From Anesthesia to Popular Club Drug to Fast-Acting Antidepressant: Ketamine Continues to Impress and Confound Researchers

Ketamine as a Fast-Acting Antidepressant

A novel glutamatergic hypothesis of depression, using a 50-year-old anesthesia medicine, has had a remarkable run as of late. First an anesthetic, then a popular club drug in the 90s known as “Special K” (and currently still popular in Hong Kong as a “Rave Drug”), and now a novel, fast acting antidepressant, ketamine is a N-Methyl D-Aspartame (NMDA) receptor antagonist. Ketamine was FDA-approved in the U.S. as an anesthetic nearly 50 years ago. It is used primarily by anesthesiologists in both hospital and surgical settings. As an N-Methyl D-Aspartame (NMDA) receptor antagonist with dissociative properties, NMDA receptors possess high calcium permeability, which allows ketamine to reach its target quickly. Increasing clinical evidence has shown that a single sub-anesthetic dose (0.5 mg/kg) of IV-infused ketamine exerts impressive antidepressant effects within hours of administration. These effects have stabilized suicidality in severely depressed, treatment-resistant individuals. The effects of low-dose ketamine infusion therapy can last up to seven days, although the dosing and patient characteristics regarding its optimal effectiveness have not been established.

Why Does This Matter?

In my book, “The Good News About Depression: Cures And Treatments In The New Age of Psychiatry”–Revised (1996), I said there was never a better time to be depressed, due in part to recent breakthroughs in understanding of the underlying biology of depression, plus the discovery of novel therapeutics e.g., the SSRIs. Today that book might be called the “Better News About Depression” as a result of the effectiveness of novel treatments such as Transcranial Magnetic Stimulation (TMS) and now ketamine, which has illuminated and broadened our understanding and view of treating depression.

Why Is This Better News?

New clinical and preclinical studies suggest that dysfunction of the glutamatergic system is perhaps more relevant and important than the current catecholamine hypothesis and therapy that targets serotonin, norepinephrine and sometimes dopamine. These medications often take four to six weeks to exert any therapeutic benefit, whereas rapid reductions in depressive symptoms have been observed in response to a single dose of ketamine. This is a vast departure from the SSRIs and SSNRIs that have occupied the mainstream of pharmacological therapy for depression and anxiety disorders for more than 30 years.

Lastly, the mechanism of action of NDMA antagonists are comparatively underexplored but vitally important to our understanding of depression, reversal of suicidality, as well as the debilitating, depressive symptoms induced by abuse of alcohol and other drugs. This review highlights the current evidence supporting the antidepressant effects of ketamine as well as other glutamatergic modulators, such as D-cycloserine, riluzole, CP-101,606, CERC-301 (previously known as MK-0657), basimglurant, JNJ-40411813, dextromethorphan, nitrous oxide, GLYX-13, and esketamine. This all adds up to some very good news for depressed persons and especially those who do not respond to previous SSRI or SSNRI treatments.