literature (≥5% and greater than was found, other NMDA receptor antago- placebo) are dizziness, headache, confusion, nists that are considered safer, such as and constipation although usually at high memantine, were studied for their possible doses of 40–60 mg day−1 (Lipton 2006). It antidepressant effects (Ladarola et al. 2015). should be used with caution in patients with So far, based on the meta‐analysis of the severe renal impairment. three studies which used memantine at or about a daily dose of 20 mg during an eight‐ Other Information week trial, its efficacy to treat depression did When circulatory function parameters and not exceed the results of the placebo groups respiratory function parameters were (Newport et al. 2015). compared to baseline in five female beagle 178 N‐Methyl‐D‐Aspartate (NMDA) Receptor Antagonists

dogs at 3, 10 and 30 mg kg−1 of oral meman- that was the peak improvement for the dog tine, a dose‐related decrease in cardiac so far. At this point, fluoxetine 1 mg kg−1 minute output at 10 mg kg−1 (7.5% of the dogs) q24h was added and the memantine dose and 30 mg kg−1 (20% of the dogs) and a was reduced to 0.4 mg kg−1, every 12 hours. decrease in stroke volume at 10 mg kg−1 (14% After two weeks of this combination therapy, of the dogs) and 30 mg kg−1 (32% of the dogs) the improvement level was 50–75% (higher were observed compared to controls, 10 minutes than when fluoxetine was used as after dosing. monotherapy for five weeks previously). Due Systolic left ventricular blood pressure to the cost of memantine, dextromethorphan decreased at 30 mg kg−1 compared to control 2 mg kg−1 every 12 hours was added at 15 minutes (9% of the dogs) and 30 minutes (fluoxetine’s dose was still at 1 mg kg−1) but (18% of the dogs) after administration no positive change was observed in the first (Center for Drug Evaluation and Research two weeks of this combination. The dose of 2003). dextromethorphan was increased to 2 mg kg−1 every eight hours and the owner Effects Documented in Nonhuman Animals reported 50–75% improvement, i.e. similar Dogs than what was observed with memantine and Maurer and Dodman (2007) published a case fluoxetine combination. After one week, the report on a miniature Dachshund with daily dose of dextromethorphan was increased to repetitive circling behavior (spinning) that 3 mg kg−1 every eight hours but the owner also had a history of grand mal seizures. reported little change. Fluoxetine was After no improvement had occurred when increased to 2 mg kg−1 q24h at that time. As the dog was treated with a monotherapy of the result the highest improvement level fluoxetine for three weeks or clomipramine (85%) was reported and it continued or got for four weeks previously, in addition to better for four months of the treatment behavior modification and environmental period. No adverse effects were reported management, using a liquid preparation of during the treatment period of this dog. memantine (2 mg ml−1) at 0.4 mg kg−1, every According to the case‐series by Schneider 12 hours by mouth was started as a et al. (2009b), 11 dogs that had compulsive monotherapy. On the second day of treatment disorders in different clinical manifestations the client reported about 25% improvement such as light or shadow chasing, spinning/ in the circling behavior (decreased frequency circling or tail‐chasing for longer than and intensity) as well as becoming more six weeks were enrolled for a 4‐week study of playful. After three days, the dosage of either memantine monotherapy (7 out of 11 memantine was increased to 0.5 mg kg−1 dogs) or augmentation therapy of the ongoing every 12 hours. After that, the client reported fluoxetine treatment (4 out of 11 dogs). All about 50% of clinical improvement. After dogs were prescribed behavior modification, five days at a dosage of 0.5 mg kg−1 (PO, every adapted appropriately to each case. 12 hours) with stable improvement, the Memantine was administered orally twice a dosage was increased to 0.8 mg kg−1 (PO day at a starting dose of 0.3–0.5 mg kg−1. The every 12 hours) for one day and then to dose was increased over time if necessary, 1 mg kg−1 (PO every 12 hours) in an attempt and side effects permitting, to a dose not to gain further improvement. However, the higher than 1 mg kg−1. Seven out of 11 dogs dog relapsed at this higher dosage rate to the showed a reduction in the severity of their point that the repetitive behavior returned to compulsive disorder symptoms, assessed by its pretreatment level. The dosage was the clients. Within two weeks of the reduced to 0.6 mg kg−1 in the morning and memantine treatment, reduction of the 0.8 mg kg−1 at night. With this reduced dose, clinical signs was reported but considerable the improvement level was not much as 50% improvement was seen by the third week in Seii Medication 179 most dogs. Possible adverse effects were the elimination half‐life was 288.5 minutes, observed in one dog (increased frequency of allowing a b.i.d. or t.i.d. dosing in humans urination), which subsided when the owner (Qian et al. 1995; Ferreira et al. 2016). Li et al. withdrew the dog from the study. Based on the (2007) used a single oral therapeutic dose results of this investigation, the authors con- (0.4 mg) to study the pharmacokinetic in cluded that memantine may be an effective, humans and reported the peak plasma con- well‐tolerated option for the treatment of com- centration (Cmax of 2.59 ± 0.37 ng ml−1) was pulsive disorders in dogs either as a sole treat- reached at 58.33 ± 3.89 minutes (Tmax) while ment or as an augmentation to fluoxetine. the mean elimination half‐life was longer than the previous result (716.25 ± 130.18 minutes) IV. Huperzine A despite its lower dose administration. In the pharmacokinetic study using beagle Chemical Compound: Chinese folk medi- dogs, the peak serum concentration (Cmax cine Huperzia serrata (Qian Ceng Ta) 9.8 ± 1.0 ng ml−1) by giving a 500 μg tablet was DEA Classification: Not a controlled reached in three hours (Tmax) and the half‐life substance was 5.9 ± 1.3 hours (Ye et al. 2005). In toxicologi- Preparations: Nutraceutical product is cal studies, histopathological changes were available in the USA by tablet, capsule and found in the liver, the kidney, the heart, the lung, transdermal patch. and the brain in rats (1.5 mg kg−1 oral administration) and dogs (0.6 mg kg−1 IM injection) Clinical Pharmacology (Tang and Han 1999). According to a study, in Huperzine A (Hup A) is derived from rats, no tolerance phenomena occur after multi- Huperzia serrata (Qian Ceng Ta). It is a ple dosing treatments (Little et al. 2008). licensed drug to treat Alzheimer’s disease (AD) in China and was classified as a dietary Use in Humans supplement by the FDA in 1997 for memory In the US, Huperzine A is available in a twice‐ impairment. Huperzine A is a reversible, daily tablet or in capsule forms (200–400 μg day−1) potent, and selective acetylcholinesterase for memory impairment (Perry and Howes (AChE) inhibitor and a noncompetitive 2011). NMDA receptor antagonist (Tang and Han 1999; Zhang et al. 2002). Several pharmaco- Overdose and Side Effects logical properties have been reported such as Huperzine A is well tolerated in humans, anti‐inflammatory, antinociceptive (see over- rodents, and dogs. Its adverse effects are less dose section below), and anticonvulsant pronounced than other AChE inhibitors properties (Ferreira et al. 2016) as well as the (Tang and Han 1999). Side effects observed ability to reverse or attenuate cognitive defi- in published studies are mild and only cits in rodents (Tang and Han 1999; Wang observed at high doses, with no adverse signs and Tang 2005). Additionally, some clinical seen at doses lower than 0.3–0.5 mg kg−1 in trials have also demonstrated that Huperzine rats, 0.1 mg kg−1 in monkeys, and 0.5 mg kg−1 A significantly relieves memory deficits in in humans (Filliat et al. 2002). aged subjects, patients with benign senescent In rodent studies, an antinociceptive effect forgetfulness, AD, and vascular dementia was also reported, though it is noted that its (Wang and Tang 2005). effective dose is much higher than the median A pharmacokinetic study in six Chinese toxic dose (TD50) (Ferreira et al. 2016). volunteers after a single oral dose of 0.99 mg, which is the double the therapeutic dose in Effects Documented in Nonhuman Animals humans, showed its peak serum concentration Dogs (Cmax of 8.4 μg l−1) was reached at 79.6 minutes Schneider et al. (2009a) published a case (Tmax) post‐dosing. The estimated value for report on the use of Huperzine A to treat 180 N‐Methyl‐D‐Aspartate (NMDA) Receptor Antagonists

putative complex partial seizures in a 34‐ months (six months from the initiation of the month‐old Bernese Mountain dog. The dog treatment). The patient relapsed when pre- presented with clinical signs of “star gazing,” senting a joint condition. At this point, “fly snapping,” licking, vacuous chewing, and Huperzine A was discontinued and switched ongoing anxiety. The authors used a starting to phenobarbital. No side effects were dose of Huperzine A 50 μg (approximately reported during the treatment of Huperzine 1 μg kg−1) twice a day. The client noticed a A in this case. reduction of the clinical signs within one The authors of this case report discussed week from the initiation of treatment. Within the potential use of Huperzine A for patients four weeks of the treatment, the owner presenting benign focal seizures due to its noticed mild regression of the episodes and antiseizure and NMDA receptor antagonist the dose was increased from twice a day to effects, and the fact that Huperzine A has so three times a day, which kept the clinical far caused less side effects compared to con- signs decreased or absent for another five ventional medications in dogs.

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Monoamine Oxidase Inhibitors Leticia Mattos de Souza Dantas and Sharon L. Crowell‐Davis

University of Georgia, Athens, GA, USA

Action coupling (Knoll et al. 1996). Thus, they should not be considered solely as drugs that Monoamine oxidase (MAO) is an enzyme of just have a simple and specific activity. the outer mitochondrial membrane that They are also likely to exhibit substantially occurs in a variety of tissues, including the different actions on different species heart, the liver, kidneys, the spleen, platelets, because there are species differences in the peripheral nervous system, and the cen- the ratios of MAO‐A to MAO‐B, both over- tral nervous system (CNS) (Obata et al. 1987). all and in given organ systems. For example, In the CNS, MAO, primarily MAO‐B, catab- in humans and monkeys, dopamine in the olizes the oxidative deamination of catechola- brain is a substrate of both MAO‐A and mines, including dopamine, norepinephrine, MAO‐B (Glover et al. 1977; O’Carroll et al. epinephrine, β‐phenylethylamine (2‐pheny- 1983). As a consequence, basal levels of brain lethylamine), and serotonin. In the intestinal dopamine increase with chronic adminis- tract and liver, MAO, primarily MAO‐A, is tration of l‐deprenyl in these species also important in catabolizing exogenous (Riederer and Youdim 1986; Boulton et al. amines, for example, tyramine, derived from 1992). MAO‐B has little effect on dopamine various foods and drugs. The name is not metabolism in the rat brain, however. entirely accurate since MAO enzymes can Thus, dopamine levels in the brain of the rat also deaminate long‐chain diamines (Gerlach are less affected by l‐deprenyl treatment et al. 1993). than those of humans (Kato et al. 1986; MAO inhibitors prevent the action of Paterson et al. 1991). The guinea pig appears MAO‐A, MAO‐B, or both. Drugs in this to be a better model of dopamine metabo- category, while classified according to their lism by MAO in humans than either mice or action of inhibiting MAO, also have a variety rats (Ross 1987). Human platelet MAO is pri- of other actions, many of which enhance the marily or entirely of the B form, while dog activity of catecholamines. For example, l‐ platelet MAO is of both the A and B forms deprenyl, in addition to inhibiting MAO (Collins and Sandler 1971; Donnelly and activity, inhibits presynaptic catecholamine Murphy 1977; Obata et al. 1987). As a conse- receptors, inhibits the uptake of catechola- quence of these species variations in the mines, induces the release of catecholamines metabolism, initiation of use of a MAO from their intraneuronal stores, and stim- inhibitor in a new species should be done ulates action potential‐transmitter release cautiously.

Overview of Indications Specific Medications

MAO‐B inhibitors, specifically selegiline, I. Selegiline Hydrochloride have been shown to increase the life span Chemical Compound: (R)‐(−)‐N,2‐dimethyl‐ when given to healthy mice, rats, hamsters, N‐2‐propynylphenethylamine hydrochloride and dogs (Knoll 1988; Knoll et al. 1989; DEA Classification: Not a controlled Milgram et al. 1990; Kitani et al. 1992; Ivy substance et al. 1994; Ruehl et al. 1997b). (−)Deprenyl Preparations: Generally available as 2‐, 5‐, was found to enhance anti‐oxidant enzyme 10‐, 15‐, and 30‐mg tablets and as 5‐mg activities not only in the brain’s dopaminergic capsules. FDA approved for use in dogs regions but also in extra‐brain tissues such as with canine cognitive dysfunction. the heart, the kidneys, the adrenal glands, and the spleen (Kiray et al. 2007, 2008, 2009). Several studies have also observed Clinical Pharmacology mobilization of many humoral factors and Selegiline is an irreversible inhibitor of MAO. enhancement of natural killer (NK) cell It has a substantially greater affinity for functions with (−)deprenyl administration MAO‐B than for MAO‐A and therefore (Kitani et al. 2002). Selegiline also increases functions as a selective MAO‐B inhibitor the survival of human patients with when given at clinically appropriate doses Parkinson’s disease (Birkmayer et al. 1985). (Knoll and Magyar 1972; Yang and Neff 1974; Selegiline likewise causes a decreased Glover et al. 1977; Pfizer Animal Health and accumulation of lipofuscin in various parts of Product Information 2000). It was the first the brain of aging rats (Amenta et al. 1994a, drug to be developed that was specific in its 1994b, 1994c; Zeng et al. 1994; Tseilikman inhibition of MAO‐B (Knoll 1983). Inhibition et al. 2009). It also appears to facilitate of MAO happens in two stages: an initial activation of astrocytes that are associated reversible reaction followed by a second with increased secretion of trophic factors, irreversible reaction (Heinonen et al. 1994). resulting in increased neuronal survival and However, selectivity is not absolute, and rare growth (Biagini et al. 1994). It blocks the patients may exhibit signs of MAO‐A pathological changes induced by the inhibition. In average adult humans, the neurotoxin 1‐methyl,4,phenyl‐1,2,3,6‐ selectivity of selegiline’s MAO inhibition tetrahydropyridine (MPTP) (Battistin et al. seems to disappear at a dose of about 1987). Selegiline’s protective central nervous 30–40 mg total dose per day (Somerset system and anti‐aging effects also seem to be Pharmaceuticals Inc. 2003). due to its action potentiating the activity of Following administration of 1 mg kg−1 of the free radical scavenging enzymes, and selegiline PO, absorption in dogs is rapid, possibly to a counteraction of free radicals with peak plasma concentration occurring and a membrane‐stabilizing action (Takahata after 20–30 minutes. Measurable concen- et al. 2006; Subramanian and James 2010a, trations are detectable in the plasma up to 2010b). three hours later. The absorption half‐life is Medications that significantly inhibit about 41 minutes whereas the elimination MAO‐A exist but are not used in the half‐life is about 78 minutes (Mahmood treatment of behavioral and mental problems et al. 1994). in animals. Only the MAO‐B inhibitor Selegiline also inhibits the reuptake of selegiline will be discussed in detail. dopamine, norepinephrine, and serotonin Therefore, all discussion of contraindications, into presynaptic nerves, inhibits dopamine side effects, adverse drug interactions, and autoreceptors, increases the turnover of treatment of overdose is presented in cover- dopamine, reduces oxidative stress caused by age of that drug. the degradation of dopamine, increases free Spcfc Medication 187 radical elimination by enhancing superoxide and anxiety disorders such as social phobia dismutase and catalase activity, potentiates and panic disorder (Stahl 2011, 2013). neural responses to dopamine by the indirect mechanism of elevating phenylethylamine, a Contraindications neuromodulator of dopaminergic responses, Selegiline is contraindicated in patients with and enhances scavenger function in the CNS. a known history of sensitivity to this drug. At clinically appropriate doses, it does not Severe CNS toxicity, potentially resulting in have the “cheese effect,” that is, it does not death, can ensue from combining selegiline potentiate the hypertensive effects of with various other drugs, particularly tyramine, which is characteristic of MAO‐A tricyclic antidepressants (TCAs), for and mixed MAO inhibitors (Lai et al. 1980; example, amitriptyline, clomipramine, and Knoll 1983; Fagervall and Ross 1986; Knoll selective serotonin reuptake inhibitors 1987; Heinonen and Lammintausta 1991; (SSRIs), for example, fluoxetine and Berry et al. 1994; Fang and Yu 1994; Hsu et al. paroxetine. The phenomenon is called 1996; Pfizer Animal Health and Product serotonin syndrome (see Chapter 19 for Information 2000). Nevertheless, it is further discussion). The detailed mechanism probably best to avoid regular use of cheese of this serious drug interaction is poorly as a treat for dogs on selegiline, since a rare understood. Therefore, these drugs should dog may, as happens in humans, exhibit a never be combined. Because of medication cheese response despite selegiline generally half‐life, no TCA or SSRI should be given for being very MAO‐B specific. at least two weeks following discontinuation Selegiline has three principal metabolites: of selegiline. Due to fluoxetine’s long half‐ l‐(−)amphetamine, l‐(−)methamphetamine, life, selegiline should not be given for at least and N‐desmethylselegiline (Reynolds et al. five weeks following discontinuation of that 1978a, 1978b; Philips 1981; Yoshida et al. 1986; drug. Even after a five‐week washout period, Dirikolu et al. 2003), and some of its pharma- MAO inhibitors should be initiated with cological actions appear to be the result of the caution and the patient closely monitored, sympathomimetic properties caused by its because metabolites of fluoxetine may metabolites (Fozard et al. 1985). See Chapter remain in the system for longer periods of 15, CNS Stimulants, for further discussion of time and still induce serotonin syndrome amphetamine. Phenylethylamine, a modula- (Coplan and Gorman 1993; Pfizer Animal tor of catecholamine neurotransmission in the Health and Product Information 2000; CNS, is a substrate of MAO‐B, and levels of Somerset Pharmaceuticals 2003). this molecule also increase following treat- Selegiline should not be given with ment with selegiline (Philips and Boulton potential MAO inhibitors including amitraz, 1979; Philips 1981; Paterson et al. 1990; a topical ectoparasiticide (Pfizer Animal Durden and Davis 1993). A study by Schrickz Health and Product Information 2000). and Fink‐Gremmels (2014) found that sele- Possible drug interactions have been giline did not inhibit the function of the drug observed in dogs concurrently on metronida- transporter P‐gp in the dog. zole, prednisone, and trimethoprim sulfa. Combining selegiline with meperidine, a Uses in Humans synthetic narcotic analgesic, is also Selegiline is used to treat Parkinson’s disease, contraindicated in humans due to the in which it potentiates the effects of l‐dopa, occurrence of stupor, muscular rigidity, and Alzheimer’s disease (see, e.g. Tariot et al. severe agitation, and elevated temperature in 1987; Parkinson Study Group 1989, 1993; some patients receiving this combination. Tariot et al. 1993; Olanow et al. 1995; Sano While it is not known if this will occur in et al. 1997; Heikkila et al. 1981). Selegiline is veterinary patients, it is recommended that also used to treat major depressive disorder this combination also be avoided in 188 Monoamine Oxidase Inhibitors

nonhuman animals as well (Somerset and pup survival. At the highest dose Pharmaceuticals 2003). (64 mg kg−1) no pups survived to postpar- Also, in humans, concurrent use of MAO tum day 4 (Somerset Pharmaceuticals Inc. inhibitors in conjunction with α‐2 agonists 2003). sometimes results in extreme fluctuations of blood pressure (Somerset Pharmaceuticals Overdose 2003). Blood pressure monitoring is therefore In early overdose, induction of emesis or recommended in veterinary patients gastric lavage may be helpful, otherwise concurrently given selegiline and any α‐2 provide supportive treatment. Convulsions agonist. A study that investigated the and other signs of CNS overstimulation influence of selegiline (10 mg daily−1, orally should be treated with diazepam. Avoid use for one week) on vascular alpha‐1‐ and of phenothiazine derivatives and all CNS alpha‐2 adrenoceptor responsiveness in stimulants. Treat hypotension and vascular conscious unrestrained dogs showed that collapse with IV fluids. treatment induced vascular alpha‐1 and alpha‐2 adrenoceptor‐hyposensitivity Discontinuation (probably associated with the increase in Because selegiline is used to treat an sympathetic tone) (Pelat et al. 2001). irreversible degeneration of the CNS, it should not be discontinued in patients that Side Effects respond to it. It is worth noting that in In one clinical trial of dogs treated with veterinary medicine, it is recommended that selegiline, 4% of the study population treatment is initiated as early as possible for experienced events sufficiently adverse to better results in controlling clinical signs of result in a reduction of dose or withdrawal cognitive decline (Overall 2013) even though from medication. Side effects experienced by long‐term studies are lacking (Studzinski these dogs included restlessness, agitation, et al. 2005). vomiting, disorientation, diarrhea, and diminished hearing. Also, during clinical Other Information trials conducted on dogs as a part of safety The term cognitive dysfunction syndrome and efficacy testing, three dogs showed an (CDS), as used in veterinary clinical increase in aggression (Pfizer Animal Health behavioral medicine, refers to geriatric onset and Product Information 2000). changes in behavior that cannot be attributed Studies to date have not identified any to medical conditions such as neoplasia or mutagenic or chromosomal damage potential. organ failure in dogs and cats. In dogs, a No evidence of teratogenic effects was number of categories of behavior may be identified in rats given 4, 12, or 36 mg kg−1 altered. First, dogs with CDS often exhibit selegiline daily during pregnancy or in rab- various behaviors that suggest disorientation, bits given 5, 25, or 50 mg kg−1 during preg- for example, they may wander around the nancy. However, in the two higher doses house in an aimless fashion, appear not to be given to rats, fetuses exhibited a decreased able to find something, such as their bed, or body weight. At the highest dose given to get stuck behind open doors. Second, there is rabbits, there was an increase in resorption often altered social interaction. Usually, this and percentage of postimplantation losses, is noted as a decrease in social interaction with a concurrent decrease in the number of with human family members, other pets in live fetuses. In another study in which preg- the household, or both. Third, there is a loss nant rats were given 4, 16, or 64 mg kg−1 of prior learned behaviors, including house‐ daily, there was an increase in the number of training and basic obedience cues, such as stillbirths and a concurrent decrease in pup “sit.” Fourth, sleep habits change. Total sleep body weight, the number of pups per dam, increases, but nighttime wakefulness may Spcfc Medication 189 develop. Finally, overall activity, particularly layer was significantly lower as well. purposeful activity, decreases. Clinical signs Astrocytes were significantly denser with are progressive (Bain et al. 2001; Neilson hypertrophy of cell bodies, and Purkinje cells et al. 2001) and early treatment is warranted. showed fewer neurofilament immunoreactive A detailed discussion on CDS is beyond the dendrites. The authors concluded that these scope of this book but age‐related behavioral findings might underlie the functional changes have a high prevalence among decline of afferent efficacy and information geriatric dogs and cats and should not be integration in the aging cerebellum. Other overlooked (Azkona et al. 2009). Consult reported pathological changes in the aging Araujo et al. (2005), Landsberg (2005), Head cat brain are neuronal loss with cerebral et al. (2008), Landsberg et al. (2012), and atrophy, widening of sulci, and increases in Cory (2013) for comprehensive reviews. ventricular size. Similar to dogs, perivascular Histologic lesions identified postmortem changes such as microhemorrhage or infarcts in the brains of dogs with CDS closely in periventricular vessels, increase in resemble lesions in the brains of humans oxidative damage, and diminished cholinergic with Alzheimer’s disease (Cummings et al. function have also been reported. Dogs and 1996b). Specifically, dogs that exhibited cats show Aβ brain deposition and pre‐tangle geriatric behavior problems before death pathology with increasing age, but cats have been identified as having meningeal demonstrate more diffuse Aβ plaques than fibrosis, lipofuscinosis, generalized gliosis, humans with Alzheimer’s disease and dogs and ubiquitin‐containing granules in the with CDS (Head et al. 2005; Gunn‐Moore white matter upon postmortem histological et al. 2006; reviewed by Landsberg et al. examination (Ferrer et al. 1993). There are 2012). Among the most frequent behavioral also age‐related cerebral vascular changes changes in feline CDS are spatial or temporal and gliosis, dilation of the ventricles, and disorientation, altered social interactions, thickening of the meninges (Uchida et al. changes in sleep–wake cycles, house‐soiling 1992; Shimada et al. 1992). β‐Amyloid with inappropriate urination or defecation, plaques develop in the brains of old dogs that changes in activity, and increased are similar to those found in the brains of vocalizations (Gunn‐Moore et al. 2007). humans with Alzheimer’s disease (Cummings The mechanisms by which selegiline et al. 1993). Deficits in discrimination reverses CDS are not fully understood. It learning, reversal learning, and spatial increases dopamine activity by several mech- learning are strongly associated with degree anisms, inhibition of MAO‐B (a dopamine of deposition of β‐amyloid in the dog brain metabolizer), increasing the impulse‐medi- (Cummings et al. 1996a). ated release of catecholamines, decreasing Dogs with CDS have hypothalamic– presynaptic dopamine reuptake, increasing pituitary–adrenal axis dysregulation that concentrations of phenylethylamine, which occurs without typical signs of Cushing’s potentiates dopamine action, and increasing syndrome or other medical conditions synthesis of aromatic l‐amino acid decarbox- expected to activate the hypothalamic–pitui- ylase, which results in increasing dopamine tary–adrenal axis (Ruehl et al. 1997a). synthesis (e.g. Heinonen and Lammintausta Geriatric cognitive decline also occurs in 1991; Knoll et al. 1996; Jurio et al. 1994). the cat, although it is not as well studied as in Selegiline also decreases free radical produc- the dog. A study by Zhang et al. (2006) found tion and increases the activity of superoxide that the thickness of the molecular layer and dismutase, which scavenges free radicals total cerebellar cortex of older cats was (Carillo et al. 1994). These actions are benefi- significantly decreased when compared to cial to the aging brain since free radicals young adults. The granular layer was contribute to the pathogenesis of neurode- increased and the density of neurons in each generative disorders (Gerlach et al. 1993). 190 Monoamine Oxidase Inhibitors

Table 13.1 Doses of selegiline for dogs and cats. in superoxide dismutase activity in the striatum but not in the hippocampus (Carillo Dose et al. 1994). Dogs given 1 mg kg−1 of selegiline daily PO −1 Cat 0.5–1.0 mg kg for one year do not show any sign of hepatic Dog 0.5–1.0 mg kg−1 damage or dysfunction. There was no significant difference in bile acid concentrations between treated and placebo groups (Ruehl Better results with selegiline treatment are et al. 1993). generally reported when the medication is A detailed discussion of its use in the treat- started early in the progression of the disease ment of pituitary‐dependent hyperadreno- and clinical signs are still mild (Overall 2013). corticism is beyond the scope of this book. Nonetheless, only a subset of dogs seems to Further discussion can be found in Bruyette benefit from selegiline use, with minimal et al. (1995), Bruyette et al. (1997a, 1997b), clinical improvement and no research has Peterson (1999), and Reusch et al. (1999). established long‐term benefits in dogs or cats Ruehl and Hart (1998) suggested that sele- (Studzinski et al. 2005). giline prolongs life in otherwise healthy Doses for treating cats and dogs with sele- elderly dogs (>10 years) when given at a dose giline are given in Table 13.1. of 1 mg kg−1 daily. Further studies are necessary to confirm if these results apply to Effects Documented in Nonhuman Animals the general dog population. Cats In clinical trials of the treatment of CDS Although selegiline is not approved for use in with selegiline at recommended doses, dogs cats, signs of Alzheimer’s disease‐like show improvement in sleeping patterns, pathology have been reported in them house‐training, and activity level after four (Cummings et al. 1996b) and signs of CDS weeks of treatment (Ruehl et al. 1994), with are common in aging cats (Gunn‐Moore treated dogs showing significant et al. 2007; Landsberg et al. 2012). Cats have improvement over dogs receiving placebo been treated with up to 10 times the (Head et al. 1996). Individual response varies therapeutic dose with no toxicity (Ruehl et al. substantially and some dogs continue to 1996), and geriatric cats treated with show additional improvement for up to three selegiline for signs of cognitive decline have months. Geriatric, but not young, dogs given shown improvement (Landsberg 1999). l‐deprenyl exhibit improved spatial short‐ term memory over dogs given placebo. The Dogs best effect occurred at 0.5–1.0 mg kg−1, with In dogs, selegiline hydrochloride is used to smaller or larger doses being less effective treat CDS at a dose of 0.5–1.0 mg kg−1 given (Head et al. 1996). once daily in the morning, and pituitary‐ Selegiline causes a dose‐dependent inhibi- dependent hyperadrenocorticism is treated tion of MAO‐B activity in the striatum, the at a dose of 1.0–2.0 mg kg−1 daily. It has also hippocampus, the liver, and the kidney of dogs. been shown to have anticataleptic activity in When selegiline is given at doses of 0.5– research dogs, though this effect is due to 1.0 mg kg−1 over a two‐week period, it has no activity of the stimulant metabolites rather detectable effect on MAO‐A activity in the than by MAO‐B inhibition (Milgram et al. same tissues (Milgram et al. 1995). This con- 1993; Nishino et al. 1996; Nishino and trasts with the rat, in which a single dose of Mignot 1997). Activity is specific to certain selegiline does not cause MAO‐A inhibition, brain regions. In dogs, three weeks of medi- but repeated doses do cause MAO‐A inhibition cation with 0.1, 0.5, or 1.0 mg kg−1 day−1 PO (Waldmeier et al. 1981; Zsilla et al. 1986; caused significant, dose‐dependent increases Terleckyi et al. 1990; Murphy et al. 1993). Spcfc Medication 191

Likewise, there are no significant changes in dermatological disorders (2.2%), disorienta- levels of dopamine, 3,4‐dihydroxyphenylacetic tion (2.0%), hindlimb paresis and ataxia acid, homovanillic acid, 3‐methoxy‐turamine, (2.0%), lethargy (1.9%), orthopedic disorders 5‐hydroxytryptamine, or 5‐hydroxyindoleac- (1.7%), polydipsia (1.7%), and seizures (1.6%) tic acid in the striatum or cortex (Milgram were also mentioned but the majority of et al. 1995). At least in the rat, sex, as well as these reports were not considered to be dose and route of administration, affect the drug‐related. Treatment was discontinued activity of selegiline on MAO‐A and MAO‐B. due to side effects in 5% of dogs and due to Females respond to selegiline at a lower dose lack of response to treatment in 2% of dogs. than do males, and subcutaneous injection is Dogs with disorientation, decreased social more efficient than oral dosing (Murphy et al. interactions, and loss of house‐training had a 1993). better response to therapy than dogs with Healthy adult dogs given 0, 0.1, 0.5, or changes in activity and/or sleep‐wake cycle 1 mg kg−1 of selegiline for two weeks exhibit on day 30. Most dogs continued to show no changes in locomotor activity, inactivity, improvement by day 60, with the greatest sniffing, or urination as assessed in an open improvement seen in dogs with disorienta- field test. At this dose range, the development tion and decreased social interactions of repetitive behavior has not been observed (77.8%) and less (68.6%) in dogs with loss (Milgram et al. 1995). However, a single dose of house‐training and changes in activity of 3 mg kg−1 produces repetitive locomotion and/or sleep‐wake cycle (Campbell et al. in females, decreased frequency of urination 2001). in males, and decreased exploratory sniffing Plasma levels of the L form of ampheta- in both genders (Head and Milgram 1992). mine in dogs given selegiline are detectable In safety studies, beagle dogs have been within two hours of medication and exhibit a given selegiline at doses of 0, 1, 2, 3, and significant dose‐dependent effect (Salonen 6 mg kg−1 daily, that is, up to three times the 1990; Milgram et al. 1995). Levels continue maximum recommended daily doses. Dogs to increase for the seven days of daily dosing on the 3 and 6 mg kg−1 dose exhibited until the end of the first week of medication, increased salivation, decreased pupillary after which there is no further increase. response, and decreased body weight. The Plasma levels of amphetamine after two latter occurred despite normal to increased weeks of administration of selegiline at feed consumption. Additionally, at the 1.0 mg kg−1 daily are about 30 ng ml−1. This 6 mg kg−1 dose, the dogs exhibited increased level of amphetamine is unlikely to have panting, dehydration, and increased stereo- significant behavioral effects (Milgram et al. typic behaviors, that is, weaving. Interestingly, 1995). Within 24 hours of discontinuation of this latter problem was observed several selegiline, plasma amphetamine levels are hours after dosing but was no longer present substantially decreased and are undetectable 24 hours later. There were no changes in five days after discontinuation of selegiline. blood pressure, ophthalmic assessment, heart When dogs are given 3 mg kg−1 of selegiline, rate, or electrocardiogram parameters. The amphetamine and methamphetamine are drug was assessed as being safe in the dogs detectable in the serum for 48 hours, while given 2 mg kg−1 daily or less. desmethylselegiline is detectable for only In a study with 641 dogs with CDS clinical about 80 minutes. When dogs are given signs treated with selegiline (0.5–1.0 mg kg−1 10 mg kg−1, desmethylselegiline is detectable orally once daily) for 60 days, 77.2% of dogs in the serum for up to four hours (Salonen showed clinical improvement but side effects 1990). such as diarrhea (4.2%), anorexia (3.6%), Plasma levels of phenylethylamine likewise vomiting and salivation (3.4%) were reported. increase in dogs given selegiline, though it is Anxiety, restlessness, or hyperactivity (2.2%), only by the second week of treatment that 192 Monoamine Oxidase Inhibitors

plasma levels are significantly greater than did not include a placebo group. The only dogs given placebo. Plasma phenylethylamine adverse effect noted in the selegiline group levels decrease within 24 hours of was one case of cystitis, which was not administration. Levels of phenylethylamine considered to be associated with treatment in the hypothalamus and striatum, but not (Beata et al. 2007). the cortex, are significantly elevated in dogs In a study on a rat model for impulsive given 0.1 mg kg−1 for two weeks, with levels behavior, treatment with selegiline had no in the striatum increasing almost 400% and effect in impulse control and decreased levels in the hypothalamus increasing about motor activity (Bert et al. 2006). 1000% (Milgram et al. 1995). In a study on experimental model of anxiety Selegiline may have beneficial effects on in mice, De Angelis and Furlan (2000) investi- learning in young, healthy dogs. Specifically, gated the anxiolytic‐like properties of sele- in a study conducted on various breeds aged giline and moclobemide (another selective one to seven years, dogs given 0.5 mg kg−1 MAOI). The investigators used a standard and daily for three weeks prior to training and an enhanced light/dark aversion test. testing exhibited greater success when Selegiline failed to significantly alter the anxi- trained with motivationally significant cues ogenic‐like behaviors in the subjects. and were more likely to walk near novel Additionally, research investigating the poten- objects and were less distracted than a tial protective effects of selegiline on the cen- placebo group (Mills and Ledger 2001). tral nervous system neurons of individuals Selegiline has been shown to improve spatial exposed to social isolation has at times found short‐term memory in aged dogs in a dose‐ beneficial effect in rats, but results are still dependent fashion (Ivy et al. 1994). inconsistent and cannot be applied to dogs Selegiline has also been used to treat anxi- without further studies (Pascual and Zamora‐ ety and emotional disorders in dogs (Notari Leon 2007; Pascual et al. 2013). 2006; Beata et al. 2007; Pageat et al. 2007; Pageat (1996) reported an 85% success rate Landsberg et al. 2013). In a study of 141 when treating cocker spaniels with “rage dogs of various breeds, ages, and sexes, with syndrome” with selegiline. a variety of behavior problems considered Selegiline, at a dose of 2 mg kg−1 PO, to be based on dysfunctional emotional sta- suppresses cataplexy in dogs (Nishino et al. tus, 80% of the cases were considered 1996). improved or cured after treatment with 0.5 mg kg−1 of selegiline daily for periods of Horses time ranging from 36 days to over a year. Selegiline is considered to have high abuse Behavior modification specific to the case potential in racehorses and is classified as a was also used. Improvement at 30 days after class 2 agent by the Association of Racing initiation of treatment was a good predictor Commissioners International (ARCI). Traces of the final outcome of treatment. Vomiting of selegiline, amphetamine, and metham- or diarrhea was occasionally observed in phetamine can be recovered in thoroughbred dogs in this study (Pobel and Caudrillier horse urine when a single oral dose of 40 mg is 1997). given. Relatively higher urinary concentra- In a 56‐day trial of 38 dogs diagnosed with tions of N‐desmethylselegiline (2‐methyl‐ anxiety disorders, treatment with either N‐2‐propynylphenethylamine) are found in selegiline (at 0.5 mg kg−1 orally every the horse. N‐desmethylselegiline concentra- 24 hours) or alphacasozepine (a tryptic tion peaks in horse urine at 480 ng ml−1 at bovine as1‐casein hydrolysate) at 15 mg kg−1 two hours. Amphetamine peaks in the urine orally every 24 hours was sufficient to at 38 ng ml−1 24 hours after oral dosing, while decrease the EDED score (emotional disorder methamphetamine peaks in the urine at evaluation in dogs) in all subjects. This study 6.1 ng ml−1 after four hours. Horses given References 193

30 mg kg−1 of selegiline orally or intravenously not exhibit any significant changes in heart while confined to box stalls (3.4 × 3.4 m) do rate or motor activity (Dirikolu et al. 2003).

