Diabetes Care 1 Hiroyuki Miidera,1 Minori Enomoto,1,2 Association Between the Use of Shingo Kitamura,1 Hisateru Tachimori,3,4 Antidepressants and the Risk of and Kazuo Mishima1,5,6 Type 2 Diabetes Mellitus: A Large, Population-Based Cohort Study in Japan https://doi.org/10.2337/dc19-1175 OBJECTIVE This study aimed to reveal the associations between the risk of new-onset type 2 diabetes mellitus and the duration of antidepressant use and the antidepressant dose, and between antidepressant use after diabetes onset and clinical outcomes. RESEARCH DESIGN AND METHODS In this large-scale retrospective cohort study in Japan, new users of antidepressants (exposure group) and nonusers (nonexposure group), aged 20–79 years, were included between 1 April 2006 and 31 May 2015. Patients with a history of diabetes mellitus or receipt of antidiabetes treatment were excluded. Covariates were adjusted by using propensity score matching; the associations were analyzed between risk of new-onset type 2 diabetes and the duration of antidepressant use/ 1Department of Sleep-Wake Disorders, National dose of antidepressant in the exposure and nonexposure groups by using Cox Institute of Mental Health, National Center of CARDIOVASCULAR AND METABOLIC RISK proportional hazards models. Changes in glycated hemoglobin (HbA1c) level were Neurology and Psychiatry, Tokyo, Japan 2 examined in groups with continuous use, discontinuation, or a reduction in the dose Department of Medical Technology, School of Health Science, Tokyo University of Technology, of antidepressants. Tokyo, Japan 3TranslationalMedicalCenter,NationalCenterof RESULTS Neurology and Psychiatry, Tokyo, Japan Of 90,530 subjects, 45,265 were in both the exposure and the nonexposure group 4Institute for Global Health Policy Research, Bureau after propensity score matching; 5,225 patients (5.8%) developed diabetes. of International Health Cooperation, National Cen- ter for Global Health and Medicine, Tokyo, Japan Antidepressant use was associated with the risk of diabetes onset in a time- and 5Department of Neuropsychiatry, Akita Univer- dose-dependent manner. The adjusted hazard ratio was 1.27 (95% CI 1.16–1.39) for sity Graduate School of Medicine, Akita, Japan short-term low-dose and 3.95 (95% CI 3.31–4.72) for long-term high-dose antide- 6International Institute for Integrative Sleep Med- icine, Tsukuba, Japan pressant use. HbA1c levels were lower in patients who discontinued or reduced the dose of antidepressants (F[2,49] 5 8.17; P < 0.001). Correspondingauthor:KazuoMishima,mishima@ med.akita-u.ac.jp CONCLUSIONS Received 14 June 2019 and accepted 18 January 2020 Long-term antidepressant use increased the risk of type 2 diabetes onset in a time- and dose-dependent manner. Glucose tolerance improved when antidepressants This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/suppl/ were discontinued or the dose was reduced after diabetes onset. doi:10.2337/dc19-1175/-/DC1. © 2020 by the American Diabetes Association. Antidepressants are widely prescribed in developed countries (1). Selective serotonin Readers may use this article as long as the work is properly cited, the use is educational and not for reuptake inhibitors (SSRIs) are prescribed for psychiatric disorders such as depression, profit, and the work is not altered. More infor- anxiety disorder, panic disorder, and obsessive-compulsive disorder; the prescription mation is available at http://www.diabetesjournals rate is ;1.5% in Japan (2). We know empirically that patients who have been taking .org/content/license. Diabetes Care Publish Ahead of Print, published online February 12, 2020 2 Antidepressant Use and Diabetes Risk Diabetes Care antidepressants for a long time are RESEARCH DESIGN AND METHODS concrete evidence exists about the time prone to impaired glucose tolerance and Study Design requiredforglucosetolerancetobecome that glucose tolerance improves after This was a retrospective cohort study in impaired in patients taking antidepres- antidepressants are discontinued. An which we used linked anonymized data sants, it is ; $1 year (4,11,14). Accord- observational study (3) and a case- from medical claims and health checks ingly, prescription for only 1 month and control study (4) previously suggested an for 3,382,567 employees and their family prescriptions that changed were not in- association between long-term antide- members, aged 20–79 years, who were cluded in the prescription period. When pressant use and the risk of developing insured by the five main employee health prescriptionsweremissedfor1–3months, type 2 diabetes mellitus. However, sev- insurance associations in Japan; the data those months were included in the ex- eral observational studies did not con- were provided by JMDC Inc. (Tokyo, posure