Atypical Antipsychotic Augmentation in the Treatment of Depression

Unpublished studies
Several additional studies have been presented at national meetings but not yet published. Dunner and colleagues¹⁸ randomized patients with treatment- resistant depression to an 8-week trial of sertraline(Drug information on sertraline) monotherapy (n = 20) or sertraline plus ziprasidone(Drug information on ziprasidone) (n = 40). Patients with a history of non-SSRI treatment resistance (but not those who were poorly responsive to SSRIs) showed significantly greater improvement with combination treatment than with monotherapy.

Keitner and associates¹⁹ presented the results of a large (N = 97) randomized, double-blind, placebo-controlled study of risperidone(Drug information on risperidone) augmentation for patients with difficult-to-treat depression. Although both study groups improved significantly over a 4-week trial, patients receiving risperidone augmentation had significantly greater odds for remitting (odds ratio, 3.33) and responded faster than those augmented with placebo. The augmented risperidone group also reported having significantly better quality of life and more satisfaction with their medication.¹⁹

Patients with depression (N = 605) who were not responsive to SSRI treatment were enrolled in 2 parallel 8-week, double-blind studies comparing a combination of olanzapine(Drug information on olanzapine) plus fluoxetine(Drug information on fluoxetine), olanzapine alone, and fluoxetine alone.²⁰ Response rates were 40%, 30%, and 26%, respectively. Pooled results from the 2 studies demonstrated significantly greater symptomatic improvement in the combination group. Patients taking olanzapine had greater weight gain and an increase in cholesterol level.

Treatment was augmented with quetiapine(Drug information on quetiapine) in an 8-week, double-blind, placebo-controlled trial of patients with treatment-resistant depression.²¹ Significantly more patients who received treatment with the quetiapine augmentation responded to treatment (67%) or achieved remission (43%) than did those whose treatment was augmented with placebo (27% and 15%, respectively). A smaller (N = 15) randomized, double-blind, placebo-controlled study with quetiapine augmentation also found significantly greater improvement in the quetiapine group than in the placebo-augmented group.²²

In the only study comparing the efficacy and tolerability of atypical antipsychotics, Ravindran and associates²³ conducted a 6-week randomized, double-blind study of low and high doses of risperidone or olanzapine in 43 patients who had difficult-to-treat depression. Both low-dose groups (risperidone 0.5 to 1 mg/d and olanzapine 2.5 to 5 mg/d) did better than the high-dose groups (risperidone 2 to 3 mg/d and olanzapine 10 to 15 mg/d) but were comparable to each other. Interestingly, there was no reported difference in adverse effects between the low- and high-dose groups, while patients in the olanzapine group reported more adverse effects than did those in the risperidone groups.

Clinical implications
What can we conclude from these studies about when and how to use atypical antipsychotics for patients with depression? Overall, it appears that some patients respond well to augmentation with atypical antipsychotics. To date, no study has been able to identify predictors of which patients are more likely to benefit from such augmentation. One study has suggested that patients whose symptoms failed to improve on non- SSRIs are likely to have better responses than those whose symptoms failed to improve on SSRIs,¹⁸ but most studies have noted symptom improvement in SSRI nonresponders as well.

The most clinically useful and reasonably consistent finding is that treatment augmentation with an atypical antipsychotic is associated with a faster response than continuing the primary antidepressant alone. A majority of the studies suggest that a significant ben-efit to augmentation is evident with- in 1 to 2 weeks after initiating the treatment.^{8,9,11,12,15,17,19}