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Antipsychotics Lynne Seibert1 and Sharon Crowell‐Davis2

1 Veterinary Behavior Consultants, Roswell, GA, USA 2 University of Georgia, Athens, GA, USA

Introduction side effects. High‐potency antipsychotics show a greater affinity for D2 receptor sites, Antipsychotics are used to treat most forms have fewer autonomic effects, less cardiac of psychosis, including schizophrenia, in toxicity, a higher incidence of extrapyramidal humans. They do not have the same signifi signs, and are effective in smaller doses −1 cance in animal behavior therapy and are (0.5–1 mg kg ) (Simpson and Simpson 1996). usually most appropriately used on a short‐ The phenothiazine neuroleptics are antipsy term, intermittent basis. The first antipsy chotics that are commonly used in veterinary chotic, chlorpromazine, was developed in medicine for sedation and restraint. 1950. Individual antipsychotic drugs show a wide range of physiological effects, resulting in tremendous variation in side effects. The Action most consistent pharmacological effect is an affinity for dopamine receptors. In humans, Antipsychotic agents block the action of antipsychotics produce a state of relative dopamine, a catecholamine neurotransmitter indifference to stressful situations. In ani that is synthesized from dietary tyrosine. mals, antipsychotics reduce responsiveness Dopamine regulates motor activities and to a variety of stimuli, exploratory behavior, appetitive behaviors. Dopamine depletion is and feeding behavior. Conditioned avoidance associated with behavioral quieting, responses are lost in animals that are given depression, and extrapyramidal signs. Excess antipsychotics. dopamine is associated with psychotic Antipsychotic agents are divided into two symptoms and the development of groups based on side effect profiles (low‐ stereotypies. A large proportion of the brain’s potency and high‐potency drugs) or by dopamine is located in the corpus striatum structural classes (Table 14.1). Low‐potency and mediates the part of the extrapyramidal antipsychotics have a lower affinity at D2 system concerned with coordinated motor receptor sites, higher incidence of anticho activities. Dopaminergic neurons project to linergic effects (sedation), stronger α‐adren the basal ganglia and extrapyramidal ergic blockade (cardiovascular side effects), neuronal system. Side effects associated with and require larger doses (1–3 mg kg−1), but blockade of this system are called extrapy have a lower incidence of extrapyramidal ramidal responses. Dopamine is also high in

Table 14.1 Classes of antipsychotic drugs. regions that control thermoregulation, basal metabolic rate, emesis, vasomotor tone, and Phenothiazine tranquilizers hormonal balance. Antipsychotics produce High potency ataraxia: a state of decreased emotional Fluphenazine (Prolixin) arousal and relative indifference to stressful Low potency situations. They suppress spontaneous move Acepromazine (Promace) ments without affecting spinal and pain reflexes. Chlorpromazine (Thorazine) Promazine (Sparine) Thioridizine (Melleril) Overview of Indications Butyrophenones Haloperidol (Haldol) Antipsychotic agents are most often used in Droperidol (Innovar) veterinary practice when chemical restraint is necessary. Antipsychotic agents are used Azaperone (Stresnil, Suicalm) for restraint or the temporary decrease of Diphenylbutylpiperidines motor activity in cases of intense fear or Pimozide (Orap) stereotypic behavior. A complete behavioral Dibenzoxazepines and medical history is necessary to determine Clozapine (Clozaril) which pharmacological agents will be the Atypical antipsychotics most beneficial for any given case. A comprehensive treatment plan that includes Sulpiride (Sulpital) behavior modification exercises and environmental modifications, along with some regions of the limbic system (Marder drug therapy, has the best chance for success and Van Putten 1995). (Overall 1997). The nigrostriatal pathway consists of cell Antipsychotic agents have poor anxiolytic bodies originating in the substantia nigra and properties and should not be the sole mediates motor activities. The mesolimbic treatment for any anxiety‐related disorder. pathway consists of neuronal cell bodies that Therefore, while they can be useful in originate in the ventral tegmental area, preventing self‐injury or damage to the project to ventral striatum and limbic environment by an animal exhibiting a high‐ structures, and mediate appetitive behaviors. intensity fear response, they are not Dopamine is broken down by monoamine appropriate for long‐term therapy and oxidase inside the presynaptic neuron or by treatment of phobias. catechol‐O‐methyltransferase outside the Antipsychotic agents are indicated for the presynaptic neuron. There are five dopamine treatment of intense fear responses requiring receptor subtypes. Traditional antipsychotics heavy sedation to prevent self‐injury or are D2 receptor antagonists and block property damage. Sedation to the point of 70–90% of D2 receptors at therapeutic doses. ataxia may be necessary to control frantic Antipsychotics have a wide spectrum of responses in storm‐phobic dogs, but owners physiological actions. Traditional antipsy often report that their dogs still appear to be chotics have antihistaminic activity, dopa frightened. mine receptor antagonism, α‐adrenergic Antipsychotic agents have also been used blockade, and muscarinic cholinergic block in game capture operations and to allow ade. Blocking the dopamine receptors in the physical examination in intractable animals. basal ganglia and limbic system produces Antipsychotics can also be used as behavioral quieting, as well as depression of antiemetics and for the treatment and the reticular‐activating system and brain prevention of motion sickness. When used as Overdos 203 preanesthetic agents, antipsychotics may postsynaptic receptor density due to induce a state of indifference to a stressful dopamine blockade can result in the inability situation. to control movements or torticollis, and Antipsychotic agents produce inconsistent hyperkinesis. The dopaminergic system is results for the treatment of aggressive unique in that intermittent use of behavior, and in some cases have induced antipsychotic medications can result in the aggressive behavior in animals with no upregulation of postsynaptic receptors. history of aggressiveness (Overall 1997). Chronic side effects may occur after three months of treatment. At least 10–20% of human patients treated with antipsychotics General Pharmacokinetics for more than one year develop tardive dyskinesia, and the symptoms are potentially Antipsychotic agents have a high hepatic irreversible even after the medication is extraction ratio. Metabolites are generally discontinued. inactive compounds and excreted in the Bradycardia and transient hypotension due urine. Maximal effect occurs about one hour to α‐adrenergic blocking effects can occur. after administration. Duration of action Syncope has been reported, particularly in ranges from 4 to 24 hours. Half‐lives range brachycephalic breeds. Hypertension is from 10 to 30 hours in humans. These agents possible with chronic use. are highly lipid soluble and highly protein Endocrine effects include an increase in bound. serum prolactin, the luteinizing hormone, follicle‐stimulating hormone suppression, gynecomastia, gallactorhea, infertility, and weight gain. Parasympatholytic autonomic Contraindications, Side reactions are possible. Other side effects Effects, and Adverse Events include lowered seizure threshold, hematological disorders (thrombocytopenia), Significant side effects can occur with acute hyperglycemia, and electrocardiographic antipsychotic use because of decreased changes. Priapism has been reported in dopaminergic activity in the substantia nigra. stallions. Side effects may include motor deficits or Antipsychotic agents should be used with Parkinsonian‐like symptoms, such as caution, if at all, in patients with seizure difficulty initiating movements (akinesis), disorders, hepatic dysfunction, renal muscle spasms (dystonia), motor restlessness impairment, or cardiac disease, and in young (akathisia), and increased muscle tone or debilitated animals, geriatric patients, resulting in tremors or stiffness. pregnant females, giant breeds, greyhounds, Behavior effects include indifference and boxers. (ataraxia), decreased emotional reactivity, and decreased conditioned avoidance responses. Antipsychotic agents may also Overdose cause a suppression of spontaneous movements, a decrease in apomorphine‐ Neuroleptic malignant syndrome is a rare, induced stereotypies, a decrease in social and but potentially fatal, complex of symptoms exploratory behaviors, a decrease in operant associated with antipsychotic use. It results in responding, and a decrease in responses to muscular rigidity, autonomic instability, non‐nociceptive stimuli. hyperthermia, tachycardia, cardiac dysrhyth Tardive dyskinesia occurs as a result of the mias, altered consciousness, coma, increased upregulation of dopamine receptors with liver enzymes, creatine phosphokinase, and chronic antipsychotic use. An increase in leukocytosis. Mortality reaches 20–30% in 204 Antipsychotics

affected humans. Treatment includes discon 96 hours after dosing. Horses should not be tinuation of the antipsychotic medication, ridden within 36 hours of treatment. symptomatic treatment, and medical monitoring. Indications Acepromazine is indicated as a preanesthetic agent, for control of intractable animals, as Clinical Guidelines an antiemetic agent to control vomiting due to motion sickness in dogs and cats, and as a Antipsychotic agents will typically have an tranquilizer in horses. immediate effect on behavior and so do not require chronic dosing, but can be used as Contraindications needed for their behavioral quieting effects. Acepromazine can produce prolonged When used intermittently, antipsychotic depression when given in excessive amounts agents do not need to be gradually withdrawn. or when given to animals that are sensitive to An owner consent form is helpful to outline the drug. The effects of acepromazine may be potential adverse events and ensure that the additive when used in combination with other owner is aware of these. tranquilizers and will potentiate general anes thesia. Tranquilizers should be administered in smaller doses during general anesthesia and Specific Medications to animals that are debilitated, animals with cardiac disease, or animals with sympathetic I. Acepromazine Maleate blockage, hypovolemia, or shock. Phenothiazines should be used with caution during epidural anesthetic procedures Chemical Compound: 2‐Acetyl‐10‐(3‐dimeth because they may potentiate the hypotensive ylaminopropyl) phenothiazine hydrogen effects of local anesthetics. Phenothiazines maleate should not be used prior to myelography. DEA Classification: Not a controlled Acepromazine should not be used in substance patients with a history of seizures and should Preparations: Generally available in 5‐, 10‐, −1 be used with caution in young or debilitated 25‐mg tablets and 10 mg ml injectable animals, geriatric patients, pregnant females, forms. giant breeds, greyhounds, and boxers. Studies in rodents have demonstrated the Clinical Pharmacology potential for embryotoxicity. Phenothiazines Acepromazine is a low‐potency phenothia should not be used in patients with bone zine neuroleptic agent that blocks postsynap marrow depression. tic dopamine receptors and increases the turnover rate of dopamine. Acepromazine Side Effects has a depressant effect on the central nervous Phenothiazines depress the reticular system (CNS) resulting in sedation, muscle activating system and brain regions that relaxation, and a reduction in spontaneous control vasomotor tone, basal metabolic rate, activity. In addition, there are anticholinergic, and hormonal balance. They also affect antihistaminic, and α‐adrenergic blocking extrapyramidal motor pathways and can effects. produce muscle tremors and akathisia Acepromazine, like other phenothiazine (restlessness, pacing, and agitation). derivatives, is metabolized in the liver. Cardiovascular side effects include hypo Both conjugated and unconjugated metab tension, bradycardia, cardiovascular collapse, olites are excreted in the urine. Metabolites and reflex tachycardia. Hypertension is can be found in the urine of horses up to possible with chronic use. Syncope, collapse, Specifi Medication 205 apnea, and unconsciousness have been hypotension produced by phenothiazine reported. Other side effects include hypother tranquilizers because further depression of mia, ataxia, hyperglycemia, excessive seda blood pressure can occur. tion, and aggression. Paradoxical excitability Overdosage of phenothiazine antipsychotics has been reported in horses, cats, and dogs. in human patients is characterized by severe Hematological disorders have been CNS depression, coma, hypotension, extrapy reported in human patients taking ramidal symptoms, agitation, convulsions, phenothiazines, including agranulocytosis, fever, dry mouth, ileus, and cardiac arrhyth eosinophilia, leukopenia, hemolytic anemia, mias. Treatment is supportive and sympto thrombocytopenia, and pancytopenia. matic, and it may include gastric lavage, airway There is anecdotal evidence that chronic support, and cardiovascular support. use may result in the exacerbation of noise‐ related phobias. Startle reactions to noise Doses in Nonhuman Animals can increase with acepromazine use. Dosages should be individualized depend Acepromazine is contraindicated in aggres ing upon the degree of tranquilization sive dogs, because it has been reported to required. Generally, as the weight of the facilitate acute aggressiveness in rare cases. animals increases, the dosage requirement Priapism, or penile prolapse, may occur in in terms of milligram of medication per male large animals. Acepromazine should be kilogram weight of the animal decreases. used with caution in stallions, as permanent Doses that are 10 times lower than the paralysis of the retractor muscle is possible. manufacturer’s recommended dose may be In a safety study, no adverse reactions to effective. acepromazine occurred when it was Arousal is most likely in the first 30 min administered to dogs at three times the upper utes after dosing. Maximal effects are gener limit of the recommended daily dosage ally reached in 15–60 minutes, and the (1.5 mg lb−1). This dose caused mild duration of effect is approximately 3–7 depression that resolved within 24 hours hours. There may be large individual varia after termination of dosing. The LD50 (the tion in response (Table 14.2 and Table 14.3). dose that kills half of the animals [mice] tested) is 61 mg kg−1 for intravenous Effects Documented in Nonhuman Animals administration and 257 mg kg−1 for oral Several incidences of idiosyncratic aggres administration. sion in dogs and cats treated with aceproma zine have been reported (Meyer 1997; Adverse Drug Interactions Waechter 1982). In an incident report Additive depressant effects can occur if received by the United States Pharmacopeia acepromazine is used in combination with Veterinary Practitioners’ Reporting Program, anesthetics, barbiturates, and narcotic a German shepherd dog being treated with agents. Concurrent use of propranolol can acepromazine following orthopedic surgery increase blood levels of both drugs. attacked and killed the other dog in the Concurrent use of thiazide diuretics may household, with no prior history of potentiate hypotension. aggression. There were two incidences of aggression following acepromazine Overdose administration identified by the FDA Adverse Gradually increasing doses of up to Drug Experience Summary between 1987 220 mg kg−1 PO were not fatal in dogs, but and 1994. There are reports of aggressive resulted in pulmonary edema. Hypotension behavior following oral and parenteral can occur after rapid intravenous injection administration of acepromazine. While causing cardiovascular collapse. Epinephrine this is a rare side effect, the potential for is contraindicated for the treatment of acute serious injury should prompt practitioners 206 Antipsychotics

Table 14.2 Doses for antipsychotics for dogs and cats.

Drug Dogs Cats

Acepromazine 0.5–2.0 mg kg−1 PO q8h or prn 1.0–2.0 mg kg−1 PO prn Chlorpromazine 0.8–3.3 mg kg−1 PO q6h 3.0–6.0 mg kg−1 PO Promazine 2.0–6.0 mg kg−1 IM or IV q4–6h prn 2.0–4.5 mg kg−1 IM Thioridizine 1.0–3.0 mg kg−1 PO q12–24h Haloperidol 0.05–2.0 mg kg−1 PO q12h 0.1–1.0 mg kg−1 PO Pimozide 0.03–0.3 mg kg−1 PO Clozapine 1.0–70 mg kg−1 PO Sulpiride 5.0–10.0 mg kg−1 PO

prn, according to need.

Table 14.3 Doses of antipsychotics for horses. Indications Azaperone is labeled for control of aggres Drug Dose sion when mixing or regrouping weaning or feeder pigs and as a general tranquilizer for −1 Acepromazine 0.02–0.1 mg kg IM swine. It is not approved for use in other spe Promazine 0.4–1.0 mg kg−1 IV or cies and should not be used in horses. 1.0–2.0 mg kg−1 PO q4–6h Haloperidol 0.004 mg kg−1 IM Doses in Nonhuman Animals decanoate Azaperone is administered at a dose of 1.0 mg kg−1 IM for sedation, 2.2 mg kg−1 IM for mixing feeder pigs, 2.0–4.0 mg kg−1 IM as to educate owners about this possibility and −1 a preanesthetic, and 5.0–10.0 mg kg for suggest appropriate precautions immobilization. In horses, acepromazine can be detected in the urine for at least 25 hours after injection of 0.1 mg kg−1 (Smith and Chapman 1987). III. Chlorpromazine Chemical Compound: 10‐(3‐Dimethy II. Azaperone laminopropyl)‐2‐chlorphenothiazine DEA Classification: Not a controlled 4′‐Fluoro‐4‐[4‐(2‐ Chemical Compound: substance pyridyl)‐1‐piperazinyl] butyrophenone Preparations: Generally available as 10‐, Not a controlled DEA Classification: 25‐, 50‐, 100‐, 200‐, and 300‐mg tablets; substance 30‐, 75‐, 150‐, 200‐, and 300‐mg capsules; Generally available as a −1 Preparations: 2, 30, and 100 mg ml oral orange‐flavored 40 mg ml−1 injectable form. syrup; 25‐ and 100‐mg suppositories; and a 25 mg ml−1 injectable dose. Clinical Pharmacology Azaperone is a butyrophenone antipsychotic Clinical Pharmacology agent that blocks dopamine receptors. The Chlorpromazine is a phenothiazine antipsy peak sedative effect occurs approximately chotic agent with properties similar to 30 minutes after intramuscular injection, and acepromazine. It has anticholinergic, anti the effects last two to four hours. Azaperone adrenergic, antihistaminic, and antiseroto is metabolized by the liver, with 13% excreted nin activity. It is less potent than acepromazine in feces. and has a longer duration of action. It is Specifi Medication 207 highly protein bound and metabolized exten IV. Clozapine sively in the liver, with more than 100 poten Chemical Compound: 8‐Chloro‐11‐(4‐ tial metabolites, some that are active. methyl‐1‐piperazinyl)‐5H‐dibenzo[b,e] Uses in Humans [1,4] diazepine DEA Classification: Not a controlled Chlorpromazine is indicated in humans for substance the treatment of psychotic disorders, nausea Preparations: Generally available as 25‐ and and vomiting, mania, intractable hiccups, 100‐mg tablets. and as an adjunct in the treatment of tetanus. Clinical Pharmacology Indications in Veterinary Medicine Clozapine is an atypical antipsychotic agent, Chlorpromazine is used primarily as an a tricyclic dibenzodiazepine derivative. antiemetic, but also as a preanesthetic agent Clozapine blocks dopaminergic activity at in dogs and cats. It is not recommended for D1, D2, D3, and D5 receptors and has high use in horses. affinity for D4 receptor subtypes. It is more active at limbic system sites than at nigrostri Contraindications atal receptors, resulting in fewer extrapyram Contraindications and precautions are simi idal symptoms. In addition to dopaminergic lar to acepromazine. Horses given chlor receptors, clozapine has blocking activity at promazine may develop ataxia and serotonergic receptors. It is an adrenergic, excitability with potentially violent conse cholinergic, and histaminergic antagonist. quences. In human patients being adminis Traditional neuroleptic agents block 70–90% tered lithium in combination with of D2 receptors at therapeutic doses. chlorpromazine, an encephalopathic syn Clozapine blocks 30–60% of D2 receptors drome has been reported, which resulted in and 85–90% of 5‐HT2 receptors (Tarsy et al. irreversible brain damage in a few cases. 2002). Clozapine is highly protein bound and Side Effects almost completely metabolized by the liver Side effects are similar to acepromazine. prior to excretion. The major metabolites Chlorpromazine may cause significant have been measured in dogs following a extrapyramidal side effects in cats if given in single dose administration of clozapine high doses, including tremors, rigidity, leth (Mosier et al. 2003). argy, and loss of sphincter tone. Electrocardiographic changes include pro Uses in Humans longation of Q‐T and P‐R intervals, S‐T Clozapine is indicated for the treatment of depression, and T wave blunting. There is severe psychotic disorders in human patients evidence that chlorpromazine is excreted in who have failed to respond to traditional breast milk of nursing mothers. therapy.

Effects Documented in Nonhuman Animals Contraindications The effects of chlorpromazine, compared Clozapine is contraindicated in patients with with diazepam, were evaluated in dogs in a myeloproliferative disease or seizure placebo‐controlled trial (Hart 1985). disorder. Friendliness, excitability, and fearfulness were measured in response to human han Side Effects dling. Chlorpromazine significantly reduced Clozapine can cause life‐threatening bone excitability, but did not affect fear responses marrow suppression or agranulocytosis. In or friendliness. human patients, 32% of agranulocytosis 208 Antipsychotics

cases were fatal. White blood cell counts (trifluoromethyl) phenothiazin‐2‐yl] must be monitored during treatment. propyl‐1‐piperazine ethanol Cardiac side effects are also possible. DEA Classification: Not a controlled Anticholinergic effects may include increased substance intraocular pressure, urinary retention, Preparations: Generally available as 1‐, 2.5‐, constipation, and ileus. 5‐, and 10‐mg tablets; 2.5, 5, and 25 mg ml−1 solution; a 2.5 mg/5 ml elixir; a 2.5 mg ml−1 Doses in Nonhuman Animals short‐acting injectable; and 25 and −1 Reliable dose–response data have not been 100 mg ml long‐acting injectables (flu established for veterinary patients phenazine decanoate or enanthate). (Table 14.2). Clinical Pharmacology Effects Documented in Nonhuman Animals Fluphenazine is a high‐potency phenothia According to Dodman (1998), preliminary zine agent, showing a greater affinity for D2 results of treatment of aggressive dogs with receptor sites, fewer autonomic effects, less clozapine were disappointing. Antiaggressive cardiac toxicity, but a higher incidence of properties of clozapine have been reported in extrapyramidal signs. other species (Chen et al. 2001; Garmendia et al. 1992). Contraindications and Side Effects In a review of animal models of acute Contraindications and side effects are similar neuroleptic‐induced akathisia, Sachdev and to those noted for other phenothiazines. Brune (2000) compared the effects of haloperidol and clozapine in dogs. Effects Documented in Nonhuman Animals −1 Haloperidol (0.3 mg kg ) induced more Fluphenazine was used as a sedative in an hyperkinesia and stereotypic movements −1 equine patient (thoroughbred filly) at a than clozapine (7 mg kg ), measured dose of 0.1 mg kg−1 IM (Brewer et al. 1990). four hours after administration. Persistent The onset of extrapyramidal symptoms scratching, licking, rotating, self‐grooming, occurred at 15 hours after injection when and continuous walking were considered the horse began sweating, pawing at the air, evidence of extrapyramidal symptoms. circling, head swinging, and licking her The effects of orally administered forelimbs. Rhythmic neck flexion, facial neuroleptic agents on conditioned avoidance grimacing, and muscle fasciculations were tasks in dogs were evaluated for observed. Periods of hyperexcitability were chlorpromazine, thioridazine, haloperidol, interspersed with periods of immobility. and clozapine (Cohen 1981). All drugs Serum fluphenazine levels were 20.3 ng ml−1 blocked conditioned avoidance responses, at admission and <1 ng ml−1 24 hours after inhibited escape behavior, and caused ataxia. admission. Symptoms persisted 45 hours Clozepine produced excessive salivation. after the initial intramuscular dose. The Sedation was most common with horse was treated with 250 mg intravenous chlorpromazine and thioridazine, and diphenhydramine (centrally acting anticho haloperidol and thioridazaine produced linergic agent), was behaving normally tremors. within three minutes, and remained normal for 18 hours. She was re‐treated with V. Fluphenazine 300 mg diphenhydramine and then required no further treatment. Chemical Compound: 10‐[3‐[4‐(2‐ Fluphenazine has been used successfully in Hydroxyethyl)‐piperazin‐1‐yl] propyl]‐2‐ individual cases to treat flank biting in horses (trifluoromethyl)‐phenothiazine; 4‐[3–2‐ (Dodman 1994). Specifi Medication 209

VI. Haloperidol iting, dry mouth, urinary retention, priapism, laryngospasm, bronchospasm, visual distur Chemical Compound: 4‐[4‐(p‐Chlorophenyl)‐ bances, and sudden death (Physicians’ Desk 4‐hydroxypiperidino]‐4′‐fluorobutyrophe Reference 2002). none Reported side effects in psittacine birds DEA Classification: Not a controlled include sedation, incoordination, vomiting, substance agitation, severe depression, and anorexia. Preparations: Generally available as 0.5‐, 1‐, −1 Haloperidol may lower the seizure threshold. 2‐, 5‐, 10‐, and 20‐mg tablets; a 2 mg ml −1 The LD50 (dog) is 90 mg kg when given solution (haloperidol lactate); 50 and −1 −1 orally, and 18 mg kg for intravenous 100 mg ml long‐acting injectables (halo −1 −1 injection. A dose of 12 mg kg day for peridol decanoate); and a 5 mg ml−1 short‐ 12 months resulted in liver toxicity, tremors, acting injectable. and convulsions in dogs. The therapeutic index for dogs is 900 (50% of the lethal dose/ Clinical Pharmacology the median effective dose or LD50/ED50). Haloperidol is a butyrophenone antipsy Fatal cases of bronchopneumonia have chotic that has dopamine‐blocking activity. been reported in human patients, resulting There is one major metabolite with low activ from lethargy, decreased sensation of thirst ity. Haloperidol decanoate may require three leading to dehydration, hemoconcentration, months in human patients to reach steady and reduced pulmonary ventilation. state. Substantial plasma concentrations can be detected months after treatment has been Overdose discontinued. Because it is administered Overdose in human patients is characterized once per month, patients require significantly by severe extrapyramidal signs, hypotension, less medication per month and potentially sedation, respiratory depression, lower their risk of developing extrapyramidal electrocardiographic changes, and shock. side effects. There is no specific antidote, so treatment primarily involves supportive care. Uses in Humans Haloperidol is indicated for use in the man Doses in Nonhuman Animals agement of psychotic disorders and to con Reliable dose–response data have not been trol tics associated with Tourette’s disorder. established for veterinary patients (Tables 14.2–14.4). Contraindications Neurotoxicity is possible in patients with Effects Documented in Nonhuman Animals thyrotoxicosis that are also receiving Dodman (1998) has reported minimal suc haloperidol. cess using haloperidol to treat aggression in dogs. Luescher (1998) also reported lack of Side Effects The most common side effects experienced Table 14.4 Doses of antipsychotics for parrots. by human patients in clinical trials were extrapyramidal reactions, including involun Drug Dose tary facial, arm, leg, and body movements. Tardive dyskinesia is also possible, as well as Haloperidol 0.2 mg/kg–0.4 mg kg−1 q12h; cardiovascular side effects, hematological begin at lowest dose and increase disorders, and endocrine abnormalities. in 0.02 increments q2d to effect −1 Additional side effects reported in human Haloperidol 1–2 mg kg IM q14–21d; lower patients include jaundice, anorexia, constipa decanoate dose for cockatoos, African gray parrots, and Quaker parakeets tion, diarrhea, hypersalivation, nausea, vom 210 Antipsychotics

success and undesirable side effects when identified that, while both treatments using haloperidol in dogs to treat stereotypic resulted in improvement, the specific behaviors. environmental enrichments used resulted in Yen et al. (1970) evaluated the effects of greater improvement than the haloperidol. antipsychotic agents, chlorpromazine and (Telles et al. 2015). haloperidol, on conflict‐induced behaviors in Haloperidol given at a dose of 0.50 mg kg−1 laboratory cats. In this experimental situa to domestic chickens did not cause sedation tion, cats were taught to press a pedal for a and resulted in a significant decrease in food reward and then were later punished for feather‐pecking but not of aggression (Kjaer opening the reward box with a compressed et al. 2004). air blast. Cats displayed a variety of conflict‐ Haloperidol has been used successfully in induced behaviors after four to five weeks, game capture operations to increase the including restlessness, depression, immobil tractability of wild hoof stock (Hofmeyer ity, pupil dilation, altered feeding behavior, 1981). It may be most effective for antelope and avoidance of the pedal. Chlorpromazine species. Doses ranging from 0.1 to 0.4 mg kg−1 administration resulted in mild improve IV facilitated handling for 7 to 12 hours, ment of conflict‐induced behaviors. resulting in a decrease in injuries and Haloperidol administration caused a com mortality during transportation. The plete normalization of operant responding, presence of extrapyramidal signs was species‐ and even increased reward‐seeking activity specific and was believed to be exacerbated despite the air blasts. Treatment with by hyperthermia, noise, and excitability. amphetamine facilitated the development of conflict‐induced behaviors, and pretreat VII. Pimozide ment with neuroleptics blocked the effects of amphetamine‐induced behaviors. Chemical Compound: 1‐[1‐[4,4‐Bis(4‐fluo There are case reports of haloperidol use rophenyl)butyl]‐4‐piperidinyl]‐1, 3‐dihydro‐ for the treatment of self‐mutilation in 2H‐benzimidazole‐2‐one psittacine birds (Iglauer and Rasim 1993; DEA Classification: Not a controlled Lennox and VanDerHeyden 1993). Lennox substance and VanDerHeyden reported that haloperidol Preparations: Generally available as 1‐ and was more effective for birds that mutilate soft 2‐mg tablets. tissue, when compared with birds that limit self‐trauma to feathers. They report agitation, Clinical Pharmacology depression, decreased appetite, and Pimozide is a diphenylbutylpiperidine antip excitability in patients treated with sychotic agent with dopamine‐blocking haloperidol. Response to treatment occurred activity. It undergoes extensive first‐pass within two to three days. Iglauer and Rasim metabolism. Two major metabolites are pro (1993) report great variability in response to duced by dealkylation in the liver. Pimozide haloperidol and length of treatment required. has a long half‐life in humans (55 hours). They medicated patients by placing haloperidol in the drinking water, so dosing Uses in Humans may have been less reliable. Cockatoo species Pimozide is indicated for the treatment of and Quaker parakeets may require lower Tourette’s syndrome in human patients when doses than other species (Cooper and other standard treatments have failed. Harrison 1994). One study compared feather‐picking behavior in White Eyed Contraindications parakeets (Aratinga leucophthalma) treated Pimozide is contraindicated with cardiac with environmental enrichment vs. disease and in patients taking macrolide haloperidol given at a dose of 0.9 mg kg−1 and antibiotics, antifungal agents, or other drugs Specifi Medication 211 metabolized by cytochrome P450 3A enzyme VIII. Promazine system. Chemical Compound: 10‐[3‐(Dimethyl Side Effects amino)propyl]‐phenothiazine DEA Classification: Not a controlled Side effects are similar to those of other substance antipsychotic agents. Pimozide can cause Preparations: Generally available as 25‐, prolongation of the QT interval, predisposing 50‐, and 100‐mg tablets, a 2 mg ml−1 oral patients to ventricular arrhythmias. Sudden syrup, 2 mg/ml and 5 mg ml−1 injectables, death has been reported. Electrocardiographic and granules approved for use in horses. monitoring is recommended. Pimozide produces anticholinergic side effects and Clinical Pharmacology may lower the seizure threshold. According to Luescher (1998), the presence Promazine is a phenothiazine agent with of side effects in dogs given relatively low properties similar to acepromazine. It is doses of pimozide limits its usefulness. The metabolized by the liver to glucuronide −1 conjugates, which are excreted by the LD50 in dogs is 40 mg kg . Oral doses as low as 0.16 mg kg−1 can cause catalepsy and kidneys. sedation. Chronic dosing at 3 mg kg−1 Indications resulted in weight loss, muscle tremors, and mammary and gingival dysplasia. Promazine has been used as a preanesthetic agent, tranquilizer, and antiemetic in dogs Doses in Nonhuman Animals and as a tranquilizer in cats, horses, cattle, Reliable dose response data have not been and swine. established for veterinary patients (see Table 14.2). Contraindications There are reports of violent reactions in Effects Documented in Nonhuman Animals horses and increased sensitivity to noise. The effects of pimozide on human avoidance in the Arkansas line of nervous pointer dogs Side Effects were evaluated in a placebo‐controlled Side effects are similar to acepromazine. crossover design (Angel et al. 1982). The human interaction test was used to assess IX. Sulpiride behaviors. Positive responses included approaching, wagging tail, sniffing hands, Chemical Compound: N‐[(1‐Ethyl‐2‐pyrro jumping up, and nuzzling the human subject. lidinyl)‐methyl]‐5‐sulfamayl‐o‐anisamide Negative responses included retreating, DEA Classification: Not a controlled circling, trembling, urinating, or defecating. substance Dogs were given 0.3 mg kg−1 daily for seven Preparations: Generally available as 50‐mg days. Pimozide treatment attenuated capsule, 200‐ and 400‐mg tablets, avoidance responses. Maximum effect 25 mg/5 ml and 200 mg/5 ml oral solution. occurred at four days, and the effects persisted nine days past treatment. Pimozide Clinical Pharmacology was more effective than a benzodiazepine in Sulpiride is a substituted benzamide deriva attenuating avoidance responses. tive with selective dopamine D2 antagonist Pimozide was not effective in the treat properties. Other benzamide derivatives ment of a Doberman pinscher with acral include metoclopramide, tiapride, and sul lick dermatitis (Dodman 1994). The dog topride. In contrast to other neuroleptics, developed head bobbing at a dose of sulpiride appears to lack effects on norepi 4 mg day−1. nephrine, acetylcholine, serotonin, and 212 Antipsychotics

histamine. Specificity may explain the rela induced profound motor impairment tively low incidence of extrapyramidal and (ataxia). Emotional reactions, including rest other adverse effects observed with sulpir lessness and aggression, and autonomic ide use. Sulpiride also stimulates secretion changes were inconsistent with chlorproma of prolactin. Sulpiride has also been shown zine, haloperidol, and droperidol administra to improve blood flow and mucus secre tion. Sulpiride injection did not produce any tion in the gastroduodenal mucosa and has behavioral, autonomic, or motor activity been investigated for the treatment of changes. ulcers. Bruhwyler and Chleide (1990) evaluated Sulpiride does not appear to be extensively the behavioral, motor, and physiological metabolized by the liver and thus is primarily effects of neuroleptic agents in dogs. excreted renally. No metabolites have been Subjects were trained in an operant task identified. The half‐life in humans is six to and then given chlorpromazine, haloperi eight hours and is prolonged with renal dol, thioridazine, pimozide, clozapine, insufficiency. sulpiride, and several other anxiolytic agents in a random order prior to each trial. Uses in Humans There was a decrease in operant respond Sulpiride is indicated for the treatment of ing and an increase in incomplete responses depression, duodenal ulcer, Huntington’s with neuroleptic administration. The drugs disease, inadequate lactation, neuroses, causing the most neurovegetative effects schizophrenia, and Tourette’s syndrome, and (palpebral ptosis and urination) were to suppress the symptoms associated with clozapine, thioridazine, pimozide, and tardive dyskinesia in human patients. sulpiride. Low doses of thioridazine and clozapine caused excitation. Loss of moti Contraindications vation was significant for haloperidol, Sulpiride is contraindicated with pimozide, clozapine, and sulpiride. pheochromocytoma and Parkinson’s disease. Pimozide cause significant hyperkinesia. Caution is advised in patients with Ataxia occurred with all drugs except cardiovascular disease, mania, renal pimozide and sulpiride. Catalepsy was not insufficiency (dose reductions appropriate produced by haloperidol or clozapine. for the individual patient and extent of renal Sulpiride did not produce akinesia. insufficiency), patients with epilepsy, hyperthyroidism, pulmonary disease, or X. Thioridazine urinary retention, and elderly patients. Chemical Compound: 10‐[2‐(1‐Methyl‐2‐ Side Effects piperidinyl)ethyl]‐2‐(methylthio)‐ Side effects are similar to those of other phenothiazine neuroleptic agents. DEA Classification: Not a controlled substance Doses in Nonhuman Animals Preparations: Generally available as 10‐, Reliable dose–response data have not been 15‐, 25‐, 50‐, 100‐, 150‐, and 200‐mg tab established for veterinary patients (see lets; 30 and 100 mg ml−1 solution; and 5 Table 14.2). and 20 mg ml−1 suspension.

