Use of Selective Serotonin Reuptake Inhibitors and Outcomes in Pulmonary Arterial Hypertension

Abstract

531T he serotonin hypothesis of pulmonary arterial hypertension (PAH) emerged . 40 years ago and was reemphasized in the 1990s following the association of pulmonary hypertension (PH) 1 with anorexic agents such as aminorex fumarate and fenfl uramine. [2][3][4][5] Serotonin promotes pulmonary arterial smooth muscle cell and fi broblast proliferation, pulmonary arterial vasoconstriction, and local microthrombosis-all key pathogenic features in PAH. These effects of serotonin are mediated by interactions between serotonin and its transporter and receptors. [6][7][8][9][10] In particular, the serotonin transporter (SERT) plays a key role in the pathogenesis of experimental PH; in animal models, SERT overexpression predisposes to the development of PH, whereas pharmacologic blockade of SERT is protective. 1,[11][12][13][14] In humans, a functional polymorphism in the SERT gene correlates with more severe PH associated with COPD. 15 Selective serotonin reuptake inhibitors (SSRIs) act via blockade of SERT, resulting in an extracellular accumulation of serotonin and increased activation of serotonin receptors. 16 SSRIs have been associated with both protection against and regression of PH in animal models, suggesting a possible role in the treatment of PAH in humans. 1,14,17 Early observational studies have suggested therapeutic effi cacy of SSRIs in patients with Background: Selective serotonin reuptake inhibitors (SSRIs) have been suggested to offer therapeutic benefi t in patients with pulmonary arterial hypertension (PAH). We conducted two analyses to explore the association between SSRI use and PAH outcomes using the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL Registry). Methods: First, new users (SSRI-naive patients who initiated treatment after enrollment, incident use analysis, n 5 220) were matched (1:2) with non-SSRI users (nonusers, n 5 440) by enrollment center, sex, date of most recent visit, age, and 6-min walk distance. Second, a cross-sectional design was used to compare nonusers (n 5 2,463), high-affi nity SSRI users (n 5 430), and non-high-affi nity SSRI users (n 5 125) at enrollment. Mortality and a composite end point defi ned by events indicative of clinical worsening were evaluated. Results: New users had a higher risk of death (unadjusted hazard ratio [HR], 1.74; 95% CI, 1.19-2.54; P 5 .004) and were less likely to be free from the composite end point 2 years after enrollment vs nonusers (25.7% vs 43.2%, respectively; P , .001). Similarly, among prevalent SSRI users (patients with a history of SSRI use at enrollment), high-affi nity SSRI users were less likely to be free from the composite end point vs nonusers (unadjusted HR, 1.20; 95% CI, 1.07-1.36; P 5 .003). In both analyses, differences in outcome were maintained after adjustment for clinical variables previously associated with PAH outcomes. Conclusions:In a large population of patients with PAH, incident SSRI use was associated with increased mortality and a greater risk of clinical worsening, although we could ...

Novel Targets of Drug Treatment for Pulmonary Hypertension

“…Several clinical studies have suggested that SSRIs may be associated with a decreased development of PH and mortality in PH patients [68,69]. However, one phase II clinical trial failed to show the beneficial effects of SSRIs (paroxetine, sertraline, or fluoxetine) in the treatment of PH, while a separate trial showed that the use of SSRIs correlated to even higher mortality and a greater risk of clinical worsening [70,71]. Because these trials may have failed to appropriately match all clinical variables of the treated and control patient populations, further studies are necessary to conclusively determine whether SSRIs are an appropriate therapeutic category for PH.…”

Current and Emerging Therapies for Pulmonary Arterial Hypertension

“…56,57 Furthermore, recent evidence suggests SSRI use may be associated with an increased risk of mortality or clinical worsening. 58 Terguride, a serotonin receptor antagonist, received orphan drug designation from the FDA in 2008 for the treatment of PAH and is currently under investigation in studies in Europe. 59,60 …”