Among the antidepressants your doctor may consider prescribing, ketamine, commonly known as a dissociative anesthetic and illicit party drug, might not be the first that springs to mind. However, recent studies continue to bolster ketamine’s capacity for applications in depression-related treatment due to its speedy antidepressant effects, which can offer results in a fraction of the time it takes for traditional drugs. The mechanisms by which these effects transpire have long been hazy, but researchers at the Yale School of Medicine have inched closer to an answer by studying the role of the endogenous opioid system—our body’s intrinsic pain-relieving system, which releases natural endorphins that aid in regulating depression—in activating these effects. Understanding this relationship may one day bring about more comprehensive and targeted depression treatment in humans.
In their study, Yale psychiatric research scientist Cheng Jiang and collaborators used various pharmaceutical and behavioral techniques to localize ketamine’s antidepressant effects to opioid receptors in the prefrontal cortex, a region of the brain responsible for regulating actions and emotions. The team began by replicating previous studies by injecting naltrexone—a drug used to treat opioid abuse disorders by blocking the effects of opioids—into male rats.
The rats were subjected to various behavioral tests, including a forced swim test, a suppressed feeding test, and a female urine sniffing test. These models were used to evaluate levels of behavioral despair and signs of pleasure during each task by measuring variables such as time spent being stationary and time spent sniffing. “We found that this naltrexone pretreatment thirty minutes before ketamine injection blocked the antidepressant-like effect in all of these tests,” Jiang said. These results suggested that the endogenous opioid system plays an important role in producing ketamine’s rapid antidepressant effects.
Next, the researchers wanted to study how this activation mechanism operates more precisely by confirming that activity in the brain was responsible for these antidepressant actions. This was achieved by infusing naltrexone directly into the prefrontal cortex before the ketamine treatment. The results of behavioral tests following this pretreatment confirmed the researchers’ hypothesis. “We saw the same thing—that local infusion of naltrexone [blocks] ketamine’s antidepressant effect,” Jiang said.
The road to publication was not without its struggles. Jiang joined the project in late 2019 as a postdoctoral researcher under neuroscientist Ronald Duman. Duman’s passing in 2020 and the COVID-19 lockdowns temporarily restricted research progress. However, under the mentorship of Yale professor of psychiatry Christopher Pittenger, Jiang and his collaborators finally shared their compelling findings four years later.
Jiang noted that their results are crucial for building a complete mechanistic understanding of the opioid system’s role in producing antidepressant effects. He foresees that the team will expand their study to include female rats, as there are known sex-based differences in ketamine responses. Additionally, the team wants to determine how ketamine increases the presence of beta-endorphin—a naturally occurring pain blocker—in the prefrontal cortex due to its potential in antidepressant treatments. “If we know how ketamine increases the presence of this peptide in the brain, this knowledge may inform the development of novel treatment strategies for depression in the future,” Jiang said.
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