DOCSLIB.ORG

A Randomized Trial of an N-Methyl-D-Aspartate Antagonist in Treatment-Resistant Major Depression

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
A Randomized Trial of an N-Methyl-D-Aspartate Antagonist in Treatment-Resistant Major Depression ORIGINAL ARTICLE A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Carlos A. Zarate, Jr, MD; Jaskaran B. Singh, MD; Paul J. Carlson, MD; Nancy E. Brutsche, MSN; Rezvan Ameli, PhD; David A. Luckenbaugh, MA; Dennis S. Charney, MD; Husseini K. Manji, MD, FRCPC Context: Existing therapies for major depression have at 40, 80, 110, and 230 minutes and 1, 2, 3, and 7 days a lag of onset of action of several weeks, resulting in con- postinfusion. siderable morbidity. Exploring pharmacological strate- gies that have rapid onset of antidepressant effects within Main Outcome Measure: Changes in scores on the a few days and that are sustained would have an enor- primary efficacy measure, the 21-item Hamilton Depres- mous impact on patient care. Converging lines of evi- sion Rating Scale. dence suggest the role of the glutamatergic system in the pathophysiology and treatment of mood disorders. Results: Subjects receiving ketamine showed significant improvement in depression compared with subjects re- Objective: To determine whether a rapid antidepres- ceiving placebo within 110 minutes after injection, which sant effect can be achieved with an antagonist at the remained significant throughout the following week. The N-methyl-D-aspartate receptor in subjects with major effect size for the drug difference was very large (d=1.46 depression. [95% confidence interval, 0.91-2.01]) after 24 hours and moderate to large (d=0.68 [95% confidence interval, 0.13- Design: A randomized, placebo-controlled, double- 1.23]) after 1 week. Of the 17 subjects treated with ket- blind crossover study from November 2004 to Septem- amine, 71% met response and 29% met remission criteria ber 2005. the day following ketamine infusion. Thirty-five percent of subjects maintained response for at least 1 week. Setting: Mood Disorders Research Unit at the National Institute of Mental Health. Conclusions: Robust and rapid antidepressant effects re- sulted from a single intravenous dose of an N-methyl-D- Patients: Eighteen subjects with DSM-IV major depres- aspartate antagonist; onset occurred within 2 hours postin- sion (treatment resistant). fusion and continued to remain significant for 1 week. Interventions: After a 2-week drug-free period, sub- Trial Registration: clinicaltrials.gov Identifier: jects were given an intravenous infusion of either ket- NCT00088699. amine hydrochloride (0.5 mg/kg) or placebo on 2 test days, a week apart. Subjects were rated at baseline and Arch Gen Psychiatry. 2006;63:856-864 HE TREATMENT OF DEPRES- achieve their full effects and in the mean- sion was revolutionized time, patients continue to suffer from their about a half century ago by symptoms and risk self-harm as well as the serendipitous discov- harm to their personal and professional ery of monoamine oxidase lives. Indeed, the lag period in onset of ac- Tinhibitors and tricyclic antidepressants. tion of several weeks of traditional anti- Since then, the availability of a host of depressants is recognized as a major limi- newer medications with better adverse- tation, resulting in considerable morbidity effect profiles has greatly increased our and high risk of suicidal behavior espe- ability to safely treat a significant percent- cially in the first 9 days after starting an- Author Affiliations: Mood and age of patients. However, the newer medi- tidepressant treatment.1 Pharmacologi- Anxiety Disorders Program, National Institute of Mental cations are largely “me too” drugs in as cal strategies that have rapid onset of Health, National Institutes of much as they exert their primary bio- antidepressant effects within hours or even Health, and Department of chemical effects by increasing the intra- a few days and that are sustained would Health and Human Services, synaptic levels of monoamines. Unfortu- therefore have an enormous impact on Bethesda, Md. nately, these medications take weeks to public health. (REPRINTED) ARCH GEN PSYCHIATRY/ VOL 63, AUG 2006 WWW.ARCHGENPSYCHIATRY.COM 856 ©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 A very useful “initiation and adaptation” paradigm for thermore, that directly targeting the NMDA receptor understanding the delayed therapeutic actions of anti- would bring about rapid antidepressant effects. Indeed, depressants has been an important line of research for in a preliminary study of 8 subjects with major depres- several years now2; more