In a study published online August 13th in the Journal of Pyschopharmacology, researchers at the Yale School of Medicine found that ketamine––a fast-acting, but still experimental antidepressant––relieves depression most effectively in patients whose brains have a small hippocampus. (The hippocampus is a structure in the interior of the brain that is associated with learning, memory, and emotion.) The research team was led by two-time (2012 and 2014) NARSAD Young Investigator grantee Chadi Abdallah, M.D., and colleagues at the Yale School of Medicine. The team included other NARSAD-funded scientists.*

A smaller-than-normal hippocampus is often seen in patients with severe depression. Those with small hippocampal volumes often respond poorly to traditional antidepressants. Dr. Abdallah and colleagues used magnetic resonance imaging (MRI) to assess the size of the hippocampus in 13 patients with major depression, then gave each patient a single dose of ketamine. For 10 individuals, the treatment effectively reduced symptoms of depression within 24 hours.

Those patients who responded best to the ketamine were those with the smallest hippocampi on the brain’s left side, the scientists found. (Humans have two hippocampi, one on each side of the brain.) Although the size of the right hippocampus varied among patients, this did not appear to correlate with the effectiveness of ketamine treatment.

Millions of people take antidepressant medicines, but for many patients suffering from major depressive disorder, commonly prescribed selective serotonin reuptake inhibitors such as fluoxetine (Prozac) and sertraline (Zoloft) are ineffective. Some recent studies have suggested that ketamine, a drug most commonly used as an anesthetic, may be an effective alternative for the most seriously depressed of these patients.

Scientists do not yet fully understand how ketamine reduces the symptoms of depression. This new information on which patients respond best to the drug could help researchers tease out exactly how it exerts its antidepressant effects. The Yale scientists hope their findings will also offer insight into what makes some patients resistant to more traditional antidepressants. That, in turn, could guide the development of better treatments for the future.

Ketamine has not been approved for treatment of depression, but clinical studies have found that it can exert potent antidepressant effects within four hours of treatment, at doses lower than those used for anesthesia. Like traditional antidepressants, it is not effective for all patients.

* Other NARSAD grantees involved in this study:

Ramiro Salas, Ph.D. (2012 Young Investigator)

Sanjay Mathew, M.D. (2009 Independent Investigator; 2001 and 2006 Young Investigator)

Read the abstract.