Real-World Effectiveness of Antipsychotic Treatments in a Nationwide Cohort of 29 823 Patients With Schizophrenia

Abstract

Importance: It has remained unclear whether there are clinically meaningful differences between antipsychotic treatments with regard to preventing relapse of schizophrenia, owing to the impossibility of including large unselected patient populations in randomized clinical trials, as well as residual confounding from selection biases in observational studies.

Objective: To study the comparative real-world effectiveness of antipsychotic treatments for patients with schizophrenia.

Design, setting, and participants: Prospectively gathered nationwide databases were linked to study the risk of rehospitalization and treatment failure from July 1, 2006, to December 31, 2013, among all patients in Sweden with a schizophrenia diagnosis who were 16 to 64 years of age in 2006 (29 823 patients in the total prevalent cohort; 4603 in the incident cohort of newly diagnosed patients). Within-individual analyses were used for primary analyses, in which each individual was used as his or her own control to eliminate selection bias. Traditional Cox proportional hazards multivariate regression was used for secondary analyses.

Main outcomes and measures: Risk of rehospitalization and treatment failure (defined as psychiatric rehospitalization, suicide attempt, discontinuation or switch to other medication, or death).

Results: There were 29 823 patients (12 822 women and 17 001 men; mean [SD] age, 44.9 [12.0] years). During follow-up, 13 042 of 29 823 patients (43.7%) were rehospitalized, and 20 225 of 28 189 patients (71.7%) experienced treatment failure. The risk of psychiatric rehospitalization was the lowest during monotherapy with once-monthly long-acting injectable paliperidone (hazard ratio [HR], 0.51; 95% CI, 0.41-0.64), long-acting injectable zuclopenthixol (HR, 0.53; 95% CI, 0.48-0.57), clozapine (HR, 0.53; 95% CI, 0.48-0.58), long-acting injectable perphenazine (HR, 0.58; 95% CI, 0.52-0.65), and long-acting injectable olanzapine (HR, 0.58; 95% CI, 0.44-0.77) compared with no use of antipsychotic medication. Oral flupentixol (HR, 0.92; 95% CI, 0.74-1.14), quetiapine (HR, 0.91; 95% CI, 0.83-1.00), and oral perphenazine (HR, 0.86; 95% CI, 0.77-0.97) were associated with the highest risk of rehospitalization. Long-acting injectable antipsychotic medications were associated with substantially lower risk of rehospitalization compared with equivalent oral formulations (HR, 0.78; 95% CI, 0.72-0.84 in the total cohort; HR, 0.68; 95% CI, 0.53-0.86 in the incident cohort). Clozapine (HR, 0.58; 95% CI, 0.53-0.63) and all long-acting injectable antipsychotic medications (HRs 0.65-0.80) were associated with the lowest rates of treatment failure compared with the most widely used medication, oral olanzapine. The results of several sensitivity analyses were consistent with those of the primary analyses.

Conclusions and relevance: Clozapine and long-acting injectable antipsychotic medications were the pharmacologic treatments with the highest rates of prevention of relapse in schizophrenia. The risk of rehospitalization is about 20% to 30% lower during long-acting injectable treatments compared with equivalent oral formulations.

Figure 1.. Flowchart of the Study Population

The diagnoses are indicated according to the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, classification. F20 indicates schizophrenia; F21, schizotypal disorder; F22, persistent delusional disorders; F23, acute and transient psychotic disorders; F24, induced delusional disorder; F25, schizoaffective disorders; F28, other nonorganic psychotic disorders; and F29, unspecified nonorganic psychosis. A total of 23 316 patients were excluded because of having a diagnosis other than F20 or F25.

Figure 2.. Adjusted Hazard Ratios (HRs) and 95% CIs for Psychiatric Rehospitalization During Monotherapy Compared With No Use of Antipsychotic in Within-Individual Analyses in the Prevalent Population

Paliperidone long-acting injectable (LAI) is a once-monthly injection. The vertical dashed line shows the reference value (no use of antipsychotic). The arrow indicates that the higher end of the 95% CI (2.08) is beyond the scale (up to 2.00).

Figure 3.. Adjusted Hazard Ratios (HRs) and 95% CIs for Treatment Failure During Each Monotherapy Compared With Oral Olanzapine Use

Clozapine (P < .001), long-acting injectable (LAI) perphenazine (P < .001), LAI haloperidol (P < .001), LAI zuclopenthixol (P < .001), LAI paliperidone (P < .001), LAI flupentixol (P < .001), and LAI risperidone (P < .001) differed significantly from oral olanzapine after Bonferroni correction. The vertical dashed line shows the reference value (oral olanzapine use). The arrow indicates that the lower end of the 95% CI (0.45) is beyond the scale (to 0.50).