Abstract
Objective:
Most of the existing studies investigating the impact of schizophrenia on utility have focused on the different stages of the disease. The objective of this study was to describe and quantify the impact of treatment-related side-effects on utility in patients with schizophrenia, using data from an observational study.
Methods:
This study used data from the European Schizophrenia Cohort (EuroSC), a multi-center 2-year cohort study conducted in France, England, and Germany. The EQ-5D questionnaire was completed every 6 months, as well as the Subjective Side Effect Rating Scale, assessing patient distress over extrapyramidal symptoms (EPS), weight gain, sedation, and sexual dysfunction, used to assess whether or not the patient experienced the side-effect. At first a bivariate analysis was conducted to describe utility values with and without side-effects. Then, a random effects regression analysis was performed on utility, where random effects were controlled for repeated measures on the same subjects, with potential confounding factors. Finally, findings were compared with those of previous publications.
Results:
This sample consisted of 1208 patients with schizophrenia. At the baseline visit, the most reported side-effect was EPS (almost 60% of patients), followed by sedation and weight gain (∼50% of patients for each), and sexual dysfunction (almost 30% of patients). Significant association with severity of symptoms, functioning abilities, and utility were found. Patients reporting none of the studied side-effects had an average EQ-5D index score of 0.81, found to be higher than scores of patients reporting EPS (0.70), sexual dysfunction (0.67), sedation (0.70), or weight gain (0.72). The random effects model reported a utility decrement of 0.042 for EPS, 0.022 for weight gain, 0.022 for sexual dysfunction, and 0.019 for sedation. Although the external validation was difficult due to the different methods or definitions of the side-effects, as well as the paucity of data for weight gain, sedation and sexual dysfunction, the results were generally consistent with previous studies.
Conclusion:
This study aimed at quantifying the direct impact of main side-effects associated with antipsychotics on patients’ utility. Results suggested a significant direct impact of side-effects, with EPS being the most impactful.
Introduction
Schizophrenia is a chronic and disabling psychiatric disorder afflicting ∼1% of the global populationCitation1. Although antipsychotic medication offers benefits for controlling the symptoms and preventing relapse, both first (FGA) and second generation antipsychotics (SGA) are known to be associated with a range of side-effects, affecting the drug’s acceptability and adherence as well as the patients’ quality-of-lifeCitation2–4. This has been demonstrated for extrapyramidal symptoms (EPS), weight gain, sedation, and sexual dysfunctionCitation5–7.
EPS refer to various involuntary movement disorders, including acute dyskinesia and dystonic reaction, tardive dyskinesia, Parkinsonism, akinesia, and akathisiaCitation8,Citation9. EPS are primarily associated with FGA, but still present with some SGACitation10. EPS have been shown to be associated with discomfort and social stigmaCitation7. Weight gain is a common feature of SGACitation11, and patients who experience antipsychotic-induced weight increase exhibit elevated rates of morbidity and decreased compliance with the treatment along with the overall quality-of-life, even though the psychopharmacological treatment is effectiveCitation12,Citation13. Sedation is also a common side-effect of FGA, especially at relatively high doses, and to a lesser extent one of SGA’s (less frequent and less severe)Citation14. The published literature indicates a prevalence of sedation, or sleep disorders ranging between 5–20%Citation15. This can be bothersome to patients trying to re-integrate into societyCitation14 or making efforts to engage in normal socializationCitation16. Finally, sexual dysfunction is widely reported in schizophrenic patients. Hormonal disturbances associated with antipsychotics entail a progressive deterioration of their sexual and socio-sexual function, including libido, arousal, and orgasmCitation17.
Several studies have previously investigated the impact of schizophrenia on quality-of-life, focusing mainly on the different stages of the disease (relapse, maintenance) or severity of symptomsCitation18,Citation19. Many of these studies also captured the impact of side-effectsCitation20,Citation21 on quality-of-life, but only a few have reported evidence of the impact on utility.
