Medications don’t augment ketamine, but psychotherapy has promise
STUDY: Janssen-Aguilar R et al, Journal of Affective Disorders 2026
STUDY TYPE: Systematic review and meta-analysis
FUNDING: Independent
Background
Ketamine is often used when antidepressants don’t work. But does anything augment ketamine? Seven randomized trials have attempted to, and this review analyzes them.
The Study
- Seven randomized trials, 346 adults with treatment-resistant depression, in the United States and Taiwan.
- Ketamine plus glutathione, riluzole, lamotrigine, lithium, D-cycloserine, cognitive behavioral therapy, or a brief cognitive-training program, against ketamine plus placebo, sham, or usual care.
- Follow-up from 24 hours to 14 weeks.
Results
Ketamine improved depression in every trial, but none of the five pharmacologic augmentations beat placebo.
Therapy approaches performed better. The authors looked at two trials, and a third was published as the analysis was going to press.
- CBT: outperformed treatment as usual in two small trials, although in only the secondary outcomes were positive in one of them. These studies used traditional CBT, starting two weeks after the infusions (not ketamine assisted therapy).
- Cognitive-training program: This computer assisted program is based on positive psychology and is undertaken during ketamine infusions. It improved response rates at 24 hours (52% versus 25%).
Side Effects
Lithium and D-cycloserine added sedation and tremor.
Limitations
Seven small trials, 26 to 154 patients each, used different add-ons and follow-up windows, making this estimate exploratory. Most trials raised some concern on bias, and GRADE certainty was low. The cognitive training program is a patented product and the study had financial ties to the developer.
Practice Implications
- Lithium may extend the benefits of ECT and TMS, but it does not augment ketamine; nor does glutathione, riluzole, lamotrigine, and D-cycloserine.
- Therapy has potential, particularly for maintaining benefits. This makes sense. Other trials show better preventative effects with psychotherapy than antidepressants in depresison.
—Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
