Ketamine a Viable Option for Severe Depression?

Megan Brooks

October 11, 2012

October 11, 2012 — The discovery that ketamine produces rapid antidepressant effects in patients with severe treatment-resistant depression is fueling basic neuroscience research, leading to a greater understanding of the neurobiology of depression and maybe more effective treatments, a new review suggests.

Ketamine, an N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, is best known in medicine as an anesthetic but also has some notoriety as a street drug, sometimes dubbed "Special K," and is taken illicitly for its psychedelic effects.

However, recently ketamine has gained interest among researchers for its potential as a unique, rapid-acting antidepressant.

Typical antidepressants such as the serotonin selective reuptake inhibitors (SSRIs) take weeks to months to have an effect and are only moderately effective, leaving more than one third of depressed patients resistant to drug therapy.

"The rapid therapeutic response of ketamine in treatment-resistant patients is the biggest breakthrough in depression research in half a century," review author Ronald Duman, PhD, professor of psychiatry and neurobiology at Yale University in New Haven, Connecticut, said in a statement.

However, Dr. Dunham told Medscape Medical News, although clearly promising for depression, ketamine does have some roadblocks.

"It produces transient side effects [for about 1 hour], including mild hallucinations and dissociative effects in some patients, subsequent to the antidepressant response. Ketamine is also a drug of abuse, so caution is needed when considering widespread use of this agent."

"Nevertheless, there are millions of depressed patients who do not respond to conventional antidepressants and are in dire need of a drug like ketamine," Dr. Duman added.

With Dr. Duman and coauthor George Aghajanian, MD, professor emeritus of psychiatry at Yale University, the review was published October 5 in Science.

Timely, Authoritative

Commenting for Medscape Medical News, James W. Murrough, MD, from Mount Sinai School of Medicine's Mood and Anxiety Disorders Program in New York City, described the article as a "timely, well written, and authoritative review by 2 neuroscience researchers who have really done the bulk of the work looking at the biological basis for how ketamine might bring about a rapid antidepressant effect."

The original link between ketamine and relief of depression was made by John Krystal, MD, chair of the Department of Psychiatry at Yale, and Dennis Charney, MD, formerly of Yale, now professor of psychiatry, neuroscience, and pharmacology and dean at Mount Sinai School of Medicine.

In 2000, they published results of a small, double-blinded, placebo-controlled study showing that intravenous infusions of ketamine produced significant and rapid antidepressant effects (Berman et al; Biol Psychiatry, 2000;47:351-354).

"That was the first controlled study that showed that ketamine had sort of an unexpected rapid antidepressant effect in patients," said Dr. Murrough. "We knew it was a glutamate antagonist, but at this time (in 2000), the role of glutamate in depression was not at all on the radar."

That study was followed by an article published in 2006 that also showed rapid (within 2 hours) and significant antidepressant effects after a single infusion of ketamine in 18 patients with treatment-resistant depression (Zarate Jr et al; Arch Gen Psychiatry, 2006;63:856-864).

Since then, a number of studies replicated and extended the findings — including a study by Carlos Zarate Jr, MD, and colleagues published in 2010 in Archives of General Psychiatry and reported by Medscape Medical News at the time.

These studies sent neuroscientists on a quest to figure out at a cellular level, using animal models, how ketamine worked and what it could reveal about depression.

Jury Still Out

The literature suggests that depression is caused by disruption of homeostatic mechanisms that control synaptic plasticity, resulting in destabilization and loss of synaptic connections in mood and emotion circuitry, the authors note. Ketamine appears to target synaptic dysfunction in depression.

The findings highlight the "central importance of homeostatic control of mood circuit connections and form the basis of a synaptogenic hypothesis of depression and treatment response," the review authors write.

Is ketamine currently used to treat refractory depression?

"A year ago, I would have said no, it's not being used clinically. But in the last year, I've run into patients who've said they had been treated with low-dose ketamine by their psychiatrist, and doctors at national meetings who've said they've used it in their practice, but it's very sparse, it's far from widespread," said Dr. Murrough.

It is important to note, he added, that to date, most of the research has been limited to the effects of a single dose.

At a medical conference in June, as reported by Medscape Medical News, Dr. Murrough and colleagues demonstrated that administration of 6 low-dose infusions of ketamine over 2 weeks improved symptoms in a small study of patients with treatment-resistant depression.

It helped "at least while they were getting the ketamine, then there was a relapse that came in as few as a couple days to several months or longer in a few cases," he said.

Dr. Murrough said he and his colleagues are now "closing out" another study of ketamine that should be published in a couple of months. Other trials are ongoing.

"The jury is still out on whether ketamine itself could be developed into a bona fide treatment. We happen to believe that it can be. We advocate a cautious approach, but we are cautiously optimistic that ketamine could be a treatment option for severe refractory depression," he said.

"The benchmark treatment right now for severe refractory depression is electroconvulsive therapy [ECT]," Dr. Murrough pointed out, "so you'd have to believe that ketamine has a worse risk-benefit profile than ECT, and so far, we don't see that; it appears to be very well tolerated."

Dr. Duman and Dr. Aghajanian have disclosed no relevant financial relationships. In the past 2 years, Dr. Murrough has received research support from Evotec Neurosciences and Janssen Research & Development. Dr. Charney has been named as an inventor on a use patent of ketamine for the treatment of depression. If ketamine were shown to be effective in the treatment of depression and received approval from the US Food and Drug Administration for this indication, Dr. Charney and Mount Sinai School of Medicine could benefit financially.

Science. 2012;338:68-72. Abstract