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 (N = 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, P < 0.001; Sweden: aHR 0.35, 95% CI 0.24-0.50, P < 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.