Controversial studies have suggested that moderate to high daily doses of certain antidepressants for more than 2 years are associated with a substantially higher risk for type-2 diabetes (T2D), whereas other studies have shown to such correlation. The increased risk was particularly notable for the selective serotonin-reuptake inhibitor (SSRI) paroxetine and the tricyclic antidepressant (TCA) amitriptyline, but not for fluoxetine, citalopram, or sertraline. However, inactivity and weight gain are associated with depression itself –– indicating that these caveats might increase the risk for diabetes.
A meta-analysis of 2,934 screened articles [Korean J Fam Med 2o13; 34: 228-240] concluded that use of antidepressants was significantly associated with an increased risk of T2D in a random-effect model (relative risk [RR] = 1.49; 95% confidence interval [CI] = 1.29 to 1.71). The subgroup results –– considering body weight, depression severity, and physical activity –– also showed a (slight) positive association (RR = 1.14; 95% CI = 1.01 to 1.28). A publication bias was observed in the selected studies (Egger’s test, P for bias = 0.09).
Although various mechanisms are suggested for their diabetogenic potential, whether a direct effect of antidepressants on pancreatic b-cells is involved is unclear. In the attached study, authors examined this idea for three antidepressants: paroxetine, clomipramine and, with particular emphasis, fluoxetine –– on insulin secretion, mitochondrial function, cellular bioenergetics, the ATP-sensitive K+ channel (KATP channel) activity, and caspase activity –– in mouse and human cell-line models of pancreatic b-cells. Metabolic assays showed that these antidepressants decreased the redox, oxidative respiration, and energetic potential of b-cells in a time- and concentration-dependent manner. This was found, even at a concentration of 100 nM, well within the therapeutic window.
Authors found that these effects were related to inhibition of mitochondrial complexes I and III. Consistent with impaired mitochondrial function, lactate output was increased and insulin secretion was decreased. Neither fluoxetine, antimycin, nor rotenone could reactivate KATP channel activity blocked by glucose –– unlike the mitochondrial uncoupler p-triflouro-methoxy-phenylhydrazone (FCCP). Chronic, but not acute, antidepressant treatment increased oxidative stress and activated caspases-3, -8, and -9. The rates of oxidative respiration, lactate output and modulation of KATP channel activity in MIN6 cells closely paralleled those of primary mouse cells; these data therefore support MIN6 as a valid model to study beta-cell bioenergetics. In summary, paroxetine, clomipramine and fluoxetine were all cytotoxic at therapeutic concentrations in pancreatic beta-cells –– believed to arise by inhibition of mitochondrial bioenergetics, oxidative stress (reactive oxygen species formation), and induction of apoptosis (programmed cell death). These findings might be relevant in explaining the diabetogenic potential of these antidepressants in clinical studies.
Toxicol Sci Aug 2o17; 158: 286–301