With origins in the 1960s as an anesthetic, ketamine is remarkably effective and fast-acting for treatment-resistant depression (1-3). However, in randomized controlled trials, clinicians and researchers have a difficult time masking whether patients receive ketamine or placebo treatment because of ketamine’s unique dissociative and psychoactive properties. Because of this, researchers have never completely separated ketamine’s effects from those of placebo. To overcome this challenge, Boris Heifets, an anesthesiologist at Stanford University, and his team developed a clever strategy that they described in a new study published in Nature Mental Health (4). 

Theresa Lii, an anesthesiologist in Heifet’s group and coauthor of the study reasoned that because of growing interest in ketamine for antidepressant purposes, “It would probably lend itself to almost an experiment of convenience where we would just study patients who had moderate to severe levels of depression who were already scheduled for major surgery at Stanford and track their depression scores before and after surgery.” By administering ketamine or placebo to patients while under general anesthesia, for the first time, researchers hid the treatment from patients. 

The researchers asked patients to rate their depression severity on the Montgomery-Åsberg Depression Rating Scale before, and one, two, and three days after surgery. Patients who received ketamine achieved similar improvements in depression severity to those who received placebo, suggesting that placebo was as effective as ketamine in improving depression symptoms. Importantly, only 36.8% of patients correctly guessed their treatment group, which indicated to the researchers that the masking was effective.

Improvements in depression symptoms for both ketamine and placebo-treated patients were comparable to those seen in clinical studies evaluating ketamine’s efficacy in awake patients. This suggests that both placebo and ketamine had clinically significant effects on depression symptoms. 

While researchers have demonstrated the importance of the ketamine’s dissociative effects for its role as an antidepressant, Heifets’ team’s study suggests that some other component of ketamine may also contribute to its mechanism of action (5). “Almost by accident, we had the surgery, a big salient event. And the first time you go for a ketamine infusion, that is also unlike anything before. You had to outcompete 99 other applicants to get into that study, so there is that sense of specialness, ritual, and something that happens,” said Heifets. 

In fact, scientists have pointed to the role of expectancy in mediating placebo effects in clinical trials (6). (Expectancy refers to a patient's anticipation or belief in the effectiveness of a treatment). According to Heifets, expectancy should be measured in clinical trials, and “We should be treating expectancy as a drug effect,” he said. “We want to be able to look at how varying expectancy in a controlled way, [in terms of] what we tell patients, may influence outcomes.”

All antidepressant trials of any substance really ought to be measuring expectations. 
– Theresa Lii, Stanford University 

Todd Gould, a psychiatrist and neuropharmacologist at the University of Maryland who was not involved in the study said, “It’s a really exciting study, and I’m glad the authors did it.” However, Gould noted that most ketamine clinical studies have focused on treating patients with treatment-resistant depression. “The individuals who were enrolled in the study didn’t have treatment-resistant depression,” he said. “So that may, in part, be a reason why they have such a robust placebo effect that doesn’t separate from the drug.” 

Gould also questioned the effects of anesthetic agents that patients received during surgical procedures. “The majority of individuals received sevoflurane, and sevoflurane has been shown to have antidepressant effects in rodents.” The majority of patients also received propofol, which is a GABA agonist, meaning that it acts in the opposite direction of ketamine (7). The number of patients receiving additional anesthetics did not match between treatment groups. Given researchers’ descriptions of how anesthetics broadly affect the brain and the lack of anesthetic matching between placebo- and ketamine-treated groups, further studies are needed to directly compare ketamine to placebo without confounding variables (8, 9).

While humans in clinical trials can often discern ketamine versus placebo and therefore expect a certain response, “A mouse has no expectancy about receiving an injection,” Gould said. “Yet, we see very rapid and pronounced effects of ketamine in rodents that model some of the symptoms or circuits that are involved in depression pathologies.” This may suggest that ketamine’s effects are independent of any expectancy confounds. However, multiple research studies have pointed out the differing underlying neural mechanisms that appear to mediate ketamine’s antidepressant effects in humans compared to mice (10, 11). Therefore, it is possible that the expectancy effect associated with ketamine may play a role in mediating antidepressant effects in humans but not in animals.

As researchers continue to separate ketamine’s effects from expectancy, the field of researchers studying other psychoactive drugs, such as psilocybin and MDMA, continues to grow. It is thus increasingly imperative to develop effective clinical trials that measure the abilities of these novel therapeutics to treat their respective indications. 

“The confound that a lot of people have raised with these clinical trials on MDMA and psilocybin that are now reaching pretty late phases, is how much of this is expectancy?” said Heifets. Lii also noted, “All antidepressant trials of any substance really ought to be measuring expectations.”

References

1. Alshammari, T.K. The ketamine antidepressant story: new insights. Molecules  25, 5777 (2020).
2. Serafini, G. et al. The role of ketamine in treatment-resistant depression: a systematic review. Curr Neuropharmacol  12, 444-461 (2014).
3. Hashimoto, K. Rapid-acting antidepressant ketamine, its metabolites and other candidates: a historical overview and future perspective. Psychiatry Clin Neurosci  73, 613-627 (2019).
4. Lii, T.R. et al. Randomized trial of ketamine masked by surgical anesthesia in patients with depression. Nat Mental Health  1, 876-886 (2023).
5. Luckenbaugh, D.A. et al. Do the dissociative side effects of ketamine mediate its antidepressant effects? J Affect Disord  159, 56-61 (2014).
6. Rutherford, B.R. et al. Patient expectancy as a mediator of placebo effects in antidepressant clinical trials. Am J Psychiatry  174, 135-142 (2017).
7. Shin, D.J. et al. Propofol is an allosteric agonist with multiple binding sites on concatemeric ternary GABA-A receptors. Mol Pharmacology  93, 178-189 (2018). 
8. Guo, Z. et al. Sevoflurane exerts an anti-depressive action by blocking the HMGB1/TLR4 pathway in unpredictable chronic mild stress rats. J  Mol Neurosci  69, 546-556 (2019).
9. Eisen, A.J. et al. Propofol anesthesia destabilizes neural dynamics across cortex. BioRxiv (2023). 
10. Abdallah, C.G. et al. Modulation of the antidepressant effects of ketamine by the mTORC1 inhibitor rapamycin. Neuropsychopharmacology  45, 990-997 (2020). 
11. Williams, N.R. et al. Attenuation of antidepressant effects of ketamine by opioid receptor antagonism. Am J Pscyhiatry  175, 1205-1215 (2018).