Carefully designed, exquisitely controlled experiments sometimes don't produce the result predicted in advance—the research “hypothesis” that is the starting point for a program of research. That is one way in which science advances: in some instances, failure of the hypothesis actually shines new light, and unexpectedly generates new, positive knowledge about the question.

This is precisely what happened when a team that included eight BBRF grantees, prize winners and Scientific Council members put to the test an idea they had about how the drug ketamine functions in the brain to produce antidepressant effects that within hours can dramatically help patients who have been highly resistant to multiple other forms of antidepressant treatment.

John H. Krystal, M.D. and Gerard Sanacora, M.D., Ph.D., both BBRF Scientific Council members and recipients of multiple BBRF grants, were senior members of a team at Yale University that, with first author Chadi G. Abdallah, M.D., a 2014 and 2012 BBRF Young Investigator, and others, proposed to extend a finding from animal tests to human subjects. Their surprising results appeared in the journal Neuropsychopharmacology.

In rodents that modeled depression, it had been previously shown that a drug called rapamycin (generic name sirolimus), when administered prior to an infusion of ketamine, prevented ketamine from alleviating depressive-like symptoms in the animals. This was interesting for several reasons, among them that rapamycin is known to block a protein complex called mTORC1, which separate research has suggested is an important mediator of ketamine’s action in the brain.

The team’s hypothesis was simple: is it true that in depressed people, as in rodents, administering rapamycin before giving a dose of ketamine will diminish or block ketamine’s remarkable antidepressant effects? The expected answer—yes—would tend to confirm what was thought about the importance of mTORC1 in ketamine’s therapeutic effects in people.

Serious study of ketamine as an antidepressant began in the laboratories of Dr. Krystal and then-mentor and Yale collaborator Dennis Charney, M.D., in the early 1990s. The BBRF awarded both men the Colvin Prize in 2019 for Outstanding Achievement in Mood Disorders Research, for laying scientific foundations for the development of esketamine, approved by the FDA last year as the first rapid-acting antidepressant.

Drs. Krystal, Sanacora, Abdallah, and colleagues established in a small group of patients that rapamycin and ketamine could be administered safely together, clearing the way for a randomized placebo-controlled trial. The group of 23 patients with active, treatment-resistant depression was randomized, with one subgroup receiving rapamycin followed 2 hours later by a ketamine infusion, the other subgroup receiving placebo followed by ketamine. After two weeks, the groups “crossed over,” switching roles, one getting placebo plus ketamine, the other rapamycin plus ketamine. Doctors and patients were blinded throughout the trial, so no one knew who was getting placebo or rapamycin at any point.

The results were a real surprise, in two major respects. First, results of the rodent experiments were not confirmed in people: patients who received 6 mg of oral rapamycin received just as great a benefit from ketamine after 24 hours as those who received placebo. Rapamycin blocks mTOR1, but does not in itself prevent ketamine from exerting rapid antidepressant effects.

The second surprise delighted the research team. When patients took rapamycin prior to receiving ketamine, 41% still showed a clinical antidepressant response after two weeks, with 29% in full remission. This compared with 13% response and 7% remission when placebo was given prior to ketamine instead of rapamycin. In other words, rapamycin pretreatment apparently extended ketamine’s antidepressant effectiveness, for at least some patients.

“While preliminary, the unanticipated finding of prolonged response is highly important,” the researchers wrote, “considering the urgent need for treatment approaches to prolong the antidepressant effects of ketamine and other rapid-acting antidepressants.” In most patients, when ketamine is given alone, its effects are robust for several days and fade after about a week.

Even as failure occasionally generates new insight, sometimes, as in this case, it suggests new paths. While the pharmacology of both ketamine and rapamycin are complicated, one point that intrigues researchers is that rapamycin is a potent suppressor of inflammation. Inflammation has often been suspected of involvement in the biology of depression, although the details remain obscure. The research team speculates that the anti-inflammatory effects of rapamycin may protect new or restored synaptic connections between neurons in the cortex that are forged after an infusion of ketamine.

The “failure” of the hypothesis in this study is therefore likely to generate much additional research, which promises to not only explain why ketamine acts as it does, but to find even better molecules that can sustain antidepressant effects, ideally, indefinitely—what might be thought of as a cure. “The ultimate goal is and should be to find a cure for clinical depression and related illnesses,” Dr. Abdallah commented. “These unexpected rapamycin findings may have got us a step closer toward realizing this goal. As a field, we next need to figure out how to maintain the restored synaptic and functional connections following ketamine treatment, and how to prevent the relapse of depressive symptoms.”

Among others, the Yale research team also included: the late Ronald S. Duman, Ph.D., 2005 BBRF Distinguished Investigator, 2002 Falcone Prize winner, 1997 Independent Investigator and 1989 Young Investigator; Deepak Cyril D’Souza, M.D., 2013 BBRF Independent Investigator; Kyung-Heup Ahn, M.D., 2009 BBRF Young Investigator; Mohini Ranqanathan, M.D., 2007 BBRF Young Investigator; and Lynette Averill, Ph.D., 2015 BBRF Young Investigator. In addition to serving on the BBRF Scientific Council, Dr. Krystal is a 2006 and 2000 BBRF Distinguished Investigator and 1997 Independent Investigator; Dr. Sanacora is a 2014 BBRF Distinguished Investigator, 2007 Independent Investigator, and 2001 and 1999 Young Investigator.