By Garry Cooper
A More Powerful Antidepressant
Every few years, a promising new medication for a mental disorder--Prozac and the other SSRIs or the atypical antipsychotics, for instance--comes along. Typically, a few years later, their effectiveness turns out to be less than promised and their side effects worse than anticipated. So it's appropriate to greet the news about a recent study of ketamine hydrochloride that's gotten heavy media play with a healthy degree of skepticism. But this time, the optimism may be justified: in a small clinical trial, a single injection of the drug significantly alleviated treatment-resistant major depression within two hours, and the effects lasted at least a week.
The study of 18 people reported in the August Archives of General Psychiatry found that on the day after infusion of ketamine, 71 percent of the people had significant improvement in their depression and 29 percent actually had remission after receiving this drug. Meanwhile, none of the 14 people who received a placebo injection improved after seven days. Put another way, the effect size of the drug on depression was 1.46 after 24 hours and .68 a week later. By comparison, an effect size of .50 is considered high.
The study, led by psychiatrist Carlos Zarate under the auspices of the Mood and Anxiety Disorders Program of the National Institute of Mental Health, is part of growing research on the role of the amino acid glutamate (methyl-d-aspartate) in the brain. In the past few years, fluctuating glutamate levels have been implicated in such disorders as epilepsy, Parkinson's, Alzheimer's, bipolar disorder, and schizophrenia, as well as in depression. Glutamate, which Zarate calls "the director of the orchestra," is thought to control the firing of neurons, which transport and process neurotransmitters like serotonin and dopamine. Thus working on glutamate levels might be a more precise way of alleviating problems related to the brain's neurotransmitters. Targeting the neurotransmitters with SSRIs is like trying to fix static in the phone lines by adding amplifiers to the phone; targeting glutamate works directly on the transmission problem.
When you tinker with such a basic level of the brain, of course, you want to make certain you're using a accurate instrument, and researchers are a long way from knowing how to regulate glutamate levels just enough to only alleviate the intended symptoms. Ketamine is already in use illegally and has caused much damage--it's better known as the club drug Ecstasy. In Zarate's study, ketamine, in far lower doses than the street drug, caused euphoria, disorientation, dizziness, and depersonalization, and even though these effects lasted less than two hours after the injection, a medication with those kinds of strong, immediate effects needs considerably more research and fine tuning. Nevertheless, Zarate's study seems to imply that we've taken a major step toward developing antidepressant medications that act within an hour rather than days and have a much higher success rate.