Uncovering ketamine’s mechanisms helps identify depression treatment

Researchers at the Karolinska Institute, Sweden, have identified novel mechanistic insights underlying ketamine’s antidepressant effects. According to the team, their findings could lead to new treatment options for major depressive disorder (MDD) in the future.

The most commonly prescribed antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), affect nerve signalling via monoamines in the brain. However, it can take a long time for these drugs to help, and over 30 percent of sufferers experience no relief at all.

Ketamine is a more rapid and effective drug that has previously been registered in the form of a nasal spray for the treatment of intractable depression. Unlike other antidepressants, it affects the nerve signalling that occurs via the glutamate system, although it is unclear how the antidepressant effect it mediated. While an effective antidepressant, ketamine can cause side effects such as hallucinations and delusions.

The researchers therefore investigated ketamine’s molecular mechanisms so that they could identify substances that have the same rapid effect without the side effects. Using experiments on both cells and mice, the team were able to show that the drug reduced presynaptic activity and the persistent release of the neurotransmitter glutamate.

“Elevated glutamate release has been linked to stress, depression and other mood disorders, so lowered glutamate levels may explain some of the effects of ketamine,” explained Professor Per Svenningsson, the study’s last author.

The team observed that ketamine directly stimulated AMPA receptors, which sit post-synaptically, in the part of the nerve cell that receives signals. This leads to the increased release of the neurotransmitter adenosine which inhibits presynaptic glutamate release. Moreover, the effects of ketamine could be counteracted by the researchers inhibiting presynaptic adenosine A1 receptors.

“This suggests that the antidepressant action of ketamine can be regulated by a feedback mechanism. It is new knowledge that can explain some of the rapid effects of ketamine,” added Svenningsson. Specifically, the retrograde adenosinergic feedback mechanism works by mediating inhibitory actions of ketamine on glutamate release, potentially contributing to its rapid antidepressant action, the team said in their paper.

The study was published in Molecular Psychiatry.