DOCSLIB.ORG

With Lorazepam: Discontinuation Effects

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
With Lorazepam: Discontinuation Effects Research Paper Articlel de recherche Safety of ipsapirone treatment compared with lorazepam: discontinuation effects Usoa E. Busto, PharmD; Claudio A. Naranjo, MD; Karen E. Bremner, BSc; John E. Peachey, MD; Monica Bologa, MD, MSc Busto Addiction Research Foundation, Psychopharmacology Research Program, Sunnybrook Health Science Centre, and Dept. of Psychiatry, University of Toronto, Toronto, Ont.; Naranjo - Psychopharmacology Research Program, Sunny- brook Health Science Centre, and Depts. of Psychiatry, Pharmacology and Medicine, University of Toronto; Bremner Psychopharmacology Research Program, Sunnybrook Health Science Centre; Peachey - University of Ottawa and Royal Ottawa Hospital, Ottawa, Ont.; Bologa Bayer Canada Inc., Toronto, Ont. Objective: To determine discontinuation effects of ipsapirone, a novel azapirone and partial 5-HT,A ago- nist that has anxiolytic effects clinically and has not caused dependence or withdrawal symptoms in animals, and to compare these effects with those of the benzodiazepine lorazepam, owing to concern about depen- dence or withdrawal symptoms following use of these drugs. Design: Prospective, randomized, double- blind, placebo-controlled trial. Setting: Outpatient and inpatient treatment. Participants: Sixty-five healthy male volunteers who had experience with sedative-hypnotics or anxiolytics and did not meet DSM- Ill-R criteria for abuse or dependence. Interventions: Participants were randomized to receive ipsapirone 15 mg per day (n = 17), ipsapirone 22.5 mg per day (n = 16), lorazepam 3 mg per day (n = 16), or placebo (n = 16) as outpatients for 36 days (treatment) followed by single-blind placebo as inpatients for 3 days and as outpatients for 6 days (withdrawal). Outcome measures: Hamilton Anxiety Rating Scale (HAM-A), Hamilton Depression Scale (HAM-D), Spielberger State Anxiety Scale, Sleep Quality Questionnaire, Gen- eral Symptom Checklist, self-rated intoxication, Clinical Institute Withdrawal Assessment Benzodi- azepines (CIWA-Benzo), psychomotor testing and urine drug screen. Results: Only 45 subjects com- pleted the study; discontinuation rates did not significantly differ among treatment groups. At day 39, fewer and less severe symptoms (e.g., insomnia and fatigue) were found on the CIWA-Benzo scale after treat- ment with ipsapirone or placebo than after treatment with lorazepam (p < 0.05). Subjects reported longer sleep latency and poorer sleep quality after receiving lorazepam than after receiving ipsapirone or placebo. Scores on the HAM-D, Spielberger State Anxiety and HAM-A scales did not change from baseline. Con- clusions: Withdrawal symptoms were detected after discontinuation of therapeutic doses of lorazepam. Significantly fewer symptoms were observed after withdrawal from anxiolytic doses of ipsapirone. Objectif: Determiner les effets de l'interruption de l'ipsapirone, nouvel azapirone et agoniste partiel 5- HTIA qui a des effets anxiolytiques sur le plan clinique et n'a pas provoque de sympt6mes de dependance Correspondence to: Dr. Usoa E. Busto, University of Toronto, Sunnybrook Health Science Centre, Psychopharmacology Research Program, 2075 Bayview Ave., Room F327, North York, ON M4N 3M5; fax 416 480-4708; [email protected] Medical subject headings: Anti-anxiety agents; anti-anxiety agents, benzodiazepine; lorazepam; substance dependence; substance withdrawal syndrome J Psychiatry Neurosci 1998;23(l):35-44. Submitted Mar. 24, 1997 Revised Oct. 21, 1997 Accepted Oct. 22, 1997 (c) 1998 Canadian Medical Association Vol. 23, no I, 199B Journal of Psychiatry & Neuroscience VL1 ho |Y1998 3 6f,. Mumscience 35 Busto, Naranjo, Bremner, et al ou de sevrage chez les animaux, et