Adequately dosed racemic ketamine shots beneficial in treatment-resistant depression

A 4-week course of racemic ketamine, when given by subcutaneous injection at adequate doses, appears to be safe and efficacious in people with treatment-resistant depression, according to a phase III trial.

Conducted at seven centres across Australia and New Zealand, the trial included adults with major depressive disorder of at least 3 months’ duration, insufficient response to at least two adequate trials of antidepressant medications, any concurrent antidepressant medication at stable dosage ≥4 weeks prior to and during the trial, and a score of ≥20 on the Montgomery–Åsberg Rating Scale for Depression (MADRS).

The participants were randomly assigned to receive twice-weekly subcutaneous racemic ketamine or midazolam for 4 weeks. Initially, the participants were given fixed-dose ketamine 0.5 mg/kg vs midazolam 0.025 mg/kg (cohort 1). Following a Data Safety Monitoring Board recommendation, dosing was revised to flexible-dose ketamine 0.5–0.9 mg/kg or midazolam 0.025–0.045 mg/kg, with response-guided dosing increments (cohort 2).

The final analysis included 68 participants in cohort 1 (fixed dose) and 106 in cohort 2 (flexible dose). At the end of treatment at week 4, the primary outcome of remission (MADRS score ≤10) occurred with greater frequency with ketamine than with midazolam in cohort 2 (19.6 percent vs 2.0 percent; odds ratio [OR], 12.1, 95 percent confidence interval [CI], 2.1–69.2; p=0.005).

There was no significant between-group difference seen in cohort 1 (remission rate, 6.3 percent vs 8.8 percent; OR, 1.3, 95 percent CI, 0.2–8.2; p=0.76).

Ketamine was well tolerated. Acute adverse effects such as psychotomimetic and elevations in blood pressure all resolved within 2 hours.

The present data suggest that the subcutaneous route for racemic ketamine is practical and feasible.