Sertraline inhibits increases in body fat and carbohydrate dysregulation in adult female cynomolgus monkeys

Abstract

Selective serotonin reuptake inhibitor (SSRI) antidepressants are widely prescribed for depression and other disorders. SSRIs have become one of the most commonly used drugs in the United States, particularly by women. Acute effects on body composition and carbohydrate metabolism have been reported, but little is known regarding the effects of chronic SSRI use. We evaluated the effects of chronic administration of a commonly prescribed SSRI, sertraline HCl, on body weight and composition, fat distribution, carbohydrate metabolism, as well as activity, 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. 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. Sertraline treatment altered adiponectin in an unusual way — reducing circulating adiponectin in depressed monkeys without affecting fat mass or body weight. Deleterious effects on adiponectin, a potentially insulin-sensitizing and atheroprotective protein, may result in adverse effects on cardiovascular health despite otherwise beneficial effects on body composition and carbohydrate metabolism.

Relationships of depressive behavior and sertraline treatment with walking speed and activity in older female nonhuman primates

“…Secondly, the use of remotely monitored accelerometry to determine 24-h activity counts and sedentariness is an important strength. Though the effects of sertraline treatment on total physical activity measured by an accelerometer in monkeys have been published previously (Silverstein-Metzler et al 2016), to our knowledge, this is the first study to report daytime sedentariness. This distinction is clinically important, as emerging clinical evidence suggests that sedentary time may be as, or more, predictive of functional decline, disability, and death in older persons and represents a novel strategy for interventions (Katzmarzyk 2010;Biddle et al 2016;Owen et al 2010).…”

“…As previously observed, depressed animals had a greater frequency of observed depressive behavior and were of lower social rank. Depressed animals also had significantly lower body mass, BMI, body fat, and lean mass and higher 24-h heart rates than nondepressed animals, though no differences were observed in anxiety behaviors (Shively et al 2008Willard and Shively 2012;Silverstein-Metzler et al 2016). Pre-treatment of the sertraline-and placebo-treated groups did not differ in depressive behavior, body mass, atherosclerotic extent, anxiety behaviors, social rank, body composition, or heart rate between the treatment groups (all p > 0.10).…”

“…In the latter part of both the pre-treatment and treatment phases, the primary outcomes for this analysis were assessed: (1) walking speed, (2) accelerometry-derived 24-h total physical activity counts, and (3) accelerometry-derived daytime sedentariness (number of 60-s epochs without recorded activity) mean rate across the pre-treatment phase were classified as depressed (19/42 monkeys depressed). Towards the end of the pre-treatment phase, primary outcomes of walking speed and remote physical activity monitoring (accelerometry) were assessed (Shively et al 2014Silverstein-Metzler et al 2016). Monkeys were then trained to run into a dosing cage for daily oral administration of study drug or vehicle (in pudding) and randomized to either sertraline HCl (Zoloft®; 20 mg/kg/day; n = 21) or placebo (n = 21) using a stratified procedure balanced on pre-treatment depressive behavior, body weight, and iliac artery atherosclerotic extent (Shively et al 2014.…”

“…Body mass index (BMI) was calculated from ratio of the weight to the square of the trunk length (Silverstein-Metzler et al 2016). Body composition including total body fat and lean mass was determined using dual-energy X-ray absorptiometry (Hologic Discovery A Dual X-ray Bone Densitometer, Bedford, MA) on anesthetized animals; percent fat and lean mass were calculated as a percent of whole body mass (Silverstein-Metzler et al 2016).…”

“…Physical activity was assessed by recording activity counts during 24 h monitoring using Actigraph accelerometry units (Actigraph 7164 uniaxial activity monitor, analyzed with ACTILIFE-Desktop Software, Pensacola, FL) (Silverstein-Metzler et al 2016). Each monkey was sedated and fitted with a nylon mesh protective jacket over a portable actigraphy unit.…”