comparer ces effets a ceux de la benzodiazepine lorazepam parce que l'on craint que l'usage de ces medicaments provoque des sympt6mes de dependance ou de sevrage. Conception: Etude prospective randomisee a double insu contr6lee par placebo. Contexte : Traitement en service externe et en service interne. Participants: Soixante-cinq hommes benevoles en bonne sante qui avaient de 1'experi- ence des nooleptiques ou des anxiolytiques et ne satisfaisaient pas aux criteres DSM-111-R relatifs a I'abus ou a la dependance. Interventions : On a administre au hasard de l'ipsapirone a 15 mg par jour (n = 17), de l'ip- sapirone a 22,5 mg par jour (n = 16), du lorazepam a 3 mg par jour (n = 16) ou un placebo (n = 16) aux partici- pants qui ont ete traites en service externe pendant 36 jours (traitement) et ont requ ensuite un placebo a sim- ple insu en service interne pendant 3 jours et en service externe pendant 6 jours (sevrage). Mesures de resultats: Echelle d'evaluation de I'anxiete de Hamilton (HAM-A), echelle de la depression de Hamilton (HAM- D), echelle de 1'etat d'anxiete de Spielberger, questionnaire sur la qualite du sommeil, liste de contr6le des symptomes generaux, intoxication autoevaluee, evaluation du sevrage en institut clinique benzodiazepines (CIWA-Benzo), test psychomoteur et test de depistage dans l'urine. Resultats: Seulement 45 sujets ont ter- mine 1'etude; les taux d'interruption n'ont pas differe de faqon significative entre les groupes de sujets. Au 39e jour, on a constate des sympt6mes moins nombreux et moins graves (par exemple, insomnie et fatigue) selon 'echelle CIWA-Benzo apres le traitement a l'ipsapirone ou au placebo qu'apres le traitement au lorazepam (p < 0,05). Les sujets ont signale une plus longue latence du sommeil, qui etait aussi de moins bonne qualite, apres avoir requ du lorazepam qu'apres avoir requ de l'ipsapirone ou un placebo. Les resultats sur les echelles HAM- D, 'echelle de 'etat d'anxiete de Spielberger et HAM-A n'ont pas change par rapport a la ligne de base. Con- clusions: On a detecte des sympt6mes de sevrage apres une interruption de doses therapeutiques de loraze- pam. On a observe beaucoup moins de symptomes apres le sevrage de doses anxiolytiques d'ipsapirone. Introduction been reported with the use of benzodiazepines,7,8 but substantial tolerance develops to many of these effects Benzodiazepines have been prescribed for the treat- after several days of use.8 Medications that have com- ment of anxiety disorder for decades, because of their parable efficacy and cause fewer unwanted effects are proven efficacy and safe side-effects profile.' However, desirable. long-term treatment with benzodiazepines is limited A variety of alternatives to the benzodiazepines by the agents' capacity to produce a variety of discon- have been developed and studied in the past few tinuation syndromes. Abrupt discontinuation has been years; these include partial agonists to the GABA- shown to be associated with withdrawal symptoms benzodiazepine-chloride receptor, such as melamine, and rebound phenomena.2'3 Strategies to alleviate dis- and drugs that act at the serotonin-receptor level, continuation syndromes, such as gradual tapering of such as the 5-HT3 receptor antagonist ondansetron9 the medication or substitution with a benzodiazepine and the 13-carboline abecarnil.'0 Partial agonists of the with a longer half-life, are usually employed but do 5-HTlA receptor have also been studied in the treat- not completely overcome the difficulties of discontinu- ment of anxiety." Buspirone, an ipsapirone 5-HT1 par- ing prolonged treatment.' Discontinuation of benzodi- tial agonist, is now marketed for this indication and azepines may produce various syndromes: 1) recur- may offer some advantages over benzodiazepines, in- rence, which is the reappearance of the original cluding a less sedative effect."2 condition for which the patient sought treatment (e.g., Ipsapirone is a novel azapirone that has been devel- anxiety, insomnia), with symptoms similar in type and oped as an alternative to benzodiazepines for the intensity to the original complaint; 2) rebound, which treatment of anxiety, panic disorder and depres- is the worsening of the initial condition; or 3) physical sion.'