A randomized, double-blind, active placebo-controlled study of efficacy, safety, and durability of repeated vs single subanesthetic ketamine for treatment-resistant depression

Ketamine, an NMDA (glutamate) receptor antagonist approved for anaesthesia, has shown rapid antidepressant effects at subanaesthetic doses in some patients with treatment-resistant depression (TRD), with benefits peaking around 24 hours and typically waning within about a week. Prior open-label and saline-controlled studies suggested that multiple ketamine infusions might increase response rates and prolong durability compared with a single infusion, but those designs left uncertainty because of limited masking and placebo control. Shiroma and colleagues therefore conducted a two-arm, randomized, double-blind, active placebo-controlled trial to compare efficacy, safety, and durability of repeated ketamine versus a single ketamine exposure in patients with TRD. To balance infusion number and provide an active comparator, the single-ketamine arm received five infusions of midazolam (an active placebo with some sedative and dissociative-like effects) followed by one ketamine infusion, while the repeated-ketamine arm received six ketamine infusions over 12 days. The primary endpoint was change in clinician-rated depression severity at 24 hours after the last infusion, with follow-up extending up to 6 months to assess durability and safety.

This single-centre trial took place at the Minneapolis Veterans Affairs Medical Center between April 2015 and March 2019. Outpatients aged 18–75 meeting DSM-IV criteria for major depressive disorder (MDD) on the Structured Clinical Interview and showing treatment resistance (failure of at least two adequate antidepressant trials during the current episode) were eligible. Additional inclusion required an IDS-C30 score ≥32. Exclusion criteria included lifetime PTSD as the primary problem, moderate traumatic brain injury, psychotic or bipolar disorder, recent alcohol/substance use disorder (within 6 months), imminent suicidal/homicidal intent, MMSE ≤27, positive toxicology or pregnancy, and unstable medical illness. Participants were randomised 1:1 using permuted blocks to receive either six ketamine infusions at 0.5 mg/kg or five midazolam infusions (0.045 mg/kg) followed by a single ketamine infusion. Infusions lasted 40 minutes and were given on a Monday–Wednesday–Friday schedule over 12 days. Doses were calculated by ideal body weight. Investigators, raters, and patients were masked to assignment; group allocation was concealed by sealed envelopes and pharmacy procedures. Vital signs and monitoring were performed before, during and for 2 hours after each infusion, with predefined thresholds for clinically significant changes and procedures for management of adverse events. The primary outcome was change in Montgomery–Åsberg Depression Rating Scale (MADRS) score at 24 hours after the final infusion (T +24). Response was prespecified as ≥50% reduction in MADRS from baseline and remission as MADRS <10. Secondary outcomes included MADRS change over time, rates of response and remission at multiple time points, Clinical Global Impression (CGI), Beck Anxiety Inventory (BAI), patient-rated side effects (PRISE), dissociation (CADSS), psychotomimetic symptoms (BPRS+), mania (YMRS), and suicidality (C-SSRS). Raters were trained with an interrater reliability of 0.92 for MADRS. Statistical analysis included repeated-measures ANOVA and multilevel models across MADRS measures; tests were two-sided with α = 0.05. A priori power calculations estimated that 21 patients per group would detect a 10-point difference in MADRS change under specified assumptions, though the authors later report that detecting a 4-point difference would have required 87 per group.

