DOCSLIB.ORG

(12) United States Patent (10) Patent No.: US 6,835,728 B2 Andrews Et Al

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
(12) United States Patent (10) Patent No.: US 6,835,728 B2 Andrews Et Al USOO6835728B2 (12) United States Patent (10) Patent No.: US 6,835,728 B2 Andrews et al. (45) Date of Patent: Dec. 28, 2004 (54) DRUG COMBINATION FOR THE FOREIGN PATENT DOCUMENTS TREATMENT OF DEPRESSION AND WO 94 19026 A 1/1994 RELATED DISORDERS COMPRISING WO 98.43646 A 8/1998 MRTAZAPINE OTHER PUBLICATIONS (75) Inventors: John Stuart Andrews, Schilde (BE); Wilhelmus Drinkenburg, Molenschot Chemical Abstracts 110:108817, “5-HT1Agonists Reduce 5-Hydroxytryptamine Release ... ', Sharp et al (1989).* (NL); Nicholas Matthew Ward, Koe B K et al: “Effects of Serotoninergic Agents on Down Scotland (GB) regulation of beta-Adrenoceptors by the Selective Serotonin (73) Assignee: Akzo Nobel N.V., Arnhem (NL) Reuptake Inhibitor Sertraline.'; Archives Internationales de Pharmacodynamie et de Therapie, vol. 329, No. 2, 1995, pp. * Y NotOtice: Subjubject to anyy disclaimer,disclai theh term off thisthi 231-244. patent is extended or adjusted under 35 Bailer Ursula et al: “The use of mirtazapine in depressed U.S.C. 154(b) by 0 days. inpatients.” Wiener Klinische Wochenschrift, vol. 110, No. 18, Oct. 2, 1998, pp. 646–650. (21) Appl. No.: 10/181,843 Mulrow C.D. et al: “Efficacy of newer medications for (22) PCT Filed: Jan. 15, 2001 treating depression in primary care patients.” American Journal of Medicine, (2000), 10/81,(54–64). (86) PCT No.: PCT/EP01/00407 Williams J.W. Jr. et al: “A systematic review of newer pharmacotherapies for depression in adults: Evidence report S371 (c)(1), summary.” Annals of Internal Medicine, (May 2, 2000), pp. (2), (4) Date: Oct. 8, 2002 743-756. (87) PCT Pub. No.: WO01/52855 * cited by examiner PCT Pub. Date:Jul. 26, 2001 Primary Examiner Frederick Krass (65) Prior Publication Data (74) Attorney, Agent, or Firm Mark W. Milstead US 2003/0105083 A1 Jun. 5, 2003 (57) ABSTRACT (30) Foreign Application Priority Data The invention relates to a combination comprising an amount of mirtazapine, or a pharmaceutically acceptable Salt Jan. 19, 2001 (NL) ........................................... OO2OO189 or Solvate thereof, and an amount of gepirone, or a phar (51) Int. Cl. ................................................ A61K 31/55 maceutically acceptable Salt or Solvate thereof, optionally in (52) U.S. Cl. ................... 514/214.02; 514/220; 514/922 asSociation with one or more pharmaceutically acceptable (58) Field of Search ............................ 514/214.02, 220, carriers, whereby the amount of gepirone and the amount of 514/922 mirtazapine are Such that the effect of the composition is more favourable than the added effects of the amounts of (56) References Cited each drug Separately. This combination can be used in the treatment of depression and related disorders, whereby the U.S. PATENT DOCUMENTS invention also provides for a new method of treatment of 5,114,976 A 5/1992 Norden ....................... 514/646 depression and related disorders. 5,977,099 A * 11/1999 Nickolson ................... 514/214 6,150,353 A * 11/2000 Broekkamp et al. ... 514/214.02 2 Claims, No Drawings US 6,835,728 B2 1 2 DRUG COMBINATION FOR THE with one or more pharmaceutically acceptable carriers, TREATMENT OF DEPRESSION AND whereby the amount of gepirone and the amount of mir RELATED DISORDERS COMPRISING tazapine are Such that the effect of the combination is more MRTAZAPINE favourable than the added effects of the amounts of each drug Separately. Thus, gepirone and mirtazapine truly have a Synergistic interaction when used in the treatment of This application is the National Stage of International depression and related disorders. As a consequence, the Application PCT/EP01/00407, filed Jan. 15, 2001, claims combined use of mirtazapine and gepirone has better effects priority to EP 00200189.9, filed Jan. 19, 2000. in more patients in comparison to each drug alone. The FIELD OF THE INVENTION better effect can reside in leSS Side effects or a faster or more complete recovery in individual patients or in the overall The invention relates to a combination comprising result of the treatment of a group of patients. The preferred mirtazapine, to a package containing dosage units compris use of the combination will be in the treatment of the before ing mirtazapine, and to a method of treatment of depression mentioned treatment-resistant depression, also known as and related disorders. refractory depression or treatment refractory depression. 