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      Pharmacotherapy of Bipolar Disorder with Quetiapine: A Recent Literature Review and an Update

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          Abstract

          Bipolar disorder is a chronic, recurrent condition with the usual onset during adolescence or early adulthood. In the Diagnostic and Statistical Manual of Mental Disorders 5th edition, it is conceptualized as a spectrum disorder usually associated with such comorbidities as anxiety disorders and substance use disorders. It is a relatively prevalent condition often complicated by mixed episodes, rapid cycling, subsyndromal symptoms, and treatment refractoriness. In spite of carrying substantial morbidity and mortality, effective treatments are few and far between and conventional mood stabilizers are often unsuccessful in controlling the various manifestations of the disorder. In this scenario, second generation antipsychotics are emerging as treatments with valid efficacy in all phases of bipolar disorder. Quetiapine is a versatile atypical antipsychotic which was first approved for the treatment of schizophrenia, but latter on the basis of controlled studies earned United States Food and Drug Administration’s approval for acute as well as maintenance treatment of this difficult to treat condition. In this review, recently published studies in the last 10 years were examined to update the knowledge about the efficacy and safety of quetiapine in the treatment of bipolar disorder. The medication’s clinical pharmacology was first considered followed by a literature review summarizing its uses in bipolar disorder. The conclusion was that quetiapine was efficacious in manic, mixed and depressive episodes and as a maintenance agent with a good tolerability profile.

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          Atypical antipsychotics: mechanism of action.

          Although the principal brain target that all antipsychotic drugs attach to is the dopamine D2 receptor, traditional or typical antipsychotics, by attaching to it, induce extrapyramidal signs and symptoms (EPS). They also, by binding to the D2 receptor, elevate serum prolactin. Atypical antipsychotics given in dosages within the clinically effective range do not bring about these adverse clinical effects. To understand how these drugs work, it is important to examine the atypical antipsychotics' mechanism of action and how it differs from that of the more typical drugs. This review analyzes the affinities, the occupancies, and the dissociation time-course of various antipsychotics at dopamine D2 receptors and at serotonin (5-HT) receptors, both in the test tube and in live patients. Of the 31 antipsychotics examined, the older traditional antipsychotics such as trifluperazine, pimozide, chlorpromazine, fluphenazine, haloperidol, and flupenthixol bind more tightly than dopamine itself to the dopamine D2 receptor, with dissociation constants that are lower than that for dopamine. The newer, atypical antipsychotics such as quetiapine, remoxipride, clozapine, olanzapine, sertindole, ziprasidone, and amisulpride all bind more loosely than dopamine to the dopamine D2 receptor and have dissociation constants higher than that for dopamine. These tight and loose binding data agree with the rates of antipsychotic dissociation from the human-cloned D2 receptor. For instance, radioactive haloperidol, chlorpromazine, and raclopride all dissociate very slowly over a 30-minute time span, while radioactive quetiapine, clozapine, remoxipride, and amisulpride dissociate rapidly, in less than 60 seconds. These data also match clinical brain-imaging findings that show haloperidol remaining constantly bound to D2 in humans undergoing 2 positron emission tomography (PET) scans 24 hours apart. Conversely, the occupation of D2 by clozapine or quetiapine has mostly disappeared after 24 hours. Atypicals clinically help patients by transiently occupying D2 receptors and then rapidly dissociating to allow normal dopamine neurotransmission. This keeps prolactin levels normal, spares cognition, and obviates EPS. One theory of atypicality is that the newer drugs block 5-HT2A receptors at the same time as they block dopamine receptors and that, somehow, this serotonin-dopamine balance confers atypicality. This, however, is not borne out by the results. While 5-HT2A receptors are readily blocked at low dosages of most atypical antipsychotic drugs (with the important exceptions of remoxipride and amisulpride, neither of which is available for use in Canada) the dosages at which this happens are below those needed to alleviate psychosis. In fact, the antipsychotic threshold occupancy of D2 for antipsychotic action remains at about 65% for both typical and atypical antipsychotic drugs, regardless of whether 5-HT2A receptors are blocked or not. At the same time, the antipsychotic threshold occupancy of D2 for eliciting EPS remains at about 80% for both typical and atypical antipsychotics, regardless of the occupancy of 5-HT2A receptors. The "fast-off-D2" theory, on the other hand, predicts which antipsychotic compounds will or will not produce EPS and hyperprolactinemia and which compounds present a relatively low risk for tardive dyskinesia. This theory also explains why L-dopa psychosis responds to low atypical antipsychotic dosages, and it suggests various individualized treatment strategies.
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            Update on typical and atypical antipsychotic drugs.

