This double-blind RCT (n=158) assessed 8 repeated doses of intravenous ketamine administered twice weekly at a low dose (0.2 mg/kg; n = 53), standard dose (0.5 mg/kg; n = 51) ketamine or placebo (n=54) in veterans and service members with PTSD. It was found that the standard dose of ketamine reduced MADRS scores significantly more than placebo. However, the trial failed to find a significant dose-related effect of ketamine on PTSD symptoms measured using the CAPS-5.
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.
Posttraumatic stress disorder (PTSD) has limited effective pharmacotherapies and veterans often show smaller drug–placebo differences in trials. Ketamine, an NMDA receptor antagonist with rapid antidepressant effects, has shown mixed results in small prior studies of PTSD: some uncontrolled or pilot trials reported reductions in PTSD and depressive symptoms following standard intravenous ketamine (0.5 mg/kg), whereas other controlled or open-label studies found no significant benefit. Prior work had tested only the standard ketamine dose and often used active controls such as midazolam, which may be problematic in PTSD trials. Abdallah and colleagues therefore designed a larger, multi-centre, double-blind, randomized, placebo-controlled trial to test whether repeated intravenous ketamine reduces PTSD symptoms in Veterans and active-duty military personnel with antidepressant-resistant PTSD. The trial compared placebo (saline) with a low ketamine dose (0.2 mg/kg) and a standard dose (0.5 mg/kg), delivered twice weekly for eight 40-minute infusions, with the primary hypothesis that the standard dose would produce a rapid reduction in PTSD symptoms that would be maintained through the end of treatment and during a 4-week follow-up. Secondary aims included assessment of depressive outcomes and dose-related dissociative/psychotomimetic adverse effects and tolerability.
Papers cited by this study that are also in Blossom
Abdallah, C. G., Sanacora, G., Duman, R. S. et al. · Chronic Stress (2018)
Feder, A., Parides, M. K., Murrough, J. W. · JAMA Psychiatry (2014)
Feder, A., Costi, S., Rutter, S. B. et al. · American Journal of Psychiatry (2021)
Albott, C. S., Lim, K. O., Forbes, M. K. et al. · Journal of Clinical Psychiatry (2018)
Su, T. P., Chen, M. H., Li, C. T. et al. · Neuropsychopharmacology (2017)
Singh, J. B., Fedgchin, M., Daly, E. J. et al. · American Journal of Psychiatry (2016)
Murrough, J. W., Iosifescu, D. V., Chang, L. C. et al. · American Journal of Psychiatry (2013)
Papers in Blossom that reference this study
Macconnel, H. A., Earleywine, M., Radowitz, S. · OSF Preprints (2024)
Borgogna, N. C., Owen, T., Vaughn, J. et al. · European Journal of Psychotraumatology (2024)
Danböck, S. K., Duek, O., Ben-Zion, Z. et al. · Psychopharmacology (2023)
Hartland, H., Mahdavi, K., Jelen, L. A. et al. · Journal of Psychopharmacology (2023)
This was a double-blind, randomized, parallel three-arm trial conducted at three centres between September 2016 and March 2020. Participants were Veterans and active duty service members aged 18–70 years with a CAPS-5 diagnosis of PTSD and CAPS-5 score ≥23, and a documented history of nonresponse to at least one adequate antidepressant trial. Participants were required to be unmedicated or stable on antidepressant or PTSD-focused psychotherapy, not to have psychotic or manic features, unstable medical conditions, recent moderate/severe substance use disorder, significant suicidality, severe brain injury, or contraindicated medications; physiological entry criteria for blood pressure and heart rate were also applied. Randomisation allocated participants to one of three arms: placebo (normal saline), low-dose ketamine (0.2 mg/kg), or standard-dose ketamine (0.5 mg/kg). Each participant received eight intravenous infusions (40 min each) administered twice weekly, and assessments were performed prior to each infusion, at 24 h after the first and last infusions, and weekly during a 4-week follow-up. The primary outcome was the self-report PTSD Checklist for DSM-5 (PCL-5) measured repeatedly to capture rapid effects; secondary outcomes included clinician-rated CAPS-5 (baseline, end of treatment, end of follow-up) and Montgomery–Åsberg Depression Rating Scale (MADRS). Dissociative and psychotomimetic effects were assessed using the Clinician-Administered Dissociative State Scale (CADSS) and the Positive and Negative Syndrome Scale (PANSS) at 30 and 120 min after infusion start. At end of treatment participants guessed their treatment assignment to assess blinding. Nonresponders (defined as <25% improvement in CAPS-5) were offered a single open-label standard ketamine infusion, and their follow-up data were excluded from durability analyses. Statistical analysis plans (detailed elsewhere and in supplementary material) treated PCL-5 as the primary outcome. Primary inference used mixed-effects models including dose (three levels), repeated time points (eight infusions), and dose-by-time interactions; a significant dose-by-time interaction would indicate efficacy. Secondary contrasts tested rapid (24 h post-first infusion) and end-of-treatment effects with adjustment for multiple comparisons. Durability analyses during follow-up used similar mixed models, excluding participants who received open-label dosing. CADSS and PANSS were analysed with mixed models including interval (30 vs 120 min) and interactions. The investigators had targeted n = 198 but closed enrollment prematurely due to COVID-19-related restrictions; the analysed sample comprised participants who began treatment (n = 158).
