This study is being conducted to determine if losartan, an angiotensin receptor blocker (ARB), is safe and effective in the treatment of posttraumatic stress disorder (PTSD) symptoms. The study is also intended to determine if certain genetic markers are useful in predicting PTSD symptom reduction with losartan. Approximately 160 subjects with chronic PTSD ages 18-65 will participate in this study across five sites. Subjects will be assigned by chance to take either flexibly dosed losartan (up to a maximum dosage of 100 mg) or placebo (which resembles the study drug but has no active ingredients), once a day for 10 weeks. Furthermore, it is hypothesized that CC homozygotes for rs4311 SNP in the ACE gene will have a superior response to losartan on PTSD symptoms compared to T carriers.

There are limited current treatments available for PTSD, and the only FDA-approved medications are SSRIs, which were empirically found to be somewhat helpful. Losartan provides a potentially important and exciting development in that it is readily available, safe, inexpensive (available as a generic drug), and has a neurobiological mechanism based on recent exciting discoveries, as outlined below. This proposal is designed to test, in a multisite RCT, this novel, mechanistically-determined, safe and well-tolerated, potentially powerful treatment for PTSD symptoms.

[Below is a synopsis of relevant eligibility criteria. For details please refer to the protocol by contacting the Principal Investigator]

Inclusion Criteria

1. Subject must be a man or woman between 18 and 70 years of age, inclusive.
2. Subjects must have a primary DSM-5 diagnosis of Posttraumatic Stress Disorder.
3. Subjects must have a Clinical Administered PTSD Scale for PTSD (CAPS-5) ≥ 25 persistent at Screening for at least 3 months duration.
4. Subject must be willing and able to adhere to the prohibitions and restrictions specified in this protocol.
5. Subject must be willing and able to fill out self-administered questionnaires.
6. Subject must be able to be compliant with self-administration of medication.
7. Subject must be able to swallow the study medication whole with aid of water.
8. Subject must sign an informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study.

Exclusion Criteria

1. Subjects who have current or imminent risk of suicide as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS) at each study visit.
2. Subject with active psychosis.
3. Subject has a history of moderate or severe drug or alcohol use disorder according to DSM-5 criteria within 3 months before screening.
4. Subject has a history of allergy to losartan or other angiotensin receptor blockers (ARBs).
5. Subject has a medical illness likely to result in imminent hospitalization or for which treatments are contraindicated based on lab results, medical history and physical exam.
6. Subject has serious cognitive impairment felt likely to interfere with the ability to participate meaningfully in the study. Participants with mild to moderate traumatic brain injury (TBI) will not be excluded from the study. Only those who evidence significant cognitive impairment at Screening (as evidenced by confusion, inability to track discussion or answer questions, or other clear and significant indicators of cognitive impairment) will be excluded.
7. Concurrent ACE Inhibitors or Angiotensin Receptor Blockers or Prazosin; patients on other antihypertensives may be enrolled if, after consultation with their prescribing physician, it is determined that the addition of losartan would not be contraindicated.
8. Concurrent antidepressants or antipsychotics. Subjects, who have elected, in consultation with their health care provider, to discontinue any antidepressants or antipsychotics, must be off the medications for a minimum of 2 weeks prior to study randomization. Stable bedtime doses of sleep agents (e.g., trazodone ≤ 200mg; eszopiclone; zolpidem; lorazepam) will be allowed as long as the dose has been stable for at least 2 weeks prior to study randomization. Benzodiazepines taken for other than sleep are not permitted.
9. Subject is a woman who is pregnant, or breast-feeding, or planning to become pregnant.
10. Subject is unable to comply with the study-specific requirements
11. Subjects with abnormal liver, renal or EKG findings as determined by physician.
12. Subject exhibits clinically-significant hypertension as determined by medical evaluation and/or BP > 190/100.
13. Systolic Blood Pressure (SBP) < 90mmHg.
14. Liver function Tests (LFT's) > 2 times the upper limit of normal.
15. Patients with Chronic Kidney Disease 4, as determined by history, baseline labs (including eGFR < 45ml/minute) and evaluation by a physician will be excluded

The primary outcome (CAPS-5) was analyzed using an MMRM (mixed model repeated measures) approach based on a modified intent-to-treat (mITT) population, defined as randomized subjects who initiated treatment and had both a baseline and at least one post-baseline outcome score during the blinded phase of the study (Week 10). Participants from the mITT population who were included in the MMRM model also required both a baseline and at least one post-baseline CAPS-5 score.

10 Weeks (Study Duration)