Approved by regulators as a tranquilizer and favored by some as a party drug, ketamine continues to show promise as a serotonergic antidepressant offering speedier relief for even the most severe cases of major depression.

In brain imaging experiments on rhesus monkeys, investigators from RIKEN Center for Life Science Technologies in Japan found that ketamine boosted activity among serotonergic neurons in brain areas responsible for regulation motivation, perhaps explaining the antidepressant effect seen in some human studies. Hajime Yamanaka and Hirotaka Onoe, of the center, worked with an international team of scientists using positron emissions tomography (PET) to glean insight into how the drug may lead to newer serotonergic antidepressants.

“To elucidate the involvement of the serotonergic system in the antidepressant action of ketamine in the living brain, we performed a PET imaging study using nonhuman primates and two PET radioligands,” the investigators wrote in a paper published Tuesday in Translational Psychiatry. By using the radioactive biochemical substances, they were able to focus on a couple of important serotonergic brain receptors, including the 5-HT1B serotonin receptor and the serotonin transporter SERT.

To date, at least one clinical physician in the United States presently prescribes ketamine off-label as a pediatric treatment for major depression, though the practice remains exceedingly rare. Last year, Scientific American reported on ketamine use among adult patients for major depression, including Dennis Hartman, a 47-year-old former Illinois business executive. For 30 years, Hartman had tried Prozac-class antidepressants, along with tranquilizers, mood stabilizers, supplements, and complementary medicine — to no avail.

But Hartman found salvation one sleepless night at the computer when he learned of a clinical trial underway by the U.S. National Institutes of Health.

“I received a single infusion as part of that study,” Hartman said, “and I achieved 100 percent remission — a complete relief of all symptoms, which for me was dysphoria, anhedonia, extreme anxiety, cognitive impairment, very severe physical fatigue. I felt normal and healthy and happy within three or four hours after the infusion.” However, the study only provided a single infusion of ketamine, whose seemingly miraculous effects gradually dissipated over the course of a few weeks, when Hartman found himself once again deeply depressed.

Crisscrossing the country, Harman first found a doctor in San Diego for treatment before visiting New York Ketamine Infusions in New York City, where he received six treatments for $525 apiece — higher than the street price for an dissociative trip to what recreational users refer to as the “k hole.”

Aside from merely observing an effect, the investigators were able to glean a fair amount of insight into the underlying biological mechanisms of the drug action. The Japanese-led international team found that ketamine’s effect on the 5-HT1B receptor was blocked — in a rodent experiment — by treatment with NBQX, a drug known to inhibit ketamine’s effect by blocking the glutamate AMPA receptor, though leaving the transporter SERT untouched. The investigators said ketamine may offer antidepressant relief by increasing the expression of post-synaptic 5-HT1B receptors, a process mediated by the AMPA receptor.

Source: Yamanaka H, Yokoyama C, Mizuma S et al. A Possible Mechanism Of The Nucleus Accumbens And Ventral Pallidum 5-HT1B Receptors Underlying The Antidepressant Action Of Ketamine: A PET Study With Macaques. Translational Psychiatry. 2013.