15 The present invention thus concerns the administration of BACKGROUND OF THE INVENTION two different psychotropic drugs from different pharmaco Disorders of the central nervous System, Such as depres logical categories, each drug enhancing the therapeutic Sion and anxiety are illnesses that affect people of all ages. efficacy of the other drug in the treatment of depression and Although there are many effective drugs available for treat related disorders. ment of these diseases, the currently available methods of The following specifications of the terms used above treatment are often Still not adequate. Most noteworthy is serve to clarify better what is provided by this invention. that there are no positive treatment results in about one third The drug name mirtazapine also refers to the individual of all Subjects with depression or anxiety and recovery in the (R) and (S) enantiomers of mirtazapine. These can be used effectively treated group is slow, with an onset of effect at as their Salts, Substantially free, i.e. associated with less than the earliest two weeks after the Start of drug treatment. 25 5%, preferably less than 2%, in particular less than 1% of the Mirtazapine (Org 3770; disclosed in U.S. Pat. No. 4,062, other enantiomer or as mixtures of Such enantiomers in any 848), or the newly introduced drug gepirone (disclosed in proportions including racemic mixtures containing Substan U.S. Pat. No. 4,423,049), are examples of modern drugs for tially equal amounts of the two enantiomers. the treatments of depression and anxiety with favourable Unless otherwise Stated all amounts of the active com side effect profiles and very low risks for a lethal overdose. ponents refer to the weights of mirtazapine or gepirone as For more effective treatment there is hope that the different base. According to the terminology in this description the mechanisms of action of drugs enables complementary use, drugs gepirone and mirtazapine are the active ingredients or in the Sense that patients not responding to one drug, may active components of the combination. turn out to be responsive to another drug. Sometimes, drugs Pharmaceutically acceptable Salts include acid addition with the same therapeutic indication are prescribed as com 35 Salts, for example, hydrochloric, fumaric, maleic, citric or bination therapy in order to profit from Such a mutually Succinic acid, these acids being mentioned only by way of Supplementary effect although it is generally not recom illustration and without implied limitation. mended to combine antidepressant drugs in View of risks for The terms pharmaceutically acceptable carriers and cumulative side effects or Synergistic toxic interactions excipients refer to those Substances known in the art to be (Schweitzer and Tuckwell, in Drug Safety, Vol. 19, pp 40 allowable as filler or carrier material in pills, tablets, cap 455-464, 1998). Usually, if a seemingly positive effect of a Sules etc. The Substances are usually approved for this known drug combination occurs in an individual patient, the purpose by health-care authorities and are inactive as phar positive effect is due to only one of the drugs in the macological agents. A compilation of pharmaceutically combination. More desirable is a truly synergistic effect of acceptable carriers and excipients can be found in the two drugs with the same indication, in the Sense that the effect of the combination is Superior over an additive effect 45 Handbook of Pharmaceutical excipients (2" edition edited of the effects of both drugs in an individual patient. There are by A. Wade and P. J. Weller; Published by the American only very few synergistic therapeutic drug interactions Pharmaceutical Association, Washington and The Pharma known which have found acceptance in the area of treatment ceutical Press, London in 1994). Specifically, lactose, starch, of central nervous System diseases. Most information is cellulose derivatives and the like, or mixtures thereof, can be available on So-called augmentation therapy of treatment 50 used as carriers for the active components of the combina resistant depression by addition of lithium to anti-depressant tion according to this invention. drugs. The use of Such a combination is viewed with caution DETAILED DESCRIPTION OF THE in view of the side effects of lithium (Hardy et al., Journal INVENTION Clin. Psychopharmacology, vol. 17, pp. 22-26, 1997). The The term combination refers to any presentation form in results of a combination of lithium with mirtazapine has 55 which the intention for combined use of mirtazapine and been disclosed with favourable results, but the augmentation gepirone can be recognised. Such combinations of mirtaza is not So Strong that this combination would be selected as pine and gepirone may in this description also be referred to first choice treatment of depressive disorders (Bruijn et al., as combinations according to the invention. It will be Journal Clin. Psychiatry, Vol. 59, pp 657–663, 1998). appreciated that the compounds of the combination may be 60 BRIEF SUMMARY OF THE INVENTION administered concomitantly, either in the same or different pharmaceutical
