Background: Major depression affects 121 million persons worldwide and is a significant cause of increased mortality and morbidity, including disability and decreased productivity. Major depressive disorder can also be difficult to treat successfully; 30 to 40 percent of patients do not achieve remission with first-line antidepressant medications (typically, selective serotonin reuptake inhibitors [SSRIs] or serotonin-norepineph-rine reuptake inhibitors). Supplementing these first-line medications with an atypical antipsychotic can sometimes improve depression symptoms. Risperidone (Risperdal), an atypical antipsychotic used in bipolar mania and schizophrenia, has been studied in patients with depression who are resistant to antidepressant monotherapy. Mahmoud and colleagues studied risperidone augmentation to determine if it reduces symptoms and increases response to standard antidepressant therapy.

The Study: This randomized, double-blind, placebo-controlled study compared first-line antidepressants with the addition of risperidone or placebo. Patients were recruited from primary care and psychiatric practices, and were eligible if their depression symptoms were not significantly improved with adequate doses and duration of their first-line agent. After a four-week prospective open-label run-in period with their current antidepressant monotherapy, patients were randomized to add risperidone or placebo. The dosing schedule increased from 0.25 mg for the first three days, to 0.5 mg for days 4 to 15, to 1 mg for days 16 to 28. Those whose clinical response was insufficient at day 29 had the choice of increasing medication to 2 mg, continuing at the 1-mg dose, or discontinuing the double-blind treatment. The intention-to-treat analysis evaluated the 268 randomized patients who received at least one dose of study medication; the six-week completion rate was 81.0 percent for the risperidone group and 87.8 percent for the placebo group.

Results: Depression symptoms improved modestly but significantly more in the risperidone group compared with the placebo group, as measured by clinician-rated symptom response and patient-rated self-assessment. The 17-item Hamilton Rating Scale for Depression score improved more in the risperidone group versus the placebo group (13.4 ± 0.54 versus 16.2 ± 0.53; P < .001). Remission rates at week 6 were 24.5 versus 10.7 percent (P < .004), and each measure of patient improvement (Quality of Life Enjoyment and Satisfaction Questionnaire, the Patient Global Improvement Scale, and the Sheehan Disability Scale) were more improved in the risperidone group.

The adverse event rate was higher in the placebo group, but discontinuation rates were higher in the risperidone group (5.8 versus 2.3 percent); no motor symptoms requiring medication occurred in either group. Patients in the risperidone group had some improved symptoms within one week of starting therapy, and those benefits increased over the six-week study.

Conclusion: Risperidone is an effective adjunct treatment in some patients on standard antidepressant therapy, although the duration of benefit is not known from this short-term study. At the low doses used for augmentation, adverse motor effects from antipsychotic medication are uncommon.