Nonadherence to oral antipsychotic drugs is a major issue in clinical psychiatry giving rise to treatment failure. Further, polypharmacy is common in the treatment of psychotic disorders due to insufficient treatment effect during monotherapy. As a potential circuit problem, we hypothesized that antipsychotic polypharmacy is associated with increased risk of nonadherence. To investigate this, in terms of 'complete' nonadherence, the rates of undetectable serum drug concentrations during prescribing of doses used in psychotic disorders were compared during antipsychotic 'monotherapy' vs 'polypharmacy' treatment using therapeutic drug monitoring (TDM) data of 24,239 patients. A complete nonadherence patient was objectively defined as the detection of at least one event of undetectable serum concentration of a prescribed antipsychotic drug. The rate of complete nonadherence patients was compared between antipsychotic monotherapy and polypharmacy by multivariate logistic regression analyses. The overall rate of complete nonadherence in the population was 6.8% (n = 1,644; 95%CI: 6.5-7.1). Compared to monotherapy patients, the rate of nonadherence increased significantly with the number of co-prescribed antipsychotic drugs. After adjusting for sex (p = 0.091) and age (p < 0.001) as covariates, the rates of nonadherence vs monotherapy were 1.69-fold (95% CI: 1.48-1.92; p < 0.001) for two, 2.60-fold (95% CI: 1.88-3.59; p < 0.001) for three, and 3.54-fold (95% CI: 1.46-8.58; p = 0.005) for four or more co-prescribed antipsychotics, respectively. The present naturalistic study shows that antipsychotic polypharmacy significantly increases the rate of complete nonadherence, which is positively correlated with increasing number of concurrently used antipsychotic drugs. Thus, the intended clinical benefit of combining oral antipsychotic drugs may probably be reduced by increased nonadherence.
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