recent versions of this para- sion, it was reported that a single dose of the noncom- digm have focused attention away from monoaminergic petitive NMDA receptor antagonist ketamine resulted in systems to adaptive changes in other systems.3 This para- a rapid and short-lived antidepressant effect.26 There- digm posits that the effect of acute drug administration fore, the objective of the present double-blind trial was is mediated via an initial direct target protein perturba- to determine if ketamine exerts rapid antidepressant ef- tion (eg, binding to a monoamine transporter, thereby fects in a relatively refractory population and, further- inhibiting monoamine reuptake); with repeated admin- more, if the effects of a single dose of ketamine are sus- istration, the same initial event, over time, leads to en- tained. during adaptive changes in critical neuronal networks, thereby resulting in stable long-term antidepressant ef- METHODS fects. Thus, this paradigm posits that the delay in the thera- peutic actions of existing pharmacologic agents is due PATIENT SELECTION to the fact that they initially act on substrates that are con- siderably upstream of targets that are ultimately respon- Subjects were recruited from referrals from local inpatient psy- sible for the antidepressant effects. In this context, the chiatric units or through advertisements placed in the local news- major systems that have been postulated to mediate the papers of the Washington, DC, metropolitan area; the Inter- delayed adaptive effects of antidepressants are neuro- net; and local and national referrals from physicians. Men and trophic signaling cascades and the glutamatergic sys- women, aged 18 to 65 years, who were inpatients with a diag- tem.4,5 These systems should not necessarily be viewed nosis of major depressive disorder recurrent without psy- chotic features as diagnosed by means of the Structured Clini- as separate, and the interested reader is referred to sev- 27 eral excellent reviews on the link between neurotro- cal Interview for Axis I DSM-IV Disorders–Patient Version were 5-7 eligible to participate. Patients with a DSM-IV diagnosis of bi- phins and glutamate systems ; herein we discuss the role polar disorder or who had a history of antidepressant- or sub- of the glutamatergic system, most notably the N-methyl- stance-induced hypomania or mania were excluded. All sub- D-aspartate (NMDA) system, in the actions of anti- jects were studied at the National Institute of Mental Health depressants.8-11 Clinical Research Center in Bethesda, Md, between November N-methyl-D-aspartate receptor antagonists have anti- 2004 and September 2005. Subjects were required to have a depressant effects in many animal models of depres- score of 18 or higher on the 21-item Hamilton Depression Rat- sion, including the application of inescapable stressors, ing Scale (HDRS)28 at screening and at the start of ketamine/ forced-swim, and tail suspension–induced immobility placebo infusions and to have previously failed at least 2 ad- tests; in learned helplessness models of depression; and equate antidepressant trials (adequacy of antidepressant trials was determined with the Antidepressant Treatment History in animals exposed to a chronic mild stress proce- 29 12-17 Form). dure. A single dose of the NMDA antagonist ket- All subjects were in good physical health as determined by amine hydrochloride in male Wistar rats interferes with medical history, physical examination, blood laboratory re- the induction of behavioral despair for up to 10 days af- sults, electrocardiogram, chest radiography, and urinalysis and ter its administration.18 Additionally, repeated adminis- toxicology findings. Subjects were free of comorbid substance tration of different classes of antidepressants—in a time abuse or dependence for at least 3 months, had a negative urine frame consistent with the delayed therapeutic effects— toxicology screen, and were judged clinically not to be a seri- brings about alterations in the expression of NMDA sub- ous suicide risk. Comorbid Axis I anxiety disorder diagnoses unit messenger RNA19 and radioligand binding to these were permitted if they did not require current treatment. Final receptors in regions of the brain implicated in the patho- selection was made by consensus of the investigator team. physiology of depression.8 The study was approved by the National Institute of Men- tal Health institutional review board. All subjects provided writ- Although clearly not unequivocal, several lines of evi- ten informed consent before entry into the study. Informed con- dence from diverse studies also suggest that dysfunc- sents and ongoing study participation were monitored by the tion of the glutamatergic system may play an important Central Office for Recruitment and Evaluation at the National role in the pathophysiology of depression.20,21 Notably, Institute of Mental Health. a recent study by Sanacora et al22 showed glutamate lev- The study was initially planned to include 22 patients; how- els in the occipital cortex
