The preclinical discovery and development of cariprazine for the treatment of schizophrenia

ABSTRACT

Introduction: Cariprazine is approved in the United States and Europe for the treatment of manic or mixed episodes associated with bipolar I disorder and for the treatment of schizophrenia in adult patients. It is typically administered orally once a day (a dose range 1.5 – 6 mg/day), does require titration, and may be given with or without food. It has a half-life of 2 – 4 days with an active metabolite that has a terminal half-life of 2 – 3 weeks.

Areas covered: This review article focuses on the preclinical discovery of cariprazine providing details regarding its pharmacological, behavioral, and neurochemical mechanisms and its contribution to clinical therapeutic benefits. This article is based on the available literature with respect to the preclinical and clinical findings and product labels of cariprazine.

Expert opinion: Cariprazine shows highest affinity toward D₃ receptors, followed by D₂, 5-HT_2B, and 5-HT_1A receptors. It also shows moderate affinity toward σ₁, 5-HT_2A, and histamine H₁ receptors. Long-term administration of cariprazine altered the abundance of dopamine, serotonin, and glutamate receptor subtypes in different brain regions. All these mechanisms of cariprazine may contribute toward its unique preclinical profile and its clinically observed benefits in the treatment of schizophrenia, bipolar mania, and possibly other psychiatric disorders.

KEYWORDS:

• Abuse
• bipolar mania
• cariprazine
• cognition
• depression
• rodent models
• schizophrenia

Article highlights

• Cariprazine is approved in the United States and Europe for the treatment of manic or mixed episodes associated with bipolar I disorder and the treatment of adult patients with schizophrenia. It is typically administered orally once a day, does require titration, may be given with or without food, has active metabolites with a half-life of 2-3 weeks and highly bound to plasma proteins.

• Clinical trials reported that cariprazine is generally safe when administered at a recommended dose range of 1.5 - 6 mg/day for schizophrenia.

• Cariprazine shows highest affinity toward D₃ receptors, followed by D₂, 5-HT_2B, and 5-HT_1A receptors. It also shows moderate affinity toward σ₁, 5-HT_2A, and histamine H₁ receptors, and negligible affinity toward a wide range of neurotransmitter receptors, transporters, and enzymes. It is D₃/D₂ receptor partial agonist.

• Behavioral studies indicated that cariprazine is active in different animal models predictive of antipsychotic, antidepressant and anxiolytic activity. It also displays procognitive effects in several animal models of memory, cognitive and executive functions in rodents.

• Following are the advantages of cariprazine treatment: clinical ability in improving negative symptoms, ability to be useful in young patients with a relatively short duration of schizophrenia, ability to decrease substance abuse, and/or ability to maintain efficacy in cases of missed doses.

• Further trials are warranted to evaluate the long-term efficacy of cariprazine and its metabolic profile. Preclinical discovery and clinical development of cariprazine should expand the therapeutic options available for improved treatment of schizophrenia and bipolar mania, and other psychiatric/cognitive disorders.

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The authors are supported by funds for their statutory activity from the Jagiellonian University Medical College (K/ZDS/006133).