Neurobiological bases and clinical aspects of the use of aripiprazole in treatment-resistant major depressive disorder.

Addition of atypical antipsychotics to the therapeutic regimen of patients with unipolar major depressive disorder not responding adequately to their treatment has become a common intervention. With all these agents the observation that low doses that are ineffective in schizophrenia, and thus not blocking dopamine D2 receptors effectively, indicate that their beneficial action is attributable to their action at other receptors. Preclinical research has shown that atypical antipsychotics can reverse the suppression of firing of norepinephrine neurons produced by selective serotonin reuptake inhibitors through their antagonism of 5-HT₂(A) receptors. In the case of aripiprazole, three large placebo-controlled studies in more than 1,000 patients individually concluded to significant antidepressant responses and remissions after a six-week treatment. Aripiprazole addition did not produce more discontinuations due to adverse events than placebo. The most frequently encountered adverse events were akathisia and restlessness. Weight gain was minimal but significant in two of the three studies, suggesting that this side effect is not major problem. There was no significant laboratory abnormalities noted with this strategy. It is proposed that because of its long half-life (approximately 3 days), the doses of aripiprazole were escalated too rapidly in these controlled trials. More gradual titration may lead in routine clinical practice to better outcomes, minimizing side effects and improving remission rates.