Effects of chronic selective serotonin reuptake inhibitor use on carotid artery atherosclerosis

Selective serotonin reuptake inhibitor (SSRI) antidepressants, widely prescribed for depression and other disorders, have been associated with increased ischemic stroke risk in several observational studies. Previously the Shively lab has reported that long-term SSRI treatment and depression independently increased coronary artery atherosclerosis; however effects on carotid artery atherosclerosis, a precursor to ischemic stroke, are unknown. Whether SSRI use affects risk factors for stroke and atherosclerosis is also unclear as results from clinical trials and observational studies are mixed. The overall objective of this dissertation research was to determine the effects of long-term SSRI treatment on carotid artery atherosclerosis and associated risk factors using a translational nonhuman primate model of depression.;The effects of chronic administration of a commonly prescribed SSRI, sertraline HCl (ZoloftRTM), were evaluated in adult female depressed and nondepressed cynomolgus monkeys (Macaca fascicularis; n=42) using a placebo-controlled, longitudinal, randomized study design. Phenotypes were evaluated prior to and after 18 months of oral sertraline (20 mg/kg) or placebo.;Atherosclerosis extent was measured post-mortem via histomorphometry. Over the 18-month treatment period, the placebo group experienced increases in body weight, body fat (visceral and subcutaneous) fasting insulin concentrations, and homeostasis model assessment of insulin resistance scores (HOMA-IR). Sertraline treatment prevented increases in body weight, fat, insulin, and HOMA-IR (all p < 0.05), without significantly altering activity levels. Atherosclerosis extent in the right common carotid artery was 40-85% greater in sertraline-treated depressed monkeys compared to all other groups (sertraline x depression interaction effect, p = 0.03). Sertraline-treated depressed animals also tended to have more extensive atherosclerosis at the right carotid artery bifurcation (sertraline x depression interaction effect, p=0.06). Neither sertraline treatment nor depression independently affected atherosclerosis extent on carotid artery atherosclerosis. Linear regression analysis revealed that sertraline and depression effects on atherosclerosis were not mediated by effects on any of the numerous, well-accepted cardiovascular risk factors measured in this experiment. The results of this research suggest that, despite having beneficial effects on body composition and carbohydrate metabolism, long-term SSRI treatment may promote carotid artery atherosclerosis in depressed women, which may increase their risk of ischemic stroke.