Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder

Posttraumatic stress disorder (PTSD) is a chronic, disabling condition marked by persistent re‑experiencing, avoidance, and hyperarousal following severe trauma. The authors note that existing pharmacotherapies (for example selective serotonin reuptake inhibitors and serotonin–norepinephrine reuptake inhibitors) often leave many patients with residual symptoms or nonresponse. Emerging preclinical and clinical evidence implicates glutamate in stress responsivity and traumatic memory formation, and intravenous (IV) ketamine—an N‑methyl‑D‑aspartate (NMDA) receptor antagonist—has demonstrated rapid antidepressant effects at sub‑anesthetic doses in treatment‑resistant depression, suggesting a potential therapeutic role in PTSD. Feder and colleagues therefore conducted a proof‑of‑concept, randomised, double‑blind, crossover trial to test whether a single sub‑anesthetic IV ketamine infusion would rapidly reduce core PTSD symptoms compared with an active placebo (midazolam). Their primary hypothesis was that ketamine would produce a significantly greater reduction in PTSD symptom severity 24 hours after infusion; a secondary hypothesis was that ketamine would produce a rapid antidepressant effect in patients with PTSD.

The trial was conducted at a single site and enrolled adults aged 18–55 with a primary diagnosis of chronic PTSD confirmed by structured clinical interview and a Clinician‑Administered PTSD Scale (CAPS) score of at least 50. Key exclusion criteria were lifetime psychotic or bipolar disorder, current eating‑disorder, recent alcohol abuse or dependence, unstable medical illness, active suicidal or homicidal ideation, current psychotropic medication use, and active substance use; all participants underwent physical, laboratory, toxicology and electrocardiographic screening. The extracted text does not clearly report detailed demographic breakdowns beyond noting chronic, typically long‑standing PTSD and that fewer than 50% had prior psychotropic medication exposure. Using a randomised, double‑blind, crossover design, participants received a single IV infusion of ketamine hydrochloride 0.5 mg/kg or midazolam 0.045 mg/kg administered over 40 minutes, with the order randomised and infusions separated by 2 weeks. Midazolam served as an active placebo because it produces transient psychoactive effects and has similar pharmacokinetics. The research pharmacy was the only unblinded party; investigators, clinicians, raters, anaesthesiologists and patients were blinded. Ratings during and after infusion were performed by trained raters, and a different blinded rater conducted baseline and follow‑up assessments at 24, 48, 72 hours and 7 days; additional assessments occurred at 10 and 13 days but analyses focused on the first week. The primary outcome was PTSD symptom severity at 24 hours measured with the Impact of Event Scale‑Revised (IES‑R). Secondary outcomes included clinician‑rated depressive symptoms (Montgomery‑Åsberg Depression Rating Scale, MADRS), self‑reported depressive symptoms (QIDS‑SR), Clinical Global Impression scales (CGI‑S and CGI‑I), and safety/tolerability measures including dissociation (Clinician‑Administered Dissociative States Scale), psychotomimetic symptoms (Brief Psychiatric Rating Scale positive‑symptoms items), and a patient‑rated side‑effect inventory. The primary statistical approach used mixed models to test treatment, period and carryover effects in the crossover sample; a modified intention‑to‑treat analysis included 29 patients with outcome data from both periods, and an additional first‑period analysis (analysis of covariance) used first‑period data from all 41 randomised participants. Tests were two‑sided at the 0.05 level and safety was summarised descriptively. The planned sample size was 40 to provide 80% power to detect a large effect (0.9 SD) on the IES‑R at 24 hours.

