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Brief Cognitive Training May Extend the Antidepressant Effects of Ketamine

Research Highlight

Many effective treatments are available for depression, but some people continue to have debilitating symptoms even after trying several antidepressant medications. For these people, ketamine can be a helpful treatment option. A study supported by the National Institute of Mental Health (NIMH) suggests that a brief cognitive training program after a single ketamine infusion can help extend the antidepressant effects of ketamine over at least 30 days.

A key advantage of ketamine is that it works quickly—most people report their symptoms easing within hours. However, unlike more common antidepressant medications, ketamine must be administered by a certified health care provider in a clinical setting. And although ketamine may act rapidly, most people require more than one treatment session to see lasting effects.

Research suggests that ketamine has molecular effects that lead to new connections between brain cells and a period of brain plasticity that promotes learning. In a clinical trial, Rebecca Price, Ph.D. , of the University of Pittsburgh School of Medicine, and colleagues tested whether introducing an automated training program during this hypothesized window of plasticity might shift participants’ negative self-beliefs, a hallmark feature of depression. They hypothesized that this self-association training program could help extend the antidepressant effects of ketamine.

The trial was supported by an NIMH Biobehavioral Research Award for Innovative New Scientists, which aims to encourage potentially transformative research from exceptional early stage researchers.

The clinical trial included 154 participants with treatment-resistant depression. The researchers randomly assigned participants to one of three treatment groups:

  • ketamine infusion plus self-association training
  • placebo saline infusion plus self-association training
  • ketamine infusion plus placebo cognitive training

The participants received an infusion (either ketamine or saline) in the lab. Over the following 4 days, they completed a cognitive training program (either self-association training or placebo) via laptop computer, which took about 30-40 minutes each day. The researchers continued to measure participants’ depression symptoms over a 30-day follow-up period.

Participants who received the self-association training viewed pairings of words and images that reinforced associations between positive traits and self-referential stimuli. For example, participants might see words like “sweet” and “attractive” and photos of smiling actors paired with a photo of themselves. Participants who received the placebo cognitive training also saw word and image pairings, but the pairings were neutral and not self-referential.

Consistent with previous findings, the two groups that received the ketamine infusion showed a drop in depression symptom scores within 24 hours. However, for participants who received ketamine and the placebo cognitive training, those depression scores gradually rose over the following 30 days. By comparison, depression scores remained low and stable for those who received ketamine and the implicit association training.

The study is noteworthy for its relatively large sample size and randomized clinical trial design. These strengths lend weight to the findings, although additional studies are needed to confirm these results. Further research can help clarify whether the effects are specific to the self-association training or extend to other types of brief cognitive training.

If the observed effects are replicated, this combined treatment approach could offer a safe, low-cost, portable means of enhancing ketamine treatment for people with treatment-resistant depression.


Price, R. B., Spotts, C., Panny, B., Griffo, A., Degutis, M., Cruz, N., Bell, E., Do-Nguyen, K., Wallace, M. L., Mathew, S. J., & Howland, R. H. (2022). A novel, brief, fully automated intervention to extend the antidepressant effect of a single ketamine infusion: A randomized clinical trial. The American Journal of Psychiatry, 179(2), 959–968. 



Clinical Trial