Repeated Ketamine Treatment to Accelerate Efficacy of Prolonged Exposure in PTSD

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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 simultaneously with PE session 1. Infusions will be administered 24 hrs. prior to PE session for the first 3 weeks. After PE is completed (session 10), patients will be assessed during a 3-month follow-up period at various time points. We estimate that out of 100 veterans, 80 will reach time point for primary outcome measure (CAPS score at week 10) and will be considered for primary analysis. Secondary outcomes include severity of depression and anxiety scores, safety and tolerability of ketamine-enhanced PE therapy, cognitive performance during treatment and early improvement during PE related to the rate of dropouts/completers during PE therapy. Results of the proposed RCT could provide scientific foundation to distinguish the essential components of this approach, enhance the methodology, elucidate the mechanisms involved, and identify sub- PTSD populations that most likely benefit from this intervention.