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Randomized Controlled Trial
. 2022 Jul;47(8):1574-1581.
doi: 10.1038/s41386-022-01266-9. Epub 2022 Jan 19.

Dose-related effects of ketamine for antidepressant-resistant symptoms of posttraumatic stress disorder in veterans and active duty military: a double-blind, randomized, placebo-controlled multi-center clinical trial

Chadi G Abdallah  1   2   3   4   5 , John D Roache  6   7 , Ralitza Gueorguieva  8 , Lynnette A Averill  9   10   11   12 , Stacey Young-McCaughan  6   7 , Paulo R Shiroma  13 , Prerana Purohit  9   10 , Antoinette Brundige  6   7 , William Murff  6 , Kyung-Heup Ahn  10 , Mohamed A Sherif  10   14 , Eric J Baltutis  13 , Mohini Ranganathan  10 , Deepak D'Souza  10 , Brenda Martini  9   10 , Steven M Southwick  9   10 , Ismene L Petrakis  9   10 , Rebecca R Burson  15 , Kevin B Guthmiller  16   17 , Argelio L López-Roca  15 , Karl A Lautenschlager  16 , John P McCallin 3rd  18 , Matthew B Hoch  18 , Alexandar Timchenko  18 , Sergio E Souza  18 , Charles E Bryant  18 , Jim Mintz  6   7 , Brett T Litz  19   20 , Douglas E Williamson  21   22 , Terence M Keane  20   23 , Alan L Peterson  6   7   24 , John H Krystal  9   10
Affiliations
Randomized Controlled Trial

Dose-related effects of ketamine for antidepressant-resistant symptoms of posttraumatic stress disorder in veterans and active duty military: a double-blind, randomized, placebo-controlled multi-center clinical trial

Chadi G Abdallah et al. Neuropsychopharmacology. 2022 Jul.

Erratum in

Abstract

This study tested the efficacy of repeated intravenous ketamine doses to reduce symptoms of posttraumatic stress disorder (PTSD). Veterans and service members with PTSD (n = 158) who failed previous antidepressant treatment were randomized to 8 infusions administered twice weekly of intravenous placebo (n = 54), low dose (0.2 mg/kg; n = 53) or standard dose (0.5 mg/kg; n = 51) ketamine. Participants were assessed at baseline, during treatment, and for 4 weeks after their last infusion. Primary analyses used mixed effects models. The primary outcome measure was the self-report PTSD Checklist for DSM-5 (PCL-5), and secondary outcome measures were the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) and the Montgomery Åsberg Depression Rating Scale (MADRS). There were no significant group-by-time interactions for PTSD symptoms measured by the PCL-5 or CAPS-5. The standard ketamine dose ameliorated depression measured by the MADRS significantly more than placebo. Ketamine produced dose-related dissociative and psychotomimetic effects, which returned to baseline within 2 h and were less pronounced with repeated administration. There was no evidence of differential treatment discontinuation by ketamine dose, consistent with good tolerability. This clinical trial failed to find a significant dose-related effect of ketamine on PTSD symptoms. Secondary analyses suggested that the standard dose exerted rapid antidepressant effects. Further studies are needed to determine the role of ketamine in PTSD treatment. ClinicalTrials.gov identifier: NCT02655692.

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Conflict of interest statement

