Work functioning impairment in the course of pharmacotherapy treatment for depression

This study investigated the association between the duration of pharmacotherapy treatment for depression, or discontinuation from treatment, and work functioning impairment. This was a retrospective cohort study examining 30,409 workers. Work functioning impairment was assessed using a questionnaire, and treatment status was assessed using medical claims data. Odds ratios (ORs) of workers with severe work functioning impairment compared with healthy workers (control group) were calculated using logistic regression analysis. Continuous medical treatment was associated with severely impaired work functioning regardless of treatment period [continuous medical treatment; 4 months <: OR = 3.2, 4 months ≥, 10 months <: OR = 2.6, 10 months ≥, 14 months <: OR = 2.3, 14 months ≥, 16 months <: OR = 2.3, which are all statistically significant (p < 0.05)]. Workers who initially received pharmacotherapy treatment but discontinued in < 11 months had a significantly higher OR (treatment discontinuation period; 3 months <: OR = 2.3, 3 months ≥, 8 months <; OR = 2.0, 8 months ≥, 11 months <; OR = 3.0), while those who discontinued at ≥ 11 months did not (OR = 1.4, 95% CI 0.6–3.5). The sensitivity analysis excluding participants with at least one psychiatric comorbidity other than depression did not change the final result. It is important for the occupational health practitioners and attending psychiatrists to follow up in cooperation with each other, paying attention to the decrease in work functioning in addition to the symptoms.


Scientific RepoRtS
| (2020) 10:15712 | https://doi.org/10.1038/s41598-020-72677-1 www.nature.com/scientificreports/ treatment for preventing relapse 11,14 . American Psychiatric Association guidelines recommend treating patients with primary depression with the same dose of antidepressants as used in the acute phase, for 4-9 months or longer after remission, and assuming good and consistent control of depression symptoms 11,15 . Meanwhile, discontinuation and dose reduction of antidepressant drugs in the early phases can increase the risk of exacerbating symptoms; early discontinuation of antidepressants results in a 77% increase in the risk of relapse and recurrence of depression in two years 16 . In order to decide the treatment policy, it is important not only to monitor the patient's psychiatric status but also to evaluate functional impairment and quality of life 11 . Many depressed patients present with cognitive dysfunction such as slowed thoughts, poor concentration, distractibility, and reduce capacity to process information 11 . Understanding the type and extent of cognitive dysfunction is important in assessing the course of treatment. Attending physicians can evaluate functional impairment for their patients, and neuropsychological testing can be performed in the hospital 17 . However, it is difficult for the attending physician to intervene if the treatment is interrupted. If the patients were workers, the occupational health staff such as occupational physician and occupational health nurse can intervene with them in the workplace. Workers with depression tend to appear disabilities as work functions. Therefore, if the work functioning can be evaluated, it will be possible to find the timing of intervention by the occupational health staff. We previously developed and validated a self-administered questionnaire using the work functioning impairment scale (WFun) for assessment 18 . We also verified that the results of WFun assessments were correlated with the results of fit-to-work assessments conducted by occupational health nurses 19 .
Clinical treatment aims not only to relieve related symptoms, but to help patients recover their social functioning. Work functioning is an important social function for workers with depression. Information on the degree of work functioning in each phase of the treatment process is useful when deciding the necessity of cooperation between the occupational health staff and the attending physician, and when the attending physician decides the treatment content. However, to the best of our knowledge, there are no reports on changes in work functioning impairment based on treatment duration and discontinuation.
The purpose of this study is to describe the degree of work functioning impairment according to the course of pharmacotherapy treatment for depression (Objective 1: the duration of pharmacotherapy treatment, and Objective 2: the duration of discontinuation from pharmacotherapy treatment).

Methods
This was a retrospective cohort study of 45,404 workers, from 13 companies in Japan. All 13 companies were manufacturers (five pharmaceutical, six automobile-related, one nonferrous metals, and one precision equipment).

