Dopamine Receptor Partial Agonists: Do They Differ in Their Clinical Efficacy?

Abstract

Dopamine receptor partial agonists (DRPAs; aripiprazole, brexpiprazole, and cariprazine) constitute a novel class of antipsychotics. Although they share a similar mechanism of action, DRPAs differ in their pharmacodynamics, pharmacokinetics, drug interactions, or safety and tolerability. The antipsychotic efficacy of all three drugs was established in several placebo-controlled randomized trials (RCTs) in schizophrenia, both acute phase and relapse prevention. In addition, each of the DRPA agents has been tested in other psychiatric disorders, including bipolar disorder or major depression. However, a few studies have examined their comparative clinical efficacy. There are no head-to-head comparisons between aripiprazole, brexpiprazole, or cariprazine. In two acute schizophrenia RCTs of cariprazine and brexpiprazole, aripiprazole was used as an indirect comparator to control for study sensitivity. To assess potential differences in the efficacy of DRPAs, we reviewed data from controlled trials, systematic reviews, and meta-analyses. Our results showed that the acute antipsychotic effects of DRPAs, as measured by the number needed to treat, are comparable. The three agents were superior to placebo in acute treatment, and cariprazine was found to be effective in the reduction of primary negative symptoms of schizophrenia. In the therapy of bipolar disorder, aripiprazole and cariprazine showed antimanic efficacy, cariprazine was also effective in the management of bipolar depression, and aripiprazole was effective for relapse prevention. The addon administration of aripiprazole or brexpiprazole reduced symptoms of major depression. Aripiprazole can control acute agitation associated with psychosis or bipolar disorder; brexpiprazole showed the potential to manage agitation in dementia patients. Aripiprazole has also established evidence of efficacy in children and adolescents and other conditions: OCD, tic disorders, and autism spectrum disorder. Our review of published data suggests that in terms of clinical efficacy, DRPAs are a heterogeneous group, with each drug possessing its own therapeutic benefits.

Challenges in defining treatment‐resistant mania in adults: A systematic review

“…Our definition does not distinguish between different antipsychotics (e.g., first‐ or second‐generation antipsychotics) because we are not aware of any convincing evidence associating specific classes or mechanisms of action (MOA) of antipsychotics with specific outcomes in the treatment of mania 71‐73 . Thus, as most (but not all) reviewed authors, our proposed definition requires the persistence of mania despite treatment with (at least) one antipsychotic (in addition to one traditional mood stabilizer) and we do not differentiate between antipsychotics of different classes or with putative different MOAs.…”

“…Our definition does not distinguish between different antipsychotics (e.g., first-or second-generation antipsychotics) because we are not aware of any convincing evidence associating specific classes or mechanisms of action (MOA) of antipsychotics with specific outcomes in the treatment of mania. [71][72][73] persistence of despite treatment with (at least) one antipsychotic (in addition to one traditional mood stabilizer) and we do not differentiate between antipsychotics of different classes or with putative different MOAs. Similarly, we do not differentiate antipsychotics that have been approved or not approved by the US Food and Drug Agency or the European Regulatory Agency for the treatment of mania because these approvals have been related to historical or commercial reasons rather than scientific or clinical ones (e.g., no first-generation antipsychotics-including clozapine-is approved, while almost all second-generation antipsychotics are approved).…”

Dopamine D1–D5 Receptors in Brain Nuclei: Implications for Health and Disease

“…One approach is to develop D2 receptor partial agonists, which have lower intrinsic activity than full agonists, and can act as antagonists in the presence of high dopamine levels or agonists in the presence of low dopamine levels. Examples of D2 receptor partial agonists are aripiprazole and brexpiprazole, which are approved for the treatment of schizophrenia, bipolar disorder, and major depressive disorder [226,227]. Another approach is to develop D2 receptor allosteric modulators, which bind to a distinct site from the orthosteric site and enhance or inhibit the binding and efficacy of the endogenous ligand or other drugs.…”

Efficacy of Serotonin and Dopamine Activity Modulators in the Treatment of Negative Symptoms in Schizophrenia: A Rapid Review

“…Focusing on the specificity of each SDAM, aripiprazole has very high binding affinities with dopamine D2, D3, and serotonin 5-HT 2B receptors; high binding affinities with serotonin 5-HT 1A and 5-HT 2A receptors; and moderate binding affinities with serotonin 5-HT 2C, 5-HT 7 receptors, dopamine D4 receptors, adrenergic α 2C, α 1B and α 1A receptors, and histamine H1 receptors [ 99 ]. Aripiprazole is distinguished from earlier antipsychotics by its partial agonist activity at D2, D3, 5-HT 1A receptor targets [ 100 ]; intrinsic activity is 60%, compared to 28%, and 73% for dopamine and serotonin, respectively [ 101 ].…”