Effects Documented in Nonhuman Animals Clinical Pharmacology The effects of neuroleptic drugs in cats were Thioridazine has pharmacological activity evaluated following intracerebroventricular similar to other phenothiazine agents, but injection (Beleslin et al. 1985). Chlorproma may produce less extrapyramidal symptoms. zine, haloperidol, and droperidol injection Thioridazine has minimal antiemetic References 213

properties. Some metabolites may be more cent antibody for distemper was negative. active than the parent compound. The patient had failed to respond to pheno barbital. The patient responded within two Uses in Humans days of starting the higher dose of thiori Thioridazine is used to treat psychotic disor dazine. Symptoms recurred with two missed ders in human patients, and for the short‐ doses. Side effects observed were mild tach term treatment of depression, agitation, ycardia and dry feces, but no extrapyrami anxiety, tension, and sleep disturbances. dal signs.

Contraindications Contraindications are similar to those noted Important Information for acepromazine. for Owners of Pets Being Placed on an Antipsychotic Side Effects Side effects are similar to acepromazine. The following should be considered when Extrapyramidal responses are generally min placing an animal on an antispychotic: imal. Electrocardiography abnormalities (marked T‐wave effects), arrhythmias, and 1) Antipsychotic agents have minimal anxio sudden death are reported. lytic properties and are not appropriate as the sole treatment for anxiety or phobias. Doses in Nonhuman Animals 2) A wide range of side effects is possible, Reliable dose response data have not been and some may occur acutely with a single established for veterinary patients (see dose. Table 14.2). 3) Idiosyncratic aggressive responses may occur with some of the drugs in this Effects Documented in Nonhuman Animals class and precautions should be taken to Thioridazine was used in the treatment of a prevent injury to humans and other dog with motor disturbances (Jones 1987). animals. A male Pekinese dog that presented with fly 4) Chronic treatment with antipsychotic biting, barking, restlessness, nocturnal agents has been associated with tardive activity, muscular tremor, self‐trauma, and dyskinesia in human patients, which in unprovoked aggression was treated with some cases is irreversible. 1.1–2.2 mg kg−1 of thioridazine. The dog’s 5) The effects of antipsychotics in animals physical examination was unremarkable, vary greatly in the degree of sedation and skin scrapings were negative, and fluores the duration of effect.

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Chen, N.C., Bedair, H.S., McKay, B. et al. laying hens. Applied Animal Behaviour (2001). Clozapine in the treatment of Science 86: 77–91. aggression in an adolescent with autistic Lennox AM and VanDerHeyden N (1993). disorder. Journal of Clinical Psychiatry 62 Haloperidol for use in treatment of (6): 479–480. psittacine self‐mutilation and feather Cohen, B.M. (1981). Effects of orally plucking. In Proceedings of the Association administered psychotropic drugs on dogs’ of Avian Veterinarians. conditioned avoidance responses. Archives Luescher, U.A. (1998). Pharmacologic Internationales de Pharmacodynamie et de treatment of compulsive disorder. In: Thérapie 253: 11–21. Psychopharmacology of Animal Behavior Cooper, J.E. and Harrison, G.J. (1994). Disorders (ed. N.H. Dodman and Dermatology. In: Avian Medicine: Principles L. Shuster), 203–221. Malden, MA: and Application (ed. B.W. Ritchie, Blackwell Sciences. G.J. Harrison and L.R. Harrison), 608–639. Marder, S.R. and Van Putten, T. (1995). Lake Worth, FL: Wingers. Antipsychotic medications. In: Textbook of Dodman, N.H. (1994). Equine self‐mutilation Psychopharmacology (ed. A.F. Schatzberg syndrome: a series of 57 cases. Journal of the and C.B. Nemeroff), 247–262. Washington, American Veterinary Medical Association DC: American Psychiatric Press. 204 (8): 1219–1223. Meyer, K.E. (1997). Rare, idiosyncratic reaction Dodman, N.H. (1998). Pharmacologic to acepromazine in dogs. Journal of the treatment of aggression in veterinary American Veterinary Medical Association patients. In: Psychopharmacology of Animal 210 (8): 1114–1115. Behavior Disorders (ed. N.H. Dodman and Mosier, K.E., Song, J., McKay, G. et al. (2003). L. Shuster), 17–30. Malden, MA: Blackwell Determination of clozapine, and its Sciences. metabolites, N‐desmethylclozapine and Garmendia, L., Sanchez, J.R., Azpiroz, A. et al. clozapine N‐oxide in dog plasma using (1992). Clozapine: strong anti‐aggressive high‐performance liquid chromatography. effects with minimal motor impairment. Journal of Chromatography B 783: 377–382. Physiology & Behavior 51 (1): 51–54. Overall, K.L. (1997). Clinical Behavioral Hart, B.L. (1985). Behavioral indications for Medicine for Small Animals, 293–322. phenothiazine and benzodiazepine St. Louis, MO: Mosby. tranquilizers in dogs. Journal of the PDR Staff (2002). Physicians’ Desk Reference American Veterinary Medical Association (ed. Medical Economics). Montvale, NJ: 186: 1192–1194. Data Production Co. Hofmeyer, J.M. (1981). The use of haloperidol Sachdev, P.S. and Brune, M. (2000). Animal as a long‐acting neuroleptic in game capture models of acute drug‐induced akathisia—a operations. Journal of the South African review. Neuroscience and Biobehavioral Veterinary Association 52 (4): 273–282. Reviews 24 (3): 269–277. Iglauer, F. and Rasim, R. (1993). Treatment of Simpson, B.S. and Simpson, D.M. (1996). psychogenic feather picking in psittacine Behavioral pharmacotherapy. Part I: birds with a dopamine antagonist. Journal of antipsychotics and antidepressants. Small Animal Practice 34: 564–566. Compendium on Continuing Education for Jones, R.D. (1987). Use of thioridazine in the the Practicing Veterinarian 18 (10): treatment of aberrant motor behavior in a 1067–1081. dog. Journal of the American Veterinary Smith, M.L. and Chapman, C.B. (1987). Medical Association 191: 89–90. Development of an enzyme‐linked Kjaer, J.B., Hjarvard, J.K.H. et al. (2004). Effects immunosorbent assay for the detection of of haloperidol, a dopamine D2 receptor phenothiazine tranquilizers in horses. antagonist, on feather pecking behavior in Research in Veterinary Science 42: 415–417. References 215

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CNS Stimulants Sharon L. Crowell‐Davis

University of Georgia, Athens, GA, USA

Action increased blood pressure, tachycardia, and cardiac arrhythmias. CNS stimulants Central nervous system (CNS) stimulants are contraindicated in animals with cardio- increase synaptic dopamine and vascular disease or glaucoma. norepinephrine. CNS stimulants should not be given to patients with significant anxiety, because these symptoms may be exacerbated. Overview of Indications

CNS stimulants are used to treat attention Adverse Drug Interactions deficit disorder (ADD), also called attention deficit hyperactivity disorder (ADHD), or Do not give CNS stimulants with monoam- hyperkinesis in dogs (Corson et al. 1976). ine oxidase inhibitors (MAOIs) or within 14 days of discontinuing MAOIs. Contraindications, Side Effects, and Adverse Events Overdose

While CNS stimulants may decrease overall In case of overdose, the main goals are decon- activity in animals with true hyperkinesis, tamination, control of body temperature, the effects that give the medications their correction of any acid‐base and electrolytic names will occur in animals that do not have disturbances, and symptomatic control of true hyperkinesis. Therefore, during a testing any CNS or cardiovascular symptoms. situation, preparations should be made for Removal of the stomach contents can be this possibility. A variety of other side effects initiated with 3% hydrogen peroxide or can occur in animals with and without apomorphine. However, if the patient is hyperkinesis. These include pain and showing CNS signs, such as hyperactivity, do difficulty with urination due to contraction not induce emesis. In some cases, it can be of the urethral sphincter, gastrointestinal beneficial to anesthetize the patient and disturbance, decreased appetite, anorexia, conduct gastric lavage or nasogastric intuba- dry mouth, convulsions, hyperthermia, tion and aspiration after an endotracheal tube

has been placed and cuffed. Acepromazine out‐of‐control pet on their hands because or chlorpromazine may be beneficial in they are unable to meet the dog’s need for reducing the symptoms of hyperactivity, basic exercise. tremors, and other behavioral changes Sometimes owners unintentionally rein- related to stimulation (Genovese et al. 2010). force intensely active behaviors, especially in Diazepam is not recommended in dogs since dogs and parrots. These and other pets may it has caused cases of increased arousal in learn that they do not get attention when they dogs with amphetamine toxicosis (Albretsen are quiet, but they do get attention when they 2002). Propofol and phenobarbital can be are noisy and rambunctious, specifically used to control seizures, while propranolol engaging in such behaviors as barking, can be used to control tachycardia. Muscle screaming, spinning, running, or jumping. If tremors can be controlled with methocarba- the pet is primarily motivated by the need for mol (Genovese et al. 2010). Minimize exter- social contact, even reprimands and scream- nal stimuli that will exacerbate the existing ing at the pet may simply make the problem drug‐induced hyperexcitement. Provide sup- worse. portive therapy, including procedures to cool Owners of pet dogs may focus more on the body if hyperthermia is occurring. issues of training and consider the dog to be inattentive because it is not learning well in obedience school. In this case, again, Clinical Guidelines environmental factors rather than a true pathology in the pet are likely to be the cause True hyperkinesis, or ADD, appears to be of the problem. Inappropriate training rare in animals, but it has been identified in techniques include issues of failure to use dogs. In a group of telomian dogs that had appropriate reinforcers, use of inappropriate hyperkinetic syndrome and were therefore or excessive punishment, and inappropriate used as research models for the study of timing on the part of the trainer and/or ADD in humans, dogs that responded to owner can all result in failure of obedience treatment with amphetamines were training. In particular, the use of inappropriate identified as being biochemically different and excessive punishment is quite common from dogs that did not respond. Specifically, in dog training in the United States. This can they had low levels of norepinephrine, lead to problems of chronic anxiety that dopamine, and homovanillic acid (HVA) in interfere with the dog’s ability to learn the brain and low levels of HVA in the because of emotional arousal. cerebrospinal fluid (Bareggi et al. 1979a). If a dog persists in hyperactive and/or However, if the chief complaint is inattentive behavior despite adequate exer- hyperactivity, care should be taken to ensure cise, reinforcement of quiet, calm behavior, that other, more common, possibilities are ignoring of rambunctious behaviors, and ruled out before a trial with a CNS stimulant appropriate obedience training techniques, it is conducted. Young, healthy animals are may have true hyperkinesis and respond to normally very active. One possible cause of a medication with CNS stimulants. Specifically complaint of hyperactivity is that the owner look for: (i) a short attention span, (ii) con- is simply not exercising their pet enough. stant movement, and (iii) failure to learn obe- Owners may have unrealistic expectations of dience, even with strong rewards. The truly how quiet and calm their pet will be or be hyperkinetic dog is likely to be unable to learn keeping the pet in an unsuitable environment. to sit on command, not because it does not For example, an elderly, sedentary couple want a delicious treat held over its head, but living in a small apartment may get a Great because it is unable to maintain the sitting Dane, supposedly for protection, and position even for the brief moment required then find that they have a “hyperactive,” to reinforce a sit. Behavioral signs must have Specifi Medication 219 been present for an extended period of time DEA Classification: d‐Amphetamine is a and the patient must have been unresponsive DEA class II, non‐narcotic medication. to appropriate attempts to facilitate calmer While there are recognized medical uses, behavior. Not all humans with ADD respond it has a high potential for abuse. d‐ to medication, and this is likely to be the case Amphetamine is more potent than l‐ with dogs. amphetamine (e.g. Taylor and Snyder If a dog with an appropriate history 1970; Angrist and Gershon 1971; Wallach becomes calmer and more attentive when et al. 1971; Balster and Schuster 1973) given a CNS stimulant, the diagnosis of Preparations: Generally available in 5‐, 7.5‐, hyperkinesis is confirmed. It is important 10‐, 12.5‐, 15‐, 20‐, and 30‐mg tablets; when working with families that have a Adderall XR available in 5‐, 10‐, 15‐, 20‐, hyperkinetic dog to discuss the fact that and 30‐mg extended‐release capsules; identifying a useful medication is just the Dexedrine is available in 5‐mg tablets and beginning. Historically, the dog is likely to in 5‐, 10‐, and 15‐mg sustained‐release have not learned any basic obedience due to capsules; Spansule available as sustained‐ its inability to be attentive. Additionally, its release capsules. Extended‐ and sustained‐ previous hyperactivity may have led to the release capsules are designed for the development of various bad habits that the human digestive system and may not func- owners have given up on. Once responsiveness tion in an equivalent fashion in dogs and to medication has been identified, it is other veterinary patients. important that appropriate training techniques, using positive reinforcement, be Clinical Pharmacology initiated immediately to teach the dog what Amphetamines are believed to block reup- is acceptable and desirable behavior. take of norepinephrine and dopamine into Table 15.1 gives the doses of CNS stimulants the presynaptic neuron and to increase the used for ADD in dogs. release of norepinephrine and dopamine into the extraneuronal space. They are noncat- echolamine, sympathomimetic amines that Specific Medications stimulate the CNS. Peripherally, they stimulate both systolic and diastolic blood pre ssure, I. Amphetamine stimulate respiration, and dilate the bronchi (Shire US, Inc. 2003). Chemical Compound: (+)‐α‐methylpheneth- Gastrointestinal acidifying agents will ylamine; (−)‐β‐methylphenethylamine and lower the absorption of any amphetamine, d,l‐amphetamine aspartate monohydrate; while urinary acidifying agents increase dextro‐isomer of the d,l‐amphetamine excretion. Thus, either type of medication sulfate will decrease the efficacy of amphetamine. In contrast, gastrointestinal alkalinizing agents Table 15.1 Doses of CNS stimulants for dogs increase the absorption of amphetamine, with true hyperkinesis or canine ADD. while urinary alkalinizing agents decrease the excretion of amphetamines. Either of CNS stimulant Dose these types of medications will therefore increase blood levels of amphetamines Dextroamphetamine 0.1–1.3 mg kg−1 −1 (GlaxoSmithKline 2003). Levoamphetamine 1–4 mg kg In the dog, plasma levels of amphetamine −1 Methylphenidate 2–4 mg kg peak at about 1.5 hours after oral Source: Dodman and Shuster (1994), Overall (1994). administration, while cerebral spinal fluid Note: Medication should only be given as needed, but (CSF) levels peak at about 2.5 hours (Bareggi can be repeated several times a day et al. 1978). However, differences between 220 CNS Stimulants

breeds have been identified. Telomian‐beagle increased risk of low birth weight and hybrids form less of the active metabolite of premature birth. They may also exhibit signs amphetamine, p‐hydroxyamphetamine, than of withdrawal, including both agitation and do purebred beagles and exhibit less lassitude. Amphetamines are excreted in stereotypic behavior and hyperthermia when milk (GlaxoSmithKline 2003). given the same dose of amphetamine (Bareggi et al. 1979b). Overdose In case of overdose, conduct gastric lavage Uses in Humans and give activated charcoal, cathartics, and Amphetamines are used to treat ADD and sedatives. Acidifying the urine increases narcolepsy. renal excretion, but increases the probability of acute renal myoglobinuria occurring. Contraindications Chlorpromazine blocks the stimulant effects Do not use amphetamines in patients that of amphetamines and can be used in the have known hypersensitivity to sympathomi- treatment of overdose. In rats, the LD50 (the metic amines, cardiovascular disease, hyper- dose that kills half of the animals tested) is thyroidism, or glaucoma. Do not give 96.8 mg kg−1 (GlaxoSmithKline 2003). amphetamines with an MAOI or within 14 days of discontinuing medication with an Discontinuation MAOI. Amphetamines can increase the Chronic use can result in both tolerance and activity of tricyclic antidepressants and any dependence. If a patient has been on sympathomimetic agents. Avoid using these amphetamines for an extended period, medications together. gradual withdrawal is recommended. MAOIs and a metabolite of furazolidone decrease the rate of metabolism of ampheta- Other Information mines, thus increasing their effects and side Do not give amphetamines in the evening, effects. The CNS stimulant effects of amphet- because they may cause nighttime amines are blocked by a variety of drugs, restlessness. including chlorpromazine, haloperidol, and Amphetamines may cause increases in lithium (GlaxoSmithKline 2003). plasma corticosteroid levels and interfere with measurements of urinary steroids Side Effects (GlaxoSmithKline 2003). Patients that do not have hyperkinesis will exhibit increased arousal and activity. Effects Documented in Nonhuman Animals Stereotypic behavior may also occur, as well as Dogs cardiac effects, including tachycardia, gastro- Healthy, fasted laboratory beagles given intestinal disturbances, dry mouth, urticaria, 2.5 mg kg−1 or 0.6 mg kg−1 amphetamine orally and decreased libido. In dogs, d‐ampheta- exhibited increased amounts of stereotypic mine is 1.4 times more potent than levo‐ behavior that peaked 2.5 hours after adminis- amphetamine in inducing stereotypic tration, as did CSF levels of amphetamine. behavior. Doses of 1–2 mg kg−1 given as a Stereotypic behaviors were elevated between single intravenous injection induce various 2.5 and 6.5 hours after administration and stereotyped behavior, including bobbing, head then began to decrease. The relationship turning, circling, pacing, and sniffing (Wallach between stereotypic behavior and levels of et al. 1971). amphetamine was exponential, suggesting Amphetamines have been shown to have that the amphetamine metabolite p‐hydroxy- embryotoxic and teratogenic effects in mice, amphetamine contributes to stereotypic but not in rabbits. Human infants born to behavior when this drug is given. Increasing women addicted to amphetamines have body temperature, on the other hand, has a Specifi Medication 221 linear relationship with the amount of lasted more than four hours. Two of eight amphetamine in the plasma, peaking at about cats (25%) vomited and died about two hours 1.5 hours after administration, suggesting after amphetamine administration. One cat, that this phenomenon is related to the pres- that was otherwise friendly, hissed and spat ence of amphetamine in the plasma (Bareggi during the head movements (Randrup and et al. 1978). Munkvad 1967). In a telomian‐beagle hybrid used as a To date, a behavior problem analogous to model for research on ADD in children, dogs human ADD has not been reported in cats, exhibited hyperactivity, impulsiveness, and nor has the author had any feline cases in this impaired learning ability. When these dogs category. are given d‐amphetamine, 1.2–2.0 mg kg−1 by mouth (PO), some dogs show significant Other Species improvement. Dogs that improved had Stereotypic behaviors have been observed in higher peak blood levels of amphetamine rats given 5 mg kg−1 subcutaneously (SC), than those that did not improve, and mice given 7.5–10 mg kg−1 SC, guinea pigs improvements paralleled blood levels of given 5–20 mg kg−1 SC, and squirrel monkeys amphetamine (Bareggi et al. 1979b). given 1.7 mg kg−1 intramuscularly (Randrup Five of six pet dogs of various breeds and Munkvad 1967). diagnosed with canine hyperkinesis responded positively to treatment with d‐ II. Atomoxetine HCl amphetamine at doses ranging from −1 −1 0.21 mg kg twice a day (b.i.d.) to 0.83 mg kg Chemical Compound: R(−) isomer of b.i.d., although the duration of response (−)‐N‐methyl‐3‐phenyl‐3‐(o‐tolyloxy)‐ varied. For some patients, the improvement propylamine hydrochloride was only transient, while for others the DEA Classification: Not a controlled positive response was both substantial and substance. Atomoxetine does not cause permanent (Luescher 1993). dependence or have stimulant or euphori- Brown et al. (1987), during evaluation of a ant properties. While it is not a CNS stimu- bull terrier with severe compulsive tail‐ lant, it is included in this section because it chasing, gave it a test dose of 1.0 mg kg−1 of is used to treat the same behavioral problem d‐amphetamine orally. By subjective for which stimulants are used assessment, clinical signs worsened between Preparations: Generally available in ca psules two and four hours after administration of containing 10‐, 18‐, 25‐, 40‐, or 60‐mg of the d‐amphetamine. atomoxetine. d‐amphetamine has been successfully used to treat narcolepsy in a long‐haired dachs- Clinical Pharmacology hund. However, treatment was discontinued Atomoxetine is a selective inhibitor of the because the dog also exhibited undesirable presynaptic norepinephrine transporter. In side effects, including hyperactivity, anorexia, humans, atomoxetine is rapidly absorbed excessive sniffing of the ground, and substan- after oral administration and can be given tially increased activity of climbing into with or without food. It is metabolized by the inaccessible spaces (Van Heerden and P450 enzyme CYP2D6 with subsequent Eckersley 1989). glucuronidation, but does not inhibit the CYP2D6 pathway. In humans, it has a mean Cats half‐life of 21.6 hours. When doses were Cats given 13 mg kg−1 amphetamine IP standardized to a milligram per kilogram exhibited stereotyped head movements basis, atomoxetine had similar starting 20 minutes to two hours after pharmacokinetics in children, adolescents, injection. Stereotypic behavior subsequently and adults. There are also no gender effects. 222 CNS Stimulants

Maximum plasma concentrations occur in results in orthostatic hypotension or urinary one to two hours. retention. Some patients may have impaired The major oxidative metabolite of atomoxetine sexual function. is 4‐hydroxyatomoxetine, which is pr imarily Rats given up to 47 mg kg−1 day−1 and mice formed by CYP2D6, but also by other given up to 458 mg kg−1 day−1 for a period of cytochrome P450 enzymes. 4‐hydroxyato- two years exhibit an increased rate of cancer. moxetine inhibits transport of norepineph- A variety of tests have not identified rine as much as the parent compound. atomoxetine as being mutagenic. Rats given CYP2C19 and some other cytochrome P450 doses of 57 mg kg−1 day−1 did not exhibit enzymes form N‐Desmethylatomoxetine, impaired fertility. which has less pharmacological activity than Pregnant rabbits given up to atomoxetine. 100 mg kg−1 day−1 through the period of Atomoxetine is excreted primarily in the organogenesis exhibited a decrease in live urine as 4‐hydroxyatomoxetine‐O‐glucuronide. fetuses and an increase in early resorptions. Less than 17% is excreted in the feces. There There was also a small increase in incidents is extensive biotransformation, so that <3% of atypical arterial origin. There were no of atomoxetine is excreted in an unchanged harmful effects at doses of 30 mg kg−1 day−1. form (Eli Lilly 2003). In studies of rats, females were treated with doses of up to 50 mg kg−1 day−1 from Uses in Humans two weeks prior to mating through all of Atomoxetine is used to treat ADHD. pregnancy and lactation, while males were treated with comparable doses from 10 weeks Contraindications prior to mating. This resulted in decreases in Atomoxetine should not be given to patients pup weight and survival at the highest dose. with a history of hypersensitivity to the drug. There was decreased pup survival only at It should not be given concurrently with an 25 mg kg−1 and no decrease in survival or MAOI or within 14 days of discontinuing an weight at 13 mg kg−1. In a similar study in MAOI. There is an increased risk of which the rats were given 20 or mydriasis; therefore, atomoxetine should not 40 mg kg−1 day−1 only through the period of be given to patients that have narrow‐angle organogenesis, there was a decrease in the glaucoma. It should be used with caution in weight of female fetuses and an increase in patients with cardiovascular disease, because the occurrence of incomplete ossification of it can cause increased blood pressure and the vertebral arch at the higher dose. heart rate, and with patients with a history of However, no adverse effects occurred if preg- urinary retention, because it can cause nant female rats were given up to urinary retention. 150 mg kg−1 day−1 only during the period of Paroxetine and fluoxetine can significantly organogenesis. Atomoxetine is excreted in inhibit the CYP2D6 liver enzyme pathway, milk (Eli Lilly 2003). thus decreasing the rate of metabolism of atomoxetine. Giving these drugs in Overdose combination should be avoided or carried Gastric lavage and repeated administration out at lower doses. of activated charcoal, with or without Atomoxetine doses need to be decreased in cathartics, may prevent or minimize systemic patients with hepatic insufficiency, but not in absorption. Provide supportive therapy (Eli patients with renal disease (Eli Lilly 2003). Lilly 2003).

Side Effects Discontinuation Atomoxetine can cause increased blood Atomoxetine does not require dose tapering pressure and heart rate. Occasionally, its use for discontinuation (Eli Lilly 2003). Specifi Medication 223

Other Information acetic acid (ritalinic acid). Methylphenidate In humans, atomoxetine does not affect the has a low rate of binding to plasma protein, binding of warfarin, acetylsalicylic acid, with a range of 10–52%. In children the aver- phyenytoin, or diazepam to albumin. Drugs age half‐life of methylphenidate is 2.5 hours, that change gastric pH have no effect on whereas in adults it is 3.5 hours. The half‐life atomoxetine bioavailability (Eli Lilly 2003). of ritalinic acid is three to four hours. After a single, oral dose of immediate‐release Effects Documented in Nonhuman Animals methylphenidate, almost all is excreted in the There are no publications on the use of ato- urine within 48–96 hours, most as ritalinic moxetine for the use of clinical behavior dis- acid, although some is excreted as other, orders in nonhuman animals. In the future, minor metabolites. Very little, <1%, is however, it may prove to be useful for the excreted as the parent compound (Novartis treatment of hyperkinesis in dogs, as it is in Pharmaceuticals Corporation 2003). The dog the treatment of ADD in humans, without has multiple metabolites of methylphenidate, the concomitant problem of using a Class II including α‐phenyl‐2‐piperidineacetic acid medication. (24%) and the lactam acid of 6‐oxo‐α‐ phenyl‐2‐piperidineacetate (27%) (Egger III. Methylphenidate Hydrochloride et al. 1981). Dogs absorb oral methylphenidate more rapidly than humans, with maximum Chemical Compound: Methyl α‐phenyl‐2‐ blood levels occurring only 0.21 hours after piperidineacetate hydrochloride administration for immediate release methyl- DEA Classification: DEA class II, non‐ phenidate and 0.46 hours after administration narcotic medication; while there are of sustained release methylphenidate (Giorgi recognized medical uses, it has a high et al. 2010; Lavy et al. 2011). potential for abuse Methylphenidate can be given with or with- Preparation: Generally available in 5‐, 10‐, out food. The effects of renal impairment and and 20‐mg tablets; Ritalin‐SR in 20‐mg hepatic insufficiency on metabolism of slow‐release tablets; Ritalin‐LA in 20‐, 30‐, methylphenidate have not been adequately or 40‐mg capsule with an extended‐release studied. However, renal and hepatic impair- formulation; Concerta in 18‐, 27‐, 36‐, and ment should have little effect on the metabo- 54‐mg tablets designed to have 12 hours of lism and the excretion of methylphenidate. effect due to delayed absorption in the Metabolism occurs primarily due to the human digestive tract. The delay of the SR activity of nonmicrosomal hydrolytic ester- and LA forms of Ritalin and of Concerta ases, which are distributed widely throughout may or may not occur in an equivalent the body. fashion in canine and other veterinary No gender differences have been identi- patients. fied in the metabolism of methylphenidate (Novartis Pharmaceutals Corporation Clinical Pharmacology 2003). Methylphenidate is a mild CNS stimulant. It Concerta tablets are designed to use is believed to activate the brain stem and osmotic pressure for the delivery of cortical arousal system, but the mechanism methylphenidate at a controlled rate over an by which it has its behavioral and mental extended period of time. There is an effects is not truly understood (Novartis immediate‐release outer layer within which Pharmaceuticals Corporation 2003). lies an osmotically active core with a precision Therapeutic activity is mainly due to the laser‐drilled orifice. When the tablet enters parent compound. Methylphenidate is the gastrointestinal tract, the outer layer rapidly biotransformed, resulting in rapid dissolves, providing immediate release. de‐esterification to α‐phenyl‐2‐piperidine Subsequently, as water enters the interior of 224 CNS Stimulants

the tablet, the osmotically active portion and sleeplessness are all side effects that may expands, pushing methylphenidate out of the be expected in the pet population. orifice. The inert shell is eliminated in the In humans, there is some evidence of stool. Obviously, this tablet cannot be split, growth suppression in some cases of long‐ because doing so would destroy the term use of stimulants. A causal relationship mechanism for gradual release. In adult has not been established, and the mechanism humans this medication minimizes the peaks of this effect is unknown (Novartis and troughs that result from repeated dosing Pharmaceuticals Corporation 2003). The of the regular, short‐acting form of effect identified in humans is not substantial methylphenidate (ALZA Corporation 2003). and not likely to be of concern in veterinary Nevertheless, this tablet was designed for the patients. While it might theoretically be of length and chemical mix of the human concern in animals destined to be show and digestive tract, not the digestive tract of any breeding stock, it is probably not appropriate domestic animal, so it is probably not very to show an animal with true hyperkinesis, useful to veterinarians. given the unverified possibility of some degree of genetic effect. Uses in Humans Methylphenidate may lower the seizure Methylphenidate is used to treat ADD and threshold in patients with a history of sei- narcolepsy. ADD is characterized by zures, with abnormal electroencephalo- impulsivity, emotional lability, moderate to grams (EEGs) but no seizures, and, very severe distractibility, a short attention span, rarely, patients with no history of seizures and, in some cases, hyperactivity (Novartis and no abnormalities of the EEG. The Pharmaceuticals Corporation 2003). safety of concurrent use of methylphenidate and anticonvulsants has not been Contraindications determined; therefore, treatment with Do not give to patients that exhibit significant methylphenidate should not be initiated in symptoms of anxiety, because these symp- patients with seizures and should be dis- toms may be exacerbated. Do not give to continued in patients that develop seizures patients with any history of intolerance to while on it. CNS stimulants, cardiac disease, or glau- Some humans have reported difficulties of coma. Do not give with MAOIs or within accommodation and blurring of vision when 14 days of administering MAOIs. taking methylphenidate. The possibility of Methylphenidate may decrease the worsening of vision should be considered in metabolism of coumarin anticoagulants, assessing a nonhuman animal’s response to anticonvulsants, tricyclic antidepressants, medication. and phenylbutazone. If these drugs are given Methylphenidate is teratogenic in rabbits concurrently with methylphenidate, the dose when given at doses of 200 mg kg−1 day−1, but should be decreased. not when given at 60 mg kg−1 day−1 during the period of organogenesis. In rats, the terato- Side Effects genic effect is not evident at doses of Side effects have not been reported in 75 mg kg−1 day−1. Pups of rats given up to veterinary patients given clinically relevant 45 mg kg−1 day−1 during both pregnancy and doses of methylphenidate, except that lactation exhibited decreased weight gain. patients given test doses may exhibit Weight gain was normal if the mothers were increased arousal and activity. This finding is given 15 mg kg−1 day−1 throughout pregnancy interpreted as indicating that the drug will and lactation. Methylphenidate has not been not likely be useful in that particular patient, found to be mutagenic (ALZA Corporation and no further medication is conducted with 2003; Novartis Pharmaceuticals Corporation this drug. Decreased appetite, tachycardia, 2003). Specifi Medication 225

