In this cross-sectional survey of patients in the US with schizophrenia, nearly 80% of patients reported at least one side effect that was at least somewhat bothersome to them, and less than half of patients reported complete adherence to their medications. There were few differences in the characteristics of adherent and nonadherent patients. However, we observed consistently strong relationships between medication side effects and nonadherence. Our finding that cognitive-related side effects and weight gain were associated with nonadherence is consistent with prior research [17
EPS/agitation-related side effects were the most strongly associated with nonadherence, and were commonly reported. This is a striking finding because atypical antipsychotics are generally thought to have lower risk for EPS compared to typical antipsychotics [26
]. Though, it should be noted, not all patients in this study were on an atypical medication the vast majority were. Both EPS and endocrine side effects of antipsychotic medications are mediated by dopamine receptor 2 (D2) blockade [28
]. The mechanism behind metabolic side effects to antipsychotics is less clear, but may be related to histaminergic blockade, which is also implicated in sedative side effects [28
Aside from side effects, a few other variables were significantly associated with adherence. Specifically, patients who were older, less educated, and employed were more likely to be adherent. Prior evidence has suggested that longer illness duration is associated with greater adherence [30
]; therefore, age may be serving as a proxy for years diagnosed. Employment may be serving as a proxy for level of functioning (i.e., patients with improved functioning are more likely to be in the labor force), as poor disease insight has been shown to be associated with poorer adherence [30
]. Interestingly, few studies have uncovered a relationship between education and adherence. Because of the lack of support in the literature, it is possible education also serves as a proxy for another unmeasured variable (e.g., negative attitudes toward medications), though additional research is warranted.
Consistent with previous studies [11
], nonadherence is a significant risk factor for hospital and emergency room use. In our study, we found that both mental health and non-mental health hospital use was increased in nonadherent patients. Antipsychotic medications demonstrate high variability in their risk of inducing various side effects, and this may be mediated by differential affinities for D2, 5HT2A, and other receptors [28
]. Clinicians may be faced with the challenge of choosing between medications with a lower risk for EPS yet higher risk for metabolic complications, and vice versa, but we find that both side effects are associated with significant nonadherence that may lead to both psychiatric and non-psychiatric hospitalizations. Therefore, preventing, identifying, and minimizing the frequency and severity of medication-related side effects may lead to greater adherence and fewer hospitalizations.
This study has several limitations. Because all data were self-reported, diagnoses, treatments, adherence levels, and healthcare resource utilization were not confirmed by clinicians, patient records, or administrative claims data. Patients may have either underreported or overreported their experience with side effects (perhaps attributing a medication side effect to a symptom of a comorbid condition or vice versa) and their level of adherence. However, this patient perspective can still be valuable. Regardless of the true reason for the experienced "side effect", a patient's perception of the reason for the side effect may be more important in predicting adherence. Even if the side effect is not due to their schizophrenia medication, attributing it as such can result in greater non-adherence.
The cross-sectional design prevents robust ascertainment of causality. Although the hypothesis was that the presence of side effects leads to greater non-adherence it is possible that non-adherence (particularly sudden medication suspension followed by a full dose) can increase the presence of side effects. It is also possible that increasing adherence may lead to more side effects.
It is possible that unobserved confounding may have influenced the observed results. For example, severity of schizophrenia, polypharmacy, complexity of medication regimen, medication costs, among other variables, are likely associated with non-adherence but were not included in the current study. Similarly, limited information was available with respect to the number of non-antipsychotic medications. The greater the number of medications, the more difficult it may be for patients to determine which side effects are due to which treatments. Finally, the use of a convenience sample may have resulted in a sample that does not generalize to the community-dwelling population of patients with schizophrenia, as all patients were willing and functionally able to participate in survey research. The usage of both online and offline sample sources was implemented to ensure variability in patient types but these patient types may not be representative of the larger population.