Data collection and ethical approval. The participants completed the WFun questionnaire between
July and October 2015. The objectives of the study were explained to the participants, who were informed that participation was voluntary and that only the researchers, who were unaffiliated with the companies, would have access to the data. Ultimately, of the 45,404 workers, 33,415 (73.6%) participated.
We obtained participants' medical claims data from the companies' health insurance unions retrospectively, back to 15 months before the WFun questionnaire was given. These claims contained information on the date of any visits to a medical institution (outpatient or inpatient), the name of the institution, the disease(s), treatment/ medication(s), and medical expenditures. Because Japan has a universal health insurance system, these claims data contained complete records on services used by the participants and covered under the system.
All methods were carried out in accordance with relevant guidelines and regulations. All data were labelled with unique codes assigned to each participant for personal information protection. Informed consent including implied consent was obtained from all subjects. The study was approved by the Ethics Committee of University of Occupational and Environmental Health, Japan (H26-026).
Measurements for treatment of depression with pharmacotherapy. Medical claims data were used for determining whether the participants had visited medical institutions and received pharmacotherapy treatment for depression there each month within the 15 months prior to their completing the WFun questionnaire. Participants were determined to have received pharmacotherapy treatment if they satisfied both of the following two inclusion criteria and one exclusion criteria: We included by two criteria as follow.
We excluded workers who had International Classification of Diseases 10 (ICD 10) codes F30 (Manic episode) or F31 (Bipolar affective disorder) given as the disease name of the claims data. A total of 126 participants had F30 (Manic episode) or F31 (Bipolar affective disorder), and we excluded their data in the final analysis.
Based on information obtained from medical claims data and WFun, the participants were divided into five categories in accordance with their duration of pharmacotherapy treatment (Objective 1) and duration of discontinuation from treatment (Objective 2). Detailed definitions are provided below and in Fig. 1.
Objective 1: Association between the duration of pharmacotherapy treatment for depression and work functioning impairment. A total of 315 participants were not classified under any of the above categories because they had received irregular pharmacotherapy treatment. Accordingly, we excluded their data in the final analysis.
Objective 2: Association between the duration of discontinuation of pharmacotherapy treatment for depression and work functioning impairment.
A total of 546 participants were not classified under any of the above categories because they had received irregular pharmacotherapy treatment. Accordingly, we excluded their data in the final analysis. outcome measurements. WFun is a self-administered questionnaire developed using the Rasch model 18 .
It assesses the severity of work functioning impairment and has been validated in accordance with the Consensus-based Standards for the Selection of Health Measurement Instruments (COSMIN). Items of WFun and the scoring method was shown in Table 1. A higher total suggests greater work functioning impairment due WFun: work functioning impairment scale * month in which WFun was conducted ○ pharmacotherapy treatment for depression -no pharmacotherapy treatment for depression Objective 1: Relationship between the duration of pharmacotherapy treatment for depression and work functioning impairment Relationship between the duration of discontinuation of pharmacotherapy treatment for depression and work functioning impairment   other measurements. We used a self-administered questionnaire to determine the participants' sex, age, job type and job title. Age in years was categorised into five groups (< 30, 30-39, 40-49, 50-59, and ≥ 60 years), as was job type (clerical and administrative support, sales, research and development, production line, and other), while job title was categorised as manager or rank-and-file employee.

Statistical analysis.
In addressing each of the two objectives indicated above, we performed logistic regression analyses using each category as an explanatory variable and a total WFun score of ≥ 21 points as an outcome variable. Using the category of no pharmacotherapy treatment (healthy workers) as a reference, we calculated the OR (and 95% CI) for each category. Stata version 14.2 (StataCorp LLC; TX, USA) was used for analyses, with significance set at < 0.05.

Sensitivity analysis.
Many patients can be expected to have at least one psychiatric comorbidity and this can quite significantly alter work functioning. Sensitivity analysis was performed in order to confirm that the results did not change even if these individuals were excluded. We excluded participants below (exclusion criteria) and performed logistic regression analyses in the same way.

Results
participants' characteristics. Among the 33,415 participants, we were unable to obtain the medical claims data of 2,533 participants and 473 did not answer at least one of the seven WFun questions. After excluding them, we had data from 30,409 participants for analysis. Table 2 shows the participants' characteristics. Male employees comprised 85% of the participants, and the largest proportion of participants (32%) were 40-49 years old, followed by 30-39 (24%), 50-59 (22%). Participants primarily worked in research and development (20%), clerical and administrative support (18%), and sales (18%).
Objective 1. Table 3 shows the association between the duration of pharmacotherapy treatment for depression and work functioning impairment. Table 1. Items of Work Functioning Questionnaire (WFun) and the scoring method. The total score is the sum of the scores of all items. The score range is 7 to 35 points. A high score means that the work impairment is large.

Items of Work Functioning Questionnaire (WFun)
(1) I have not been able to behave socially 1 2 3 4 5 ( Objective 2. Table 4 shows the association between the duration of discontinuation from pharmacotherapy treatment for depression and work functioning impairment. Workers who initially received pharmacotherapy treatment but discontinued in < 11 months had a significantly higher OR (treatment discontinuation period; 3 months <: OR = 2.3, 3 months ≥, 8 months <; OR = 2.0, 8 months ≥, 11 months <; OR = 3.0), while those who discontinued at ≥ 11 months did not show a significantly higher risk of work functioning impairment (OR = 1.4, 95% CI 0.6-3.5).
A sensitivity analysis was performed on both objectives 1 and 2. The results excluding participants with at least one psychiatric comorbidity other than depression did not change (Supplementary Table S1, S2).