            Antipsychotic drugs (APDs) are best classified as typical or atypical. The distinction is based solely on their ability to cause extrapyramidal side effects (EPS), including tardive dyskinesia (TD). The two classes differ in mechanism of action, with atypical APDs providing important modulation of serotonergic neurotransmission. TD increases the death rate and can be minimized by limiting use of typical APDs. Clozapine is unique among the atypical APDs in its efficacy for ameliorating psychosis in patients with treatment-resistant schizophrenia (TRS), for reduction of suicide, and for improving longevity. The typical and atypical APDs do not differ in improving psychopathology in non-TRS. The atypicals vary in metabolic side effects: some have little burden. Cognitive benefits of the atypical APDs may be superior for some domains of cognition and require less use of anticholinergic drugs, which impair memory, for treatment of EPS. Overall, choosing among the atypical APDs as first-line treatment represents the best course for schizophrenia and most likely other disorders for which APDs are used.
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              A double-blind, placebo-controlled study of quetiapine and lithium monotherapy in adults in the acute phase of bipolar depression (EMBOLDEN I).

              The aim of this study was to compare the efficacy and tolerability of quetiapine and lithium monotherapy with that of placebo for a major depressive episode in bipolar disorder. 802 patients with DSM-IV-defined bipolar disorder (499 bipolar I, 303 bipolar II) were randomly allocated to quetiapine 300 mg/d (n = 265), quetiapine 600 mg/d (n = 268), lithium 600 to 1800 mg/d (n = 136), or placebo (n = 133) for 8 weeks. Primary endpoint was the change in Montgomery-Asberg Depression Rating Scale (MADRS) total score. The study was conducted from August 2005 to May 2007. Mean MADRS total score change from baseline at week 8 was -15.4 for quetiapine 300 mg/d, -16.1 for quetiapine 600 mg/d, -13.6 for lithium, and -11.8 for placebo (P < .001 for both quetiapine doses, P = .123 for lithium, vs placebo). Quetiapine 600 mg/d was significantly more effective than lithium in improving MADRS total score at week 8 (P = .013). Quetiapine-treated (both doses), but not lithium-treated, patients showed significant improvements (P < .05) in MADRS response and remission rates, Hamilton Depression Rating Scale (HDRS), Clinical Global Impressions-Bipolar-Severity of Illness and -Change, and Hamilton Anxiety Rating Scale (HARS) scores at week 8 versus placebo. Both quetiapine doses were more effective than lithium at week 8 on the HDRS and HARS. The most common adverse events were somnolence, dry mouth, and dizziness with quetiapine (both doses) and nausea with lithium. Quetiapine (300 or 600 mg/d) was more effective than placebo for the treatment of episodes of acute depression in bipolar disorder. Lithium did not significantly differ from placebo on the main measures of efficacy. Both treatments were generally well tolerated. clinicaltrials.gov Identifier: NCT00206141. Copyright 2010 Physicians Postgraduate Press, Inc.
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                Author and article information

                Journal
                Clin Psychopharmacol Neurosci
                Clin Psychopharmacol Neurosci
                Clinical Psychopharmacology and Neuroscience
                Korean College of Neuropsychopharmacology
                1738-1088
                2093-4327
                April 2015
                30 April 2015
                : 13
                : 1
                : 25-35
                Affiliations
                Islamic International Medical College, Riphah International University, Rawalpindi, Pakistan
                Author notes
                Address for correspondence: Ather Muneer, MD, Islamic International Medical College, Riphah International University, 274 Peshawar Road, Rawalpindi 4622, Pakistan, Tel: +92-0515481828, Fax: +92-0515125170, E-mail: muneerather2@ 123456gmail.com
                Article
                cpn-13-25
                10.9758/cpn.2015.13.1.25
                4423161
                25912535
                8efc6505-0890-4e7a-9d8b-95d49c0c2bad
                Copyright © 2015, Korean College of Neuropsychopharmacology

                This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 10 October 2014
                : 19 November 2014
                : 20 November 2014
                Categories
                Review

                bipolar disorder,bipolar depression,mania,atypical antipsychotic agent,mood stabilizer

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