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 ...

Drug- and toxin-induced pulmonary arterial hypertension: Current state of the literature

“…This observation raised the possibility that selective serotonin reuptake inhibitors (SSRIs) could be used as therapeutic agents in PAH. However, later studies conducted in humans demonstrated that SSRIs are not effective in the treatment of PAH once the disease is diagnosed (42).…”

“…Two of these patients had RA, one had PA and one had an undiagnosed arthritis. Of the reported cases, pre-capillary PH was confirmed in all patients (mPAP [35][36][37][38][39][40][41][42][43][44][45][46][47][48] and the pulmonary pressures improved in all patients at 2-4 month follow up after discontinuation of drug. Three of the four were found to have improvement in their PA pressures with addition of PAH therapies while one of the RA cases improved with discontinuation of leflunomide and washout with cholestyramine alone (136).…”

Classification and pathophysiology of pulmonary hypertension

“…Benfluorex, a hypoglycemic and hypolipidemic drug used in Europe to treat diabetes and metabolic syndrome, shares an active metabolite with fenfluramine and has recently been shown to trigger PAH development . SSRI use during pregnancy increases the risk of PPHN and is also associated with mortality and clinical worsening in adults with established PAH .…”

Anorexigen-Associated Pulmonary Arterial Hypertension and the Serotonin Hypothesis: A Story Worth Telling

“…These studies had mixed results, with improved outcomes in 2 studies, 39,42 similar outcomes vs untreated patients in one study, and worse outcomes for the SSRI-treated patients in a fourth study. 40,43 Finally, animal studies have found a protective effect in both monocrotaline-and chronic hypoxia-induced PH in adult rats and mice. 44,45 Given the absence of randomized controlled clinical trials of SSRIs in PAH, a firm conclusion is not currently possible.…”