Mortality risk from long-term treatment with antipsychotic polypharmacy vs monotherapy among adults with serious mental illness: A systematic review and meta-analysis of observational studies.

Background: Long-term use of more than one concurrent antipsychotic [antipsychotic polypharmacy (APP)] is widely believed to contribute to excess mortality in people with serious mental illness (SMI) compared to those taking only one antipsychotic (monotherapy). However, no conclusive evidence is available.

Methods: We conducted a systematic search in 6 major electronic databases from inception until December 2019, identifying observational studies examining the association between mortality and exposure to long-term APP vs monotherapy. Studies were eligible if they adopted a follow-up design and antipsychotic exposure was >3 months among adults with SMI. We determined the pooled mortality risk using random-effects meta-analyses. The review was registered in PROSPERO (CRD42019148044).

Results: A total of 12 studies fulfilled all eligibility criteria reporting quantitative data for 834, 534 person years. No difference was found in the association between all-cause mortality and APP vs monotherapy use, in both crude (rate ratio = 0.94, 95% CI 0.81-1.10, p = 0.446; I = 83.2%, p < 0.001; 10 studies) and adjusted models (adjusted HR = 0.98, 95% CI 0.80-1.19, p = 0.802; I = 58.3%, p < 0.05; 5 studies). Meta-regression did not identify any moderators influencing all-cause mortality risk. For natural causes of death, risk estimates followed the same pattern: (i) crude rate ratio = 0.88, 95% CI 0.67-1.14, p = 0.324; I = 77.7%, p = 0.01 (5 studies); (ii) adjusted HR = 1.04, 95% CI 0.90-1.99, p = 0.590; I = 0.0%, p = 0.744 (5 studies).

Conclusion: Mortality risk of APP use in people with SMI appears to be comparable to that of monotherapy use, although work to date remains heterogeneous, precluding firm conclusions from made. Complex real-world clinical scenarios may be contributing to this lack of variation between these two types of antipsychotic use.