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No. 1 (2026)

GENERAL THERAPY QUESTIONS AND REVIEWS

Pharmacogenetic Aspects of the Use of a Combination of Cariprazine and Clozapine in Patients with Treatment-Resistant Schizophrenia

https://doi.org/10.48612/psyph/aez2-rv9r-kzu9

Published 2026-03-30

  • A.V. Kidyaeva
    • ,
  • A.S. Shumilova
    • ,
  • R.F. Nasyrova

A.V. Kidyaeva
V.M. Bekhterev National Medical Research Center for Psychiatry and Neurology; St. Petersburg State Psychiatric Hospital of St. Nicholas

A.S. Shumilova
St. Petersburg State Psychiatric Hospital of St. Nicholas

R.F. Nasyrova
V.M. Bekhterev National Medical Research Center for Psychiatry and Neurology; St. Petersburg State Psychiatric Hospital of St. Nicholas

Abstract

Background. Treatment-resistant schizophrenia is one of the most challenging clinical problems in psychiatry. Despite the recommendation of clozapine as a firstline agent, a significant proportion of patients fail to achieve remission. This necessitates the search for new treatment strategies, particularly rational combination therapy with antipsychotics.

Aim — to evaluate the efficacy and pharmacogenetic aspects of the cariprazine and clozapine combination in treatment-resistant schizophrenia.

Methods. A search of full-text articles published from January 1, 2021, to January 1, 2026, was conducted in the PubMed, eLIBRARY.RU, and Google Scholar databases.

Results. An analysis of publications demonstrates that the addition of cariprazine to clozapine therapy is a promising treatment strategy for patients with treatmentresistant schizophrenia, particularly when negative symptoms predominate. This may be due to the complementary pharmacogenetic effects of this combination. Cariprazine, a partial D2 receptor agonist with high affinity for D3 receptors, can compensate for the relatively weak effect of clozapine on dopamine systems. Unlike clozapine, the efficacy of cariprazine is likely independent of DRD3 gene polymorphism. Furthermore, unlike most antipsychotics, cariprazine is not a P-glycoprotein substrate, potentially avoiding the development of pseudoresistance associated with increased activity of this transporter during antipsychotic therapy.

Conclusion. Despite encouraging data indicating the efficacy and safety of combination therapy with cariprazine and clozapine in patients with treatment-resistant schizophrenia, existing evidence is based primarily on small studies and case reports. Large controlled studies are needed to introduce this treatment regimen into widespread practice and develop clinical guidelines.

Keywords

treatment-resistant schizophrenia, clozapine, cariprazine, D3 receptor, P-glycoprotein, pharmacogenetics

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