Preference-weighted measures, or utilities, are typically used to generate quality-adjusted life-years (QALYs). Utilities reflect the individual’s valuation of their state of well-being derived from the use of healthcare interventions, with zero reflecting states of health equivalent to death and one reflecting perfect health. Several methods exist to derive utility, including direct and indirect approaches. Main direct measurements of utility (preference elicitation) include standard gamble (SG), time trade-off (TTO), and visual analogic scale (VAS)Citation22. Indirect approaches, also called health state valuation, requires a valuation of health states results using instruments that not only measure, but also value the health-related quality-of-life associated with a health condition, according to the expressed preferences.
Utility measures in schizophrenia are important to weigh the benefits of a treatment against the harm due to side-effects, and to populate future pharmacoeconomic models. This study aims at assessing the impact of the treatment side-effects of antipsychotics in patients with schizophrenia on utility measures. The data collected from the EuroSC will be examined to quantify the utility decrements associated with each of the four main side-effects (EPS, sedation, sexual dysfunction, and weight gain).
Methods
Data source
EuroSC is a naturalistic follow-up of a cohort of people suffering from schizophrenia over a period of 2 years, with five visits at 6-month intervalsCitation23. The subjects were selected to provide a representative sample of the patients treated in each catchment area. The data collected included psychiatric and service history, socio-demographic information, and clinical information. The centers and sampling procedures were chosen to suit the national organization of mental healthcare and the information systems that could be exploited for the study. The study was carried out in nine European centers, two in Britain, four in Germany, and three in France, and included 1208 patients (288 in France, 618 in Germany, and 302 in the UK). This project was conducted in accordance with the Declaration of HelsinkiCitation24 and French Good Clinical PracticesCitation25). Subjects were aged between 18–64 years at the time of enrolment in the study, had a diagnosis of schizophrenia according to DSM IV criteriaCitation26, and had provided a signed informed consent. Patients who were hospitalized for the last 12 months or who were roofless at the time of inclusion were not included (homeless patients could be included).
Collected data
Demographic characteristics were collected at baseline. Information included gender, age (categorized as less than 35, between 35–45, and more than 45), family situation, living conditions, employment, and type of schizophrenia diagnosis.
Utility values were computed from the EQ-5D questionnaire, using the English tariff (preferences estimated in UK), at each visit.
To evaluate whether the patient experienced side-effects, the subjective side-effects rating scale was used at each visitCitation27. This self-reported scale rates the level of distress related to different side-effects for the previous week. The distress was measured with five levels for each dimension; (0) patient does not report the relative side-effects as being present, (1) no distress, (2) a little or mildly distressed, (3) moderately distressed and (4) seriously or severely distressed. Side-effects were coded as present or absent: patients who answered one or more were considered as experiencing the side-effect. The questionnaire included one item for weight gain and one for sedation (actually labeled as sleepiness). EPS included akinesia (question 1), akathisia (question 2), rigidity (question 4), and tremor (question 5), and sexual dysfunction included sexual difficulties (question 5) and hyperprolactinemia (question 12).
At each visit, the level of psychiatric symptoms and the level of social functioning were measured using the Positive and Negative Symptoms Scale (PANSSCitation28,Citation29) and the Global Assessment of Functioning (GAFCitation30) scale, respectively.
Statistical analysis
Descriptive analyses were performed at the baseline visit. The proportion of patients experiencing at least one of the four mentioned side-effects and each side-effect were described, together with associated utility values derived from EQ-5D, PANSS and GAF scores. Student test for continuous data and Chi-square test for categorical data were conducted as appropriate to compare outcomes of patients with and without side-effects.
To estimate utility decrements associated with the side-effects of interest, a generalized linear mixed model (random effects regression analysis) was performed on the overall set, taking into account several assessments per patient (random effects were used to control for repeated measures on the same subjects). This approach is similar to the one used by Briggs et al.Citation31 (on EQ-5D), and will allow comparability of our findings. The independent variable was utility, as derived from EQ-5D, dependent variables were experience of side-effects, and potential confounding factors, likely to be associated a priori with quality-of-life. This model allowed estimating utility increments (positive coefficient) or decrements (negative coefficient) for each side-effect. In addition to country, age, and gender, potential confounding factors included severity of positive and negative symptoms, as measured by PANSS, and level of functioning, as measured by GAF.
