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Epidemiology of Depressive Disorders 21 Aetiology 22 Treatment of Depressive Disorders 40 Prognosis 51

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Epidemiology of Depressive Disorders 21 Aetiology 22 Treatment of Depressive Disorders 40 Prognosis 51 The assessment of serotonin function in major depression MD Thesis William Richard Whale 2005 1 UMI Number: U201052 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. Dissertation Publishing UMI U201052 Published by ProQuest LLC 2014. Copyright in the Dissertation held by the Author. Microform Edition © ProQuest LLC. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 Abstract Major depression is a common psychiatric disorder with considerable associated morbidity and mortality. Investigations to understand the causes of depression and how it can be more effectively treated are high priority. The serotonergic system has been implicated in the aetiology and treatment of depression by a wealth of preclinical and clinical evidence. This includes findings that drugs increasing serotonin neurotransmission have antidepressant action and inhibition of serotonin synthesis (via tryptophan depletion) can induce relapse of symptoms in depressed patients. Neuroendocrine challenges are an established method of indirectly examining brain serotonergic function, utilising changes in the secretion of pituitary hormones influenced by tonic serotonergic activity at the level of the hypothalamus. This thesis describes the development of two such neuroendocrine challenge tests, using the selective serotonergic probes, zolmitriptan and citalopram. Orally administered zolmitriptan, licensed for the treatment of migraine, clearly elevated plasma growth hormone in healthy subjects. This growth hormone response was antagonised by ketanserin suggesting mediation by postsynaptic 5-HTm receptors. The response to zolmitriptan was attenuated in melancholic depressed subjects, and further reduced following antidepressant treatment. This implies a dysfunction of postsynaptic 5 -H Tid receptor function in melancholia, and further 5 -H Tid functional downregulation following antidepressant treatment. 2 Citalopram, a selective serotonin reuptake inhibitor, administered at low dose intravenously was associated with an increase in plasma prolactin and cortisol in healthy subjects. The postsynaptic serotonin receptor subtype mediating these responses was not clearly elucidated from experiments using available 5 -HT2 and 5-HTiA ligands. Depressed subjects demonstrated an attenuated prolactin response to citalopram suggesting impaired presynaptic 5-HT neuronal function. These findings confirm impaired brain 5-HT function in depressed patients and assist in more clearly defining the nature of this impairment. 3 Contents PART 1 INTRODUCTION 13 CHAPTER 1 5-HT AND DEPRESSION_____________________________________ 14 INTRODUCTION 15 DEPRESSIVE DISORDERS 16 CLINICAL FEATURES 16 CLASSIFICATION AND HISTORICAL PERSPECTIVE 18 EPIDEMIOLOGY OF DEPRESSIVE DISORDERS 21 AETIOLOGY 22 TREATMENT OF DEPRESSIVE DISORDERS 40 PROGNOSIS 51 THE DISCOVERY AND BIOCHEMISTRY OF 5-HT 53 BRAIN DISTRIBUTION OF 5-HT NEURONES 56 5-HT RECEPTORS AND THEIR FUNCTIONAL SIGNIFICANCE 57 5-HT, FAMILY 58 5-HT2 FAMILY 69 5-HT3 FAMILY 74 5 -HT4 FAMILY 76 5-HTs FAMILY 79 5-HT6 FAMILY 79 5 -HT7 FAMILY 81 5-HT FUNCTION AND DEPRESSION 84 CHAPTER 2 NEUROENDOCRINE STUDIES AND FINDINGS IN DEPRESSED SUBJECTS______________________________________________________________ 92 INTRODUCTION 93 PRECURSORS OF 5-HT 103 5-HT RELEASERS 107 5-HT REUPTAKE INHIBITORS 108 5-HT RECEPTOR AGONISTS 109 4 AIMS OF THE THESIS 116 PART 2 EXPERIMENTAL STUDIES 121 CHAPTER 3 GENERAL METHODS______________________________________ 122 SELECTION AND RECRUITMENT OF SUBJECTS 123 N o r m a l v o l u n t e e r s 123 D e p r e s s e d su b je c t s 123 C o n tr o ls f o r d e p r e s s e d su b jec ts 124 C o n se n t 125 GENERAL PROCEDURE FOR NEUROENDOCRINE STUDIES 125 St u d y d e s ig n 126 Z olmitriptan t e s t 126 C ita lo pr a m t e s t 127 MONITORING VITAL SIGNS AND SIDE EFFECTS 127 Pl a sm a s a m pl e s 128 B io c h e m ic a l a ssa y s 128 A n a ly sis o f r e su l t s 129 CHAPTER 4 THE ZOLMITRIPTAN CHALLENGE IN NORMAL SUBJECTS 132 THE NEUROENDOCRINE EFFECTS OF ZOLMITRIPTAN IN NORMAL SUBJECTS INTRODUCTION 133 METHODS 136 Su b jec ts 136 N euroendocrine t e st s 137 B io c h e m ic a l measurements 137 A n a l y sis o f r e su l t s 138 RESULTS 138 5 DEFINING THE MODE OF ACTION OF THE NEUROENDOCRINE RESPONSE TO ZOLMITRIPTAN INTRODUCTION 143 METHODS 145 Su b je c t s 145 N euroendocrine t e st s 145 B io c h e m ic a l M easurements a n d A