If a person responds to ketamine, it can quickly reduce suicidality (life-threatening thoughts and actions) and relieve other serious depression symptoms. Ketamine can also be used to treat depression in conjunction with anxiety. A new study has discovered how ketamine can be used to treat difficult-to-treat depression.
The discovery that the anesthetic ketamine can help people suffering from severe depression has raised hopes for new treatment options. Researchers at Sweden’s Karolinska Institutet have discovered new mechanistic insights into how the drug exerts its antidepressant effect. The research was published in the journal Molecular Psychiatry.
According to the World Health Organization, depression is the leading cause of disability worldwide, affecting over 360 million people each year. Both genetics and environmental factors influence the risk of suffering. The most commonly prescribed antidepressants, such as SSRIs, affect nerve signaling in the brain via monoamines. However, these drugs can take a long time to work, and more than 30% of sufferers experience no relief at all.
As a result, there is a significant need for new types of antidepressants with faster action and a broader effect. The anesthetic ketamine, which has been registered for several years in the form of a nasal spray for the treatment of intractable depression, is a significant breakthrough.
The discovery that the anesthetic ketamine can help people with severe depression has raised hopes of finding new treatment options for the disease. Researchers have now identified novel mechanistic insights how the drug exerts its antidepressant effect.
Unlike traditional antidepressants, ketamine affects nerve signaling via the glutamate system, but it is not clear how the antidepressant effect is mediated. When the medication takes effect, it quickly relieves depressive symptoms and suicidal thoughts.
However, ketamine can cause undesirable side effects such as hallucinations and delusions, and there is a risk of abuse, so alternative medications are required. The researchers want to learn more about how ketamine works so that they can develop substances that have the same rapid effect but without the side effects.
Karolinska Institutet researchers have conducted additional research into the molecular mechanisms underlying ketamine’s antidepressant effects in a new study. The researchers demonstrated that ketamine reduced so-called presynaptic activity and the persistent release of the neurotransmitter glutamate using experiments on both cells and mice.
“Because increased glutamate release has been linked to stress, depression, and other mood disorders, lowered glutamate levels may explain some of the effects of ketamine,” says Per Svenningsson, professor at Karolinska Institutet’s Department of Clinical Neuroscience and the study’s last author.
When nerve signals are transmitted, they pass from one neuron to the next via synapses, which are small gaps where two neurons meet. The researchers discovered that ketamine directly stimulated AMPA receptors, which are located postsynaptically, that is, in the part of the nerve cell that receives signals, resulting in increased release of the neurotransmitter adenosine, which inhibits presynaptic glutamate release.
Ketamine’s effects could be mitigated by inhibiting presynaptic adenosine A1 receptors, according to the researchers. “This suggests that ketamine’s antidepressant action can be regulated by a feedback mechanism. It is new knowledge that can explain some of the ketamine’s rapid effects “according to Per Svenningsson.
The same research group recently reported on the disease mechanism in depression in collaboration with Rockefeller University. The findings, which were also published in the journal Molecular Psychiatry, show how the molecule p11 influences the onset of depression by affecting cells on the surface of the brain cavity, ependymal cells, and the flow of cerebrospinal fluid.
Ketamine’s mechanism of action is not completely understood. Ketamine may be able to help people successfully manage depression when other treatments have failed because it exerts an antidepressant effect via a novel mechanism.
Ketamine’s likely target in the brain is NMDA receptors. Ketamine appears to increase the amount of a neurotransmitter called glutamate in the spaces between neurons by binding to these receptors. Glutamate then activates connections in a different receptor known as the AMPA receptor. The initial blockade of NMDA receptors and activation of AMPA receptors results in the release of other molecules that aid neurons in communicating with one another via new pathways. This process, known as synaptogenesis, is thought to influence mood, thought patterns, and cognition.