WHY ANTIDEPRESSANTS MAY NEED ATYPICAL ANTIPSYCHOTIC RX TO HELP IMPROVE MOOD

There is growing evidence that for people with a partial response to antidepressants, adding an atypical antipsychotic medication can rapidly improve mood [within 7-10 days] McIntyre et al.,JAMA Psychiatry 2026 with improvement being considered clinically meaningful as the clinical improvements represents a 2 point improvement [the minimal clincally importance difference] on the MADRAS compared to placebo over 6-12 weeks with some adverse effects . The FDA has approved aripiprazole, brexpiprazole, caripraszine were the most acceptable and lumateperone and quetiapine XR, plus olonzapine-fluoxetine had more adverse effects. It was only lumateperone that did not have >7% weight gain. Cochrane 2019 (TRD) showed high quality indication of benefit for quetiapine and caripraszine and ziprasidone showed a more moderate benefit with reduced depressive symptoms at 8-12 weeks by 1.5-2.7 points, an SMD of abouut 0.18-0.42. Only the quetiapine reduced remissions and adverse events were consistently higher than on placebo for the atypicals. There was a suggestion that for patients over 60 years old bupropion may come close to having similar benefits compared to atypicals.

My experience supports the benefit of 5 mg of aripiprazole and 200-300 mg of quetiapine XR in reducing depressive symptoms. I have found that it is frequently necessary to reduce the doses after a benefit has been achieved and the benefit can also be maintained at the lower dose to reduce adverse side effects without losing the benefit. Stoping the atypicals will lose the benefit and yet after 16-18 months of very low depressive symptoms it is possible to stop these medications and not have a worsening of depressive symptoms.