In a study of the effect of methylphenidate from 0.36 to 117.0 mg kg−1. While the severity on development, rat pups were given doses of clinical signs was not strongly associated of up to 100 mg kg−1 day−1, starting at day 7 of with dose, more severe and prolonged clinical life and continuing through week 10. Tests signs occurred in dogs that had ingested administered at weeks 13 to 14 demonstrated extended release forms of methylphenidate. decreased spontaneous locomotor activity at Three dogs that had consumed the extended doses of 50 mg kg−1 day−1 and higher. There release form died. The minimum dose that was a deficit in the acquisition of specific was considered toxic, i.e. the dogs showed learning tasks in females that had been given adverse clinical signs were 0.59 mg kg−1 and, the highest dose of 100 mg kg−1 day−1. There for the extended release form, 0.39 mg kg−1. were no long‐term effects in rats that Note that the toxic dose for regular had been given 5 mg kg−1 day−1 (Novartis methylphenidate is lower than the clinical Pharmaceuticals Corporation 2003). dose. This is not surprising since, in dogs that The fertility of male and female rats given do not have ADHD, the usual effects of a up to 160 mg day−1 was not impaired (ALZA stimulant drug would be expected (Genovese Corporation 2003). et al. 2010). In a 13‐week oral toxicity study Carcinogenicity studies carried out on mice in dogs that were treated with 7.5 mg kg−1 resulted in increased frequencies of hepato- daily or 15 mg kg−1 daily, dogs exhibited cellular adenomas in both genders and, in effects of CNS stimulation, including males, an increase in hepatoblastomas when increased locomotor activity, excitement, the mice were dosed at 60 mg kg−1 day−1. The and body weight loss secondary to the total number of malignant hepatic tumors did increased activity (Bakhtiar et al. 2004). not increase, however. Carcinogenicity studies conducted on rats at doses up to Doses in Nonhuman Animals 45 mg kg−1 day−1 did not result in any increase When it is effective for a given dog, methyl- in tumor development. A study conducted on phenidate can be given on an as‐needed basis, a transgenic mouse strain that was sensitive which is useful given the need to compromise to genotoxic carcinogens and using doses of between making the dog a functional family up to 74 mg kg−1 day−1 did not reveal any pet and minimizing the amount of medica- increase in cancers (ALZA Corporation 2003; tion it receives. For example, if the dog is only Novartis Pharmaceuticals Corporation 2003). with the family during the evenings and some weekends, and is kept in a large pen of suita- Overdose ble size and with toys present for it to exercise Various sequelae may be produced by and play with during the day and weekends overstimulation of the CNS and excessive when the family is away from home, medica- sympathomimetic arousal. Evacuate the tion can be given that fits the times that the stomach contents with gastric lavage. If dog needs to be calm and attentive. When the necessary, give a short‐acting barbiturate to first adult arrives home in the late afternoon allow for this procedure. Also give activated or gets up on a weekend morning, they can charcoal and cathartics. Place the animal in a medicate the dog, then leave it alone for a dim, quiet location to avoid further minimum of 30 minutes while the methylphe- stimulation induced by the environment. nidate has time to take effect. After this time, Monitor vital signs, and provide supportive the dog can be released from its pen to therapy. interact with the family. A report of 128 cases of methylphenidate The slow‐release and long‐acting forms of toxicosis in dogs from 2001 to 2008 found methylphenidate (Ritalin‐SR, Ritalin‐LA, that the most common clinical signs were and Concerta) have tremendously benefited hyperactivity, tachycardia, vomiting, humans with ADD because of the drugs’ agitation, and hyperthermia. Doses ranged extended activity, so that only one or per haps 226 CNS Stimulants

two doses need be taken during the day. resulted in gradual lessening of the clinical These forms, however, tend to be substan- signs (Gustafson 1996). tially more expensive than the regular release form and are not desirable for working fami- Dogs lies that interact significantly with their dog A Yorkshire terrier diagnosed with canine hyper- only in the evenings. Additionally, the various kinesis that did not respond to d‐amphetamine slow‐release forms have been designed for the subsequently responded to treatment with human digestive tract and may act differently methylphenidate at a dose of 1.25 mg kg−1 t−1.i.d. in the digestive tracts of veterinary patients. In A 10‐month‐old Weimaraner diagnosed with the author’s experience, when regular release attention deficit hyperactivity disorder was methylphenidate is used in dogs, they appear treated with methylphenidate, 120 mg t.i.d. to metabolize it very rapidly, with clinical for 12 months, at which time medication was efficacy existing for only two or three hours. discontinued without a relapse (Piturru 2014). Thus, owners need to be aware of the neces- Methylphenidate, given at a dose of sity of remedicating regularly so long as the 0.25 mg kg−1 PO daily has some anticataleptic dog is remaining with the family. effects in dogs (Baker et al. 1983; Chrisman For canine cataplexy, methylphenidate is 1991; Braund 1994; Shell 1995). given once daily, in the morning (Shell 1995). Horses Discontinuation Although illegal, methylphenidate may be Chronic administration of methylphenidate given to racing and performance horses. In can result in dependence. Therefore, discon- one study of both pharmacokinetic and tinuation after administration for several behavioral effects of methylphenidate on weeks or longer should be done gradually. thoroughbred horses, the horses increased their rate of responding to an operant task Other Information when given methylphenidate. Subcutaneous Periodic complete blood counts, differential injection of 0.35 mg kg−1 of methylphenidate and platelet counts are recommended if meth- is followed by a rise in plasma concentration ylphenidate is prescribed in the long term. for about one hour, after which plasma concentrations decreased with a half‐life of about Effects Documented in Nonhuman Animals 1.5 hours. Urine concentrations peaked at Cats about three times the plasma concentrations, One case of methylphenidate toxicosis in a at two hours after injection. Subsequently cat has been reported. A 10‐year‐old, 5.1 kg urine concentration decreased with a half‐life spayed female domestic longhair cat had acci- of about one hour. IM injection of the same dentally been given 5 mg of methylphenidate −1 dose gave similar results (Shults et al. 1981). (1 mg kg ), When she was presented to the Plasma levels can be detected at levels lower veterinarian 13 hours after being given the than 1 ng ml−1, and can be quantitated at medication, she presented with restlessness, levels down to 2 ng ml−1 (Huffman et al. 1974). vocalization, episodes of hurtling into walls, hyperresponsiveness to external stimuli, significant generalized tremors, ataxia, Important Information for mydriasis and a sluggish light response, sinus tachycardia and elevated blood pressure. Owners of Pets Being Placed Repeated treatments with diazepam on CNS Stimulants (1 mg kg−1 IM) and lactated Ringer’s solution (180 ml SC) to facilitate removal of the meth- Do not medicate your pet in the evening, ylphenidate via the kidneys, combined with because this may result in nighttime being placed in a dark, padded, quiet location, restlessness. References 227

Clinical Examples Diagnosis Brownie was diagnosed with ADHD. Case 1 Treatment Plan Signalment The owners were instructed to give Brownie was a tan‐and‐white, one‐year‐old, Brownie a test dose of 5 mg of methylphe- spayed female cocker spaniel weighing 11.7 kg. nidate and observe her for any changes from her typical behavior. Behavior man- Presenting Complaint agement of dogs with hyperactivity was Brownie presented with hyperactivity. discussed. The owners had already raised a child with ADHD and understood that History finding a medication that helped was only The owners had gotten Brownie from a pet the beginning and that they would have to store as a 10‐week‐old puppy. They reported put a lot of effort into training Brownie in that since they first had her, she had been new ways of behaving. extremely active, climbed onto countertops, chewed clothes and shoes whether the owners Follow‐Up were home or absent, did poorly in obedience The owners reported that about 30–45 min- class, rested very little, and did not seem to be utes after being medicated Brownie became able to focus her attention. The owners calmer and lay down. She subsequently lay reported that, at home, Brownie would only lie still for about 30 minutes. The owners were down for any significant period of time when instructed to increase the methylphenidate she was locked in her crate at night. During the to a test dose of 10 mg the next day. Brownie’s interview, she was almost constantly active, response to 10 mg was better than to 5 mg, though friendly, investigating and walking that is, she was even calmer and appeared to around the room. She lay down for about be able to focus her attention when one 10 seconds three times, but was panting and owner attempted a training session using looking around alertly while she did so. positive reinforcement. Obedience training and paroxetine had Brownie’s behavior continued to improve been attempted to treat her behavior. The with the combination of methylphenidate physical exam was unremarkable. and training using positive reinforcement.

References

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Tricyclic Antidepressants Sharon L. Crowell‐Davis

University of Georgia, Athens, GA, USA

Action but are long, somewhere in the range of 24 hours. In the liver, they undergo The tricyclic antidepressants (TCAs) act as demethylation, aromatic hydroxylation, and inhibitors of both serotonin and norepineph glucuronide conjugation of the hydroxy rine. They also have antihistaminic and metabolite (Potter et al. 1995). anticholergic effects and are α‐1 adrenergic Tricyclic antidepressants are so named antagonists. The extent of these effects varies because of their central three‐ring structure. widely between the different TCAs (see The tertiary amines have two methyl groups Table 16.1). Some have strong serotonin at the end of their side chain, while the sec reuptake inhibition and weak norepinephrine ondary amines have only one. The type of reuptake inhibition. Others have strong nor side chain is substantially related to the epinephrine reuptake inhibition and weak molecular action. Tertiary amines have a pro serotonin reuptake inhibition. Other molecu portionately greater effect on blocking sero lar activities vary widely as well. For example, tonin transport, while the secondary amines amitriptyline has much stronger antihista have a proportionately greater effect on minic effects than clomipramine. blocking norepinephrine transport (Bolden‐ Chronic administration of TCAs results in Watson and Richelson 1993; Tatsumi et al. decreased numbers of β‐adrenoceptors and 1997; Nelson 2004). Only the six TCAs that serotonin receptors and altered function of have been most commonly used in veterinary various serotonin receptors in the forebrain behavior will be discussed in this chapter: the (Vetulani and Sulser 1975; Sulser et al. 1978; tertiary amines amitriptyline, clomipramine, Heninger and Charney 1987; Potter et al. doxepin, and imipramine, and the secondary 1995). These long‐term changes in receptor amines desipramine and nortriptyline. number and function are believed to contribute to the significant changes in behavior that evolve over time when a pet is Overview of Indications maintained on these medications. All of the TCAs are readily absorbed from Like the selective serotonin reuptake inhibitors the gastrointestinal tract. Peak plasma levels (SSRIs), the TCAs have anxiolytic, anticompul occur over a wide range of time, two to sive, and antiaggressive effects, in addition to six hours being the mean peak time for antidepressant effects. In veterinary clinical various drugs. Half‐lives vary widely as well, behavioral medicine, they are used primarily

Table 16.1 Acute in vitro biochemical activity of selected tricyclic antidepressants.

TCA NE 5‐HT α‐1 α‐2 H1 Musc

Amitriptyline ± ++ +++ ± ++++ ++++ Clomipramine + +++ ++ 0 + ++ Desipramine +++ 0 + 0 0 + Doxepin ++ + ++ 0 +++ ++ Imipramine + + + + 0 + ++ Nortriptyline ++ ± + 0 + ++

Source: (Potter 1984; Potter et al. 1991; Richelson and Nelson 1984; Richelson and Pfenning 1984; Potter et al. 1995).

for the first three effects. As with the SSRIs, the There is some evidence from the human onset of effect takes several days to several literature that antidepressant drugs that have weeks, and clients whose pets are placed on a a sedative action and an antimuscarinic effect TCA need to be cautioned of that so that they can interfere with memory. Amitriptyline is do not have unrealistic expectations. While an example of one such medication that has occasional pets have a rapid response to a sin both a high occurrence of antimuscarinic and gle dose, as a general rule, they should not be sedative effects. Clomipramine, on the other prescribed on an as‐needed basis. hand, has some antimuscarinic and sedative One of the TCAs, clomipramine, is the only effects, but not as much as amitriptyline, and psychoactive medication with anxiolytic prop has no measurable effect on learning and erties to be FDA‐approved for an anxiety disor memory (Liljequist et al. 1974; Thompson der. Specifically, Clomicalm is approved for the 1991). However, mice injected with 10 mg kg−1 treatment of separation anxiety in dogs, when of either amitriptyline or clomipramine did used in combination with behavior modifica not show any deficits in learning or memory tion. Clomipramine is the most serotonin‐ when tested in a maze test (Nurten et al. 1996). selective of the commercially available TCAs. Common uses in domestic animals include anxiety, affective aggression, compulsive Adverse Drug Interactions disorder, and urine marking. TCAs should never be given in combination with MAOIs. This includes such various Contraindications, Side Effects, compounds as selegiline, which is used for and Adverse Events the treatment of canine cognitive dysfunc tion, and amitraz, which is used for the treat Side effects vary widely, as there is a substan ment of demodicosis and is also a common tial range of effect on serotonin and norepi compound in collars designed to prevent nephrine between the various TCAs, as well infestation with ticks. as substantial variation between the TCAs in molecular effects other than those on seroto nin and norepinephrine. In general, side Overdose effects may include sedation, constipation, diarrhea, urinary retention, appetite changes, There is no antidote for overdose of any of ataxia, decreased tear production, mydriasis, the TCAs, although physostigmine given cardiac arrhythmias, tachycardia, and intravenously has been shown to be useful in changes in blood pressure. alleviating cardiac and central nervous Specifi Medication 233

Table 16.2 Doses of selected tricyclic antidepressants in dogs and cats.

TCA Cat Dog

Amitriptyline 0.5–2.0 mg kg−1 q12–24 h 1–6 mg kg−1 q12h Clomipramine 0.25–1.3 mg kg−1 q24h 1.0–3.0 mg kg−1 q12h Desipramine 1.5–3.5 mg kg−1 q24h Doxepin 0.5–1.0 mg kg−1 q12h 3.0–5.0 mg kg−1 q8–12 h Imipramine 0.5–1.0 mg kg−1 q12–24 h 0.5–2.0 mg kg−1 q8–12 h Nortriptyline 0.5–2.0 mg kg−1 q12–24 h 1.0–2.0 mg kg−1 q12h

Note: Always start with a low dose and titrate up as necessary if the patient does not exhibit side effects. All doses are given orally. system (CNS) toxic effects in humans others that ultimately have a good response (Falletta et al. 1970; Slovis et al. 1971). may not respond for several weeks. Treatment must consist of decontamination and supportive therapy; however, emesis is contraindicated. Specific Medications

Doses of selected TCAs in cats, dogs, horses, Discontinuation and parrots are given in Tables 16.2 and 16.3.

While discontinuation of a TCA does not I. Amitriptyline generally produce significant withdrawal symptoms per se, it is generally recom Chemical Compound: 3‐(10,11‐Dihydro‐5H‐ mended that a patient that has been medi dibenzo [a,d]cycloheptene‐5‐ylidene)‐N, cated with a TCA for several months be N‐dimethyl‐1‐propanamine hydrochloride weaned off gradually. It may be that, while a DEA Classification: Not a controlled behavior problem has resolved at a given substance dose, it recurs when the patient is off medica Preparations: Generally available in 10‐, 25‐, tion or even on a lower dose. Therefore, 50‐, 75‐, 100‐, and 150‐mg tablets and as a tapering of the dose while monitoring can sterile solution for intramuscular injection. allow for identification of dose levels at which the problem returns, and initiation of appro priate management and behavior modifica Table 16.3 Doses of selected tricyclic antidepressants in horses and parrots. tion protocols.

Animal Dose

Clinical Guidelines Parrots Clomipramine 2.0–4.0 mg kg−1 q12h As with the SSRIs, the TCAs should not be Doxepin 0.5–5.0 mg kg−1 q12h given on an as‐needed basis, because they act by producing a gradual shift in levels of sero Horses −1 tonin and/or norepinephrine and by down‐ Imipramine 0.75–2.0 mg kg regulation of the postsynaptic neurons. While Note: Always start with a low dose and titrate up as some patients may begin to exhibit a response necessary if the patient does not exhibit side effects. All after just a few days of daily administration, doses are given orally. 234 Tricyclic Antidepressants

Clinical Pharmacology been shown to cause cardiac arrhythmias, Amitriptyline inhibits the reuptake of nor tachycardia, and prolonged conduction time. epinephrine and serotonin. It is rapidly While dogs do not appear to be as susceptible absorbed and metabolized. Plasma concen to cardiotoxic side effects as humans (e.g. trations correlate with total intake of Reich et al. 2000), it should be avoided or used amitriptyline (Rudorfer and Robins 1982). In cautiously in veterinary patients with existing dogs, the primary metabolic pathways are cardiac disease. Sufficiently large doses can hydroxylation, glucuronide hydroxylation, induce cardiotoxicity. In a study in which methyl hydroxylation and N‐demethylation, anesthetized dogs were given a continuous respectively (Lee et al. 2015), It is metabo intravenous infusion of amitriptyline until lized into nortriptyline and a variety of other cardiotoxicity occurred, toxic effects were metabolites (Diamond 1965). observed at an average of 25 mg kg−1 (range In dogs, the peak concentration occurs at 15–80 mg kg−1) in one study and an average two hours (Kukes et al. 2009). The half‐life in 36 mg kg−1 in another study (Lheureux et al. humans is 5–45 hours (Nelson 2004), and the 1992a, 1992b). Rabbits given amitriptyline by half‐life in dogs given amitriptyline orally is intravenous injection exhibit decreased blood 4.5–8 hours (Shanley and Overall 1992; pressure and increased heart rate (Elonen Kukes et al. 2009; Norkus et al. 2015a). Being et al. 1974). Amitriptyline may enhance the fed vs. fasted prior to administration of oral effects of barbiturates and other CNS depres amitriptyline does not significantly affect the sants (Merck 1998). half‐life (Norkus et al. 2015a). However, Amitriptyline is metabolized in the liver giving amitriptyline IV extends the half‐life and excreted through the kidneys. It should to 10–11 hours (Norkus et al. 2015b). therefore be used cautiously and at lowered Amitriptyline is excreted in the milk. In doses in patients with mild to moderate liver rabbits given carbon‐14‐labeled amitripty disease and avoided entirely in patients with line, the concentration of radioactivity in the severe liver disease. milk is equivalent to concentrations in the Levels of amitriptyline may be elevated in serum. Concentrations of radioactivity in patients concomitantly given drugs that are neonates consuming the milk are substan metabolized by cytochrome P450 2D6 (Merck tially lower than concentrations in the equiv 1998). alent organs in the mother (Aaes‐Jørgensen Systemic absorption of amitriptyline is and Jørgensen 1977). poor when administered transdermally as opposed to orally. Therefore, transdermal Uses in Humans administration of amitriptyline is not recom Amitriptyline is approved for the treatment mended at this time (Mealey et al. 2004). of depression. Side Effects Contraindications The most common side effects in cats and Amitriptyline is contraindicated in patients dogs are sedation, miosis, and urinary reten with a history of sensitivity to this or other tion. Weight gain, decreased grooming, and TCAs. It should not be given concurrently transient cystic calculi may also occur (Chew with MAOIs, because serious side effects, et al. 1998). A variety of cardiovascular, CNS, including convulsions and death, may result. anticholinergic, hematologic, gastrointesti If a patient is to be changed from an MAOI to nal, and endocrine side effects are reported in amitriptyline, discontinue the MAOI for at humans. least two weeks before beginning amitripty Amitriptyline has teratogenic effects in line. Avoid or use it cautiously in patients mice and hamsters when pregnant females with a history of seizures, urinary retention, are given doses of 28–100 mg kg−1 day−1. In or glaucoma. In humans, amitriptyline has the rat, medicating pregnant females with Specifi Medication 235

25 mg kg−1 day−1 results in delayed ossifica Effects Documented in Nonhuman Animals tion in the fetal vertebrae. In rabbits, if Cats pregnant females are medicated with In a retrospective study, two of three cats 60 mg kg−1 day−1, ossification of the cranial with psychogenic alopecia that were treated bones is delayed. Amitriptyline crosses the with amitriptyline at doses of 2.5 mg q12h or placenta, and there have been some reports of 5.0 mg q24h (total dose) responded (Sawyer adverse events in human babies when the et al. 1999). mother was medicated with amitriptyline Amitriptyline has been used successfully to during pregnancy. However, there is insuffi treat hypervocalization in a cat (Houpt 1994). −1 cient documentation to determine if the ami Amitriptyline (2 mg kg orally [PO], daily) triptyline was the cause of the adverse events. may decrease clinical signs of severe Amitriptyline is also excreted into breast recurrent idiopathic cystitis in cats, possibly milk. Because of the potential for adverse in part because of analgesic effects such as effects on fetuses or young, pregnant or those that occur in human patients (Hanno lactating females should not be medicated et al. 1989; Chew et al. 1998). −1 with amitriptyline. High doses of amitriptyline, 7–10 mg kg The intravenous LD50 (the dose that kills intravenously (IV) result in loss of electroen 50% of the animals tested) is 18–22 mg kg−1 in cephalogram changes in cats that are sub mice and 6–11 mg kg−1 in rabbits. The oral jected to loud tones or pinching. Lower doses −1 LD50 is 286–359 mg kg in rats and 100– result in attenuation of the response (Vernier 216 mg kg−1 in mice (Ribbentrop and 1961). Schauman 1965). Toxic signs include respira tory depression, ataxia, tremors, convulsions, Dogs and prostration. Dogs given amitriptyline at a dose range of 0.74–2.5 mg kg−1 q12h for ≥45 days do not Overdose exhibit any electrocardiogram (EKG) There is no specific antidote for overdose of changes. P‐wave duration has a significant amitriptyline. Decontaminate and provide negative correlation with serum concentra supportive therapy. Emesis is contraindi tion of amitriptyline at clinically usual doses, cated. Lipid therapy may be beneficial in ami but remains within normal parameters (Reich triptyline overdose (Kiberd and Minor 2012). et al. 2000). In a retrospective study of 103 dogs with Discontinuation various presentations of compulsive disorder, Patients that have been on amitriptyline daily amitriptyline was found to be significantly for several weeks should be withdrawn less effective than clomipramine (Overall gradually. and Dunham 2002). In a prospective, randomized, double‐ Other Information blind, placebo‐controlled trial of treatment Amitriptyline has historically been com of canine aggression with amitriptyline plus monly used in general practice for the treat behavior modification versus clomipramine ment of anxiety disorders in dogs and cats, plus behavior modification, amitriptyline apparently initially for economic reasons and, was no more effective than placebo (Virga later, because of familiarity with the medica et al. 2001). One dog diagnosed with a tion. However, compared with other drugs combination of “dominance aggression” and such as fluoxetine and clomipramine, which food‐defense aggression responded posi have become much more economically feasi tively to a combination of amitriptyline and ble for the pet owner in recent years, amitrip behavior modification (Reich 1999). tyline has a relatively low clinical efficacy and In an open trial, 15 of 27 dogs (56%) with high incidence of side effects. separation anxiety that were treated with 236 Tricyclic Antidepressants

amitriptyline in addition to behavior modifi most of the remainder being excreted via the cation improved (Takeuchi et al. 2000). kidneys in the same amount of time. In Suspected neuropathic pain may be suc humans, more clomipramine is excreted via cessfully treated with amitriptyline (Cashmore the kidneys than the bile (Faigle and Dieterle et al. 2009). 1973). Following intravenous injection, clomi Horses pramine is rapidly distributed throughout the Amitriptyline is rapidly metabolized in the body, penetrating various tissues and organs, horse. A single dose of 750 mg followed by as demonstrated by whole‐body autoradiog collection of urine through a catheter during raphy performed on mice given 10 mg kg−1. the zero‐ to three‐week period after High concentrations initially occur in the administration revealed that almost all of the lung, adrenal gland, thyroid, the kidney, the medication being excreted during this period pancreas, the heart, and the brain, which was nortriptyline (Fenwick 1982). would be predicted based on clomipramine’s lipophilic nature. The affinity of clomi II. Clomipramine Hydrochloride pramine for tissues containing fat results in rapid decreases in blood levels (Faigle and Chemical Compound: 3‐Chloro‐5‐[3‐(dimethyl‐ Dieterle 1973). amino)propyl]‐10,11‐dihydro‐5H‐ In humans, there is no relation between dibenz[b,f]azepine monohydrochloride dose and plasma level of clomipramine, but DEA Classification: Not a controlled plasma concentrations of desmethylclomi substance pramine, the primary active metabolite, are Preparations: Generally available as 25‐, correlated with dose (Jones and Luscombe 50‐, and 75‐mg capsules (Anafranil and 1977). generic), and as 20‐, 40‐, and 80‐mg chew After both single‐dose and multiple‐dose able tablets (Clomicalm). oral treatment of dogs with clomipramine, peak concentrations of clomipramine occur Clinical Pharmacology in the plasma within three hours, while peak Clomipramine affects both the serotonergic concentrations of the primary active metabo and noradrenergic neural transmission in the lite, desmethylclomipramine, usually occur CNS. The primary mechanism of action is within four to six hours. Subsequently, plasma probably prevention of reuptake of serotonin levels decline rapidly, with a plasma half‐life in the CNS, and it is the most serotonin‐spe for clomipramine of about four hours. cific of the commercially available TCAs (see However, there is a substantial range in elimi Table 16.1). It is highly lipophilic and therefore nation half‐life, and it can be as great as passes easily through lipophilic membranes. 16 hours. The measured plasma half‐life for The major route of biotransformation is desmethylclomipramine is likewise about demethylation, resulting in desmethylclomi four hours, but since this is a combination of pramine. Subsequently, further metabolic the interaction between generation of new processes produce various water‐soluble sub desmethylclomipramine as clomipramine is stances that are eliminated through the bile or metabolized, and elimination of desmethyl the urine (Faigle and Dieterle 1973). In humans, clomipramine, the actual half‐life of des the half‐life is 15–60 hours (Nelson 2004). methylclomipramine is shorter. With In the dog, it is almost totally absorbed intravenous administration in dogs, the mean when given orally. In the dog and the rat, the elimination half‐life is five hours (Hewson main mode of excretion is through the bile, et al. 1998a; King et al. 2000a, 2000b). The with the dog eliminating about 80% of an oral half‐life in humans is longer, with a mean of or intravenous dose of 5 mg kg−1 of about 20 hours when given orally (Nagy and clomipramine via the bile within four days, Johansson 1977; Evans et al. 1980). Specifi Medication 237

In dogs, plasma concentrations of clomi Desmethylclomipramine has anticholiner pramine are higher than concentrations of gic effects on gastrointestinal smooth mus desmethylclomipramine (about 3 : 1), which cle, inhibiting motility and antagonizing is the opposite of humans, in which plasma muscarinic receptors, but does not do so as concentrations of clomipramine are lower much as clomipramine. It is a more potent than those of desmethylclomipramine (about inhibitor of norepinephrine and dopamine 1 : 2.5) (Broadhurst et al. 1977; Jones and reuptake than clomipramine. It has antide Luscombe 1977; Kuss and Jungkunz 1986; pressant activities that are probably due to its Hewson et al. 1998a; King et al. 2000a; King monoamine uptake inhibition (Benfield et al. et al. 2000b). This may be one of the reasons 1980). that adverse events appear to be less frequent There is a faster rate and higher levels of in dogs than in humans, since clomipramine absorption in dogs that are fed than in dogs is the molecule that acts predominantly on that are fasted. Overall bioavailability is serotonin whereas desmethylclomipramine about 25% greater in dogs that are fed as has stronger anticholinergic activity (Benfield opposed to fasted. Plasma half‐life is 2 to et al. 1980). When dogs are dosed daily with 9 hours in fed dogs, but 3 to 21 hours in fasted clomipramine, steady‐state plasma levels are dogs, presumably due to delayed absorption achieved within four days (King et al. 2000a). (Novartis 2000; King et al. 2000b). In vitro, cat microsomes transform When dogs are repeatedly dosed, the half‐ clomipramine more slowly than do rat or dog lives of clomipramine and desmethylclomi microsones. The cat also exhibits a gender pramine increase with increased dosage. At difference, with male cat microsomes being doses of 1, 2, and 4 mg kg−1 twice a day (b.i.d.), less efficient demethylators and hydroxylators the accumulation ratios for clomipramine are than female cat microsomes (Lainesse et al. 1.4, 1.6, and 3.8, respectively, while for des 2007b) methylclomipramine they are 2.1, 3.7, and In a study of the pharmacokinetics of 7.6. There are two main possibilities for this clomipramine in six adult spayed cats, the observation. First, the main route of elimina mean half‐life of clomipramine after tion of both clomipramine and desmethylclo administration of a single IV dose of mipramine may be saturable. Second, the 0.25 mg kg−1 was 12.3 hours, with a range of increasing numbers of molecules may them 7.7 hours to 18.7 hours (Lainesse et al. 2006) selves directly inhibit the elimination process Seventy‐six spayed and neutered cats given a (King et al. 2000a). single dose of clomipramine in the dose In dog cells, clomipramine inhibits P‐glyco range of 0.32 to 0.61 mg kg−1 orally had peak protein, a multidrug transporter that removes levels of clomipramine occur at one to toxins and certain other molecules from cells six hours, with a mean of three hours, while (Schrickx and Fink‐Gremmels 2014). peak doses of the active metabolite desmethylclomipramine occurred at 1 to Uses in Humans 24 hours, with a mean of seven hours. Clomipramine is used to treat obsessive‐ Females had a significantly faster Cl F−1 compulsive disorder in humans. (0.36 l h−1 kg−1) than males 0.21 l h−1 kg−1) and a significantly higher mean MR (0.53 Contraindications compared to 0.36) (Lainesse et al. 2007a). Clomipramine should not be given to Normal dogs treated with 3 mg kg−1 clomi patients with a history of sensitivity to pramine daily, PO, have a lower ratio of 5‐ clomipramine or other TCAs. It should not hydroxyindoleacetic acid (HIAA) to 3‐methyl be given in conjunction with an MAOI or 4‐hydroxyphenylglucol (MHPG) in the cere within two weeks of discontinuation of brospinal fluid than do dogs treated with administration of an MAOI. Avoid or use placebo (Hewson et al. 1995). cautiously in patients with a history of 238 Tricyclic Antidepressants

epilepsy, cardiac arrhythmias, glaucoma, or Overdose urine or stool retention. There is no specific antidote for overdose While clomipramine is not as cardiotoxic with clomipramine. Decontaminate and in dogs as it is in humans, sufficiently large provide supportive therapy. Emesis is doses can induce cardiotoxicity. In a study in contraindicated. which anesthetized dogs were given a continuous intravenous infusion of Discontinuation clomipramine until cardiotoxicity occurred, Animals that have been given clomipramine toxic effects were observed at an average of daily for several weeks should be withdrawn 65 mg kg−1 (range 53–72). This is much gradually. higher than the dose at which cardiotoxicity occurred in dogs infused with amitriptyline Effects Documented in Nonhuman Animals (Lheureux et al. 1992a). Cats Clomipramine should not be given to male Cats given up to five times the clinical dose for breeding dogs, as testicular hypoplasia may 28 days exhibited mild sedation, occasional occur (Novartis 2000). pupillary dilatation, and a slight decrease in In humans, concurrent administration of food consumption (Landsberg 2001). −1 phenobarbital with clomipramine results in Cats given 10 mg day of clomipramine increased plasma levels of clomipramine. did not exhibit any significant changes in their electrocardiogram. Cats given Side Effects 10 mg day−1 of clomipramine for 28 days did Side effects include sedation, mydriasis, exhibit some decreases in total thyroxine regurgitation, appetite changes, and urinary (T4), triiodothyronine (T3), and free throxine retention (Pfeiffer et al. 1999; Litster 2000). (fT4), specifically 25%, 24%, and 16% serum Clomipramine may also potentiate the side values, respectively. This effect could lead to effects of various CNS depressants, including a misdiagnosis of euthyroidism in cats with benzodiazepines, barbiturates, and general subclinical hyperthyroidism (Martin 2010). anesthetics. In humans, on which there is In an open trial of cats with various anxi much more data than in the veterinary ety‐related and compulsive disorders, six population, a broad spectrum of side effects cases of urine spraying, three cases of over‐ has been reported, including cardiovascular grooming, and one case of excessive vocaliza effects, mania, hepatic changes, hematologic tion resolved or were substantially improved changes, CNS disorders, sexual dysfunction, when treated with clomipramine at a dose of −1 and weight changes (Novartis 1998). 0.2–0.55 mg kg daily, combined with behav Rats given approximately five times the ior modification. Some cats became sedated maximum daily human dose exhibited no at the higher dose range, but were success impairment of fertility, while rats given up to fully treated when the dose was lowered 20 times the maximum daily human dose (Seksel and Lindeman 1998, 1999). exhibited no clear evidence of carcinogenic In a double‐masked clinical trial of spray −1 ity of clomipramine. A rare tumor, hemangi ing cats, clomipramine at 0.5 mg kg q24h oendothelioma, did occur in a small number was found to be equally effective as fluoxe −1 of the rats. When pregnant rats and mice tine given at 1 mg kg q24h (Hart et al. 2005). were given up to 20 times the maximum In a single‐blind trial Dehasse (1997) daily human dose, there were no teratogenic reported a 75% decrease in the number of effects, although there was some evidence of urine‐spraying incidents in 80% of cats given −1 fetotoxic effects. Clomipramine does enter 5 mg day of clomipramine as opposed to the milk (Novartis 1998). Use in pregnant when they were on placebo. A few of the cats and nursing females should be avoided if were mildly sedated while on medication. possible. Landsberg (2001) and Landsberg and Wilson Specifi Medication 239

