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Comparative Effectiveness of Adjunctive Psychotropic Medications in Patients With Schizophrenia

Importance People with schizophrenia are commonly treated with psychotropic medications in addition to antipsychotics, but there is little evidence about the comparative effectiveness of these adjunctive treatment strategies. Objective To study the comparative real-world effectiveness of adjunctive psychotropic treatments for patients with schizophrenia. Design, Setting, and Participants This comparative effectiveness study used US national Medicaid data from January 1, 2001, to December 31, 2010, to examine the outcomes of initiating treatment with an antidepressant, a benzodiazepine, a mood stabilizer, or another antipsychotic among adult outpatients (aged 18-64 years) diagnosed with schizophrenia who were stably treated with a single antipsychotic. Data analysis was performed from January 1, 2017, to June 30, 2018. Multinomial logistic regression models were used to estimate propensity scores to balance covariates across the 4 medication groups. Weighted Cox proportional hazards regression models were used to compare treatment outcomes during 365 days on an intention-to-treat basis. Main Outcomes and Measures Risk of hospitalization for a mental disorder (primary), emergency department (ED) visits for a mental disorder, and all-cause mortality. Results The study cohort included 81 921 adult outpatients diagnosed with schizophrenia (mean [SD] age, 40.7 [12.4] years; 37 515 women [45.8%]) who were stably treated with a single antipsychotic and then initiated use of an antidepressant (n = 31 117), a benzodiazepine (n = 11 941), a mood stabilizer (n = 12 849), or another antipsychotic (n = 26 014) (reference treatment). Compared with initiating use of another antipsychotic, initiating use of an antidepressant was associated with a lower risk (hazard ratio [HR], 0.84; 95% CI, 0.80-0.88) of psychiatric hospitalization, whereas initiating use of a benzodiazepine was associated with a higher risk (HR, 1.08; 95% CI, 1.02-1.15); the risk associated with initiating use of a mood stabilizer (HR, 0.98; 95% CI, 0.94-1.03) was not significantly different from initiating use of another antipsychotic. A similar pattern of associations was observed in psychiatric ED visits for initiating use of an antidepressant (HR, 0.92; 95% CI, 0.88-0.96), a benzodiazepine (HR, 1.12; 95% CI, 1.07-1.19), and a mood stabilizer (HR, 0.99; 95% CI, 0.94-1.04). Initiating use of a mood stabilizer was associated with an increased risk of mortality (HR, 1.31; 95% CI, 1.04-1.66). Conclusions and Relevance In the treatment of schizophrenia, initiating adjunctive treatment with an antidepressant was associated with reduced risk of psychiatric hospitalization and ED visits compared with initiating use of alternative psychotropic medications. Associations of benzodiazepines and mood stabilizers with poorer outcomes warrant clinical caution and further investigation.