Of 262 screened, 158 participants were eligible, randomised, began treatment, and were included in analyses (placebo n not explicitly restated here in the Results section but reported elsewhere as similar group sizes). Discontinuation rates did not differ significantly across groups (placebo 19%, low 15%, standard 16%), and baseline demographics and symptom severity were comparable across arms. Nearly all participants (156/158; 99%) met criteria for a current major depressive episode. Primary outcome (PCL-5): Mixed-effects models found no significant treatment main effect (F(2,148)=1.8, p=0.17) and no treatment-by-time interaction (F(18,137)=1.1, p=0.38), while there was a significant time effect (F(9,133)=37.1, p<0.0001), indicating symptom improvement across all groups over time. Pre-specified between-group contrasts showed a 24-h post-first-infusion mean PCL-5 difference for standard dose versus placebo of 6.6 (±3.1), t(149)=2.1, p=0.04 but adjusted p=0.11; end-of-treatment contrasts were similarly non-significant after adjustment. Low-dose contrasts versus placebo were also non-significant after correction. No significant differences emerged between the two ketamine doses. Responder analysis: At 24 h post-first infusion, 47% of participants in each active dose group met the ≥25% improvement threshold on PCL-5 versus 33% in placebo; this difference did not reach statistical significance (Chi-square(2)=5.0, p=0.08). Odds ratios for responder status were 1.88 (95% CI 0.84–4.22) for standard dose and 1.82 (95% CI 0.82–4.05) for low dose versus placebo, not statistically significant. Secondary clinician-rated PTSD outcome (CAPS-5): CAPS-5 showed a strong time effect (F(1,124)=103.4, p<0.0001) but no treatment effect (F(2,145)=0.8, p=0.46) and no significant treatment-by-time interaction (F(2,124)=2.7, p=0.07). Individual contrasts versus placebo showed reductions for low and standard doses that did not survive adjustment for multiple comparisons. Depression (MADRS): The mixed model showed a significant treatment-by-time interaction (F(18,135)=1.7, p=0.04) and time effect (F(9,133)=35.0, p<0.0001). Standard-dose ketamine produced a rapid reduction in MADRS at 24 h post-first infusion versus placebo (mean difference 4.6±1.9, t(148)=2.5, p=0.02, adj. p=0.05) and a significant reduction at end of treatment (mean difference 6.4±2.2, t(140)=2.9, p=0.004, adj. p=0.01). The low dose did not show significant acute antidepressant effects during treatment; the standard versus low dose contrast did not survive correction for multiple comparisons. Durability: Many participants who were nonresponders were offered open-label ketamine (standard dose); excluding those participants, follow-up mixed models over 4 weeks post-treatment showed time effects but no treatment or treatment-by-time interactions on PCL-5, CAPS-5, or MADRS. At 4 weeks post-treatment PCL-5 scores were significantly lower in the low-dose group versus placebo in an unadjusted contrast (mean difference 15.3±5.8, t(68)=2.6, p=0.01, adj. p=0.03), but comparisons involving the standard dose were not significant after adjustment. CAPS-5 and MADRS comparisons at 4 weeks did not show statistically robust treatment differences after multiple comparison correction. Adverse effects and tolerability: CADSS analyses demonstrated dose-dependent increases in dissociative symptoms (treatment effect F(2,147)=20.2, p<0.0001) with a marked treatment-by-interval interaction (F(2,803)=102.1, p<0.0001); dissociative symptoms peaked during infusion and largely resolved by ~80 minutes after infusion start. PANSS showed comparable acute psychotomimetic effects with significant treatment*interval interaction (F(2,148)=13.9, p<0.0001) that reduced by 120 minutes. Dissociative and psychotomimetic effects decreased over the course of repeated infusions. Overall, 87% of participants reported at least one adverse event (402 total AEs), with 162 rated at least possibly treatment-related. AEs more associated with active ketamine included agitation, anxiety, irritability and constipation; headache was more common in the low-dose group; nausea occurred across groups including placebo. There was no evidence of differential treatment discontinuation by dose, and the regimen was considered feasible and generally well tolerated in this population.
