Placebo-controlled pilot trial testing dose titration and intravenous, intramuscular and subcutaneous routes for ketamine in depression

Objective This pilot study assessed the feasibility, efficacy and safety of an individual dose‐titration approach, and of the intravenous (IV), intramuscular (IM) and subcutaneous (SC) routes for treating depression with ketamine. Method Fifteen treatment‐refractory depressed participants received ketamine or midazolam (control treatment) in a multiple crossover, double‐blind study. Ketamine was administered by IV (n = 4), IM (n = 5) or SC (n = 6) injection. Dose titration commenced at 0.1 mg/kg, increasing by 0.1 mg/kg up to 0.5 mg/kg, given in separate treatment sessions separated by ≥1 week, with one placebo control treatment randomly inserted. Mood, psychotomimetic and hemodynamic effects were assessed and plasma ketamine concentrations assayed. Results Twelve participants achieved response and remission criteria, achieved at doses as low as 0.1 mg/kg. All three routes of administration resulted in comparable antidepressant effects. Fewest adverse effects were noted with the SC route. Antidepressant response, adverse effects and ketamine concentrations were dose‐related. Conclusion Antidepressant response occurred at a range of doses and at