Associations between antipsychotic use, substance use and relapse risk in patients with schizophrenia: real-world evidence from two national cohorts.

Background: Research on the effectiveness of pharmacotherapies for schizophrenia and comorbid substance use disorder (SUD) is very sparse, and non-existent on the prevention of the development of SUDs in patients with schizophrenia.

Aims: To compare the real-world effectiveness of antipsychotics in schizophrenia in decreasing risk of developing an initial SUD, and psychiatric hospital admission and SUD-related hospital admission among patients with an SUD.

Method: Two independent national cohorts including all persons diagnosed with schizophrenia ( = 45 476) were followed up for 22 (Finland: 1996-2017) and 11 (Sweden: 2006-2016) years. Risk of developing an SUD was calculated with between-individual models, and risks of psychiatric and SUD-related hospital admission were calculated with within-individual models, using Cox regression and adjusted hazard ratios (aHRs) for using versus not using certain antipsychotics.

Results: For patients with schizophrenia without an SUD, clozapine use (Finland: aHR 0.20, 95% CI 0.16-0.24, < 0.001; Sweden: aHR 0.35, 95% CI 0.24-0.50, < 0.001) was associated with lowest risk of developing an initial SUD in both countries. Antipsychotic polytherapy was associated with second lowest risk (aHR 0.54, 95% CI 0.44-0.66) in Sweden, and third lowest risk (aHR 0.47, 95% CI 0.42-0.53) in Finland. Risk of relapse (psychiatric hospital admission and SUD-related hospital admission) were lowest for clozapine, antipsychotic polytherapy and long-acting injectables in both countries. Results were consistent across both countries.

Conclusions: Clozapine and antipsychotic polytherapy are most strongly associated with reduced risk of developing SUDs among patients with schizophrenia, and with lower relapse rates among patients with both diagnoses.