(2005) likewise have had improvement in double‐blind, placebo‐controlled, multicenter over 80% of spraying cats given 0.5 mg kg−1 clinical trial. Sixty‐seven neutered cats were for one month. Six of 25 cats, or about a treated with placebo, 0.125–0.25 mg kg−1 quarter of the patients, became calmer, daily (low dose), 0.25–0.5 mg kg−1 daily friendlier and more affectionate while on (moderate dose), or 0.5–1.0 mg kg−1 daily clomipramine. The most common side‐ (high dose) for three months. Various other effects were increased sleep and lethargy, treatments had been tried previously and decreased appetite and anticholinergic been unsuccessful, including pheromones (17 effects, including decreased frequency of cats), amitriptyline (7), buspirone (2), diaze urination or defecation, and dry mouth pam (4), megestrol acetate (12), pro gestogens (Landsberg and Wilson 2005). In a meta‐ (4), and corticosteroids (1). analysis of the use of clomipramine as a At all doses, clomipramine was more effec treatment for urine spraying in cats, Mills tive than placebo. The moderate and high et al. (2011) found a significant association doses were more effective than the low dose. between clomipramine use and the number There was no effect of age, sex, whether or of cats that ceased urine spraying or not previous attempts had been made to decreased the behavior by 90%. treat the urine spraying and whether or not Clomipramine has also been used to suc the cat lived in a single‐cat household versus cessfully treat cats with psychogenic alopecia. a multicat household. Aggression toward In a retrospective study, five of five cats familiar cats, unfamiliar cats, and animals treated with clomipramine at doses of 1.25– other than cats was significantly decreased in 2.5 mg (total dose) q24h responded (Sawyer the high‐dosage group. During the third et al. 1999). In a prospective, double‐blind, month of treatment, the amount of time placebo‐controlled, randomized trial, clomi spent in stereotypic behaviors other than pramine, at a dose of 0.5 mg kg−1 q12h PO was licking or grooming was also significantly more effective than placebo in the treatment decreased in both the moderate and high‐ of feline psychogenic alopecia (Mertens and dosage groups as compared with the low‐ Torres 2003; Mertens et al. 2006). A cat with dosage group. Sedation was the most psychogenic alopecia manifesting as mutila common side effect and always occurred tion of the tail responded with a treatment of during the first month of treatment. The clomipramine at 0.5 mg kg−1 daily, combined frequency and severity of sedation were dose with behavior modification and environmen related. However, the overall behavior tal changes for two months. The cat had pre patterns were not changed, and it is possible viously had a partial caudectomy because of that some of what the owners were reporting the self‐mutilation of the tail. The caudec as sedation was simply the consequence of tomy failed to resolve the problem (Talamonti the cat being less confrontational and more et al. 2017). relaxed with its housemates. This possibility Of 14 cats treated with clomipramine for a requires further study (King et al. 2004a). variety of anxiety‐related behavior problems, The substantial variation in rate of metab including spraying (12 cats), tail‐chasing olism of clomipramine in cats, discussed in (one cat), nocturnal vocalization (one cat), the Clinical Pharmacology section, may and aggression to the owner (one of the cats explain some of the variation in clinical that sprayed), the problem resolved in six response to this medication (Lainesse et al. cats and was improved in the remaining 2007a; Lainesse et al. 2007b). eight cats. The total daily dose ranged from 0.4 to 1.32 mg kg−1 (Litster 2000). Dogs The most definitive results on the efficacy In humans, only moderate overdoses of of clomipramine in the treatment of urine clomipramine are cardiotoxic, with such spraying in cats were obtained in a randomized, sequelae as increased heart rate, decreased 240 Tricyclic Antidepressants

blood pressure, and slow intracardiac modification alone. Only dogs that exhibited conduction. Research conducted on dogs has both anxiety when their owner was absent demonstrated that this drug is more benign and hyperattachment when their owner was in this species. Dogs given 20 mg kg−1 daily present were included in this study. A low‐ for seven days, which is five times the dose group, given 0.5 to <1 mg kg−1 PO q12h maximum recommended label dose, did not have a better response than dogs exhibited a significant reduction in heart given placebo. Mild and transient vomiting rate, with the peak effect occurring about due to gastritis and mild and transient 12 hours after medication. Doses of 4 or sleepiness, attributable to clomipramine, 12 mg kg−1 of clomipramine did not induce occurred in some dogs. One greyhound col any changes in heart rate. There were no lapsed with hyperthermia, which may or significant changes in the electrocardiogram may not have been an idiosyncratic response (EKG) (Pouchelon et al. 2000). In another to the clomipramine. Beagle dogs given study, canine patients given clomipramine at doses of up to 50 mg kg−1 PO q24h have doses of 1.5–2.49 mg kg−1 q12h for ≥45 days never exhibited this response (Simpson did not exhibit EKG changes. Duration of the 1997; King et al. 2000c). P‐wave significantly positively correlates Long‐term follow‐up of the dogs in the with serum concentration of clomipramine, trial described above did not identify any but in studies to date has remained within undesirable effects in the dogs given the the clinically normal range for dogs given highest dose (1–2 mg kg−1 q12h). Acute clinically appropriate doses (Reich et al. worsening of separation anxiety occurred in 2000). three dogs that had been given the low‐dose In healthy dogs given 3 mg kg−1 of clomi clomipramine (King et al. 2004b). pramine q12h for 112 days, there are signifi Another study compared four different cant decreases in total thyroxin (T4), free dose ranges for the treatment of separation thyroxin (fT4), and 3, 3′, 5′–triiodothyronine anxiety with clomipramine. A total daily dose −1 (reverse T3, rT3). T4 decreased 35% while fT4 of 2.1–4.0 mg kg was found to be more decreased 38%. However, clinical hypothy effective than 1.1–2 mg kg−1, 0.51–1 mg kg−1, roidism was not reported at this dose. There or 0.25–0.5 mg kg−1 (Petit et al. 1999). was no change in basal or post‐thyrotropin‐ Dogs diagnosed with separation anxiety releasing hormone stimulation at serum that were filmed at days 0, 7 and 14 of treat thyroid‐stimulating hormone concentrations ment with clomipramine at a dose of 1 mg kg−1 (Gulikers and Panciera 2003). q12h for seven days, followed by an increase Testicular hypoplasia has occurred in male in dose to 2 mg kg−1, showed improvement at dogs given 12.5 times the maximum daily seven days and greater improvement at dose for one year (Novartis 2000). It is not 14 days (Cannas et al. 2014). known whether usual clinical doses induce One trial that was based on owner surveys some degree of compromise of testicular rather than recording of the dogs’ actual function. behaviors compared placebo with clomi Clomicalm, a chewable tablet form of pramine at 0.5–1.0 mg kg−1 q12h or clomi clomipramine, is FDA‐approved for the pramine at 1.0–2.0 mg kg−1 q12h failed to treatment of separation anxiety in dogs, but find a significant effect of clomipramine for only in conjunction with behavior modifica signs the authors considered “typical” of tion. In a prospective, randomized, double‐ separation anxiety (Podberscek et al. 1999). blind, placebo‐controlled, parallel‐group, However, general activity and attachment‐ international, multicenter clinical trial, clo related behaviors did decrease with clomi mipramine, given at a dose of 1–<2 mg kg−1 pramine. The authors also did not evaluate PO q12h plus behavior modification was whether or not the dogs had improved in shown to be more effective than behavior some fashion that was relevant to the Specifi Medication 241

particular case based on baseline symptoms; previously been unsuccessfully treated with that is, there was no global assessment. phenobarbital, while the other two had previ Clomipramine is also used in the treatment ously been unsuccessfully treated with ami of various forms of compulsive disorder, triptyline. Treatment was conducted over a including acral lick dermatitis (ALD), a con period of months (Overall 1994). dition in which the dog persistently licks A dog that exhibited stereotypic motor itself, producing a dermatitis. In an 11‐week‐ behavior whenever the owner departed or long crossover trial, clomipramine has been was out of the dog’s sight, that had not shown to be more effective than desipramine responded to previous treatment with in the treatment of ALD, when both drugs amitriptyline or buspirone, did respond well were titrated up to 3 mg kg−1 daily (Rapoport to treatment with clomipramine combined et al. 1992). Similarly, in a 15‐week A‐B‐A with behavior modification. In this case, an design study, clomipramine was more effec increasing dosage schedule of 1 mg kg−1 PO tive than desipramine in the treatment of q12h for two weeks, then 2 mg kg−1 PO q12h canine acral lick dermatitis (Goldberger and for two weeks, then 3 mg kg−1 PO q12h, was Rapoport 1991). Subsequently, in a retrospec used (Overall 1998). tive open trial, clomipramine given at Brain imaging using single‐photon emis 2 mg kg−1 q24h resulted in decreased self‐licking sion computed tomography and the dopa and the healing of ALD lesions in eight of ten mine transporter specific radiopharmaceutical cases (Mertens and Dodman 1996). 123I‐FP‐CIT on a Cavalier King Charles Clomipramine given at 3 mg kg−1 PO q12h Spaniel with shadow‐chasing identified that for four weeks has been shown to be more the dog had an elevated dopamine trans effective than placebo in the treatment of porter activity in the left and right striatum. compulsive disorder. However, treatment for The dog was treated with clomipramine, such a short period of time was not curative 2.5 mg kg−1 PO q12h. The shadow‐chasing (Hewson et al. 1998b). steadily decreased over several weeks. At In a prospective study of tail‐chasing terri two months after the initiation of treatment, ers (bull terrier, miniature bull terrier, the brain imaging was repeated and the dopa American Staffordshire terrier, and Jack mine activity in the striatum had decreased Russell terrier), 18 dogs were started on on both the left and right sides to normal or treatment with clomipramine at 1 mg kg−1 near normal levels. The dog was continued q24h, which was subsequently titrated on clomipramine. Discontinuation of the upward depending on side effects and clini medication resulted in a resumption of cal response. Four dogs were withdrawn shadow‐chasing within two days (Vermeire from the study between four and eight weeks. et al. 2010). Of the remaining 14 dogs, 9 had a 75% or In a clinical trial comparing clomipramine, greater improvement in tail chasing when fluoxetine, and placebo for the treatment of given doses of clomipramine ranging tail‐chasing in dogs, both clomipramine and between 1 and 5 mg kg−1 total daily dose fluoxetine were found to be more effective (Moon‐Fanelli and Dodman 1998). In a sepa than placebo. There was no significant rate case report, a Cairn terrier exhibiting difference in the efficacy of clomipramine vs. stereotypic tail‐chasing was successfully fluoxetine (Yalcin 2010). treated with clomipramine titrated up to A randomized, double‐blind, placebo‐ 3 mg kg−1 q24h (Thornton 1995). controlled, clinical trial of the use of clomipra Three dogs with compulsive disorder mani mine (1.5 mg kg−1 q12h) to treat human‐directed fested as stereotypic motor behavior were “dominance‐motivated aggression” in dogs successfully treated with clomipramine failed to demonstrate a significant difference titrated up to a maximum dose of approxi between medicated and placebo‐treated mately 3 mg kg−1 PO q12h. One dog had dogs. In this trial, medication was the only 242 Tricyclic Antidepressants

treatment; there was no behavior modifica Clomipramine has also been used effec tion at all (White et al. 1999). Therefore, this tively to treat cataplexy in a dog (Soo‐Yeon trial only addressed the question of whether 2013). or not clomipramine is better than nothing, In a study of 24 dogs with various disorders, not whether it facilitates improvement if given including OCD, separation anxiety, noise in conjunction with behavior modification. phobia and global fear, the dogs were given Clomipramine’s licensure for the treatment of clomipramine at a starting dose of 1 to separation anxiety is specifically with behav 2 mg kg−1 b.i.d. along with instructions for ior modification, precisely because of the environmental management and behavior expectation that clomipramine will allow and modification. As needed, the dose was facilitate learning taking place that ultimately titrated up to a maximum dose of 4 mg kg−1 results in changed behavior. Again, as dis b.i.d. Some dogs had only one disorder, while cussed in Chapter 1, all medications for the others had multiple disorders. Fifteen of the treatment of behavior problems in nonhuman dogs exhibited resolution of the problem or animals should be used only in conjunction great improvement. Four of the dogs with appropriate environmental management exhibited moderate improvement, while 5 of and behavior modification. the dogs showed no improvement. Some of In a case report of interdog aggression, clo the dogs were able to be successfully weaned mipramine was prescribed for one dog that off of their medication after the problem was was highly reactive. Treatment began at resolved, while others had to be maintained 1.38 mg kg−1 b.i.d. for one week, and was on medication because the problem resumed subsequently increased to 2.76 mg kg−1 b.i.d. when medication was withdrawn (Seksel and The other dog, which was not highly reactive, Lindeman 2001). was treated with fluoxetine. Both dogs were also treated with environmental management Horses and behavior modification. The dog treated Clomipramine (2.2 mg kg−1 IV) combined with clomipramine gradually became less with xylazine (0.5 mg kg−1 IV) has been used reactive. After several months of treatment, to successfully obtain semen from a stallion the problem was resolved (Siracusa 2016). that was disabled due to a fracture of the In a retrospective study of 103 dogs with radius (Turner et al. 1995b). various presentations of compulsive disorder, clomipramine was found to be significantly Parrots more effective than amitriptyline (Overall In an open trial of the treatment of feather‐ and Dunham 2002). picking disorder in various parrot species Clomipramine has also been used, at a (five Moluccan cockatoos, one umbrella dose of 2 mg kg−1 b.i.d. in combination with cockatoo, one sulfur‐crested cockatoo, two the benzodiazepine alprazolam to success cockatiels, one yellow‐headed Amazon, and fully treat storm phobia in dogs. Over 90% of one scarlet macaw), birds were titrated over dogs treated with this combination improved. several weeks up to 1.0 mg kg−1 daily. The Improvement over baseline continued for at sulfur‐crested cockatoo, the yellow‐headed least eight months after discontinuation of Amazon, and the scarlet macaw all exhib treatment, which was as long as the dogs ited dramatic decreases in feather‐picking were followed. Storm phobia, while problem and/or self‐mutilation within the first atic when dogs exhibit intense fear of even month of treatment. The two cockatiels and light rain, is not a behavior that can always be the Moluccan cockatoo had positive per expected to be totally resolved, because some sonality changes, but the feather‐picking degree of fear of intense storms is normal did not improve. The other five birds exhib behavior (Crowell‐Davis et al. 2003; see also ited no response. Three birds exhibited Case 1). post‐treatment regurgitation. Drowsiness Specifi Medication 243 was observed in three birds, and one III. Desipramine Moluccan cockatoo exhibited ataxia for one Chemical Compound: 5H‐Dibenz[bf] day (Ramsay and Grindlinger 1992). Some azepine‐5‐propanamine, 10,11‐dihydro‐ birds on clomipramine gain weight N‐methyl‐monohydrochloride (Grindlinger and Ramsay 1991). Later DEA Classification: Not a controlled research (see below) suggests that the poor substance response rate may have been due to the dose Preparations: Generally available in 10‐, 25‐, being too low. 50‐, 75‐, 100‐, and 150‐mg tablets. Seibert et al. (2004) conducted a double‐ blind, placebo‐controlled trial of the Clinical Pharmacology treatment of feather‐picking disorder in cockatoos. A dose of 3 mg kg−1 q12h, Desipramine inhibits the reuptake of norepi suspended in raspberry syrup with 2% nephrine and serotonin. Desipramine is the carboxymethyl cellulose as a suspending opposite of clomipramine in that it has sub agent, was more effective than placebo, based stantially more effect on norepinephrine than on the evaluations of both the owner and an on serotonin, and is the most norepinephrine avian veterinarian who was blinded to selective of the TCAs. The primary metabo treatment. Species used in this study included lite is 2‐hydroxydesipramine. In humans, the Goffin’s, umbrella, Moluccan, sulfur‐crested, half‐life is 10–30 hours (Nelson 2004). and citron‐crested cockatoos. No adverse Desipramine is rapidly absorbed from the events were reported. gastrointestinal tract, metabolized in the A Congo African gray parrot with feather‐ liver, and, primarily, excreted through the picking and self‐injurious behavior kidneys. In humans, 70% is excreted through responded well to treatment with 9.47 mg kg−1 the kidneys (Merrell Pharmaceuticals 2000), of clomipramine combined with 0.5 mg kg−1 and the half‐life is about 18 hours (Potter buspirone q12h. The initial dose of clomi et al. 1995). pramine was 4 mg kg−1 PO q12h, and the Desipramine is metabolized by the P450 dose was subsequently titrated to effect. At a 2D6 cytochrome. Therefore, levels may be dose of 18.8 mg kg−1 q12h PO the bird became elevated in patients concurrently being given paradoxically fearful and appeared to be hal drugs that also use this pathway (Merrell lucinating. It was at this time that buspirone Pharmaceuticals 2000). was added to the treatment regimen, with Uses in Humans the dose of clomipramine being concurrently titrated downward. Seventeen months after Desipramine is used in humans to treat initiation of treatment, the bird was fully depression. feathered except for its wing tips (Juarbe‐ Diaz 2000). Contraindications A blue and gold Macaw treated with Desipramine should not be given to patients clomipramine for three days at a dose of with a history of sensitivity to TCAs, to patients 3.9 mg kg−1 q12h presented with extrapy currently taking MAOIs or within two weeks ramidal symptoms, included disseminated of taking a MAOI. It should be avoided or used dystonia, intermittent ataxia, and coarse‐ cautiously in patients with cardiovascular muscle tremors. This had been going on for disease, a history of urinary retention or 60 hours when the bird was presented. It was glaucoma, thyroid disease, or a seizure disor treated with oral and IM diphenhydrame at der (Merrell Pharmaceuticals 2000). 2 mg kg−1 q12h, and a steadily decreasing dose of clomipramine. Resolution of clinical Side Effects signs occurred with this treatment (Starkey A variety of side effects have been reported et al. 2008). in humans, including adverse cardiovascular 244 Tricyclic Antidepressants

effects, neurologic effects, anticholinergic plasma levels peaking in 30–60 minutes, effects, gastrointestinal effects, endocrine declining thereafter (Hobbs 1969; Kimura effects, and hematologic effects (Merrell et al. 1972). Repeated administration Pharmaceuticals 2000). produces higher concentrations than a single −1 The oral LD50 in male mice is 290 mg kg , dose (Hobbs 1968). Doxepin and some of its while in female rats it is 320 mg kg−1 (Merrell metabolites enter various tissues. Initial high Pharmaceuticals 2000). levels occur in the kidney, the liver, the spleen, and the lung (Hobbs 1969; Kimura Overdose et al. 1972). When doxepin is administered to There is no specific antidote. Decontaminate rabbits, concentrations in the heart range and provide supportive therapy. Emesis is from 40 to 200 times more than occur in the contraindicated. plasma at the same time (Elonen et al. 1975). The active metabolite, desmethyldoxepin, Effects Documented in Nonhuman Animals also occurs in appreciable amounts in various Dogs tissues (Ribbentrop and Schaumann 1965). One small trial has been conducted compar Only desmethyldoxepin and doxepin enter ing desipramine to clomipramine and pla the brain (Hobbs 1969; Kimura et al. 1972). cebo for the treatment of compulsive licking Dogs excrete various metabolites, including behavior in dogs. Desipramine was not as desmethyldoxepin, doxepin‐N‐oxide, a effective as clomipramine and was no more hydroxydoxepin and its glucuronide, as well effective than placebo (Rapoport et al. 1992). as doxepin, in their urine (Hobbs 1969). Desipramine has also been shown to be Doxepin is marketed as a mixture of geo effective in the treatment of cataplexy in dogs. metric isomers. The more active cis‐isomer However, it is not as effective as nortriptyline comprises 15% of a total doxepin dose while for this disorder (Mignot et al. 1993). the trans‐isomer comprises 85% of the dose. In human plasma the ratio of the isomers IV. Doxepin remains the same (cis/trans = 15 : 85) or shifts so that the cis‐isomer is even less than 15%. Chemical Compound: 1‐Propanamine, 3‐ The ratio of the isomers of the desmethyldox dibenz [b,e]oxepin‐11(6H)ylidene‐N, N‐ epin metabolite change so that they are dimethyl‐, hydrochloride approximately equal or the proportion of the DEA Classification: Not a controlled cis‐isomer is even greater than the trans‐isomer. substance There is wide individual variation (Midha Preparations: Generally available as 10‐, et al. 1992; Yan et al. 1997). In the rat, the 25‐, 50‐, 75‐, 100‐, and 150‐mg capsules metabolites are similar to humans, but in the and as a cream containing 50 mg of doxepin dog, rabbit, and guinea pig, the percentage of per gram of cream. cis‐desmethyldoxepin remains proportion ately lower than trans‐desmethyldoxepin, Clinical Pharmacology averaging 26% in the dog and 32% in the Doxepin prevents the reuptake up rabbit and guinea pig (Yan et al. 1997). In norepinephrine and serotonin. It also has H1 horses, the relative composition of the cis and and H2 receptor‐blocking activity, which is trans metabolites likewise remain similar to believed to be the basis for its antipruritic the original ratio (Hagedorn et al. 2001). effect. It undergoes hepatic metabolism into In dogs, doxepin and its metabolite, desmethyldoxepin and nordoxepin desmethyldoxepin, peak at one to three hours (GenDerm 1997). In humans, it has a half‐life after administration of an oral dose. of 8–25 hours (Ziegler et al. 1978; Potter et al. Approximately 50% of radioactive doxepin is 1995; Nelson 2004). In the dog, it is rapidly excreted in the urine in this species (Hobbs absorbed after oral administration with 1969). Specifi Medication 245

Dogs given 15 mg kg−1 daily for 30 days show Use of the cream may result in stinging or mild sedation and vomiting, while increased burning sensations or drowsiness (Drake heart rate, miosis, sedation, and twitching occur et al. 1994). at a dose of 50 mg kg−1 for 30 days. Dogs given Rats given 5, 10, 20, 40, or 80 mg kg−1 day−1 5 mg kg−1 daily for a year were almost asympto PO for 180 days exhibited no adverse effects matic. Dogs given 25 mg kg−1 daily for a year at 5, 10, or 20 mg kg−1 day−1. At doses of exhibited occasional vomiting. Dogs given 40 mg kg−1 day−1 there was decreased weight 50 mg kg−1 daily for a year exhibit ptosis, sedation, gain. No changes were observed in hematol tremors, and vomiting (Brogden et al. 1971). ogy, urine analysis, blood chemistries, or food Both the cis‐ and trans‐isomers of the intake (Noguchi et al. 1972b). In rats, males metabolite desmethyldoxepin are detectable appear to be more susceptible to toxic effects in horses’ urine and plasma up to at least than females (Noguchi et al. 1972a). The oral −1 48 hours after an intravenous injection of LD50 in the dog is 200 mg kg whereas the −1 −1 1 mg kg of doxepin (Hagedorn et al. 2002). intravenous LD50 is 16 mg kg in this species. −1 When doxepin is given intravenously, the In mice the oral LD50 is 117–178 mg kg and −1 half‐life of the more active cis‐isomer is the intravenous LD50 is 14.6–30 mg kg . In −1 3.1 hours, whereas the half‐life of the trans‐ rats the oral LD50 is 114–460 mg kg and the −1 isomer is 3.5 hours (Hagedorn et al. 2001). intravenous LD50 is 12.7–19 mg kg . In rab −1 bits, the intravenous LD50 is 8–14 mg kg Uses in Humans (Ribbentrop and Schaumann 1965; Noguchi Doxepin is recommended for anxiety and et al. 1972c). depression in humans. Doxepin cream is used as an antipruritic (Drake et al. 1994; Overdose Breneman et al. 1997). There is no antidote for doxepin. Decontaminate and provide supportive Contraindications therapy. Emesis is contraindicated. Doxepin is contraindicated in individuals with a history of sensitivity to doxepin or Effects Documented in Nonhuman Animals other TCAs. It should not be given in Dogs conjunction with MAOIs or within two Doxepin centrally and dose‐dependently weeks of administration of MAOIs. inhibits 2‐deoxy‐d‐glucose‐stimulated gas tric acid secretion in dogs (Leitold et al. 1984; Side Effects Shimatani et al. 2001). Various side effects related to the CNS, cardiovascular, hematologic, gastrointestinal, Parrots and endocrine areas have been observed in humans (Pfizer 1996). Dogs given 10 mg kg−1 Johnson (1987) reported successful use of exhibit some sedative effect (Yan et al. 1997). doxepin in the treatment of destructive Rabbits given doxepin by intravenous preening and mutilation, post‐shipment injection exhibit decreased blood pressure stress, and as a general aid to taming and and increased heart rate (Elonen et al. 1974). handling birds. In humans, doxepin is considered safe in elderly patients. Reproductive studies con Horses ducted in dogs, rats, rabbits, and monkeys Doxepin is banned in competition horses have failed to demonstrate adverse effects. where it may be used to attempt to calm Doxepin is metabolized by the P450 2D6 excited horses. When given at a dose of enzyme system; therefore, levels may be 1 mg kg−1 IV, it can be detected up to at least elevated in patients concurrently given other 48 hours later in both blood and urine. drugs that also use this enzyme system. Higher concentrations are present in the 246 Tricyclic Antidepressants

blood than in the urine. It is therefore 10 minutes exhibited decreased peripheral recommended that blood be used for vascular resistance, resulting in decreased assaying the presence of doxepin metabolites mean blood pressure. This dose also caused in competition horses (Hagedorn et al. 2002). prolonged PR and AH intervals, indicating After administration of 1 mg kg−1 IV, res that imipramine at this dose can inhibit car piratory rate remains stable, heart rate diac Ca2+ channels. QRS and HV intervals decreases, and body temperature decreases also increased at this dose, indicating that slightly but returns to normal within five imipramine can inhibit Na+ channels hours. Heart rate also returns to normal (Mitsumori et al. 2010). within five hours. Within the first hour after MAO‐A and MAO‐B activity are both injection, horses may appear to be moderately inhibited in the brains of the dog, mouse, rat, sedated (Hagedorn et al. 2001). and monkey in a dose‐dependent fashion. In the rat and mouse, imipramine inhibits V. Imipramine MAO‐B more potently than MAO‐A. In the dog and monkey, MAO‐B activity is more Chemical Compound: 5‐[3‐(Dimethylamino) inhibited than MAO‐A activity at low con propyl]‐10, 11‐dihydro‐5‐H‐dibenz [b,f] centrations, while MAO‐A activity is more azepine monohydrochloride inhibited than MAO‐B activity at relatively DEA Classification: Not a controlled higher concentrations (Egashira et al. 1999). substance Preparations: Generally available as 10‐, Uses in Humans 25‐, and 50‐mg tablets; 75‐, 100‐, 125‐, and Imipramine is used in humans to treat 150‐mg capsules; and ampules for intra depression and childhood enuresis. muscular injection. Contraindications Clinical Pharmacology Imipramine should not be given to patients Imipramine primarily blocks the reuptake of with a history of sensitivity to imipramine or norepinephrine at adrenergic synapses and, other TCAs. It should not be given in to a lesser degree, blocks the reuptake of conjunction with an MAOI or within two serotonin. weeks of giving an MAOI. In humans, When given orally, imipramine is substan imipramine can cause cardiac arrhythmias. tially demethylated in the liver during first‐ While studies of cardiac function in normal pass metabolism, resulting in higher blood dogs given clomipramine and amitriptyline levels of desipramine as opposed to the parent have revealed that this species does not have molecule. The other active metabolite is nori the same sensitivity to cardiac effects that mipramine. When imipramine is injected, the humans do, similar studies have not been absence of first‐pass metabolism results in conducted on the use of imipramine in dogs. higher blood levels of imipramine than It should be avoided in patients with cardiac desipramine (Gram and Christiansen 1975; arrhythmias (Ciba‐Geigy 1996). Dencker et al. 1976; Nagy and Johansson Imipramine is metabolized by the P450 1977). In humans, it has a half‐life of 2D6 cytochrome; therefore, levels may be 5–30 hours (Potter et al. 1995; Nelson 2004). elevated if drugs that are also metabolized by In cattle, imipramine has a terminal elimi this pathway are given concurrently. nation half‐life of 140 ± 15 minutes. It has extensive peripheral distribution, probably Side Effects due to high lipid solubility and low plasma Side effects in humans include various binding (Cordel et al. 2001). cardiovascular problems, anticholergic Halothane anesthetized dogs given IV effects, gastrointestinal effects, and endo imipramine at a dose of 10 mg kg−1 over crine changes. Specifi Medication 247

In humans, children are known to be more bladder to pelvic nerve stimulation. It also sensitive to overdose than adults. While it is reduces response of the bladder, but not the not known if the same sensitivity occurs in urethra, to histamine, and causes some other species, imipramine should be used reduction in bladder and urethra responses cautiously in juveniles. to acetylcholine and 5‐hydroxytryptamine. It When imipramine is given to mice and rats is possible that imipramine acts selectively as at 2.5 times the maximum human dosage and a local anesthetic agent in the urinary tract to the rabbit at up to 25 times the maximum of the dog (Creed and Tulloch 1982). human daily dose, there is no teratogenic Imipramine also causes increased tone of the effect. There is some evidence of embryotoxic urethral sphincter of the dog (Khanna et al. effect, as shown by a reduced litter size, an 1975; Tulloch and Creed 1979). increase in the stillborn rate, and a reduction A golden retriever given imipramine −1 in the mean birth weight. Acute oral LD50 is (1.85 mg kg PO q24h) for the treatment of 100–215 mg kg−1 in the dog and 355– storm phobia initially had no problems. 682 mg kg−1 in the rat (Ciba‐Geigy 1996). However, after two weeks of treatment, the Cattle and horses given 2 mg kg−1 may owner removed the three‐month‐old tick exhibit generalized weakness and ataxia. collar and replaced it with a new one. The Hemolysis and discolored urine may also collar contained amitraz, a nonspecific occur (McDonnell et al. 1987; McDonnell MAOI that is commonly used in the and Odian 1994; Cordel et al. 2001). treatment of demodicosis and that is present In guinea pigs, potency for QTC prolonga in some collars designed to prevent tick bites. tion is 1.7 fold greater with imipramine than The dog subsequently became lethargic, with fluvoxamine, an SSRI (Ohtani et al. weak, anorexic, ataxic, and brady‐cardic. 2001). After the collar was removed, clinical signs resolved within eight hours (Simpson 1997). Overdose Dogs given imipramine intramuscularly at There is no specific antidote for imipramine. doses ranging from 1.4 to 6.25 mg kg−1 exhibit Decontaminate and provide supportive decreased motor activity in open field tests. therapy. Emesis is contraindicated. Improved learning and decreased fear also occurred in some dogs (Zagrodzka et al. Effects Documented in Nonhuman Animals 1981). Cats Cats that were known mouse‐killers but that Horses had consistently deferred to another cat In horses, imipramine commonly induces when competing for access to a mouse, that mild sedation, erection, and masturbation. is, were considered to be “subordinate” by Intravenous injection of imipramine the experimenters, rose in “rank” when (2.0 mg kg−1), with or without supplemental injected intramuscularly with 12.5 or 25 mg injection of xylazine (0.3 mg kg−1), may be of imipramine (Zagrodzka et al. 1985). effective in the treatment of ejaculatory dysfunction in stallions (McDonnell et al. Dogs 1987; McDonnell and Odian 1994). It can Imipramine is used for nocturnal enuresis in also be given orally as 500–1000 mg added to human children and may be particularly the grain feed two to four hours before breed helpful for treatment of fear-based and ing (McDonnell 1999). excitement urination in dogs, although no Imipramine has also been used to assist in controlled studies addressing this specific the treatment of urospermia in a stallion with use have been published. Research on dogs a dysfunctional bladder (Turner et al. 1995a). has shown that 1 mg kg−1 imipramine Imipramine may be useful for the treat decreases the responses of the urethra and ment of narcolepsy in horses. Narcoleptic 248 Tricyclic Antidepressants

horses given a single dose of 4 mg kg−1 of or other TCAs. It should not be used imipramine IV exhibited hyperexcitability, concurrently with MAOIs or within two muscle fasciculations, hypersalivation, and weeks of using an MAOI. overreaction to external stimuli. Horses given Nortriptyline is metabolized by the P450 this dose also exhibited hemolysis. Horses 2D6 cytochrome system. Therefore, given 2 mg kg−1 as a single IV dose had milder concurrent administration of nortriptyline adverse reactions (Peck et al. 2001). with other drugs metabolized by this system may result in increased blood levels (Sandoz Rodents Pharmaceuticals 1996). Single doses of imipramine have been shown to decrease digging behavior, aggressive Side Effects behavior, and social investigation in mice, Side effects reported in humans have included while chronic dosing results in increased various cardiovascular, neurologic, anticho social investigation indicative of anxiolytic linergic, gastrointestinal, and endocrine effects (Gao and Cutler 1994). effects. Rabbits given nortriptyline by intravenous VI. Nortriptyline injection exhibit decreased blood pressure and increased heart rate (Elonen et al. 1974).

