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Interestingly, the onset of the antidepressant effect of SSRIs has been reported to coincide with a reduction in
the circulating levels of proinflammatory biomarkers . A novel hypothesis posits these changes to be due to
[22]
a T helper (Th1)-like response, triggering inflammatory activity via interferon γ (IFNγ)-related pathways .
[23]
SSRIs appear to decrease the production of INFγ and stimulate the release of IL-10, by modulating the
[24]
corresponding mRNA in immune cells . Consistent with this, SSRIs also appear to upregulate the
expression of genes involved in apoptotic pathways in T cells . In addition, blockade of serotonin reuptake
[25]
results in increased circulating serotonin levels, which have been reported to be able to suppress cytokine
synthesis by T cells, B cells, natural killer cells and monocytes/macrophages [26-29] , resembling what occurs in
sepsis after massive platelet degranulation .
[30]

Macrophages may be particularly relevant regarding the immunomodulatory effects of SSRIs due to their
high expression of serotonin receptors [31,32] . By acting as ambient serotonin level sensors, macrophages could
modulate genotype expression patterns in macrophages: activation of 5HT receptors in macrophages has
7
been noted to induce polarization towards the antiinflammatory M2 phenotype [33,34] . Inhibition of TNFα and
IL-6 release, as well as promotion of IL-10 synthesis, are prominent among the antiinflammatory features of
M2 macrophages [33,35,36] .

Nevertheless, these antiinflammatory effects have been speculated to occur only at doses greater than
the usual therapeutic range , and SSRIs may rather be proinflammatory at lower doses, especially with
[37]
prolonged use . This is consistent with evidence from Kubera et al. , who found physiological levels of
[38]
[27]
intracellular serotonin tend to promote TNFα and IL-6 synthesis in macrophages, whereas supraphysiological
levels of extracellular serotonin were linked with downregulation of serotonin receptors serotonin receptors
and with decreased release of with decreased release of proinflammatory cytokines. Further research is
required to elucidate the clinical correlates and significance of this molecular framework for SSRI-mediated
immunomodulation.

Chronic inflammation is also closely linked to insulin resistance and obesity, two fundamental elements
of the MS. Thus, by intervening through immunomodulation, SSRIs could have a pivotal role in the
pathophysiology of this cluster of manifestations . Paroxetine may be a particularly powerful inductor of
[39]
insulin resistance by interfering with IRS-1 signaling . Indeed, each SSRI seems to exert distinct effects
[40]
on insulin resistance, body weight composition, and serum lipids, independently of their impact on chronic
inflammation. For example, paroxetine has been linked with higher low-density lipoprotein cholesterol
(LDL-C) levels, possibly due to increased appetite ; whereas fluoxetine, by inhibiting PON1 activity, may
[41]
favor lower high-density lipoprotein cholesterol (HDL-C) levels . In addition, certain pharmacokinetic
[42]
interactions, such as that of fluoxetine with statins - including inhibition of CYP3A and modulation of
glucuronidation, P-glycoprotein (Pgp) and organic anion transport peptide 1B1 (OATP), may result in
potentiated reduction of cholesterol . This complexity warrants further insight and an individual assessment
[43]
of each specific SSRI in this context. In stark contrast, SSRIs seem to be relatively innocuous regarding blood
pressure, unlike other antidepressant drug classes such as serotonin-norepinephrine reuptake inhibitors,
monoamine oxidase inhibitors, and tricyclic antidepressants [44-46] .

Lastly, the prominent role of serotonin in platelet physiology has ignited speculation regarding SSRIs as
antiplatelet agents [47,48] . The higher concentrations of circulating serotonin induced by SSRIs could reduce
platelet aggregation [49,50] and impair reactivity to vasoconstriction . However, SSRIs do not appear to
[51]
[48]
intervene in the functionality of vitronectin - a fundamental component of glycoprotein IIb/IIIa - or
fibrinogen ; but are able to regulate the expression of vascular adhesion molecules such as VCAM-1, ICAM-
[52]
1, P-selectin and E-selectin [53,54] . Nevertheless, the relative relevance of these effects remains unknown in the
context of the chronic inflammatory milieu which SSRIs could promote simultaneously, as does the clinical
significance of this antiplatelet activity.