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Scientists may have the mystery of how ketamine treats depression so quickly



In recent years, the drug and anesthetic drug ketamine has been adopted as a rapid-acting, though not yet prescriptive, drug for some cases of depression and suicidal thoughts that are unresponsive to other treatments. But there is still much that we do not understand, how it actually works so fast to treat the crippling disease. A new study, published Wednesday by Stanford University, suggests that at least some of the ketamine is based on the same receptors in the brain that activate opioid analgesics.

The researchers started with 12 volunteers who had treatment-resistant depression and gave them ketamine infusions. However, some volunteers were fortuitously given an additional dose of naltrexone ̵

1; an opioid that can block and reverse the effects of opioids – while others only received an extra saline solution.

In contrast to other ketamine studies, many volunteers in placebo saline quickly suffered from depression relief, with more than half of patients reporting at least 90 percent reduction in their symptoms in the first three days after infusion. But there was no improvement in those who received naltrexone at the same time. The results were so dramatic that researchers decided to abandon the study rather than force more people to useless treatment (initially, they planned a total of 30 volunteers). Interestingly, the authors noted who took ketamine with the opioid blocker still dysphoric feelings as much as the placebo group did. This suggests that it is not the trippy out-of-body experience that some ketamine users report is responsible for the rapid increase in mood.

The results were published in the American Journal of Psychiatry.

This is not the first study to show that the opioid system is involved in ketamine manipulation of the body, especially when used as an anesthetic. But the results, if they hold, could have a significant impact on the future of depression research.

The researchers were excited about the potential of ketamine because it does not alter our brain chemistry as other established antidepressants do. Because ketamine is known to block the brain's receptors to glutamate, an important neurotransmitter that helps us learn and create memories, scientists have suggested that this activity may be the key to its antidepressant properties. And research has been trying to create or discover other antidepressants that do exactly the same thing. But these attempts have not had much success in mimicking the fast-acting effects of ketamine.

"Many people have agreed on the glutamate hypothesis based on the fact that ketamine is such an effective antidepressant," said co-author Boris Heifets, a clinical assistant professor of anesthesiology, perioperative and pain medicine at Stanford, to Gizmodo , "[But] The literature has always been there, showing that ketamine is a versatile drug, with many targets."

"There is a lot of money invested in the development of others [glutamate blockers]but this may not be the right approach to creating ketamine-like drugs," added lead author Nolan Williams of the Stanford Neurosciences Institute.

Glutamate could still be a key element of the puzzle for treating depression in some people, but if ketamine-like drugs require opioid receptors that has its own risks.

"Ketamine has been a rave drug for decades – I mean, it was the first time I heard about it before I became an anesthesiologist, and the fact that it interacts with the opioid system suggests that it has potential for abuse "Credibility," said Heifets. "And that should make us think a little bit more about how we can use it as an antidepressant for millions of people."

At the same time, better understanding of the complex nature of ketamine and opioids can only help us create new treatments for depression. This includes the development of drugs that act like ketamine on different receptors simultaneously, as well as drugs that can safely activate opioid receptors without triggering a dependency. Similarly, opioids such as morphine have shown an antidepressant effect in the short term, but appear to aggravate or increase the risk of depression the longer they are taken. Finding a way to short this pattern could help pain patients. And because ketamine is also promising for other diseases such as obsessive-compulsive disorder, it is worth investigating if opioids also play a role there.

"There is clearly a link between depression, pain and opioids," Heifets said. "Therefore, the mechanistic understanding we have gained through this study is very important in formulating further treatments for all the common medical problems."

[American Journal of Psychiatry]


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