RCT · 2026
Repeated IV ketamine did not worsen thinking skills in treatment-resistant depression
- Original title
- Association between Intravenous Ketamine Treatment and Cognitive Function in Patients with Treatment-Resistant Depression: A Double-Blind, Randomized, Placebo-Controlled Trial.
- Authors
- Nomoto K, Ohtani Y, Yatomi T, et al.
- Journal
- Pharmacopsychiatry, 2026
- Molecules
- Ketamine
- Conditions
- Treatment-resistant depression
- Participants
- 34
- Evidence grade
- Moderate
- Source
- Read the original paper
The question
Does a course of intravenous ketamine harm or help thinking skills in people with depression that has not responded to other treatments? And does baseline thinking ability predict who responds?
What they did
Thirty-four Japanese patients with treatment-resistant depression were randomly assigned to receive either ketamine (0.5 mg/kg) or salt water (saline) placebo through a vein, for four doses. Neither patients nor researchers knew who got what. A broad battery of tests measured thinking skills, both objectively (performance tests) and subjectively (self-reported). Depression was rated with the Montgomery-Asberg Depression Rating Scale (MADRS), with response defined as at least a 50% drop in score.
What they found
There were no significant differences between the ketamine and placebo groups in changes on objective or subjective measures of thinking. Among those who took ketamine, people whose depression responded reported significantly greater improvement in their own sense of thinking ability than non-responders. Participants who showed weaker inhibitory control (the ability to hold back an automatic response) before treatment had larger reductions in MADRS depression scores after ketamine.
The fine print
The sample was small (34 people in total, split between two groups), which limits the ability to detect smaller cognitive changes or to be confident about subgroup findings. The analysis linking baseline thinking ability to treatment response was exploratory, not a planned primary test. The abstract does not report how long participants were followed after the four doses, and the participants were all from one country. This summary is based on the abstract only.
What it means
In this small trial, four ketamine infusions did not appear to worsen thinking skills compared with placebo, which is reassuring for cognitive safety, though larger studies are needed to confirm this and to test whether baseline cognitive control really predicts who benefits.
Evidence grade: Moderate. A double-blind, randomized, placebo-controlled trial, but with only 34 participants and cognitive outcomes measured alongside the main depression study.
This summary is based on the study’s published abstract.