n a ly sis o f R e su l t s 146 RESULTS 146 DISCUSSION OF ZOLMITRIPTAN STUDIES IN HEALTHY SUBJECTS 150 CHAPTER 5 THE ZOLMITRIPTAN CHALLENGE IN DEPRESSED PATIENTS AND THE EFFECT OF ANTIDEPRESSANT TREATMENT_________________________ 155 INTRODUCTION 156 METHODS 157 Su b je c t s 157 N euroendocrine te st s 157 B io c h e m ic a l measurements 159 A n a l y sis o f r e su l t s 159 RESULTS 159 DISCUSSION 169 CHAPTER 6 THE CITALOPRAM CHALLENGE IN HEALTHY SUBJECTS 174 THE NEUROENDOCRINE EFFECTS OF CITALOPRAM IN HEALTHY SUBJECTS INTRODUCTION 175 METHODS 178 Su b jec ts 178 N euroendocrine t ests 178 B io c h e m ic a l measurements 179 A n a l y sis o f r e su l t s 179 RESULTS 179 DEFINING THE MODE OF ACTION OF THE NEUROENDOCRINE RESPONSE TO INTRAVENOUS CITALOPRAM 6 THE EFFECT OF CYPROHEPTADINE ON THE NEUROENDOCRINE RESPONSE TO CITALOPRAM INTRODUCTION 185 METHODS 187 Su b je c t s 187 N euroendocrine tests 187 B io c h e m ic a l measurements 188 A n a l y sis o f r e su l t s 188 RESULTS 188 THE EFFECT OF PINDOLOL AND PENBUTOLOL ON THE NEUROENDOCRINE RESPONSE TO CITALOPRAM INTRODUCTION 192 METHODS 195 Su b jec ts 195 N euroendocrine tests 195 B io c h e m ic a l measurements 196 A n a l y sis o f r e su l t s 196 RESULTS 196 DISCUSSION OF CITALOPRAM STUDIES IN HEALTHY SUBJECTS 202 CHAPTER 7 THE CITALOPRAM CHALLENGE IN DEPRESSED SUBJECTS 207 INTRODUCTION 208 METHODS 208 Su b je c t s 208 N euroendocrine tests 209 B io c h e m ic a l measurements 209 A n a l y sis o f r e su l t s 210 RESULTS 210 DISCUSSION 213 PART 3 CONCLUSIONS 219 CHAPTER 8 CONCLUSIONS____________________________________________ 220 5-HT FUNCTION IN DEPRESSION 221 NEUROENDOCRINE STUDIES 222 THE ZOLMITRIPTAN CHALLENGE 223 7 THE CITALOPRAM CHALLENGE 226 INVESTIGATIONS OF 5-HT FUNCTION IN DEPRESSION 228 INVESTIGATIONS OF THE EFFECT OF SSRIS 231 FURTHER INVESTIGATIONS INTO DEPRESSIVE DISORDERS 232 APPENDIX _____________________________________________________ 237 CRITERIA FOR MAJOR DEPRESSIVE EPISODE 237 CRITERIA FOR MELANCHOLIC FEATURES 239 ABBREVIATIONS 240 REFERENCES 243 TABLES 1.1 5-HT receptors and selective agonists / antagonists. 83 2.1 Neuroendocrine challenges of serotonergic neurotransmission. 115 4.1 Comparisons of neuroendocrine effects and 5-HTi receptor affinity 154 for sumatriptan and zolmitriptan. 5.1 Endocrine response to zolmitriptan in depressed patients and controls. 163 6.1 Endocrine response to citalopram and placebo in healthy subjects. 182 6.2 Endocrine response to citalopram in the presence of pindolol, penbutolol and 199 placebo in healthy subjects. 8 FIGURES 1.1 5-HT synthesis and metabolism. 55 4.1 The chemical structure of zolmitriptan. 135 4.2 Growth hormone response to zolmitriptan in healthy subjects. 140 4.3 Prolactin response to zolmitriptan in healthy subjects. 141 4.4 Temperature response to zolmitriptan in healthy subjects. 142 4.5 Growth hormone response to zolmitriptan in the presence of ketanserin. 148 4.6 Plasma zolmitriptan levels following administration of zolmitriptan with 149 ketanserin. 5.1 Growth hormone response to zolmitriptan in depressed patients and controls. 164 5.2 Growth hormone response to zolmitriptan in non-melancholic depressed 165 patients and controls. 5.3 Growth hormone response to zolmitriptan in melancholic depressed 166 patients and controls. 5.4 Growth hormone response to zolmitriptan in depressed patients following 167 SSRI treatment. 5.5 Growth hormone response in healthy subjects rechallenged with zolmitriptan. 168 6.1 The chemical structure of citalopram 176 6.2 Prolactin response to different doses of citalopram in healthy subjects. 183 6.3 Cortisol response to different doses of citalopram in healthy subjects. 184 6.4 Prolactin response to citalopram in the presence of cyproheptadine. 190 6.5 Cortisol response to citalopram in the presence of cyproheptadine. 191 6.6 Prolactin response to citalopram in the presence of pindolol or penbutolol. 200 9 6.7 Cortisol response to citalopram in the presence of pindolol or penbutolol. 201 7.1 Prolactin response to citalopram in depressed subjects and controls. 215 7.2 Individual prolactin responses to citalopram in depressed subjects and 216 controls. 7.3 Cortisol response to citalopram in depressed subjects and controls. 217 7.4 Individual cortisol responses to citalopram in depressed subjects and controls. 218 10 Acknowledgements Firstly, my overwhelming thanks go to Professor Phil Cowen who supervised this thesis and who I hold largely responsible for my interest in psychopharmacology. Professor Roger Horton was the University of London affiliated supervisor who gave much help in the preparation of this work.
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