The Association between Antidepressant Use and Disturbances in Glucose Homeostasis: Evidence from Spontaneous Reports

Abstract

Objectives Depression is common in patients with diabetes, and the use of antidepressants may impair glycaemic control. We assessed the association between antidepressant use and hyper-and hypoglycaemia. Methods Based on spontaneous reports listed in the World Health Organization (WHO) Adverse Drug Reaction Database, a case-control study was conducted. The study base consisted of all adverse drug reactions (ADRs) ascribed to antidepressants, antipsychotics and benzodiazepines between 1969 and 2005. Cases were defined as reported ADRs classified as hyper-or hypoglycaemia and separated in different study populations. All other reports were considered as controls. Exposure to antidepressants was the primary determinant investigated. Benzodiazepines and antipsychotics were chosen as reference groups. Potential confounding factors, namely, age, gender, use of antidiabetic medication, use of hyper-or hypoglycaemiainducing comedication and reporting year, were determined on the index date. Multivariate logistic regression was used to evaluate the strength of the association, which was expressed as reporting odds ratios (RORs) with 95% confidence intervals (95% CI). Results Overall, the use of antidepressants was associated with hyperglycaemia [ROR 1.52 (95% CI: 1.20-1.93)] and of hypoglycaemia [ROR 1.84 (95% CI: 1.40-2.42)]. The association with hyperglycaemia was most pronounced for antidepressants with affinity for the 5-HT 2c receptor, histamine-1 receptor and norepinephrinic (NE) reuptake transporter. The association with hypoglycaemia was most pronounced for antidepressants with affinity for the serotonin reuptake transporter. Conclusion The results of this study strengthen the findings in individual case reports that the use of antidepressants is associated with disturbances in glucose homeostasis.

High H1-affinity antidepressants and risk of metabolic syndrome in bipolar disorder

“…In particular, clozapine and olanzapine, which have the highest affinity for H1 receptor, were the antipsychotics associated with the highest weight gain. In more recent years, Derijks et al, employing the described pharmacodynamic classification for antidepressants, found higher fasting glucose levels in patients taking antidepressants with high antihistaminergic activity (Derijks et al 2008a). A classification of antidepressants based on pharmacological profiles is supported by other findings that explain the neurobiological basis of anti-H1 induced weight gain: an experimental study found that 4 weeks of treatment with amitryptiline and mirtazapine led to an increase in leptin plasma levels and weight gain, while treatment with paroxetine and venlafaxine did not (Schilling et al 2013).…”

“…Ki is the concentration of the ligand in which the receptor is occupied for 50 % by the ligand; thus, the lower the value of Ki, the higher is the affinity of the ligand for the receptor. Values of Ki for all antidepressants were mainly obtained from Derijks et al, which derived Ki values from the Psychoactive Drug Screening Program (PDSP) Ki database, employing not only Ki values coming from experiments with cloned human cell lines but also human receptors from the brain tissue, (frontal) cortex, choroids plexus tissue, striatum tissue, cortical membranes, and platelets (Derijks et al 2008b). Ki value for the antidepressant trimipramine was directly taken from the PDSP database: the value had been obtained from human cortical membranes.…”

“…The third cluster comprises maprotiline, nortriptyline, mianserin, and mirtazapine which all show high affinity for the histamine H1 receptor and 5-HT2c receptor and less affinity for the 5-HT reuptake transporter. Finally, the fourth cluster comprises trazodone, reboxetine, and bupropion, identified as a group with no specific similarities to the others (Derijks et al 2008b). Since we were only interested in H1 receptor affinity of antidepressants, we grouped together clusters 2 and 3 (in our sample, amitriptyline, imipramine, nortriptyline, trimipramine, and mirtazapine) including patients taking those medications in the H1-R high-affinity group, while patients taking SSRIs, clomipramine, venlafaxine, duloxetine, reboxetine, and bupropion, were included in the H1-R low affinity group.…”

“…For instance, antipsychotics inducing weight gain in the short-term have a strong antihistaminergic activity, while affinity to the muscarinic or the 5HT2c receptor could not predict increase in weight (Kroeze et al 2003). Also, a recent study found an association between antihistaminergic antidepressants and disturbances in glucose homeostasis resulting in hyperglycemia (Derijks et al 2008a). H1-R blockade might cause such metabolic anomalies due to counteracting the central anorexigenic effects of histamine (Jørgensen et al 2007) or increasing adipose tissue deposition (He et al 2013).…”

Co-administration of paroxetine and pravastatin causes deregulation of glucose homeostasis in diabetic rats via enhanced paroxetine exposure

“…Antidepressants such as selective serotonin reuptake inhibitors (SSRIs), including paroxetine, are commonly used in diabetic patients. Paroxetine improved glucose metabolism and insulin sensitivity via alleviating depression [10,11] , although antidepressant use that was associated with disturbances in glucose homeostasis has been reported [12,13] .…”