period, because clear evidence firm this significant association (5–8). Japan). The data identification technol- regarding the duration of the effect of Such discrepancies may be due to the ogy used by JMDC links individual monthly antidepressants on glucose tolerance is study design and sample size, biased medical claims to the corresponding health lacking, and in previous studies, the expo- assessment of antidepressant exposure, check results, enabling continuous follow- sure period included up to 3 months after confounding factors, and patient char- up of individuals’ history of medical care an antidepressant prescription had been acteristics. Among confounding factors, without revealing personally identifiable discontinued (4). depression is an independent risk factor information. The population comprised of type 2 diabetes (9,10). However, the individuals who were insured between 1 Ethical Considerations associations among depression, antide- April 2005 and 30 April 2016 and had The medical claims and health check data pressants, and type 2 diabetes remain information about joining or leaving the were initially provided by main employee unclear, as do the mechanisms. Type 2 insurance programs, or both. Clinical claims health insurance associations in Japan to diabetes is more strongly associated with data and health check data were ex- JMDC, which linked and anonymized the antidepressant use than with depression tracted monthly. A 110-month cohort entry data using identifiers before providing them (11). A case-control study in Taiwan period was used, starting in April 2006 and to the National Center of Neurology and showed that antidepressant use for $2 ending in May 2015, and patients pre- Psychiatry. Identifiers were unique to the years increased the risk of type 2diabetes scribed antidepressants were extracted. data set provided, and no personally identifi- (12), but such an association has not yet The antidepressants used by those patients able information was attached. Consent for been investigated in Japan. It would be arelistedinSupplementaryTable1. using information was obtained from the clinically important to evaluate the as- The date of cohort entry was defined patients who underwent a health checkup. sociation between antidepressant and as the month of the first prescription of type 2 diabetes among various Asian an antidepressant. Inclusion criteria were Definitions of Variables, End Points, ethnicities, using an adequate sample 1)age20–79 years and 2) information and Confounding Factors size after considering the confounding available for prescriptions and health check The primary end point was type 2 di- factors. The results of this research can fill results during the 12-month period before abetes mellitus onset, defined as 1)afirst in the knowledge gap by adding new and the 12-month period after cohort prescription of antidiabetes drugs or in- information to the existing literature, entry. Exclusion criteria were any of the sulin injections in monthly medical claims particularly that the use of antidepres- following within the 12-month period be- data or 2) HbA1c $6.5% (per the National sants also increases the risk of type 2 fore cohort entry: 1)aprescriptionforan Glycohemoglobin Standardization Program) diabetes in Japanese, and the risk in- antidepressant, 2)aprescriptionforan in health check data (13). Predictors of creases in relation to dose and duration. antidiabetes treatment, 3)glycatedhemo- risk were depression, duration of anti- Furthermore, to our knowledge, no stud- globin (HbA1c) $6.5% (per the National depressant use, mean monthly dose of ies have investigated the status of anti- Glycohemoglobin Standardization Program prescribed antidepressant(s), and use of depressant use in patients who developed [NGSP]), and 4) diagnosis of type 1 diabetes combined antidepressants. Three cate- type 2 diabetes after taking antidepres- mellitus in medical claims data (ICD-10 code gories were defined for the duration sants; as a result, the association be- E10.x) (13). The observation period was of antidepressant use: short term (,12 tween antidepressant use and the clinical from the date of cohort entry to April 2016. months),intermediateterm(12–24months), outcome of type 2 diabetes is unknown. Data were censored when any of the fol- and long term ($25 months). The mean Identifying racial differences in the re- lowing occurred: 1) type 2 diabetes onset, 2) monthly dose of prescribed antidepres- lationship between antidepressant use leaving an employee health insurance asso- sants was calculated by dividing the cu- and diabetes, as well as the clinical out- ciation, 3)death,4) end of the observation mulative antidepressant dose prescribed comes after adjusting for antidepressant