Chemical Compound: 1‐Propanamine, 3‐ Overdose (10, 11‐dihydro‐5H‐dibenzo[a,d]cyclohep There is no specific antidote for nortriptyline. ten‐5‐ylidene)‐N‐methyl‐, hydrochloride Decontaminate and provide supportive DEA Classification: Not a controlled therapy. Emesis is contraindicated. substance Preparations: Generally available in 10‐, 25‐, Effects Documented in Nonhuman Animals 50‐, and 75‐mg capsules. Dogs Nortriptyline is one of the most effective Clinical Pharmacology drugs in the treatment of cataplexy in dogs Nortriptyline is antihistaminic and blocks (Mignot et al. 1993). A study of the effects of the reuptake of serotonin and norepinephrine. nortriptyline on the QT interval, conducted In humans, it has a half‐life of 20–55 hours on Beagles, concluded that it is unlikely that (Nelson 2004). nortriptyline has an effect on the ventricular Nortriptyline is excreted in the milk. In repolarization process when used at thera rabbits given carbon‐14‐labeled nortriptyline, peutic doses (Jeon et al. 2011). the concentration of radioactivity in the milk is equivalent to concentrations in the serum. Concentrations of radioactivity in neonates Important Information for consuming the milk are substantially lower Owners of Pets Being than concentrations in the equivalent organs Placed on any TCA in the mother (Aaes‐Jørgensen and Jørgensen 1977). The following should be considered when Uses in Humans placing an animal on a TCA. Nortriptyline is used to treat depression in 1) It is essential that owners inform their humans. veterinarian of all other medication, herbal supplements, and nutritional sup Contraindications plements they are giving their pet because Nortriptyline is contraindicated in patients some of these may interact with the with a history of sensitivity to nortriptyline medication. References 249

2) While their pet may respond within a few for nonhuman animals is extra‐label use. days, it may be a month before their pet This does not mean that the drug is not begins responding. indicated for the problem. It means that 3) If their pet exhibits mild sedation in the the extensive testing required by the FDA beginning, they will probably return to for on‐label usage of the drug for their normal levels of activity in two or three particular species of pet and their par weeks as their body adjusts to the ticular pet’s problem has not been con medication. ducted, or, if in progress, been completed. 4) If their pet should experience any adverse Exceptions to this may occur after the events such as vomiting, diarrhea, or sei publication of this book if the FDA subse zures, they should contact their veterinar quently approves any of the TCAs for ian immediately. treatment of various behavior problems 5) With the exception of Clomicalm being in domestic animals or approves used in combination with behavior modi Clomicalm for uses other than separation fication for the treatment of separation anxiety in dogs. anxiety in dogs, all use of the medication

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Opioids and Opioid Antagonists Leticia Mattos de Souza Dantas and Sharon L. Crowell‐Davis

University of Georgia, Athens, GA, USA

Action While both morphine (0.1–0.5 mg kg−1) and oxymorphone (0.125–0.50 mg kg−1) have Opioids and opioid antagonists are a hetero- been reported as alleviating the crying of sep- genic group of pharmaceuticals, included in aration distress in puppies, they also this textbook due to the clinical use of some decreased motor activity, indicating sedation drugs for particular mental conditions. (Panksepp et al. 1978). Timid beagle/telomian Narcotic antagonists can be effective in the hybrids have also been treated with morphine −1 treatment of stereotypies and compulsive dis- at 0.25 mg kg . While they did show some orders in nonhuman animals. One possibility improvement with the combination of mor- is that stress, such as an overstimulating or phine and behavior modification, they also understimulating environment, causes an became less socially solicitous than placebo‐ animal to initiate stereotypic behavior. treated dogs, possibly as a consequence of the Carrying out the stereotypic behavior then sedative effects (Panksepp et al. 1983). causes the release of endogenous endorphins, Morphine has also been shown to decrease a which reinforce the behavior. Narcotic antag- variety of aggression types in laboratory ani- onists would block this release of the endog- mals (Gianutsos and Lal 1978). Nevertheless, enous endorphins, thereby blocking the these medications are not recommended for reinforcement. This would result in the ani- these or other problems, which are best mal discontinuing the behavior. However, treated with safer medications that can be studies confirming this theory are lacking in used in the long term in association with veterinary medicine. An alternative hypothe- behavior therapy. sis is that opioids are directly involved in the initiation of the stereotypic behavior. The narcotic antagonists then block the opioids, Overview of Indications thereby preventing their inducing stereotypic behavior. This hypothesis is supported by the Indications of opiate antagonists include rapid clinical response that occurs when opi- stereotypic behavior, obsessive-compulsive oid antagonists are administered. Opioids do disorder, including lick granulomas and tail‐ enhance amphetamine‐induced stereotypic chasing in dogs, and self‐mutilation and crib- behavior, and naloxone blocks this bing in horses. Opiate antagonists have been enhancement. found to be beneficial in the treatment of some

forms of self‐injurious behavior in humans as kept in confinement. During cribbing, the well as nonhuman animals (Richardson and horse grabs a horizontal object with its teeth, Zaleski 1983; Herman et al. 1987; Smith and bites down hard, and flexes its neck. It may or Pittelkow 1989; Sandman et al. 1990). may not swallow air as it does this. Diprenorphine was twice administered to a horse with a problem with cribbing behavior, once at 0.02 mg kg−1 and the second time at Contraindications, Side Effects, −1 and Adverse Events 0.03 mg kg intramuscularly (IM). In both cases, after a latency period of 30 minutes, injection of diprenorphine resulted in almost Gastrointestinal effects, especially diarrhea, total discontinuation of cribbing for periods may occur with the use of opioid antagonists. of 3–5.5 hours. Animal doses are given in Table 17.1. Clinical Guidelines Specific Medications While opioid antagonists have shown substantial promise in the treatment of stereo- I. Nalmefene typic behaviors in multiple species, their use is not yet widespread for a number of Chemical Compound: 17‐(Cyclopropylme- α reasons. Some can only be given parenter- thyl)‐4,5 ‐epoxy‐6‐methylenemorphinan‐ ally and all are expensive. Also, opioid 4,14‐diol, hydrochloride salt antagonists may be more effective in the DEA Classification: Not a controlled early phases of obsessive‐compulsive dis- substance order, though this phenomenon has not Preparations: Generally available as 1‐ml ampules containing 100 μg ml−1 and been studied across all species and all man- −1 ifestations of compulsive behaviors. 2‐ml ampules containing 1 mg ml of a Nevertheless, dramatic results in some sterile solution suitable for intravenous, cases make them a class of drugs that intramuscular, and subcutaneous admin- should be considered in the treatment of istration (Baker Norton Pharmaceuticals, any stereotypic behavior, especially if the Inc. 1997). patient’s safety is at stake. Diprenorphine, which is not reviewed Clinical Pharmacology below, has been used in the treatment of Nalmefene reverses and prevents the effects cribbing in horses (Dodman et al. 1987). of opioids, including respiratory depression, Cribbing is a behavior that occurs in horses sedation, and hypotension. It has a longer

Table 17.1 Doses of various opiate antagonists inhibitors for dogs, cats, horses, and parrots.

Opiate antagonist Cat Dog Parrot Horse

Naltrexone 25–50 mg cat−1 1–2.2 mg kg−1 q12–24 h 1.5 mg kg−1 q12h 0.7 mg kg−1 q24h q24h Naloxone 0.01 mg kg−1 SC as a test dose Pentazocine 2.5 mg kg−1 q12h

All doses for naltrexone are oral. Source: Brown et al. (1987a); Turner (1993); Overall (1997); Nurnberg et al. (1997). Seii Medication 259 duration of action than naloxone. It is equally disease, there is a decrease in plasma bioavailable if given by intravenous, clearance (Baker Norton Pharmaceuticals intramuscular, or subcutaneous routes. Peak 1997). levels are reached within minutes if it is given intravenously. However, there is a delay to Side Effects maximum plasma concentration if it is given Side effects have not been reported in non‐ subcutaneously (about 1.5 hours in humans) addicted animals given clinically relevant or intramuscularly (about 2.3 hours in doses. humans). If nalmefene is given parenterally, Administration of up to 1200 mg m−2 day−1 it blocks 80% of brain opioid receptors within to rats has not resulted in any decrease in five minutes (Baker Norton Pharmaceuticals, fertility, reproductive performance or Inc. 1997). offspring survival. Giving up to Nalmefene is primarily metabolized by glu- 2400 mg m−2 day−1 orally to rats or up to curonide conjugation, which occurs in the 96 mg m−2 day−1 intravenously to rabbits did liver, after which the metabolites are excreted not result in any harm to the fetuses. in the urine. Less than 5% of the urinary Administration of up to 205 mg m−2 day−1 in excretion is the parent compound. Fecal rat pups did not cause any adverse events excretion accounts for only 17% of a nalme- (Baker Norton Pharmaceuticals 1997). fene dose (Baker Norton Pharmaceuticals 1997). Other Information The pharmacokinetics of nalmefene have Nalmefene has been administered to humans been studied in three mixed‐breed dogs −1 after administration of benzodiazepines with given 0.5–0.9 mg kg IV. Elimination half‐ no adverse interactions (Baker Norton life was 120–218 minutes (Dodman et al. Pharmaceuticals 1997). 1988b). In the horse, nalmefene has a half‐life of Effects Documented in Nonhuman Animals three to five hours following intramuscular Dogs injection of 1 mg kg−1. With intravenous injection the half‐life is only 50 minutes. Dodman et al. (1988b) studied the use of After oral administration of 2 mg kg−1, no various narcotic antagonists for the treatment intact nalmefene is detectable in the plasma. of stereotypic self‐licking, self‐chewing, and High levels of nalmefene glucuronide appear scratching in nine dogs. Nalmefene was injected subcutaneously (SC) at a dose of rapidly after oral administration and are −1 detectable for up to 16 hours. In this species, 1–4 mg kg after a baseline rate of self‐ therefore, nalmefene must be administered licking, self‐chewing, and scratching was parenterally, as it has poor oral bioavailability measured. During the 90‐minute period with extensive first‐pass metabolism (Dixon following the injection, the amount of time et al. 1992). spent in these behaviors was significantly reduced in six of the nine dogs. The problem Uses in Humans behaviors were completely suppressed for Nalmefene is used in humans for reversal of 75 minutes in two dogs. No side effects were the effects of opioid medications. It has also reported. been used to treat pathological gambling (Grant et al. 2006). Horses Dodman et al. (1987) treated five crib‐biting Contraindications horses with nalmefene across 20 trials by a Nalmefene is contraindicated in patients variety of routes, specifically intramuscularly with a known history of intolerance to the (IM), subcutaneously, intravenously via medication. In humans with hepatic or renal continuous infusion and via a sustained 260 Opioids and Opioid Antagonists

release implant. Doses for the IM and SC produce dependence or tolerance. The injections ranged from 0.08 to 0.1 mg kg−1. A mechanism of action is not fully understood, single injection resulted in discontinuation of but it appears to act by competing with opi- cribbing for 2.75–13 hours. The sustained oids for receptor sites (Endo Pharmaceuticals release preparations resulted in a substantial 2001). decrease in cribbing for a minimum of Naloxone undergoes glucuronide conjuga- two days. tion in the liver and is excreted in the urine. Dodman et al. (1988a) reported a case In human adults, the serum half‐life is study of a 500‐kg Arabian stallion with a 30–81 minutes (Endo Pharmaceuticals four‐year history of self‐mutilation, 2001). specifically biting the flank and pectoral region. The stallion was treated, on successive Uses in Humans days, with doses of 0.2 mg kg−1, 0.4 mg kg−1, In humans, naloxone is used for reversal of 0.8 mg kg−1, and 1.6 mg kg−1 given IM as a opioid depression, including respiratory single dose. There was a dose‐specific depression. It is also used as an adjunctive decrease in acts of self‐mutilation or agent in the management of septic shock, in attempted self‐mutilation during the four which situation it facilitates the raising of hours following the injection, with a 94% blood pressure (Endo Pharmaceuticals decrease at the highest dose. While this 2001). result seems promising, the authors report that, in preliminary pharmacokinetic studies, Contraindications horses excrete nalmefene rapidly and the Naloxone is contraindicated in patients with bioavailability of nalmefene given to a known sensitivity to it. It should be used horses is low. with caution in patients with preexisting cardiac disease (Endo Pharmaceuticals 2001). II. Naloxone HCl Side Effects Chemical Compound: (−)‐17‐Allyl‐4,5a‐ Some decrease in activity has been observed epoxy‐3, 14‐dihydroxy morphinan‐6‐one‐ in cats (see below). Studies of reproduction hydrochloride in mice and rats given high doses of naloxone DEA Classification: Not a controlled have not resulted in any impairment of substance reproduction or teratogenicity (Endo Phar- Preparations: Generally available as a maceuticals 2001). 0.02 mg, 0.4 mg or 1 mg ml−1 solution for Chemical impurities in naloxone, specifi- subcutaneous, intramuscular, or intrave- cally noroxymorphone and bisnaloxone, nous injection. may produce emesis in dogs when administered intravenously at high doses (Endo Clinical Pharmacology Pharmaceuticals 2001). Naloxone is a pure opioid antagonist. As The intravenous LD50 (the lethal dose that such, it prevents or reverses the effects of kills 50% of the animals tested) is 150 mg kg−1 opioids, such as respiratory depression, in rats and 109 mg kg−1 in mice. Subcutaneous hypotension, and sedation. Product litera- injection of 100 mg kg−1 day−1 for three weeks ture for humans states that in the absence of produces transiently increased salivation and opioids or opioid agonists, it exhibits essen- partial ptosis. No side effects were observed tially no pharmacological activity. However, at 10 mg kg−1 day−1 for three weeks. it is precisely because of its efficacy in some animals exhibiting stereotypic behavior that Overdose it is used in clinical behavioral medicine (as Treat an overdose symptomatically and opposed to veterinary behavior). It does not monitor. Seii Medication 261

Doses in Nonhuman Animals SC. This resulted in nearly complete cessation Because it is injected and short‐acting, of the tail‐chasing behavior within naloxone is not a practical medication for 20 minutes. The effect lasted about three maintenance treatment of stereotypic hours. This dose was repeated multiple times behaviors or obsessive‐compulsive disorders. over the next two days with the same effect. It is best used as a tool for testing whether or The patient was sent home on an oral, mixed not opioid antagonists are likely to be narcotic agonist–antagonist combination of effective in the treatment of a given patient. pentazocine (50 mg, see below) and naloxone In this capacity, they can be very useful. The (0.5 mg) given b.i.d. The pentazocine/ patient should be checked into the hospital naloxone combination was readily and monitored to determine a baseline for administered by the owners and resulted in a exhibition of the stereotypic behavior and to low rate of compulsive tail‐chasing in the allow the patient time to acclimate to the home environment. Eventually, the dog hospital environment. Naloxone is then was weaned off the pentazocine/naloxone injected at a time when the patient can be combination and maintained fairly normal closely monitored for at least the next two behavior. It continued to chase its tail during hours, and preferably longer. periods of intense excitement, but was In the first case, one of the authors otherwise a normal pet. (Crowell‐Davis) was involved in treating the patient, a dog, which chased its tail incessantly Horses to the point of exhaustion. It was covered Dodman et al. (1987) gave naloxone to one with bruises and lacerations from running cribbing horse in a series of three trials at into walls. It would not eat or drink unless it 0.02 mg kg−1, 0.03 mg kg−1, and 0.04 mg kg−1 IV. was physically restrained and its head was After a 12‐ to 23‐minute latent period, crib‐ held still in a food or water bowl. When biting stopped for an average of 20 minutes. naloxone was injected, it began exploring its environment, interacting with students Pigs and clinicians, and voluntarily eating and Sows injected with naloxone, 0.64– drinking for the first time since presentation 1.0 mg kg−1, exhibit a 57% decrease in the to the hospital (see Brown et al. 1987a, 1987b amount of time spent in stereotypic behaviors for further information). such as sham chewing, chain chewing, and tether chain chewing. The decrease begins Discontinuation about 10–15 minutes after injection and lasts Since only a few doses should be given to test two to three hours (Cronin et al. 1985, 1986). the patient’s response to an opioid antagonist, discontinuation is not an issue. III. Naltrexone Hydrochloride

Chemical Compound: 17‐(Cyclopro Effects Documented in Nonhuman Animals α Cats pylmethyl)‐4,5 ‐epoxy‐3, 14‐dihydroxy- morphine‐6‐one hydrochloride Cats given 0.4 mg kg−1 of naloxone IV are DEA Classification: Not a controlled somewhat less active than when not given substance naloxone, but exhibit no cardiac changes Preparations: Generally available in 50‐mg, (Waldrop et al. 1987). scored tablets.

Dogs Clinical Pharmacology In a case of severe compulsive tail‐chasing in Naltrexone hydrochloride is an opioid a 20‐kg Bull terrier, Brown et al. (1987a, antagonist, with no opioid agonist properties, −1 1987b) gave 0.2 mg (0.01 mg kg ) of naloxone that acts by competitive binding. It does not 262 Opioids and Opioid Antagonists

produce tolerance or dependence. It is well q24h exhibited drowsiness. This side effect absorbed orally, after which it undergoes resolved after withdrawal of the medication extensive first‐pass metabolism. In humans, for 48 hours (White 1990). oral bioavailability ranges from 5% to 40%. Rats given 100 mg kg−1 day−1 of naltrexone Both the parent drug and one of the over two years had a slightly increased metabolites, 6‐ β‐naltrexol, are active, with incidence of mesotheliomas in males and of peak plasma levels of both occurring about vascular tumors in both males and females. A one hour after oral dosing. Most of a dose is dose of 100 mg kg−1 day−1 results in an excreted as various metabolites, primarily by increase in pseudopregnancy and a decrease the kidney. Very little fecal excretion occurs. in true pregnancy in the rat. Male fertility is In humans, the half‐life for naltrexone is unaffected at this dose. Naltrexone is both four hours and for 6‐ β‐naltrexol is 13 hours. embryocidal and fetotoxic in rats and rabbits While hepatic metabolism occurs, there are when given at doses of 30 mg kg−1 day−1 (rats) also extrahepatic sites of metabolism or 60 mg kg−1 day−1 (rabbits). However, there (Mallinckrodt Inc. 2002). is no evidence of teratogenicity when Its pharmacological efficacy in humans pregnant rabbits and rats are given doses of is 24–74 hours, depending on the dose up to 200 mg kg−1 day−1 during the period of (Mallinckrodt Inc. 2002). organogenesis (Mallinckrodt Inc. 2002). In the mouse, rat, and guinea pig, the oral −1 −1 Uses in Humans LD50 for each is 1100 mg kg , 1450 mg kg , Naltrexone is used in the treatment of and 1490 mg kg−1, respectively. In the mouse, alcoholism, opioid addiction, and impulse rat, and dog, death occurs due to clonic– control disorders (Raymond et al. 2002; tonic convulsions and/or respiratory failure Grant et al. 2009). when given large doses in acute toxicity studies. In one study, humans given 800 mg Contraindications daily for up to one week did not exhibit A history of sensitivity to naltrexone, liver toxicity (Mallinckrodt Inc. 2002). failure, kidney failure. Overdose Side Effects Treat an overdose of naltrexone Pupillary constriction may occur. The symptomatically and monitor the situation. mechanism for this effect is not known (Mallinckrodt Inc. 2002). Discontinuation Naltrexone can cause hepatocellular injury Patients that have been maintained on when given in overdose. In humans, the naltrexone for treatment of severe stereotypic apparently safe dose of naltrexone and the behavior should undergo gradual dose causing hepatic injury is only a fivefold discontinuation. increase. Five of 26 human patients given 300 mg day−1 exhibited elevated ALT after Other Information three to eight weeks of treatment The liver function of patients that are (Mallinckrodt Inc. 2002). This ratio is maintained on naltrexone for the treatment unknown in dogs, cats, and other veterinary of stereotypic behavior problems should be patients. monitored regularly. One case has been reported of naltrexone‐ induced pruritus in a dog that was being Uses Documented in Nonhuman Animals given naltrexone at 1 mg kg−1 q6h, which is at Dogs the high end of the normal clinical dose range Seven of 11 dogs with acral lick dermatitis (Schwartz 1993). Another dog being that were treated with naltrexone, 2.2 mg kg−1 medicated with naltrexone at 2.2 mg kg−1 q12–24 h, responded positively to treatment. Seii Medication 263

When naltrexone was discontinued, all months. Thirty‐five of the 41 birds responded responders relapsed after durations of time positively to treatment. However, relapse ranging from one week to three years. Five of often occurred within a few months. Pre‐ and these dogs again responded to naltrexone posttreatment blood panels did not identify treatment. The other two were euthanized any changes. Undesirable behavioral effects due to unrelated health problems (White were not induced. 1990). Dodman et al. (1988b) gave naltrexone, Pigs 1 mg kg−1 SC, to two dogs with stereotypic Naltrexone, at a dose of 1.0–1.3 mg kg−1 IM, self‐licking, self‐chewing, and scratching partially blocks the relaxation response in behavior. Both showed a significant reduction pigs (Grandin et al. 1989). in these behaviors for at least 90 minutes after the injection. No side effects were Other Species reported. Turner (1993) reported remission of a tail Intense pruritus has occurred in one dog wound in a cougar that was maintained by given a dose of 1 mg kg−1 q6h (Schwartz self‐mutilation when the cougar was treated 1993). with naltrexone, but did not report the dose. The cougar was monitored for a subsequent Horses two years, with no relapse. Dodman et al. (1988a) gave naltrexone to Kenny (1994) used naltrexone to treat a three horses with crib‐biting behavior at a variety of psychogenically induced dose of 0.04–0.4 mg kg−1 IV. After a brief dermatoses in zoo animals, as follows, with latent period, crib‐biting was substantially variable efficacy. decreased or completely suppressed for A 36‐kg Amur leopard (Panthera pardus 1.5–7 hours. One horse was subsequently orientalis) that was pulling hair out of the implanted with a pellet of 0.6 g of naltrexone. dorsal part of its tail and back was initially Its crib‐biting was substantially decreased treated with prednisone, 20 mg PO 124 h. for two days, with occasional breakthroughs. After an initial small improvement, the A 10‐year‐old thoroughbred mare with a behavior worsened, and naltrexone was five‐year history of weaving exhibited a 30% added to the treatment at 25 mg (1.4 mg kg−1) reduction in weaving behavior when given PO q24h. After one week, no adverse effects naltrexone at 0.7 mg kg−1 day−1 PO. Specifically, had been noted, so the dose was increased to weaving decreased from 43.5 min−1 to 50 mg (2.8 mg kg−1) q24h. The prednisone 32.3 min−1 (Nurnberg et al. 1997). dose was gradually reduced and discontinued. Relapses occurred after a loud concert was Parrots held close to the hospital and subsequent to Turner (1993) treated 41 birds with feather‐ the keeper discovering the leopard removing picking with naltrexone, 1.5 mg kg−1 b.i.d. A the naltrexone tablets from its meat. The solution was created by dissolving a 50‐mg tablets were thereafter crushed and mixed tablet of naltrexone, which is highly soluble in into the meat. Total remission of the hair‐ water, in 10 ml of sterile water. The species pulling occurred after this protocol, and the treated were, specifically, 2 eclectus, 6 African leopard was subsequently maintained on gray, 1 cockatiel, 7 Amazons (1 orange wing, 3 50 mg of naltrexone daily (Kenny 1994). yellow nape, 1 red‐lored, 1 blue front, and 1 A clouded leopard (Panthera nebulosa) double), 9 macaws (2 hyacinth, 1 scarlet, 4 that was excessively grooming the medial blue/gold, 1 green wing, and 1 Catalina) and surface of her thighs was treated with 16 cockatoos (4 umbrellas, 1 rosebreast, 6 prednisone, 25 mg PO q12h for five days, Moluccan, 2 citron, and 3 lesser sulfur). after which the prednisone was discontinued. Treatment duration ranged from one to six The behavior relapsed and the leopard was 264 Opioids and Opioid Antagonists

treated with prednisone seven times over the rhesus macaques (Macaca mulatta), Kempf following three years. When the leopard was et al. (2012) showed that both the frequency immobilized for examination, she was found and the percentage of time spent displaying to have a subacute to chronic ulcerative SIB decreased during the treatment phase, pyogranulomatous dermatitis. She was and the percentage of time remained initially treated with 1.6 mg kg−1 naltrexone, decreased during the post‐treatment phase. q24h. When she was immobilized three The authors did not report any side effects of months later, the lesions were completely treatment for the time of the study. Lee et al. resolved. There were no changes in values for (2015) demonstrated that innate immune alanine transaminase before and after activation of astrocytes (which was increased treatment. The dose of naltrexone was then in rhesus macaques with SIB in the study) decreased to 0.8 mg kg−1, resulting in was markedly decreased in animals receiving recurrence of the problem. Returning to the naltrexone, as was atrophy of both gray and higher dose did not result in improvement white matter astrocytes. These findings were until prednisone (40 mg, q24h) was added. concomitant with a decrease in SIB. Once the prednisone was discontinued, she −1 was maintained on 1.6 mg kg without IV. Pentazocine further relapse (Kenny 1994). A tricolored squirrel (Callosciuis prevostii) Chemical Compound: 1,2,3,4,5,6‐Hexahydro‐6, had repeated episodes of self‐mutilation that 11–dimethyl‐3‐3(3‐methyl‐2‐butenyl)‐2,6‐ responded to treatment with glucocorticoid. methano‐3‐benzazocin‐8‐ol hydrochloride Skin scrapings and fungal cultures taken DEA Classification: DEA Schedule IV con- after immobilization were unremarkable. trolled substance The squirrel was treated with naltrexone at Preparations: Generally available as a tablet 1.0 mg kg−1 q24h, which resulted in resolution containing 50 mg of pentazocine and of the problem. Serum transaminase levels 0.5 mg of naloxone (see naloxone). were not notably different before and after six weeks and 10 weeks of treatment (Kenny Clinical Pharmacology 1994). Pentazocine is an analgesic with some opiate An Arctic wolf (Canis lupus hudsonicus) antagonistic effects. The naloxone is with repeat episodes of acute moist dermatitis combined with pentazocine in this did not respond to treatment with 1.0 mg kg−1 medication because at the dose of 0.5 mg it PO of naltrexone given q24h. This problem antagonizes both pentazocine and various responded only to high doses of gluco narcotics; misuse of pentazocine by grinding corticoids. No adverse events were reported the tablets up and injecting them as a solution from the treatment attempt with naltrexone is effectively prevented. Naloxone at this (Kenny 1994). dose does not counteract pentazocine when A polar bear (Ursus maritimus) mutilated given orally (Synofi‐Synthelabo, Inc. 1999). its perineum by rubbing it on concrete as In humans, onset of analgesia typically part of ritualized pacing behavior. Treatment occurs 15–30 minutes after oral administra- with 1.2 mg kg−1 q24h had no beneficial effect tion (Synofi‐Synthelabo, Inc. 1999). and treatment was discontinued after one month (Kenny 1994). No adverse events were Uses in Humans reported. For humans, pentazocine is for oral use only Naltrexone has also been used to treat for cases of moderate to severe pain. macaques with self‐injurious behaviors. In a study to assess the efficacy of extended‐ Contraindications release naltrexone in the pharmacologic Do not give pentazocine to patients with a treatment of self‐injurious behavior (SIB) in history of sensitivity to either naloxone or References 265 pentazocine. Use with caution in patients ment of pets with stereotypic behavior prob- with renal or liver disease. lems that exhibit a positive response to a naloxone trial. Cost may be a prohibitive Side Effects factor. The use of pentazocine may be con- Seizures may occur in patients with a history sidered after consideration of the potential of seizures, though the mechanism for this is for human abuse, the risk of side effects, and not known. Various side effects include car- the fact that pentazocine is not a pure opiate diovascular (e.g. hypotension, tachycardia, antagonist. While pentazocine has been syncope), respiratory (respiratory depres- shown to be effective in at least some cases sion), central nervous system (e.g. hallucina- of stereotypic behaviors, trials comparing tions, disorientation, sedation, weakness), the relative efficacy of pentazocine with vari- gastrointestinal (e.g. emesis, constipation, ous pure opiate agonists have not been diarrhea), and decreased white blood cell conducted. count (Synofi‐Synthelabo, Inc. 1999).

Overdose Effects Documented in Nonhuman Animals Dogs In case of overdose, provide supportive therapy and monitor. If respiratory depression A dog with severe compulsive tail‐chasing occurs, administer naloxone, a specific responded well to a test treatment with antagonist. naloxone given subcutaneously (Brown et al. 1987a, 1987b). It was subsequently success- Discontinuation fully treated at home with Talwin, at a combi- Discontinue pentazocine by gradual tapering nation of 50 mg pentazocine and 0.5 mg of dose. naloxone given orally b.i.d. The medication was eventually discontinued, and the dog Other Information remained relatively normal, exhibiting tail‐ Pure opiate antagonists, such as naltrexone, chasing only during periods of intense should be the first drug of choice for treat- excitement.

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Hormones Sharon L. Crowell‐Davis

University of Georgia, Athens, GA, USA

Introduction behaviors toward both conspecifics and human partners (Romero et al. 2014). While progestins were used to treat behavior Furthermore, oxytocin has been identified as problems in the 1970s and 1980s, they fell having an effect on dog’s responses to specific out of favor as better, safer medications human behaviors and human‐related stimuli became available. Recent research into the (e.g. Hernádi et al. 2015; Kis et al. 2015; Oliva use of oxytocin for social anxiety and autism et al. 2015a, 2015b; Kovács et al. 2016a; in humans (e.g. Kanat et al. 2017; Procyshin Kovács et al. 2016b; Macchitella et al. 2017). et al. 2017) has led to the beginnings of With generations of selective breeding, attempts to identify their potential for treat- humans have modified the distribution of ing various behavior disorders in domestic oxytocin receptor gene polymorphisms in animals. different breeds (Kis et al. 2014; Kis et al. Historically, studies of oxytocin have 2017). For example, Border Collies, which focused on its relevance in reproduction and have been bred for cooperative work with birth. Research conducted in the last several each other and with humans, are more years has identified oxytocin as being critical responsive to the intranasal administration of to prosocial and co‐operative behavior in oxytocin than are Siberian Huskies, which many species (see Romero et al. 2016 for a have been bred to work more independently review). Oxytocin has been found to be (Kovács et al. 2016a, 2016b). One study spec- important in the positive psychosocial and ulates on its possible use in the treatment of psychophysiological changes that occur separation anxiety, but emphasizes that care- during a variety of human‐animal interactions ful study must be done to identify the stage of (see Beetz et al. 2012 for a review). behavior modification at which the use of In the dog, an oxytocin‐gaze positive loop oxytocin might be beneficial (Thielke and has been identified, with oxytocin levels Udell 2017). However, to the author’s knowl- increasing in both human and dog when they edge, no case reports or clinical studies have gaze at each other (Fiset and Plourde 2015; been published on the use of oxytocin for any Nagasawa et al. 2015). This loop has been kind of anxiety disorders in dogs. hypothesized to be important in the coevolu- Less research has been conducted on the tion of the human‐dog social bond (Buttner effect of oxytocin on cats than on dogs. In 2016; Kekecs et al. 2016). Being sprayed with one study in which the temperament of cats oxytocin has been shown to increase prosocial was assessed via owner questionnaire and

their oxytocin receptor genes were analyzed, Effects Documented in Nonhuman it was found that, among neutered females, Animals cats with the A allele in the single nucleotide A compounded formulation of 40 units/mL polymorphism G738A had higher scores for of oxytocin that is administered transmu- “roughness,” than cats without the A allele. cosally via the buccal pouch appears to While extensive further study is needed, in have facilitated resolution of multiple cases purebred cat breeding it may be that selecting of intercat aggression (Stephanie Borns‐Weil, for specific types of oxytocin receptor genes pers. comm.). will facilitate selection of optimal temperaments (Arahori et al. 2016). Progestins

Oxytocin This section is included for completeness and historical reference, rather than because Chemical Compound: Oxytocin is a neuro- progestins are recommended for the treat- peptide with the chemical formula C43H66 ment of behavior problems in nonhuman N12O12S2 animals. Progesterone and its metabolites act DEA Classification: Not a controlled in various parts of the body (e.g. brain, substance smooth muscle, uterus, sperm, oocyte) Preparations: Available for intravenous (IV) through multiple mechanisms of action or intramuscular (IM) injection at a con- (Mahesh et al. 1996). Therefore, progester- centration of 10 IU ml−1. It is also available one’s effects are not discrete and specific, but over the counter (OTC) in various nasal instead are widespread and varied. A variety sprays, usually advertised as having 10 IU of side effects, including polydypsia, polyu- per spray. These sprays may or may not ria, polyphagia, weight gain, sedation, over- contain other molecules. There is cur- production of growth hormone, suppression rently no universal standard for verifying of the hypothalamic–pituitary‐adrenocorti- quantity and dose in each spray. cal axis, insulin resistance, and cancer, make their use for the treatment of behavior prob- Clinical Pharmacology lems very risky for the patient. Behavioral effects are attributable to both an antiandro- Oxytocin stimulates contraction of the genic effect and a calming effect on the lim- smooth muscle of the uterus. bic system (Henik et al. 1985). The use of a hormone, methyloestrenolone, Indications which is not currently available commercially, in the treatment of behavior problems of dogs Intercat aggression and anxiety disorders. and cats was first reported in 1964 (Gerber and Sulman 1964). It was found that, in bitches Side Effects and queens, estrus could be postponed or prevented and pseudopregnancy could be termi- No studies have been conducted on the car- nated with this medication. In male cats, cinogenicity or toxicity of oxytocin in roaming and urine marking were also reported humans or animals. as being effectively treated, as were roaming, urine marking, and mounting in male dogs. Doses in Nonhuman Animals Action Cats: 2–8 international units (IU) per cat daily; dogs: 10–40 IU per dog daily (Stephanie The progestins have a variety of actions. They Borns‐Weil, pers. comm.). inhibit the secretion of pituitary gonadotropin, Progestin 271 suppress the production of testosterone, alter activity, roaming, digging holes, self‐mutilation, the binding of transcription factor to DNA, night howling, attention‐seeking behavior, alter membrane fluidity, act on the GABAA and urine marking. However, no data from receptors to produce effects similar to those either retrospective or prospective clinical caused by benzodiazepines, and possibly surveys were given, except for urine spraying increase the levels of β‐endorphin and met‐ in cats. A success rate of 80% was reported enkephalin in the hippocampus. There are for this problem, a rate that has not been various mechanisms of action, including an replicated in other studies. intracellular receptor‐mediated mechanism, a steroid action involving phospholipid lay- Contraindications, Side Effects, ers, a steroid action mediated by second mes- and Adverse Events senger systems, a steroid action exerted at the cell membrane, and steroid effects initiated The use of progestins is contraindicated in by interaction with the GABA receptors and breeding animals and diabetics. There are ligand insertion (Mahesh et al. 1996). many side effects. In the author’s experience, polyphagia, polydipsia, and sedation are all Overview of Indications so common that the owner should be told to expect them. In a retrospective clinical In‐depth discussion of the use of progestins report, 25% of cats treated with progestins to modify reproductive status is beyond the for behavior problems exhibited an increased scope of this book and is covered elsewhere, appetite and about 20% of cats exhibited for example, Evans and Jemmett (1978). sedation; that is, the owner reported that Progestins can be useful in cases of excessive they were depressed, lethargic, or inactive. sexual behavior, aggression in dogs and cats, Mammary gland enlargement, without urine marking, persistent mounting by neu- tumor development, occurred in three of the tered males, excess vocalization in neutered 50 cats (Hart 1979a). male cats responding to estrous queens, and Various pathological changes have been human‐directed sexual aggression in cats. identified as occurring in the uteruses of More generally, progestins can be effective in both cats and dogs given progestins, with the suppressing behaviors that are more pre- changes being dependent on both dose and dominant in males than in females (Hart duration of medication (e.g. Dow 1958; 1979c; Hart and Eckstein 1998). These effects Anderson et al. 1965; Brodey and Fidler 1966; occur even with castrated males. Withers and Whitney 1967; Cox 1970; Austin In an early report on 50 cats treated with and Evans 1972; Teale 1972). Even remnants either medroxyprogesterone acetate (MPA) of reproductive tissue left after neutering or megestrol acetate (MA), Hart (1979a) have been reported to undergo changes and reported that about one‐third of 31 spraying infection (Jones 1975). Other side effects cats improved to the client’s satisfaction. Two include elevated blood glucose, mammary of 11 cats with inappropriate urination hyperplasia (e.g. Hinton 1977), diabetes, resolved, and five of eight aggressive cats endometrial hyperplasia, pyometra, and showed improvement. carcinoma. These side effects, while serious, Pemberton (1980, 1983) subsequently generally occur when a patient has been on reported that progestins were effective in the progestins for weeks or months. treatment of a spectrum of behavior problems including territorial aggression, “jeal- Overdose ousy,” dog fighting, hyperkinesis, persistent barking, anorexia nervosa, tail‐chasing, To treat progestin overdose, evacuate stom- timidity, destructiveness, phobias, predatory ach if within first 30 minutes and then pro- aggression, viciousness, unacceptable sexual vide supportive therapy. 272 Hormones

Clinical Guidelines 50 mg kg−1 SC at three‐week intervals exhibited a variety of histologic changes. The Because of the common and potentially very adrenal cortex atrophied, foci of hyperplastic serious side effects that can occur with pro- ductular epithelium developed in the gestins, and the availability of many drugs mammary glands, benign mammary tumors that are safer for use in the treatment of developed, steroid‐induced hepatopathy behavior problems, their use is not standard occurred, and the cells of the islets of practice at this time. They are included only Langerhans became vacuolated. There were for historical reasons and to verify that they no significant differences between the dogs are not a drug of choice for behavior treated with MPA and the dogs treated with disorders. PROL (Selman et al. 1995).

