In a new study from Stanford University, when researchers compared intravenous ketamine to an active placebo, the supposed rapid antidepressant effect of ketamine disappeared. The drug failed to beat the placebo for treating depression.
“A single dose of intravenous ketamine compared to placebo has no short-term effect on the severity of depression symptoms in adults with major depressive disorder,” the researchers write.
Additionally, one patient died of a heart attack in the ketamine group, although this was considered unrelated to the ketamine infusion.
The article was posted before peer review on the preprint server medRxiv.org.
The benefit of ketamine, according to its proponents, is that it has a rapid but transient antidepressant effect—an effect noticeable within hours of use and which peaks within a few days before declining.
However, ketamine has many effects that make it challenging to do a genuinely blinded trial, such as dizziness, nausea, and dissociative states. Because of these effects, patients are easily able to guess whether they are actually receiving ketamine or not. Thus, some researchers have suggested that the placebo effect is responsible for much of the improvement seen in the clinic.
To gain a clearer picture of the drug’s effects, an active placebo must be used—a drug that causes similar side effects but doesn’t have the same proposed antidepressant properties. In this case, the researchers used surgical anesthesia as the active placebo. (Ketamine itself is an anesthetic drug.)
The researchers, led by Theresa Lii and Boris Heifets at Stanford University, recruited 40 participants (70% female; 65% white), all of whom were experiencing a diagnosed episode of major depression for at least a month. They were gathered from people who were going to undergo surgery, which allowed the researchers to give them the anesthetic as an active placebo. During surgery, all participants were given standard surgical anesthetic; half were randomly assigned to receive ketamine.
The study was triple-blinded, meaning that none of the participants, anesthesiologists, or researchers knew whether the participant was given ketamine or not until after the study.
The researchers then followed up with the participants at 1 day, 2 days, and 3 days afterward, as well as later time points (5, 7, and 14 days) for other analyses. The primary outcome was a change in MADRS depression score (a 60-point scale); the secondary outcome was clinical response on the MADRS; other outcomes included remission rates on the MADRS, HADS score (a 42-point anxiety and depression self-report scale), pain intensity, and opioid use.
On the primary outcome of change in depression severity, there was no significant difference between groups at any time point. No matter how the change in MADRS score was measured (the researchers used a couple of different statistical methods), those who received ketamine did not improve any more than those who received the placebo.
“Depression scores at 1, 2, and 3 days post-infusion did not differ between trial groups,” the researchers write.
On the secondary outcome, response to treatment (defined as a 50% reduction in MADRS score), 60% of those who received ketamine (12 people) met this criterion after 1 day, compared to 50% of those who received placebo (10 people). But by day 2, more people in the placebo group had “responded” to treatment: 60% in the placebo group compared to 50% in the ketamine group. On day 3, the placebo group continued to do better: 50% “responded” compared to 45% in the ketamine group. This continued; even at 14 days, the placebo group had 57.9% “responded” compared to 42% in the ketamine group.
In terms of remission—no longer meeting the criteria for depression—ketamine actually did far worse than placebo. Just one week after receiving a placebo, more than half of the patients (57.9%) no longer had depression, compared with less than a third (31.6%) of those who received ketamine.
At day 1, 50% of those in the ketamine group were classified as “in remission” versus 35% of those in the placebo group. However, this difference also disappeared quickly, and by day 3, both groups had a 40% “remission” rate. By the end of a week, the placebo group had 57.9% of patients in remission, compared to just 31.6% of those who received ketamine. By 14 days, the placebo group was still doing better: 47.4% in remission compared with 42.1% who received ketamine.
Opioid consumption, pain intensity, and HADS scores were also not significantly different between groups.
“Secondary and exploratory outcomes also found no evidence of benefit for ketamine over placebo,” the researchers write, adding:
“Our results suggest that ketamine may actually be ineffective for the short-term treatment of MDD.”
The researchers suggest that the placebo effect (which they refer to as “expectancy bias”) may be responsible for the supposed powerful antidepressant effects of ketamine. They argue that future research must use active placebos in order to detect whether the drug is actually doing something effective, particularly for drugs like ketamine that have obvious side effects.
“While it is impractical to use surgical anesthesia for most placebo-controlled trials, future studies of novel antidepressants with acute psychoactive effects should make stronger efforts to mask treatment assignment to minimize the effects of subject-expectancy bias.”
In an article in late 2022, researchers wrote that ketamine for depression poses a “significant risk to the public” due to poor evidence of efficacy and many safety concerns. Ketamine does not have FDA approval for treating depression and is used “off-label.” Ketamine variant esketamine, which was approved by the FDA in 2019, failed to beat the placebo in five of its six clinical trials.
Ketamine has also been associated with suicide deaths; in one recent study, it failed to beat a placebo for reducing suicide attempts, and one person died by suicide after taking the drug. Another person died by suicide in a 2016 open-label study that included only 12 people, and another patient was hospitalized after expressing suicidal intent.
Lii, T. R., Smith, A. E., Flohr, J. R., Okada, R. L., Nyongesa, C. A., Cianfichi, L. J., . . . & Heifets, B. D. (2023). Trial of ketamine masked by surgical anesthesia in depressed patients. medRxiv.org. Published on May 1, 2023. https://doi.org/10.1101/2023.04.28.23289210 (Link)