Effects of Long-Term Sertraline Treatment and Depression on Coronary Artery Atherosclerosis in Premenopausal Female Primates

Abstract

Objectives Major depressive disorder and coronary heart disease (CHD) often co-occur in the same individuals. Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed for depression and other disorders, but their effects on CHD risk remain unclear. We determined the effects of a SSRI on coronary artery atherosclerosis (CAA) in an established nonhuman primate model used to clarify the association between depression and CAA. Methods 42 adult female cynomolgus macaques consuming a Western diet were characterized during an 18-month pretreatment phase, and assigned to SSRI (sertraline HCl 20 mg/kg, po, once/day) or Placebo balanced on pretreatment depression, body weight (BW), and iliac artery atherosclerosis extent measured via biopsy. After 18 months CAA extent was measured using histomorphometry. Results Before and during treatment depressed monkeys had lower BW, body mass index (BMI), and plasma high density lipoprotein cholesterol, and higher heart rates during the pretreatment (p<0.01) but not the treatment phase (p=0.17). There were no pretreatment differences between the sertraline and placebo groups. Sertraline reduced anxious behavior but had no effect on BW, BMI, heart rate, plasma lipids, or depression. CAA, analyzed by a 2 (Depressed, Nondepressed) × 2 (Placebo, Sertraline) × 3 (coronary arteries) analysis of covariance adjusted for pretreatment iliac atherosclerosis, was greater in depressed than nondepressed monkeys (p<0.036), and in sertraline than placebo-treated monkeys (p=0.040). The observed CAA extent in depressed monkeys treated with sertraline was 4.9 times higher than in untreated depressed monkeys, and 6.5 times higher than in non-depressed monkeys, on average. Conclusions Depressed animals develop more CAA, and that longterm treatment with sertraline promotes CAA.

Long-term sertraline treatment and depression effects on carotid artery atherosclerosis in premenopausal female primates

“…Details about the animals; diets and methods used to evaluate circulating sertraline and desmethylsertraline concentrations, 35 , cardiac function 36 cardiovascular risk factors 34,37 , and coronary artery atherosclerosis 34 have been published previously. Briefly, forty-five reproductively-aged female cynomolgus were imported from Indonesia (Institut, Pertanian Bogor, Bogor, Indonesia) and quarantined in single cages for a one-month.…”

“…Monkeys consumed an atherogenic diet (containing 44% of calories from fat and 0.29 mg/Cal cholesterol) during an 18-month pretreatment phase, during which behavior was recorded. Stratified randomization was used to assign the monkeys by social group to either oral placebo (n=21) or SSRI (n=21) treatment balanced on pretreatment rate of depressive behavior, body weight, and iliac artery atherosclerosis extent (Figure 1) 34 . Sertraline HCl (Zoloft ® ) was chosen due to the need to dose monkeys according to body weight and its lack of effect on body weight in macaques 38 .…”

“…30–33 Previously we have reported that sertraline HCl treated monkeys exhibited exacerbated coronary artery atherosclerosis, independent of depression, but did not experience adverse effects on traditional cardiovascular risk factors such as plasma lipids, adiposity, and insulin resistance. 34 In this report we describe the effects of depression and SSRI on atherosclerosis extent in several anatomical sites within the carotid arteries.…”

Social Inequalities in Health in Nonhuman Primates

“…Interobserver agreement in the identification of depressive behavior was greater than 92% in all experiments. Rates of depression were similar in the three experiments (38e45%) (Shively et al, Apr 15, 1997;Shively et al, Apr 2005;Shively et al, 2014). Depressive behavior was more common in subordinate females; 61% of subordinates displayed depressive behavior while only 10% of dominants exhibited this behavior (Shively et al, Apr 15 1997).…”

Long-Term Haloperidol Treatment Prolongs QT Interval and Increases Expression of Sigma 1 and IP₃ Receptors in Guinea Pig Hearts

“…On the other hand, administration of sigma 1 antagonist results in negative cardiovascular effects. A recent study described coronary artery atherosclerosis after sertraline treatment in female pre meno pausal primates (Shively et al 2015).…”