Introduction Antipsychotic polypharmacy (APP), the concomitant use of ≥2antipsychotics, is common in clinical practice. Prior reviews have focused on the efficacy of APP, but no systematic review exists regarding the safety and tolerability of this practice. Areas covered in this review We conducted a systematic review of adverse effects associated with APP. Case series with ≥2 patients, chart reviews, naturalistic, data base, cohort and randomized studies that reported on the association between APP in general or specific APP combinations and global or specific adverse effect were included. We discuss methodological limitations of available studies and provide recommendations for clinicians and future research. Expert Opinion Across mostly small and uncontrolled studies, APP has been associated with increased global side effect burden, rates of Parkinsonian side effects, anticholinergic use, hyperprolactinemia, sexual dysfunction, hypersalivation, sedation/somnolence, cognitive impairment, and diabetes. Effects on akathisia and mortality were inconclusive. Although some combinations, particularly aripiprazole augmentation of an agent with greater side effect burden, may reduce weight gain, dyslipidemia, hyperprolactinemia and sexual dysfunction, APP should remain a last resort treatment option after monotherapy, switching and non-antipsychotic combinations have failed. More and high quality data are needed to further inform the individualized risk-benefit evaluation of APP.

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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