All regression analyses were performed using SAS version 9.3.
Comparison with previously published studies
A literature review was undertaken to retrieve published utility decrements associated with EPS, weight gain, sedation, and sexual dysfunction from the literature. Two search strategies were implemented in Embase and Medline databases. Each strategy included terms related to population (patients with schizophrenia for weight gain, sedation and sexual dysfunction, and patients under antipsychotics or with schizophrenia for EPS), side-effect description, and quality-of-life. Screening of references and extraction of data were performed by two independent reviewers.
The collected data included reference description, objectives, study design, population interviewed, utility elicitation/measure approach, side-effects definition, utility decrement calculation approach, and results.
Results
In total, 1208 patients were recruited for EuroSC and interviewed every 6 months during 2 years. Demographic and main clinical characteristics of patients at the baseline visit are presented in .
Table 1. Demographic and main clinical characteristics at baseline (n = 1208).
Patients were mostly males (62%), they were aged on average 41 years old, and had suffered from schizophrenia for ∼14 years on average. More than half of the sample was single when entering in the cohort. The majority of cases were of the paranoid sub-type of schizophrenia.
Regarding clinical characteristics at baseline, the mean EQ-5D utility was found to be 0.73 at the baseline visit, the mean PANSS was 57.3, and the mean GAF score was 51.3.
As shown in , at the baseline visit, ∼20% of patients reported they did not experience any of the four mentioned side-effects in previous weeks, while ∼80% reported at least one. The most reported side-effect was EPS, with almost 60% of patients, followed by sedation and weight gain (∼50% of patients), and sexual dysfunction (almost 30% of patients).
Table 2. Proportion of patients experiencing side-effects at the baseline visit (n = 1208).
The average PANSS score was 58.2 for patients reporting at least one of the four studied side-effects, which was statistically higher than 53.9, as recorded by patients reporting none of the side-effects (p = 0.01), suggesting an association between severity of the symptoms and side-effects experienced. The same trend was observed concerning functioning (GAF: 50.9 vs 52.7, p = 0.14), suggesting patients were more severely afflicted in terms of functioning when side-effects were experienced (although significance was not reached). Utility was consistently lower in patients reporting at least one of the four studied side-effects (EQ-5D: 0.71 vs 0.81, p < 0.0001).
When compared to patients not reporting EPS, patients reporting EPS had significantly more severe symptoms (PANSS: 59.9 vs 53.8, p < 0.001) and more severe functioning (GAF: 53.2 vs 50.9, p < 0.001). They consistently reported a lower utility (EQ-5D: 0.78 vs 0.67, p < 0.001). A similar conclusion can be applied to patients reporting sexual dysfunction. The same trend is also observed for patients reporting sedation and weight gain, although significance was not reached for all outcomes.
Multivariate analysis
presents the results of a regression model, showing the impact of each side-effect, controlling for country, gender, age, severity of symptoms (PANSS), and functioning (GAF) on the utility value.
Table 3. Multivariate model.
The model was performed on the total set, accounting for several visits per patient. Overall, 4864 assessments were used (1208 patients at baseline, 1024 at visit 2, 962 at visit 3, 860 at visit 4, and 810 at visit 5).
The constant term represents the utility of a patient with schizophrenia without any side-effect, with null PANSS, and GAF, and coefficients for each side-effect represent changes in utility relative to this value.
Each coefficient for side-effect was significant. These results show that EPS has the greatest impact in association with the reduction in utility ranging at 0.042 (0.008) points. Weight gain, sedation and sexual dysfunction were associated with reductions in utility of 0.021 (0.008), 0.018 (0.008), and 0.023 (0.01) points, respectively.
