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<p class="title-left"><span class="bold">A Proof-of-Concept Study of Subanesthetic Intravenous Ketamine Combined With Prolonged Exposure Therapy Among Veterans With Posttraumatic Stress Disorder</span></p>
<p class="byline-regular">Paulo R. Shiroma, MD<span class="superscript">a,b,</span><span class="asterisk">*</span>; Paul Thuras, PhD<span class="superscript">a,b</span>; Joseph Wels, MD<span class="superscript">a,c</span>; Christopher Erbes, PhD<span class="superscript">a,b</span>; Shannon Kehle-Forbes, PhD<span class="superscript">d,e,f</span>; and Melissa Polusny, PhD<span class="superscript">a,b</span></p>
<p class="drop-cap-with-body-text"><span class="bold-14pt-for-cap"><span class="bold">P</span></span>rolonged exposure (PE) is a gold-standard trauma-focused therapy<span class="htm-cite"><a href="#ref1">1</a></span>; however, clinical trials of trauma-based therapies in the military and veteran populations showed that up to 50% of participants failed to attain clinically meaningful symptom improvement.<span class="htm-cite"><a href="#ref2">2</a></span> Emerging research indicates that PE efficacy may be improved by the use of adjunctive medications. The efficacy of single and repeated ketamine administration in posttraumatic stress disorder (PTSD) seems comparable with that in depression. Below, we present pilot data on the feasibility of combining standardized PE therapy with repeated ketamine administration in PTSD.</p>
<p class="subheads-subhead-2">Methods</p>
<p class="body-text">In a 10-week pilot conducted April–June 2019, veterans aged 18–75 years with chronic (><span class="thinspace"> </span>6 months) and at least moderate PTSD (Clinician-Administered PTSD Scale for <span class="italic">DSM-5</span> [CAPS-5] score<span class="thinspace"> </span>≥<span class="thinspace"> </span>23 and PTSD Checklist for <span class="italic">DSM-5</span> [PCL-5] score<span class="thinspace"> </span>><span class="thinspace"> </span>33) received intravenous (IV) ketamine (0.5 mg/kg) 24 hours prior to weekly PE for the first 3 weeks followed by up to 7 additional PE sessions. PE was delivered by nationally certified clinical therapists. Exclusion criteria were<span class="thinspace"> </span><<span class="thinspace"> </span>6 months of alcohol/substance use disorder, moderate/severe traumatic brain injury, bipolar disorder, or psychosis. Concurrent psychotropics were stable<span class="thinspace"> </span>≥<span class="thinspace"> </span>4 weeks. The primary outcome was the change in CAPS-5 scores from baseline to the last PE session administered by an independent evaluator. Linear mixed model with intent-to-treat analysis included baseline CAPS-5 score, time as fixed effects, and random patient effect. Secondary outcomes, which included the Montgomery-Asberg Depression Rating Scale (MADRS), PCL-5, and Clinical Global Impression-Severity of Illness scale (CGI-S), were measured at baseline and weeks 1, 2, 3, 4, 6, 8, and 10. Informed consent was obtained from all participants. The study was approved by the Minneapolis Health Care System institutional review board and registered in ClinicalTrials.gov (<a href="https://clinicaltrials.gov/ct2/show/NCT03960658" target="_blank"><span class="hyperlink">NCT03960658</span></a>).</p>
<p class="subheads-subhead-2">Results</p>
<p class="body-text">In 4 months, out of 12 subjects who provided consent, 10 completed treatment infusions with at least 1 follow-up PCL-5 (N<span class="thinspace"> </span>=<span class="thinspace"> </span>10) or CAPS-5 (N<span class="thinspace"> </span>=<span class="thinspace"> </span>9) assessment. Demographic and clinical characteristics are shown in <span class="callout"><a href="/JCP/article/_layouts/ppp.psych.controls/BinaryViewer.ashx?Article=/JCP/article/Pages/ketamine-plus-prolonged-exposure-therapy-for-veterans-with-ptsd.aspx&Type=Supplement" target="_blank">Supplementary Table 1</a></span>. PCL-5 scores for each patient at several weeks of treatment are shown in <span class="callout"><a href="#" onclick="createFigure('F1'); return false;" title="">Figure 1</a>, and</span> complete PE sessions and pre- and posttreatment scores of CAPS-5, PCL-5, MADRS, and CGI-S are shown in <span class="callout"><a href="/JCP/article/_layouts/ppp.psych.controls/BinaryViewer.ashx?Article=/JCP/article/Pages/ketamine-plus-prolonged-exposure-therapy-for-veterans-with-ptsd.aspx&Type=Supplement" target="_blank">Supplementary Table 2</a></span>. Scores significantly decreased from baseline to end of treatment in CAPS-5 (<span class="italic">t</span><span class="subscript">11</span><span class="thinspace"> </span>=<span class="thinspace"> </span>4.21, <span