-"" Like buspirone, it is a partial agonist of the 5- dependence, which is a withdrawal syndrome after HTlA receptor. Ipsapirone has agonist properties at the discontinuation of long-term use.4-6 Appearance of 5-HT,A presynaptic sites, which include decreased symptoms not experienced before or during treat- serotonergic tone and transmission.'6 In humans, ip- ment, such as hypersensitivity to sensory stimuli and sapirone is rapidly and extensively absorbed after perceptual distortions, have also been observed after oral administration, reaching a maximal plasma con- benzodiazepine discontinuation.7 Attentional, psy- centration between 0.5 and 1.3 hours after ingestion. It chomotor, cognitive and memory impairments have is highly protein-bound (91% to 94%), mainly to albu- 36 Revue de psychiatrie et deI neuroscience 1998 36 Rt*.e. de psychii.We et ae neuroscience AA. 21 W, l, E970 Safet f ipsapirone Vs. lorazepam min. Elimination of ipsapirone is biphasic, with a ter- cording to the Diagnostic and Statistical Manual ofMental minal half-life of 1 to 2 hours. Three metabolites, with Disorders, 3rd edition, Revised (DSM-III-R). Subjects had no important clinical activity, have been identified in no medical or psychiatric conditions, as determined by urine."7 Hence, ipsapirone is a potential nonbenzodi- medical examination and laboratory tests, drank fewer azepine alternative for the treatment of anxiety. than 28 alcoholic drinks per week and had not used Ipsapirone lacks the side-effects profile of benzodi- any psychoactive medications for at least 6 months be- azepines. In animal studies, it does not produce
Load more

Recommended publications
  • Guaiana, G., Barbui, C., Caldwell, DM, Davies, SJC, Furukawa, TA
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Explore Bristol Research Guaiana, G., Barbui, C., Caldwell, D. M., Davies, S. J. C., Furukawa, T. A., Imai, H., ... Cipriani, A. (2017). Antidepressants, benzodiazepines and azapirones for panic disorder in adults: a network meta-analysis. Cochrane Database of Systematic Reviews, 2017(7), [CD012729]. https://doi.org/10.1002/14651858.CD012729 Publisher's PDF, also known as Version of record Link to published version (if available): 10.1002/14651858.CD012729 Link to publication record in Explore Bristol Research PDF-document This is the final published version of the article (version of record). It first appeared online via Cochrane Library at https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD012729/full . Please refer to any applicable terms of use of the publisher. University of Bristol - Explore Bristol Research General rights This document is made available in accordance with publisher policies. Please cite only the published version using the reference above. Full terms of use are available: http://www.bristol.ac.uk/pure/about/ebr-terms Cochrane Database of Systematic Reviews Antidepressants, benzodiazepines and azapirones for panic disorder in adults: a network meta-analysis (Protocol) Guaiana G, Barbui C, Caldwell DM, Davies SJC, Furukawa TA, Imai H, Koesters M, Tajika A, Bighelli I, Pompoli A, Cipriani A Guaiana G, Barbui C, Caldwell DM, Davies SJC, Furukawa TA, Imai H, Koesters M, Tajika A, Bighelli I, Pompoli A, Cipriani A. Antidepressants, benzodiazepines and azapirones for panic disorder in adults: a network meta-analysis. Cochrane Database of Systematic Reviews 2017, Issue 7.
