This study will evaluate the safety, tolerability and efficacy of open-label fluoxetine for three months among patients with pulmonary arterial hypertension.

Idiopathic pulmonary arterial hypertension (PAH) is a life-threatening disorder of uncertain cause that leads to progressive right heart failure and death. Average survival has improved from about 2.8 years in the early 1990s to approximately 5-7 years with current treatments, but most patients will still die of their disease. Two classes of oral medications are approved for use in PAH: endothelin-1 antagonists, and phosphodiesterase-5 inhibitors. Both improve walk distance and symptoms in PAH, but most patients still have continued dyspnea, fatigue and significant elevations in pulmonary pressures. Those who remain severely impaired are generally started on a continuous intravenous prostacyclin. For those who are less ill but still symptomatic, few options are available.

Primary endpoint: the primary endpoint will be change in pulmonary vascular resistance (PVR) measured by right heart catheterization after three months of therapy.

Secondary endpoints

• Six minute walk distance
• QIDS-SR depression scale

Safety and tolerability endpoints will include a tabulation of adverse events to include but not limited to:

• Death
• Hospitalization
• Symptomatic hypotension
• Gastrointestinal side effects
• Depression

Inclusion Criteria:

1. Signed informed consent prior to any study-mandated procedure
2. PAH of the following subtypes: idiopathic PAH WHO functional class II-III
3. Catheterization within one week showing mPAP >=25, wedge or LV end diastolic pressure ≤15, and PVR > 4 wood units, and baseline fick cardiac output results available
4. Age 16-75
5. Able to complete a six minute walk distance
6. Women of childbearing potential*: negative serum pre-treatment pregnancy test + consistently and correctly uses a reliable method of contraception** Oral approved PAH therapy for >3 months with no change in dose for > 1 month

Exclusion Criteria:

1. PAH with connective tissue disease, congenital heart disease, portal hypertension, glycogen storage disease, Gaucher's disease, hereditary hemorrhagic telangiectasia, hemoglobinopathy, myeloproliferative disorders.
2. Moderate to severe obstructive or restrictive lung disease: forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) < 70% and FEV1 < 60% of predicted value after bronchodilator administration. -or- total lung capacity (TLC) < 60% of predicted.
3. Systemic systolic blood pressure <100 mmHg Breastfeeding
4. Significant liver, renal or other medical disease preventing completion of the study procedures or with life expectancy <12 months, or any other acute or chronic physical impairment (other than dyspnea), limiting the ability to comply with study requirements

12 weeks