Once-Weekly Ketamine Infusions Keep Resistant Depression at Bay

Batya Swift Yasgur, MA, LSW

April 11, 2019

Weekly ketamine infusions have rapid, cumulative, and sustained antidepressant effects in people with treatment resistant depression (TRD), new research suggests.

Investigators randomly assigned 41 participants with TRD using a double-blind crossover model to compare single infusions of ketamine to midazolam, a short-acting benzodiazepine that served as a placebo control.

Participants who relapsed after their first infusion received a course of 6 open-label ketamine infusions, administered three times weekly over a 2-week period.

Patients who received a single ketamine infusion showed greater reduction in depressive symptoms compared with those who received midazolam, and repeated infusions doubled the antidepressant response rate.

"This is the first study to my knowledge that has shown we can decrease the frequency of the [ketamine] infusions once somebody has had a response, and still maintain the antidepressant effects," lead author Jennifer L. Phillips, PhD, from the Royal's Institute of Mental Health Research in Ottawa, Canada, told Medscape Medical News.

"Through this study, we were able to test a much more practical way of administering ketamine in a clinical setting," she said.

The study was published online March 29 in the American Journal of Psychiatry.

Filling a Treatment Gap

"The study was motivated by two major unmet needs in the treatment of depression, namely the need for medications that elicit higher response and remission rates for patients and the need for medications with faster antidepressants effects," Phillips said.

"Relative to other medications used to treat depression, ketamine has these unique properties," she added.

However, although ketamine "elicits a rapid decrease in depressive symptoms, its effects are not long lasting, so the goal of our study was to better understand how we can best administer ketamine to maximize and prolong its antidepressant effects," Phillips said.

To investigate the question, the researchers randomly assigned 41 adults with TRD (mean [SD] age 41.7 [12.3] years, 56% female) to 1 of 2 groups, which were compared in a three-phase process.

Participants were required to meet DSM-IV-TR criteria for major depressive disorder (MDD) and to be treatment resistant (defined as failure to respond to two or more antidepressant medications of different pharmacologic classes and two augmentation strategies at adequate doses for 6 or more weeks each during the present episode).

In addition, participants were required to score 25 or higher on the Montgomery-Åsberg Depression Rating Scale (MADRS) at screening and randomization, with no more than 20% improvement between these visits.

In phase 1, participants were randomly assigned 1:1 to receive a single infusion of either ketamine or midazolam and were then "crossed over" to receive the opposite infusion from what they had initially received.

"After either 7 days or return of depressive symptoms (if the participant had an antidepressant response to the first drug), participants received a single infusion of the second drug and we measured change in depressive symptoms with each medication," said Phillips.

To be considered to have relapsed into depression, participants were required to have a return of 80% of their baseline MADRS score to proceed to the second phase 1 infusion, and then to begin phase 2. The goal of phase 2 was to test reinstatement of antidepressant response after relapse and evaluate the efficacy of repeated infusions.

During phase 2, participants who had relapsed received a course of 6 open-label ketamine infusions, administered three times a week over a 2-week period.

Those who experienced an antidepressant response to ketamine (defined as a ≥50% decrease [improvement] on the MADRS total score from baseline until post-phase 2 assessment) entered phase 3.

The goal of phase 3 was to test maintenance of the antidepressant effects when the frequency was reduced to once-weekly infusions for an additional 4 weeks.

Those who did not respond to ketamine during phase 2 exited the study.

"The benefit of a crossover design is that each participant acts as their own control, and we can directly compare the antidepressant effects of each medication being tested in the same individuals," Phillips explained.

Not a Placebo Response

Participants who completed phase 1 received the two infusions an average (SD) of 10 (6) days apart.

The researchers used random-effects modeling, adjusted for baseline MADRS score and order of drug administration, and found significant main effects for drug (F = 8.84; df = 1, 40; P < .001) and time (F = 30.77; df = 3, 40; P < .001).

There was also a significant drug-by-time interaction (F = 13.15; df = 3, 40, P < .001).

Simple-effects analyses showed that participants had significantly lower MADRS total scores at each post-infusion time point after ketamine infusion compared with midazolam infusion.

Researchers noted that 24 hours after infusion with ketamine, participants had a mean decrease of 10.9 points (SD = 8.9) in MADRS total score relative to pre-infusion scores, compared with a mean decrease of just 2.8 points (SD = 3.6) with midazolam.

