Is Ketamine's Potent Antidepressant Effect Due to a Placebo Effect?

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Is Ketamine’s Potent Antidepressant Effect Due to a Placebo Effect?

Depression is a common mental disorder characterized by symptoms such as low mood, reduced interest, slow thinking, poor appetite, sleep disturbances, and even tendencies towards pessimism, hopelessness, and suicide.

Moreover, depression is associated with an increased risk of cardiovascular diseases, diabetes, and Alzheimer’s disease.

According to the World Health Organization (WHO), depression has become the fourth-largest global disease, affecting over 300 million people worldwide, with this number continually on the rise.

Ketamine is a promising treatment for depression, with numerous studies demonstrating its ability to rapidly and significantly alleviate severe depression.

However, these studies have a significant flaw – participants can typically distinguish whether they are receiving ketamine or a placebo. This is because ketamine is a hallucinogenic substance, making it easily recognizable.

On October 19, 2023, researchers from Stanford University School of Medicine published a study in the Nature Mental Health sub-journal titled “Randomized trial of ketamine masked by surgical anesthesia in patients with depression” [1].

This study employed a clever approach to conceal ketamine’s hallucinogenic properties when used for depression treatment.

The research team recruited 40 participants with moderate to severe depression who underwent routine surgeries.

During the surgery and general anesthesia, they were administered either ketamine or a placebo, with both the participants and clinical staff remaining unaware of the treatment administered.

Two weeks later, when the treatment details were revealed, researchers were astonished to find that both groups, those who received ketamine and those who received the placebo, showed significant improvements in their depression symptoms, with no superior effect observed in the ketamine group.

Is Ketamine's Potent Antidepressant Effect Due to a Placebo Effect?

What does this discovery imply?

The researchers acknowledged that their study took an unexpected turn and raised more questions than it answered.

“At this point, all bets are off,” said Dr. Alan Schatzberg, a co-author of the study and the Kenneth T. Norris Professor of Psychiatry and Behavioral Sciences. “It’s like looking at a painting by Picasso.”

The research team believes that surgery and general anesthesia are unlikely to be the reasons for participants’ depression improvement, as post-surgery depression typically doesn’t improve and sometimes even worsens. A more plausible explanation is that participants’ positive expectations may play a crucial role in ketamine’s efficacy.

During the final follow-up, participants were asked to guess which intervention they had received (ketamine or placebo). Approximately one-quarter of the participants claimed not to know. Among those who made guesses, over 60% believed they had received ketamine, which wasn’t related to their actual treatment but was linked to their perception of improved depression symptoms.

People who showed greater improvements in depression scores were more likely to think they had received ketamine, even if they belonged to the placebo group. This suggests that they had pre-existing positive expectations of ketamine, indicating that at least part of ketamine’s efficacy in treating depression comes from the placebo effect.

Not Just a Placebo

The research team emphasized that this study does not conclude that ketamine is “just a placebo.” In fact, there might be some physiological resonance between the placebo effect and ketamine’s actions, possibly mediated by the brain’s μ-opioid receptors, responsible for processing pain.

These findings also suggest that the hallucinogenic effect may not be crucial for ketamine’s depression-alleviating benefits, although it may encourage participants to generate more positive expectations. Therefore, developing ketamine-like drugs without hallucinogenic effects could yield similar results in depression treatment.

Non-Hallucinogenic Fast-Acting Antidepressants

On September 14, 2023, the research group of Yelin Chen at the Center for Biological and Chemical Cross-Research, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, published a study in the journal Nature Neuroscience titled “GluN2A mediates ketamine-induced rapid antidepressant-like responses” [1].

This study reported that a previously overlooked NMDA receptor subtype, GluN2A, is the direct target of (R)-ketamine’s antidepressant effects, while the previously studied GluN2B is not the true target.

Most importantly, the hallucinogenic effects of (R)-ketamine do not depend on GluN2A, providing a theoretical basis for developing fast-acting antidepressants with no hallucinogenic side effects based on this target.

Is Ketamine's Potent Antidepressant Effect Due to a Placebo Effect?