Load more

Recommended publications
  • Serotonin and Drug-Induced Therapeutic Responses in Major Depression, Obsessive–Compulsive and Panic Disorders Pierre Blier, M.D., Ph.D
    Serotonin and Drug-Induced Therapeutic Responses in Major Depression, Obsessive–Compulsive and Panic Disorders Pierre Blier, M.D., Ph.D. and Claude de Montigny, M.D., Ph.D. The therapeutic effectiveness of antidepressant drugs in major development of treatment strategies producing greater efficacy depression was discovered by pure serendipity. It took over 20 and more rapid onset of antidepressant action; that, is lithium years before the neurobiological modifications that could addition and pindolol combination, respectively. It is expected mediate the antidepressive response were put into evidence. that the better understanding recently obtained of the Indeed, whereas the immediate biochemical effects of these mechanism of action of certain antidepressant drugs in drugs had been well documented, their antidepressant action obsessive– compulsive and panic disorders will also lead to generally does not become apparent before 2 to 3 weeks of more effective treatment strategies for those disorders. treatment. The different classes of antidepressant [Neuropsychopharmacology 21:91S–98S, 1999] treatments were subsequently shown to enhance serotonin © 1999 American College of Neuropsychopharmacology. neurotransmission albeit via different pre- and postsynaptic Published by Elsevier Science Inc. mechanisms. Clinical trials based on this hypothesis led to the KEY WORDS: Antidepressant; Electroconvulsive shocks; electroconvulsive shock treatment (ECT), which was Lithium; Pindolol; Hippocampus; Orbito-frontal cortex generally given only to hospitalized patients. It took several years after the demonstration of the In the late 1950s, the therapeutic effect of certain drugs antidepressant effect of iproniazide and imipramine to in major depression was discovered by serendipity. An understand that these drugs could interfere with the ca- antidepressant response was observed in patients with tabolism of monoamines.
    [Show full text]
  • Comparative Efficacy and Acceptability of Pharmacological Treatments in the Acute Phase Treatment of Bipolar Depression: a Multi
    COMPARATIVE EFFICACY AND ACCEPTABILITY OF PHARMACOLOGICAL TREATMENTS IN THE ACUTE PHASE TREATMENT OF BIPOLAR DEPRESSION: A MULTIPLE TREATMENT META-ANALYSIS [PROTOCOL] Tomofumi Miura, Toshi A. Furukawa, Hisashi Noma, Shiro Tanaka, Keisuke Motomura, Hiroshi Mitsuyasu, Satomi Katsuki, Andrea Cipriani, Sarah Stockton, John Geddes, Georgia Salanti, Shigenobu Kanba Background Description of the condition In late 19th century, Emil Kraepelin classified the major endogenous psychoses into two psychotic illnesses, manic-depressive illness and dementia praecox (Kraepelin’s dichotomy) (Trede et al. , 2005). His concept of manic-depressive illness had covered all of the major clinical forms of severe, moderate and mild melancholia. In 1957, Leonhard proposed to distinguish Kraepelin’s manic-depressive illness into bipolar illness, in which patients had histories of both depression and mania, and monopolar illness, in which patients only had histories of depression (Leonhard, 1979). This basic idea of the bipolar-unipolar distinction was supported by Angst and by Perris in 1966 (Angst, 1966, Perris, 1966), and it continues in the recent diagnostic classification system of mood disorders in DSM-IV(American Psychiatric Association, 1994) and ICD-10 (WHO, 1993). Bipolar disorder is a complex disorder, which is characterized by recurrent episodes of depression and mania (bipolar I disorder) or hypomania (bipolar II disorder)(American Psychiatric Association, 1994). The lifetime prevalence of any bipolar disorders, bipolar I and II disorders have been estimated at 1.1%, 0.7% and 0.5% respectively using the World Mental Health Survey version of the WHO Composite International Diagnostic Interview (Suppes et al. , 2001). The mean age at onset of bipolar disorder is reported to be in the early 20s, but its complex clinical features make its diagnosis difficult and there is a difference of about 8 years between age at onset and age at first treatment (Suppes, Leverich, 2001).