    [Show full text]
  • Smoking Modulates Neuroendocrine Responses to Ipsapirone in Patients with Panic Disorder A
    Smoking Modulates Neuroendocrine Responses to Ipsapirone in Patients with Panic Disorder A. Broocks, M.D., Ph.D., B. Bandelow, M.D., Ph.D., K. Koch, U. Bartmann, J. Kinkelbur, M.D., U. Schweiger, M.D., Ph.D., F. Hohagen, M.D., Ph.D., and G. Hajak, M.D., Ph.D. Reduced 5-HT1A-receptor responsiveness has been reported temperature. In comparison to placebo, administration of in patients with panic disorder(PD) and/or agoraphobia ipsapirone was associated with significant increases of (PDA). Although many of these patients are regular various psychological symptoms and plasma cortisol smokers, it has not been examined whether psychological or concentrations. The subgroup of PD patients who were neurobiological effects induced by the selective 5-HT1A- smokers showed significantly higher cortisol responses to receptor agonist, ipsapirone, are affected by the smoking ipsapirone than non-smokers. status of the patients. In conclusion, smoking status has to be taken into In order to clarify this question neuroendocrine account when assessing the responsiveness of 5-HT1A challenges with oral doses of ipsapirone (0.3 mg/kg) and receptors in patients with psychiatric disorders. The placebo were performed in 39 patients with PDA, and prevention of smoking during challenge sessions might not results were compared between patients who smoked (Ͼ10 be the ideal approach in heavy smokers, since sudden cigarettes per day, n ϭ 17) and patients who had been non- abstinence from smoking is likely to affect neurobiological smokers for at least two years (n ϭ 22). and possibly psychological responses to ipsapirone. Patients who were smokers (but did not smoke during [Neuropsychopharmacology 27:270–278, 2002] the challenge procedure) had significantly reduced baseline © 2002 American College of Neuropsychopharmacology.
    [Show full text]
  • Serotonergic Modulation of Suicidal Behaviour: Integrating Preclinical Data with Clinical Practice and Psychotherapy
    Serotonergic modulation of suicidal behaviour: integrating preclinical data with clinical practice and psychotherapy Vasileios Boulougouris, Ioannis Malogiannis, George Lockwood, Iannis Zervas & Giuseppe Di Giovanni Experimental Brain Research ISSN 0014-4819 Exp Brain Res DOI 10.1007/s00221-013-3669-z 1 23 Your article is protected by copyright and all rights are held exclusively by Springer- Verlag Berlin Heidelberg. This e-offprint is for personal use only and shall not be self- archived in electronic repositories. If you wish to self-archive your article, please use the accepted manuscript version for posting on your own website. You may further deposit the accepted manuscript version in any repository, provided it is only made publicly available 12 months after official publication or later and provided acknowledgement is given to the original source of publication and a link is inserted to the published article on Springer's website. The link must be accompanied by the following text: "The final publication is available at link.springer.com”. 1 23 Author's personal copy Exp Brain Res DOI 10.1007/s00221-013-3669-z SeroTONIN Serotonergic modulation of suicidal behaviour: integrating preclinical data with clinical practice and psychotherapy Vasileios Boulougouris · Ioannis Malogiannis · George Lockwood · Iannis Zervas · Giuseppe Di Giovanni Received: 6 May 2013 / Accepted: 30 July 2013 © Springer-Verlag Berlin Heidelberg 2013 Abstract Many studies have provided important infor- with personality disorders), aiming to invite the reader to mation regarding the anatomy, development and func- integrate some aspects of the neurobiology of human sui- tional organization of the 5-HT system and the alterations cidal behaviour into a model of suicide that can be used in in this system that are present within the brain of the sui- a clinical encounter.
    [Show full text]
  • 5-HT1A Receptor Agonist Affects Fear Conditioning Through Stimulations of the Postsynaptic 5-HT1A Receptors in the Title Hippocampus and Amygdala
    5-HT1A receptor agonist affects fear conditioning through stimulations of the postsynaptic 5-HT1A receptors in the Title hippocampus and amygdala Author(s) Li, XiaoBai; Inoue, Takeshi; Abekawa, Tomohiro; Weng, ShiMin; Nakagawa, Shin; Izumi, Takeshi; Koyama, Tsukasa European Journal of Pharmacology, 532(1-2), 74-80 Citation https://doi.org/10.1016/j.ejphar.2005.12.008 Issue Date 2006-02-17 Doc URL http://hdl.handle.net/2115/8408 Type article (author version) File Information EJP22907revisedFinal.pdf Instructions for use Hokkaido University Collection of Scholarly and Academic Papers : HUSCAP 5-HT1A receptor agonist affects fear conditioning through stimulations of the postsynaptic 5-HT1A receptors in the hippocampus and amygdala. XiaoBai Lia, b, Takeshi Inouea, Tomohiro Abekawaa, ShiMin Weng b, Shin Nakagawaa, Takeshi Izumia, Tsukasa Koyamaa a Department of Psychiatry, Neural Function, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-ku, Sapporo, 060-8638, Japan bShanghai Mental Health Center, 600, Wan Ping Nan Lu, Shanghai 200030, China Correspondence to: Takeshi Inoue, MD, PhD, Department of Psychiatry, Neural Function, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-ku, Sapporo 060-8638, Japan. Tel: +81-11-706-5160; Fax: +81-11-706-5081; E-mail: [email protected] Abstract Evidence from preclinical and clinical studies has shown that 5-HT1A receptor agonists have anxiolytic actions. The anxiolytic actions of 5-HT1A receptor agonists have been tested by our previous studies using fear conditioning. However, little is known about the brain regions of anxiolytic actions of 5-HT1A receptor agonists in this paradigm. In the present study, we investigated the effects of bilateral microinjections of flesinoxan, a selective 5-HT1A receptor agonist, into the hippocampus, amygdala and medial prefrontal cortex on the expression of contextual conditioned freezing and the defecation induced by conditioned fear stress in rats.
