A Chinese-led study has uncovered the mechanism behind why ketamine is being prescribed by some psychiatrists to rapidly treat depression.
The researchers from China and the United States said the use of ketamine was “arguably the most important advance in mental health in decades” and it was important to understand how it worked.
“Given ketamine’s rapid and potent antidepressant activity, a great challenge in neuroscience is to understand its direct brain target(s),” said the team, in a paper published last week in the peer-reviewed journal Science.
The researchers said their study found the drug triggered widespread positive effects in the brain by suppressing activity in a region that is known to become hyperactive during a depressive state.
Ketamine – which can mitigate depressive symptoms within minutes and have a sustained impact for days – was introduced as an anaesthetic in the 1960s and became widely used as a recreational drug because of its dissociative and hallucinogenic impacts.
The recreational use of ketamine is illegal around the world, including in China. Beijing has submitted multiple petitions to the United Nations urging for the drug to be reclassified as an illicit narcotic, due to rising levels of abuse.
Some of the long-term side effects that have been associated with ketamine abuse include irreversible bladder damage, cognitive deficits, and even liver damage.
It was not until the 2000s that clinical trials showed ketamine’s potential as an antidepressant, even in patients with treatment-resistant depression, but scientists were still unsure exactly how the drug was achieving its remarkable results.
Previous research indicated that ketamine’s primary target was likely to be the N-methyl-D-aspartate receptor (NMDAR), but the receptor’s presence throughout the brain made it unclear exactly how.
Ketamine is a use-dependent blocker, meaning it inhibits NMDARs when they are open and activated, a trait that led the scientists to test if it targets regions of the brain that show increased neuronal activity when in a depressive state.
The team, led by neuroscientists from Zhejiang University, found that ketamine administered to mice placed in a depressive-like state selectively suppressed neural activity in the lateral habenula, a region of the brain associated with depression.
The researchers found that a single injection of ketamine blocked NMDARs in the lateral habenula, which is known to exhibit hyperactivity, including increased neural firing and bursting, during depression.
At the same time, the ketamine did not block NMDARs in the hippocampal neurons, despite this being another brain region linked to depression. This was because the hippocampus has lower intrinsic NMDAR activity during a depressive state, the study said.
To confirm their findings, the researchers found that they could swap the brain’s sensitivity to ketamine by increasing the activity of the hippocampal neurons or taking the reverse action in the lateral habenula neurons of the mice.
The scientists’ findings could lead to a more unified understanding of ketamine as an antidepressant and the development of more efficient and precise treatments for the condition, which affects around 280 million people worldwide.
Traditional antidepressant drugs that target neurotransmitters like dopamine and serotonin often take weeks to become effective.
The researchers also questioned how ketamine sustained its efficacy. Despite its short half-life, the drug’s antidepressant effects on humans can continue for days.
According to the paper, while the hippocampus has a large pool of open NMDARs to exchange with blocked receptors, leading to a faster recovery, the lateral habenula’s pool is “nearly 10-fold smaller”, causing it to recover more slowly from a ketamine blockade.
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Mice that were not in a depressive-like state did not receive the same effects from ketamine, suggesting that the drug “should have fewer effects on non-depressed individuals” with lower lateral habenula activity, the researchers said.
The scientists noted that a 2019 study by researchers in the United States had similar findings.
“Indeed, in [the] double-blind, placebo-controlled trial, ketamine administered at a subanaesthetic dosage only had mood-elevating effects in major depressive disorder patients, not in healthy controls,” they wrote.
Although the lateral habenula was found to be the primary target of ketamine action, the team said it might not be the only one, as other brain regions with similar properties might be recruited at later times by the drug.
“The combination of use-dependent block, activity levels, and receptor reserves as a mechanism for region-specific action on a ubiquitously expressed receptor may inspire new ways of thinking about region-specific issues in neuropathology and neuropharmacology,” the team said.
“The present work may provide a more unified understanding of the complex results from previous studies on the antidepressant effects of ketamine and aid in the design of more precise and efficient treatments for depression.”
