FDA Clears New Agent for Schizophrenia, Major Depression

Megan Brooks


July 13, 2015

The US Food and Drug Administration (FDA) has approved brexpiprazole (Rexulti, Lundbeck, Inc, and Otsuka Pharmaceutical Co, Ltd) for adults with schizophrenia and as an adjunctive therapy to antidepressant medication in adults with major depressive disorder (MDD).

Brexpiprazole is expected to be available in the United States in early August.

The approval was supported by four placebo-controlled phase 3 studies ― two in patients with MDD, and two in patients with schizophrenia.

Patients enrolled in the MDD studies met DSM-IV-TR criteria for MDD, with or without symptoms of anxiety, and had previously failed multiple trials of antidepressant therapy. Brexpiprazole (2 mg and 3 mg) plus antidepressant therapy was superior to placebo plus antidepressant therapy on the primary endpoint ― change in Montgomery-Åsberg Depression Rating Scale scores, the companies note in a news release.

Adverse reactions led 3% of patients receiving brexpiprazole to discontinue treatment. The most common adverse reactions included akathisia and weight gain.

"For some patients with MDD, antidepressant monotherapy is not enough, and these patients continue to suffer from unresolved symptoms," study investigator Michael E. Thase, MD, director, Mood and Anxiety Program, University of Pennsylvania Perelman School of Medicine, in Philadelphia, said in the release. "In the clinical trials that led to the FDA's approval, adding brexpiprazole to ongoing antidepressant therapy helped MDD patients improve unresolved symptoms of MDD."

In the schizophrenia trials, brexpiprazole, administered at an adequate dose for 6 weeks, demonstrated statistically significant efficacy compared with placebo for the primary endpoint of Positive and Negative Syndrome Scale scores.

"We saw a combination of efficacy and symptom improvement within a tight target dose range with one adverse event, weight increase, occurring in at least 4% of patients and with twice the incidence of placebo," Christoph U. Correll, MD, from Hofstra North Shore–Long Island Jewish School of Medicine, in Hempstead, New York, and lead author of one of the studies, said in the release.

The mechanism of action of brexpiprazole in MDD and schizophrenia is not known but may be mediated through a combination of partial agonist activity at serotonin 5-HT1A and dopamine D2 receptors and antagonist activity at serotonin 5-HT2A receptors, the companies say. Brexpiprazole also "exhibits high affinity (subnanomolar) for these receptors, as well as for noradrenaline alpha1B/2C receptors."

Brexpiprazole is given in a once-daily oral dose with a "well-defined" titration schedule and can be taken with or without food, the companies note. For MDD, the drug should be initiated at 0.5 g or 1 mg once daily, titrated at weekly intervals to 1 mg once daily, then up to the target dosage of 2 mg once daily on the basis of the patient's clinical response and tolerability.

For schizophrenia, brexpiprazole should be initiated at 1 mg once daily for the first 4 days, titrated to 2 mg once daily on days 5 through 7, then to 4 mg on day 8, on the basis of patient's clinical response and tolerability.

Boxed Warning Reminders

In a statement, the FDA reminds clinicians that brexpiprazole and other drugs used to treat schizophrenia carry a boxed warning noting an increased risk for death associated with the off-label use of these drugs to treat behavioral problems in older people with dementia-related psychosis.

"No drug in this class is approved to treat patients with dementia-related psychosis," the FDA notes.

The boxed warning also alerts physicians and patients about an increased risk for suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants. "Patients should be monitored for worsening and emergence of suicidal thoughts and behaviors," the FDA says. Brexpiprazole will be dispensed with a patient medication guide that describes information about the drug's uses and risks.

"Schizophrenia and major depressive disorder can be disabling and can greatly disrupt day-to-day activities," Mitchell Mathis, MD, director of the Division of Psychiatry Products in the FDA's Center for Drug Evaluation and Research, said in the statement. "Medications affect everyone differently, so it is important to have a variety of treatment options available for patients with mental illnesses."


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