Load more

Recommended publications
  • Investigation of the Cardiac Effects of Pancuronium, Rocuronium, Vecuronium, and Mivacurium on the Isolated Rat Atrium
    Current Therapeutic Research VOLUME ,NUMBER ,OCTOBER Investigation of the Cardiac Effects of Pancuronium, Rocuronium, Vecuronium, and Mivacurium on the Isolated Rat Atrium Sinan Gursoy, MD1; Ihsan Bagcivan, MD2; Nedim Durmus, MD3; Kenan Kaygusuz, MD1; Iclal Ozdemir Kol, MD1; Cevdet Duger, MD1; Sahin Yildirim, MD2; and Caner Mimaroglu, MD1 1Department of Anesthesiology, Cumhuriyet University School of Medicine, Sivas, Turkey; 2Department of Pharmacology, Cumhuriyet University School of Medicine, Sivas, Turkey; and 3Ministry of Health of Turkey, General Directorate of Pharmacy and Pharmaceuticals, Ankara, Turkey ABSTRACT Background: Pancuronium, vecuronium, rocuronium, and mivacurium are nondepolarizing neuromuscular blocking agents that affect the cardiovascular system with different potencies. Their cardiovascular effects are clinically significant in the anesthetic management of patients, particularly those undergoing cardiac surgery. Objective: We aimed to compare the cardiac effects of these compounds, such as heart rate and developed force, in one species under identical experimental conditions in isolated rat atria. Methods: The left or right atria of rats were removed and suspended in organ baths. Pancuronium, vecuronium, rocuronium, or mivacurium were added cumula- tively (10–9–10–5 M) in the presence and absence of the nonselective ␤-blocker propranolol (10–8 M) and the noradrenaline reuptake inhibitor desipramine (10–7 M), and heart rate changes were recorded in spontaneously beating right atria. Left atrial preparations were stimulated by electrical field stimulation using a bipolar platinum electrode, and the effects of cumulative concentrations of these nondepolarizing neuromuscular blocking agents on the developed force in the presence and absence of propranolol (10–8 M) and desipramine (10–7 M) were recorded. Results: Pancuronium increased heart rate in a dose-dependent manner com- pared with the control group (P Ͻ 0.027).
    [Show full text]
  • Additional Antidepressant Pharmacotherapies According to A
    orders & is T D h e n r Werner and Coveñas, Brain Disord Ther 2016, 5:1 i a a p r y B Brain Disorders & Therapy DOI: 10.4172/2168-975X.1000203 ISSN: 2168-975X Review Article Open Access Additional Antidepressant Pharmacotherapies According to a Neural Network Felix-Martin Werner1, 2* and Rafael Coveñas2 1Higher Vocational School of Elderly Care and Occupational Therapy, Euro Academy, Pößneck, Germany 2Laboratory of Neuroanatomy of the Peptidergic Systems, Institute of Neurosciences of Castilla y León (INCYL), University of Salamanca, Salamanca, Spain Abstract Major depression, a frequent psychiatric disease, is associated with neurotransmitter alterations in the midbrain, hypothalamus and hippocampus. Deficiency of postsynaptic excitatory neurotransmitters such as dopamine, noradrenaline and serotonin and a surplus of presynaptic inhibitory neurotransmitters such as GABA and glutamate (mainly a postsynaptic excitatory and partly a presynaptic inhibitory neurotransmitter), can be found in the involved brain regions. However, neuropeptide alterations (galanin, neuropeptide Y, substance P) also play an important role in its pathogenesis. A neural network is described, including the alterations of neuroactive substances at specific subreceptors. Currently, major depression is treated with monoamine reuptake inhibitors. An additional therapeutic option could be the administration of antagonists of presynaptic inhibitory neurotransmitters or the administration of agonists/antagonists of neuropeptides. Keywords: Acetylcholine; Bupropion; Dopamine; GABA; Galanin; in major depression and to point out the coherence between single Glutamate; Hippocampus; Hhypothalamus; Major depression; neuroactive substances and their corresponding subreceptors. A Midbrain; Neural network; Neuropeptide Y; Noradrenaline; Serotonin; question should be answered, whether a multimodal pharmacotherapy Substance P with an agonistic or antagonistic effect at several subreceptors is higher than the current conventional antidepressant treatment.