Abdallah and colleagues interpret the trial as failing to support the a priori hypothesis that repeated twice-weekly ketamine infusions (0.5 mg/kg) reduce PTSD symptoms in Veterans and active-duty service members with antidepressant-resistant PTSD. The primary mixed-model analyses for the PCL-5 and CAPS-5 did not show dose-related benefits over placebo, despite clear time-related improvements across all groups. In contrast, the study did detect rapid and end-of-treatment antidepressant effects for the standard ketamine dose on MADRS, although these effects were not durable across the 4-week follow-up. The authors compare their null PTSD result to earlier smaller or pilot studies that reported positive effects, noting important differences that may account for divergent findings: this trial enrolled a military population (largely male) with a required history of antidepressant nonresponse, used placebo rather than an active benzodiazepine control, included a low-dose arm, and delivered treatment twice weekly for 4 weeks (eight infusions). They acknowledge that military samples have shown lower treatment response in prior work and that the sex imbalance (only 23% female here) may have influenced outcomes, although the study lacked power to test sex effects. The investigators also emphasise the problem of high placebo response: effect sizes for ketamine were in the expected large range, but placebo improvement was larger than anticipated, reducing between-group contrasts. Blinding and expectation effects are discussed: functional unblinding due to ketamine's acute subjective effects is a known concern, and while midazolam has been used as an active control in other ketamine studies, benzodiazepines may negatively affect PTSD outcomes. Blinding assessments in this trial suggested many participants suspected they received low-dose ketamine and only 37% correctly guessed standard-dose assignment, and there was no evidence of pessimism about placebo allocation. The authors propose that the intensive clinical contact inherent in repeated IV infusion protocols may have contributed to the substantial within-group improvements, including in placebo. On safety, the study provides evidence that repeated intravenous ketamine at these doses is feasible and has a tolerable short-term safety profile in patients with PTSD. Ketamine-induced dissociative and psychotomimetic symptoms were transient, resolved within about 2 hours, and decreased over successive infusions. The lower dose produced significantly smaller dissociative effects than the standard dose, suggesting a potential tolerability advantage if lower doses prove efficacious. Key limitations acknowledged by the authors include premature study closure due to the COVID-19 pandemic (the target sample was not achieved), the high placebo response, and limited ability to explore moderators such as sex because of the sample composition. They conclude that further research is needed to clarify ketamine's role in PTSD, including exploration of lower doses and investigation of ketamine's antidepressant benefits in this difficult-to-treat comorbid population.
Power calculation and analysis plans were previously reportedand are further detailed in the online Supplementary Information. Briefly, the PCL-5 was considered the primary outcome, while CAPS-5 and MADRS were considered secondary measures. The primary analysis used mixed effects models, with dose (3-levels), time (8 infusions), and dose-by-time interactions with efficacy determination evidenced as a dose-by-time interaction. The secondary analyses examined the rapid and sustained effects of ketamine compared to placebo, at 24 h post-first and post-last infusion, respectively, by focused contrasts in the mixed models adjusted for multiple comparison. Sustainability of the effects of ketamine on PTSD symptoms was assessed with similar mixed models for PCL-5 and CAPS-5 during the follow-up period; considering that this analysis included only the responders (non-responders received open label ketamine). However, there was no difference in pretreatment severity and the results are similar without covarying for severity. The dissociative and psychotomimetic effects were examined using comparable mixed models for CADSS and PANSS, while adding interval (30 min vs. 120 min) and appropriate interactions to the models.