    [Show full text]
  • Conformational Flexibility of Buspirone Analogues from X-Ray in the Solids and Nmr in Solution
    CONFORMATIONAL FLEXIBILITY OF BUSPIRONE ANALOGUES FROM X-RAY IN THE SOLIDS AND NMR IN SOLUTION Anna Bielenica 1, Andrzej Zimniak 2, Izabela Dyba áa3, Anna E. Kozio á3, Marta Struga 1 1 Department of Medical Chemistry, Medical University of Warsaw, Warsaw, Poland 2 Department of Physical Chemistry, Medical University of Warsaw, Warsaw, Poland 3 Faculty of Chemistry, Maria Curie-Sk áodowska University, Lublin, Poland Bioactive molecular conformation of a drug is one of the key points for understanding the ligand-receptor interactions. N-substituted arylpiperazines are important class of 5-HT receptor ligands (particularly 5-HT 1A , 5-HT 2A and 5-HT 7) widely used in the treatment of anxiety, depression, schizophrenia, sleep and memory disorders. Majority of compounds of this group possess hydrocarbon linker of different length and type, which connects the arylpiperazine moiety with the second terminal group, e. g. cyclic imide. According to SAR (structure-activity relationship) analyses, the presence of an aryl group at N4 atom of the piperazine ring is critical in respect to the biological activity of these compounds. The protonated nitrogen atom forms the hydrogen bond with the carboxyl oxygen of the Asp 3.32 side chain, that is crucial for the interaction with the 5-HT receptors. In addition, the aromatic ring stabilizes the ligand binding by a CH…ʌ interaction with the Phe 6.52 residue. Nowak et al. claimed that o-methoxy-phenyl moieties of a ligand form a hydrogen bond with the hydroxyl group of Ser 5.42 [1]. Some authors have underlined also a role of the terminal hydrophobic imide part in a stabilization of the ligand-receptor complex by ʌ…ʌ and/or dipole…dipole interactions [2].
    [Show full text]
  • Hallucinogens: an Update
    National Institute on Drug Abuse RESEARCH MONOGRAPH SERIES Hallucinogens: An Update 146 U.S. Department of Health and Human Services • Public Health Service • National Institutes of Health Hallucinogens: An Update Editors: Geraline C. Lin, Ph.D. National Institute on Drug Abuse Richard A. Glennon, Ph.D. Virginia Commonwealth University NIDA Research Monograph 146 1994 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service National Institutes of Health National Institute on Drug Abuse 5600 Fishers Lane Rockville, MD 20857 ACKNOWLEDGEMENT This monograph is based on the papers from a technical review on “Hallucinogens: An Update” held on July 13-14, 1992. The review meeting was sponsored by the National Institute on Drug Abuse. COPYRIGHT STATUS The National Institute on Drug Abuse has obtained permission from the copyright holders to reproduce certain previously published material as noted in the text. Further reproduction of this copyrighted material is permitted only as part of a reprinting of the entire publication or chapter. For any other use, the copyright holder’s permission is required. All other material in this volume except quoted passages from copyrighted sources is in the public domain and may be used or reproduced without permission from the Institute or the authors. Citation of the source is appreciated. Opinions expressed in this volume are those of the authors and do not necessarily reflect the opinions or official policy of the National Institute on Drug Abuse or any other part of the U.S. Department of Health and Human Services. The U.S. Government does not endorse or favor any specific commercial product or company.
