Combining Ketamine Infusions and Written Exposure Therapy for Chronic PTSD: An Open-Label Trial

Adriana Feder, MD ; Oneysha Brown, BA ; Sarah B. Rutter, MA ; Leah Cahn, LCSW ; Jessica R. Overbey, DrPH ; Saren H. Seeley, PhD ; Alex Yu, MD ; Philip A. Bonanno, MD ; Rachel A. Fremont, MD, PhD ; Andrew A. Delgado, PhD ; Manish K. Jha, MD ; Sara Costi, MD ; Rachel Yehuda, PhD ; Daniela Schiller, PhD ; Robert H. Pietrzak, PhD, MPH ; Dennis S. Charney, MD ; Denise M. Sloan, PhD ; James W. Murrough, MD, PhD

J Clin Psychiatry 2025;86(2):24m15622

Abstract

Objective: This open-label clinical trial examined the preliminary efficacy of combining a course of 6 ketamine infusions with a brief, evidence-based exposure-based psychotherapy—written exposure therapy (WET)—in patients with chronic posttraumatic stress disorder (PTSD).

Methods: The trial was conducted between June 2021 and October 2023. Patients with chronic PTSD and high-moderate to severe symptom levels received 6 intravenous ketamine infusions (0.5 mg/kg), 3 times a week for 2 consecutive weeks, plus 5 WET sessions over 2 weeks, beginning after the first 4 infusions and administered on different days than infusion days. The primary outcome was change in the Clinician Administered PTSD Scale for DSM-5 (CAPS-5) scores from baseline (before the first infusion) to 12 weeks from start of WET (“Week 12”).

Results: Fourteen eligible patients began treatment, and 13 completed all infusions and WET. The combined treatment was associated with large-magnitude improvement in PTSD symptom severity from baseline (mean CAPS 5 = 41.6 [SD = 6.2]) to Week 12 (CAPS 5 = 20.8 [14.8], Cohen d [95% CI] = 1.9 [1.0–2.8], P < .001). Nine (69%) patients were treatment responders (≥30% improvement on the CAPS-5). Response was rapid and also durable in 8 (61.5%) patients, assessed up to 6 months from baseline.

Conclusions: Preliminary findings from this open-label clinical trial suggest that the combined treatment may yield large magnitude and durable reductions in PTSD symptoms for patients with more severe chronic PTSD. Large-scale randomized controlled trials are needed to determine the efficacy and potential synergistic effect of this promising combined treatment in this patient population.

Trial Registration: ClinicalTrials.gov identifier: NCT04889664

J Clin Psychiatry 2025;86(2):24m15622

Author affiliations are listed at the end of this article.

Continue Reading...

Members enjoy unlimited free PDF downloads as part of their subscription! Subscribe today for instant access to this article and our entire library in your preferred format. Alternatively, you can purchase the PDF of this article individually.

Subscribe Now

Already a member? Login

Buy PDF for $40

Please sign in or purchase this PDF for $40.

References (44)

