Metabolic risk in depression and treatment with selective serotonin reuptake inhibitors: are the metabolic syndrome and an increase in cardiovascular risk unavoidable?

Abstract

Depression is one of the most common psychiatric disorders, and has become an epidemic in modern medical practice; notorious for frequently co-occurring with multiple comorbidities, especially cardiovascular disease (CVD), type 2 diabetes mellitus (DM2), and its various risk factors comprised in the metabolic syndrome (MS). Selective serotonin reuptake inhibitors (SSRIs) are the most widely used class of psychotropic drugs in this and many other clinical scenarios; yet their impact on cardiometabolic health has not been elucidated. The objective of this review was to summarize current views on the pharmacology of SSRIs and cardiometabolic risk, as well as available epidemiological evidence regarding its clinical significance. SSRIs appear to intervene in cardiometabolic physiology fundamentally by modulating chronic inflammation, a key pathophysiologic phenomenon in MS, DM2 and CVD. However, the dosing necessary to achieve a beneficial impact in this regard, as well as their clinical correlations, remain controversial. Each SSRI displays a particular profile regarding each of the components of the MS: weight gain seems to be the most common effect of SSRIs, more frequent with paroxetine, followed by citalopram and escitalopram. As a drug class, SSRIs also appear to promote hypercholesterolemia rather uniformly, while fluoxetine and citalopram appear to particularly increase triacylglyceride levels. In contrast, fluvoxamine and paroxetine seem to have the greatest impact on dysglycemia. Lastly, most SSRIs appear to be innocuous or even beneficial regarding blood pressure and high-density lipoprotein cholesterol. Nevertheless, many of these effects may vary significantly upon specific clinical circumstances, especially timing. This topic remains rather unexplored in clinical psychopharmacology, and further, larger-scale epidemiological studies are needed in order to offer improved care in this field.

The Influence of CYP2D6 and CYP2C19 Genetic Variation on Diabetes Mellitus Risk in People Taking Antidepressants and Antipsychotics

“…However, recent studies and meta-analyses have yielded inconclusive or negative findings and the clinical significance of CYP450 metabolic phenotypes is still in question [30,63]. Several studies agree that long-term antidepressant treatment increases risk of developing diabetes [4,[64][65][66], but the extent to which this specific adverse drug reaction is impacted by genetics is unknown. To our knowledge, this study is the first to explore if variation in the CYP2D6 and CYP2C19 genes influences HbA1c levels in indi- Several tricyclic antidepressants were reported too infrequently to allow for single-drug analysis.…”

Antidepressants stimulate lipoprotein(a) macropinocytosis via serotonin-enhanced cell surface binding

“…Links between depression and increased atherosclerotic cardiovascular disease development have been long observed (Chávez-Castillo et al, 2018; Hare et al, 2014). Exacerbating the increased atherosclerosis risk in depression is the well-established relationship between antidepressant use and increased circulating levels of the atherogenic LDL (McIntyre et al, 2006; Pan et al, 2018; Wei et al, 2009).…”

“…Links between depression and increased atherosclerotic cardiovascular disease development have long been observed 61,62 . Circulating Lp(a) levels are increasingly recognised to be elevated in patients with depression, an increase that correlates with unfavourable cardiovascular outcomes 63–66 .…”

The influence of CYP2D6 and CYP2C19 genetic variation on diabetes mellitus risk in people taking antidepressants and antipsychotics

“…However, recent studies and meta-analyses have yielded inconclusive or negative findings and the clinical significance of CYP450 metabolic phenotypes is still in question (30,63). Several studies agree that long-term antidepressant treatment increases risk of developing diabetes (4,(64)(65)(66), but the extent to which this specific adverse drug reaction is impacted by genetics is unknown. To our knowledge, this study is the first to explore if variation in the CYP2D6 and CYP2C19 genes influences HbA1c levels in individuals taking antidepressants and antipsychotics.…”