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

hemoglobin levels in patients with DM2 and MDD at 10 weeks of treatment , and escitalopram has been
[76]
linked with significant reductions in fasting glucose levels . Fluoxetine has been related to improved insulin
[77]
sensitivity in patients with DM2, independently of weight loss ; while citalopram does not appear to impact
[78]
measures of insulin sensitivity or be associated with DM2 .
[58]
[79]
Evidence regarding paroxetine on this aspect is more controversial. Although this SSRI tends to be
associated with increased risk of DM2 and obesity , in short-term uses, it has proved to be innocuous,
[75]
or even beneficial regarding glucose homeostasis: in a 5-week double-blind, randomized study by Weber-
Hamann et al. on non-diabetic patients with MDD, paroxetine was associated with improved insulin
[80]
sensitivity. Paile-Hyvärinen et al. echoed these findings in a 10-week, single-blind study on 15 patients
[81]
with MDD. The time-dependent effects of paroxetine on glucose metabolism highlight the importance of
long-term prospective clinical studies in the characterization of the effects of SSRIs in cardiometabolic risk.

In summary, although SSRIs as a drug class are typically believed to increase the risk of DM2 , current
[82]
clinical evidence supports this notion predominantly for fluvoxamine and paroxetine . This underlines
[75]
the importance of pondering the metabolic profiles for each individual SSRI, especially in subjects with risk
factors for DM2 or CVD.

Dyslipidemia
Similar to dysglycemia, SSRIs have been frequently linked to dyslipidemia. In the large Hordaland Health
Study, subjects who used SSRIs were more prone to presenting components of the MS in comparison to
subjects who did not use any psychotropic drugs, especially high triacylglycerides (TAG), high LDL-C, and
low HDL-C . Yosmaoğlu et al. obtained similar results in an Anatolian sample after 3 months of SSRI use,
[83]
[58]
although comparable changes have been ascertained as early as after 5 weeks of treatment . Nevertheless,
[84]
some findings also suggest SSRIs to have no impact on or be beneficial for lipid profiles [85-87] .
These discrepancies may reflect the distinct characteristics of each specific SSRI. For example, in an 8-week
case-control study on patients with symptoms of depression and anxiety, use of escitalopram was linked
with a significant increase in HDL-C . In contrast, in a 20-week follow-up study, both paroxetine and
[66]
sertraline were related to higher total cholesterol and LDL-C [88,89] . Similarly, after a 16-week follow-up,
Beyazyuz et al. found paroxetine to increase total cholesterol and TAG levels, while fluoxetine lowered
[90]
both parameters. Lastly, most SSRIs - including fluoxetine, paroxetine, sertraline, and citalopram, as well as
venlafaxine - have been associated with high TAG after 8-12 weeks of therapy [91-93] .

Thus, in general, SSRI use tends to be associated with high TAG in the earlier weeks, and then with
hypercholesterolemia in the later months; while the effect on HDL-C appears not to be significant. This
outlines SSRIs as important promoters of atherogenic dyslipidemia, and may worsen cardiometabolic risk
in conjunction with other factors.

Hypertension
In contrast to the previously discussed risk factors, the impact of SSRIs on the development of hypertension
may be more negligible [94-100] . Hypertension is notoriously not among the most frequent cardiovascular side
effects of SSRIs, which include cardiac dysrhythmias, orthostatic hypotension, bradycardia, first-degree
atrioventricular block, and syncope [94-96] . Among these, dysrhythmias are the most common (4%), whether
as a consequence of overdose or chronic use; in the case of the latter, the dysrhythmias tend to be well-
tolerated . This profile renders SSRIs relatively safe regarding atherothrombotic risk .
[97]
[98]
Various large-scale clinical epidemiological studies have reported that, as a drug class, SSRIs seem to be
unrelated to significant increases in systolic or diastolic blood pressure, in patients with depression, anxiety