Feder A, Parides MK, Murrough JW, et al. Efficacy of intravenous ketamine for treatment of chronic posttraumatic stress disorder: a randomized clinical trial. JAMA Psychiatry. 2014;71(6):681–688.
Feder A, Costi S, Rutter SB, et al. A randomized controlled trial of repeated ketamine administration for Chronic Posttraumatic Stress Disorder. Am J Psychiatry. 2021;178(2):193–202.
Fremont R, Brown O, Feder A, et al. Ketamine for treatment of posttraumatic stress disorder: state of the field. Focus (Am Psychiatr Publ). 2023;21(3):257–265.
Krystal JH, Davis LL, Neylan TC, et al. It is time to address the crisis in the pharmacotherapy of posttraumatic stress disorder: a consensus statement of the PTSD Psychopharmacology Working Group. Biol Psychiatry. 2017;82(7):e51–e59.
Marazziti D, Foresi Crowther L, Arone A. An overview of the differences in the pharmacological management of post-traumatic stress disorder between women and men. Expert Rev Neurother. 2024;24(6):575–584.
Steenkamp MM, Litz BT, Hoge CW, et al. Psychotherapy for military-related PTSD: a review of randomized clinical trials. JAMA. 2015;314(5):489–500.
Stein MB, Rothbaum BO. 175 Years of progress in PTSD therapeutics: learning from the past. Am J Psychiatry. 2018;175(6):508–516.
Krystal JH, Abdallah CG, Averill LA, et al. Synaptic loss and the pathophysiology of PTSD: implications for ketamine as a prototype novel therapeutic. Curr Psychiatry Rep. 2017;19(10):74.
Homan P, Levy I, Feltham E, et al. Neural computations of threat in the aftermath of combat trauma. Nat Neurosci. 2019;22(3):470–476.
Levy I, Schiller D. Neural computations of threat. Trends Cogn Sci. 2021;25(2):151–171.
Stojek MM, McSweeney LB, Rauch SAM. Neuroscience informed prolonged exposure practice: increasing efficiency and efficacy through mechanisms. Front Behav Neurosci. 2018;12:281.
Girgenti MJ, Ghosal S, LoPresto D, et al. Ketamine accelerates fear extinction via mTORC1 signaling. Neurobiol Dis. 2017;100:1–8.
Ju LS, Yang JJ, Lei L, et al. The combination of long-term ketamine and extinction training contributes to fear erasure by BDNF methylation. Front Cell Neurosci. 2017;11:100.
Sala N, Paoli C, Bonifacino T, et al. Acute ketamine facilitates fear memory extinction in a rat model of PTSD along with restoring glutamatergic alterations and dendritic atrophy in the prefrontal cortex. Front Pharmacol. 2022;13:759626.
Li N, Liu RJ, Dwyer JM, et al. Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry. 2011;69(8):754–761.
Deyama S, Duman RS. Neurotrophic mechanisms underlying the rapid and sustained antidepressant actions of ketamine. Pharmacol Biochem Behav. 2020;188:172837.
Norbury A, Rutter SB, Collins AB, et al. Neuroimaging correlates and predictors of response to repeated-dose intravenous ketamine in PTSD: preliminary evidence. Neuropsychopharmacology. 2021;46(13):2266–2277.
Duek O, Korem N, Li Y, et al. Long term structural and functional neural changes following a single infusion of ketamine in PTSD. Neuropsychopharmacology. 2023;48(11):1648–1658.
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. J Clin Psychiatry 2020;81(6):20l13406.
Sloan DM, Marx BP. Written Exposure Therapy for PTSD: A Brief Treatment Approach for Mental Health Professionals. American Psychological Association; 2019. CrossRef
Thompson-Hollands J, Marx BP, Sloan DM. Brief novel therapies for PTSD: written exposure therapy. Curr Treat Options Psychiatry. 2019;6(2):99–106.
Thompson-Hollands J, Marx BP, Lee DJ, et al. Long-term treatment gains of a brief exposure-based treatment for PTSD. Depress Anxiety. 2018;35(10):985–991.
Sloan DM, Marx BP, Lee DJ, et al. A brief exposure-based treatment vs cognitive processing therapy for posttraumatic stress disorder: a randomized noninferiority clinical trial. JAMA Psychiatry. 2018;75(3):233–239.
Sloan DM, Marx BP, Resick PA, et al. Effect of written exposure therapy vs cognitive processing therapy on increasing treatment efficiency Among military service members with posttraumatic stress disorder: a randomized noninferiority trial. JAMA Netw Open. 2022;5(1):e2140911.
Sloan DM, Marx BP, Acierno R, et al. Written exposure therapy vs prolonged exposure therapy in the treatment of posttraumatic stress disorder: a randomized clinical trial. JAMA Psychiatry. 2023;80(11):1093–1100.
First MB, Williams JBW, Karg RS, et al. Structured Clinical Interview for DSM-5, Research Version. American Psychiatric Association; 2015.
Weathers FW, Bovin MJ, Lee DJ, et al. The Clinician-Administered PTSD Scale for DSM-5 (CAPS-5): development and initial psychometric evaluation in military veterans. Psychol Assess. 2018;30(3):383–395.
DeJesus CR, Trendel SL, Sloan DM. A systematic review of written exposure therapy for the treatment of posttraumatic stress symptoms. Psychol Trauma. 2024:10.1037/tra0001659. doi: 10.1037/tra0001659. CrossRef
Villarreal G, Hamner MB, Canive JM, et al. Efficacy of quetiapine monotherapy in posttraumatic stress disorder: a randomized, placebo-controlled trial. Am J Psychiatry. 2016;173(12):1205–1212.
Golier JA, Caramanica K, Demaria R, et al. A pilot study of mifepristone in combat related PTSD. Depress Res Treat. 2012;2012:393251.
Markowitz JC, Petkova E, Neria Y, et al. Is exposure necessary? A randomized clinical trial of interpersonal psychotherapy for PTSD. Am J Psychiatry. 2015;172(5):430–440.
Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979;134:382–389.
Guy W. ECDEU Assessment Manual for Psychopharmacology. US Department of Health, Education, and Welfare; 1976.
Sheehan DV, Harnett-Sheehan K, Raj BA. The measurement of disability. Int Clin Psychopharmacol. 1996;11(suppl 3):89–95.
Wilkinson ST, Toprak M, Turner MS, et al. A survey of the clinical, off-label use of ketamine as a treatment for psychiatric disorders. Am J Psychiatry. 2017;174(7):695–696.
Sloan DM, Marx BP, Bovin MJ, et al. Written exposure as an intervention for PTSD: a randomized clinical trial with motor vehicle accident survivors. Behav Res Ther. 2012;50(10):627–635.
Li N, Lee B, Liu RJ, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329(5994):959–964.
Wisco BE, Baker AS, Sloan DM. Mechanisms of change in written exposure treatment of posttraumatic stress disorder. Behav Ther. 2016;47(1):66–74.
Sloan DM, Marx BP. A closer examination of the structured written disclosure procedure. J Consult Clin Psychol. 2004;72(2):165–175.
Helpman L, Marin MF, Papini S, et al. Neural changes in extinction recall following prolonged exposure treatment for PTSD: a longitudinal fMRI study. Neuroimage Clin. 2016;12:715–723.
Mathai DS, Mora V, Garcia-Romeu A. Toward synergies of ketamine and psychotherapy. Front Psychol. 2022;13:868103.
Philipp-Muller AE, Stephenson CJ, Moghimi E, et al. Combining ketamine and psychotherapy for the treatment of posttraumatic stress disorder: a systematic review and meta-analysis. J Clin Psychiatry. 2023;84(2):22br14564.
van Rooij SJ, Kennis M, Vink M, et al. Predicting treatment outcome in PTSD: a longitudinal functional MRI study on trauma-unrelated emotional processing. Neuropsychopharmacology. 2016;41(4):1156–1165.
Fonzo GA, Goodkind MS, Oathes DJ, et al. PTSD psychotherapy outcome predicted by brain activation during emotional reactivity and regulation. Am J Psychiatry. 2017;174(12):1163–1174.