Comparison with previously published studies
From the search strategies implemented, nine published studies were retrieved. presents the utility decrements available in these studies.
Table 4. Utility decrements associated to EPS, weight gain, sedation, and sexual dysfunction in literature.
In 1993, Morss et al.Citation32 interviewed chronic schizophrenic patients and provided multiplicative decrements for akathisia, Parkinsonism, and tardive dyskinesia, using the SG and the VAS methods. The survey was implemented on a computer and a moderator assisted patients with use of the survey. In 1997, Glennie et al.Citation33 interviewed seven patients in Canada with the SG technique and evaluated disutility for EPS. In 1998, Cummins.Citation34 linked health states observed in people with schizophrenia participating in an international RCT of olanzapine vs haloperidol with specific health states. The methodology used was not clearly described. In 2000, Lenert et al.Citation35 quantified differences in utility between states with and without pseudo-Parkinsonism according to patients, family members, and healthcare providers. Participants viewed videotaped depictions of simulated patients with mild or severe symptoms of schizophrenia, with and without EPS, and then provided SG and VAS ratings of desirability of these states. Additive decrements were then computed. In the same year, Lee et al.Citation36 used a multimedia survey to evaluate utilities from the SG method among persons with schizophrenia, family members of persons with schizophrenia, health professionals and the public, and calculated additive decrements for EPS. In 2001, Oh et al.Citation37 also used the SG approach to generate additive utility decrements for EPS. Again, in 2004, Lenert et al.Citation38 used the SG approach to generate additive utility decrements of health states that included the presence of common AE of medication (weight gain, tardive dyskinesia, pseudo-Parkinsonism, and akathisia). More recently, in 2008, Briggs et al.Citation31 examined the impact of treatment side-effects related to antipsychotics, on quality-of-life from the perspective of schizophrenia patients and laypersons, using both direct (TTO) and indirect (EQ-5D) approaches. Utility decrements were provided for weight gain, hyperprolactinemia, and EPS. Finally, Adrianzén et al.Citation39 used data from the Schizophrenia Outpatient Health Outcome study to generate additive utility decrements associated with sexual dysfunction, EPS, tardive dyskinesia, and clinically significant weight gain.
Thus, a large variety of methods has been used. SG was the most used (seven out of nine), and other approaches included regression on EQ-5D, TTO, EQ-VAS, or VAS. It is also noteworthy that there was a large variation in the side-effects definitions used in the different studies, when they were mentioned. Finally, these results are based on a large variety of populations: patients, carers, professionals, or laypersons.
All of the nine studies identified evaluated utility decrements for EPS. Subtractive results ranged from 0.038 (from Lee et al.Citation36, interviewees = professionals, milder state) to 0.291 (Briggs et al.Citation31, interviewees = laypersons), and multiplicative results ranged from 0.84 (Morss et al.Citation32, interviewees = patients, for Parkinsonism) to 0.898 (Morss et al.Citation32, interviewees = laypersons, for akathisia). Only three studies identified utility decrements for weight gain, with results ranging from −0.01 (from Adrianzen et al.Citation39, interviewees = patients) to 0.094 (Briggs et al.Citation31, interviewees = patients). Only two studies identified utility decrements for sexual dysfunction, with results ranging from 0.04 (from Adrianzen et al.Citation39, interviewees = patients) to 0.104 (Briggs et al.Citation31, interviewees = patients). No publication evaluating utility decrements for sedation were found.
Discussion
In the context of health economics evaluation for pharmaceutical market access decision-making, cost-utility studies are widely used. As the key outcome of such studies are QALYs, availability of appropriate utility measures is critical. Moreover, measuring utility values for health states is useful to quantify the extent of health impairments.