class="italic">P</span><span class="thinspace"> </span>=<span class="thinspace"> </span>.001, –15.25 [95% CI, 7.27–23.23], <span class="italic">d</span><span class="thinspace"> </span>=<span class="thinspace"> </span>1.21), PCL-5 (<span class="italic">t</span><span class="subscript">11</span><span class="thinspace"> </span>=<span class="thinspace"> </span>6.35, <span class="italic">P</span><span class="thinspace"> </span><<span class="thinspace"> </span>.001, –30.75 [20.09–41.41], <span class="italic">d</span><span class="thinspace"> </span>=<span class="thinspace"> </span>1.83), and MADRS (<span class="italic">t</span><span class="subscript">11</span><span class="thinspace"> </span>=<span class="thinspace"> </span>4.68, <span class="italic">P</span><span class="thinspace"> </span>=<span class="thinspace"> </span>.001, –11.5 [6.09–16.91], <span class="italic">d</span><span class="thinspace"> </span>=<span class="thinspace"> </span>1.35). After controlling for mean change in MADRS score over time, changes in total PCL-5 scores (<span class="italic">F</span><span class="subscript">1,10</span><span class="thinspace"> </span>=<span class="thinspace"> </span>5.69, <span class="italic">P</span><span class="thinspace"> </span>=<span class="thinspace"> </span>.038, <span class="italic">h</span><span class="superscript">2</span><span class="thinspace"> </span>=<span class="thinspace"> </span>0.36) and PCL-5 Avoidance (<span class="italic">F</span><span class="subscript">1,10</span><span class="thinspace"> </span>=<span class="thinspace"> </span>6.31, <span class="italic">P</span><span class="thinspace"> </span>=<span class="thinspace"> </span>.031, <span class="italic">h</span><span class="superscript">2</span><span class="thinspace"> </span>=<span class="thinspace"> </span>0.36) remained significant. However, changes in PCL-5 Intrusion (<span class="italic">F</span><span class="subscript">1,10</span><span class="thinspace"> </span>=<span class="thinspace"> </span>4.48, <span class="italic">P</span><span class="thinspace"> </span>=<span class="thinspace"> </span>.06, <span class="italic">h</span><span class="superscript">2</span><span class="thinspace"> </span>=<span class="thinspace"> </span>0.31), Arousal (<span class="italic">F</span><span class="subscript">1,10</span><span class="thinspace"> </span>=<span class="thinspace"> </span>1.25, <span class="italic">P</span><span class="thinspace"> </span>=<span class="thinspace"> </span>.29, <span class="italic">h</span><span class="superscript">2</span><span class="thinspace"> </span>=<span class="thinspace"> </span>0.11), and Negative mood and cognition (<span class="italic">F</span><span class="subscript">1,10</span><span class="thinspace"> </span>=<span class="thinspace"> </span>3.83, <span class="italic">P</span><span class="thinspace"> </span>=<span class="thinspace"> </span>.079, <span class="italic">h</span><span class="superscript">2</span><span class="thinspace"> </span>=<span class="thinspace"> </span>0.28), as well as CAPS-5 (<span class="italic">F</span><span class="subscript">1,10</span><span class="thinspace"> </span>=<span class="thinspace"> </span>1.18, <span class="italic">P</span><span class="thinspace"> </span>=<span class="thinspace"> </span>.30, <span class="italic">h</span><span class="superscript">2</span><span class="thinspace"> </span>=<span class="thinspace"> </span>0.11), were no longer significant.</p>

                <div id="figure-2"> <a href="#" onclick="createFigure('F1'); return false;"><img src="20l13406F1.jpg" alt="Figure 1" id="F1" border="0" /></a>
      <p class="click-to-enlarge">Click figure to enlarge</p>
    </div>



<p class="subheads-subhead-2">Discussion</p>
<p class="body-text">This small, open-label, proof-of-concept study suggests that repeated IV ketamine administration can be concurrently used with standardized PE therapy to treat PTSD. Previously, a single infusion of ketamine significantly decreased PTSD symptoms 24 hours postinfusion compared to midazolam.<span class="htm-cite"><a href="#ref3">3</a></span> Findings with repeat open-label IV ketamine administration in comorbid PTSD and refractory depression suggested that ketamine increases the efficacy for both PTSD and depressive symptoms beyond a single infusion.<span class="htm-cite"><a href="#ref4">4</a></span></p>
