Efficacy and tolerability of co-administration of clozapine with atypical antipsychotics in patients with treatment-resistant schizophrenia, comorbid with chemical addictions

Objective. To compare the efficacy and tolerability of combination therapy with clozapine and atypical antipsychotics for patients with treatment-resistant schizophrenia, comorbid with chemical addictions. Material and methods. A clinical study was conducted from 2018 to 2026 in various psychiatric departments in the North-Western, Siberian, and Ural regions of the Russian Federation. The study included a total of 470 male and female participants diagnosed with therapeutically resistant paranoid schizophrenia, comprising individuals with and without concomitant chemical addictions: n=80 without addictions; n=390 with unrelated chemical addictions (opioid, cannabinoid, psychostimulant, and ethanol dependence). Participants were randomly allocated into six treatment groups receiving distinct combinations of medications: clozapine with cariprazine (n=84), lurasidone (n=84), aripiprazole (n=78), risperidone (n=84), olanzapine (n=70), or brexpiprazole (n=70). The clinical status of patients was assessed at weeks 2 and 6 of the therapeutic regimen. Results. A comparative analysis of treatment efficacy indicated significant differences between therapy groups across various psychometric scales (p<0.05). The co-administration of clozapine with cariprazine, and to a lesser extent with lurasidone, demonstrated the most pronounced therapeutic effect within a 42-day treatment period (p<0.05), specifically in alleviating psychotic symptoms and reducing the negative symptoms characteristic of schizophrenia, as compared to alternative combinations, thereby extending the duration of outpatient treatment. Conclusions. A comprehensive treatment strategy for therapeutically resistant schizophrenia, irrespective of concomitant addictions, is the combination of clozapine with cariprazine; lurasidone serves as an alternative option. The selection of an effective adjunctive therapy should consider the specific type of addiction: lurasidone or aripiprazole is recommended for cannabinoid, psychostimulant, and alcohol dependencies; risperidone or olanzapine is advised for opioid and alcohol dependencies. The combination with brexpiprazole is deemed ineffective. Notable advantages of this approach include a marked effect on negative symptoms and an extension of the outpatient treatment period. No adverse events associated with the combination therapy were reported.