We found that antipsychotic polypharmacy in schizophrenic patients was not statistically associated with an increase in relapse in this observational study relying on a propensity score adjustment. Although a recent meta-analysis showed that antipsychotic polypharmacy may be superior to monotherapy [2
], the majority of previous studies reported higher rates of side effects and relapse [3
Several hypotheses can be proposed to explain our result.
One hypothesis is that previous studies have varied in design, potential predictors, sample examined, and the manner in which relapse was defined and measured [6
]. Our study presents characteristics that can explain why our results are not entirely consistent with those of other studies. Our findings are based on naturalistic observational data. The results of observational studies reflect the patterns of practice and can be considered as more meaningful than clinical trials to evaluate effectiveness, notably on long-term outcomes such as relapse. We also conducted a 2-year follow up of schizophrenic patients, which is longer than those used in the majority of clinical trials and observational studies [3
]. Clinical trials with antipsychotics thus far have been of relatively short duration [2
]. Finally, we used a propensity score adjustment rarely performed on the previous observational studies. A propensity score is a better option than multivariate logistic regression when events are few and various confounding factors coexist [46
Our findings suggest that the most severely ill patients were given polypharmacy, which can potentially bias findings of previous studies. In our study, the age at illness onset was lower in the polypharmacy group than in the monotherapy group. The age of illness onset is widely accepted as having particularly powerful clinical and prognostic significance. A recent meta-analysis supports the view that severity of disease process is associated with early onset [47
]. Patients receiving polypharmacy also presented a higher general psychopathology PANSS score than patients with monotherapy. However, this statistically significant difference may not be clinically relevant, and no statistically significant difference was found in the PANSS total score or the PANSS positive or negative subscales. They were also more likely to be given prescriptions for sedative drugs than patients receiving monotherapy. These findings are consistent with a study showing that patients who received antipsychotic combinations exhibited more positive and excited symptoms than patients given prescriptions for monotherapy [48
]. Additionally, the findings support clinicians' reports of using polypharmacy for refractory psychotic symptoms [49
]. To a lesser extent, patients with polypharmacy were more likely to receive antidepressant medications. This result is concordant with a recent study showing that receiving antidepressants was significantly associated with receiving polypharmacy [52
]. This association suggests that patients receiving polypharmacy present displayed more depressive symptoms than did patients receiving monotherapy, and studies have shown that schizophrenic patients with depressive symptoms have poorer long-term functional outcomes [53
]. Consequently, the purported association between polypharmacy and poor outcome does not necessarily mean that polypharmacy leads to poor outcome; it may be that poor outcome may lead to aggressive prescription practices that includes high doses and polypharmacy [54
]. This major confound, which is not systematically assessed, needs to be addressed in future studies.
Consistent with the results of previous reports [49
], in our study, patients receiving polypharmacy were more likely to also receive drugs for side-effects than patients with monotherapy. Interestingly, we note in our study that the side effects were assessed with three different standardised instruments, and the adherence of the patients did not differ between the two groups. This can also explain our result by controlling the relation between polypharmacy, side effects as predictor of poor medication adherence, and relapse. Indeed, experts have endorsed side effects or a general fear of side effects as one important factor leading to adherence problems in schizophrenia [56
]. In the same way, experts have rated persistent positive or negative symptoms in schizophrenia as the most important symptomatic contributors to adherence problems [56
]. The combination of polypharmacy and sedative drugs can explain the absence of differences in persistent positive or negative symptoms between monotherapy and polypharmacy groups. Consequently, this may explain that antipsychotic polypharmacy was not associated to an increase of relapse.
Perspectives and limitations
Our study had several limitations.
First, the treatment (monotherapy or polypharmacy) was not based on random assignment; therefore, the results may be confounded by other factors. Although the propensity score can adjust for confounding by indication and selection bias, we cannot eliminate residual confounding due to unobserved factors [57
]. This limitation of the current work can be moderated by the broad spectrum of characteristics collected in our study. However, well-designed randomised controlled trials are needed to determine the impact of polypharmacy on relapse in schizophrenia.
Second, several interesting data were not analysed. Information regarding dosages of different antipsychotic was not available. Moreover, antipsychotic combinations can be considered as a heterogeneous group, and the different combinations might be associated with different risks of relapse. However, our sample was not sufficient to determine the effect of specific polytherapy combinations.
Third, our sample may not be representative of schizophrenic patients in all of France and in other countries. However, the proportion of polypharmacy and relapse that are in line with previous studies [3
] may indicate a good representativeness.
Fourth, it is possible that our study lacked statistical power to detect a difference in the rate of relapse. However, our analytical sample comprised 183 patients, 50 of whom had a relapse. This sample size was larger than that of several published randomised controlled trials designed to test the efficacy of polypharmacy vs. monotherapy, especially when we consider the length of the follow up, which were usually shorter in these prior studies than in our study [2
Finally, a major methodological problem remains in the definition of relapse for schizophrenic patients and the definition of monotherapy and polypharmacy. There are no generally accepted criteria for relapse [42
]. However, we have chosen the most consensual definition in the recent scientific literature [42
]. Methodological issues to be addressed in future trials should include clinically relevant relapse criteria. In the same way, the definitions of monotherapy and polypharmacy are not consensual. We defined the exposure treatment groups at baseline in a standard way: receiving one antipsychotic at baseline, regardless of medication class or molecule, compared with receiving two or more antipsychotics. We assumed that exposure was relatively stable over time and that the occurrence of relapse may be related to the exposure treatment at baseline. The clinical significance of this study should be cautiously interpreted in accordance with this chosen definition.