Adjunctive Brexpiprazole May Reduce Irritability in Patients With MDD

Although research suggests that up to 50 percent of individuals with major depressive disorder (MDD) experience irritability and anger attacks, there are limited options for treating irritability associated with a major depressive episode. Findings from a study published in the Journal of Clinical Psychiatry now suggest that adding the atypical antipsychotic brexpiprazole to antidepressants may help those affected individuals.

“Brexpiprazole binds to a number of receptors that have been implicated in the regulation of aggressive behavior,” said the study’s lead author, Maurizio Fava, M.D., a professor of psychiatry at Harvard Medical School. He explained to Psychiatric News that brexpiprazole acts as a partial agonist at serotonin 5-HT1A receptors and D2 receptors, a mechanism that has been shown to reduce aggression in animals. In addition, the antipsychotic is an antagonist at norepinephrine alpha1 receptors; the alpha1-receptor antagonist prazosin is used to treat agitation and aggression in Alzheimer’s disease.

For the current study, Fava and colleagues recruited 54 patients aged 18 to 65 with MDD and irritability whose symptoms did not improve (as documented by a self-report of a less than 50 percent response) after two-week monotherapy with antidepressants.

Patients continued on the same antidepressant regimen, but received open-label adjunctive brexpiprazole (ranging from 1 mg to 3 mg daily) for six weeks. After this period, brexpiprazole was discontinued, and patients continued treatment with antidepressants alone for four weeks.

The researchers compared changes in depression, irritability, and anger from baseline to week 6 and from week 6 to week 10. Multiple rating scales were used to assess these changes, including the Montgomery-Asberg Depression Rating Scale, the Sheehan Irritability Scale, and the Kellner Symptom Questionnaire.

At week 6, clinically relevant improvements were observed in irritability, anger, and depressive symptoms; however, no further improvements in irritability, anger, and depressive symptoms were observed after brexpiprazole was discontinued at six weeks. Overall, adjunctive brexpiprazole was well tolerated with no clinically meaningful changes from baseline to endpoint in mean fasting metabolic parameters.

“In this exploratory study, irritability symptoms improved together with depressive symptoms in patients with MDD treated with adjunctive brexpiprazole,” the authors wrote. “These findings are consistent with the brexpiprazole pharmacologic profile.”

Fava added, “If these findings are replicated in [larger] placebo-controlled studies, then clinicians will be able to consider augmentation options such as this one when treating patients who continue to experience irritability or anger attacks despite adequate antidepressant therapy.”

The study was supported by H. Lundbeck A/S and Otsuka Pharmaceuticals. ■