Of 57 people who consented, 41 met eligibility criteria and were randomised; all 41 received the first infusion and completed 24‑hour ratings. Twenty‑nine participants completed both infusion periods and corresponding ratings. Twelve participants did not complete both periods: six (all randomised to ketamine first) had sustained improvement (CAPS <50) at 2 weeks and therefore did not receive the second infusion per protocol; two others had CAPS <50 but received their second infusion one week later; remaining reasons included one early infusion discontinuation after incorrect higher dosing and one dropout due to discomfort during infusion. Primary outcome: In the crossover analysis (n = 29), ketamine produced a significantly greater reduction in IES‑R total score at 24 hours compared with midazolam (mean difference 12.7, 95% CI 2.5 to 22.8; P = .02). There was no evidence of period or carryover effects. The first‑period analysis including all 41 randomised participants yielded a similar result (mean difference 8.6, 95% CI 0.94 to 16.2; P = .03). Neither a comorbid major depressive disorder diagnosis at screening nor baseline MADRS score significantly influenced the 24‑hour IES‑R change in these analyses. Secondary outcomes: Ketamine produced comparable improvements across the three IES‑R symptom clusters. In the crossover sample, clinician global ratings (CGI‑S and CGI‑I) at 24 hours were significantly better following ketamine; first‑period analyses supported these findings. By contrast, crossover analyses of depressive symptom scales at 24 hours (MADRS and QIDS‑SR) did not show significant ketamine benefit over midazolam. CAPS scores at 7 days did not differ significantly between treatments (mean difference 8.7, 95% CI −4.8 to 22.2; P = .20). Additional modelling of first‑period data across 24, 48 and 72 hours and day 7 found a significant overall treatment effect on IES‑R (least‑squares difference −8.32; P = .046) and on QIDS‑SR (−2.73; P = .050), with the effect on MADRS approaching significance (−3.99; P = .052). Time effects were significant for IES‑R, MADRS and QIDS‑SR, and no treatment‑by‑time interactions were detected. Adverse events and tolerability: Dissociative effects after ketamine peaked at 40 minutes and had resolved by 120 minutes post‑start of infusion. No clinically significant emergence of psychotic or manic symptoms was observed. One participant discontinued after a second ketamine infusion because of infusion‑related discomfort; another had infusion stopped after 15 minutes because of dosing error. Three patients required acute β‑blocker treatment for elevated blood pressure during ketamine infusion (systolic >180 mm Hg and/or diastolic >100 mm Hg). Patient‑reported adverse effects in the first 24 hours were more frequent with ketamine than midazolam for several symptoms: blurred vision 36% vs 19%, dry mouth 21% vs 16%, restlessness 23% vs 10%, nausea/vomiting 21% vs 3%, poor coordination 15% vs 3%, while fatigue and headache rates were similar or slightly higher with midazolam for fatigue (21% vs 23%) and equal for headache (13% vs 13%).

Feder and colleagues interpret their findings as the first randomised, controlled evidence that modulation of the NMDA glutamate receptor with a single sub‑anesthetic IV ketamine infusion can produce a rapid reduction in core PTSD symptoms in patients with chronic PTSD. Improvements were evident at 24 hours and in many cases persisted beyond 24 hours; seven patients randomised to ketamine first had CAPS scores below 50 at two weeks, compared with one patient randomised to midazolam first. The authors note that the ketamine effect on PTSD symptoms remained significant after adjusting for baseline and 24‑hour depressive symptom severity, suggesting an effect on PTSD beyond antidepressant action, although reductions in depressive symptoms were also observed. Positioning the results within prior literature, the authors acknowledge mixed findings from observational studies of ketamine in trauma‑exposed populations but highlight preclinical data implicating glutamate dysregulation and synaptic loss in stress and PTSD. They cite mechanistic hypotheses from animal work showing rapid synaptogenesis and activation of signalling pathways (for example mammalian target of rapamycin and brain‑derived neurotrophic factor) after ketamine, which might underlie rapid clinical effects. The authors acknowledge several limitations: several participants did not receive a second infusion (although in half this was because of sustained clinical improvement), ketamine produced transiently higher rates of dissociative symptoms that may have affected blinding, and the study does not address safety or efficacy of ketamine when combined with other psychotropic medications. They also note that the study was a proof‑of‑concept single‑site trial with a modest sample size and that findings require replication. Suggested next steps include studies of repeated or maintenance ketamine dosing, investigation of ketamine in perioperative settings to prevent PTSD, mechanistic studies, and efforts to identify predictors of response.

The authors conclude that a single IV sub‑anesthetic dose of ketamine was associated with rapid reduction of core PTSD symptoms and with reduction in comorbid depressive symptoms in patients with chronic PTSD, and that the treatment was generally well tolerated without clinically significant persistent dissociative symptoms. They recommend replication and further trials to examine safety and efficacy of repeated dosing, potential preventive use in surgical patients with trauma histories, investigation of mechanisms of action, and identification of pretreatment predictors of response.