The results of this study show that about half of the patients experienced EPS, and that they consistently report a lower utility than patients who do not experience any. Decrement of utility, as reported by the regression model, was 0.042, and EPS were the largest contribution to the utility variations in the presence of side-effects. Weight gain has a large impact too: more than half of the patients reported weight gain, and this was associated to a lower utility. The regression model results show a decrement in utility of 0.022. More than half of the patients reported experience of sedation while receiving antipsychotic therapy. As expected, patients with schizophrenia experiencing sedation associated with antipsychotic therapy report lower utilities than those who do not experience sedation. The regression model reports a utility decrement of 0.019. Finally, findings from the present study suggest that sexual dysfunction was associated to a utility decrement of 0.022.
In summary, the impact of side-effects was significant when compared to the impact that treatment had on the symptoms. It, thus, seems essential to consider utilities decrements associated with side-effects in future health economic models.
Comparison of our results with previously published studies was difficult due to the shortfall of results for weight gain, sedation, and sexual dysfunction, and due to the large variability of results for EPS. Also the main limitations of the existing studies ought to be mentioned.
Most of them were conducted over a small set of interviewees, and only three studies included more than 100 intervieweesCitation35,Citation38,Citation39. Decrements in utility values varied considerably according to the population from which the values were derived, and the differences in health values between patients and community members participating could be important. This variability is likely to be due to key potential biases in any health-related utility study that relate to the description and/or identification of the health states, the time period used as the benchmark in the TTO procedure, and the risk of death used as the benchmark in the SG procedure. Nevertheless, our findings in terms of decrement were found to be within the same range as the previous studies.
Lenert et al.Citation38 only included laypersons, and, as such, results as such may not be used for pharmacoeconomic studies in every country. For both direct and indirect approaches, the question of the type of person (patients, laypersons, etc.) from whom utilities should be derived is legitimate. Recommendations from health technology assessment agencies vary between countries: as an example, in the UK, the NICE requests utility to be derived using EQ-5D data collected in patients with UK societal tariffs applied or, alternatively, a TTO valuation using a representative sample of laypersonsCitation40, whereas, in Sweden, the Pharmaceutical Benefit Board reported a preference for utilities derived from patients and not laypersonsCitation41.
In the EuroSC study, utility values available were collected from an indirect approach (EQ-5D utility, evaluated by the patients, with UK societal tariffs applied). At first, this deferred the problem of benchmark identification, as in TTO studies, and the problem of risk of death, as in the SG procedure. Second, as EQ-5D tariffs were based on preferences of the general population, findings of our study focused on the patient point of view in addition to the societal point of view, which is complementary of healthcare professionals, caregivers, and layperson findings in other studies. Indeed, it is noteworthy that healthcare professionals, caregivers, and laypersons may have intrinsic biases, affecting their responses, as shown by literature, reporting very different ratings according to the population interviewed for measuring utility. For several authorsCitation42,Citation43, quality-of-life can be suitably measured only by determining the opinions of patients, because quality-of-life is a uniquely personal perception. Although the reliability of schizophrenic patients’ responses have been questioned for a long time, several studies have now presented evidence that they are able to accurately describe their health state and assign them utilities with a satisfactory degree of reliability and validityCitation31,Citation44–46.
Most existing studies have exclusively studied EPS, and only three studies have investigated other side-effects such as weight gain, sedation, and sexual dysfunction. Moreover, only three studies reported a decrement for sedation, weight gain, and sexual dysfunction. Nevertheless, our results are generally in line with previously published results. Three exceptions, however, should be cited. First, Briggs et al.Citation31 decrement for EPS based on EQ-5D is 0.256, 6-times higher than 0.042. Although the methodology used by Briggs et al. is strong, the low number of patients (n = 49) may limit the generalizability of the results, and one cannot exclude that the populations have different characteristics explaining these differencesCitation39. Second, this is the first published analysis reporting decrement for sedation. One abstract was previously cited in a previous economic model including sedation as a side-effectCitation47, but the decrement was multiplicative and could not be compared to the result presented in this study. Third, Adrianzen et al.Citation39 findings showed a greater impact of sexual dysfunction than EPS and tardive dyskinesia, while Briggs et al.Citation31 findings are closer to the results of our study. It could be mentioned that Adrianzen et al. used the data from the SOHO cohort, leading to a very large number of patients, but the results were reported on the EQ-VAS, which is usually not considered as the preferable method.
