Oral prolonged-release ketamine in treatment-resistant depression - A double-blind randomized placebo-controlled multicentre trial of KET01, a novel ketamine formulation - Clinical and safety results

Treatment-resistant depression (TRD), commonly defined as insufficient response to multiple adequate antidepressant trials, affects roughly 20–30% of people with major depressive disorder and is associated with higher mortality and poorer quality of life. Ketamine and its S-enantiomer esketamine have shown rapid antidepressant effects when administered intravenously or intranasally, but these routes produce rapid peak plasma concentrations that require supervised administration and are associated with transient increased blood pressure, sedation and perceptual changes. Oral ketamine has been explored previously and offers practical advantages including easier, at-home dosing and lower cost, but oral bioavailability is lower and onset of effect tends to be slower than parenteral routes. Colla and colleagues evaluated KET01, a novel prolonged-release oral racemic ketamine tablet, as an add-on treatment for adults with TRD. The study was conceived as a Phase II proof-of-concept, randomised, double-blind, placebo-controlled trial testing two dose levels (160 mg/day and 240 mg/day, given as twice-daily dosing) administered for 14 days, with the primary efficacy endpoint being change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to day 15. The investigators aimed to assess both clinical efficacy and safety/tolerability of this formulation when added to ongoing antidepressant therapy.

The trial ran from April 2019 to December 2021 across three Swiss psychiatric hospitals, with a recruitment hiatus during the height of the COVID-19 pandemic. Ethics approval was obtained and the trial was registered with the Swiss National Clinical Trials Portal. This was an investigator-initiated, randomised, double-blind, placebo-controlled multicentre study. Participants aged 18–70 years with an ICD-10 diagnosis of a major depressive episode and a MADRS score ≥19 were eligible if they met a definition of treatment resistance (inadequate response to at least two adequate antidepressant trials). Major exclusions included serious medical comorbidity, BMI <18 or >30 kg/m2, schizophrenia-spectrum or dementia, active suicidality, and current substance dependence other than nicotine. KET01 was given as adjunctive therapy to patients’ ongoing antidepressant medication without washout. Randomisation used computer-based block randomisation (block size 6) stratified by age (<40 / ≥40 years), sex, and body weight (<70 kg / ≥70 kg) in a 1:1:1 ratio to placebo, KET01 160 mg/day (80 mg twice daily) or KET01 240 mg/day (120 mg twice daily) for 14 days. Sample size calculations had targeted 33 patients per arm (allowing for 10% drop-out) to detect a Cohen's d of 0.8, but recruitment was curtailed. The primary outcome was change in MADRS from baseline to day 15, with MADRS also measured on days 1, 2, 4, 7 and 11 to characterise onset and trajectory. Safety assessments included adverse event (AE) monitoring, Suicide Status Form-II (SSF-II), Dissociative Symptom Scale-4 (DSS-4), vital signs (blood pressure and heart rate) and routine labs including white blood cell (WBC) count; detailed safety methods were reported in a supplement. The primary efficacy analysis used analysis of variance (ANOVA) with pairwise least-squares comparisons, and a mixed model for repeated measures (MMRM; a model that accounts for within-subject repeated observations) was applied post hoc. Standardised effect sizes (Cohen's d) were reported where appropriate. Analyses included all participants who received at least one dose of study medication.

Screening and enrolment were substantially affected by recruitment difficulties during the COVID-19 pandemic. Of 1,819 patients screened, 1,422 were excluded for at least one criterion and 335 did not meet TRD criteria; 30 of 62 eligible patients consented, but two withdrew before dosing and one had pre-existing hypertension, yielding 27 participants who received study medication. All 27 completed the double-blind phase: seven were assigned to KET01 160 mg/day, ten to KET01 240 mg/day and ten to placebo. MADRS scores fell significantly from baseline to day 15 within each arm. Reported mean reductions (with 95% CIs) were: placebo −8.7 units (95% CI −13.16 to −4.24), KET01 160 mg/day −7.43 units (95% CI −12.76 to −2.10), and KET01 240 mg/day −12.4 units (95% CI −16.86 to −7.94). Between-group comparisons favoured the 240 mg/day arm numerically: at day 7 the 240 mg/day group showed an improvement of 5.67 MADRS units versus placebo, and at day 15 the difference was 4.99 units; these differences did not reach statistical significance (the reported p-value for day 15 was p = 0.1499). The trial therefore observed a numerical, clinically suggestive effect for the 240 mg/day dose but was underpowered to confirm efficacy. In exploratory analyses, baseline WBC (leukocyte) count was associated with antidepressant response to KET01. A repeated-measures ANCOVA identified a significant WBC × time interaction (df = 6, F = 6.337, p = 0.03). Combining the KET01 dose groups, the MADRS difference score (day 15 − day 2) correlated with baseline leukocytes: Pearson r = −0.693 and Spearman's rho = −0.585 (p = 0.0136), indicating that higher baseline leukocyte counts were associated with greater MADRS reductions on active treatment; no such relationship was seen in the placebo group. Safety and tolerability findings were broadly favourable. Frequency of adverse events did not differ markedly between arms. Repeated-measures ANOVA of SSF-II core scores showed an overall time effect (p = 0.008) but no group × time interaction; there were no significant effects or interactions for SSF-II risk, DSS-4 scores, heart rate, systolic or diastolic blood pressure. The investigators reported no increase in suicidality, dissociation, blood pressure or heart rate attributable to KET01 during the double-blind period, and dissociative symptoms were in fact lower in the active groups than in placebo in this sample.

Colla and colleagues interpret their findings as indicating that adjunctive prolonged-release oral ketamine at 240 mg/day produced a numerical, clinically relevant reduction in depressive severity compared with placebo (approximately −5.7 units at day 7 and −5.0 units at day 15), but the differences did not achieve statistical significance owing to early termination and consequent underpowering. The trial experienced a high placebo response, which the authors note is common in depression research and may have been amplified here because patients knew there was a 2 in 3 chance of receiving active drug, potentially increasing expectation effects. The investigators place their results in context with prior ketamine studies: the magnitude of within-group MADRS reductions in the active arms (7.4 units for 160 mg/day and 12.4 units for 240 mg/day at day 15) aligns with some oral ketamine reports but is generally lower than reductions typically seen with intravenous ketamine infusions or intranasal esketamine in some trials. They highlight several methodological and pharmacokinetic considerations that may explain a reduced effect size here, including the prolonged-release formulation which produces lower peak blood levels, the relatively short 14-day observation period that may have missed a delayed onset, and the very severe and chronic illness profile of the enrolled patients. The observed association between higher baseline leukocyte counts and greater response to KET01 is discussed as consistent with hypotheses that ketamine’s effects may involve immune modulation; the authors reference emerging literature linking inflammatory mediators to ketamine response and suggest that if replicated, baseline inflammatory markers could help predict treatment response. Safety conclusions emphasise good tolerability for KET01 in this small sample with no clinically relevant increases in vitals or dissociative symptoms compared with placebo. Key limitations acknowledged by the investigators include premature trial termination leading to a small sample size, limited statistical power, short treatment and follow-up duration, and the potential impact of high expectancy and placebo response. The authors note that these constraints prevent confirming efficacy and recommend larger, longer trials; they report that a larger international multicentre study is underway with modified design features (placebo, 120 mg/day and 240 mg/day arms, three-week treatment) to more definitively assess oral prolonged-release ketamine as an accessible treatment option for TRD.