WORRISOME SIDE EFFECTS of antidepressants—that they incite children and adults to kill themselves—have made headlines in recent years; accordingly, the Food and Drug Administration began to require warnings on these medications in 2005. Most experts, however, agree that this labeling is unwarranted, that the science in support of it is flawed and that the warning itself is detrimental to public health—reasoning that it is likely, if anything, to increase suicide by discouraging treatment of depression. Prescriptions for antidepressants have already gone down.
Although it is true that antidepressants can trigger unpleasant symptoms, including agitation, sexual dysfunction and weight gain, these side effects are not the drugs’ main problem. Their biggest shortcoming is that often they do not work very well; fewer than half the patients who take them get complete relief, and that effect takes an unacceptably long time—two to three weeks—to kick in.
This is why a 2006 study led by Carlos A. Zarate, chief of the National Institute of Mental Health’s Mood and Anxiety Disorders Research Unit, deserves more than a passing mention: it showed that a single infusion of ketamine, a drug already used as a painkiller and anesthetic, relieves depressive symptoms in some patients within hours and that the relief persists for several days. The finding holds out the possibility of a far more effective new class of antidepressants.Not a Fluke
It would be easy to dismiss this report if it were a one-off observation. But this is not the first time ketamine has been shown to be a powerful antidepressant. A small study in 2000, which, like the more recent experiment, compared a single ketamine infusion with a placebo saline infusion, yielded identical results. And a study in 2002 that used a very different approach reached similar conclusions. Patients with major depression who underwent orthopedic surgery were randomly assigned to receive or not receive ketamine as part of their anesthesia regimen. Only the group that received ketamine showed postoperative relief of depression.
Ketamine binds selectively and strongly to the N-methyl-d-aspartate (NMDA) receptor on neurons, blocking the neurotransmitter glutamate from activating this receptor. Like ketamine’s illicit chemical cousin, PCP, it is also used recreationally and has potential for abuse. It produces short-lived hallucinations, delusions and euphoria. Nevertheless, these psychedelic properties, though experienced by many of the depressed patients in the studies, appear to be independent of the antidepressant effect. The mind-altering effects occur within minutes and last for less than two hours, whereas the antidepressant benefits begin as the psychedelic effects start to subside and persist far longer. Robert Berman of Yale University, co-author of the 2000 report, notes that in his study the depressed patient who showed the most dramatic antidepressant response with ketamine experienced no ketamine-related psychotic symptoms. These observations suggest that it should be possible to design drugs that have ketamine’s ability to alleviate depressive symptoms without any psychedelic side effects.A New Understanding
Although the more recent report about ketamine has garnered attention, Berman’s report was largely ignored. Berman suspects that the idea that a drug that blocks NMDA receptors could be an antidepressant seems more plausible now than it did seven years ago. That rise in acceptability is because the hypothesis that has dominated depression research and drug development for the past 40 years—that depression involves a deficiency of the neurotransmitter serotonin or norepinephrine—is beginning to lose its grip. Several lines of evidence point to a key role of the NMDA glutamate receptor in the action of antidepressants: NMDA receptor blockers have antidepressant effects in animal models of depression; almost all antidepressants that are given for weeks or more modify NMDA receptor function in a time frame consistent with their delayed therapeutic effects; and antidepressants alter the activity of genes that encode the protein components of NMDA receptors.
Notwithstanding the significance of the ketamine findings, Berman strikes some cautionary notes. Because of the psychedelic symptoms, patients and investigators in the 2000 and 2006 studies could often distinguish between ketamine and placebo. Depression is known to be responsive to expectation, so the obvious side effects of ketamine might well have biased the results in favor of a treatment effect for this drug.
On the other hand, Berman says that in his study he had intended to assess the cognitive effects of ketamine, not to examine its antidepressant properties. Its therapeutic pluses, he says, were a surprise. And the depressed patients in the recent study were resistant to treatment—they had not improved with at least two previous courses of antidepressant treatment. Such patients typically have a low rate of response to both further antidepressant treatment and placebo, and yet, encouragingly, 71 percent showed substantial improvement within one day of the ketamine infusion. Thus, although it is not out of the question that the profound antidepressant response to ketamine was a placebo effect, it is unlikely.
Zarate points out that the glutamate system’s probable role in the action of antidepressants does not necessarily implicate it in the causes or physiological underpinnings of depression. The little available data bearing on the link between depression and the glutamate system—one study showed that depressed patients have elevated levels of glutamate in one area of the brain—are, so far, less than convincing. To figure out how ketamine may alleviate depression, Zarate and his colleagues are using brain-imaging techniques and searching for other promising antidepressant drugs that block the NMDA receptor.
But simply fiddling with the NMDA receptor or glutamate does not bring immediate depression relief. Zarate’s team found that memantine, an NMDA receptor drug used to treat Alzheimer’s disease, does not relieve depression. Similarly, riluzole, which inhibits glutamate release (and, therefore, may cause similar effects to those of blocking glutamate’s receptor) and is used for amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, does improve depression but with the same time delay as conventional antidepressants. Zarate and his co-workers are about to launch a study of a substance that blocks one of the subunits (NR2B) of the NMDA receptor. They hope that it will retain ketamine’s antidepressant potency without triggering perceptual disturbances.