    [Show full text]
  • Sex Differences in Serotonergic and Dopaminergic Mediation of LSD Discrimination in Rats
    Western Michigan University ScholarWorks at WMU Dissertations Graduate College 8-2017 Sex Differences in Serotonergic and Dopaminergic Mediation of LSD Discrimination in Rats Keli A. Herr Western Michigan University, [email protected] Follow this and additional works at: https://scholarworks.wmich.edu/dissertations Part of the Psychology Commons Recommended Citation Herr, Keli A., "Sex Differences in Serotonergic and Dopaminergic Mediation of LSD Discrimination in Rats" (2017). Dissertations. 3170. https://scholarworks.wmich.edu/dissertations/3170 This Dissertation-Open Access is brought to you for free and open access by the Graduate College at ScholarWorks at WMU. It has been accepted for inclusion in Dissertations by an authorized administrator of ScholarWorks at WMU. For more information, please contact [email protected]. SEX DIFFERENCES IN SEROTONERGIC AND DOPAMINERGIC MEDIATION OF LSD DISCRIMINATION IN RATS by Keli A Herr A dissertation submitted to the Graduate College in partial fulfillment of the requirements for the degree of Doctor of Philosophy Psychology Western Michigan University August 2017 Doctoral Committee: Lisa Baker, Ph.D., Chair Cynthia Pietras, Ph.D. Heather McGee, Ph.D. Missy Peet, Ph.D. SEX DIFFERENCES IN SEROTONERGIC AND DOPAMINERGIC MEDIATION OF LSD DISCRIMINATION IN RATS Keli A. Herr, Ph.D. Western Michigan University After decades of opposition, a resurgence of interest in the psychotherapeutic potential of LSD is gaining acceptance in the medical community. Future acceptance of LSD as a psychotherapeutic adjuvant may be predicated on knowledge about its neural mechanisms of action. Preclinical drug discrimination assay offers an invaluable model to determine the neural mechanisms underlying LSD’s interoceptive stimulus effects.
    [Show full text]
  • Synergistic Action of 5-HT2A Antagonists and Selective Serotonin Reuptake Inhibitors in Neuropsychiatric Disorders
    Neuropsychopharmacology (2003) 28, 402–412 & 2003 Nature Publishing Group All rights reserved 0893-133X/03 $25.00 www.neuropsychopharmacology.org Synergistic Action of 5-HT2A Antagonists and Selective Serotonin Reuptake Inhibitors in Neuropsychiatric Disorders ,1 2 3 2 Gerard J Marek* , Linda L Carpenter , Christopher J McDougle and Lawrence H Price 1Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA; 2Department of Psychiatry and Human, Brown Medical School, Mood 3 Disorders Program, Behavior, Butler Hospital, Providence, RI, USA; Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA Recently, the addition of drugs with prominent 5-HT2 receptor antagonist properties (risperidone, olanzapine, mirtazapine, and mianserin) to selective serotonin reuptake inhibitors (SSRIs) has been shown to enhance therapeutic responses in patients with major depression and treatment-refractory obsessive–compulsive disorder (OCD). These 5-HT antagonists may also be effective in 2 ameliorating some symptoms associated with autism and other pervasive developmental disorders (PDDs). At the doses used, these drugs would be expected to saturate 5-HT2A receptors. These findings suggest that the simultaneous blockade of 5-HT2A receptors and activation of an unknown constellation of other 5-HT receptors indirectly as a result of 5-HT uptake inhibition might have greater therapeutic efficacy than either action alone. Animal studies have suggested that activation of 5-HT1A and 5-HT2C receptors may counteract the effects of activating 5-HT2A receptors. Additional 5-HT receptors, such as the 5-HT1B/1D/5/7 receptors, may similarly counteract the effects of 5-HT receptor activation. These clinical and preclinical observations suggest that the combination of highly 2A selective 5-HT antagonists and SSRIs, as well as strategies to combine high-potency 5-HT receptor and 5-HT transporter blockade in 2A 2A a single compound, offer the potential for therapeutic advances in a number of neuropsychiatric disorders.
