ABCs of Dopamine Receptor Partial Agonists

RESEARCH UPDATE

How do the 3 FDA-approved dopamine receptor partial agonists for the treatment of MDD, schizophrenia, and other disorders stack up against each other?

Brexpiprazole and cariprazine-the latest additions to the armamentarium-were approved in 2015. Aripiprazole, which was approved in 2002, is now available as a generic medication.

In a recent review, Leslie Citrome, MD, MPH,¹ Clinical Professor of Psychiatry and Behavioral Sciences at New York Medical College, compared and contrasted the 3 drugs, using data from registration trials of patients who fulfilled restrictive entry criteria. These patients may differ from those seen in routine clinical practice, Citrome said. “Pragmatic clinical trials that are more generalizable will help place these antipsychotic medications into clinical perspective for their use in the ‘real world.’”

Schizophrenia, bipolar disorder, and MDD are heterogeneous disorders, and medication response and tolerability can vary. “Having additional choices can offer greater opportunities for success,” said Citrome.

All 3 agents are approved for the treatment of schizophrenia. Aripiprazole and brexpiprazole are also approved for adjunctive treatment of MDD, and aripiprazole and cariprazine are approved for acute treatment of manic or mixed episodes associated with bipolar I disorder. In pediatric patients, aripiprazole is approved to treat irritability associated with autistic disorder and for the treatment of Tourette disorder. A short-acting intramuscular injection of aripiprazole is indicated for agitation associated with schizophrenia or bipolar mania.

The mechanisms of action of the 3 agents are similar, but their pharmacodynamic profiles are different. Brexpiprazole has lower intrinsic activity at the dopamine D₂ receptor and has an approximately 10-fold higher affinity for serotonin 5-HT_1A and 5-HT_2A receptors than aripiprazole, which potentially enhances tolerability, Citrome noted. Cariprazine has greater dopamine D₃ versus dopamine D₂ selectivity than aripiprazole. “Theoretically, dopamine D₃–preferring agents may exert pro-cognitive effects,” Citrome said.

The contraindications for the 3 drugs are similar. Because aripiprazole and brexpiprazole are approved for the treatment of MDD, they carry additional warnings about suicidality.

All 3 agents are dosed once daily. The starting dose for brexpiprazole is lower than the recommended dose range for schizophrenia and the recommended dose for MDD; therefore, brexpiprazole requires titration.

In contrast, the starting dose for aripiprazole can be therapeutic, as can the starting dose for cariprazine for schizophrenia. For the treatment of bipolar mania, cariprazine needs to be titrated.

Citrome compared the acute efficacy of the 3 drugs in adults in placebo-controlled randomized trials. In 4 positive pivotal short-term trials of aripiprazole in adults with acute schizophrenia, response rates were 38% for aripiprazole versus 24% for placebo.

Pooled data from 2 studies for the recommended target dose of brexpiprazole showed the percentage of responders was 46% with this drug compared with 31% for the pooled placebo groups. For pooled doses of cariprazine, the percentage of responders was 31% compared with 21% for the pooled placebo groups. “An appropriately designed head-to-head trial would be necessary to directly test non-inferiority,” Citrome said.

In 4 positive pivotal trials for aripiprazole monotherapy in adults with short-term acute bipolar mania, response rates were 47% for aripiprazole versus 31% for placebo. Pooled data from 3 studies for the recommended target dose of cariprazine for bipolar mania showed the percentage of responders was 57% with cariprazine compared with 36% for the pooled placebo groups.

In 2 positive pivotal short-term trials for aripiprazole in patients with acute MDD, response rates were 33% for aripiprazole versus 20% for placebo. For brexpiprazole, the pooled results from 2 pivotal trials showed 23.2% of patients who received the drug were responders compared with 14.5% of those who received placebo.

In schizophrenia studies, all 3 drugs seem to have excellent overall tolerability. For the most common adverse event for each medication, the rank order appears to be the following:

•Propensity for weight gain: brexpiprazole > aripiprazole > cariprazine
•Propensity for somnolence: aripiprazole > brexpiprazole > cariprazine
•Propensity for akathisia: cariprazine > aripiprazole > brexpiprazole

This is by indirect comparison, Citrome noted. “Appropriately designed head-to-head clinical trials will be necessary to accurately assess these potential differences.”

Cariprazine and brexpiprazole have been studied for maintenance treatment of schizophrenia. Cariprazine is also under investigation in a phase 3 trial for the adjunctive treatment of MDD, and brexpiprazole is being tested in a phase 3 trial for the treatment of PTSD and for agitation associated with dementia of the Alzheimer type.

References:

1. Citrome L. The ABC's of dopamine receptor partial agonists - aripiprazole, brexpiprazole and cariprazine: the 15-min challenge to sort these agents out. Int J Clin Pract. 2015;69:1211-1120.