A Double-Blind, Randomized, Placebo-Controlled, Dose-Frequency Study of Intravenous Ketamine in Patients With Treatment-Resistant Depression

This multicentre, double-blind, randomised, placebo-controlled study evaluated two dosing frequencies of intravenous ketamine in adults with treatment-resistant depression. Eligible adults were aged 18-64 years and had treatment-resistant depression; the active treatment was ketamine 0.5 mg/kg administered intravenously over 40 minutes. Patients were randomised to receive ketamine or placebo given either twice weekly or thrice weekly for up to 4 weeks. Patients who discontinued double-blind treatment after at least 2 weeks for lack of efficacy could enter an optional 2-week open-label phase receiving ketamine at the same frequency as in the double-blind phase. The primary outcome was change from baseline to day 15 in total score on the Montgomery-Åsberg Depression Rating Scale (MADRS). Secondary and other assessments included clinician- and patient-rated global impressions (CGI and PGI scales) and the Clinician-Administered Dissociative States Scale (CADSS) to assess dissociative/perceptual changes. Pharmacokinetic sampling for ketamine and norketamine was performed and noncompartmental parameters (including Cmax and AUC6h) were summarised descriptively, with comparisons between day 1 and day 15 planned. The intent-to-treat (ITT) efficacy set comprised all randomised patients who received at least one dose and had baseline plus at least one postbaseline assessment; the safety set included all randomised patients who received at least one dose. For MADRS any missing individual item scores were imputed; for other scales a visit score was left blank if any item was missing. The primary and day-29 MADRS changes were analysed using a mixed-effects model with repeated measures, with baseline MADRS as a covariate, centre and time-by-treatment as fixed effects, and patient as a random effect. The study used a relatively liberal threshold for detecting a therapeutic signal (one-sided alpha of 0.15), and the sample size calculation assumed an 8-point treatment difference on MADRS, yielding a planned 14 patients per group (56 total); in practice 68 patients were randomised and 67 received treatment.

Sixty-eight patients were randomised and 67 received at least one dose of study drug. Efficacy analyses were performed on the ITT set; patients entering open-label treatment were analysed in an open-label ITT set and all treated patients contributed to the safety analyses. On the primary endpoint (change from baseline to day 15 in MADRS score), both ketamine dosing frequencies showed greater improvement than placebo. In the twice-weekly groups the mean change in MADRS at day 15 was −18.4 (SD=12.0) for ketamine versus −5.7 (SD=10.2) for placebo. In the thrice-weekly groups the mean change at day 15 was −17.7 (SD=7.3) for ketamine versus −3.1 (SD=5.7) for placebo. The authors report that MADRS improvement with ketamine progressed through the first 8–11 days and was consistent across time points through day 15. Using responder definitions, reported response rates at day 15 were 68.8% for the twice-weekly ketamine group and 53.8% for the thrice-weekly ketamine group. During the optional open-label phase ketamine showed similar early improvements: twice-weekly open-label dosing reached a mean MADRS change of −12.2 (SD=12.8) by day 4 and thrice-weekly open-label dosing reached −14.0 (SD=12.5) by day 5. The authors note that most participants receiving placebo were nonresponders and discontinued after day 15 to enter open-label ketamine per protocol, though a subset of placebo-treated patients who remained on placebo appeared to respond. Adverse events occurring in 20% or more of ketamine-treated patients included headache, anxiety, dissociation, nausea, and dizziness. Dissociative and perceptual-change adverse events, as measured by CADSS, were transient and attenuated with repeated dosing. Two serious treatment-emergent adverse events were reported in the twice-weekly ketamine group (anxiety and a suicide attempt), and no deaths occurred. The paper indicates pharmacokinetic parameters were summarised and day-15 versus day-1 comparisons of Cmax and AUC6h were planned, but the extracted text does not clearly report the numerical pharmacokinetic results.

Cooper and colleagues interpret their findings as demonstrating that repeated intravenous ketamine at 0.5 mg/kg administered either twice weekly or thrice weekly produced greater antidepressant effects than placebo through day 15 in patients with treatment-resistant depression. Because the magnitude of the antidepressant signal did not differ significantly between the two dosing frequencies, the authors suggest a twice-weekly initiation regimen is sufficient as an initial repeated-dose strategy. They note a progressive increase in response rate beyond the first dose, consistent with prior multiple-dose pilot studies cited in the paper. The authors report that the safety and tolerability profile observed was consistent with earlier studies of ketamine in treatment-resistant depression; dissociative symptoms were generally transient and diminished with successive doses. They acknowledge several limitations: the study’s relatively short duration (induction and maintenance assessed over 4–6 weeks), absence of an active control (which raises the possibility of unblinding due to ketamine’s characteristic adverse effects), and that the trial was not powered to detect statistically significant differences between the two dosing frequencies or to compare adverse-event profiles between ketamine groups. The authors state that longer-duration studies are needed to determine whether clinical benefits of ketamine can be maintained over time and whether dosing frequency can be reduced during chronic treatment.

The study concludes that intravenous ketamine at 0.5 mg/kg administered over 40 minutes, given either twice weekly or thrice weekly, produced significant improvements in MADRS score versus placebo at day 15, with both dosing frequencies similarly maintaining antidepressant efficacy over the study period. Given the comparable effect sizes, a twice-weekly initiation regimen appears sufficient as an initial repeated-dose strategy in patients with treatment-resistant depression. Safety findings were consistent with prior reports, dissociative effects attenuated with repeated dosing, and further, longer-duration studies are recommended to characterise maintenance of benefit and optimal dosing frequency.