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.

IMPORTANCE Antipsychotics are used increasingly in youth for nonpsychotic and off-label indications, but cardiometabolic adverse effects and (especially) type 2 diabetes mellitus (T2DM) risk have raised additional concern. OBJECTIVE To assess T2DM risk associated with antipsychotic treatment in youth. DATA SOURCES Systematic literature search of PubMed and PsycINFO without language restrictions from database inception until May 4, 2015. Data analyses were performed in July 2015, and additional analyses were added in November 2015. STUDY SELECTION Longitudinal studies reporting on T2DM incidence in youth 2 to 24 years old exposed to antipsychotics for at least 3 months. DATA EXTRACTION AND SYNTHESIS Two independent investigators extracted study-level data for a random-effects meta-analysis and meta-regression of T2DM risk. MAIN OUTCOMES AND MEASURES The coprimary outcomes were study-defined T2DM, expressed as cumulative T2DM risk or as T2DM incidence rate per patient-years. Secondary outcomes included the comparison of the coprimary outcomes in antipsychotic-treated youth with psychiatric controls not receiving antipsychotics or with healthy controls RESULTS Thirteen studies were included in the meta-analysis, including 185 105 youth exposed to antipsychotics and 310 438 patient-years. The mean (SD) age of patients was 14.1 (2.1) years, and 59.5% were male. The mean (SD) follow-up was 1.7 (2.3) years. Among them, 7 studies included psychiatric controls (1 342 121 patients and 2 071 135 patient-years), and 8 studies included healthy controls (298 803 patients and 463 084 patient-years). Antipsychotic-exposed youth had a cumulative T2DM risk of 5.72 (95% CI, 3.45-9.48; P < .001) per 1000 patients. The incidence rate was 3.09 (95% CI, 2.35-3.82; P < .001) cases per 1000 patient-years. Compared with healthy controls, cumulative T2DM risk (odds ratio [OR], 2.58; 95% CI, 1.56-4.24; P < .0001) and incidence rate ratio (IRR) (IRR, 3.02; 95% CI, 1.71-5.35; P < .0001) were significantly greater in antipsychotic-exposed youth. Similarly, compared with psychiatric controls, antipsychotic-exposed youth had significantly higher cumulative T2DM risk (OR, 2.09; 95% CI, 1.50-52.90; P < .0001) and IRR (IRR, 1.79; 95% CI, 1.31-2.44; P < .0001). In multivariable meta-regression analyses of 10 studies, greater cumulative T2DM risk was associated with longer follow-up (P < .001), olanzapine prescription (P < .001), and male sex (P = .002) (r 2 = 1.00, P < .001). Greater T2DM incidence was associated with second-generation antipsychotic prescription (P Յ .050) and less autism spectrum disorder diagnosis (P = .048) (r 2 = 0.21, P = .044). CONCLUSIONS AND RELEVANCE Although T2DM seems rare in antipsychotic-exposed youth, cumulative risk and exposure-adjusted incidences and IRRs were significantly higher than in healthy controls and psychiatric controls. Olanzapine treatment and antipsychotic exposure time were the main modifiable risk factors for T2DM development in antipsychotic-exposed youth. Antipsychotics should be used judiciously an...

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