This randomized, controlled trial was the largest sample and longest treatment duration for ketamine studied to date to treat PTSD symptoms in Veterans, and the only one to treat active duty military. The study found that 4 weeks of twice-weekly ketamine infusions failed to demonstrate significant efficacy on PTSD symptoms in a priori planned comparisons to placebo in this population of Veterans and service members. This was true despite observing significant antidepressant effects of ketamine in these patients who had considerable depressive symptoms at baseline. To address comorbid depression in PTSD, our secondary analyses showed significant superiority of the standard Ketamine dose over placebo to reduce depressive symptoms measured by the MADRS. Beneficial effects of the standard dose were seen acutely after the first standard dose and at the end of treatment, but these effects were not sustained during the 4 weeks of posttreatment follow-up. Depression symptoms, which were substantial in the current cohort, are commonly associated with PTSD, and have been reported to respond relatively poorly to traditional antidepressants. For example, in the VAST-D study, depressed patients with PTSD had poorer overall outcomes than depressed patients without PTSD. In the current study, ketamine showed significant effect in the mixed model and in the secondary analyses, reflecting rapid antidepressant effects on Day 1 and at the end of treatment in the standard dose group. Consistent with the depression literature, the low dose ketamine had no rapid antidepressant effect during treatment. However, at the end of the 4-week follow-up, participants in the low dose group were found to have reduced depressive symptoms compared to placebo, suggesting a possible cumulative effect of repeated low doses on depression. The current study does not support the pilot findings by Feder and colleagues, which reported significant effects of standard dose ketamine on PTSD symptoms. Several differences between the trials may have contributed to the differing results. Our study was in military population, while the previous report was primarily in civilians. Notably, previous trials indicated low treatment response in military population suffering from PTSD. Furthermore, our participants were mostly males with only 23% females compared to the previous study with 77% females. The sex differences may have played a role in the differing outcomes. Considering the low number of females per group, we were not able to statistically assess the effect of sex in our cohort. Other differences in the previous studycompared to the current trial, include: (1) smaller cohort of 15 subjects per group, (2) using benzodiazepine as control, (3) no low dose arm, (4) administering the study drugs 3 times per week, (5) treatment was for 2 weeks, and () the previous study did not require history of nonresponse to an antidepressant. the previous study found no rapid effects ketamine on PTSD or depression symptoms at 24 h post first infusion. This could be due to the small sample size but it also underscores the challenges of demonstrating the therapeutic effects of standard dose ketamine in PTSD patients. A major challenge in ketamine research is the potential for functional unblinding due to the distinguishing acute dissociative effects of ketamine. Concerns relate to functional unblinding that may lead to negative outcome expectations from placebo exaggerating differences from the study drug. Midazolam, has been used as a putative "active control" in ketamine studies. However, the potential negative effects of benzodiazepine on PTSD are previously documented and may actually exacerbate drug vs. control differences in PTSD treatment studies. Very large pre to post improvements in the current study (even within the placebo group), coupled with no differential dropout, suggest that expectations were not negative in our placebo-treated participants. In the current study, blinding assessment (see Supplements & Table) showed the majority of participants supposed they were on low dose ketamine and even within the placebo group, this number was 35%. Only 37% of participants in the standard dose correctly guessed their high dose assignment. The most common reason identified to be the basis for their guess of dose assignment was participant's perception of effects during the infusionwhich produced only moderate proportions of participants being "reasonably sure" in that guess. Together, these data suggest that the use of low dose ketamine in a 2:1 design randomization to ketamine may have enhanced participant's expectation of benefit. The effect sizes of both ketamine doses on PCL-5 scores were large and in the predicted range (0.93-1.61), but the effect size of placebo was larger than expected (0.75-1.13), resulting in small ketamine vs. Placebo differences. Unfortunately, failed clinical trials due to high placebo response are not uncommon in this field. Other factors also may have contributed to the high placebo response, including the repeated invasive medical interventions of intravenous infusion twice per week requiring 2-3 weekly visits ~4 h each over 4 weeks in a protocol including comprehensive assessments in a supportive medical milieu of attending to the participant needs during the study period (e.g., booking transportations, meals, etc.). Finally, the current study demonstrated the feasibility and shortterm safety of repeated intravenous ketamine in a large cohort of patients with PTSD. A major concern in the field was whether adverse effects of repeated ketamine doses would exacerbate PTSD symptoms. However, consistent with a recent report, the study treatment regimen was found to be well tolerated, showing significant reductions in the dissociative and psychotomimetic symptoms over the treatment period. Moreover, the ketamine-induced dissociative and psychotomimetic effects were transient, returning to normal levels within 2 h of starting the ketamine infusion. These dissociative effects were not so severe as to have an impact on retention in treatment over 8 intravenous infusions. Importantly, as has been reported in depressed patients, the ketamine-induced dissociative effects were significantly lower during ketamine 0.2 mg/kg compared to the standard dose (0.5 mg/kg) commonly used to treat depression. The latter finding suggests that using lower doses, if they were found efficacious in PTSD, might offer superior tolerability. In summary, the current study failed to support the a priori hypothesis test of ketamine efficacy on PTSD symptoms in Veterans and military personnel with symptoms of PTSD. Nonetheless, there were evidence of benefit due to ketamine particularly the rapid antidepressant effects in this population, which has been difficult to treat in other studies. The study provided data supporting the safety and tolerability of repeated ketamine doses in this population. Together, these findings suggest the need to further investigate lower doses of ketamine in the treatment of PTSD and that ketamine may help to manage the complex of symptoms associated with PTSD, particularly for patients have not responded to prior pharmacotherapies.
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Bentley, S., Artin, H., Mehaffey, E. et al. · Pharmacotherapy (2022)