    [Show full text]
  • Current P SYCHIATRY
    Current p SYCHIATRY N ew Investigators Tips to manage and prevent discontinuation syndromes Informed tapering can protect patients when you stop a medication Sriram Ramaswamy, MD Shruti Malik, MBBS, MHSA Vijay Dewan, MD Instructor, department of psychiatry Foreign medical graduate Assistant professor Creighton University Department of psychiatry Omaha, NE University of Nebraska Medical Center Omaha, NE bruptly stopping common psychotropics New insights on psychotropic A —particularly antidepressants, benzodi- drug safety and side effects azepines, or atypical antipsychotics—can trigger a discontinuation syndrome, with: This paper was among those entered in the 2005 • rebound or relapse of original symptoms Promising New Investigators competition sponsored • uncomfortable new physical and psycho- by the Neuroleptic Malignant Syndrome Information Service (NMSIS). The theme of this year’s competition logical symptoms was “New insights on psychotropic drug safety and • physiologic withdrawal at times. side effects.” To increase health professionals’ awareness of URRENT SYCHIATRY 1 C P is honored to publish this peer- the risk of these adverse effects, this article reviewed, evidence-based article on a clinically describes discontinuation syndromes associated important topic for practicing psychiatrists. with various psychotropics and offers strategies to NMSIS is dedicated to reducing morbidity and anticipate, recognize, and manage them. mortality of NMS by improving medical and psychiatric care of patients with heat-related disorders; providing
    [Show full text]
  • PRESCRIBED DRUGS and NEUROLOGICAL COMPLICATIONS K a Grosset, D G Grosset Iii2
    J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.2004.045757 on 16 August 2004. Downloaded from PRESCRIBED DRUGS AND NEUROLOGICAL COMPLICATIONS K A Grosset, D G Grosset iii2 J Neurol Neurosurg Psychiatry 2004;75(Suppl III):iii2–iii8. doi: 10.1136/jnnp.2004.045757 treatment history is a fundamental part of the healthcare consultation. Current drugs (prescribed, over the counter, herbal remedies, drugs of misuse) and how they are taken A(frequency, timing, missed and extra doses), drugs tried previously and reason for discontinuation, treatment response, adverse effects, allergies, and intolerances should be taken into account. Recent immunisations may also be of importance. This article examines the particular relevance of medication in patients presenting with neurological symptoms. Drugs and their interactions may contribute in part or fully to the neurological syndrome, and treatment response may assist diagnostically or in future management plans. Knowledge of medicine taking behaviour may clarify clinical presentations such as analgesic overuse causing chronic daily headache, or severe dyskinesia resulting from obsessive use of dopamine replacement treatment. In most cases, iatrogenic symptoms are best managed by withdrawal of the offending drug. Indirect mechanisms whereby drugs could cause neurological problems are beyond the scope of the current article—for example, drugs which raise blood pressure or which worsen glycaemic control and consequently increase the risk of cerebrovascular disease, or immunosupressants
    [Show full text]
  • Involvement of Nicotinic Receptor Subtypes in the Behavioral Effects of Nicotinic Drugs in Squirrel Monkeys
    1521-0103/366/2/397–409$35.00 https://doi.org/10.1124/jpet.118.248070 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS J Pharmacol Exp Ther 366:397–409, August 2018 Copyright ª 2018 by The American Society for Pharmacology and Experimental Therapeutics Involvement of Nicotinic Receptor Subtypes in the Behavioral Effects of Nicotinic Drugs in Squirrel Monkeys Sarah L. Withey,1 Michelle R. Doyle,1,2 Jack Bergman, and Rajeev I. Desai Preclinical Pharmacology Laboratory, McLean Hospital/Harvard Medical School, Belmont, Massachusetts Received January 27, 2018; accepted May 17, 2018 ABSTRACT Evidence suggests that the a4b2, but not the a7, subtype of the except for lobeline, the nicotinic agonists produced either full nicotinic acetylcholine receptor (nAChR) plays a key role in [(1)-epibatidine, (2)-epibatidine, and nicotine] or partial (vare- Downloaded from mediating the behavioral effects of nicotine and related drugs. nicline, cytisine, anabaseine, and isoarecolone) substitution for However, the importance of other nAChR subtypes remains (1)-epibatidine. In interaction studies with antagonists differing unclear. The present studies were conducted to examine the in selectivity, (1)-epibatidine discrimination was substan- involvement of nAChR subtypes by determining the effects of tively antagonized by mecamylamine, slightly attenuated selected nicotinic agonists and antagonists in squirrel monkeys by hexamethonium (peripherally restricted) or dihydro- b a either 1) responding for food reinforcement or 2) discriminating the -erythroidine, and not altered by methyllycaconitine ( 7 jpet.aspetjournals.org nicotinic agonist (1)-epibatidine (0.001 mg/kg) from vehicle. In selective). Varenicline and cytisine enhanced (1)-epibati- food-reinforcement studies, nicotine, (1)-epibatidine, varenicline dine’s discriminative-stimulus effects.