    [Show full text]
  • Clinical Utility of Vilazodone for the Treatment of Adults with Major Depressive Disorder and Theoretical Implications for Future Clinical Use
    Neuropsychiatric Disease and Treatment Dovepress open access to scientific and medical research Open Access Full Text Article REVIEW Clinical utility of vilazodone for the treatment of adults with major depressive disorder and theoretical implications for future clinical use Mandeep Singh Background: Vilazodone is the latest approved antidepressant available in the United States. Thomas L Schwartz Its dual mechanism of action combines the inhibition of serotonin transporters while simultane- ously partially agonizing serotonin-1a (5-HT1A) receptors. This combined activity results in SUNY Upstate Medical University, Psychiatry Department, Syracuse, serotonin facilitation across the brain’s serotonergic pathways, which has been termed by the NY, USA authors as that of a serotonin partial agonist and reuptake inhibitor, or SPARI. Objective: The authors to review laboratory, animal model data, and human trial data to synthesize a working theory regarding the mechanism of antidepressant action of this agent and regarding its potential for additional indications. Methods: A MEDLINE and Internet search was conducted and the resultant evidence For personal use only. reviewed. Results: Vilazodone has randomized, controlled empirical data which has garnered it an approval for treating major depressive disorder. It combines two well-known pharmacodynamic mechanisms of serotonergic action into a novel agent. Although no head-to-head studies against other antidepressants are published, the efficacy data for vilazodone appears comparable to other known antidepressants, with associated gastrointestinal side effects similar to serotonin selective reuptake inhibitor and serotonin norepinephrine reuptake inhibitor antidepressants, but potentially with a lower incidence of sexual side effects and weight gain. Discussion: As a new option for the treatment of major depressive disorder, vilazodone, due to its unique SPARI mechanism of action, may hold promise for patients who cannot tolerate or have not responded to previous antidepressant monotherapies.
    [Show full text]
  • A Brief Summary for 5-HT Receptors
    ndrom Sy es tic & e G n e e n G e f T o Watry and Lu, J Genet Syndr Gene Ther 2013, 4:2 Journal of Genetic Syndromes h l e a r n a r p DOI: 10.4172/2157-7412.1000129 u y o J & Gene Therapy ISSN: 2157-7412 Short Commentary Open Access A Brief Summary for 5-HT Receptors Watry S and Lu J* Department of Neuroscience and Department of Neurology, School of Medicine and Public Health, Waisman Center, University of Wisconsin, Madison, WI 53705, USA As a group of G protein-coupled receptors (GPCRs) and ligand- (Anpirtoline) [42]; CGS 12066B [43]; SB 216641 [44]; RU 24969 [45]; gated ion channels (LGICs), the serotonin (5-HT) receptors are CP 93129 [46]. found in the central and peripheral nervous systems. After activated Application value: Depression [47]; Anxiety [48]; Aggression by the neurotransmitter serotonin, their natural ligand, 5-HT [49]; Migraine [50]; Drug Addicton [51]; increased locomotor activity receptors mediate both excitatory and inhibitory neurotransmission [52]; brain reward mechanisms (agonist); Alcoholism [53]; Sleep [54]; by modulating the release of many neurotransmitters, including hypothermia [55]. glutamate, GABA, dopamine, epinephrine/norepinephrine, and acetylcholine, as well as many hormones, including oxytocin, prolactin, Receptor: 5-HT 1D [56] vasopressin, cortisol, corticotropin, and substance P, among others. 5-HT receptors influence various biological and neurological processes Structure: GPCR [56]. such as aggression, anxiety, appetite, cognition, learning, memory, Localization: Raphe nuclei; Cortex, Caudate, Globus Pallidus mood, nausea, sleep, and thermoregulation. Accordingly, 5-HT [57]; Basal Ganglia, Substantia Nigra, Hippocampal Formation, receptors are the target of a variety of pharmaceutical drugs, including Raphe Nuclei [58]; Caudate Nucleus, Lateral Geniculate Nuclei, Spinal many antidepressants, antipsychotics, anorectics, antiemetics, Trigominal Nucleus [32]; Globus Pallidus [59].