<p class="body-text">Clinical studies have demonstrated the feasibility of combining IV ketamine and cognitive-behavioral therapy in obsessive-compulsive disorder<span class="htm-cite"><a href="#ref5">5</a></span> and treatment-resistant depression.<span class="htm-cite"><a href="#ref6">6</a></span> PE efficacy may be improved through medications that target 1 or more mechanisms.<span class="htm-cite"><a href="#ref7">7</a></span> Ketamine could augment the biological processes of extinction memory. In mice models of PTSD, a single dose of ketamine followed by extinction training enhances the recall of extinction learning and decreases fear renewal.<span class="htm-cite"><a href="#ref8">8</a></span> Ketamine plus extinction exposure increases synaptic protein promoter and neuronal activation in the medial prefrontal cortex,<span class="htm-cite"><a href="#ref8">8</a></span> exerting a possible top-down inhibitory drive over excitatory responses of fear conditioning such as the amygdala.</p>
<p class="body-text">As an alternative, early gains by ketamine’s rapid antidepressant and anxiolytic effects can strengthen confidence in the therapeutic approach, improve rapport, and increase treatment adherence. Rapid improvement in depression is associated with lower rate of dropout and lower posttreatment severity score during PTSD treatment.<span class="htm-cite"><a href="#ref9">9</a></span> A potential backfire of this rapid response is reducing the motivation to complete PE. Given preliminary findings, larger randomized clinical trials should prove whether ketamine has a synergistic effect over trauma-based therapy for PTSD.</p>
<p class="end-matter"><span class="bold-italic">Published online:</span> November 10, 2020.</p>
<p class="end-matter"><span class="bold-italic">Potential conflicts of interest:</span> None.</p>
<p class="end-matter"><span class="bold-italic">Funding/support:</span> This work was supported by the United States Department of Veterans Affairs Clinical Sciences Research and Development Merit Review Award (grant I01 CX001191 to Dr Shiroma).</p>
<p class="end-matter"><span class="bold-italic">Role of the sponsor:</span> The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data, preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.</p>
<p class="end-matter"><span class="bold-italic">Previous presentation:</span> Presented as a poster at the 75th Annual Meeting of the Society of Biological Psychiatry; New York, New York; April 30–May 2, 2020.</p>
<p class="end-matter"><span class="bold-italic">Acknowledgments:</span> The authors thank Emily Voeller, PhD; Eliza McManus, PhD; Matthew Kaler, PhD; Eric Baltutis, BS; Debra Condon, RN; Amber Hoeschler, RN; and the nursing staff and clerkship personnel of the 2E Unit at Minneapolis VA Health Care System for providing technical and clinical support. No compensation was received outside of usual salary.</p>
<p class="end-matter"><span class="sm">Supplementary material</span>: <a href="/JCP/article/_layouts/ppp.psych.controls/BinaryViewer.ashx?Article=/JCP/article/Pages/ketamine-plus-prolonged-exposure-therapy-for-veterans-with-ptsd.aspx&Type=Supplement" target="_blank">See accompanying pages.</a></p>
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<p class="front-matter-rule"><span class="superscript">a</span>Mental Health Service Line, Minneapolis VA Health Care System, Minneapolis, Minnesota</p>
<p class="front-matter"><span class="superscript">b</span>Department of Psychiatry, University of Minnesota, Minneapolis, Minnesota</p>
<p class="front-matter"><span class="superscript">c</span>University of Minnesota Medical School, Minneapolis, Minnesota</p>
<p class="front-matter"><span class="superscript">d</span>Center for Chronic Disease Outcomes Research, Minneapolis, Minnesota</p>
<p class="front-matter"><span class="superscript">e</span>Women’s Health Sciences Division of the National Center for PTSD, Boston, Massachusetts</p>
<p class="front-matter"><span class="superscript">f</span>Department of Medicine, University of Minnesota, Minneapolis, Minnesota</p>
<p class="front-matter"><span class="asterisk">*</span><span class="italic">Corresponding author:</span> Paulo R. Shiroma, MD, One Veterans Dr 116-A, Minneapolis, MN 55417 <span class="hyperlink">(<a href="mailto:paulo.shiroma@va.gov">paulo.shiroma@va.gov</a>)</span>.</p>
<p class="front-matter"><span class="italic">J Clin Psychiatry 2020;81(6):20l13406</span></p>
<p class="front-matter-rule"><span class="bold-italic">To cite:</span> Shiroma PR, Thuras P, Wels J, et al. A proof-of-concept study of subanesthetic intravenous ketamine combined with prolonged exposure therapy among veterans with posttraumatic stress disorder. <span class="italic">J Clin Psychiatry</span>. 2020;81(6):20l13406.</p>
<p class="doi-line"><span class="bold-italic">To share:</span> https://doi.org/<span class="doi">10.4088/JCP.20l13406</span></p>
<p class="front-matter"><span class="italic">© Copyright 2020 Physicians Postgraduate Press, Inc.</span></p>
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