There is a growing evidence linking antidepressant drug (AD) use with type 2 diabetes (T2D).1,2 Given the high prevalence of both diabetes and AD use in many countries, researchers at the ASST Fatebenefratelli-Sacco in Milan, Italy, and the University of Eastern Piedmont in Novara, Italy, set out to provide a comprehensive evaluation of the risk for diabetes associated with AD use in a systematic literature review of relevant studies in PubMed, PsychINFO, and International Pharmaceutical Abstracts. The updated meta-analysis, recently published in PLoS One, confirmed the association between AD use and the risk for T2D.3

Twenty studies, published between January 1, 2000, and December 31, 2016, evaluating the incidence of new-onset diabetes in patients treated with ADs compared with nonusers were included. Thus, cross-sectional studies were excluded. Moreover, only studies published in the English language and those that included participants aged at least 18 years were included in the meta-analysis.

The Newcastle-Ottawa Scale (NOS) was used to calculate the quality of the studies included. One star each was awarded to studies controlling for baseline body mass index and presence of depression or depressive severity assessed by rating scales. A study awarded a star score ≥8 was considered a high-quality study. In addition, there was substantial heterogeneity among the studies (I2 statistic=71%).

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After the inclusion of recent negative studies, a statistically significant association between AD use and diabetes was observed (pooled relative risk, 1.27; 95% CI, 1.19 to 1.35; P <.001). These results did not change substantially in secondary analysis stratified by:

  • Type of AD used (SSRI vs non-SSRI)
  • Country in which the study was conducted (United States vs other countries)
  • Study design (cohort/randomized controlled trials vs nested case-control)
  • Source of information about AD treatment (self-report vs medical prescriptions)
  • Source of information about the diagnosis of diabetes (self-report vs antidiabetics prescriptions or clinical diagnosis)
  • Studies adjusting for body mass index and presence of depression or, when available, severity of depressive symptoms
  • NOS score (less than 8 vs 8 or more)

In fact, when the researchers restricted the analyses to the 6 high-quality studies (NOS score of 8 or 9), the relative risk further increased to 1.40. Finally, a sensitivity analysis using the leave-one-out approach resulted in minimal change, ranging from 1.25 to 1.28. 

In an interview with Endocrinology Advisor, lead investigator Virginio Salvi, MD, PhD, explained that “given a 13% prevalence of antidepressant use in the US,4 a 1.3-fold increase in diabetes risk would result in a population attributable risk of 4%. In absolute terms, this would translate [to] over 1 million of diabetes cases that could be due to concurrent antidepressant use.”

Although it still remains a matter of debate whether the association between AD use and incident diabetes is causal or not, Dr Salvi stated that because of ascertainment bias, some authors have downplayed the causal association between use of AD and diabetes risk. For example, the Whitehall II5 and DESIR6 studies “did not find differences in blood glucose of subjects exposed or not to antidepressants, but did so after having excluded the patients already diagnosed with diabetes outside the study, thus causing an underestimation of the effects of antidepressants,” noted Dr Salvi. Furthermore, 1 cohort study that reported higher diabetes risk with ADs did not find any difference in the number of prescribed glucose tests in the 2 groups.7 

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Because abdominal fat is a determinant of insulin resistance, antidepressants that induce weight gain should be prescribed with caution in patients at risk for diabetes, advised Dr Salvi. More specifically, “since weight gain and metabolic syndrome have been associated with the use of antidepressants with high histamine H1-receptor affinity, antidepressant drugs such as amitriptyline, mianserin, mirtazapine, and nortriptyline should probably be avoided in these patients,” Dr Salvi noted. Dr Salvi further noted that antidepressants antagonizing cholinergic M3-receptors, such as desipramine or paroxetine, might increase diabetes risk and should be prescribed with caution in these patients, as reported in a recent study.8

Given the possible heterogeneity of effect, future studies “should be powered to evaluate diabetes risk of single ADs, rather than lumping them together as it has been done so far,” as “a classification of ADs according to their pharmacological profiles could be useful in better elucidating the nature of this association,” the researchers concluded.


  1. Andersohn F, Schade R, Suissa S, Garbe E. Long-term use of antidepressants for depressive disorders and the risk of diabetes mellitus. Am J Psychiatry. 2009;166:591-598.
  2. Deuschle M. Effects of antidepressants on glucose metabolism and diabetes mellitus type 2 in adults. Curr Opin Psychiatry. 2013;26:60-65.
  3. Salvi V, Grua I, Cerveri G, Mencacci C, Barone-Adesi F. The risk of new-onset diabetes in antidepressant users – A systematic review and meta-analysis. PLoS One. 2017;12:e0182088. doi: 10.1371/journal.pone.0182088
  4. Kantor ED, Rehm CD, Haas JS, Chan AT, Giovannucci EL. Trends in prescription drug use among adults in the United States from 1999-2012. JAMA. 2015;314:1818-1831.
  5. Kivimäki M, Batty GD, Jokela M, et al. Antidepressant medication use and risk of hyperglycemia and diabetes mellitus: a noncausal association? Biol Psychiatry. 2011;70:978-984.
  6. Da Silva MA, Dugravot A, Balkau B, et al; D.E.S.I.R. Study Group. Antidepressant medication use and trajectories of fasting plasma glucose, glycated haemoglobin, β-cell function and insulin sensitivity: a 9-year longitudinal study of the D.E.S.I.R. cohort. Int J Epidemiol. 2015;44:1927-1940.
  7. Wu CS, Gau SS, Lai MS. Long-term antidepressant use and the risk of type 2 diabetes mellitus: a population-based, nested case-control study in Taiwan. J Clin Psychiatry. 2014;75:31-38.
  8. Tran YH, Schuiling-Veninga CCM, Bergman JEH, Groen H, Wilffert B. Impact of muscarinic M(3) receptor antagonism on the risk of type 2 diabetes in antidepressant-treated patients: A case-controlled study. CNS Drugs. 2017;31:483-493.

This article originally appeared on Endocrinology Advisor