Specific Medications Adverse Drug Interactions Aminoglutethimide significantly depresses I. Medroxyprogesterone Acetate (MPA) serum concentrations of MPA (Pharmacia and Upjohn 1999). Chemical Compound: Pregn‐4‐ene‐3,20‐ dione, 17‐(acetyloxy)‐6‐methyl‐,(6α) Effects Documented in Nonhuman Animals DEA Classification: Not a controlled Cats substance MPA, given as a single injection of 100 mg to Preparations: Generally available as 2.5‐, 5‐, −1 males and 50 mg to females, resulted in and 10‐mg tablets and as a 150 mg ml successful treatment of urine spraying or injectable solution. urine marking in 29% of cases. Less than 10% of the treated cats exhibited depression and/ Clinical Pharmacology or increased appetite. Both males and cats MPA inhibits the secretion of gonadotropins. from single‐cat homes responded better than In humans, a single intramuscular injection did females or cats from multicat homes, of MPA results in increasing plasma with males from single‐cat homes having the concentrations of MPA for three weeks, best response. Some cats that were initially followed by an exponential decrease in treated with MA subsequently responded to plasma concentrations. MPA levels in the MPA (Hart 1980). When used as a treatment plasma become undetectable in 120–200 days for urine spraying or marking in cats, (Pharmacia and Upjohn 1999). injections of MPA are repeated once per month or as needed. Uses in Humans In a later study of 35 male and 25 female MPA is used in humans to treat abnormal cats, Cooper and Hart (1992) found that MA uterine bleeding, amenorrhea, renal or endo- and MPA were equally effective, with about metrial cancer, and endometrial hyperplasia. 42% of cats treated with a progestin showing a positive response to treatment. Progestins Contraindications were less effective for females than for males Use of MPA is contraindicated when sensitiv- and, in females, were less effective than diaz- ity to MPA, pregnancy, liver disease, or mam- epam or buspirone. In males, progestins mary tumors are present. Do not use MPA to were about as effective as diazepam or treat behavior problems in intact females. buspirone.

Side Effects Dogs Dogs treated with eight doses of MPA at Male dogs given MPA at 10–20 mg kg−1 SC 10 mg kg−1 SC or proligestone (PROL) at have been observed to exhibit 75–100% Specifi Medication 273 improvement of various problems, including Clinical Pharmacology aggression toward other males, urine mark- MA is a steroid with rapid onset of action. It ing, and mounting of dogs, people, or inani- has antigonadotropic and antiandrogenic mate objects. There was poor efficacy for effects and glucocorticoid activity. There is human‐directed aggression in the male (Hart slight mineralocorticoid activity. It does not 1979b). Three out of four males treated with have anabolic or estrogenic activity and does 10 mg kg−1 MPA SC for fighting with other not have masculinizing effects on the devel- males responded to therapy, whereas only oping fetus (David et al. 1963; Gupta et al. one out of seven males given the same treat- 1978; Muller et al. 1983; Henik et al. 1985). ment for human‐directed aggression exhib- In humans, the major route of elimination ited improvement. Side effects observed is the urine, although some fecal excretion included increased appetite and weight gain occurs (Bristol‐Myers Squibb 2000). The (Hart 1981). opposite occurs in the dog. When MA is −1 MPA was once used as a canine contracep- given to bitches at a dose of 2 mg kg PO for tive. However, this was discontinued in the eight days, it is rapidly eliminated, primarily early 1970s due to problems with endometri- through the feces (about 87%) and to some tis and pyometra. While these problems are degree in the urine (about 9%). One week most likely to occur when MPA is given dur- after the last dose, 90% of the medication has ing proestrus, estrus, in overdose, or in dogs been excreted, although there is further with genital disease, it should not be used in gradual elimination up to three weeks later intact females (Stabenfeldt 1974). Spayed (Chainey et al. 1970). female beagles given doses of MPA as low as 3 mg kg−1 every three months almost invari- Uses in Humans ably develop mammary nodules within four MA is used to treat anorexia, cachexia (e.g. years. At the higher dose of 30 mg kg−1 there Aisner et al. 1990), and adenocarcinoma of is a threefold increase in the development of the breast and endometrium in humans. nodules. In addition, levels of serum growth hormone and insulin increase in a dose‐ Contraindications dependent fashion, while levels of triiodothy- MA should not be used in dogs with evidence ronine, cortisol, and 17 β‐estradiol decrease of any disease of the reproductive organs, (Frank et al. 1979). prior to first estrus, in pregnant dogs, or in dogs with mammary tumors (Schering‐ Parrots Plough 2003). MPA has been used in the treatment of MA should not be used for treatment of feather‐picking in parrots at a dose of behavior problems in intact females. 0.07 mg g−1 IM as a single dose. Side effects reported include increased appetite, polydip- Adverse Drug Interactions sia, polyuria, and sedation (Galvin 1983; Concurrent administration of MA with Ryan 1985). dofetilide, an antiarrhythmic drug, causes decreased dofetilide elimination and II. Megestrol Acetate increased dofetilide plasma concentrations. This can result in ventricular arrhythmias Chemical Compound: 17 α ‐(acetyloxy)‐6‐ (Yamareudeewong et al. 2003). methylpregna‐4,6‐diene‐3,20‐dione DEA Classification: Not a controlled Side Effects substance Side effects reported in cats include mam- −1 Preparations: Generally available as 40 mg ml mary hyperplasia, induction of lactation, oral suspension and as 5‐, 20‐, and 40‐mg mammary carcinoma, pyometra, diabetes tablets. mellitus, polyphagia with weight gain, 274 Hormones

adrenocortical atrophy, and personality Effects Documented in Nonhuman Animals changes including listlessness and depres- Cats sion (e.g. Aspinall and Turner 1972; Long In a clinical trial of the treatment of urine 1972; Wilkins 1972; Baker 1973; Chesney marking and spraying using megestrol 1976; Nelson and Kelly 1976; Oen 1977; acetate, 13 cats were treated as follows: −1 Nimmo‐Wilkie 1979; Hart 1980; Chastain 5 mg cat were given daily PO for 7–10 days. et al. 1981; Gosselin et al. 1981; Kwochka and If improvement occurred within seven days, Short 1984; Tomlinson et al. 1984; Middleton the frequency of dosing was decreased to 1986; Middleton et al. 1987). every other day for two weeks. If this dose MA given at 0.25 mg lb−1 for 32 days during continued to control the problem, the fre- the second half of pregnancy in the bitch quency of dosing was further reduced to results in decreased litter size and increased twice a week for one month. Frequency of mortality in the puppies. No adverse events dosing was then further reduced to once a are reported when it is given during the week for two to six months. If the behavior first half of pregnancy. Dogs treated with recurred when frequency of dosing was 2 mg kg−1 day−1 for 64 days exhibit signs decreased, the client was instructed to return of early cystic endometritis. When MA to the previously effective frequency of was administered orally at 0.5 mg kg−1 for dosing (Hart 1980). five months, mild uterine hyperplasia has This treatment resulted in 36% of the been observed, which subsequently regresses. patients showing substantial improvement. MA at 0.1–0.25 mg kg−1 day−1 for 36 months Both males and cats from single‐cat homes also results in cystic endometrial hyperplasia, responded better than did females or cats which likewise reverses if dosing is from multicat homes, with males from single‐ discontinued (Schering‐Plough 2003). cat homes having the best response. Some In a two‐year chronic toxicity/carcino- other cats that were initially treated with MPA genicity study in rats, there was evidence of subsequently responded to treatment with decreased lymphocyte counts, increased MA. Over 30% of the cats exhibited increased neutrophil counts, and increased frequency appetite, while almost 30% of the cats became of respiratory infections (Bristol‐Myers depressed. In addition, one female developed Squibb 2000). mammary gland enlargement that regressed MA induced both benign and malignant when treatment was discontinued (Hart mammary tumors in female beagles given 1980). In the author’s experience, this regimen 0.01, 0.1, or 0.25 mg kg−1 day−1 for up to seven almost invariably produces decreased activity. years (Nelson et al. 1973; Owen and Briggs Fewer side effects are achieved with a faster 1976). Female monkeys did not develop mam- regimen of decreasing frequency for cats that mary tumors. Male offspring of females treated are responding to treatment. with MA during pregnancy exhibit decreased Romatowski (1989) recommends, for −1 −1 fertility. Additionally, female rats treated with behavioral abnormalities, 2 mg kg day for −1 −1 MA had a reduction in the number of live five days, followed by 1 mg kg day for five −1 −1 births and fetal weight and feminization of days, and then 0.5 mg kg day for five days. male offspring (Bristol‐Myers Squibb 2000). Of 244 cats that were given MA to delay estrus, five owners reported that their cats Overdose exhibited increased aggression while 34 Single doses of up to 5 g kg−1 in mice and owners reported that their cats were less 1600 mg day−1 in humans have not produced aggressive (Oen 1977). Additionally, two toxic effects. There is no specific treatment. nonaggressive cats have been reported to In case of large overdose, monitor the patient become aggressive when placed on MA and provide supportive therapy. (Baker 1973). References 275

Cats treated with MA at 5 mg cat−1 day−1 2003). When given at a dose of 2.2 mg kg−1 for for eight days exhibit increased fasting blood eight days during proestrus, it suppresses glucose concentration and decreased glucose estrus in 92% of bitches (Burke and Reynolds excretion rate (Middleton and Watson 1985). 1975). Cats treated with MA at a dose of 5 mg cat−1 day−1 Pemberton (1980) has recommended for two weeks, and then 5 mg cat−1 three times doses as high as 15 mg kg−1 daily in dogs. This a week for a total of one year of treatment, is substantially higher than doses the author have been shown to produce a progressive has used. When treating dogs with MA, deterioration in glucose tolerance, an increase the author has typically used the following in mean fasting plasma glucose concentration, schedule: 2.0 mg kg−1 q24h for 14 days, and a decrease in mean plasma glucose clear- followed by 1.0 mg kg−1 q24h for 14 days, fol- ance rate. There was also a progressive decrease lowed by 0.5 mg kg−1 q24h for 14 days, then in resting plasma cortisol concentrations and discontinue. If the problem resumes when cortisol concentrations subsequent to adminis- the dose is decreased, go back up to the last tration of ACTH. The glucose intolerance dose that worked for two to three weeks, resolved three months after discontinuation of then try reducing again. Even on this sched- treatment (Peterson 1987). ule, decreased activity, polyphagia, and poly- Cats given 1 mg kg−1 of MA every other day dypsia may be observed during the initial for three weeks did not exhibit changes in two weeks of treatment. plasma glucose or insulin concentrations in response to intravenous glucose administra- Parrots tion (Mansfield et al. 1986). MA has been used in the treatment of feather‐picking at a dose of 1.25 mg PO daily Dogs for 7–10 days, then twice weekly (Petrak MA is used to postpone estrus and disrupt 1969; Galvin 1983; Ryan 1985). false pregnancy in the dog (Schering‐Plough

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Combinations Leticia Mattos de Souza Dantas1, Sharon L. Crowell‐Davis1, and Niwako Ogata2

1 University of Georgia, Athens, GA, USA 2 Purdue University, West Lafayette, IN, USA

Introduction contraindications and should be avoided). Caution is always warranted when data are In the first edition of this book, the focus lacking in a given species. of this chapter was drug augmentation A common example of a synergistic effect (in (adding a second agent when a patient’s which two drugs will, together, be more effec- response to the current medication was tive than either alone) is the augmentation of a subpar). In the second edition of Veterinary serotonin reuptake inhibitor with a serotonin Psychopharmacology, this chapter has been agonist. These drugs work together to facilitate expanded to address common questions serotonin activity. Other drug combinations and concerns when it comes to using have a complementary effect. A common psychoactive drugs. example is treatment of a patient with chronic anxiety that peaks under certain conditions or have specific phobias. In these cases, daily Overview of Drug administration of a maintenance anti‐anxiety Augmentation medication (such as selective serotonin reuptake inhibitor or other antidepressant) can be When a patient fails to respond to a given supplemented with context specific adminis- drug at a given dose, the clinician has three tration of a fast‐acting drug such as a benzodi- main options. They can: (i) increase the dose azepine or an alpha‐2 agonist. of the drug currently being given if the A complementary effect can also be maximum dose has not been reached and the achieved by combining drugs with different patient is not exhibiting any undesirable speeds of onset and duration of action. For side‐effects; (ii) change drugs; or (iii) example, patients are sometimes presented augment or complement the first drug with a with severe separation anxiety disorder or second (or more) drug(s). There are not set other problems that lead to destruction and protocols or controlled clinical studies in excessive vocalization, to the point of clients veterinary clinical behavioral medicine, facing eviction or the animal being under the which leaves the clinician with a process of risk of euthanasia. In this situation, waiting trial and error to endure. However, some for a slow onset of action medication to combinations are supported by studies in take effect (which is the case with most human medicine (and others might have antidepressants used in veterinary medicine)

is not the best option. Short‐acting drugs that treatment of urine spraying in a cat (Seibert target panic signs may be chosen in the early 2004a, 2004b). This logic is also used in stages of treatment until antidepressants and human anxiety disorders (e.g. Goddard et al. behavior therapy have time to take effect. 2001; Stahl 2002). Ogata and Dodman (2011) reported a clinical case series of combination administration with either SSRI, TCA, or Potentially Beneficial azapirone with oral administration of an Combinations alpha‐2 agonist (clonidine) to manage fear‐ based behavior problems in dogs such as In cases of serotonin dysregulation leading to noise phobias, separation anxiety disorder, or anxiety and behavioral changes, augmenta- fear/territorial aggression. The owners’ tion of a serotonin reuptake inhibitor with an feedback to adding clonidine was positive in azapirone (such as buspirone) or serotonin 18 out of 22 cases in this study. Combinations antagonist and reuptake inhibitor (SARI) of SSRIs, TCAs, benzodiazepines, azapirones, (such as trazodone) may be beneficial (Bakish or antipsychotics and trazodone to treat 1991; Gruen and Sherman 2008). For exam- canine anxiety disorders (n = 56) were also ple, human patients with major depression reported by Gruen and Sherman (2008) who have been unresponsive to fluoxetine (at where 34 out of 56 clients reported that the least 30 mg daily) or citalopram (at least combination treatment helped to improve 40 mg daily) have shown better improvement their dog’s anxiety. when they received buspirone augmentation Another example of drug combination of 20–60 mg day−1 vs. placebo. No serious introduced in veterinary clinical behavioral events were observed (Appelberg et al. 2001). medicine is treatment of canine compulsive Likewise, patients with obsessive‐compulsive disorders where fluoxetine and the NMDA disorders may respond positively when receptor antagonist, memantine, were used fluoxetine treatment is supplemented with together (Maurer and Dodman 2007; buspirone (e.g. Jenike et al. 1991). The com- Schneider et al. 2009). Although the case bination of fluoxetine, a selective serotonin number of these reports was small (total of reuptake inhibitor (SSRI), and desipramine, a five cases), the author concluded that tricyclic antidepressant (TCA), results in combination of the two medications caused more rapid improvement in patients with higher improvement when it was compared major depression than treatment with desip- with monotherapy of fluoxetine. ramine alone, presumably because of more Gabapentin and pregabalin have been rapid down‐regulation of ß‐adrenergic shown to be effective in neuropathic pain receptors (Baron et al. 1988; Nelson et al. conditions, and are widely used off‐label to 1991). treat other conditions such as anxiety and Even though there are numerous clinical insomnia in humans (Smith et al. 2016). examples published to support a working Accordingly, they have been increasingly knowledge to prescribers, the level of used in clinical behavioral medicine as well. scientific evidence is still weak. The examples In a (human) randomized double‐blind, pla- are primarily combining slow onset of action cebo‐controlled study, the adjunctive effect medications (such as SSRIs or TCAs) with of pregabalin in refractory generalized anxi- fast onset of action medications (such as ety patients was shown. In this study, patients benzodiazepines, a SARI, or an alpha‐2 were randomized into two groups, receiving agonist). The combination of clomipramine either pregabalin adjunctive (n = 180) or pla- and alprazolam has been shown to be cebo (n = 176) adjunctive for eight weeks in beneficial in the treatment of storm phobia addition to their original monotherapy with in dogs (Crowell‐Davis et al. 2003). Fluoxetine an SSRI (escitalopram or paroxetine) or a and alprazolam have been combined in the serotonin norepinephrine reuptake inhibitor Avre Itrcin and Contraindication 283

(SNRI) (venlafaxine‐XR). The result was that mechanism for serotonin syndrome is not 50% of the patients who failed to respond fully understood, but most investigators adequately to SSRI or SNRI monotherapy believe the primary mechanism is excess 5‐ responded better with the addition of prega- HT1A‐receptor stimulation (Brown et al. balin. The response rate was significantly dif- 1996; Martin 1996). ferent from those with placebo but adverse Signs and symptoms can be grossly grouped effects were the same between the groups, into mental changes, neuromuscular changes, and none of the serious adverse events were and autonomic changes. In humans, the considered to be related to the study drug problem is usually mild and resolves in (Rickels et al. 2012). Since there is so far no 24–72 hours, but it can cause death literature available about combination treat- (Beaumont 1973; Mendis et al. 1981; Tackley ments in veterinary clinical behavioral medi- and Tregaskis 1987; Brennan et al. 1988; Kline cine with either gabapentin or pregabalin, a et al. 1989; Neuvonen et al. 1993; Kuisma prudent approach is recommended. 1995). The most serious cases result when an SSRI has been taken with (i) an MAO inhibitor, which decreases serotonin metabolism, Adverse Interactions (ii) a serotonin receptor agonist, such as bus- and Contraindications pirone, (iii) a tricyclic antidepressant, which is a non‐selective serotonin reuptake inhibi- In addition to potential issues of producing tor, or (iv) meperidine, tryptophan, or dex- overdoses by giving two drugs that either act tromethorphan. Specific changes in mental the same, or are metabolized by the same status symptoms reported in humans include mechanisms (and thus compete with each confusion, agitation, coma, hypomania, and other), combining drugs can present the risk anxiety. Motor abnormalities include myo- of producing adverse consequences specific clonus, hyperreflexia, muscle rigidity, rest- to the way particular drugs interact with each lessness, tremor, ataxia, shivering, nystagmus, other. and seizures. Cardiovascular changes include Serotonin syndrome has been reported in hypertension, hypotension, and sinus tachy- monkeys, rats, rabbits, dogs, and humans cardia. Gastrointestinal signs and symptoms (e.g. Oates and Sjoerdsma 1960; Hess and include nausea, diarrhea, abdominal pain, Doepfner 1961; Curzon et al. 1963; Grahame‐ and excessive salivation. Other signs include Smith 1971; Sinclair 1973; Brown et al. 1996; diaphoresis, hyperpyrexia, tachypnea, and Martin 1996). This is a consequence of tak- unreactive pupils (Brown et al. 1996). Some of ing excessive quantities of medications that these signs can be similar to the most com- increase serotonin levels and/or taking cer- mon reported side effects of antidepressants. tain medications that interact incompatibly Due to this, the authors warrant caution when in regards to serotonin metabolism. There is side effects are reported in patients. Serotonin no diagnostic test for serotonin syndrome, syndrome should be considered and increas- and diagnosis is based on a history of medi- ing the dose (to “see if the patient will get over cation with drugs that may interact incom- side effects”) is risky and not recommended. patibly or a history of medication with Treatment and management include dis- excessive quantities of drugs that facilitate continuation of all serotonergic medications serotonin activity, combined with presenting and supportive treatment. Benzodiazepines symptoms and the exclusion of other medical such as diazepam or lorazepam may be given conditions. The potential for serotonin syn- for myoclonus and the hyperthermia result- drome is one reason that it is important to ing from myoclonus. However, clonazepam get a complete listing of all herbal medica- is not effective with serotonin syndrome tions being given to a patient, as some, such (Nierenberg and Semprebon 1993; Skop et al. as St. John’s Wort, act on serotonin. The 1994; Brown and Skop 1996). In severe cases, 284 Combinations

5‐HT antagonists such as cyproheptadine, disorder with 23 studies of 2435 samples, methysergide, or propranolol can be given noradrenergic and specific serotonergic anti- (Goldberg and Huk 1992; Brown et al. 1996; depressants (NsSSA) or TCA or SSRIs were Martin 1996). associated with more adverse events such as Gwaltney‐Brant et al. (2000) reported on tremor, sweating, or weight gain. Although it 21 cases of dogs that had been exposed was sparse data, the authors suggested this through accidental poisoning to the nutri- augmentation should be chosen with caution tional supplement 5‐Hydroxytryptophan, (Galling et al. 2015). which is the immediate precursor to seroto- P‐glycoprotein (P‐gp) plays one of the nin. The dose consumed ranged from 2.5 to important roles in the pharmacokinetics and 573 mg kg−1. The dog that had been exposed clinical effects (Akamine et al. 2012). Since to 2.5 mg kg−1 received no treatment and fluoxetine and clomipramine are known to exhibited no symptoms. One dog, which had inhibit several drug‐metabolizing enzymes consumed a dose of 222 mg kg−1, had emesis as well as P‐gp in humans, a study was done induced within 30 minutes. This dog exhib- to specifically assess the risk of drug interac- ited no symptoms. The lowest dose at which tions for fluoxetine, clomipramine, and sele- signs developed was 23.6 mg kg−1. The lowest giline in dogs by assessing canine P‐gp. Its dose at which death occurred was result showed that fluoxetine and clomi- 128 mg kg−1. The time of onset of clinical pramine are weak inhibitors of canine P‐gp signs varied from 10 minutes to 4 hours after and they can cause low risk of drug‐drug ingestion. Nineteen of the dogs developed interactions, while selegiline did not inhibit clinical toxicosis. Of these, three died. Mental P‐gp. Therefore, it is unlikely to cause drug‐ status changes included depression, coma, drug interactions (Schrickx and Fink‐ and disorientation. Sensorimotor changes Gremmels 2014). Underlying mechanisms included tremors, hyperesthesia, ataxia, impacting potential interaction with psycho- paresis, hyperreflexia, and weakness. tropic drugs have not been fully understood Respiratory and cardiovascular signs in both human and veterinary medicines and included tachycardia, cyanosis, and dyspnea. further information is needed. Gastrointestinal signs included vomiting, The combination of a TCA and an alpha‐2 diarrhea, abdominal pain, flatulence, and agonist might also raise concerns. According bloat. Other signs included mydriasis, tran- to the product information of clonidine sient blindness, hypersalivation, hyperther- (Catapres®), if a patient who is receiving mia, hypothermia, and vocalization. clonidine is also taking a TCA, the Treatment included decontamination by hypotensive effect of clonidine may be inducing emesis, anticonvulsants, ther- reduced, which might warrant an increase in moregulation, and fluid therapy. The 16 dogs the clonidine dose. In the toxicology study that exhibited clinical toxicosis and recov- done in rats, concomitant administration of ered all did so within 36 hours of beginning amitriptyline and clonidine enhances the treatment. Clinical blindness, if present, was manifestation of corneal lesions (Boehringer the last sign to resolve. Ingelheim International GmbH 2016). Because of their long half‐lives, serotonin The recent interest in using alpha‐2 ago- syndrome has occurred five to six weeks or nists in clinical behavioral medicine has later after discontinuation of fluoxetine, raised questions such as the possibility of paroxetine, sertraline or irreversible MAOIs associating two drugs from this group (e.g. (Pato et al. 1991; Coplan and Gorman 1993; clonidine and dexmedetomidine). The Martin 1996). authors caution that this type of combination According to a meta‐analysis in humans is not commonly suggested in the human lit- regarding safety and tolerability of antidepres- erature and there are no studies or publica- sant co‐treatment in acute major depressive tions to support it in veterinary medicine. Interaction Ta Cn Affec Dosin 285

Hypotensive effects (among others) are likely four‐week taper is advised after longer‐term and a ceiling effect for the sedation should be treatment (Cleare et al. 2015). considered (Kuusela et al. 2000; Messenger et al. 2016). See details in Chapter 11, Cytochrome P450 (CYP) Sympatholytic Agents. The cytochrome P450 enzyme system is crit- Changing and Weaning ical in hormone biosynthesis and catabolism, Patients off Medications the biotransformation of toxins and the metabolism of a variety of drugs (He et al. It is recommended that at least 14 days 2001). While the specific distribution and should be taken between discontinuation of quantities of the various specific enzymes, selegiline (Anipryl®) and initiation of treat- including mutant variations, have been ment with a TCA or a SSRI, while a mini- extensively studied in humans, less research mum of a five‐week washout interval is has been conducted in the various species recommended for the discontinuation of treated by veterinarians (e.g. von Moltke fluoxetine due to its long half‐life and the et al. 1995). While there are many similari- long half‐life of its metabolite (norfluoxe- ties, there are also differences which, in many tine), and the initiation of any drug that may cases, have not been quantitatively identi- adversely interact with fluoxetine and nor- fied. See Tables 19.1–19.3 for a summary of fluoxetine (Zoetis 2013). relevant information. Evidence‐based data are lacking in veterinary medicine when it comes to stopping and switching guidelines of each medication. Interactions That Can In people, it is advised to avoid abruptly stop- Affect Dosing ping administration of SSRIs, TCAs, and MAOIs after more than a few weeks of Some drugs interact in a way that can affect treatment due to possible discontinuation dosing schedules or specific drug selections reactions. Usually a minimum period of a within a class when it is desired to use two or

Table 19.1 Inhibitors and inducers of CYP 450 enzymes for various BZD substrates.

CYP 450 enzyme BZD substrate Inhibitor Inducer

CYP 2C19 Diazepam Fluvoxamine Dexamethazone Omeprazole Phenobarbital Oxcarbazepine Phenytoin St. John’s wort CYP 3A4 Clonazepam Azole anti‐fungals (e.g. ketoconazole) Carbamazepine

Diazepam Cimetidine Phenobarbital Midazolam Clarithromycin Phenytoin Diltiazem St. John’s wort Erythromycin Fluoxetine Nefazodone Sertraline UGT Lorazepam Valproate Carbamazepine Oxazepam Phenobarbital Phenytoin

Source: Adapted from Riss et al. (2008). 286 Combinations

Table 19.2 Behavioral medications that are inhibitors or inducers of the CYP enzyme listed; inducers slow the rate at which the substrate medication is available, and lower the amount available; inhibitors increase the rate at which the substrate medication is available and increase the amount available.

P‐450 enzyme Substrate Inhibitor Inducer

CYP 1A2 TCAs Fluvoxamine Phenobarbital Fluvoxamine Fluoxetine Carbamazepine Mirtazapine Paroxetine Phenytoin Duloxetine Sertraline Some TCAs CYP 2A6 CYP 2B6 2 CYP C9/ CYP 2C9/10 Sertraline Fluvoxamine Carbamazepine Fluoxetine Fluoxetine Amitriptyline Sertraline 2C19/CYP2C19 Citalopram Fluvoxamine Carbamazepine Sertaline Fluoxetine Clomipramine Sertraline Imipramine CYP 2D6 Fluoxetine Duloxetine Fluvoxamine Fluoxetine Citalopram Paroxetine Duloxetine Norfluxietine Paroxetine Citalopram Venlafaxine Sertaline Trazadone Some TCAs Nefazodone TCAs CYP 2E1 CYP 3A4 Nefazodone Fluvoxamine Carbamazepine Sertaline Norfluoxetine Venlafaxine TCAs Trazodone Nefazadone TCAs

Source: Table from Overall (2013).

more classes of drugs. For example, in adult detailed interactions remain to be studied in male humans, fluoxetine impairs the clear- the veterinary population. For this reason, ance of alprazolam by microsomal oxidation, we must proceed cautiously with combina- but does not affect the rate of clearance of tions while beginning by extrapolating from clonazepam by nitroreduction. Thus, in adult human clinical trial data. human males, fluoxetine can be administered with clonazepam without affecting clonazepam’s efficacy, while co‐administra- Algorithms: Possible Future tion of fluoxetine and alprazolam will result Direction in a significantly prolonged half‐life of alprazolam (Lasher et al. 1991; Greenblatt et al. An algorithm is “a computational procedure 1992). Similarly, fluvoxamine results in a sig- whose application yields a solution to an nificantly longer half‐life for alprazolam associated class of problems” (Hartley 1999). (Fleishaker and Hulst 1994). As with many Put simply, they are a set of decision‐making other aspects of the application of psychop- protocols for patient management at different harmacology to veterinary science, these stages of treatment, depending upon response Algorithms: Possibl Futur e Directi 287

Table 19.3 Commonly used medications that could be given concomitantly with behavioral medication and that are inducers or inhibitors of the CYP enzyme listed; inducers slow the rate at which the substrate medication is available, and lower the amount available; inhibitors increase the rate at which the substrate medication is available and increase the amount available.

P‐450 enzyme Inhibitor Inducer

CYP 1A2 Fluoroquinolones Charcoal‐broiled beef Cruciferous vegetables Marijuana smoke Omeprazole Phenobarbital Phenytoin CYP 2A6 Tranylcypromine Barbiturates CYP 2B6 Phenobarbital CYP 2C9/CYP D‐Propozyphene, Disulfiram, Rifampin 2C9/10 Fluconazole, Sulfaphenazole Phenobarbital Phenytoin CYP 2C19 Omeprazole Rifamoin Phenytoin CYP 2D6 CYP 2E1 Disulfram Ethanol CYP 3A4 Fluconazole Barbiturates Ketoconazole Dexamethasone/Chronic Glucocorticoids Cimetidine Clarithromycin, Erythromycin Phenytoin (Macrolides, in general) St. John’s wort (hyperforin is the compound that Propofol is the inducer) Flucloxicillin

Source: Table from Overall (2013).

to given treatments. Algorithms for clinical data. However, the development of such decision‐making have become common in algorithms will provide a basis for developing psychiatric medicine. They also have a place in research that tests their veracity. In the long veterinary behavioral medicine, although the run, this will result in refinement, modifica- same disadvantages, as well as advantages, tion, and ultimately improvement of clinical that apply in human psychiatry, apply here. algorithms. Even when algorithms have Algorithms that are based on extensive research become well developed and well tested, they literature, particularly research that focuses on necessarily reduce a complicated medical success or failure of treatments that are initi- situation into a simple decision‐making ated after an initial non‐response, can be useful process. In so doing, they may present an in guiding clinicians into decision‐making pro- oversimplified view, failing to take into con- cesses that are based on evidence. Unfortunately, sideration all the complicating medical, man- the amount of research on success rates of vari- agement, and experiential factors that can ous primary treatments for veterinary patients, apply in a given case. Thus, they should be much less second‐tier treatments, is still small taken as guidelines, rather than irrefutable (Stein and Jobson 1996). laws. It is up to the clinician to consider all At this time, algorithms in veterinary clini- relevant information in a given case before cal behavioral medicine must be based on making a decision as to the best course of clinical experience of specialists, rather than treatment (Stein and Jobson 1996). 288 Combinations

Conclusion not recommend combination treatment as the first line of treatment because the risk of Combining medications can be useful in adverse effects have not been fully evaluated particular situations and for patients that do (Mojtabai and Olfson 2010; Rush et al. not respond to treatment with any one 2011). Ongoing research in the use of psy- drug. However, there are potential risks choactive medications for the treatment of to this approach, including competition mental health and behavior problems between drugs for metabolic pathways and in nonhuman animals will continue to pro- direct, adverse interactions between drugs. vide a stronger knowledge base for these Human medicine treatment guidelines do decisions.

