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Opioid system plays key role in ketamine’s antidepressant effects, Stanford study finds

Ketamine, a promising new treatment for depression, works through the brain's opioid system, Stanford study finds, defying long held beliefs.

For about a dozen years now, the drug ketamine has been a buzz word in psychiatric research circles. Many considered it the most exciting thing to emerge in decades to successfully treat treatment-resistant depression as well as other severe forms of psychiatric disorders such as obsessive compulsive disorder and PTSD.

Not only did studies show that the drug worked really well and really fast for short periods of time, it was also thought that its antidepressant effects stemmed solely from its impact on the glutamate system. Now, a new Stanford study has overturned this belief by reporting that ketamine works, at least in part, by activating the brain’s opioid system. The study appears in the American Journal of Psychiatry.

As Alan Schatzberg, MD, professor of psychiatry and a senior author of the study, said in a press release written by my colleague Kimber Price: "I wasn’t sure that ketamine really worked to treat depression. Now I know the drug works, but it doesn’t work like everyone thought it was working."

This is important for a number of reasons, but key among them may be the concern over the ever-growing opioid epidemic and that, perhaps, giving ketamine for depression treatment to prevent suicides, for example, could lead to addiction.

Ketamine was developed in the 1960s and has been used for decades as an anesthetic during surgery. It’s also known as a party drug that can have dissociative side effects including hallucinations and can lead to dependence. Because it was believed to work through the glutamate system, researchers were hoping to develop similar drugs that could work without addiction risks.

Stanford researchers set out to determine if the antidepressive effects of ketamine were also generated by the opioid system. They conducted a small clinical trial that enrolled 12 participants with treatment-resistant depression. The release explained how the trial worked:

Twelve participants received infusions of ketamine twice — once preceded by naltrexone, an opioid-receptor blocker, and once with placebo. Neither the study participants nor the researchers were told whether active drug or placebo was administered during each test. The researchers found that ketamine reduced depressive symptoms by about 90 percent for three days in more than half of the participants when administered with a placebo, but had virtually no effect on depressive symptoms when it was preceded by naltrexone.

While this was a small trial, results indicated that the opioid system was essential for ketamine’s antidepressant effects. Researchers surmised that perhaps ketamine worked quickly by activating the brain’s opioid receptors during its first phase of activity and then the glutamate system stepped in to sustain these effects after ketamine was metabolized.

More research is needed to fully understand ketamine’s antidepressant properties, the researchers said, but results of this study indicate clinical use of the drug should proceed with caution out of renewed concern over possible addiction potential.

As Schatzberg warned:

 Psychiatry used opioids, barbiturates and high doses of stimulants to treat depression 50 or 60 years ago. We have to properly examine the risks associated with using drugs of abuse — even in low doses — to treat depression. It’s not limited to ketamine; other antidepressant drugs that target the opioid system are in development now, too.

Photo by Maranatha Pizarras

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