Abstract
Atypical antipsychotic medications are widely prescribed for the adjunctive treatment of depression, yet their total risk-benefit profile is not well understood. We thus conducted a systematic review of the efficacy and safety profiles of atypical antipsychotic medications used for the adjunctive treatment of depression. We included randomized trials comparing adjunctive antipsychotic medication to placebo for treatment-resistant depression in adults. Our literature search (conducted in December 2011 and updated on December 14, 2012) identified 14 short-term trials of aripiprazole, olanzapine/fluoxetine combination (OFC), quetiapine, and risperidone. When possible, we supplemented published literature with data from manufacturers' clinical trial registries and US Food and Drug Administration New Drug Applications. Study duration ranged from 4 to 12 wk. All four drugs had statistically significant effects on remission, as follows: aripiprazole (odds ratio [OR], 2.01; 95% CI, 1.48-2.73), OFC (OR, 1.42; 95% CI, 1.01-2.0), quetiapine (OR, 1.79; 95% CI, 1.33-2.42), and risperidone (OR, 2.37; 95% CI, 1.31-4.30). The number needed to treat (NNT) was 19 for OFC and nine for each other drug. All drugs with the exception of OFC also had statistically significant effects on response rates, as follows: aripiprazole (OR, 2.07; 95% CI, 1.58-2.72; NNT, 7), OFC (OR, 1.30, 95% CI, 0.87-1.93), quetiapine (OR, 1.53, 95% CI, 1.17-2.0; NNT, 10), and risperidone (OR, 1.83, 95% CI, 1.16-2.88; NNT, 8). All four drugs showed statistically significant effects on clinician-rated depression severity measures (Hedges' g ranged from 0.26 to 0.48; mean difference of 2.69 points on the Montgomery-Asberg Depression Rating Scale across drugs). On measures of functioning and quality of life, these medications produced either no benefit or a very small benefit, except for risperidone, which had a small-to-moderate effect on quality of life (g = 0.49). Treatment was linked to several adverse events, including akathisia (aripiprazole), sedation (quetiapine, OFC, and aripiprazole), abnormal metabolic laboratory results (quetiapine and OFC), and weight gain (all four drugs, especially OFC). Shortcomings in study design and data reporting, as well as use of post hoc analyses, may have inflated the apparent benefits of treatment and reduced the apparent incidence of adverse events. Atypical antipsychotic medications for the adjunctive treatment of depression are efficacious in reducing observer-rated depressive symptoms, but clinicians should interpret these findings cautiously in light of (1) the small-to-moderate-sized benefits, (2) the lack of benefit with regards to quality of life or functional impairment, and (3) the abundant evidence of potential treatment-related harm. Please see later in the article for the Editors' Summary.
Highlights
Atypical antipsychotic medications are widely used in the treatment of major depressive disorder
Atypical antipsychotic medications for the adjunctive treatment of depression are efficacious in reducing observer-rated depressive symptoms, but clinicians should interpret these findings cautiously in light of (1) the small-tomoderate-sized benefits, (2) the lack of benefit with regards to quality of life or functional impairment, and (3) the abundant evidence of potential treatment-related harm
We obtained one controlled trial of aripiprazole that used low doses (2 or 5 mg); we did not include this trial because the starting dose of 2 mg was administered for 30 d prior to participants switching to the dose of 5 mg that falls within the recommended 5–10 mg range set by the Food and Drug Administration (FDA) [42]
Summary
Atypical antipsychotic medications are widely used in the treatment of major depressive disorder. Aggregate statistics mask the specific indications for use (i.e., monotherapy versus adjunctive therapy), this represents a substantial increase in antipsychotic treatment of depression over time, as there were just over 2 million such visits annually during 1995 and 1996, of which 405,000 involved prescriptions for atypical antipsychotic medications. These data are consistent with market reports from industry [2]. Three atypical antipsychotic medications have approval from the US Food and Drug Administration (FDA) as adjunctive therapies in depression for adults, while none are approved for monotherapy. Treatment of depression often involves talking treatments (psychotherapy) such as cognitive behavioral therapy, which helps people change negative ways of thinking and behaving and antidepressant drugs, most commonly ‘‘selective serotonin reuptake inhibitors’’ such as fluoxetine and paroxetine
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