How does ketamine fight depression?

A group of proteins called 4E-BP, which is involved in memory formation, is the key to unraveling the antidepressant effect of ketamine in the brain, according to researchers from three Canadian universities. The discovery could lead to better and safer treatments for certain patients suffering from depression.

With more than 30% of patients resisting selective serotonin reuptake inhibitors (SSRIs), the antidepressants are usually prescribed, finding effective treatment for major depressive disorder. challenging depression.

Initially, ketamine was approved for anesthesia and pain relief. Since its discovery, researchers have been exploring new uses for this drug, and ketamine was approved last year for patients with treatment-resistant depression. Unlike conventional antidepressants, which can take several weeks to take effect, ketamine works within hours. Until now, little was known about the molecular mechanism that stimulates the antidepressant effects of ketamine on the brain.

In the study published in Nature, researchers from McGill University, Université de Montréal, and Carleton University studied the effects of ketamine on behavior and neuronal activity in mice. Using genetic tools to remove proteins from specific brain cells, the team found that when 4E-BP is not present in the brain, especially in neurons, ketamine cannot exert its antidepressant effect. 4E-BP acts as a modifier to turn the process of protein synthesis on or off – an essential part of memory formation.

“This is another prime example of how basic research, in this case controlling protein synthesis, leads to key findings in understanding disease, and hopefully curing it,” says the co-author. Nahum Sonenberg, professor in the Department of Biochemistry at McGill University.

The researchers studied the role of 4E-BP on the effect of ketamine in two main types of neurons: excitatory neurons, which make up the majority of neurons in specific parts of the brain, and inhibitory neurons, which controls excitatory neurons and has important effects on behavior.

“We expected 4E-BP to be important only in excitatory cells, but surprisingly, removal of 4E-BP from inhibitory cells was sufficient to block the effects of ketamine,” says co-author Jean-Claude Lacaille, professor in the Department. of Neurosciences at Université de Montréal.

One-size-fits-all treatment is not the answer

The detection and approval of ketamine for patients who were resistant to treatment was considered a major improvement in today’s psychiatry. Despite its promise, ketamine is still a less-than-perfect remedy because it can be addictive. The researchers hope their findings will pave the way for better and safer antidepressant treatments for patients with major depressive disorder.

“Too many decisions are still being made with a trial-and-error approach that could exacerbate patients’ suffering and affect their quality of life, ”said co-author Aguilar-Valles, a former research assistant at McGill University and now an assistant professor at Carleton University. “Our discovery has the potential to bring us closer to finding a safer alternative to ketamine, and ultimately to a personalized treatment modality, where whether medical treatments are tailored to the individual characteristics of each patient. “

The study also included a research clinician, Dr Gabriella Gobbi, from the Department of Psychology at McGill University, who works with individuals with depression and other mental illnesses. .

As the next steps, the researchers will examine whether men and women have different responses to ketamine. This could have a significant impact on the treatment of people with depressive disorder, among whom women are largely underrepresented.