¹Mental Health Research Institute of Tomsk NRMC, Addictive States Department, Tomsk, Russian Federation, ²Almazov National Medical Research Center of the Ministry of Health of the Russian Federation, -Psychology Department, Saint Petersburg, Russian Federation, ³Mental Health Research Institute of Tomsk NRMC, Administration, Tomsk, Russian Federation, ⁴Mental Health Research Institute of Tomsk NRMC, Laboratory of Psychoneuroimmunology, Tomsk, Russian Federation, ⁵Mental Health Research Institute of Tomsk NRMC, Research Coordination Department, Tomsk, Russian Federation

Background: A study of the efficacy of clozapine and atypical antipsychotics in patients with treatment-resistant schizophrenia comorbid with addictions is relevant for improving the clinical prognosis of this disease.

Aims & Objectives: To evaluate the clinical efficacy of combination therapy with clozapine and partial dopamine agonists in treatment-resistant schizophrenia comorbid with chemical addictions, compared with other atypical antipsychotics.

Method: The study was conducted from 2018 to 2026 at psychiatric clinics in the Northwest, Siberia, and Urals regions of Russia. A total of 474 young patients (250 men and 224 women) with treatment-resistant paranoid schizophrenia were examined. Eighty-two were free of addictions, while the remaining 392 had addictions (106 to alcohol, 96 to cannabinoids, 93 to opioids, and 97 to psychostimulants). Patients were divided into groups receiving combination therapy with clozapine and cariprazine (n=84), lurasidone (n=84), aripiprazole (n=79), risperidone (n=85), olanzapine (n=71), or brexpiprazole (n=71). The CGI, GAF, PANSS, and SANS scales were used to assess patients' condition. Assessments were conducted at weeks 2 and 6 of combination therapy.

Results: A comparative analysis of treatment efficacy revealed comparable results for the CGI and GAF scales but revealed differences between treatment groups for the PANSS and SANS scales. Combined use of clozapine and cariprazine for 6 weeks demonstrates the most significant effect in alleviating the negative symptoms of schizophrenia compared to other combinations and reduces the likelihood of rehospitalization.

Discussion & Conclusions: Combination therapy with clozapine and other atypical antipsychotics produces a more pronounced antipsychotic effect during the hospitalization phase of treatment-resistant schizophrenia in patients with both substance-dependent and substance-independent conditions. The combination of clozapine and cariprazine was found to be the most effective, followed by lurasidone. Risperidone, aripiprazole, and olanzapine demonstrated a moderate antipsychotic effect, while a questionable effect was observed with the combination of brexpiprazole. A distinctive feature of the combination of clozapine and cariprazine is its more pronounced effect on the negative symptoms of schizophrenia, compared to a lesser extent with clozapine in combination with lurasidone. Combination therapy with cariprazine increases the stability of remission and reduces the risk of rehospitalization, indirectly contributing to a reduction in the frequency of psychoactive substance use.