Dr. Abdallah has served as a consultant, speaker and/or on advisory boards for Aptinyx, Genentech, Janssen, Psilocybin Labs, Lundbeck, Guidepoint, and FSV7, and as editor of Chronic Stress for Sage Publications, Inc. He also filed a patent for using mTORC1 inhibitors to augment the effects of antidepressants (Aug 20, 2018). Dr. Krystal is a consultant for Aptinyx, Inc., Atai Life Sciences, AstraZeneca Pharmaceuticals, Biogen, Idec, MA, Biomedisyn Corporation, Bionomics, Limited (Australia), Boehringer Ingelheim International, Cadent Therapeutics, Inc., Clexio Bioscience, Ltd., COMPASS Pathways, Limited, United Kingdom, Concert Pharmaceuticals, Inc., Epiodyne, Inc., EpiVario, Inc., Greenwich Biosciences, Inc., Heptares Therapeutics, Limited (UK), Janssen Research & Development, Jazz Pharmaceuticals, Inc., Otsuka America Pharmaceutical, Inc., Perception Neuroscience Holdings, Inc., Spring Care, Inc., Sunovion Pharmaceuticals, Inc., Takeda Industries, Taisho Pharmaceutical Co., Ltd. JHK also reports the following disclosures: Scientific Advisory Board: Biohaven Pharmaceuticals, BioXcel Therapeutics, Inc. (Clinical Advisory Board), Cadent Therapeutics, Inc. (Clinical Advisory Board), Cerevel Therapeutics, LLC, EpiVario, Inc., Eisai, Inc., Lohocla Research Corporation, Novartis Pharmaceuticals Corporation, PsychoGenics, Inc., RBNC Therapeutics, Inc., Tempero Bio, Inc., Terran Biosciences, Inc. Stock: Biohaven Pharmaceuticals, Sage Pharmaceuticals, Spring Care, Inc. Stock Options: Biohaven Pharmaceuticals Medical Sciences, EpiVario, Inc., RBNC Therapeutics, Inc., Terran Biosciences, Inc. Tempero Bio, Inc. Income Greater than $10,000: Editorial Board: Editor - Biological Psychiatry. Patents and Inventions: (1) Seibyl JP, Krystal JH, Charney DS Dopamine and noradrenergic reuptake inhibitors in treatment of schizophrenia. US Patent #:5,447,948.September 5, 1995. (2) Vladimir, Coric, Krystal, John H, Sanacora, Gerard – Glutamate Modulating Agents in the Treatment of Mental Disorders. US Patent No. 8,778,979 B2 Patent Issue Date: July 15, 2014. US Patent Application No. 15/695,164: Filing Date: 09/05/2017. (3) Charney D, Krystal JH, Manji H, Matthew S, Zarate C., - Intranasal Administration of Ketamine to Treat Depression United States Patent Number: 9592207, Issue date: 3/14/2017. Licensed to Janssen Research & Development. (4) Zarate, C, Charney, DS, Manji, HK, Mathew, Sanjay J, Krystal, JH, Yale University “Methods for Treating Suicidal Ideation”, Patent Application No. 15/379,013 filed on December 14, 2016 by Yale University Office of Cooperative Research. (5) Arias A, Petrakis I, Krystal JH. – Composition and methods to treat addiction. Provisional Use Patent Application no.61/973/961. April 2, 2014. Filed by Yale University Office of Cooperative Research. (6) Chekroud, A., Gueorguieva, R., & Krystal, JH. “Treatment Selection for Major Depressive Disorder” [filing date 3rd June 2016, USPTO docket number Y0087.70116US00]. Provisional patent submission by Yale University. (7) Gihyun, Yoon, Petrakis I, Krystal JH – Compounds, Compositions and Methods for Treating or Preventing Depression and Other Diseases. U. S. Provisional Patent Application No. 62/444,552, filed on January10, 2017 by Yale University Office of Cooperative Research OCR 7088 US01. (8) Abdallah, C, Krystal, JH, Duman, R, Sanacora, G. Combination Therapy for Treating or Preventing Depression or Other Mood Diseases. U.S. Provisional Patent Application No. 62/719,935 filed on August 20, 2018 by Yale University Office of Cooperative Research OCR 7451 US01. On Non-Federal Research Support: AstraZeneca Pharmaceuticals provides the drug, Saracatinib, for research related to NIAAA grant “Center for Translational Neuroscience of Alcoholism [CTNA-4] Novartis provides the drug, Mavoglurant, for research related to NIAAA grant “Center for Translational Neuroscience of Alcoholism [CTNA-4]. Dr. Gueorguieva discloses royalties from book “Statistical Methods in Psychiatry and Related Fields” published by CRC Press, honorarium as a member of the Working Group for PTSD Adaptive Platform Trial of Cohen Veterans Bioscience and a United States patent application 20200143922 by Yale University: Chekroud, A., Krystal, J., Gueorguieva, R. and Chandra, A. “Methods and Apparatus for Predicting Depression Treatment Outcomes”. Dr. Sherif is a consultant for In Silico Biosciences, Inc. Dr. Averill is a consultant for Guidepoint. All other co-authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1. The effects of ketamine on posttraumatic stress disorder (PTSD) and depression symptoms.
A The PTSD Checklist for DSM-5 (PCL-5) scores were significantly reduced over the treatment period but did not differ between the treatment groups. Secondary analysis showed reduction in PCL-5 following standard dose ketamine compared to placebo at 24 h post first infusion (red * on Day 1, p = 0.04, adj. p = 0.11). There was also significant reduction in PCL-5 at 24 h post last infusion in low dose ketamine compared to placebo (blue * on Day 26, p = 0.05, adj. p = 0.16). B There was a non-significant effect of ketamine on the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), reflecting reduction in CAPS-5 in the low dose (blue *, p = 0.03, adj. p = 0.09) and in the standard dose (red t, p = 0.09, adj. p = 0.18) over the treatment period compared to placebo. C The Montgomery-Åsberg Depression Rating Scale (MADRS) scores were significantly reduced over the treatment period. This MADRS reduction differed between the treatment groups. There was significant improvement in depression symptoms at 24 h and end of treatment in the standard dose ketamine compared to placebo (red * on Day 1 and 26, p ≤ 0.05, adj. p ≤ 0.05). There was no significant improvement in depression symptoms following low dose ketamine compared to placebo. Notes: Assessments collected prior to each study drug infusion, except on Day 1 and Day 25, which were collected 24 h post-first and post-last infusions, respectively.
Fig. 2
Fig. 2. The response rate during and following treatment.
There was no significant difference in response rate (i.e., 25% or more improvement in the PTSD Checklist for DSM-5 (PCL-5) scores) at 24 h post first infusion (Day 1), 24 h post last infusion (Week 4), and at the end of 4 weeks of follow-ups (Week 8).
Fig. 3
Fig. 3. The dissociative and psychotomimetic effects of ketamine treatment in patients with posttraumatic stress disorder (PTSD).
A There was a dose-dependent, ketamine-induced increase in the Clinician-Administered Dissociative State Scale (CADSS) scores at 30 min from the start of the infusion (During). This ketamine-induced dissociation symptoms returned to placebo levels at the 120 min time point (Post). B There was a significant time effect on CADSS scores, indicating reduction in the dissociative symptoms with repeated treatment, from the first (I1) to last infusion (I8). C The standard dose induced increase in the Positive and Negative Syndrome Scale (PANSS) scores at 30 min from the start of the infusion (During). This ketamine-induced psychotomimetic effect improved at the 120 min time point (Post). D There was a significant time effect on PANSS scores, indicating reduction in the psychotomimetic symptoms with repeated treatment, from the first (I1) to last infusion (I8). Abbreviations: ns indicates p > 0.10; t indicates p < 0.10 * indicates p < 0.05; Standard = ketamine 0.5 mg/kg; Low = ketamine 0.2 mg/kg.
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References

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