How Ketamine Affects Three Key Brain Regions – Harvard Gazette

Deployed as an anesthetic in human and veterinary medicine for decades, the synthetic compound ketamine was approved four years ago as a fast-acting antidepressant. But in addition to its anesthetic and antidepressant potency, the drug has “dissociative effects”, including hallucinations, which have led to recreational use.

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Researchers from Massachusetts General Hospital recently traced the effects of ketamine in three regions of the brain. Two of these are believed to play a role in the drug’s effectiveness as an antidepressant: the prefrontal cortex – responsible for planning and other executive functions – and the hippocampus, which influences memory formation . The third, the posteromedial cortex, in the back part of the brain, is a likely site for dissociative effects.

The Gazette discussed the results with Fangyun Tianinstructor in anesthesia Harvard Medical School and MGH and first author of the article, which was published in Nature Communications. The interview has been edited for clarity and length.

GAZETTE: Ketamine has been around as an anesthetic for a long time. What can you tell us about its use for depression?

TIAN: Administration of a sub-anaesthetic dose produces a very rapid and sustained antidepressant effect, comparable to many other traditional antidepressants. It was first approved by the FDA in 2019 for the treatment of depression, but its usefulness is limited by its abuse potential due to its psychiatric side effects, such as dissociation. Thus, if we can understand the neurocircuit mechanisms that mediate the antidepressant and dissociative effects of ketamine, this could provide important insights into the development of improved therapies, with fewer side effects and greater safety.

GAZETTE: Although the focus is on the treatment of depression, your study was on patients with epilepsy, why?

TIAN: Because they had electrodes implanted in their brains for another purpose: to locate their epileptic seizures. They were doing explant surgery to remove the electrodes, and that gave us a good chance to study the EEG [electroencephalogram, which records brain activity] dynamics of cortical and subcortical brain structures. We first took a five-minute baseline recording and then gave the patient ketamine. Then, after a 14-minute infusion period, we asked patients to answer questions to assess their dissociative states. After that, the patients were given general anesthesia for their surgery. We made EEG recordings during the whole process.

In our experiments, we separated ketamine infusion from induction of general anesthesia for surgery, during which a different anesthetic, propofol, was used.

GAZETTE: What did you find?

TIAN: We found gamma oscillations – very high frequency oscillations – in the prefrontal cortex and hippocampus. These are regions known to be involved in the antidepressant effects of ketamine based on other studies. We also found a three-hertz oscillation in the posteromedial cortex, called PMC, which another study suggests may be related to the dissociative effects of ketamine. Thus, it appears that different regions of the brain are involved in the antidepressant and dissociative effects of ketamine. It might be possible to develop future treatments that can avoid dissociation.

GAZETTE: How do patients experience these dissociative effects?

TIAN: They feel disconnected from their feelings, thoughts, surroundings, and identity. We used a questionnaire called the Clinician-Administered Dissociative State Scale, or CADSS, to assess dissociative state. We ask questions like, “Do things feel unreal to you, like you’re in a dream?” Or: “Do the colors seem to have diminished in intensity?” Responses varied by patient, but most answered “yes” to many of these questions. Dissociative effects are quite common in patients taking ketamine.

GAZETTE: Is it strong enough that people with depression who might benefit from it won’t want to take the drug?

TIAN: Maybe that’s one of the reasons. It is more serious in some patients but less so in others. It depends on the person.

GAZETTE: Is this effect also the reason it is used recreationally?

TIAN: Yes. It could cause hallucinations, make things unreal, or produce an out-of-body experience.

GAZETTE: What is next for you in this search?

TIAN: I want to do a follow-up study in patients with treatment-resistant depression to see if the brain rhythms we found in this study clearly correlate with antidepressant and dissociative effects which may vary from patient to patient.

GAZETTE: How did you get interested in this research?

TIAN: As researchers in the Department of Anesthesia, we are very interested in the mechanisms of action of anesthetic drugs so that we can provide better patient care. We are interested in the identification of biomarkers allowing the clinical measurement of cerebral states, and in particular in the search for biomarkers of unconsciousness. The main tool we use to measure brain states is the EEG. We found that different anesthetic drugs, such as propofol, ketamine, sevoflurane, and dexmedetomidine, cause very distinct brain oscillatory patterns. Ketamine is the only one that induces high frequency gamma oscillations. In high doses, ketamine can induce general anesthesia – loss of consciousness – but in low doses it causes these antidepressant and dissociative effects. It is a unique and very important medicine. We want to know what is happening at the molecular level and at the neural circuit level that could be causing these different effects.