A team of researchers has identified novel mechanistic insights on how ketamine exerts an anti-depression effect, raising the hope of finding new treatment options for the condition.
Using experiments on cells and mice, the team at the Karolinska Institutet, Sweden, has discovered that ketamine reduces presynaptic activity as well as the persistent release of glutamate.
The researchers say they wanted to better understand how ketamine works in order to find substances that can have the same rapid effect but without side effects such as hallucinations.
Understanding ketamine’s rapid effects
Selective serotonin reuptake inhibitors (SSRIs) are currently the most commonly prescribed antidepressant, however, they are not fast-acting and over 30 per cent of people with depression that use the drugs experience no benefit. With depression affecting more than 360 million people every year across the globe, according to the World Health Organization (WHO), there is a considerable need for faster-acting and wider effect antidepressants.
Anaesthetic ketamine has been registered for a number of years in the form of a nasal spray for the treatment of intractable depression, which, unlike classic antidepressants, affects the nerve signalling that occurs via the glutamate system. It has been unclear, however, how this effect is mediated.
Last author of the study, Per Svenningsson, professor at the Department of Clinical Neuroscience, Karolinska Institutet, said: ”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.”
The findings, published in the journal Molecular Psychiatry, demonstrated that ketamine directly stimulated AMPA receptors – the part of the nerve cell that receives signals, leading to the increased release of the neurotransmitter adenosine, which inhibits presynaptic glutamate release.
According to the team, the effects of ketamine could be counteracted by inhibiting presynaptic adenosine A1 receptors.
Per Svenningsson added: “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.”
