Background
The inclusion of the patient voice in clinical research is of growing interest in the field of psychiatry as well as to regulatory agencies such as the US Food and Drug Administration [
1,
2]. Attention to the patient perspective has led to research examining the effect of antipsychotic treatment on patients’ assessments of their functioning and well-being, including health-related quality of life (HRQoL) [
2‐
5].
Although some studies have evaluated the effect of antipsychotic medication on patient-rated HRQoL, most followed patients for 1 year or less [
3,
6‐
10]. For a chronic condition like schizophrenia, changes in HRQoL may evolve over several years. Additionally, some studies examining the relationship between antipsychotic therapy and HRQoL were conducted in patients receiving oral antipsychotics [
7,
11,
12], which can be associated with poor adherence. Long-acting injectable (LAI) antipsychotics were developed to provide an alternative to oral antipsychotics for long-term treatment of schizophrenia [
13]. The LAI aripiprazole lauroxil (AL), a prodrug of aripiprazole, was developed as a long-acting intramuscular formulation for the treatment of schizophrenia [
14]. Efficacy and safety of AL for the treatment of schizophrenia were demonstrated in a 12-week pivotal trial [
15]. Short-term AL treatment was associated with significant improvement from baseline in Positive and Negative Syndrome Scale (PANSS) total score, and continued therapeutic efficacy was observed in a 52-week extension study [
15,
16].
Long-term safety studies were conducted in a cohort of outpatients with schizophrenia who were followed for up to 3.5 years while receiving monthly AL treatment [
17,
18]. As part of these studies, we collected HRQoL via the SF-36v2® Health Survey (SF-36v2), which is a measure of functional health and well-being [
19]. The SF-36v2 has 2 subscales, one for quality of life pertaining to mental health and the other pertaining to physical health. The current post hoc analysis examined the changes in self-reported mental and physical HRQoL in schizophrenia outpatients followed for more than 2 years while receiving AL in these studies. We then used the long-term data for 2 descriptive comparisons. First, we compared the trajectory of HRQoL scores over time with those of the normative general population. Second, we compared the cross-sectional scores at baseline and end of study for this schizophrenia sample with other cross-sectional SF-36v2 scores obtained for 2 chronic medical conditions (hypertension and type 2 diabetes) and another mental health condition (depression).
Discussion
This post hoc study examined the trajectory of change in self-reported HRQoL in stable patients with schizophrenia maintained on therapy with AL over 124 weeks measured by the SF-36v2, a commonly used instrument for measuring function and well-being. In addition, we descriptively compared clinical trial results with publicly available normed values from the general population as well as patients with 3 chronic conditions (hypertension, type 2 diabetes, and depression). To provide further context to the interpretation of differences between the schizophrenia clinical trial population and the external populations, we used threshold values representing MIDs.
Our main finding is that mental HRQoL improved and was maintained over the course of 2 years compared with baseline scores in this population of patients with schizophrenia. This change does not seem to be an artifact of acute symptoms at baseline, given that the mean baseline PANSS score indicated that overall severity of illness was mild. Based on the MID for MCS, the baseline mean MCS score in the study population was lower than that in the general population, but by the end of the follow-up period over 2 years later, scores from the patients with schizophrenia did not differ from the normative general population scores. Some variability between post-baseline timepoints was noted in mean MCS and PCS scores; however, the magnitude of that variation was less than the MID of 3 points for the MCS and 2 points for the PCS and, therefore, is likely not clinically meaningful. In contrast, baseline PCS scores in the study population already resembled those in the general population at baseline and did not substantially change over time. Further, at week 124, mental health scores (MCS scores) in the study population were comparable to those among patients with hypertension or type 2 diabetes and were well above those among patients with depression (based on the MID). This finding is in line with findings from studies showing that major depressive disorder, as well as symptoms of depression in patients with schizophrenia, are associated with poor quality of life and that patients with depression have significantly poorer quality of life than either healthy populations or patients with other chronic diseases including hypertension [
4,
25‐
27].
Our results suggest that continuing to treat stable patients with schizophrenia with the LAI antipsychotic AL is associated with improvements in self-reported HRQoL. Previously published studies of data from our cohort demonstrated the durability of remission with AL therapy [
16] as well as the drug’s long-term safety and tolerability [
17]. The tolerability of AL may contribute to patients rating their physical HRQoL (mean PCS score) similarly to that of the general population mean. The clinical observation that patients with schizophrenia underreport physical symptoms [
28,
29] also may contribute to this finding.
