Effectiveness of Antipsychotic Use for Reducing Risk of Work Disability: Results From a Within-Subject Analysis of a Swedish National Cohort of 21,551 Patients With First-Episode Nonaffective Psychosis

We included in our analysis persons first diagnosed with nonaffective psychosis (ICD-10 codes F20–F29), ages 16–45 years, from 2006 to 2016 in Sweden. Subjects were identified in the first two of the following sources, and data were collected from all: the National Patient Register (including inpatient and specialized outpatient care); SAs and DPs recorded in the Micro-Data for Analyses of Social Insurance; the Prescribed Drug Register (dispensed medications); and the Longitudinal Integration Database for Health Insurance and Labor Market Studies (age, sex, educational level, country of birth, main occupational activity). All registers were linked by each individual’s unique personal identification number.

In Sweden, individuals from the age of 16 with income from work or unemployment benefits are covered by the public SA scheme and can claim SA benefits if their work capacity is reduced by at least 25% due to disease or injury. For employees, the first 14 days of an SA spell are paid by the employer, with the exception of the first qualifying (“waiting”) day, for which no benefit is paid. Thereafter, employees can receive SA benefits from the Social Insurance Agency, and SA benefits are also paid during hospital stays. For unemployed individuals, compensation can be granted from the second day and is paid by the Social Insurance Agency. All individuals 30–64 years of age can be granted permanent DP if their work capacity is permanently reduced due to morbidity. Individuals 19–29 years of age can be granted temporary DP if their work capacity is reduced by at least 25% or if compulsory or upper secondary schooling is not completed in due time. Both SA and DP can be granted full-time or part-time at 25%, 50%, or 75%; SA benefits cover 80% and DP 65% of lost income up to a certain level. Both SA and DP are based on assessments from a physician, after evaluation of work ability.

The results of this nationwide register-based study show that patients with first-episode nonaffective psychosis had a lower risk of work disability when using antipsychotics compared with periods when not taking them. The risk was >50% lower with LAIs and around 30% lower with oral aripiprazole, oral olanzapine, and oral risperidone. When the inclusion criteria were narrowed, focusing on patients receiving prescriptions for antipsychotics for the first time, removing those with SA at baseline, censoring first 30 days of observation, considering long-term SA or only SA as an outcome, and restricting analyses to milder clinical pictures where DP was never received, the primary results were confirmed. Importantly, the association persisted beyond 5 years after first diagnosis. Also, the results largely held across sex and education level.

The mechanism through which antipsychotics are associated with better work functioning is currently unknown. We hypothesize that antipsychotics exert their action at least partially via their effect on positive symptoms, enabling psychosocial rehabilitation (18) and/or return to functionality in a sizable subgroup of patients. Indeed, antipsychotics are particularly effective in treating positive symptoms, among other symptoms (19), and symptomatic remission is a prerequisite of functional recovery for most patients (20). Interestingly, while positive symptoms are not related to work skills at baseline (21), positive symptoms are directly associated with poorer work skills at follow-up (22). More specifically, in a network of clinical manifestations in 740 persons with schizophrenia, everyday skills and functional capacity (indirectly) had the strongest connection with work skills, while positive symptoms were not connected at all (21). Conversely, when looking at the longitudinal association between positive symptoms at baseline and working skills at follow-up in 618 patients with schizophrenia, a significant association emerged (22). The results of our study are in line with these latter findings, as reducing positive symptoms with antipsychotics is associated with better functioning at work over time. Our results advance the evidence on the association between continuous antipsychotic treatment and occupational functioning, since they go beyond the indirect evidence of the association between positive symptoms and work skills (22), linking antipsychotics to an objective and tangible real-world outcome (work disability).

Importantly, the association with work ability was the largest for LAIs. A mounting body of evidence from randomized controlled trials has shown that LAIs are superior to placebo in treating symptoms, and in some aspects superior to oral antipsychotics (23–26). LAIs are particularly effective in the early phase of psychosis, according to both experimental and observational evidence (27–29). In a cluster-randomized controlled trial involving 489 participants with early-phase schizophrenia across 39 mental health clinics in 19 U.S. states, 19 centers were randomized to once-monthly aripiprazole LAI and 20 to provide treatment as usual. The results showed that aripiprazole LAI was largely superior to treatment as usual, improving time to hospitalization with a hazard ratio of 0.56 (95% CI=0.34–0.92) and a number needed to treat of 7 (30). In a cohort study of 1,166 patients with ICD-10-defined schizophrenia starting on paliperidone LAI, those with the largest improvement were those with shorter duration of illness (31).

The present results are also informative about the best clinical choice among oral formulations. Among oral antipsychotics, aripiprazole, olanzapine, and risperidone, which were the oral antipsychotics associated with better work functioning according to the real-world data of this study, have also been found effective in experimental settings in first-episode psychosis, without any clinical or statistical differences between them (19, 32, 33). Notwithstanding individualized treatment choices that should account for patients’ symptomatic profile, comorbidities, and preferences, the metabolic safety of first-line antipsychotics should be taken into account (32, 34, 35), given that the premature mortality in schizophrenia is largely due to cardiovascular diseases (36, 37). In previous studies, antipsychotic polytherapy was associated with a relatively low risk of rehospitalization compared with antipsychotic monotherapy among patients with schizophrenia (7). However, in the present study, focusing on work ability among patients with first-episode psychosis, antipsychotic polytherapy was not associated with a beneficial outcome compared with antipsychotic monotherapies. This finding may be attributable to the different type of patient population, the different type of outcome, or both.