    [Show full text]
  • Centre for Reviews and Dissemination
    Pharmacologic treatments effective in both generalized anxiety disorder and major depressive disorder: clinical and theoretical implications Casacalenda N, Boulenger J P Authors' objectives To assess the efficacy of anxiolytics (alprazolam and azapirones) in major depressive disorder (MDD) and of antidepressants in generalized anxiety disorder (GAD), thereby exploiting the possible theoretical and clinical implications of this efficacy. Searching MEDLINE was searched from January 1980 to September 1997 for English language peer-reviewed articles using the following keywords: depressive disorders, anxiety disorders, generalized anxiety disorder, antidepressants, antianxiety agents, benzodiazepines and buspirone. Bibliographies of identified studies were examined. Study selection Study designs of evaluations included in the review Randomised, double-blind trials (RCT) with a sample size of 30 patients or more that compared anxiolytics and antidepressants in the acute treatment of GAD or MDD were included. Specific interventions included in the review The following therapies were studied: benzodiazepines including alprazolam, diazepam, and lorazepam; tricyclic antidepressants (TCA) including desipramine, amitryptilline, imipramine, and doxepin); azapirones (including buspirone, ipsapirone, and gepirone); and placebo. Duration of treatment ranged from 4 to 8 weeks. Participants included in the review Adult patients with generalised anxiety disorder (GAD) or major depressive disorder (MDD) who were not being simultaneously treated with psychotherapy
    [Show full text]
  • Blunted Temperature and Cortisol Responses to Ipsapirone in Major Depression: Lack of Enhancement by Electroconvulsive Therapy Baruch Shapira, Michael E
    Psychoneuroendocrinology 25 (2000) 421–438 www.elsevier.com/locate/psyneuen Blunted temperature and cortisol responses to ipsapirone in major depression: lack of enhancement by electroconvulsive therapy Baruch Shapira, Michael E. Newman, Yevgenia Gelfin, Bernard Lerer * Biological Psychiatry Unit, Hadassah-Hebrew University Medical Center, Ein Karem, Jerusalem, 91120, Israel Received 5 July 1999; accepted 24 September 1999 Abstract Depression has been shown in some studies to be associated with a reduction in hypothal- amic 5-HT1A receptor function, as indicated by reduced hormone and/or hypothermic responses to 5-HT1A agonists such as ipsapirone. The hypothermic response to ipsapirone was reduced in depressed patients treated with amitriptyline. Hormone and hypothermic responses to 5- HT1A agonists were reduced in normal subjects administered specific serotonin reuptake inhibi- tors. Effects of electroconvulsive therapy (ECT) on 5-HT1A receptor-mediated responses in humans have not been reported. In the present work, ten depressed patients and 15 control subjects were challenged with placebo and with 0.3 mg/kg ipsapirone, administered 48 h apart in a randomised double blind design. Hypothermic, growth hormone (GH) and cortisol responses were measured. Seven of the depressed patients were treated with a course of ECT, and placebo and ipsapirone challenges were repeated 24 and 72 h after the last treatment. The cortisol response to ipsapirone was significantly reduced in the depressed patients compared with controls. The hypothermic response to ipsapirone was totally abolished in the depressed patients. When tested after a course of ECT, the seven depressed patients again showed reduced or blunted responses. We conclude that hypothalamic 5-HT1A receptor function is reduced in depression.
