Scientists have discovered that ketamine works as an antidepressant at least in part by activating the brain's opioid system. The research is believed to be the first to address how ketamine works in the human brain to provide relief from depression. The study was published in The American Journal of Psychiatry.

The finding overturns previously held beliefs that the drug's antidepressant effects stemmed solely from its impact on the glutamate system. These beliefs led to the widespread use of ketamine to treat depression and spurred the development of glutamate-blocking drugs for use as antidepressants.

The new finding also highlights the interaction between depression, pain, and opioid addiction and presents an opportunity for clinicians to reframe treatment approaches for three of the most important public health crises today.

Ketamine's origins

Ketamine was developed in the 1960s and has been used for decades as an anesthetic during surgery. It can cause dissociative side effects, including hallucinations, and has been used as a recreational drug. If used regularly, it can lead to dependence.

Although the Food and Drug Administration has not approved the drug's use for depression, some doctors have prescribed it "off-label" in recent years as a rapid but short-acting antidepressant.

Ketamine infusions are also used to treat chronic pain, which is a common condition in depressed patients. Exactly how ketamine blunts pain is not fully understood, but it is known to work at least in part on the opioid system.

The study enrolled adults with treatment-resistant depression, meaning their condition had not improved after multiple treatment efforts. Twelve participants received infusions of ketamine twice once preceded by naltrexone, an opioid receptor blocker, and once with a placebo. Neither the study participants nor the researchers were told whether active drug or placebo was administered during each test.

Depressive Symptoms

The researchers found that ketamine reduced depressive symptoms by about 90% 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.

Antidepressant Effect

The prevailing hypothesis for ketamine's antidepressant effect was that the drug blocked a receptor for glutamate, an excitatory neurotransmitter in the brain that is implicated in memory and learning. But ketamine's mechanism is complicated, as it acts on many different receptor types beyond glutamate receptors, and it acts in three distinct phases rapid effects, sustained effects and returns to baseline.

Schatzberg noted that no other glutamate-receptor blocker has an antidepressant effect like ketamine and that attempts to develop similar drugs have largely failed.

The authors say that revealing the role of the opioid system in the antidepressant effects of ketamine is critical in the effort to develop new antidepressants. For instance, glutamate receptor blockers may not have rapid antidepressant effects unless they also involve the opioid system.

Drugs Abuse

Psychiatry used opioids, barbiturates and high doses of stimulants to treat depression 50 or 60 years ago. They 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.

People who are depressed take as much as 2.4 times as many opioids immediately after painful surgeries than those who aren't depressed, he said. "There is truly a link between depression, pain, and opioid use.