The experimental drug ketamine has been shown to reduce symptoms of major depression, even in treatment-resistant patients, within hours of a single intravenous administration.  A medicine based on ketamine—a chemical derivative called esketamine—was approved by the FDA for use in treatment-resistant depressed patients in 2019.

Yet the search continues for better versions of ketamine. This includes drugs that might act as rapidly to reduce major depression symptoms but which have fewer risks of adverse side effects, as well as agents with a longer-lasting antidepressant effect. In most patients, ketamine’s therapeutic effects fade within a week, at which point the underlying depression reasserts itself. Some patients have received repeated ketamine infusions over a period of months to maintain the antidepressant effect.  The safety profile of this strategy remains uncertain, however.

A team of researchers led by Rebecca B. Price, Ph.D., of the University of Pittsburgh School of Medicine, now report in The American Journal of Psychiatry that they have tested a way of extending ketamine’s antidepressant effect. It involves pairing a single intravenous administration of ketamine in treatment-resistant patients with a computer-administered training procedure given in the days following the treatment. Results were encouraging.

A randomized, double-blinded trial conducted by Dr. Price and colleagues who included Robert H. Howland, M.D., a 1991 BBRF Young Investigator, and Sanjay J. Mathew, M.D., a 2009 BBRF Independent Investigator and 2006 and 2001 Young Investigator, was performed with a study cohort of 154 adults with treatment-resistant depression, most in the their 30s and 40s.

The participants were divided randomly into 3 groups. One group (53 participants) received a single treatment of ketamine plus a series of computer-administered training sessions called ASAT that are designed to increase self-esteem.  A second group (50) received a placebo injection instead of ketamine plus the ASAT training. A third group (50) received ketamine and a placebo version of ASAT training.  

ASAT stands for Automated Self-Association Training.  Dr. Price and her team wanted to test it in connection with a hypothesis they hold about how ketamine exerts its therapeutic effects.  The team posits that one central reason ketamine works is because it causes a rapid and pronounced increase in the plasticity of neurons and brain circuits.  Plasticity refers to the ability of brain cells to change the strength of their connections.  It is widely thought that increases in plasticity are at least part of, and may be central to, the antidepressant effect, of ketamine and possibly other existing depression treatments.

“We have hypothesized that these [plasticity] effects [rapidly induced by ketamine] may produce a corresponding neurocognitive shift,” the team noted in its paper. It was their hope that “we can extend rapid mood relief during a window of opportunity, using behavioral learning-based approaches.”

The approach they used, ASAT, is designed “to reinforce adaptive patterns of cognition through automated [i.e., computer-administered] training.”  By adaptive, the team means patterns of behavior that help the individual adapt to or cope with challenges. This is relevant because depression is typically associated with low self-esteem and chronic, repetitive patterns of negative thinking.  

The idea of using the ASAT training program following a single ketamine treatment was that the drug would boost plasticity and thus mood, opening a “window of opportunity” in which the ASAT training might “consolidate beneficial processing patterns and prolong ketamine’s rapid [positive] mood effects.”

Nearly all of the participants in the trial—148 of the initial 154—received full courses of either ASAT training or a placebo version of it, following a single ketamine treatment or a placebo version of one. The training was given in the 4 days following ketamine or placebo injection being administered.  Two training sessions of about 20 minutes were given each of those days.

In those who received both “active” ketamine and ASAT, the team found that ketamine’s initial antidepressant effect was extended for at least 30 days.  (In-person trial monitoring ended at that point, although a questionnaire-based follow-up will continue for a year, and results will be forthcoming.)  Trial participants who received a placebo injection but an “active” version of ASAT training received relatively little benefit over the 30-day period. Those who received active ketamine and a placebo version of ASAT responded over the month as do most patients who take only ketamine; their depression symptoms steadily returned.  

The team offered this conclusion: “After priming the brain with ketamine, training positive self-associations could provide an efficient, low-cost, portable, noninvasive, and highly dissemination-ready strategy for leveraging and extending ketamine’s rapid antidepressant effects.”

Larger trials involving more diverse patient populations must follow this initial study, the team said, before ASAT or similar strategies might be paired with rapid-acting antidepressants including ketamine to extend their therapeutic effects.