Ketamine and NMDA Receptor Antagonists for Depression

In recent months, it's been the rare week that doesn't come with a report about the dangers of antidepressants. These drugs do have their drawbacks, but the dangers they pose are not their main problem. Their biggest shortcoming is that they don't work very well; fewer than half of the patients treated with them get complete relief, and that relief takes an unacceptably long time-2 to 3 weeks-to kick in.

This is why a recent report¹ showing that a single infusion of ketamine relieves depressive symptoms immediately and robustly and that the relief persists deserves more than passing interest. It holds out the possibility of a new class of antidepressants, far more effective than the ones we have now.

This is not the first time that ketamine has been shown to be a powerful antidepressant. A similar study, reported in 2000, came up with identical results.² Like the current study, the previous one compared a single ketamine infusion with a saline infusion. Ketamine brought relief of depressive symptoms within hours and the relief lasted for several days. A study reported in 2002 using a very different approach reached similar conclusions.³ Patients with major depression who underwent orthopedic surgery were randomly assigned to receive ketamine as part of their anesthesia regimen. Only the group who received ketamine showed postoperative relief of depression.

BUT IT'S PSYCHEDELIC
Like its cousin, phencyclidine, ketamine is a selective and potent N-methyl-d-aspartate (NMDA) receptor antagonist. It is approved for use as an anesthetic and is used in the treatment of chronic pain. Ketamine is also used recreationally and has potential for abuse. It produces short-lived perceptual distortion, other psychotomimetic effects, and euphoria. But these psychedelic properties, although experienced by many of the patients in these studies, appear to be independent of the antidepressant effect. The psychotomimetic effects occur within minutes and last for less than 2 hours, whereas the antidepressant effects begin as the psychotomimetic effects subside and persist for days. Robert Berman, MD,² first author of the report published in 2000, notes that the depressed patient who showed the most dramatic antidepressant response with ketamine experienced no ketamine-related psychotic symptoms.

Although the current report describing ketamine's rapid and potent relief of depression has garnered attention in both the scientific and general media, Berman and colleagues' report was ignored. Now an adjunct assistant clinical professor of psychiatry at Yale University in New Haven, Connecticut, Berman suspects that the scientific community may be more open to the idea that an NMDA receptor antagonist could be an antidepressant. The monoamine hypothesis of depression, which has dominated both depression research and drug development for the past 40 years, is beginning to lose its grip in the face of several lines of evidence, including the shortcomings of current antidepressants. Among that evidence are data that clearly implicate NMDA, a glutamate receptor, in the action of antidepressants: NMDA receptor antagonists have antidepressant effects in animal models of depression; almost all antidepressants when given long-term modify NMDA receptor function in a time frame consistent with their delayed therapeutic effects; and, antidepressants alter the expression of messenger RNA that encodes NMDA receptor subunits.¹

Carlos Zarate, MD, lead author of the current report, points out that although the glutamate system may well play a role in the action of antidepressants, this does not necessarily implicate it in the cause or pathophysiology of depression. The little available data on the link between depression and the glutamate system-one study showed that depressed patients have elevated levels of glutamate in the occipital cortex⁴-is less than convincing so far.

Notwithstanding the significance of the ketamine findings, Berman strikes some cautionary notes. Although both studies were double-blind in principle, the psychedelic symptoms produced by ketamine made it impossible for these studies to be truly double-blind. Depression is notoriously responsive to the placebo effect, and the fact that both the patients and the investigators knew when ketamine or placebo was received might have biased the results in favor of a treatment effect for ketamine.

On the other hand, Berman notes that the original purpose of his study was not to examine the antidepressant effect of ketamine but to assess the cognitive effects of ketamine in depressed patients. The "treatment effect," he says, was a "surprise." The depressed patients in the current study were treatment-resistant; they had not improved with at least 2 previous courses of antidepressant treatment. Such patients have a low rate of response to both further antidepressant treatment and placebo. Thus, although it is not out of the question that the profound antidepressant response to ketamine (71% of the patients showed substantial improvement within 1 day of the ketamine infusion) was a placebo effect, it is unlikely.

Zarate, who is chief of the Mood and Anxiety Disorders Research Unit at the National Institute of Mental Health in Bethesda, Maryland, and colleagues hope to learn something about what ketamine does to the brain that alleviates depression. They also are searching for an NMDA antagonist that might possess ketamine's antidepressant properties without its psychotomimetic effects. Zarate and his colleagues have found that the NMDA receptor antagonist memantine (Namenda) doesn't relieve depression and that riluzole (Rilutek), a drug that inhibits glutamate release, does improve depression but with the same time delay as conventional antidepressants. The researchers are about to launch a study of a substance that blocks one of the subunits (NR2B) of the NMDA receptor. It is hoped that it will retain ketamine's antidepressant potency without its psychotomimetic effects.

REFERENCES1. Zarate CA Jr, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-d-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63:856-864.
2. Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Bio Psychiatry. 2000;47:351-354.
3. Kudoh A, Takahira Y, Katagai H, Takazawa T. Small-dose ketamine improves the postoperative state of depressed patients. Anesth Analg. 2002;95: 114-118.
4. Sanacora G, Gueorguieva R, Epperson CN, et al. Subtype-specific alterations of gamma-aminobutyric acid and glutamate in patients with major depression. Arch Gen Psychiatry. 2004;61:705-713.