    [Show full text]
  • Channelopathies Influence on Neurotransmitters Monitorable By
    Medical and Clinical Archives Review Article ISSN: 2515-1053 Channelopathies influence on neurotransmitters monitorable by real time in situ voltammetry, a review and research proposal Francesco Crespi* Biology Department, GSK, Verona, Italy Introduction Ataxia Channels are pores and through them ions flow across the cell Ataxia is a non-specific clinical condition characterized by membrane and depolarize or hyperpolarize the cell. They open in dysfunction of the areas of the nervous system that control movement, response to voltage changes or binding of a chemical messenger, such as the cerebellum [10]. such as a neurotransmitter (i.e. ligand-gated ion channels). A possible link between cerebellar ataxia and the metabolism Biochemically, channels are specialized membrane macro-molecular of serotonin has been proposed as anti-ataxic effect of buspirone protein complexes divided into distinct protein units called sub-units. hydrochloride, a serotoninergic 5-hydroxytryptamine1A (5-HT1A) Each sub-unit has a specific function and is encoded by a different gene. agonist, in a homogenous group of patients characterized by the These proteins play heterogeneous physiological roles such as impulse same well-defined single condition i.e. cerebellary cortical atrophy generation and propagation, synaptic transmission and plasticity, has been reported [11]. Accordingly, it has been observed that hormonal secretion, hearth rhythm, blood pressure regulation, salt- 5-hydroxytryptophan, serotonin precursor, is more effective than water balance, cell proliferation and survival. Thus, defects in ion placebo improving neurological symptoms in patients with Friedreich channels function may cause diverse and severe diseases collectively ataxia (FA) [12]. FA is an autosomal recessive genetic illness responsible known as channelization [1,2].
    [Show full text]
  • Neurotransmission Product Guide | Edition 1
    Neurotransmission Product Guide | Edition 1 Delphinium Delphinium A source of Methyllycaconitine Contents by Research Area: • Dopaminergic Transmission • Glutamatergic Transmission • Opioid Peptide Transmission • Serotonergic Transmission • Chemogenetics Tocris Product Guide Series Neurotransmission Research Contents Page Principles of Neurotransmission 3 Dopaminergic Transmission 5 Glutamatergic Transmission 6 Opioid Peptide Transmission 8 Serotonergic Transmission 10 Chemogenetics in Neurotransmission Research 12 Depression 14 Addiction 18 Epilepsy 20 List of Acronyms 22 Neurotransmission Research Products 23 Featured Publications and Further Reading 34 Introduction Neurotransmission, or synaptic transmission, refers to the passage of signals from one neuron to another, allowing the spread of information via the propagation of action potentials. This process is the basis of communication between neurons within, and between, the peripheral and central nervous systems, and is vital for memory and cognition, muscle contraction and co-ordination of organ function. The following guide outlines the principles of dopaminergic, opioid, glutamatergic and serotonergic transmission, as well as providing a brief outline of how neurotransmission can be investigated in a range of neurological disorders. Included in this guide are key products for the study of neurotransmission, targeting different neurotransmitter systems. The use of small molecules to interrogate neuronal circuits has led to a better understanding of the under- lying mechanisms of disease states associated with neurotransmission, and has highlighted new avenues for treat- ment. Tocris provides an innovative range of high performance life science reagents for use in neurotransmission research, equipping researchers with the latest tools to investigate neuronal network signaling in health and disease. A selection of relevant products can be found on pages 23-33.
