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Page 2 of 11 Chávez-Castillo et al. Vessel Plus 2018;2:6 I http://dx.doi.org/10.20517/2574-1209.2018.02

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.

Keywords: Depression, selective serotonin reuptake inhibitors, metabolic syndrome, cardiovascular risk, cardiovascular
disease, type 2 diabetes mellitus, chronic inflammation

INTRODUCTION
Depression has become an emerging epidemic in recent years, with prevalence rates of 10%-15% across the
globe . This trend has resulted in ever-increasing financial costs, along with a significant decay in the life
[1]
quality of patients . A substantial portion of this burden may stem from the multiple medical comorbidities
[2]
associated with depression, in particular, cardiovascular disease (CVD) , with these conditions coexisting
[3]
in up to 15% of cases .
[4]
CVD remains the leading cause of morbidity and mortality worldwide , significantly driven by a myriad of
[5]
modifiable risk factors consequent upon a predominantly Westernized lifestyle . The metabolic syndrome
[6]
(MS), conceptualized as a cluster of cardiovascular risk factors - obesity, hypertension, hyperglycemia
and atherogenic dyslipidemia - which in co-occurrence substantially increase the risk of CVD and type 2
diabetes mellitus (DM2), is widely regarded as a useful clinical tool in the prevention of these conditions .
[7]
These factors also appear to be involved in the pathophysiology of depression, and may account for the
higher cardiovascular risk observed in this disorder .
[8,9]
In this context, the pharmacological management of depression presents a clinical conundrum: depression
is accompanied by increased risk of MS - and by extension, CVD and DM2 - yet many antidepressant drugs
appear to exacerbate these risks as well [10,11] . However, in contrast with antipsychotic drugs, whose clinical
relevance in regards to deleterious cardiometabolic effects has been well-characterized [12,13] , the impact of
antidepressant drugs in clinical outcomes remains less clear. This is an especially pressing matter in the field
of neuropsychopharmacology, as antidepressant drugs, and selective serotonin reuptake inhibitors (SSRIs)
in particular, have become one of the most prescribed drug classes in contemporary medical practice [14,15] .
This review aims to summarize current views on the pharmacology of SSRIs and cardiometabolic risk, as
well as available epidemiological evidence regarding its clinical significance.

SSRI-ASSOCIATED CARDIOMETABOLIC RISK: MOLECULAR PATHWAYS
SSRIs have become very popular in clinical use owing to various beneficial characteristics, including their
ease of administration, increased pharmacodynamic specificity, and enhanced tolerability with relatively
minor side effects; in contrast to the “dirtier”, less specific and tolerable older antidepressant drugs,
such as tricyclics and monoamine oxidase inhibitors . Although this distinction is notorious regarding
[16]
cardiovascular safety, the underlying molecular differences in their pharmacologic profiles remain largely
elusive .
[17]
Chronic systemic inflammation may be an especially important target for SSRIs in this context, given
the comprehensive involvement of this phenomenon in the pathophysiology of MS, CVD and DM2 .
[18]
Furthermore, this kind of low-grade inflammation is also present in depression, as patients with disorder
tend to show increased levels of proinflammatory biomarkers such as tumor necrosis factor alpha (TNFα),
C-reactive protein, interleukin (IL)-6 and IL-1β . This is compounded by the frequent accompaniment of
[19]
depression with unhealthy dietary habits and physical inactivity, which themselves also promote chronic
inflammation , and are prominent in the development of depressive symptoms such as loss of energy, sleep
[20]
disturbances and irritability .
[21]