Our study findings for SF-36 MCS scores for a schizophrenia cohort are generally consistent with those of other studies. A recent analysis of data from an international observational study aimed to provide a better understanding of the use of SF-36 and a second HRQoL scale, the EuroQol-5 Dimension questionnaire, in patients with schizophrenia by analyzing the correlation between these general scales and disease-specific instruments and disease characteristics, as well as the correlations among the instruments themselves [
30]. Sociodemographic and clinical correlates were analyzed, along with their consistency with condition-specific scale scores (PANSS and Schizophrenia Quality of Life Scale [SQLS]). Among 1379 patients with schizophrenia, the mean PANSS score was 77.98 and the mean MCS score was 40.68. Among the correlates of MCS were PANSS positive and negative dimension ratings (where higher PANSS scores were associated with lower MCS scores) and PANSS depression ratings (associated with lower MCS). The SF-36 MCS was highly correlated with the SQLS, showing internal consistency with symptom-specific HRQoL.
Several studies in the literature have examined the effects of new treatments on HRQoL in schizophrenia but over considerably shorter durations than in the current study. Our study has several strengths relative to the existing literature, the latter of which predominantly report HRQoL results associated with oral or LAI antipsychotics for up to 1 year [
3,
8,
31,
32]. We report an extended follow-up period (> 2 years) for patients with schizophrenia, measured HRQoL with a validated patient self-reported instrument, and included patients on an LAI agent, which serves to reduce adherence as a confounder.
The current analysis has several limitations. The inclusion of a subgroup of patients who successfully completed the 12-week pivotal efficacy and safety study may limit the generalizability of the results to a broader population of patients with schizophrenia, as it applies to a more stable cohort of patients. The attrition of patients who had poor tolerability or lack of clinical efficacy during the 124 weeks, as summarized in a safety analysis that included this patient population [
18], may also bias these long-term outcomes, as patients who continued were likely to be those who had a positive treatment response without major tolerability issues. Results from this study may not generalize to patient populations excluded from study enrollment, such as those with treatment-resistant schizophrenia or those experiencing their first episode of schizophrenia who are not clinically stable.
The study may also have been limited by the use of a generic (ie, non–disease-specific) measure rather than one that specifically addresses quality-of-life issues facing persons with schizophrenia. The SF-36v2, unlike tools designed for populations with serious mental illness, will not detect certain issues, such as stigma, affecting quality of life for these patients. These disadvantages are offset by the notable advantages shown here; specifically, the SF-36v2 is normed to the general population, and SF-36v2 HRQoL data are available for patients with other diseases, a feature that allows the comparisons presented in this paper. Because the SF-36v2 is a self-reported measure, its validity in patients with an illness like schizophrenia, which can affect insight, may be questioned. However, at least 2 previous studies have demonstrated that self-reported HRQoL in patients with schizophrenia is consistent over time and correlates well with clinician ratings for patients with schizophrenia who are not severely ill [
5,
12].
Additional limitations of the current analysis include the open-label and post hoc design, as well as the absence of a placebo control group. Comparing SF-36v2 scores from our study patients with normative data from other populations provides points of reference for a qualitative picture of HRQoL with AL; however, without a placebo control, possible effects on HRQoL of factors related to study procedures other than AL treatment cannot be discounted. Further, normative data were based on US population data; therefore, variability may exist between characteristics in the general population and those in the study population, as the latter was internationally based. Another limitation in the descriptive cross-disease comparisons is related to generalizability of data from a cohort from a single clinical trial to the broader disease population of schizophrenia (the same can be said for the data used for the other chronic conditions as well). Therefore, these data should not be used as a definitive comparison. To our knowledge, this is the first study of the SF-36v2 scale in a long-term clinical trial in which HRQoL of patients with schizophrenia was compared with that of patients with other diseases, and the purpose of these comparisons was to offer readers more qualitative perspectives.
Conclusions
Our major finding was that ongoing treatment with the atypical LAI antipsychotic AL was associated with significant improvements in self-reported mental health quality of life that were sustained over a follow-up period lasting over 2 years. The pattern of MCS score improvement occurred in large part within the first 4 weeks of treatment and was maintained during the observation period. By week 20, mean patient scores were similar to normative scores of the general population. Physical HRQoL was reported to be within the range of the general population norms and was sustained without much change — either improving or worsening — throughout the same follow-up period. In sum, results of this study indicate that the LAI antipsychotic AL improves (and maintains) mental HRQoL in stable patients with schizophrenia.
In the first study of its kind, we compared SF-36v2 MCS and PCS scores in this population of patients with schizophrenia to those in patients with 2 medical conditions (hypertension and diabetes) and another mental health condition (depression). The mental health scores of the schizophrenia population started lower (worse) than the scores of the population with other medical conditions but better than the scores of the population with depression. These comparisons help to anchor the baseline data to other conditions, something that has not frequently been done in quality-of-life literature in schizophrenia cohorts.
Acknowledgments
The authors acknowledge Michelle White, PhD, and Avery Rizio, PhD, of Optum, Inc., for providing a courtesy review of the manuscript. Writing and editorial assistance were provided by Eileen A. McCaffrey, MA, of Global Outcomes Group (Reston, VA), a contractor of Alkermes, Inc., and additional editorial assistance was provided by Peloton Advantage, LLC (Parsippany, NJ), an OPEN Health company, and funded by Alkermes, Inc.
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