Cariprazine, a new, orally active dopamine D_2/3 receptor partial agonist for the treatment of schizophrenia, bipolar mania and depression

Abstract

Cariprazine is a novel drug with partial agonist activity at dopamine D_2/3 receptors and six- to eightfold higher affinity for human dopamine D₃ over D₂ receptors. Results from several placebo-controlled Phase II/III trials in patients with a The Diagnostic and Statistical Manual of Mental Disorders IV diagnosis of schizophrenia or bipolar I disorder suggest that cariprazine is superior to placebo with respect to antipsychotic and antimanic activity. Reports concerning safety and tolerability of cariprazine are mainly favorable, although the rates of treatment-associated adverse events, which most commonly included akathisia and extrapyramidal symptom, are rather high. However, only minor alterations of clinical laboratory values, prolactin concentrations and ECG parameters are reported in cariprazine-treated patients. A new drug application to the U.S. F DA for cariprazine for the treatment of both schizophrenia and manic or mixed episodes associated with bipolar I disorder was submitted in November 2012. A more precise assessment of the clinical properties of this new drug will require additional studies, aimed to compare and contrast cariprazine with other antipsychotic agents.

Keywords::

• bipolar disorder
• cariprazine
• partial dopamine agonist
• schizophrenia

Acknowledgments

The authors thank Paul Cumming for critical revisions of the manuscript.

Financial & competing interests disclosure

G Gründer has served as a consultant for Bristol-Myers Squibb (New York, NY), Cheplapharm (Greifswald, Germany), Eli Lilly (Indianapolis, Ind), Forest Laboratories (New York, NY, USA), Lundbeck (Copenhagen, Denmark), Otsuka (Rockville, MD), Roche (Basel, Switzerland) and Servier (Paris, France), has served on the speakers’ bureau of Bristol-Myers Squibb, Eli Lilly, Gedeon Richter (Budapest, Hungary), Otsuka, Roche and Servier, has received grant support from Alkermes, Bristol-Myers Squibb, and Eli Lilly, and is co-founder of Pharma-Image – Molecular Imaging Technologies GmbH, Düsseldorf. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• • Cariprazine is a new, orally active dopamine D_2/3 receptor partial agonist, which has been tested for treatment of schizophrenia, bipolar mania and depression.

• • The receptor profile of cariprazine includes highest affinity for dopamine D₃ receptors, followed by D_2L and D_2S subtypes, somewhat lower affinity for serotonin 5-HT_2B and 5-HT_1A receptors, but only moderate affinity for 5-HT_2A, histamine H₁ and σ1 receptors, and a low affinity for adrenergic receptors.

• • The six- to eightfold higher affinity of cariprazine for human dopamine D₃ over D₂ receptors may predict better alleviation of cognitive impairments than is described for other antipsychotics.

• • The available results indicate a certain antipsychotic efficiency of cariprazine in the treatment of schizophrenia and likewise for manic or mixed episodes of bipolar disorder.

• • The relatively long plasma half-life (2–5 days) and the persistence of two active metabolites support single daily drug intake.

• • Doses in the range of 0.5–12.5 mg of cariprazine were well tolerated.

• • Treatment-emergent adverse events (such as EPS-related adverse events, insomnia, nausea, vomiting and anxiety) were observed in 68–86% of the cariprazine patients.

• • However, no clinically meaningful changes in metabolic parameters, prolactin elevation or QTc prolongation (>500 ms) were observed in cariprazine-treatment groups.

• • Further randomized clinical trails, in particular a direct comparison between cariprazine and established antipsychotics, are needed for a concluding evaluation of this, from actual point of view, certainly highly promising, new drug.