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Int J Mol Sci. 2016 Feb 16;17(2):241. doi: 10.3390/ijms17020241.

Atypical Antipsychotics in the Treatment of Acute Bipolar Depression with Mixed Features: A Systematic Review and Exploratory Meta-Analysis of Placebo-Controlled Clinical Trials.

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New York Psychiatric Institute, Columbia University, New York City, NY 10032, USA.
Health Service and Population Research Department, Institute of Psychiatry, King's College London, De Crespigny Park, London SE5 8AF, UK.
Physiotherapy Department, South London and Maudsley NHS Foundation Trust, London SE5 8AZ, UK.
National Health Service, Department of Mental Health, Psychiatric Service of Diagnosis and Treatment, Hospital. Mazzini, ASL 4, Teramo 64100, Italy.
Department of Clinical Neurosciences, Hermanas Hospitalarias-Villa San Benedetto Menni Hospital, FoRiPsi 22032, Italy.
Hermanas Hospitalarias-Villa San Giuseppe, Ascoli Piceno 63100, Italy.
Department of Medicine (DIMED), University of Padua, Padova 35121, Italy.
Department of Neurosciences, University of Padua, Padova 35121, Italy.
New York Psychiatric Institute, Columbia University, New York City, NY 10032, USA.
Departamento de Psiquiatria e Saúde Mental, Faculdade de Medicina, Universidade de Lisboa, Lisbon 1649-035, Portugal.


Evidence supporting the use of second generation antipsychotics (SGAs) in the treatment of acute depression with mixed features (MFs) associated with bipolar disorder (BD) is scarce and equivocal. Therefore, we conducted a systematic review and preliminary meta-analysis investigating SGAs in the treatment of acute BD depression with MFs. Two authors independently searched major electronic databases from 1990 until September 2015 for randomized (placebo-) controlled trials (RCTs) or open-label clinical trials investigating the efficacy of SGAs in the treatment of acute bipolar depression with MFs. A random-effect meta-analysis calculating the standardized mean difference (SMD) between SGA and placebo for the mean baseline to endpoint change in depression as well as manic symptoms score was computed based on 95% confidence intervals (CI). Six RCTs and one open-label placebo-controlled studies (including post-hoc reports) representing 1023 patients were included. Participants received either ziprasidone, olanzapine, lurasidone, quetiapine or asenapine for an average of 6.5 weeks across the included studies. Meta-analysis with Duval and Tweedie adjustment for publication bias demonstrated that SGA resulted in significant improvements of (hypo-)manic symptoms of bipolar mixed depression as assessed by the means of the total scores of the Young Mania Rating Scale (YMRS) (SMD -0.74, 95% CI -1.20 to -0.28, n SGA = 907, control = 652). Meta-analysis demonstrated that participants in receipt of SGA (n = 979) experienced a large improvement in the Montgomery-Åsberg Depression Rating Scale (MADRS) scores (SMD -1.08, 95% CI -1.35 to -0.81, p < 0.001) vs. placebo (n = 678). Publication and measurement biases and relative paucity of studies. Overall, SGAs appear to offer favorable improvements in MADRS and YMRS scores vs. placebo. Nevertheless, given the preliminary nature of the present report, additional original studies are required to allow more reliable and clinically definitive conclusions.


acute bipolar depression; diagnostic and statistical manual for mental disorders fifth edition (DSM-5); meta-analysis; mixed features; second generation antipsychotic (SGA); systematic-review

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