Of 178 prescreened individuals, 62 consented and 58 were randomised; 54 subjects completed baseline assessments and initiated infusions (29 in the midazolam-plus-single-ketamine arm; 25 in the six-ketamine arm) and thus contributed to the primary outcome. Baseline demographic and clinical characteristics did not differ significantly between groups; the sample was predominantly middle-aged, male Veterans with chronic, severe depression and prior treatment failures. For the primary endpoint, there was no statistically significant difference in MADRS change at 24 hours after the final infusion: mean MADRS change in the single-ketamine arm was 21.0 (95% CI 17.2–24.8) versus 17.2 (95% CI 13.2–21.2) in the six-ketamine arm (F1,52 = 2.41, P = 0.13, ηp2 = 0.044). However, when considering MADRS measures across time, a significant group-by-time effect was observed (F11,541.11 = 2.63, P = 0.003). Prior to infusion 5 and at 24 hours after infusion 5, mean MADRS scores were significantly lower in the repeated-ketamine group compared with the midazolam group (mean differences ~8 points at those time points, p ≈ 0.01); a smaller significant difference was also present prior to infusion 6 (mean difference 6.40, 95% CI 0.01–12.79, P = 0.050). Response and remission rates at the end of six infusions did not differ significantly between groups (response: χ2 1df = 0.73, P = 0.39; remission: χ2 1df = 0.56, P = 0.46). During the infusion series, significant differences emerged earlier: at 24 hours after infusion 4 remission favoured six ketamine (54.2% vs 17.9%; χ2 1df = 7.53, P = 0.006), and at 24 hours after infusion 5 response favoured six ketamine (76% vs 39.3%; χ2 1df = 7.25, P = 0.007). Among participants who achieved response after the final infusion (N = 20 in the midazolam-plus-single-ketamine group; N = 19 in the six-ketamine group), Kaplan–Meier estimates of 6-month relapse rates were 75% (95% CI 54.2–95.8%) and 68.4% (95% CI 45.4–91.4%), respectively; the difference in relapse over time was not statistically significant (log-rank χ2 1df = 1.61, P = 0.21). Median time-to-relapse was 2 weeks for the single-ketamine arm and 6 weeks for the repeated-ketamine arm, but the hazard ratio confidence interval and P-value indicated this did not reach statistical significance (P = 0.27). Safety data showed that ketamine infusions produced transient increases in dissociation and blood pressure. During infusions 1–5, CADSS dissociation scores at T +40 min were greater in the ketamine group (mean difference 12.8; ketamine mean = 15.3 vs midazolam mean = 2.5). All dissociative effects resolved within the 2-hour monitoring period and CADSS change was not significantly correlated with antidepressant response. Ketamine was associated with more frequent reports of general malaise, decreased energy, increased blood pressure, headache, fatigue, nausea/vomiting, anxiety and concentration problems compared with midazolam-plus-single-ketamine. Measured systolic and diastolic blood pressures were significantly higher at T +40 min during infusions 1–5 for ketamine (systolic mean difference = 25.6 mmHg, 95% CI 16.4–34.9; diastolic mean difference = 12.9 mmHg, 95% CI 7.2–18.8) and diastolic remained higher at T +100 min (mean difference = 12.9 mmHg, 95% CI 3.6–22.2). Two serious adverse events (post-MRI headache and prolonged headache during follow-up) were reported and judged unrelated to study drugs. Blinding was imperfect: participants were significantly more likely to guess ketamine assignment correctly, and raters’ guesses also differed though not always significantly.

Shiroma and colleagues interpret their results as showing no statistically significant superiority of six ketamine infusions versus a schedule that included five midazolam infusions followed by a single ketamine when the primary outcome was MADRS change at 24 hours after the final infusion. The investigators note, however, that repeated ketamine produced greater antidepressant effects than midazolam before the single ketamine was given, with higher remission and response rates after the fourth and fifth infusions, and that among initial responders repeated ketamine approximately tripled median time-to-relapse (6 weeks versus 2 weeks), although this durability advantage did not reach statistical significance. The authors place their findings alongside earlier studies that reported benefits of repeated ketamine, emphasising that many prior trials were open-label or used saline and that midazolam as an active placebo can yield smaller apparent ketamine effects. They also highlight mechanistic considerations from preclinical and early clinical work suggesting distinct processes for ketamine’s rapid antidepressant action and for maintenance of response, including synaptic plasticity and possible roles for ketamine metabolites and opioid-related pathways. Several limitations acknowledged by the investigators may affect interpretation: the trial was underpowered for smaller but clinically meaningful MADRS differences (they report that ~87 patients per arm would have been required to detect a 4-point difference), the absence of a pure midazolam-only control arm, allowance of stable concomitant psychiatric medications which could interact with ketamine response, and conduct at a single VA site with a predominantly older male sample limiting generalisability. The authors also note that the midazolam dose produced lower dissociative intensity than ketamine and that many participants correctly guessed treatment allocation, reducing the effectiveness of blinding and possibly inflating placebo response. In terms of implications, the study team suggests that repeated ketamine can augment and prolong antidepressant effects relative to active placebo during the acute treatment course, but larger trials are required to confirm whether repeated dosing meaningfully prolongs response over single exposure. They call for further research into mechanisms and into optimising dosing regimens to balance efficacy with minimised exposure and safety concerns.

Acute repeated ketamine produced greater antidepressant effects than midazolam after five infusions, but when a single ketamine infusion was added to the midazolam arm as the final treatment the between-group difference at 24 hours after the last infusion was not statistically significant. Larger, adequately powered studies are needed to determine whether repeated ketamine provides a durable advantage over single ketamine, and mechanistic work should inform optimal dosing strategies that maximise benefit while minimising exposure.