Moreover, when the model covariates were examined, significant main effects for baseline MADRS total score (F = 359.95; df = 1, 37; P < .001) and order of drug administration (F = 4.24; df = 1, 37; P = .047) were found, "indicating carryover effects between phase 1 infusions."

Twenty-four hours after the single ketamine infusion, 27% of participants met antidepressant response criteria and 5% achieved remission.

Notably, no participants met antidepressant response criteria with midazolam at any post-infusion time point.

"In our study, we saw that individuals who had a decrease in depressive symptoms with ketamine did not have this response when treated with comparison medication [midazolam], thus we can infer that the decrease in depressive symptoms seen with ketamine is not due to a placebo response, which helps to demonstrate its efficacy," Phillips said.

Novel Maintenance Strategy

The researchers used a random-effects model adjusted for participant and depression severity at the start of phase 2 and found a significant main effect for time (F = 11.16, df = 6, 39, P < .001).

Participants' MADRS total score decreased by 2 points (on average) with each infusion.

Of the phase 2 participants treated, 39 completed the full course of infusions. Of these 39 who finished, 23 (59%) met antidepressant response criteria and 9 (23%) achieved remission.

The median number of infusions that participants needed to first meet response criteria was three. Of phase 2 responders, 77% received 3 or more infusions before meeting response criteria.

Phase 3 consisted of 23 participants who had ≥50% improvement in MADRS scores after repeated infusions.

A linear mixed model adjusted for the random effect of participant and phase-specific baseline depression severity found no further change in MADRS score once ketamine infusions were reduced to once per week.

Antidepressant response criteria were met in 91% of phase 3 participants through maintenance infusions.

There were no serious adverse events reported during the trial; the most common ketamine-associated side effects were cardiorespiratory effects, numbness or tingling, dissociation, dizziness, and visual disturbances.

"In our trial, we first demonstrated that a single infusion of ketamine was better at decreasing depressive symptoms than a placebo medication," Phillips summarized.

"We showed that administering a series of repeated ketamine infusions resulted in further decrease in depressive symptoms with each infusion and a doubling in the number of patients who responded to ketamine treatment," she continued.

"Third, we tested a novel maintenance strategy and showed that ketamine's antidepressant effects could be maintained when we reduced the frequency of infusions to once weekly."

Artificially Unblinded?

Commenting on the study for Medscape Medical News, Dan V. Iosifescu, MD, associate professor of psychiatry, NYU Langone School of Medicine, New York City, called it "important and interesting," but stated that the researchers "are trying to make it appear much bigger than it is."

Iosifescu, who was not involved with the current research, said it was "strange" to him "that the initial infusion in this crossover study ended up with a zero percent response to the comparator. It's unusual in any depression study that there would be a zero percent response in an inactive comparator, especially in a fairly robust sample."

Iosifescu, who also heads the Clinical Research department at the Nathan Kline Institute for Psychiatric Research, pointed out that "ketamine and the placebo are significantly different, and because there are symptoms you get with ketamine that you don't get with midazolam, it's not that hard for the person taking both to figure out which one is the ketamine, making the design artificially unblinded."

He noted that in the last few years, "several studies, including one of my own, have looked at multiple administrations of either ketamine or the newly FDA-approved esketamine [Spravato, Janssen], so we already know that this works in a subset of individuals."

The study, however, has some important take-home points, Iosifescu said.

"After an initial response to a more frequent series of treatments, continuing a little while longer with once-weekly treatment may be beneficial in maintaining the response," he said. However, "even after all of this, the likelihood of people staying well, and the time that they're going to stay well, is relatively brief since most people do relapse after a relatively short period of time."

For this reason, "maintaining a response will require continuing [treatment] and you need to do something else," Iosifescu added.

The researchers remain optimistic that conquering treatment resistant depression is a battle that can be won. "This [study] and future clinical studies can provide essential information on effective administration strategies that will permit sustained therapeutic benefits for patients [with treatment resistant depression]," the authors state.

The study was supported by the Canadian Institutes of Health Research and a Tier 1 Canada Research Chair. Phillips has disclosed no relevant financial relationships. The other authors' disclosures are listed on the original paper. Iosifescu has disclosed no relevant financial relationships.

Am J Psychiatry. Published online March 29, 2019. Abstract

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