This study clearly demonstrated the relative associations of various medical and lifestyle factors with the incident use of antidepressants using large-scale real-world data from health insurance claims and health checkups in Japan. The major finding of the present study was that MetS; poor sleep; and the use of hypnotics, anxiolytics, and NSAIDs were associated with antidepressant initiation. It is noteworthy that while hospitalization was not significantly associated with the outcome, MetS and other metabolic abnormalities, which are pre-symptomatic conditions, were significantly associated with antidepressant initiation.
We also demonstrated a dose-response association between the number of metabolic components and incident antidepressant use. In particular, we found a significant association of obesity, high BP, and glucose intolerance with depression. The pathways from MetS to depression could be biological or social25, a phenomenon that can be explained by the physiological consequences of obesity, including higher inflammation26,27 and the psychological/social consequences of MetS or obesity. However, most of the health-related behaviors assessed by the questionnaire, such as exercise habits, late supper, skipping breakfast, and smoking, were not significantly different between the cases and controls. Notably, information on physical activity or exercise habits was collected using self-administered questionnaires rather than quantitative methods. More detailed research is required to investigate physical activity and exercise habits more quantitatively and accurately through a quantitative physical activity using biometric sensors and detailed questionnaires on exercise habits.
Regarding psychosocial factors, physical and mental stress can be common causes of MetS and depression. The study subjects were corporate insurance beneficiaries comprising corporate employees and their dependents, and mental stress is potentially caused by the work itself, human relationships in the workplace, and family issues in this population. Physical stress may be caused by shift work. These not only trigger depression, but can also result in obesity and MetS through overeating, sleep disorders, and effects on various metabolic systems. However, this study did not include information such as work shifts and work-related stress, and further studies are required to identify modifiable factors and identify solutions to overcome both health issues.
We also produced interesting results regarding lifestyle information. First, we found that alcohol consumption is potentially protective against depression. Several previous studies have shown consistent results regarding the protective effect of alcohol against depression.28–32 Although our results did not show a clear benefit of daily physical activity, modifiable lifestyle factors including sleep and exercise habits, are potential candidates for intervention in both conditions, that is, depression and MetS. Daily exercise habits are particularly suitable lifestyle interventions, as a large body of evidence demonstrates the effectiveness of exercise on depression and sleep disorders. 33–36
Regarding prescription medicine, the use of hypnotics, anxiolytics, and NSAIDs at baseline was associated with incident antidepressant use. Studies have shown that insomnia is associated with depression and anxiety disorders.37,38 However, depression is often underdiagnosed in primary-care settings or for older patients39, and such medications might have been prescribed as supportive care for patients with symptoms and complaints related to depression but not formally diagnosed. Hence, individuals with underdiagnosed and undertreated depression may be hidden among those who have been prescribed these drugs.
Finally, a history of hospitalization for malignant diseases was also associated with incident antidepressant use without adjusting for medication. However, the association was attenuated after adjusting for medication information. This may be due to the mediation effects of anxiety and insomnia on the association. Previous studies have demonstrated that anxiety, depression, and insomnia are associated with cancer as well as with increased adverse outcomes, including mortality and psychosocial problems in cancer survivors.40–43 The present study reaffirms the importance of psychological care for those who experience cancer-related hospitalization.
This study had certain limitations. First, the present study was observational and did not demonstrate any causality. However, our results revealed various medical and lifestyle factors associated with depression, which we believe provide valuable insights into workplace mental and physical health. Second, we classified depression based on specific, prescribed classes of antidepressants, that is, selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenalin reuptake inhibitors (SNRIs), or noradrenergic and specific serotonin antidepressants (NaSSAs), thus potentially leading to misclassification bias since those who were treated with other classes of medication or those who had not been treated with medication were not diagnosed with depression. This type of misclassification is unavoidable in large-scale database studies. However, the main purpose of this study was to explore and generate hypotheses for future research. Therefore, sufficient findings have been generated from this analysis. Third, there was a concern regarding selection bias. Those who were taking sick leave due to depression might not have undergone health checkups in the workplace. However, in our country, the number of individuals who undergo health checkups is high in the working generations. Finally, most of the lifestyle information was derived from self-administered questionnaires, thus potentially undermining accuracy and objectivity. We may consider using activity monitoring, such as gyro meters, to gain objective personal activity information in future studies.
In conclusion, metabolic abnormalities; poor sleep habits; cancer-related hospitalization; and the use of hypnotics, anxiolytics, and NSAIDs were associated with incident antidepressant use in working-age individuals. Lifestyle intervention could be the subsequent step in reducing both mental and physical burdens among individuals in their prime.