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Twice-weekly subcutaneous ketamine injections are safe and highly effective for treatment-resistant depression (TRD), results of a randomized controlled phase 3 trial show.

“In this severely treatment-resistant population, of which 24% had failed to respond to treatment with electroconvulsive therapy, adequately dosed racemic ketamine produced benefits that were large, being both clinically and statistically superior to midazolam,” report the researchers, led by Colleen Loo, quit trazodone MD, MBBS, with Black Dog Institute, University of New South Wales, Sydney, Australia.

The study was published online July 14 in the British Journal of Psychiatry.

Individualized Dosing

“Previously, most studies of racemic ketamine [administered] it by intravenous infusion over half an hour to several hours, which is a much more medically complex and expensive procedure,” Loo told Medscape Medical News.

The fact that subcutaneously administered ketamine was “highly effective” given by this practical and feasible route is a “major contribution to the field,” said Loo.

The Ketamine for Adult Depression (KADS) trial assessed the acute efficacy and safety of a 4-week course of twice-weekly subcutaneous injections of racemic ketamine or midazolam (active control) in 174 adults with TRD.

Initially, the trial tested a fixed dose of 0.5 mg/kg ketamine vs 0.025 mg/kg midazolam (cohort 1; 68 patients). Dosing was subsequently revised, after the data safety monitoring board recommended flexible-dose ketamine (0.5–0.9 mg/kg) or midazolam (0.025–0.045 mg/kg) with response-guided dosing increments (cohort 2; 106 patients).

The primary outcome was remission defined as Montgomery-Åsberg Rating Scale for Depression (MADRS) score ≤10 at week 4.

On this outcome, in the fixed-dose cohort, there was no statistically significant difference in remission rates between ketamine and midazolam (6.3% and 8.8%; odds ratio [OR], 1.34; 95% CI, 0.22 – 8.21, P = .76).

However, there was a significant difference in remission in the flexible-dose cohort, with remission rates 19.6% for ketamine vs just 2% for midazolam (OR, 12.11; 95% CI, 2.12 – 69.17, P = .005).

“The study showed that individualized dose adjustment, based on clinical response, was very important in optimizing the benefit of ketamine,” said Loo.

“It meant that one, you are more likely to respond as you receive a higher dose if needed, and two, you don’t receive a higher dose than needed, given that side effects are also dose-related,” she said.

Results also favored flexible-dose ketamine over midazolam for the secondary outcomes of response (≥ 50% reduction in MADRS: 29% vs 4%; P = .001) and remission defined by a less rigid definition (MADRS ≤ 12: 22% vs 4%; P = .007).

The results also confirm that the antidepressant effects of ketamine are not sustained when treatment stops.

“The study included careful follow-up for 4 weeks after the end of treatment. This is an important contribution to the literature, as it shows that ongoing treatment beyond the 4 weeks will be necessary for most people to maintain the benefits of ketamine treatment if you respond to the treatment. This study provided clear evidence of this, for racemic ketamine,” said Loo.

Overall, ketamine was well-tolerated, with the well-established acute effects of ketamine observed in both cohorts. The acute effects resolved or returned to pretreatment levels within the 2-hour observation period. No one required medical intervention and there was no evidence of cognitive impairment.

Rigorous Research, Compelling Data

Reached for comment, Roger McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, Canada, and head of the Mood Disorders Psychopharmacology Unit, said the data are “compelling with respect to efficacy and safety of subcutaneous ketamine in adults with major depression.”

McIntyre told Medscape Medical News the data are “highly relevant” for several reasons. “First, it is the most rigorous study conducted to-date with subcutaneous administration of ketamine for adults living with treatment-resistant depression.”

Second, it demonstrates the efficacy and safety of this route of delivery, which until now has not been studied with this level of rigor and which is a more scalable and accessible approach to administer ketamine to suitable candidates,” McIntyre said.

The study was funded by a competitive research grant from the Australian National Health and Medical Research Council.  Loo has disclosed relationships with Douglas Pharmaceuticals and Janssen Cilag and is the Medical Director of Neurostimulation and Interventional Psychiatry at Ramsay Health Care. McIntyre has received speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, AbbVie, Atai Life Sciences. McIntyre is a CEO of Braxia Scientific Corp.

Br J Psychiatry. Published online July 14, 2023. Full text

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