Comparing Outcomes of Adjunctive Medications in Patients With Schizophrenia

A variety of prescription pills lie in front of their respective bottles.
A variety of prescription pills lie in front of their respective bottles.
Researchers found antidepressants to be more effective in reducing hospitalizations for patients with schizophrenia compared with alternative psychotropic medications.

Initiating adjunctive treatment with antidepressants is associated with reduced psychiatric hospitalizations and emergency department visits for patients with schizophrenia already stabilized on a single antipsychotic compared with initiating the use of alternative psychotropic medications for such patients, according to a study published in JAMA Psychiatry.

Although patients with schizophrenia are often treated with psychotropics in addition to antipsychotics, there is little evidence concerning the comparative effectiveness of adjunctive treatment strategies for these patients. This comparative effectiveness study used national US Medicaid data from January 2001 through December 2010 to identify the association between various outcome measures and initiating treatment with antidepressants, mood stabilizers, benzodiazepines, or another antipsychotic for outpatients with schizophrenia who had been stabilized on treatment with a single second-generation antipsychotic.

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Schizophrenia was defined as 1 inpatient claim or 2 or more outpatient claims for schizophrenia in 365 consecutive days of Medicaid enrollment immediately before starting a new psychotropic medication. The primary outcome measure was risk of hospitalization for a mental disorder, and other outcome measures were emergency department visits for a mental disorder and all-cause mortality. Propensity scores to balance covariates across the medication groups were estimated using multinomial logistic regression, and treatment outcomes over 365 days on an intention-to-treat basis were compared using weighted Cox proportional hazards regression models.

The retrospective cohort included a total of 81,921 adult outpatients with schizophrenia (37,515 women [45.8%]; mean age, 40.7 years) who had been stabilized on a single antipsychotic. Subsequently, 31,117 then initiated the use of an antidepressant, 11,941 initiated the use of a benzodiazepine, 12,849 initiated the use of a mood stabilizer, and 26,014 initiated use of another antipsychotic. When compared with initiating another antipsychotic medication, initiating antidepressant use was associated with a lowered risk of psychiatric hospitalization (hazard ratio [HR], 0.84; 95% CI, 0.80-0.88), while initiating benzodiazepine use was associated with a higher risk of psychiatric hospitalization (HR, 1.08; 95% CI, 1.02-1.15). Additionally, the risk associated with the initiation of mood stabilizers (HR, 0.98; 95% CI, 0.94-1.03) was not significantly different from that of initiating another antipsychotic. Similar patterns of associations were observed in emergency department visits for a mental disorder when comparing the use of a new antipsychotic and initiating use of antidepressants (HR, 0.92; 95% CI, 0.88-0.96), benzodiazepines (HR, 1.12; 95% CI, 1.07-1.19), and mood stabilizers (HR, 0.99; 95% CI, 0.94-1.04). Compared with initiation of a new psychotic medication, mood stabilizer initiation was associated with increased mortality risk (HR, 1.31; 95% CI, 1.04-1.66) as was benzodiazepine initiation (HR, 1.22; 95% CI, 0.98-1.52).

Study investigators conclude, “Associations of benzodiazepines and mood stabilizers with poorer outcomes warrant clinical caution and further investigation. The increasing evidence base that supports adjunctive antidepressant treatment in schizophrenia suggests the need for increased clinical interest in this treatment strategy as well as further investigation into the specific situations for which antidepressants are indicated.”

Disclosures: Study authors declare professional or financial connections to Auspex Pharmaceuticals, Intra-Cellular Therapies, Inc., Eli Lilly and Company, Bristol-Myers Squibb, Merck & Co, Pfizer, and Lundbeck.


Stroup TS, Gerhard T, Crystal S, et al. Comparative effectiveness of adjunctive psychotropic medications in patients with schizophrenia [published online February 20, 2019]. JAMA Psychiatry. doi: 10.1001/jamapsychiatry.2018.4489