Cariprazine and clozapine: a systematic review of a promising antipsychotic combination for treatment-resistant schizophrenia.

Abstract

Treatment-resistant schizophrenia affects over half of individuals with schizophrenia. Clozapine is the only approved treatment in the United States but often provides limited relief. Augmenting clozapine with cariprazine (CAR) (a D3-preferring dopamine D2-D3 partial agonist) may improve outcomes. This systematic review evaluated the efficacy and safety of this combination in patients with sub-optimal response. A search of PubMed, Embase, and Cochrane Library yielded 52 cases from 21 eligible studies to be included in the analysis. Patient and treatment characteristics and clinical outcomes were synthesized. Cariprazine replaced another antipsychotic or was added to clozapine monotherapy in 44.2% and 34.6% of cases, respectively. Before treatment, 90% of patients had positive and 81% had negative symptoms. Combination therapy improved these symptoms in 66% and 83% of cases, respectively. In 19 patients with Positive and Negative Symptom Scale scores available before and after treatment, total scores decreased by 43.4%, with positive and negative subscale reductions of 23.0% and 59.1%. The combination was generally well tolerated; some patients experienced weight loss and reduced clozapine-related side effects. New adverse events occurred in 19% (most commonly akathisia at 6%). Cariprazine was discontinued in 17% of cases due to side effects or lack of efficacy. Overall, the combination appears safe and promising, especially for persistent negative symptoms, likely due to complementary neuroreceptor effects. Larger controlled trials are needed to confirm these findings.