    [Show full text]
  • Neuromodulators for Functional Gastrointestinal Disorders (Disorders of Gutlbrain Interaction): a Rome Foundation Working Team Report Douglas A
    Gastroenterology 2018;154:1140–1171 SPECIAL REPORT Neuromodulators for Functional Gastrointestinal Disorders (Disorders of GutLBrain Interaction): A Rome Foundation Working Team Report Douglas A. Drossman,1,2 Jan Tack,3 Alexander C. Ford,4,5 Eva Szigethy,6 Hans Törnblom,7 and Lukas Van Oudenhove8 1Center for Functional Gastrointestinal and Motility Disorders, University of North Carolina, Chapel Hill, North Carolina; 2Center for Education and Practice of Biopsychosocial Care and Drossman Gastroenterology, Chapel Hill, North Carolina; 3Translational Research Center for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium; 4Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds, United Kingdom; 5Leeds Gastroenterology Institute, St James’s University Hospital, Leeds, United Kingdom; 6Departments of Psychiatry and Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; 7Departments of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; and 8Laboratory for BrainÀGut Axis Studies, Translational Research Center for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium BACKGROUND & AIMS: Central neuromodulators (antide- summary information and guidelines for the use of central pressants, antipsychotics, and other central nervous neuromodulators in the treatment of chronic gastrointestinal systemÀtargeted medications) are increasingly used for treat- symptoms and FGIDs. Further studies are needed to confirm ment
    [Show full text]
  • Cannabis Use in Fibromyalgia M
    CHAPTER e16 Cannabis Use in Fibromyalgia M. Farré * , A. Farré ** , J. Fiz † , M. Torrens ‡ * Clinical Pharmacology Unit, Germans Trias i Pujol University Hospital—IGTP, and Human Pharmacology Unit, Hospital del Mar Medical Research Institute—IMIM, and Autonomous University of Barcelona, Barcelona, Spain ** Dual Disorder Unit, Addiction Program, Institute of Neuropsychiatry and Addiction—INAD, and Hospital del Mar Medical Research Institute—IMIM, Barcelona, Spain † CEDIR, Center for Diagnosis and Rehabilitation, San Martín Santa Fe, Argentina ‡ Addiction Program, Institute of Neuropsychiatry and Addiction—INAD, and Hospital del Mar Medical Research Institute—IMIM, Barcelona, Spain SUMMARY POINTS KEY FACTS OF FIBROMYALGIA • This chapter focuses on the cannabis and • Fibromyalgia is a chronic disorder characterized by fi bromyalgia and begins with the diagnosis and widespread pain and tenderness, often accompanied treatment of this condition. by fatigue, memory problems, and sleep disturbances. • Therapy includes nonpharmacological and • The origin of fi bromyalgia is unknown but it seems pharmacological treatments. to be related to a sensitization of the central nervous system. • Some drugs have demonstrated effi cacy in • The diagnosis of fi bromyalgia is based on clinical randomized controlled trials (pregabalin, symptoms, and routine laboratory and diagnostic tests duloxetine, milnacipran, amitriptyline, serotonin are normal. selective reuptake inhibitors, and cyclobenzaprine). • There is no specifi c treatment for fi bromyalgia. • Cannabis products are frequently used in patients Nonpharmacological and pharmacological therapies with fi bromyalgia. Different surveys showed that could help patients. most of the patients who tried medical marijuana • Some drugs are often used in the treatment of found it to be effective or very effective for the fi bromyalgia pain.
    [Show full text]
  • Using Fluoxetine As a Model
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by OAR@UM Review Journal of Pharmacy And Pharmacology Understanding the molecular pharmacology of the serotonergic system: using fluoxetine as a model Lino Sghendo and Janet Mifsud Department of Clinical Pharmacology and Therapeutics, University of Malta, Msida, Malta Keywords Abstract molecular and clinical pharmacology; molecular and receptor pharmacology; Objectives Serotonin is a monoamine neurotransmitter that is widely distributed pharmacokinetics and drug disposition in the body and plays an important role in a variety of psychological and other body functions such as mood, sexual desire and function, appetite, sleep, memory and Correspondence learning, temperature regulation and social behaviour. This review will assess the Janet Mifsud, Department of Clinical use of fluoxetine, one of the most commonly used selective serotonin reuptake Pharmacology and Therapeutics, University of Malta, Msida, MDS2040, Malta. inhibitors, as a model for understanding the molecular pharmacology of the sero- E-mail: [email protected] toninergic system. Key findings Seven serotonin receptor families have been discovered to date. All Received June 21, 2011 serotonin receptors, except 5-HT3, are G-protein coupled, seven transmembrane Accepted September 22, 2011 receptors that activate an intracellular second messenger cascade. The 5-HT3 recep- tor is a ligand-gated ion channel. Furthermore, 5-HT1A receptors are known as doi: 10.1111/j.2042-7158.2011.01384.x autoreceptors since their stimulation inhibits the release serotonin in nerve termi- nals.A transporter protein found in the plasma membrane of serotonergic neurones is responsible for the reuptake of this neurotransmitter.
