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

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.

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.