This study is being done to see if Prolonged Exposure (PE), a well-researched, very effective individual (one-to-one) behavioral therapy designed to help people to directly deal with traumatic events they have suffered in the past, can be combined with intranasal esketamine (ketamine) for the treatment of posttraumatic stress disorder (PTSD) to enhance treatment benefits. Ketamine nasal spray is a drug approved by the U.S. Food & Drug Administration (FDA) for treatment resistant depression. Combined with PE, intranasal ketamine may help to augment PE and further reduce participants' PTSD symptoms.

The study is an early phase II, open label, proof of concept, pilot clinical trial to explore the feasibility, acceptability, and effects of esketamine combined with PE in individuals seeking treatment for PTSD. All individuals will complete a phone screen to learn more about the study to discuss broad eligibility criteria. Study candidates will be recruited from provider referrals across the San Antonio community as well as from self-referrals. Interested individuals who appear to meet initial eligibility will be consented and the complete a baseline assessment to determine study eligibility. Eligible participants will be enrolled to receive 10 sessions of PE delivered in massed (daily) format over 2 weeks (weekdays, not including weekends and holidays). Participants will also receive intranasal esketamine six times over a 2-week period (three times a week) approximately 1 hour after PE sessions 1, 3, 5, 6, 8, and 10 over this time period.

Inclusion Criteria:

1. Individual between the ages of 18-65 years old (Young adults [18 to 24 years old] must not be taking an antidepressant).
2. PTSD diagnosis as assessed by Clinician-Administered Posttraumatic Stress Scale (CAPS-5)
3. Able to speak and read English (due to standardization of outcome measures)
4. On stable doses of current medications for at least 4 weeks
5. Weigh between 50-100 kg (110-220 pounds).

Exclusion Criteria:

1. Young adults (18-24) currently taking any antidepressant.
2. Lifetime history of psychotic disorder or history of significant psychotic symptoms.
3. Lifetime history of manic episode.
4. Moderate or greater severity for alcohol or substance use disorder (DSM-5) in the previous six months.
5. A history of ketamine or phencyclidine abuse.
6. Evidence of a traumatic brain injury severe enough to interfere with comprehension and responding to the baseline screening questionnaires.
7. Current suicidal ideation severe enough to warrant immediate attention (as determined by the Depressive Symptoms Index-Suicidality Subscale and corroborated by a clinical risk assessment by a credentialed provider)
8. Other psychiatric disorders severe enough to warrant designation as the primary disorder as determined by clinician judgment.
9. Current use (with past 4 weeks) of any prohibited concomitant medications
10. Benzodiazepines, other medications, sedatives, acute alcohol use, or recreational drug use that would put patients at risk in the judgment of clinical providers).
11. Planned use of ketamine (i.e., for pain control) or participation in another trauma-focused psychotherapy during the time of the study.
12. Uncontrolled hypertension or tachycardia
13. A history of sensitivity or adverse reaction to ketamine or its excipients
14. An unstable medical, cardiovascular, pulmonary, or neurological condition that the investigator considers a contraindication to ketamine administration
15. Aneurysmal vascular disease (including thoracic and abdominal aorta, intracranial and peripheral arterial vessels) or arteriovenous malformation.
16. Intracerebral hemorrhage.
17. Pregnancy or breastfeeding; women of childbearing potential unwilling to utilize reliable methods of contraception
18. History of nasal surgery or nasal obstructions experienced as an adult.
19. Inability to arrange for assisted transportation on ketamine treatment days due to recommendation that patient not drive for the remainder of the day following a ketamine treatment.

Presentations and publications produced as a result of this work will follow the STRONG STAR Standard Operating Procedure (STRONG STAR-ADM-001-5.0) for Review and Approval of Publications and Presentation and the International Committee of Medical Journal Editors (ICMJE) "Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals" updated January 2024.

At study completion when data are published in a peer review journal.

At study completion, data will be published in a peer review journal. Any information that is not presented in the publication may be requested through the corresponding author or the STRONG STAR Consortium Repository