ketamine research

Amit Anand

Major Depressive Disorder (MDD) is a widespread mental health condition that affects nearly 1-in-5 U.S. adults. Treatment-resistant depression is a subtype that does not respond to traditional antidepressants and is estimated to affect 30% of patients diagnosed with MDD. Traditionally, treatment–resistant patients have been referred to electroconvulsive therapy (ECT), an old but effective technique that currently involves inducing seizures in sedated patients. Amit Anand, MD, director of Psychiatry Translational Clinical Trials at Mass General Brigham, is interested in developing and evaluating new treatment options for these patients. He and his team led a large clinical trial that compared the effects of ECT with ketamine, a relatively new treatment. Anand recently co-authored a Viewpoint piece in JAMA Psychiatry about choosing between ketamine and ECT for treating treatment-resistant depression.

In this Q&A, he discusses the results of this trial, the pros and cons of ketamine therapy and its use in the treatment of other mental health disorders.

Q: Could you give us an overview of what ketamine is and its use in the treatment of depression?

AA: For the last 70-80 years, ECT has been the last resort for people with treatment-resistant depression. But it has its drawbacks — patients have to undergo anesthesia, and there is a social stigma associated with ECT.

Ketamine, on the other hand, is an anesthetic agent that has been around for 20-25 years. It works by blocking glutamate, a major neurotransmitter in the brain. A single infusion of a sub-anesthetic dose of ketamine can treat depression very quickly, often within days or hours.

Q: What did you learn from the recent study in which you compared the effects of ketamine and ECT?

AA: The question was: Is ketamine, the new kid on the block, as good as ECT, the  gold standard?

We conducted a comparative effectiveness trial involving patients with treatment-resistant depression who were referred for ECT. As part of the trial, 403 patients were randomized to receive either ECT or ketamine. We found that after three weeks of treatment, patients responded similarly to both. Our results suggest that ketamine is just as good as ECT at managing treatment-resistant depression.

Q: Could you tell us how ketamine therapy has evolved since the first discovery of its antidepressant properties?

AA: I was actually part of the team that conducted the first study from Yale that uncovered that ketamine might be useful as an antidepressant. It was a small study, with just eight patients, and we happened to find this fast antidepressant effect. It didn’t get much attention at first, but one of the researchers later did a bigger study at the National Institutes of Health (NIH), and then people started noticing how effective a single dose of ketamine could be.

The parent compound for ketamine is phencyclidine (PCP), which is a hallucinogen that has dissociative properties. Psychedelics and hallucinogens are getting renewed interest nowadays.  These agents are also being used along with psychotherapy.

In terms of evolution, we’re at a crossroads right now about the use of intravenous versus intranasal ketamine. Intravenous is more effective and medication costs is only about $4 per infusion with additonal costs for the infusion at a hospital facility, but it is still designated as an investigative drug for treating depression and so isn’t covered by insurance. Intranasal ketamine, on the other hand, is approved by the Food and Drug Administration and costs several hundreds of dollars. But insurance covers this cost, so most hospitals and treatment centers offer this option even though it’s less effective.

Q: Could you tell us more about how ketamine is being evaluated for the treatment of other disorders like alcohol use and withdrawal?

AA: Small doses of ketamine can cause euphoria, similar to alcohol. We’re doing a small NIH-funded study at BWH (primary investigator Joji Suziki, MD) right now to test the use of ketamine in the emergency room for alcohol withdrawal treatment.

Ketamine may also influence opioid receptors, but it’s unclear exactly how. So, it’s also currently being studied in opiate use disorder.

Q: What would you say are the limitations of ketamine therapy?

AA: Ketamine is very effective as an acute treatment for depression, but people tend to have a relapse in symptoms after a few months. We still don’t have answers about how to maintain long-term responses, because just giving a lot of ketamine over years is not the answer. It’s a powerful drug that has a potential for addiction. We haven’t seen much evidence for this misuse, but it’s always a possibility, and we have to be careful.

Even though it isn’t as potent as PCP, ketamine can still cause some psychotic and dissociative effects when given in large amounts. It can also cause an increase in blood pressure with regular use, and in rare cases might lead to bladder inflammation if abused in large doses.

Q: Could you tell us what you’re currently studying?

AA: We’re just starting a study at the Brigham that’s part of a bigger trial funded by the Patient-Centered Outcomes Research Institute (PCORI) involving 1,500 patients across the country. We are going to study the effects of ketamine and ECT on acute suicidal depressed subjects who need urgent care.


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