    [Show full text]
  • Clinical Utility of Vilazodone for the Treatment of Adults with Major Depressive Disorder and Theoretical Implications for Future Clinical Use
    Neuropsychiatric Disease and Treatment Dovepress open access to scientific and medical research Open Access Full Text Article REVIEW Clinical utility of vilazodone for the treatment of adults with major depressive disorder and theoretical implications for future clinical use Mandeep Singh Background: Vilazodone is the latest approved antidepressant available in the United States. Thomas L Schwartz Its dual mechanism of action combines the inhibition of serotonin transporters while simultane- ously partially agonizing serotonin-1a (5-HT1A) receptors. This combined activity results in SUNY Upstate Medical University, Psychiatry Department, Syracuse, serotonin facilitation across the brain’s serotonergic pathways, which has been termed by the NY, USA authors as that of a serotonin partial agonist and reuptake inhibitor, or SPARI. Objective: The authors to review laboratory, animal model data, and human trial data to synthesize a working theory regarding the mechanism of antidepressant action of this agent and regarding its potential for additional indications. Methods: A MEDLINE and Internet search was conducted and the resultant evidence reviewed. Results: Vilazodone has randomized, controlled empirical data which has garnered it an approval for treating major depressive disorder. It combines two well-known pharmacodynamic mechanisms of serotonergic action into a novel agent. Although no head-to-head studies against other antidepressants are published, the efficacy data for vilazodone appears comparable to other known antidepressants, with associated gastrointestinal side effects similar to serotonin selective reuptake inhibitor and serotonin norepinephrine reuptake inhibitor antidepressants, but potentially with a lower incidence of sexual side effects and weight gain. Discussion: As a new option for the treatment of major depressive disorder, vilazodone, due to its unique SPARI mechanism of action, may hold promise for patients who cannot tolerate or have not responded to previous antidepressant monotherapies.
    [Show full text]
  • Partial Dopamine D2/Serotonin 5-HT1A Receptor Agonists As New Therapeutic Agents Adeline Etievant#, Cécile Bétry#, and Nasser Haddjeri*,1
    The Open Neuropsychopharmacology Journal, 2010, 3, 1-12 1 Open Access Partial Dopamine D2/Serotonin 5-HT1A Receptor Agonists as New Therapeutic Agents Adeline Etievant#, Cécile Bétry#, and Nasser Haddjeri*,1 Laboratory of Neuropharmacology, Faculty of Pharmacy, University Lyon I, EAC CNRS 5006, 8 Avenue Rockefeller 69373 LYON Cedex 08 France Abstract: The therapeutic efficacy of current antipsychotic or antidepressant agents still present important drawbacks such as delayed onset of action and a high percentage of non-responders. Despite significant advancements in the devel- opment of new drugs with more acceptable side-effect profiles, patients with schizophrenia or major depression experi- ence substantial disability and burden of disease. The present review discusses the usefulness of partial dopamine D2/serotonin 5-HT1A receptors agonists in the treatment of schizophrenia, major depression and bipolar disorder as well as in Parkinson’s disease. Partial agonists can behave as modulators since their intrinsic activity or efficacy of a partial ago- nist depends on the target receptor population and the local concentrations of the natural neurotransmitter. Thus, these drugs may restore adequate neurotransmission while inducing less side effects. In schizophrenia, partial DA D2/5-HT1A receptor agonists (like aripiprazole or bifeprunox), by stabilizing DA system via a preferential reduction of phasic DA re- lease, reduce side effects i.e. extrapyramidal symptoms and improve cognition by acting on 5-HT1A receptors. Aripipra- zole appears also as a promising agent for the treatment of depression since it potentiates the effect of SSRIs in resistant treatment depression. Concerning bipolar disorders aripiprazole may have only a benefit effect in the treatment of manic episodes.
