ABSTRACT Background Polypharmacy is associated with adverse outcomes, particularly in older multimorbid adults. However, little is known about the negative outcomes associated with multiple central nervous system (CNS)‐active medications that are commonly prescribed to these patients. Objective To assess the association between the number of CNS‐active medications at discharge and the risk of 1‐year all‐cause hospital readmission, drug‐related hospital readmission (DRA), death, quality of life (QoL) and functional status in older multimorbid adults. Methods Among 2008 older multimorbid inpatients with polypharmacy, we assessed the association between the number of CNS‐active medications and 1‐year all‐cause hospital readmission, DRA, and death by Cox proportional hazard models. We further assessed the association of the number of CNS‐active medications with QoL (measured with EQ‐5D‐VAS) and functional status (measured with Barthel Index) using binary and quantile regression models. Analyses were adjusted for age, sex, discharge location, Charlson Comorbidity Index, depression/anxiety, and randomization arm. Additional sensitivity analyses were adjusted for the number of non‐CNS active medications, neurological and psychiatric comorbidities, alcohol or tobacco use, education level, and living arrangements. Results The risk of all‐cause hospital readmission and DRA increased by 7% with each additional CNS‐active medication (multivariable‐adjusted hazard ratio (HR) 1.07 (95% confidence interval 1.03 to 1.12) for all‐cause hospital readmission and 1.07 (1.01 to 1.14) for DRA). HR for death was 1.14 (1.07 to 1.23) for each additional CNS‐active medication. The mean differences in EQ‐5D‐VAS and Barthel Index after 1 year were −2.13 (−2.82 to −1.44) and −1.6 (−2.16 to −1.04) respectively, per additional CNS‐active medication. Conclusion The presence of CNS‐active medications at discharge is associated with a higher risk for 1‐year all‐cause hospital readmission and DRA in older multimorbid adults with polypharmacy. Additionally, CNS‐active medications were associated with lower QoL and functional status. Trail Registration: ClinicalTrials.gov NCT02986425
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