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Index

a affective (mood) disorders acepromazine 202, 204–206, 218 amines and 8–9, 35, 36, 173 buspirone and 134 bipolar 147, 148, 149, 173 acetylcholine 29–32 SSRIs 27 acetylcholinesterase (ACHE) 29 affiliative behaviors 48, 68 inhibitors 31, 177, 179 African green monkeys, benzodiazepines acral lick dermatitis (ALD) 106, 111, 113, 72, 88 121, 211, 241, 262–263 aggression action (general principles) 3–4 antipsychotics amino acid neurotransmitters 11 as adverse effect 205–206 addiction see dependency use 203, 208 α‐1‐adrenoceptors/alpha‐1‐adrenergic benzodiazepines 68 receptors 36, 157 carbamazepine 149 antagonists 157–158, 159 dominance aggression see dominance antidepressant affinities for 36 aggression tricyclic 232 progestins 271, 273, 274 α‐2‐adrenoceptors/alpha‐2‐adrenergic serotonergic agents (miscellaneous) receptors 32–33, 158, 188 129, 132, 133, 141 agonists 32, 33, 158, 159 serotonin and 25 dexmedetomidine as 34, 158 SSRIs 104, 106, 110, 112–113, selegiline combined with 188 116, 121 tricyclic antidepressant combined sympatholytics 161 with 284 tricyclic antidepressants 235, antagonists 158 239, 242 antidepressant affinities for 36 agonists (general principles) 3–4 selegiline and 188 inverse 3–4 β‐adrenoceptors/beta‐adrenergic partial 3–4, 5 receptors 157 algorithms, decision‐making 286–287 antagonists/blockers 157, 158, alopecia, psychogenic (hair pulling) 159, 165 111, 133, 135, 239, 263 norepinephrine and 32 alpacas, detomidine 163 tricyclic antidepressants and 231 alpha adrenoceptors see adrenoceptors

Chapter No.: 1 Title Name: bindex.indd Comp. by: R. RAMESH Date: 27 Dec 2018 Time: 09:34:02 PM Stage: Proof WorkFlow: Page Number: 291 292 Index

alprazolam 71, 71–73 newer 36 clomipramine and, storm phobia NMDA receptor antagonists as 171–172, 242, 282 173, 174, 175, 177 fluoxetine and 282, 286 receptor affinities of various types 36 Alzheimer’s disease 31, 32 second generation (atypical) 25, 39, MAO‐B inhibitors 187, 189, 190 202, 207 NMDA receptor antagonists 176, 177, 179 SSRI see selective serotonin reuptake amantadine 172, 173, 175–176 inhibitors amines (monamines), biogenic 8–9, 21–43 tricyclic see tricyclic antidepressants affective/mood disorders and 8–9, 35, antiepileptics see anticonvulsants 36, 173 antipsychotics (neuroleptics) 39–40, members of group 21 201–215 transporters 6, 8 atypical 39, 202, 207–208 amino acids (neurotransmitters) 11–19 general aspects/overview excitatory see excitatory amino acids action 201 aminoglutethimide interaction with clinical guidelines 204 medroxyprogesterone acetate 272 contraindications/side‐effects effects/ α‐amino‐3‐hydroxy‐5‐methyl‐4‐ adverse events/adverse drug isoxazolepropionic acid (AMPA) interactions 203 receptors AMPA receptors important information for amitriptyline 35, 36, 105, 231, 232, 233, owners 213 233–236 indications 202–203 clonidine with 284 overdose 203–204 AMPA receptors 13, 171, 174 pharmacokinetics 203 amphetamine 219–221 specific medications 204–213 selegiline metabolized to 41, 181, 187, antitussive, dextromethorphan as 174 191, 192 anxiety (and anxiety disorders) analgesic (pain‐relieving) effects antipsychotics 202 dexmedetomidine 158 benzodiazepines 67–68 gabapentin 150–151, 161 alprazolam 72, 73, 282 ketamine 14 chlordiazepoxide 74 NMDA receptor antagonists 172, clonazepam 79 175, 176 clorazepate 80 opioids 46, 264 diazepam 82, 85, 86 sympatholytics 157, 161, 162, 165 lorazepam 88, 89 animal (other than client’s pet) interacting with oxazepam 90 pet, history‐taking 61 combined drugs 282 Animal Medicinal Drug Use Clarification Act generalized 28, 61, 103, 114, 119, (AMDUCA 1994) 54–55 131, 282 antagonists 3 MAO‐B inhibitors (selegiline) 192 competitive see competitive antagonists separation anxiety 54, 67, 80, 141–142, uncompetitive/noncompetitive, at NMDA 232, 235–236, 240, 242, 249, 269 receptors 14, 47, 172 serotonergic agents (miscellaneous) anticonvulsants (antiepileptics) 147–156 azapirones 129 methylphenidate and 224 buspirone 131, 134 antidepressants 8–9 trazodone 135, 136, 139, 141 first generation 39 SSRIs 103 ketamine as 15 fluoxetine 109, 110, 111, 114 mechanisms of action 9, 36 paroxetine 117, 119 Index 293

sympatholytics 158 progestins 271, 272, 274 clonidine 160 serotonergic agents (miscellaneous) 131, tricyclic antidepressants 231, 232, 233, 134, 139, 141, 142 233–234, 238, 239, 240, 240–241, 249 SSRIs and 103–104, 110 see also panic disorder see also specific disorders apomorphine 69, 203 history‐taking 58–65 arcuate nucleus 38, 44 reward circuitry and 31, 38, 46 aromatic l‐amino acid decarboxylase stereotypic see stereotypic behavior (L‐AADC) 37, 189 benzodiazepines 16–18, 67–102 arthritis combined osteoarthritis (dogs) 172, 175 with trazodone 140 polyarthritis (cats) 151 with tricyclic antidepressants for storm aspartate 11 phobia 242 atomoxetine 221–223 cytochrome P450 enzymes and 71, 72, 81, attention deficit disorder (ADD/ADHD; 82, 91, 285 attention deficit hyperactivity general aspects/overview disorder) actions 67 dogs (hyperkinesis) 217, 218, 219, 221, clinical guidelines 70 223, 224, 226, 227 contraindications/side‐effects/adverse humans 161, 217, 219, 224 events 69 augmentation (drug) 281–282, 284 important information for owners 92 autoreceptors 6 indications 67–69 dopaminergic 38 overdose 69 noradrenergic 32 specific medications 71–92 serotonergic 25–28 Bernese mountain dog, huperzine‐A 180 azaperone 202, 206 beta adrenoceptors see adrenoceptors azapirones 129–134 bipolar disorder 147, 148, 149, 173 birds, detomidine 163 b see also owl; psittacine birds basal ganglia 38, 123, 201, 202 blood pressure see hypertension; hypotension basket muzzle 63 BNDF (brain‐derived neurotrophic factor) 15 beagle dogs Borna disease virus 173 benzodiazepines 75, 85 botulinum toxin 29 CNS stimulants 220, 220–221 brain MAO‐B inhibitors (selegiline) 191 acetylcholine/cholinergic pathways 29–32 NMDA receptor antagonists 174, 176, dopamine and 37–38, 40 177–178, 179 norepinephrine/noradrenergic pathways opioids 257 and 30, 32–33 progestins 273, 274 serotonin and 22–23, 25, 27–28 SSRIs 107, 123 see also central nervous system tricyclic antidepressants 240, 248 brain‐derived neurotrophic factor behavior (BDNF) 15 antipsychotic side/adverse effects on 203 breast milk see lactating/nursing females compulsive see compulsive disorders bull terrier 152, 221, 241, 261 conflict‐induced see conflict behavior bulldog, English, sleep‐disordered disorders (and therapeutic breathing 138 interventions) 8, 53–54, 58, 62 buprenorphine 46 combined drugs 282, 286 buspirone 129–134 duration of treatment 63–64 butyrophenones 202, 206–207, 209–210 294 Index

c gabapentin 151 calcium ion (Ca2+), excitatory amino acids imipramine 246 and 12 central nervous system (CNS) 5–8 calcium ion channels 45 acetylcholine 30, 31 NMDA receptors and 171 dopamine and 22, 37 voltage‐gated 147, 148, 152 opioids and 44 cancer risk see tumor and cancer risk serotonin (5‐HT) and 21–22, 27 canine patients see dogs see also brain; spinal cord car (motion) sickness 132, 204 central nervous system (CNS) carbamazepine 147–148, 149–150 stimulants 217–229 combined use 136 clinical example 227 carcinogenicity see tumor and cancer risk general aspects/overview cardiovascular/cardiac effects action 217 antipsychotics 204–205 clinical guidelines 218–219 CNS stimulants 222 contraindications/side‐effects/adverse serotonergic drugs (miscellaneous) 136 effects/adverse drug interactions 217 SSRIs 36 important information for owners 226 sympatholytics 159 indications 217 tricyclic antidepressants 234, 238, overdose 217–218 239–240, 246 specific medications 219–226 cat(s) (feline patients) changing medications 285 anticonvulsants 148, 149, 149–150, 150, cheese effect with MAO inhibitors 187 151, 153 children see pediatric patients antipsychotics 204, 205, 206, chlordiazepoxide 71, 73–76, 78 210, 212 chlorpromazine 202, 206–207, 210, 212, 218 benzodiazepines 69, 71, 75, 77, 80, 84–86, cholinergic neurons/ 87, 88, 91 neurotransmission 29–32 CNS stimulants 221, 226 muscarinic see muscarinic cholinergic MAO‐B inhibitors 189, 190 receptors medicating 57 choosing a drug 56–57 NMDA receptor antagonists 176 cisapride and fluvoxamine 115 opioid antagonists 258, 261 citalopram 105, 106–107 oxytocin 269–270, 270 S‐enantiomer of (escitalopram) 122–124 progestins 271, 272, 273, 274–275 Clomicalm (clomipramine) 54, 232, 236, serotonergic agents (miscellaneous) 130, 240, 249 131, 132–133, 135, 138–139 clomipramine 27, 53, 80, 105, 232, 233, SSRIs 105, 110–112, 119 236–243 sympatholytics 158, 159, 160, 161, 163, alprazolam and, storm phobia 165, 166 242, 282 tricyclic antidepressants 233, 234, 235, Clomicalm 54, 232, 236, 240, 249 237, 238–239, 247 fluoxetine and 284 doses 233 humans 177 urine spraying 84–85, 111–112, 132–133, P‐glycoprotein and 284 238–239, 271, 272, 274, 282 parrots 134 see also cougar; leopard; oncilla US prescribing law 54 catecholamines 21, 22, 32, 37, 185 clonazepam 71, 76–78, 285 cattle (incl. cows) clonidine 32, 33, 122, 158 clonidine 161 combined with other drugs 161, 284 detomidine 163 discontinuation/withdrawal 159, 161 Index 295 clorazepate 71, 78–80 NMDA receptor antagonists and 149 clozapine 202, 206, 207–208, 212 serotonergic agents (miscellaneous) cocker spaniel, CNS stimulant 227 and 130, 136 cognitive dysfunction syndrome 40, 188–189, SSRIs and 104, 105, 106, 109, 115, 118, 190, 191 120, 123, 124 combinations (drug) 281–292 tricyclic antidepressants and 234, 243, adverse interactions and 245, 248 contraindications 283–285 potentially beneficial 282–283 d see also specific (types of) drugs dachshund competition (performance) animals 58 amphetamine 221 horses see horses memantine 178 competitive antagonists 3, 5 decision‐making algorithms 286–287 at α2‐adrenergic receptors 34 delayed‐release forms see controlled/slow/ at muscarinic receptors 31 extended/delayed release and long‐ at NMDA receptor 15 acting forms complementary effect (drug delta (δ)‐opioid receptors 45, 46, 47 combinations) 281 demoxepam 74 compulsive disorders dependency and addiction combined medications (dogs) 282 benzodiazepines 70, 72–73, 79, 89, 91 NMDA receptor antagonists 178, 179 CNS stimulants 220, 226 SSRIs 104, 115 dopamine role 38 tricyclic antidepressants 235, 237, deprenyl see selegiline 241, 242 depression and amines 8–9 see also obsessive–compulsive disorder see also antidepressants Concerta 223, 225 dermatitis, acral lick (ALD) 106, 111, 113, conflict behavior 121, 211, 241, 262–263 antipsychotics 210 desipramine 35, 36, 232, 233 benzodiazepines 89 fluoxetine and 282 contraindicated combined MAOIs and 243 medications 283–285 desmethylcitalopram 106 controlled/slow/extended/delayed release and desmethylclomipramine 236, 237 long‐acting forms 57–58 desmethyldiazepam see nordiazepam alprazolam 71 desmethyldoxepin 244, 245 methylphenidate 223–224, 225–226 desmethylselegiline 187, 191, 192 cost 55–56 detomidine 158, 161–163 cougar, naltrexone 263 dexmedetomidine 34, 158, 159, 163–165 cough treatment, dextromethorphan 174 US prescribing law 54 cows see cattle dextromethorphan 47, 173–176 cribbing (horses) 47, 174, 175, 258, 260, 261 dogs 178 Cushing’s disease (pituitary‐dependent diabetic neuropathy 153 hyperadrenocorticism) with diazepam 71, 78, 80–86 selegiline 190 buspirone and 134 cytochrome P450 enzymes (CYP) 285, CYP 450 enzymes and 81, 82, 285 286, 287 dibenzoxazepines 202 anticonvulsants and 136, 149 diphenylbutylpiperidines 202 benzodiazepines and 71, 72, 81, 82, diprenorphine 46, 47, 258 91, 285 discontinuation/withdrawal/weaning 285 CNS stimulants and 221, 222 see also specific drugs 296 Index

dogs (canine patients) dopaminergic neurons/neurotransmission acral lick dermatitis (ALD) 106, 111, 113, 37–41 121, 211, 241, 262–263 dose, interactions affecting dosing 285–286 anticonvulsants 148, 149, 151–152, 153 receptor interactions 4–5 antipsychotics 205, 206, 207, 208, 209, doxepin 35, 36, 232, 233, 244–246 209–210, 211, 212, 213 droperidol 202, 212 benzodiazepines 69, 71, 75, 75–76, 76, dynorphin 44, 45 77, 79–80, 81, 82–83, 85–86, 87, 88, dyskinesia, tardive 203, 213 89, 90, 91 CNS stimulants 217, 218–219, 220–221, e 223, 225–226, 227 economic cost 55–56 dominance aggression see dominance elderly/older/geriatric animals, deprenyl/ aggression selegiline 41, 54, 189, 190 history‐taking 59 elderly/older/geriatric human patients 5‐hydroxytryptophan ingestion 23, 285 benzodiazepines 70, 87 MAO‐B inhibitors 186, 187, 188, 189, 190, serotonergic agents (miscellaneous) 130 190–192 SSRIs 90, 106, 107, 108, 115–116, 119, medicating 57 120, 122 NMDA receptor antagonists 172, 173, endorphins 44, 45, 257, 271 174–175, 176, 177–178, 178–179, English bulldog, sleep‐disordered breathing 138 179–180 enkephalins 44, 45 opioid antagonists 257, 258, 259, 261, 262, environment in history‐taking 61 262–263, 265 epilepsy see anticonvulsants; seizures oxytocin and dog–human social bond equine patients see horses 48, 269 escitalopram 122–124 progestins 270, 271, 272, 272–273, 273, etorphine 46 274, 275 exam (behavioral) 63 serotonergic agents (miscellaneous) 130, excitatory amino acids 11, 12–13, 14 132, 134, 135, 136, 137, 138, 139–142 glutamate as 171 SSRIs 105, 106, 107, 107–108, 110–111, ketamine and 14 112–114, 119, 121, 123–124 transporters (EAAT) 12 sympatholytics 158, 159, 160, 162, 163, exocytosis 5, 6 164, 166 extended‐release forms see controlled/slow/ tricyclic antidepressants 233, 234, extended/delayed release and 235, 235–236, 236–237, 238, long‐acting forms 239–242, 244–245, 245, 246, 247, extrapyramidal effects of 248, 249 antipsychotics 39–40, 201, 207, 208, dominance aggression 209, 210, 212, 213 SSRI 104, 112–113 tricyclic antidepressants 235, 241–242 f doses 233 fear responses, intense, antipsychotics donepezil 31, 177 with 202 dopamine (DA) 21, 22, 201–202 feather‐picking 86, 114, 134, 210, 242, 243, antipsychotic effects 201 273, 275 synapse 7 feline patients see cats transporter (DAT) 6, 7, 8, 38 fentanyl 46 dopamine receptors 38–40 fetus see pregnancy D2, antipsychotic blockade/ flumazenil 69, 72, 73, 75, 77, 79, 83, 85, 87, antagonism 39, 40, 201, 202, 207 89, 90, 92 Index 297 fluoxetine 7, 24, 103, 105, 108–114 promazine 211 combined use triazolam 91 alprazolam 282, 286 glutamate (glutamic acid) 11–13, 171 amoxetine 222 receptors 13–14, 47, 148 clomipramine 284 ionotropic 13, 171 clorazepate 80 metabotropic 13–14 desipramine 282 glutamatergic neurons/neurotransmission diazepam 85 16, 173 memantine 282 synapses 11–14 discontinuation 108–109, 110, 285 glutamic acid decarboxylase (GAD) 11, 15 P‐glycoprotein and 237, 284 goat, detomidine 161, 163 Reconcile 54, 103, 108 golden retriever, storm phobia 141, 247 US law 54 Great Dane 167, 244 fluphenazine 40, 202, 208 grooming 62–63 flurazepam 71, 78, 87–88 guinea pigs fluvoxamine 105, 115–119 benzodiazepine (diazepam) 82 food, medicating with 57 MAO‐B inhibitors 185 free radicals and selegiline 186, 189 tricyclic antidepressants 244, 247 g h G‐proteins hair loss/pulling (alopecia), psychogenic 111, adrenergic receptors and 32 133, 135, 239, 263 dopamine receptors and 38 hallucinogens 22, 25 glutamate receptors and, metabotropic 13 haloperidol 202, 206, 208, 209–210 5‐HT receptors and 25 heart see cardiovascular/cardiac effects muscarinic receptors and 31 hematological disorders, acepromazine 205 opioid receptors and 45 hepatic disorders see liver oxytocin and 47, 68 histamine H1 receptors, antidepressant GABA 11 affinities 36, 231, 232 GABAA receptors 16–18, 67 hormones 269–281 GABAergic neurons/neurotransmission 15–18 horses (equines) gabapentin 147, 148, 150–152, 282 anticonvulsants 152, 153 combined use 151, 282 antipsychotics 204, 206, 207, 208, 211 game capture operations 202, 210 benzodiazepines 71, 86 gamma‐aminobutyric acid see GABA CNS stimulants 226 gastrointestinal acidity and competition/performance 58 amphetamine 219 diazepam 86 generalized anxiety disorders 28, 61, 103, doxepin 245–246 114, 119, 131, 282 methylphenidate 226 genotoxicity see mutagenic and/or genotoxic cribbing 47, 174, 175, 258, 260, 261 effects NMDA receptor antagonists 175 geriatric cases see elderly opioid antagonists 258, 259–260, 261, 263 glucuronides serotonin 1A agonist 130–131, 134 atomoxetine 222 SSRIs 105, 119 diazepam 81 sympatholytics 158 lorazepam 90 tricyclic antidepressants 236, 242, 244, nalmefene 259 245, 245–246, 247, 247–248 naloxone 260 doses 233 oxazepam 90 see also stallions 298 Index

hospitalized dogs, stress 142 i humans imipramine 8, 35, 105, 136, 232, 246–248 anticonvulsants 148, 149, 150, 151, 153 doses 233 antipsychotics 201, 203, 205, 207, 209, 210, indoleamine 21, 22 211, 212, 213 insomnia benzodiazepines 72, 74, 76, 79, 82, 86–87, flurazepam 87 87, 88, 90, 91 trazodone 135 CNS stimulants 218, 219, 221, triazolam 91 222, 224 interactions (drug–drug incl. adverse drug abuse by 55 interactions) 283–284 as models of psychiatric disorders 64 antipsychotics 205 NMDA receptor antagonists 171–172, benzodiazepines 77 172, 173, 174, 175, 176, 177, 179 CNS stimulants 217 older see elderly combined medications 283–285 opioid antagonists 258, 259, 260, MAO‐B inhibitors (selegiline) 187 262, 264 P‐glycoprotein and 284 oxytocin and dog–human social bond progestins 272, 273 48, 269 serotonergic agents (miscellaneous) 129, 135 in pet’s environment, history‐taking 61 SSRIs 104–105 serotonergic agents (miscellaneous) 131, sympatholytics 162 131, 136, 137, 138 tricyclic antidepressants 232 SSRIs 106, 107, 108, 110, 115, 116, 117, inverse agonists 3–4 119, 120, 122 ionotropic glutamate receptors 13, 171 sympatholytics 157, 160, 163 iproniazid 8, 21, 35 tricyclic antidepressants 232, 234, 235, 236, 237, 238, 243, 243–244, 244, 245, k 246, 246–247, 248 kainate (KA) 13, 14, 171 young see pediatric patients kappa (κ)‐opioid receptors 45, 47 huperzine‐A 172, 179–180 kidney disorders see renal disease 4‐hydroxyatomoxetine 222 5‐hydroxyindoleindole acetic acid (5‐HIAA) l 104, 237 l‐aromatic amino acid decarboxylase 5‐hydroxytryptophan 23, 284 (L‐AADC) 37, 189 hyperadrenocorticism, pituitary‐dependent, L‐deprenyl see selegiline with selegiline 190 l‐dopa (L‐DOPA) hyperkinesis (attention deficit disorder; ADD; in dopamine synthesis 32, 37 ADHD in dogs) 217, 218, 219, 221, in norepinephrine synthesis 32 223, 224, 226, 227 therapeutic use 175, 187 hypertension lactating/nursing females (and breast milk) clonidine and 158 benzodiazepines 72, 74, 75, 77, 79, 82, 83, trazodone and 137 87, 89, 90 tyramine‐induced 187 CNS stimulants 222, 224 hypotension (as side‐effect) methylphenidate 224 alpha‐2‐agonists 285 serotonergic agents (miscellaneous) 137 antipsychotics 203, 205 SSRIs 107, 109, 116, 118, 121 hypotensive drugs and trazodone 137 tricyclic antidepressants 235 hypothalamus law (US) on prescribing 54–55 arcuate nucleus 38, 44 leopard, naltrexone 263–264 selegiline and 192 [Leu]enkephalin 44, 45 Index 299 liver (hepatic) disorders incl. failure/dysfunction opioid antagonists 262 benzodiazepine‐induced 72, 76, 81, 85, 90 serotonergic agents (miscellaneous) 131 naltrexone‐induced 262 tricyclic antidepressants 234, 235, 236, pre‐existing, SSRI use 108, 115, 116, 120 244, 245, 246, 247, 248 llamas, detomidine 163 midazolam 160, 285 long‐acting forms see controlled/slow/ monkeys extended/delayed release and long‐ amphetamine 221 acting forms benzodiazepines 68, 72, 76, 86, 89 lorazepam 71, 87–89, 285 buspirone 132 LSD 22 fluoxetine 115 monoamine oxidase (MAO) 185 m tricyclic antidepressants effects 246 macaques, rhesus see rhesus monkeys monoamine oxidase (MAO) inhibitors 8 macaws see psittacine birds combined with other drugs 187–188 malignancy see tumor and cancer risk CNS stimulants 222 malnutrition and diazepam 83–84 SARIs (serotonin antagonist and reuptake mammary tumors, progestin‐induced 272, inhibitors) 135–143 273, 274 SSRIs and 108, 120 marmoset tricyclic antidepressants 237, 243, 246 buspirone 134 general aspects/overview diazepam 86 actions 185 maternal issues see lactating/nursing females; indications 186 pregnancy MAO‐A 185, 186, 190, 246 medetomidine 34, 158 MAO‐B 185, 186, 186–193, 246 medicating patients 57–58 specific medications 186–194 medroxyprogesterone acetate (MPA) 271, mood disorders see affective disorders 272–273 morphine 45, 46, 47, 257 megestrol acetate (MA) 271, 272, 273–275 mothers see lactating/nursing females; meloxicam 151, 175 pregnancy memantine and fluoxetine 282 motion sickness 132, 204 mental health (in general) 53, 55 mouse see mice disorders (psychiatric disorders), and their mu (μ)‐opioid receptors 45, 46, 47 treatment 8, 64, 147, 288 muscarinic cholinergic receptors 31, 36 humans as models of 64 antidepressant affinities for 36, 232 meperidine and selegiline 187–188 mutagenic and/or genotoxic effects mesencephalon and dopamine 38 citalopram 107 metabotropic glutamate receptors 13–14 clonazepam 77 [Met]enkephalin 44 clorazepate 79 methamphetamine, selegiline metabolized to muzzle, basket 63 187, 191, 192 N‐methyl‐D‐aspartate see NMDA n methyloestrenolone 270 nalmefene 258–260 methylphenidate 223–226 naloxone 46, 47, 258, 260–264 clinical example 227 pentazocine and 261, 264, 265 mice (mouse) naltrexone 46, 47, 258, 261–264 benzodiazepines 72, 74, 82, 83, 89, 90, narcotics see opioids and opiates 91, 92 neglect 83–84 CNS stimulants 222, 225 neuroleptic malignant syndrome 203–204 NMDA receptor antagonists 174 see also antipsychotics 300 Index

neuron–neuron communication (CNS) 5 chronic use and sensitization 46 neuropathy (peripheral) receptors 43, 44–47 diabetic 153 antagonists 45, 47, 257–267 pain 147, 150, 151, 152, 153, 172, 173, 236 sigma (σ) 45, 174 neuropeptides 43–49 osteoarthritis (dogs) 172, 175 actions 43 other animals interacting with pet, history‐ neurotransmission (general principles) 5–8 taking 61 neurotransmitters see amines; amino acids and overdose specific transmitters alpha‐2 antagonists 159 nicotine 31–32, 38 anticonvulsants (gabapentin) 150 nicotinic receptors 31 antipsychotics 205, 209 agonists 32 benzodiazepines 69, 72, 75, 77, 79, 83, 87, NMDA (N‐methyl‐D‐aspartate) receptors 89, 90, 92 13, 171–183 CNS stimulants 217–218, 220, 222, 225 antagonists/blockers 13, 171–183 gabapentin 150 combined with fluoxetine 282 MAO‐B inhibitors (selegiline) 188 general aspects/overview 171–173 NMDA antagonists 176, 178 specific medications 173–180 opioid antagonists 260, 262, 265 nociceptin 44 progestin 271, 274 noncompetitive/uncompetitive antagonists at serotonergic agents (miscellaneous) 132, NMDA receptors 14, 47, 172 137–138 noradrenaline see norepinephrine SSRIs 105, 107, 110, 112, 116, 119, 123 nordiazepam (desmethyldiazepam) sympatholytics 159 as clorazepate metabolite 78–79, 79 tricyclic antidepressants 232–233, 235, as diazepam metabolite 80, 81 238, 239, 244, 245, 247, 248 norepinephrine (noradrenaline; NE; NA) 21, owl, gabapentin 152 22, 33 oxazepam 70, 71, 89–91, 281 reuptake inhibitor chlordiazepoxide metabolized to 74 selective (NRI) 34, 35 clorazepate metabolized to 78 and serotonin reuptake inhibitor diazepam metabolized 81, 82 (SNRI) 34, 282–283 oxymorphone 257 sympatholytic action on 157 oxytocin 47–48, 269–270 synapse 7 transporter (NAT) 6, 7, 8, 32, 35, 38 p tricyclic antidepressants effects 35, 231, P‐glycoprotein 237, 284 232, 248 P450 enzymes see cytochrome P450 enzymes nortriptyline 35, 36, 232, 233, 234, 248 pain, neuropathic 147, 150, 151, 152, 153, nursing females see lactating females 172, 173, 236 see also analgesic effects o panic disorder/behavior 72, 73, 165 obsessive–compulsive disorder (OCD) 27 Parkinson’s disease 22, 38, 40 glutamate perturbation 173 amantadine 172, 175 NMDA receptor antagonist memantine 176 (memantine) 177 selegiline 186, 187 SSRIs 27, 115, 117, 120 paroxetine 103–104, 105 see also compulsive disorders amoxetine with 222 older cases see elderly parrots see psittacine birds oncilla 134 Paxil CR 117 opioids and opiates 43–47, 257–267 pediatric patients (children) Index 301

anticonvulsants 149, 150 presynaptic terminals 5–6 CNS stimulants 221, 223 norepinephrine and 31–32 SSRIs 116, 120 primates (non‐human or great ape) see sympatholytics 160 monkeys tricyclic antidepressants 247 progesterone 133, 270 Pekinese dog, thioridazine 213 progestins 269, 270–275 pentazocine 46, 258, 264–265 promazine 206, 211 naloxone and 261, 264, 265 pro‐opiomelanocortin (POMC) 44 performance animals see competition propranolol 159, 165–166 phenobarbital 147 protein malnutrition and diazepam 83 clorazepate and 79 psittacine birds (incl. parrots and macaws) propranolol and 166 antipsychotics 209, 210 phenothiazines 202, 204–206, 206–207, benzodiazepines 71 208, 211 CNS stimulants 218 phenylethylamine 40, 187, 191–192 feather‐picking 86, 114, 134, 210, 242, 243, phobias (specific) 67, 103, 165, 281 273, 275 storm phobia 54, 67, 73, 140, 141, 242, opiate antagonists 258, 263 247, 282 opioid antagonists 258, 263 physical dependency see dependency progestins 273, 275 pigs (swine) serotonergic agents (miscellaneous) 134 antipsychotics 206 SSRIs 105, 114–115 benzodiazepines 82, 88 tricyclic antidepressants 242–243, 245 opioid antagonist 261, 263 doses 233 pimozide 202, 206, 211–212 psychiatric/mental disorders (in general) and pituitary‐dependent hyperadrenocorticism their treatment 8, 64, 147, 288 with selegiline 190 psychopharmacology, definition and polar bear, naltrexone 264 derivation of word 53 polyarthritis (cats) 151 psychosis/psychotic states (humans) 201, postsynaptic sites/neurons, serotonin and 25, 207, 209, 213 26, 28 see also schizophrenia potency 4–5 antipsychotics classified by 201, 202 r pregabalin 147, 148, 152–153 rabbits combined use 282–283 benzodiazepine 71, 92 pregnancy (maternal and fetal effects incl. serotonergic agents (miscellaneous) 131, 134 teratogenicity) rats anticonvulsants 148 alpha‐2 agonists 158, 160–161 antiepileptics 148, 152 beta‐blocker 165 benzodiazepines 75, 79, 82, 82–83, 87, benzodiazepines 72, 74, 75, 77, 80, 82, 89, 91 82–83, 83, 86, 88, 89, 90 CNS stimulants 222, 224 CNS stimulants 220, 221, 222, 224–225 MAO‐B inhibitors 188 MAO‐B inhibitors 186, 188 opioid antagonists 262 NMDA receptor antagonists 177, 179 progestins 273, 274 serotonergic agents (miscellaneous) 131, serotonergic agents (miscellaneous) 131, 132, 136 137 SSRIs 107, 108, 109, 110, 115, 116, 118, SSRIs 104, 107, 109–110, 116, 121, 123 120, 122 tricyclic antidepressants 234–235, 238 tricyclic antidepressants 235, 238, 244, prescribing in US 54–55 245, 246, 247 302 Index

reboxetine 7, 34, 35, 36 selegiline (deprenyl/L‐deprenyl) 40–41, 185, receptors (general principles) 3–4 186, 186–192, 284 agonists see agonists discontinuation 188, 285 antagonists see antagonists indications (overview) 186 dose‐dependence of drug interaction prescribing in US 54 with 4–5 US prescribing law 54 occupancy theory 4 self‐mutilation/injury 202, 210, 243, 260, see also autoreceptors 263, 264 Reconcile (fluoxetine) 54, 103, 108 separation anxiety 54, 67, 80, 141–142, 232, renal (kidney) disease/dysfunction/failure 235–236, 240, 242, 249, 269 (pre‐existing) serotonergic agents, miscellaneous 129–146 benzodiazepine 71, 82 serotonergic neurons/neurotransmission SSRIs 106, 108, 116 23–28, 36 reptiles and sertraline 121 serotonin (5‐HT; 5‐hydroxtryptamine) reserpine 8, 21, 140 21–28 reward circuitry and behavior 31, 38, 46 acute vs chronic effects of use 26 rhesus monkeys/macaques reuptake inhibitors benzodiazepines 68, 76, 86, 89 norepinephrine and (SNRIs) 34, 282–283 naltrexone 264 selective see selective serotonin reuptake serotonergic agents (miscellaneous) 132 inhibitors Ritalin‐SR and ‐LR 223, 225 synapse 7 rodents, tricyclic antidepressants 248 synthesis 22–23 see also guinea pigs; mice; rats transporter (SERT) 6, 8, 24, 25, 122, 123, 135, 136 s tryiyclic antidepressants effects 35, 231, schizophrenia and dopamine receptors 39–40 232, 248 sedation, sympatholytics 158, 159, 161, serotonin receptors 25–28, 104 163, 164 1A agonists 129–134 seizures and epilepsy 2A and 2C antagonist and reuptake anticonvulsants 147, 148, 149, 150, 151, 153 inhibitors (SARIs) 135–143, 282 NMDA receptor antagonists 179–180 tricyclic antidepressants and 231 selection of drug 56–57 serotonin syndrome (serotonergic selective serotonin reuptake inhibitors syndrome) 23, 27, 104, 137, 174, (SSRIs) 24, 34, 103–128 187, 283, 284 actions 103 sertraline 103–104, 119–121 mechanism of 27 sexual behavior inhibition in stallions 86 combined use 282, 282–283 shadow‐chasing 241 azapirones (buspirone) 129–130 sheep, detomidine 161, 163 CNS stimulants (with paroxetine or sigma (σ)‐opioid receptors 45, 174 fluoxetine) 222 Sileo (OTM dexmedetomidine) 54, 158, trazodone 140 163, 164 general aspects/overview sleep adverse interactions 104–105 breathing disorder, trazodone 138 clinical guidelines 105 triazolam effects 91 contraindications/side‐effects/adverse sleeplessness see insomnia events/adverse drug interactions 104 slow‐release forms see controlled/slow/ important information for owners 124 extended/delayed release and long‐ indications 103–104 acting forms overdose 105 sodium ions (Na+) and excitatory amino specific medications 106–124 acids 12 Index 303 spinal cord and serotonin 23 t see also central nervous system tail‐chasing 152, 241, 261, 265 spinning 142, 178 taming effects of benzodiazepines 68, 75, 78 spraying 84–85, 111–112, 132–133, 238–239, tardive dyskinesia 203, 213 271, 272, 274, 282 targets of drug action 3 squirrel, naltrexone 264 telomian dogs squirrel monkeys CNS stimulants 218, 220, 221 amphetamine 221 opioids 257 lorazepam 89 temazepam 116 SSRIs see selective serotonin reuptake inhibitors diazepam metabolized to 80, 81 stallions teratogenicity see pregnancy self‐mutilation 260 terfenadine and fluvoxamine 115 sexual behavior inhibition 86 testicular hypoplasia and tricyclic sexual dysfunction 247 antidepressants 238, 240 state law (US) 55 thioridazine 202, 212, 212–213 stereotypic behavior 47 SSRI and 108–109, 117 CNS stimulants 220, 221 thought disorder in schizophrenia 39–40 opioid antagonists 257, 258, 261, 262, 263, 265 thyroid effects, clomipramine 238, 240 serotonin antagonist/reuptake inhibitors training, history‐taking 62 (trazodone) 142 transdermal medication 57 spinning 142, 178 fluoxetine 111 SSRI 115 travel (motion) sickness 132, 204 tail‐chasing 152, 241, 261, 265 trazodone 135–142 tricyclic antidepressants 241 triazolam 91–93 storm phobia 54, 67, 73, 140, 141, 242, tricyclic antidepressants (TCAs) 247, 282 231–257 stress in hospitalized dogs 142 combined use 282 substantia nigra 22, 38, 202, 203 α‐2‐adrenoceptor agonist sulpiride 202, 206, 211–212 (clonidine) 284 swine see pigs azapirones (buspirone) 129–130 switching (changing) 285 benzodiazepine, in storm phobia sympatholytics 157–169 242 general aspects/overview MAOI 237, 243, 246 action 157 trazodone 140 clinical guidelines 159–160 first‐generation 36 contraindications/side‐effects/adverse general aspects/overview events/adverse drug‐interactions 158 action 231 indications 157–158 adverse drug interactions 232 overdose 159 adverse effects and events 35, 232 specific medications 160–166 clinical guidelines 233 sympathomimetic properties contraindications and side effects 232 amphetamines 219, 220 discontinuation 233 selegiline 187 indications 231–232 synapses 5 important information for cholinergic 29, 30, 31 owners 248–249 dopaminergic 38 specific medications 233–248 GABAergic 15–18 tryptamine 22 glutamatergic 11–14 tryptophan 23 serotonergic 24–26 SSRIs and 109, 116, 118 synergistic effects 281 trazodone and 138 304 Index

tumor and cancer risk (carcinogenicity) vervet monkeys, fluoxetine 115 benzodiazepines 92 vesicular monoamine transporter 2 megestrol acetate 274 (VMAT2) 6 methylphenidate 225 visual disturbance, methylphenidate 224 SSRIs 106, 110, 116, 120 voltage‐gated calcium channels 147, 148, 152 tyramine‐induced hypertension 187 tyrosine w dopamine synthesis from 37 warfarin and SSRIs 105, 109, 118 norepinephrine synthesis from 32 weaning/discontinuation/withdrawal 285 see also specific drugs u wolf (Arctic), naltrexone 264 uncompetitive/noncompetitive antagonists at NMDA receptors 14, 47, 172 x United States, prescribing 54–55 xylazine 33, 69, 158, 161, 242, 247 urinary pH and amphetamine excretion 219 urine spraying 84–85, 111–112, 132–133, y 238–239, 271, 272, 274, 282 Yorkshire terrier, amphetamine 226 US, prescribing 54–55 z v zoo animals venlafaxine 34, 385 anticonvulsants (gabapentin) 152 ventral tegmental area (VTA) 22, 38, 303 benzodiazepines 76