Adjunctive Atypical Antipsychotic Treatment for Major Depressive Disorder: A Meta-Analysis of Depression, Quality of Life, and Safety Outcomes

In a systematic review and meta-analysis, Glen Spielmans and colleagues find that adjunctive atypical antipsychotic medications are associated with small-to-moderate improvements in depressive symptoms in patients with depression, but there is little evidence for improvement on measures of quality of life, and these medications are linked to adverse events such as weight gain. Background: 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. Methods and Findings: 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). Conclusions: 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. Background: Everyone feels miserable occasionally. But for people who are clinically depressed, feelings of sadness and hopelessness and physical symptoms such as sleeping badly can last for months or years and can make them feel life is no longer worth living. Depression affects one in six people at some time during their life. Clinicians diagnose depression by asking their patients a series of questions about their feelings and symptoms. The answer to each question is given a score, and the total score from the questionnaire (“depression rating scale”) indicates the severity of depression. 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. Why Was This Study Done?: Atypical antipsychotic medications (for example, aripiprazole, olanzapine/fluoxetine combination [OFC], quetiapine, and risperidone) are also widely prescribed for the treatment of depression. These drugs, which were developed to treat mental illnesses that are characterized by a loss of contact with reality, are used as adjunctive therapy for depression. That is, they are used in addition to antidepressant drugs. Clinicians wrote nearly four million prescriptions for adjunctive treatment of depression with atypical antipsychotic medications in 2007–2008 in the US alone. However, it is not known whether the benefits of using these drugs to treat depression outweigh their side effects, which include weight gain, sedation, and akathisia (a feeling of inner restlessness resulting in an urge to move, which may or may not be accompanied by increased movement). Here, the researchers undertake a systematic review and meta-analysis of the efficacy and safety profiles of atypical antipsychotic medications used for the adjunctive treatment of depression. A systematic review uses predefined criteria to identify all the research on a given topic; a meta-analysis is a statistical approach that combines the results of several studies. What Did the Researchers Do and Find?: The researchers identified 14 short-term randomized controlled trials (duration 4–12 weeks) that compared adjunctive antipsychotic medications (aripiprazole, OFC, quetiapine, or risperidone) to placebo (dummy drug) in the treatment of depression that had not responded to antidepressant medication alone. All four drugs had statistically significant effects (effects unlikely to have happened by chance) on remission, which was most commonly defined as a score of less than eight at the study end point on the Montgomery–Asberg Depression Rating Scale. The researchers calculated the number of patients that would have to be treated for one patient to achieve remission (number needed to treat, or NNT). For OFC, the NNT was 19; for all the other drugs it was nine. All the drugs except OFC also significantly improved response rates (defined as a 50% improvement in depression rating score). However, the medications provided little or no benefit in terms of functioning and quality of life, except for risperidone, which had a small-to-moderate effect on quality of life. Finally, treatment with atypical antipsychotic medications was linked to several adverse effects, including weight gain (all four drugs) and akathisia (aripiprazole). What Do These Findings Mean?: These results suggest that atypical antipsychotic medications for the adjunctive treatment of depression are efficacious in reducing observer-rated depressive symptoms. However, clinicians should interpret this conclusion cautiously for several reasons. First, adjunctive treatment with atypical antipsychotics provided only small-to-moderate benefits. Moreover, shortcomings in study design and data reporting methods may have inflated the apparent benefits of treatment and reduced the apparent incidence of adverse events. Second, this study provides little evidence that adjunctive treatment with atypical antipsychotics improves patients' quality of life or reduces their functional impairment. Finally, this study highlights abundant evidence of potential treatment-related harm. This evaluation of the safety and efficacy of adjunctive treatments for clinical depression provides critical insights that should help clinicians better understand the risk–benefit profiles of this approach to the treatment of major depressive disorder. Additional Information: Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001403.