This randomised, double-blind, active placebo-controlled crossover trial (n=30) investigates the short-term efficacy of ketamine for patients with treatment-resistant depression (TRD).
Randomised, double-blind crossover comparing single IV ketamine (bolus 0.25 mg/kg then infusion 0.25 mg/kg/hr for 45 minutes) with an active remifentanil comparator; 3-week washout between sessions.
Primary outcome assessed with MADRS; ancillary measures include plasma BDNF at 4 hours post-intervention and follow-ups at days 1, 7, 14 and 21 during a 42-day study period.
Single IV ketamine session (bolus + short infusion) as active treatment in crossover.
IV bolus 0.25 mg/kg then infusion 0.25 mg/kg/hr for 45 minutes.
Active placebo comparator using remifentanil target-controlled infusion.
Target-controlled remifentanil infusion to a 1.7 ng/mL plasma concentration over 9 minutes; active placebo in crossover.
In 32 people with major depressive disorder given subanaesthetic ketamine versus an active placebo, larger 24‑hour antidepressant responses correlated with psychedelic dimensions (spirituality, unity, insight) and qualitative interviews documented pervasive perceptual changes, loss of control, emotional shifts and a lasting afterglow that altered perspectives on life and treatment. These findings give preliminary evidence that the acute psychedelic experience and afterglow contribute to ketamine’s antidepressant effects and that common questionnaires may not fully capture its phenomenology.