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Quetiapine

A Review of its Use in Acute Mania and Depression Associated with Bipolar Disorder

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Summary

Abstract

Quetiapine (Seroquel®), an atypical antipsychotic with established efficacy in the treatment of schizophrenia, shows efficacy in the treatment of acute mania and depression associated with bipolar disorder.

Quetiapine, either as monotherapy or in combination with lithium or divalproex sodium (valproate semisodium), is generally well tolerated and effective in reducing manic symptoms in adult and adolescent patients with acute bipolar mania, and is approved for use in adults for this indication. As monotherapy, the drug is also effective in reducing depressive symptoms in patients with bipolar depression. It is associated with a low incidence of extrapyramidal symptom (EPS)-related adverse events and low EPS ratings in bipolar disorder. Quetiapine thus shows potential in the treatment of bipolar depression, and represents a useful agent for the treatment of acute bipolar mania.

Pharmacological Profile

Quetiapine is a dibenzothiazepine derivative and acts as an antagonist at serotonin 5-HT1a and 5-HT2A, dopamine D1 and D2, histamine H1 and adrenergic α1 and α2 receptors. Its mechanism of action in bipolar disorder is unknown.

In patients with schizophrenia, oral quetiapine was rapidly absorbed and the mean steady-state area under the plasma concentration-time curve and maximum plasma concentration values were dose proportional. Steady-state concentrations are expected to be reached within 2 days of dosing. Quetiapine is primarily metabolised by cytochrome P450 3A4. The pharmacokinetics of quetiapine were altered in elderly patients and in patients with hepatic or renal impairment.

Therapeutic Efficacy

Monotherapy with oral quetiapine (up to 800 mg/day) reduced Young Mania Rating Scale (YMRS) scores from baseline to day 21 (primary endpoint) to a significantly greater extent than placebo in two randomised, double-blind, multicentre trials in adults hospitalised with acute bipolar mania. The scores continued to improve to the end of the trial (day 84).

At day 21 in one trial, but not in the other, the YMRS response and remission rates, Clinical Global Impression Scale-Bipolar (CGI-BP) response rate and improvement from baseline in CGI-BP severity of illness scores were all significantly greater for quetiapine than for placebo recipients. In both trials, after treatment for 84 days, results for all four endpoints were significantly better for quetiapine than placebo recipients. At days 21 and 84 in both trials, quetiapine reduced Positive and Negative Syndrome Scale (PANSS) total and subscale scores and Montgomery-Åsberg Depression Rating Scale (MADRS) scores from baseline to a significantly greater extent than placebo.

Quetiapine (up to 800 mg/day), in combination with divalproex sodium or lithium, reduced mean YMRS scores from baseline to day 21 (primary endpoint) significantly more than placebo plus divalproex sodium or lithium in a randomised, double-blind, multicentre trial in adults hospitalised with an acute manic episode associated with bipolar disorder. In the same trial, the YMRS response and remission rates, improvement in CGI-BP severity of illness score and CGI-BP response rate were all significantly greater for quetiapine plus divalproex sodium or lithium recipients than for placebo plus divalproex sodium or lithium recipients. There were no significant between-group differences for the improvement in MADRS and total PANSS scores or the rate of emergent depression.

Quetiapine, in combination with divalproex sodium, has also shown efficacy in a small, randomised, double-blind trial in adolescents hospitalised with an acute manic or mixed episode associated with bipolar disorder.

In an 8-week, randomised, double-blind trial in adult outpatients with bipolar depression, quetiapine (300 and 600 mg/day) significantly reduced MADRS scores from baseline to study end compared with placebo (primary endpoint). Both dosages of quetiapine were also significantly more effective than placebo in terms of MADRS response and remission rates, change in Hamilton Depression and Anxiety rating scale and CGI severity of illness scores, and improving quality of sleep and overall quality of life.

Tolerability

In the above-mentioned trials in patients with bipolar mania or depression, most adverse events experienced by quetiapine recipients were of mild-to-moderate intensity.

In a pooled analysis of two 12-week, randomised, double-blind trials of quetiapine monotherapy in patients with bipolar mania, and in a randomised, double-blind trial in patients with bipolar depression, significantly more quetiapine than placebo recipients experienced somnolence, dry mouth and dizziness. In the pooled analysis, significantly more quetiapine than placebo recipients experienced weight gain, and sedation and constipation occurred in significantly more quetiapine than placebo recipients in the trial in patients with depression.

Somnolence, dry mouth, asthenia and postural hypotension occurred in significantly more quetiapine plus lithium or divalproex sodium recipients than placebo plus lithium or divalproex sodium recipients in a pooled analysis of two randomised, double-blind trials (of 3 or 6 weeks duration) in patients with bipolar mania. In a randomised, double-blind trial in adolescents, sedation was the only adverse event experienced by significantly more quetiapine plus divalproex sodium than placebo plus divalproex sodium recipients.

In all above-mentioned trials, there were no significant between-group differences in changes from baseline to final assessment in symptoms of parkinsonism and akathisia, as assessed by mean Simpson-Angus Scale and Barnes Akathisia Rating Scale scores.

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Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

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Acknowledgements

At the request of the journal, AstraZeneca provided a non-binding review of this article.

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Authors and Affiliations

  1. Adis International Limited, Auckland, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland, 1311, New Zealand

    Toni M. Dando & Gillian M. Keating

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  1. Toni M. Dando
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Corresponding author

Correspondence to Toni M. Dando.

Additional information

Various sections of the manuscript reviewed by: M. Berk, Department of Clinical and Biomedical Sciences, The University of Melbourne, Geelong, Victoria, Australia; C. Bowden, Department of Psychiatry, University of Texas Health Sciences Center, San Antonio, Texas, USA; R. Chengappa, Western Psychiatric Institute and Clinic, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA; L. DeVane, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, South Carolina, USA; H. Grunze, Department of Psychiatry, Ludwig-Maximilians University, Munich, Germany; G. Mahli, Department of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia; E. Richelson, Department of Psychiatry and Psychology, Mayo Foundation & Mayo Clinic, Jacksonville, Florida, USA; P. Wang, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California, USA.

Data Selection

Sources: Medical literature published in any language since 1980 on quetiapine, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: MEDLINE search terms were ‘quetiapine’ or ‘ICI-204636’ and ([‘manic’ or ‘mania’ or ‘depression’] and ‘bipolar disorder’). EMBASE search terms were ‘quetiapine’ and ([‘manic’ or ‘mania’ or ‘depression’] and ‘bipolar’). AdisBase search terms were ‘quetiapine’ or ‘ICI 204636’ and ([‘manic’ or mania’ or ‘depression’] and ‘bipolar disorders’). Searches were last updated 10 October 2005.

Selection: Studies in patients with mania or depression associated with bipolar disorder who received quetiapine. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Quetiapine, bipolar disorder, mania, depression, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.

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Dando, T.M., Keating, G.M. Quetiapine. Drugs 65, 2533–2551 (2005). https://doi.org/10.2165/00003495-200565170-00008

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