Evidence Mounting for Ketamine for Treatment-Resistant Depression

Ketamine and other drugs targeting the brain's NMDA receptors may benefit treatment-resistant depression.

TORONTO — Treatment-resistant depression (TRD) is a serious problem for many clinicians as such patients have high levels of dysfunction impacting their work and relationships, not to mention much higher health care costs. But growing evidence is indicating that ketamine and other drugs targeting NMDA receptors are potential solutions.

“What we decided to ask is does targeting the NMDA receptor [complex] bring about rapid antidepressant effects in treatment-resistant depression,” said Carlos A. Zarate, Jr., MD, chief of the Experimental Therapeutics and the Physiology Branch and the of the Section on Neurobiology and Treatment of Mood and Anxiety Disorders at the National Institute of Mental Health. “And the answer is yes.”

Zarate, who spoke at the American Psychiatric Association Annual Meeting here on treatment and research on TRD and bipolar disorder, said that new treatments for depression are needed as pharmaceutical companies have stopped working on development of new treatments and many depression patients relapse with existing medications. In addition, TRD is related to increased morbidity and mortality.

“For some patients, there appears to be a ceiling effect in our ability to treat them despite augmentation, switching, and combined strategies.”

But research into ketamine, originally developed as an anesthetic, offers promise. He cited a study that found that that those treated with ketamine saw improvement in depressive symptoms within two hours.

In another study  — this time with an active comparator, the benzodiazepine midazolam  —  those who received a ketamine infusion had a rapid onset of depression improvement, based on the Montgomery-Asberg Depression Rating Scale (MADRS).

Janssen Pharmaceutica is developing esketamine, which would be administered in a nasal spray formulation for TRD. Esketamine, an enantiomer of ketamine, is in Phase II development as of July 2014.

Zarate mentioned a study that found esketamine also produced a rapid antidepressant effect, which was the same whether the drug was infused two or three times per week.

“The similarities between all the studies suggest an true biological effect is likely” with ketamine, he said. “Arguably, this is one of the first good [signs as] we have come up with a  target that manipulates a specific area [of the brain] that brings about a specific effect.

Zarate is about to head up a study involving another experimental NMDA receptor antagonist, 4-CI-KYN (L-4-chlorokynuerenine, which he said induces rapid and sustained anti-depressant effects, without ketamine-related side effects.


Zarate CA. An Update on the Treatment and Research of Treatment-Resistant Depression and Bipolar Disorder. Lecture at: APA 2015. May 16-20, 2015; Toronto, Canada.