More and more studies are being done on the use of antipsychotics in major depression. The vast majority of these are on the use of atypicals as an augmentation strategy and not as monotherapy, but quetiapine has recently been approved by the FDA as a monotherapy for unipolar depression. As far as I know, it’s the only atypical antipsychotic approved for this purpose. The most recent meta-analysis suggests that, as augmenting agents, atypical antipsychotics are effective in the treatment of major depression.

Studies have been done using olanzapine, risperidone, quetiapine and aripiprazole. In a pooled analysis there were no differences in the efficacy of any of the agents as an augmentation strategy; however, the rate of discontinuation due to adverse events was elevated in those who were taking the atypical antipsychotics in comparison with placebo. These trials were all acute phase trials and therefore no long-term data are available about continuation or maintenance. Long-term exposure is associated with serious side effects in this group of drugs, particularly metabolic syndrome with its risks of lipid abnormalities, elevated blood sugar, weight gain and diabetes. The risks and benefits must be weighed in each case but augmentation with an atypical agent may be an effective treatment in the short term. It remains to be seen whether the benefits outweigh the risks in the long term.

Bipolar depression is a particularly difficult condition to treat and, more than mania is highly debilitating. Patients with bipolar disorder spend an estimated 3-37 times more time depressed than manic and it’s chronic in up to 20% of patients. The use of antipsychotics in the treatment of bipolar depression has been the object of considerable investigation in the past decade. The only medications for which there is evidence of efficacy for acute bipolar depression are quetiapine, quetiapine XR, and olanzapine together with fluoxetine. These agents are also associated with a more rapid response. So far studies using aripiprazole have been negative. I’m not aware of studies using risperidone or clozapine. Since risperidone is more like a typical antipsychotic than olanzapine or quetiapine, it might predispose to more dysphoria, as the typicals often do. A trial is worthwhile, however, as individual responses vary. Clozapine may also be tried with or without an antidepressant. Olanzapine may play a role in the prevention of depressive episodes.

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