Discussion
This study investigated the association between the duration of pharmacotherapy treatment and work functioning impairment as well as the association between the duration of discontinuation from pharmacotherapy treatment and work functioning impairment. Continuous medical treatment was associated with severely impaired work functioning regardless of treatment period. Further, workers who initially received pharmacotherapy treatment but discontinued in < 11 months had a significantly higher OR compared to healthy workers (control group), while those who discontinued at ≥ 11 months did not (OR = 1.4, 95% CI 0.6-3.5).  Table 3. Number of workers, mean WFun score, and proportion of workers with a high WFun score (21 points or more), and logistic regression analyses for Objective 1: association between the duration of medical treatment for depression and work functioning impairment. OR odds ratio, CI confidence interval. www.nature.com/scientificreports/ The present results have several implications for future interventions. First, in this study, the risk of experiencing severe work functioning impairment was higher even with ≥ 1 year of antidepressant treatment. While most recent systematic reviews have shown antidepressant treatment improves functional outcomes, one reported that 60% of patients had persistent functional impairment even 6 months after symptom remission 21 . Job performance is also improved over time following symptom amelioration 22 . These results are consistent with the present findings. Based on these findings, if the symptoms were recovered by the treatment of antidepressants but the work function was deteriorated, it may be necessary to consider a side effects of antidepressants or a cognitive impairment due to causes other than depression such as Alzheimer's disease.
Second, in addition to symptom amelioration, job-related functioning and performance are important for continued employment. Our study suggests the importance of monitoring patients for ≥ 1 year after finishing treatment (Table 4), assuming work performance is only restored after recovery from symptoms. The risk of work functioning impairment is markedly higher, particularly in the acute phase (< 4 months as shown in Table 3), wherein the risk is threefold that of healthy controls. It is therefore important to assess workers' degree of recovery from impairment after starting treatment, even if their symptoms have remitted. Additionally, given that severe work functioning impairment (WFun ≥ 21 points) can increase the risk of taking sick leave in the future, such assessments are important for preventing depression-related work leave 23 .
Third, in the present study, the risk of severe work functioning impairment remained high for about 1 year after discontinuation of antidepressant treatment (Table 4). This is the first study to assess work functioning following treatment discontinuation. To deter workers impatience with their recovery, attending psychiatrists or occupational physicians should explain the likelihood of being at an increased risk of work functioning impairment for ≥ 1 year after discontinuing antidepressant treatment. This explanation may give motivation to seek medical assistance when experiencing a symptom relapse. Additionally, Japanese companies with > 50 employees are legally obliged to employ corporate healthcare professionals, mainly occupational physicians, in the workplace. In these companies, importance should be placed on collaboration between the attending psychiatrist and healthcare professionals via the patient, and these healthcare professionals should follow-up patients after the patients discontinue antidepressant treatment.
The present study has a number of strengths. It is the first study to investigate work functioning impairment in employees across several phases of antidepressant treatment for depression by comparing findings with healthy workers who have never received such treatment. The study also examined work functioning impairment across several phases after discontinuation of pharmacotherapy treatment for depression. Additionally, this study used a large-scale, workplace cohort and was based on mutually exclusive and collectively exhaustive medical claims data obtained via Japan's universal health insurance system.
The study does also have some limitations. First, we did not obtain information on the responsiveness of treatment for depression and the reason for discontinuation of treatment. We could not evaluate the effects of these situations on work functioning.
Second, we did not assess depression severity. We therefore did not account for its effect on work functioning impairment. However, a recent systematic review reported, based on several studies, that although antidepressant treatment ameliorates functional outcomes, the severity of depression at the start of treatment does not affect this amelioration 2 . We were also unable to examine non-pharmaceutical treatments, such as psychotherapy, concurrent with pharmacotherapy; therefore we did not evaluate the effects of such treatments. Additionally, we did not examine other aspects, such as the effects of job styles at certain workplaces, with relation to work performance. Finally, because the study population comprised employees from companies listed on the First Section of the Tokyo Stock Exchange, and thus generally representing those of higher socioeconomic status, care should be taken in generalising the findings. Furthermore, roughly half were pharmaceutical company employees and therefore likely have greater medical knowledge than the general public. People with higher socioeconomic attributes, such as higher education levels, are also more accepting of mental health services 24 . The proportion of participants who had depression but were not using such services was therefore likely lower than that in the general population. This limitation should be taken into account when interpreting the results. Those taking oral antidepressants accounted for 2.7% of all participants, which is similar to the proportion in Table 4. Number of workers, mean WFun score, and proportion of workers with a high WFun score (21 points or more), and logistic regression analyses for Objective 2: association between the duration of discontinuation from medical treatment for depression and work functioning impairment. OR odds ratio, CI confidence interval. www.nature.com/scientificreports/ a large-scale survey on mood (emotional) disorders among general residents in Japan (in which the 12-month prevalence of depression was 2.1%) 25 .

conclusions
The present study showed an association between the duration of pharmacotherapy treatment and work functioning impairment as well as the relationship between the duration of discontinuation from treatment and such impairment. Patients were found to be at an increased risk of severe work functioning impairment for ≥ 1 year after discontinuing antidepressants. It is important for the occupational health practitioners and attending psychiatrists to follow up in cooperation with each other, paying attention to the decrease in work functioning in addition to the symptoms.