Ketamine has long been targeted as a potential antidepressant but how and why it has such a powerful effect on the brain has remained elusive.
Researchers have now found the drug may act by stimulating a region of the prefrontal cortex – the infralimbic prefrontal cortex (IL-PFC).
Ronald S Duman and colleagues from Yale University modulated the activity of neurons in this area of the brain and monitored their behavioural responses and the changes in the neuronal structure.
Published in the Proceedings of the National Academy of Sciences, the researchers found inactivation of the IL-PFC region blocked the effects of ketamine.
They also found simulation of the area produced rapid and long-lasting antidepressant effects – reiterating ketamine's potential as a potent antidepressant.
Previously, ketamine was found to be far more effective than current antidepressants in two ways. It acts faster than other drug treatments – working within hours rather than weeks or months. Studies have also found it can be used on people who had not responded to other antidepressants.
Duman said the primary problems of ketamine at present are the side effects of the drug and the potential for abuse. At the dose they used in the study, there were some mild dissociative and psychotomimetic effects that lasted for about an hour.
The antidepressant actions started around two hours after the drugs were administered.
"There is a tremendous effort to identify ketamine-like rapid acting antidepressant drugs without the side effects or abuse potential, which are limiting extended use of ketamine," he told IBTimes UK.
"Studies to characterise the brain regions, circuits, and cell types that underlie the actions of ketamine will help toward developing novel agents with fewer side effects."
While the findings provide a step forward in the study of ketamine, the scientists said how ketamine triggers the synaptic and behavioural responses remain unclear – so more work will be needed before it is fully developed as an antidepressant. Once it is better understood, however, it could lead to "novel targets for safer antidepressant medications".
Duman added: "There is enormous potential for ketamine and ketamine-like drugs with fewer side effects to become the treatment of choice in the future. There is also new data demonstrating that ketamine is effective for treating PTSD symptoms, as well as bipolar depression."