# Repeated Ketamine Treatment to Accelerate Efficacy of Prolonged Exposure in PTSD

> **NIH VA I01** · MINNEAPOLIS VA  MEDICAL CENTER · 2022 · —

## Abstract

Only sertraline and paroxetine are currently FDA‐approved to treat PTSD. Other psychotropics are equally
limited to provide optimal respond. This efficacy gap may be particularly great in VA settings. The 2017
VA/DoD Clinical Practice Guideline for The Management of PTSD and Acute Stress Disorder recommends
individual, manualized trauma-focused such as Prolonged Exposure (PE) over other pharmacologic
interventions for the primary treatment of PTSD. However, a recent review of clinical trials of trauma-based
therapies in the military and veteran population showed that 30% to 50% of patients did not demonstrate
clinically meaningful symptom change and two-thirds of patients retained PTSD diagnosis after treatment.
Emerging research indicates that PE therapy may be improved by administration of medications that target
one or more therapeutic mechanisms. Ketamine, an FDA-approved anesthetic with potent non-competitive
glutamatergic N-methyl-D-aspartate (NMDA) antagonistic properties, has shown to promote neuroplasticity in
mood disorders and PTSD. Recent preclinical paradigms of PTSD demonstrated that ketamine enhances the
recall of extinction learning and decrease fear renewal without interference of extinction training. Ketamine
produces a glutamatergic burst that leads to a long-lasting synaptic protein (mTORC1) and neuronal activation
in the medial prefrontal cortex (mPCF). Therefore, ketamine could exert an augmented top-down inhibitory
drive from the mPFC to fear-related amygdala during PE therapy.
Our preliminary data showed that after six ketamine treatment, the remission rate for PTSD (PCL-5 score < 33)
was 80.0 %. PTSD severity by clinician interview (CAPS-5) also demonstrated a significant reduction from a
PTSD baseline of 39.7 (S.D.=9.3) to 20.8 (S.D.= 7.2) after treatment (Cohen’s d’ = 1.85). However, the median
time to relapse for PTSD and depression after six infusions were 41 and 26 days, respectively. This finding
suggests a powerful but short-term therapeutic effect from serial ketamine. We piloted the adjunctive use of
ketamine to enhance the efficacy of standardized PE therapy. Twelve Veterans were consented in 4 months
with 10 of them enrolled in the study, and 7 Veterans received treatment intervention by the time of
submission for this study. Single ketamine infusion administered 24 hours prior to PE session for the first 3
weeks showed to be acceptable, well-tolerated, and showed efficacy to accelerate reduction of PTSD symptoms.
Three Veterans ends PE therapy in 7 sessions instead of the usual 10 sessions as subjects and therapist agreed
that therapeutic goals were already achieved. We also measured cognitive performance and, interestingly, set
shifting tasks remarkably improved throughout the intervention (ketamine and PE).
We plan to conduct a single site (Minneapolis VA) RCT comparing three ketamine treatment vs. active placebo
(midazolam) adjunct to PE therapy among Veterans with PTSD. Pharmacological phase will start
sim...

## Key facts

- **NIH application ID:** 10463535
- **Project number:** 5I01CX001803-02
- **Recipient organization:** MINNEAPOLIS VA  MEDICAL CENTER
- **Principal Investigator:** Paulo R. Shiroma
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2021-01-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10463535

## Citation

> US National Institutes of Health, RePORTER application 10463535, Repeated Ketamine Treatment to Accelerate Efficacy of Prolonged Exposure in PTSD (5I01CX001803-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10463535. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*