    [Show full text]
  • 'Party Drug' Turned Antidepressant Approaches Approval
    NEWS & ANALYSIS Nature Reviews Drug Discovery | Published online 30 Oct 2018; doi:10.1038/nrd.2018.187 ‘Party drug’ turned anti depressant approaches approval Johnson & Johnson has submitted its esketamine for regulatory approval, but researchers still don’t understand how the fast-acting antidepressant lifts moods. DrAfter123/DigitalVision Vectors Sara Reardon Monteggia, a neuroscientist at Vanderbilt later learned that the antibiotic, at low doses, University. blocks the NMDA receptor, a glutamate When researchers showed in 2006 that the Yet it is far from clear how this work will receptor. Then in the late 1990s,Nature when Reviews | Drug Discovery anaesthetic ketamine — also known as the play out. Whereas early evidence suggested psychiatrist John Krystal of Yale University club drug Special K — was a rapid and potent that ketamine acted through the NMDA was curious about whether the antidepressant, big pharmaceutical receptor, many of the first-generation neurotransmitter glutamate contributed to companies quickly jumped into the game. ketamine mimetics that were designed to act schizophrenia, he decided to test the known Extensive efforts to improve on decades-old on this target failed in clinical trials (TABLE 1). NMDA receptor antagonist ketamine in nine antidepressants had floundered, but ketamine Accumulating evidence now suggests that depressed patients. finally promised a novel mechanism of action ketamine’s antidepressant activity may be At the time, glutamate had mostly been and the potential to help treatment-resistant more complicated. studied for its role in learning and memory. But patients. As a result, some companies are quietly Krystal’s group found that ketamine induced a Because ketamine is an old drug and going back to the drawing board.
    [Show full text]
  • Is the Antidepressant Activity of Selective Serotonin Reuptake Inhibitors Mediated by Nicotinic Acetylcholine Receptors?
    molecules Review Is the Antidepressant Activity of Selective Serotonin Reuptake Inhibitors Mediated by Nicotinic Acetylcholine Receptors? Hugo R. Arias 1,*,†, Katarzyna M. Targowska-Duda 2,†, Jesús García-Colunga 3,† and Marcelo O. Ortells 4 1 Department of Pharmacology and Physiology, Oklahoma State University College of Osteopathic Medicine, Tahlequah, OK 74464, USA 2 Department of Biopharmacy, Medical University of Lublin, 20-093 Lublin, Poland; [email protected] 3 Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Campus Juriquilla, Universidad Nacional Autónoma de México, Querétaro 76230, Mexico; [email protected] 4 Facultad de Medicina, Universidad de Morón, CONICET, Morón 1708, Argentina; [email protected] * Correspondence: [email protected]; Tel.: +1-918-525-6324; Fax: +1-918-280-2515 † These authors contributed equally to this work. Abstract: It is generally assumed that selective serotonin reuptake inhibitors (SSRIs) induce an- tidepressant activity by inhibiting serotonin (5-HT) reuptake transporters, thus elevating synaptic 5-HT levels and, finally, ameliorates depression symptoms. New evidence indicates that SSRIs may also modulate other neurotransmitter systems by inhibiting neuronal nicotinic acetylcholine receptors (nAChRs), which are recognized as important in mood regulation. There is a clear and strong association between major depression and smoking, where depressed patients smoke twice as much as the normal population. However, SSRIs are not efficient for smoking cessation therapy. In patients with major depressive disorder, there is a lower availability of functional nAChRs, although Citation: Arias, H.R.; their amount is not altered, which is possibly caused by higher endogenous ACh levels, which Targowska-Duda, K.M.; consequently induce nAChR desensitization. Other neurotransmitter systems have also emerged García-Colunga, J.; Ortells, M.O.
    [Show full text]