Antipsychotic polypharmacy in schizophrenia is much debated, since it is common and costly with unclear evidence for its efficacy and safety. We conducted a systematic literature search and a random effects meta-analysis of randomized trials comparing augmentation with a second antipsychotic vs. continued antipsychotic monotherapy in schizophrenia. Co-primary outcomes were total symptom reduction and study-defined response. Antipsychotic augmentation was superior to monotherapy regarding total symptom reduction (16 studies, N5694, standardized mean difference, SMD5-0.53, 95% CI: 20.87 to 20.19, p50.002). However, superiority was only apparent in open-label and low-quality trials (both p<0.001), but not in double-blind and high-quality ones (p50.120 and 0.226, respectively). Study-defined response was similar between antipsychotic augmentation and monotherapy (14 studies, N5938, risk ratio 5 1.19, 95% CI: 0.99 to 1.42, p50.061), being clearly non-significant in double-blind and high-quality studies (both p50.990). Findings were replicated in clozapine and nonclozapine augmentation studies. No differences emerged regarding all-cause/specific-cause discontinuation, global clinical impression, as well as positive, general and depressive symptoms. Negative symptoms improved more with augmentation treatment (18 studies, N5931, SMD5-0.38, 95% CI: 20.63 to 20.13, p<0.003), but only in studies augmenting with aripiprazole (8 studies, N5532, SMD5-0.41, 95% CI: 20.79 to 20.03, p50.036). Few adverse effect differences emerged: D2 antagonist augmentation was associated with less insomnia (p50.028), but more prolactin elevation (p50.015), while aripiprazole augmentation was associated with reduced prolactin levels (p<0.001) and body weight (p50.030). These data suggest that the common practice of antipsychotic augmentation in schizophrenia lacks double-blind/high-quality evidence for efficacy, except for negative symptom reduction with aripiprazole augmentation.

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ClinicalTrials.gov identifier: NCT01081418.

The higher impairment in specific symptoms observed in male schizophrenia patients was also present in subjects at HR for psychosis. Further studies are required to determine whether these symptoms are gender-specific predictors of transition to psychosis and whether they warrant gender-specific interventions. The high propensity to depression in the present cohort, which was particularly pronounced in the male cohort compared with the general population, in conjunction with the observed increase in negative symptoms and functional impairment, should alert clinicians to the necessity for the identification and treatment of HR subjects, irrespective of the degree to which these features are associated with transition risk.