    [Show full text]
  • Tcas Versus Placebo - New Studies in the Guideline Update
    TCAs versus placebo - new studies in the guideline update Comparisons Included in this Clinical Question Amitriptyline vs placebo Clomipramine vs placebo Dosulepin (dothiepin) vs placebo AMSTERDAM2003A LARSEN1989 FERGUSON1994B BAKISH1992B PECKNOLD1976B ITIL1993 BAKISH1992C RAMPELLO1991 MINDHAM1991 BREMNER1995 THOMPSON2001B CLAGHORN1983 CLAGHORN1983B FEIGHNER1979 GELENBERG1990 GEORGOTAS1982A GOLDBERG1980 HICKS1988 HOLLYMAN1988 HORMAZABAL1985 HOSCHL1989 KLIESER1988 LAAKMAN1995 LAPIERRE1991 LYDIARD1997 MYNORSWALLIS1995 MYNORSWALLIS1997 REIMHERR1990 RICKELS1982D RICKELS1985 RICKELS1991 ROFFMAN1982 ROWAN1982 SMITH1990 SPRING1992 STASSEN1993 WILCOX1994 16 Imipramine vs placebo BARGESCHAAPVELD2002 BEASLEY1991B BOYER1996A BYERLEY1988 CASSANO1986 CASSANO1996 CLAGHORN1996A COHN1984 COHN1985 COHN1990A COHN1992 COHN1996 DOMINGUEZ1981 DOMINGUEZ1985 DUNBAR1991 ELKIN1989 ENTSUAH1994 ESCOBAR1980 FABRE1980 FABRE1992 FABRE1996 FEIGER1996A FEIGHNER1980 FEIGHNER1982 FEIGHNER1983A FEIGHNER1983B FEIGHNER1989 FEIGHNER1989A FEIGHNER1989B FEIGHNER1989C FEIGHNER1992B FEIGHNER1993 FONTAINE1994 GELENBERG2002 GERNER1980B HAYES1983 ITIL1983A KASPER1995B KELLAMS1979 LAIRD1993 LAPIERRE1987 LECRUBIER1997B LIPMAN1986 LYDIARD1989 MARCH1990 17 MARKOWITZ1985 MENDELS1986 MERIDETH1983 Nortriptyline vs placebo NANDI1976 GEORGOTAS1986A NORTON1984 KATZ1990 PEDERSEN2002 NAIR1995 PESELOW1989 WHITE1984A PESELOW1989B PHILIPP1999 QUITKIN1989 RICKELS1981 RICKELS1982A RICKELS1987 SCHWEIZER1994 SCHWEIZER1998 SHRIVASTAVA1992 SILVERSTONE1994 SMALL1981 UCHA1990 VERSIANI1989 VERSIANI1990
    [Show full text]
  • Mikocka-Walus Et Al-2017
    This is a repository copy of Adjuvant therapy with antidepressants for the management of inflammatory bowel disease (Protocol). White Rose Research Online URL for this paper: https://eprints.whiterose.ac.uk/118724/ Version: Published Version Article: Mikocka-Walus, Antonina Anna orcid.org/0000-0003-4864-3956, Fielder, Andrea, Prady, Stephanie Louise orcid.org/0000-0002-8933-8045 et al. (3 more authors) (2017) Adjuvant therapy with antidepressants for the management of inflammatory bowel disease (Protocol). Cochrane Database of Systematic Reviews. ISSN 1469-493X https://doi.org/10.1002/14651858.CD012680 Reuse Items deposited in White Rose Research Online are protected by copyright, with all rights reserved unless indicated otherwise. They may be downloaded and/or printed for private study, or other acts as permitted by national copyright laws. The publisher or other rights holders may allow further reproduction and re-use of the full text version. This is indicated by the licence information on the White Rose Research Online record for the item. Takedown If you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing [email protected] including the URL of the record and the reason for the withdrawal request. [email protected] https://eprints.whiterose.ac.uk/ Cochrane Database of Systematic Reviews Adjuvant therapy with antidepressants for the management of inflammatory bowel disease (Protocol) Mikocka-Walus A, Fielder A, Prady SL, Esterman AJ, Knowles S, Andrews JM Mikocka-Walus A, Fielder A, Prady SL, Esterman AJ, Knowles S, Andrews JM. Adjuvant therapy with antidepressants for the management of inflammatory bowel disease.
