Medication use and sickness absence from work in bipolar disorder: a nationwide register‐based study
Authors: Minna Holm, Antti Tanskanen, Jari Tiihonen, Heidi Taipale
Journal: World Psychiatry (2024)

Less than half of people with bipolar disorder are employed according to population representative register-based studies from Scandinavian countries1-3. In those employed, maintenance of stable occupation is hindered, and sickness absences are common4. Antipsychotics and mood stabilizers are known to be effective in the acute treatment of mania and the prevention of relapses of bipolar disorder5-8. Although the medication regimen may have a considerable impact on the ability to work, the association between medication use and work attendance in people with bipolar disorder has not been addressed. The present study aimed to investigate whether the use of mood stabilizing, antipsychotic and antidepressant medications was associated with the risk of work disability, defined as sickness absence, among employed people with bipolar disorder in a nationwide cohort. People with a diagnosis of bipolar disorder (ICD-10 codes F30 or F31, or Finnish ICD-9 codes 2962-2964 and 2967A) between 1987 and 2017 were identified from the Finnish Care Register for Health Care. The cohort included individuals aged 18 to 63 years. The follow-up started from January 1, 2005, or at first bipolar disorder diagnosis, or when people reached the age of 18 years, whichever occurred last. The follow-up ended on December 31, 2018, or when people reached the age of 63 years, or when they died, whichever occurred first. A first-episode sample consisting of individuals with the first bipolar disorder diagnosis between 2005 and 2017 was identified from the whole cohort. Those who had used antipsychotic or mood stabilizer medications within one year before their first diagnosis were excluded from this sample. Employment periods and sick leaves from 2005 to 2018 were obtained from the registers maintained by the Finnish Centre for Pensions and the Social Insurance Institution. The primary outcome of the study was the risk of sickness absence during employment periods. Short sick leaves (i.e., less than 10 days) were not considered. Medication purchases were drawn from the Prescription register, and drug use periods were estimated by the PRE2DUP9. Antipsychotics were defined as Anatomical Therapeutic Chemical (ATC) codes belonging to N05A, excluding lithium. Mood stabilizers were lithium (N05AN01), valproate (N03AG01), lamotrigine (N03AX09) and carbamazepine (N03AF01). Antidepressants were defined as ATC codes belonging to N06A. In statistical analysis, we utilized a within-individual design where each individual served as his/her own control. We compared medication use categories (only antidepressant, only mood stabilizer, both antidepressant and mood stabilizer, only antipsychotic, both antipsychotic and antidepressant, both mood stabilizer and antipsychotic; and concomitant mood stabilizer, antipsychotic and antidepressant) to non-use of the medications by stratified Cox regression. The time-varying covariates were the age at the start of a period, the order of medication classes, the number of prior sickness absences, benzodiazepine use (N05BA and N05CD) and Z-drug use (N05CF). Separate analyses were conducted for men and women. The cohort included 50,072 individuals, of which 28,089 (56.1%) were women. Of the whole cohort, 22,408 (44.7%) had an employment period during the follow-up (57% women, mean age: 34.8±11.5 years). Of the employed, 12,812 (25.6% of the whole cohort) did not have an employment period ending to sickness absence, whereas 9,596 (19.2% of the whole cohort) had such an employment period. The first-episode sample consisted of 18,000 individuals (56% women, mean age: 37.0±13.0 years), of whom 10,000 (55.5%) had an employment period during the follow-up, and 4,216 (23.4%) experienced an employment-related sickness absence. The use of mood stabilizers, with or without concurrent antipsychotic or antidepressant use, was associated with a lower risk of sickness absence than non-use of the medications. The use of mood stabilizer only was associated with the lowest risk (hazard ratio, HR=0.79, 95% CI: 0.72-0.87), followed by the concurrent use of mood stabilizer and antipsychotic (HR=0.82, 95% CI: 0.74-0.95), and mood stabilizer and antidepressant (HR=0.88, 95% CI: 0.79-0.97). The use of antidepressant only was associated with a higher risk of sickness absence than non-use of the medications (HR=1.23, 95% CI: 1.15-1.33). Of the covariates in the analysis, the use of both benzodiazepines (HR=1.34, 95% CI: 1.24-1.46) and Z-drugs (HR=1.34, 95% CI: 1.23-1.47) was associated with an increased risk of sickness absence. In the first-episode cohort, the results were mostly similar as in the whole cohort, but the association between antipsychotic or mood stabilizer use and sickness absence was stronger than in the whole cohort. Concomitant use of both mood stabilizer and antipsychotic was associated with the lowest rate of sickness absence (HR=0.63, 95% CI: 0.53-0.74), followed by the use of both mood stabilizer and antidepressant (HR=0.65, 95% CI: 0.54-0.79), the use of mood stabilizer only (HR=0.65, 95% CI: 0.56-0.76), and the use of antipsychotic only (HR=0.77, 95% CI: 0.66-0.90). In addition, the association between the use of antidepressant only and sickness absence was only barely statistically significant (HR=1.12, 95% CI: 1.01-1.24) (see also supplementary information). We also examined the risk of sickness absence in women and men separately. The results were mostly similar as in the original analyses. In the first-episode sample, the risk of sickness absence when using mood stabilizer only, mood stabilizer and antidepressant, and antipsychotic only was slightly smaller, signifying stronger effect, in men than in women – e.g., for antipsychotic only, the HR was 0.66 (95% CI: 0.52-0.84) in men, and 0.86 (95% CI: 0.71-1.05) in women. Of note, the association between the use of antidepressant only and sickness absence was similar in men and women (see also supplementary information). Thus, our study documents a notable reduction in the risk of work disability, defined as sickness absence, among individuals with first-episode bipolar disorder who were using mood stabilizers and/or antipsychotics, compared to periods without these medications. While the effect was somewhat reduced in the entire cohort, the use of mood stabilizer, either alone or in combination with antidepressant or antipsychotic, remained significantly associated with a decreased risk of sickness absence. These results align with previous research indicating that mood stabilizers and antipsychotics are effective in the treatment of mood symptoms and in the prevention of relapses in bipolar disorder5-8. However, functional outcomes have been neglected in previous studies and, as far as we know, the association between work attendance and medication use has not been investigated previously. The results of this study underscore the importance of effective treatment especially in early stages. Treatment may also be able to reduce the secondary effects of the illness, which hinder the ability to pursue and sustain employment. On the other hand, the use of antidepressant medication only was associated with an elevated risk of sickness absence. Although this finding may be in part due to confounding by indication (depressive symptoms are known to be strongly associated with reduced work attendance), it nonetheless highlights the need for more effective medication options to manage depressive episodes in people with bipolar disorder.