Stanford University School of Medicine scientists have discovered¹ that ketamine treatment activates the brain's opioid system, overturning previously held beliefs that the antidepressant effect stems directly from the glutamate system (leading to the development of glutamate-blocking drugs as antidepressants). The research is, according to the authors, the first to address how ketamine works in the human brain to provide relief from depression.
"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 return to baseline," said co-senior author Carolyn Rodriguez, MD, PhD, assistant professor of psychiatry and behavioral sciences at Stanford University School of Medicine, in a press release.²
In the small clinical trial (n = 30) of subjects diagnosed with treatment-resistant depression, participants were given an opioid-receptor blocker (50 mg of naltrexone) or placebo, prior to taking ketamine (0.5 mg/kg IV infusion). The researchers defined response as a reduction ≥ 50% in score on the 17-item Hamilton Depression Rating Scale score on postinfusion Day 1. Results showed 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 preceded by naltrexone. Because naltrexone dramatically blocked the antidepressant but not the dissociative effects of ketamine, however, the trial was halted at the interim analysis.
Researchers theorized that the trial may help to explain why ketamine works so quickly as an antidepressant: by activating the brain's opioid receptors during its first phase of activity. The glutamate system, therefore, may be responsible for the sustaining effects after the ketamine has metabolized.
Overall, they found that ketamine’s acute antidepressant effect requires opioid system activation. The demonstrated interaction between depression, pain, and opioid receptors may also provide an opportunity for clinicians to reframe treatment approaches. The authors suggested that that revealing the role of the opioid system in the antidepressant effects of ketamine is critical in the effort to develop new antidepressants.
"Psychiatry used opioids, barbiturates and high doses of stimulants to treat depression 50 or 60 years ago," said co-senior author Alan Schatzberg, MD, professor of psychiatry and behavioral sciences at Stanford University School of Medicine, in a press release.² "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."