    [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]
  • Long-Term Antidepressant Treatments Result in a Tonic Activation of Forebrain 5-HT1A Receptors
    The Journal of Neuroscience, December 1, 1998, 18(23):10150–10156 Long-Term Antidepressant Treatments Result in a Tonic Activation of Forebrain 5-HT1A Receptors Nasser Haddjeri, Pierre Blier, and Claude de Montigny Neurobiological Psychiatry Unit, McGill University, Montre´ al, Que´ bec, Canada H3A 1A1 We report here the first direct functional evidence of an increase ministration, WAY 100635 markedly increased (60–200%) the in the tonic activation of postsynaptic 5-HT1A receptors by firing activity of CA3 pyramidal neurons. Such a disinhibition antidepressant treatments. Because 5-HT1A receptor activation was absent in rats treated with the nonantidepressant drug hyperpolarizes and inhibits CA3 pyramidal neurons in the dorsal chlorpromazine, in rats receiving only one ECS, or in rats hippocampus, we determined, using in vivo extracellular re- receiving multiple ECSs in combination with an intrahippocam- cording, whether the selective 5-HT1A receptor antagonist WAY pal pertussis toxin treatment to inactivate Gi/o-coupled 5-HT1A 100635 could disinhibit these neurons. Unexpectedly, no receptors. These data indicate that such antidepressant treat- disinhibition could be detected in controls. However, after ments, acting on entirely different primary targets, might allevi- long-term treatment with the tricyclic antidepressant imipra- ate depression by enhancing the tonic activation of forebrain mine, the selective 5-HT reuptake inhibitor paroxetine, the postsynaptic 5-HT1A receptors. a reversible monoamine oxidase-A inhibitor befloxatone, the 2- adrenergic antagonist mirtazapine, or the 5-HT1A receptor ag- Key words: antidepressants; serotonin (5-HT); 5-HT1A recep- onist gepirone or multiple electroconvulsive shock (ECS) ad- tors; WAY 100635; disinhibition; dorsal hippocampus a With a prevalence of at least 4% of the general population, major 2-adrenoceptor antagonist, increases 5-HT neurotransmission as depression is one of the most common psychiatric disorders.
    [Show full text]
  • 151201 Script Gepirone AC Meeting FINAL
    Presentation of Sarah Sorscher, Public Citizen’s Health Research Group, Before the Food and Drug Administration Psychopharmacologic Drugs Advisory Committee December 1, 2015 [Slide 1] Good afternoon, my name is Sarah Sorscher and I am a researcher with Public Citizen’s Health Research Group. I have no financial conflicts of interest. I am here today because Public Citizen is concerned that approval of gepirone would represent an unprecedented step backwards, effectively weakening the FDA’s standards for approval of these drugs, and possibly others. [Slide 2] The gepirone development program is notable not only for the sheer number of failed and negative trials, but also for the direction of treatment effect trends. This table includes the nine completed efficacy trials that were considered by the FDA in its efficacy review for gepirone, excluding the three trials that were terminated early. 1 Of these nine completed efficacy trials, four showed trends in the wrong direction, with greater observed improvement in the placebo group compared with the group receiving gepirone. These appear in red on this slide. And while two trials did achieve positive results (displayed in blue), the possibility remains that these positive findings could be due to random chance. 1 FDA Briefing Document, Psychopharmacologic Drugs Advisory Committee (PDAC) meeting, December 1, 2015. Pages 19-20. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Psych opharmacologicDrugsAdvisoryCommittee/UCM474540.pdf . Accessed November 30, 2015.
    [Show full text]
  • Lithium Augmentation Tortoise Or Hare?
    Lithium augmentation Tortoise or hare? David Cousins Director, Newcastle Magnetic Resonance Centre Newcastle University UK ACKNOWLEDGEMENTS COLLEAGUES AND COLLABORATORS Andrew Blamire Fawzi Boumezbeur Carly Flowers Pete Thelwall Fiona Smith FUNDING SOURCES MRC Clinician Scientist Fellowship EU Horizon 2020 programme CONFLICTS OF INTEREST Honorarium from Lundbeck for educational activities paid to main employer, Newcastle University OVERVIEW THIS PRESENTATION WILL COVER • Lithium use in major depressive disorder • Early observations to practice guidelines • Mechanisms and models of onset of action • Future directions MAJOR DEPRESSIVE DISORDER • High prevalence and often recurrent • Substantial morbidity and mortality • Only 40-60% of patients respond to their initial antidepressant monotherapy If there is no (or minimal improvement) with initial treatment, typical guideline recommendations include: • Dose increase • Switching antidepressants • Augmentation/combination treatment A NOTE ON STRATEGIES COMBINATION Two or more antidepressant drugs taken together AUGMENTATION Antidepressant drug together with a ‘non-antidepressant drug’ ACCELERATION Simultaneous initiation of two drugs to hasten response LITHIUM: ACUTE ANTIDEPRESSANT EFFECTS Study Comparator N Duration Outcome (weeks) Mendels 1972 Desipramine 24 3 Lithium = desipramine Watanabe 1975 Imipramine 45 3 Lithium = imipramine Worrall 1979 Imipramine 29 3 Lithium > imipramine Khan 1981 Amitriptyline 25 3 Lithium = amitriptyline Arieli 1981 Clomipramine 33 3 Lithium = clomipramine > Placebo
    [Show full text]