A patient perspective of the impact of medication side effects on adherence: results of a cross-sectional nationwide survey of patients with schizophrenia

Schizophrenia is a chronic, often debilitating psychiatric illness with a lifetime prevalence of approximately 1% of the US population [1, 2]. Typically manifesting in late adolescence or early adulthood, schizophrenia can disturb perception, cognition, emotions, and behavior [3]. In addition to pronounced effects on the well-being of patients [4] and their families [5], schizophrenia also exacts an economic burden, estimated at almost $63 billion per year in the US in 2002 [6].

Numerous antipsychotic medications are available with demonstrated efficacy in reducing the acute symptoms of schizophrenia, improving the well-being of patients, and enabling some to live more productive lives [7]. However, adherence and persistence to these medications are important to receive optimal benefits. A review of dropout rates in clinical trials found that 28%-55% of schizophrenia patients drop out of clinical trials before the study is complete; dropout rates were higher with classic antipsychotic medications compared with second generation antipsychotic medications due to side effects [8]. In the Clinical Antipsychotic Trial of Interventional Effectiveness (CATIE) study, 74% of patients discontinued their initial study medication before 18 months [9]. Approximately half of patients with schizophrenia take 70% or less of their medication [10]. Inadequate adherence to antipsychotic medications increases the risk of relapse and associated healthcare utilization and costs [11‐13]. A review by Sun et al. (2007) estimated that antipsychotic nonadherence in the US was responsible for between $1.4 and $1.8 billion in rehospitalization costs alone [11].

Studies have suggested that antipsychotic medication side effects are associated with lower levels of adherence [14, 15]. Clinicians' ratings of side effects are also associated with treatment discontinuation [16]. Specifically, side effects such as medication-related obesity, distress over weight gain, and cognitive impairment have been associated with increased rates of nonadherence [14, 15, 17, 18]. Although other studies have examined adherence in real-world settings [18], few have studied the relationship between specific side effects and nonadherence. Moreover, there are no studies assessing the relationship between patient-reported side effects and self-reported adherence. This patient perspective is valuable as it provides insight into how the perception of side effects is associated with specific non-adherent behaviors; something that cannot be obtained from objective assessments of adherence. The primary aim of the current study is to assess the relationship between patient-reported antipsychotic side effects and self-reported medication adherence in a community-dwelling sample of patients with schizophrenia. A secondary aim is to assess the relationship between medication adherence and self-reported health resource utilization.

The study sample consisted of 876 patients with schizophrenia who reported they were currently taking a medication to treat their condition. The mean age of the sample was 43 years, approximately half of the sample was male, and 61% was white (see Table 1). Over half of the sample was unemployed and 71.7% were taking atypical antipsychotics. The most commonly reported side effects that were at least moderately bothersome included difficulty thinking/concentrating (32.2%), restlessness/feeling jittery (28.2%), insomnia (28.4%), weight gain (25.8%), and sleepiness (25.1%) (see Table 2).

The frequency of nonadherent behaviors (individual items of the MMAS) are presented in Figure 1. Nearly half of patients reported that they sometimes forget to take their medication (48.4%). Only 42.5% of patients responded "no" to all four nonadherent behaviors in the MMAS. Table 3 summarizes bivariate comparisons between characteristics of adherent and nonadherent patients. Fewer adherent patients were married or had any college education. There were no other significant differences in patient characteristics between groups.

The results of the logistic regression models for each side effect are presented in Figure 2. Most of the side effects assessed were significantly associated with a decreased likelihood of medication adherence. Sensitivity analyses using the more restrictive definition of side effect presence did not change overall model results with respect to significance or magnitude (see Additional file 1: Figure S1).

Table 4 summarizes results of the logistic regression model using five side effect clusters. Younger age, unemployment, and higher education were all associated with a lower likelihood of adherence. Similarly, all of the side effect clusters except GI were associated with a lower likelihood of adherence. The EPS/agitation cluster had the strongest effect, with a 43% reduction in odds of being adherent, followed by metabolic side effects with a 36% reduction. Results of the sensitivity analysis removing agitation from the EPS/agitation cluster did not affect the significance or magnitude of the effect (see Additional file 2: Table S1).

Patients reporting complete medication adherence were significantly less likely to report a hospitalization for a mental health reason (OR = 0.51; 95%CI: 0.35-0.75, p = .0006), a hospitalization for a non-mental health reason (OR = 0.43; 95%CI: 0.28-0.67, p = .0002), or an ER visit for a mental health reason (OR = 0.60; 95%CI: 0.41-0.87, p = .008).

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, 18].

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, 27]. 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, 29].

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, 29]. 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.

Side effects of antipsychotic medications are highly prevalent and significantly associated with lower adherence, which is associated with increased healthcare resource use. Prevention of, monitoring for, and minimizing medication side effects may lead to better adherence and improved outcomes.