Continuous antipsychotic treatment in the early phases of schizophrenia is crucial, given the results of this work (i.e., better job functioning), but also in light of the fact that once multiple relapses occur, medications tend to lose some (14), but not all (15), of their efficacy in preventing relapse compared to the larger effect they have in the early phase of the disorder. Our results show that the association between use of any antipsychotic and lower risk of work disability remained the same beyond 5 years after cohort entry. This result is of clinical value, as in addition to our previous results from a Finnish nationwide cohort (1), it is the first real-world study providing evidence that might discourage antipsychotic discontinuation even 5 years after diagnosis of a nonaffective psychosis. This finding can provide useful information for clinicians, patients, and families, as well as guideline developers, given that guidelines vary in their recommendations. For example, in a systematic review of English-language schizophrenia practice guidelines, 17 of 19 (89.5%) guidelines commented on the treatment of first-episode patients (38). Of these, one guideline each recommended antipsychotic treatment for 9–12 months, 12 months, or 18 months; two guidelines recommended 1–2 years; three guidelines recommended at least 2 years; and another two guidelines recommended continuing antipsychotic treatment after resolution of first-episode symptoms but did not recommend a specific duration of therapy. Furthermore, only five (27.8%) of the reviewed guidelines recommended LAIs for first-episode psychosis, although work disability was averted the most by use of LAIs in this nationwide cohort.

Strengths of our study include a nationwide sample of patients with first-episode nonaffective psychosis and follow-up of their medication use and sickness absence and disability pension through registers. For both sickness absence and disability pension, a medical certificate is necessary. Particularly in the process for deciding on whether a disability pension will be granted, a series of medical assessments is carried out. The study therefore uses data on medically certified sickness absence or disability pension, and not self-rated data. Moreover, the data used for this study are based on payments from the Social Insurance Agency, which undertakes thorough assessments of claimants. There is therefore a twofold rigid control of these outcome measures, making the data highly reliable. All residents of Sweden are covered by the social insurance scheme. Antipsychotic use modeling was conducted with the validated PRE2DUP method and was based on medications dispensed from pharmacies (16). We utilized a within-individual design, which minimizes selection bias by comparing different exposure periods within the same individual. As the impact of time-invariant factors is eliminated by the design, we adjusted for time-varying factors, which were time since cohort entry, temporal order of treatments, and time-varying use of other psychotropic medications. Finally, the results were confirmed across several sensitivity analyses.

However, limitations of our study also call for cautious interpretation of the findings. First, we did not have information on other possible nonpharmacological treatments, such as vocational rehabilitation, as well as other within-subject factors that might change over time (e.g., alcohol use) which may have affected the ability to work. Only individuals who experienced the outcome event and had variation in exposure contributed to within-individual models. Also, the results on work disability are generalizable only to socioeconomic and health care systems resembling those of Sweden. Register data also do not indicate the severity or fluctuation of symptoms over time. Since medications are typically restarted when the symptoms get worse, it is probable that the beneficial effect of antipsychotic treatment is underestimated. However, this possibility was addressed in sensitivity analyses censoring the first 30 days of exposures, representing the period of high symptom levels before the full pharmacological effect has been reached, resulting in lower adjusted hazard ratios. Furthermore, data on sickness absence were not available from the first 14 days of a sick leave period among employees. Still, periods related to mental disorders are known to be considerably longer than 14 days (39), and sensitivity analyses censoring the first 30 days also corrected for this timing issue. The associations also remained when we restricted analyses to long-term sickness absences (>90 days). Of note, this sample included a heterogeneous set of schizophrenia spectrum disorders. While this is a limitation in terms of specificity, it is also a strength in terms of generalizability. Also, the nonsignificant findings for polytherapy may have been a result of confounding by indication—that is, with periods with polytherapy indicating more severe clinical presentations that did not respond to monotherapy. As in all register-based studies, we cannot be sure whether dispensed medications have been taken as instructed. However, blood level analyses have shown that our drug use modeling method determines the actual medication use rather accurately (40). Finally, this study does not account for dose-response relationships, which together with time consequentiality and plausible mechanism are needed to infer causality.

Taken together, the results of this study support the hypothesis that antipsychotic treatment might be continued for at least 5 years when considering work disability, and LAI formulations in particular. We acknowledge that this work needs to be considered in the context of broader evidence on the effectiveness and safety of antipsychotics to make recommendations on the need for long-term treatment, and also that more studies are needed to investigate the role of each specific LAI. Improving work ability is possible, and continuous treatment with antipsychotics, preferably LAIs, might play a role in preventing work disability in the early illness phases in individuals with nonaffective psychosis, beyond 5 years from first diagnosis, minimizing progression to disability pension and chronicity, in the context of an informed and shared decision-making process between patient and physician.