Randomized Placebo-Controlled Trial of the Angiotensin Receptor Antagonist Losartan for Posttraumatic Stress Disorder

ABSTRACT Background Evidence-based pharmacological treatments for PTSD are few and of limited efficacy. Prior work suggest that angiotensin type 1 receptor (AT1R) inhibition facilitates fear inhibition and extinction, important for recovery from PTSD. This study tests the efficacy of the AT1R antagonist losartan, an antihypertensive drug, repurposed for the treatment of PTSD. Methods Randomized controlled trial (RCT) for 10 weeks in 149 men and women meeting DSM-5 PTSD criteria. Losartan (vs. placebo) was flexibly titrated from 25 to 100 mg/d by Week 6 and held at highest tolerated dose to Week 10. Primary outcome was Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) change score. A key secondary outcome was change in CAPS-5 associated with an angiotensin converting enzyme (ACE) gene SNP. Additional secondary measures included the PCL-5, the PHQ-9, and proportion of responders with a CGI-I of “much” or “very much” improved. Results Both groups had robust improvement in PTSD symptoms, but there was no significant difference on the primary endpoint, CAPS-5 measured as week 10 change from baseline, between losartan and placebo (mean change diff =0.9, 95% CI: -3.2 – 5.0). There was no significant difference in proportion of CGI-I responders for losartan (58.6%) vs. placebo (57.9%), and no association between ACE genotype and CAPS-5 improvement on losartan. Conclusions At these doses and durations, there was no significant benefit of losartan compared to placebo for treatment of PTSD. We discuss implications for failure to determine benefit of a repurposed drug with strong a priori expectations of success based on preclinical and epidemiological data.