    [Show full text]
  • 5-HT Receptors in Depressed Patients
    5-HT1A receptors in depressed patients: Evidence from PET, post mortem and EEG based studies R. Hamish McAllister-Williams, MD, PhD, FRCPsych Reader in Clinical Psychopharmacology Newcastle University Hon. Consultant Psychiatrist Regional Affective Disorders Service, RVI 5-HT1A receptor distribution in the human brain Post synaptic receptors 2 Postsynaptic 5-HT1A receptors and depression • Function: – Prolactin and growth hormone responses to intravenous l-tryptophan • Blunted responses in depressed subjects in 5 studies1 • Number of receptors: – PET scanning of WAY-100635 binding • 10-30% decrease in binding in depressed2-5 and remitted depressed6 patients 1. Power and Cowen, 1992 Molec. Aspects Med. 13(3):205-220 2. Drevets et al. 1999 Biological Psychiatry 46:1375-1387 3. Sargent et al. 2000 Archives of General Psychiatry 57:174-180 4. Meltzer et al. 2004 Neuropsychopharmacology 29:2258-2265 5. Drevets et al. 2007 Nuclear Medicine & Biology 34:865-877 6. Bhagwagar et al. 2004 Molecular Psychiatry 9: 386-392 5-HT1A receptor binding across brain regions healthy controls () and MDD () 9 to 24% reduction in 5-HT1A binding across regions of interest in MDD Hirvonen et al. (2008) Int J Neuropsychopharm 11:465–476 5-HT1A receptor distribution in the human brain Post synaptic receptors Somatodendritic autoreceptors 5 5-HT1A receptor binding across brain regions healthy controls () and MDD () 9 to 24% reduction in 5-HT1A binding across regions of interest in MDD Hirvonen et al. (2008) Int J Neuropsychopharm 11:465–476 5-HT1A receptor binding – possible effect of antidepressant exposure Parsey et al. 2006 Biological Psychiatry 59:106 - 113 Replicated in new cohort: Parsey et al.
    [Show full text]
  • THE ROLE of the 5-HT Ta RECEPTOR in CENTRAL CARDIOVASCULAR REGULATION Printed By: Duphar B.V
    THE ROLE OF THE 5-HT tA RECEPTOR IN CENTRAL CARDIOVASCULAR REGULATION Printed by: Duphar B.V. C.J. van Houtenlaan 36 1381 CP Weesp The Netherlands Isbn 90-9004025-0 Cover design by F. W. Pompe. © G.H. Dreteler, Elst, 1991 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, mechanical, photocopying. recording, or otherwise. without written permission from the publisher. THE ROLE OF THE S-HT1A RECEPTOR IN CENTRAL CARDIOVASCULAR REGULATION DE ROL VAN DE 5-HT1A RECEPTOR IN DE CENTRALE CARDIOVASCULAIRE REGULA TIE PROEFSCHRIFT TER VERKRIJGING VAN DE GRAAD VAN DOCTOR AAN DE ERASMUS UNIVERSITEIT ROTTERDAM OP GEZAG VAN DE RECTOR MAGNIFICUS PROF.DR. C.J. RIJNVOS EN VOLGENS BESLUIT VAN HET COLLEGE VAN DEKANEN DE OPENBARE VERDEDIGING ZAL PLAATSVINDEN OP WOENSDAG 27 MAART 1991 OM 15.45 UUR door GERRIE HENDRIKA DRETELER GEBOREN TE DELDEN PROMOTIECOMMISSIE PROMOTOR: PROF.DR. P.R. SAXENA OVERIGE LEDEN: PROF.DR. A.J. MAN IN 'T VELD PROF.DR. P.A. VAN ZWIETEN DR. J.F.M. SMITS CO-PROMOTOR: DR. W. WOUTERS The investigations described in this thesis have been performed at the Institute of Pharmacology, Erasmus University Rotterdam, the Department of Pharmacology. Duphar B.V., Weesp, The Netherlands and the Department of Pharmacology, Royal Free Hospital School of Medicine, London, U.K. The work was supported by Duphar B.V., Weesp. CONTENTS page CHAPTER I General introduction 1.1 Serotonin (5-HT) I l.l.l Localisation of 5-HT I 1.1.2 Function of 5-HT 2 1.2 5-HT receptors
    [Show full text]