The main strengths of this study relied in its design: EuroSC is a large multi-center prospective study conducted over 2 years, with a high level of patient representativity. Inclusion and non-inclusion criteria were not very restrictive and the patient management reflected well the real-world clinical practiceCitation23. This study then provides estimates based on a representative sample of the Western Europe population. Although the attrition was not negligible (15%, 20%, 29%, and 33% after 6, 12, 18, and 24 months), the large number of patients and the statistical methodology allowed for reliable estimates. Moreover, in this study, a subjective measure was used to identify patients with and without side-effects. Psychiatrists traditionally use rating scales to assess side-effects associated with antipsychotics, but these scales require the psychiatrist to rate the severity of manifestations of the side-effects, while not addressing the subjective dimensions of health state experience that may be critical to determining patients’ perception of their quality-of-life. This generates physicians’ values rather than patients’.
Nevertheless, several limitations should be acknowledged. First, a problem remains with the measure of utility for patients with schizophrenia. There is currently no consensus and, as such, the use of the EQ-5D may be subject to criticism. For example, a few studies suggested that the SF-6D appears more suitable as a measure of utility than the EQ-5D for patients with schizophreniaCitation48,Citation49. However, other studies reported that EQ-5D tended to generate wider and higher scores in schizophrenia, and to be more sensitive to change than SF-6DCitation50. Finally, EQ-5D is a measure widely used in cost-utility analysis and preferred by NICECitation40. Second, the impact of the assessment method could be questioned. In our study, we exclusively considered the patient experience of side-effects using a well-validated scale, the subjective side-effects rating scale. While a few studies noted that patients may report more side-effects when they are questioned systematically than when they are asked general questions about treatment tolerabilityCitation51,Citation52, others pointed out that patients may under-report side-effects for a number of reasons, including impaired insight with misattribution of symptoms, forgetfulness, and embarrassment about raising intimate adverse effectsCitation53. Although we acknowledge that the measure is not based on a clinical diagnosis, the usefulness and the relevance of the subjective side-effects rating scale have been demonstrated in several studiesCitation54. We think this may be the principal source of difference in results with previous published studies. Third, it would have been possible to include interactions between measures of severity and side-effects in the model. This would have led to more sensitive results, as anticipated from the results of the univariate analysis. Nevertheless, this would not have addressed the objective of the analysis, which was to estimate utility decrements for side-effects, independently of severity of symptoms.
Finally, it is worth mentioning that while the utility decrements provided in this study can be used in future health economic models in schizophrenia, as measuring direct impact of side-effects, they do not take into account the indirect impact of side-effects, potentially resulting from reduced adherence and, therefore, reducing treatment effectiveness of antipsychotics. Moreover, future modellers may have to deal with the duration of these side-effects. Unfortunately the design of the study did not allow us to address this aspect. Therefore, future work is needed to ensure a good understanding of treatment-related side-effects impact on quality-of-life of patients with schizophrenia.
Conclusion
Although reduction of symptomatology should be considered as the most important treatment objective, it was demonstrated that treatment-related side-effects are associated with significant decrements in patient utility. They may also have an indirect negative impact on quality-of-life, since they may be associated with reduced treatment adherence, and, therefore reduced treatment effectiveness.
Two main implications of this study should be highlighted. First, these results further support the importance of considering schizophrenic patients’ perceptions of their medication. Secondly, the decrements in utility associated with the various side-effects considered in this study allow for incorporating reliable estimates for EPS, weight gain, sedation, and sexual dysfunction in future cost-utility evaluations.
Transparency
Declaration of funding
No funding was received for this manuscript.
Declaration of financial/other relationships
The authors have no conflicts of interest of financial disclosures relevant to this manuscript. JME peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
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