Researchers explore the antidepressant effects of ketamine

Drug treatments for depression can take many weeks for the beneficial effects to emerge. The excruciating and disabling nature of depression highlights the urgency of developing treatments that act more rapidly. Ketamine, a drug used in general medicine as an anesthetic, has recently been shown to produce improvements in depressed patients within hours of administration. A new study being published in the February 15th issue of Biological Psychiatry provides some new insight into the mechanisms by which ketamine exerts its effects.

Ketamine is classified as an N-methyl d-aspartate (NMDA) glutamate receptor antagonist. Maeng and colleagues now provide new evidence that these antidepressant effects of NMDA receptor antagonists are mediated by their ability to increase the stimulation of á-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) glutamate receptors. In other words, their findings indicate that the antidepressant-like effects of drugs like ketamine are dependent on AMPA receptor stimulation. This suggests that drugs that enhance AMPA receptor function might have rapid antidepressant properties.

Dr. Husseini Manji, corresponding author on this paper and a Deputy Editor of Biological Psychiatry, explains that “by aiming new medications at more direct molecular targets, such as NMDA or AMPA, we may be able to bypass some of the steps through which current antidepressants indirectly exert their effects — a roundabout route that accounts for the long time it takes for patients to begin feeling better with the conventional medications.” He adds, “Today’s antidepressant medications eventually end up doing the same thing, but they go about it the long way around, with a lot of biochemical steps that take time. Now we’ve shown what the key targets are and that we can get at them rapidly.”

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Lilly's Schizophrenia Drug Targets Different Brain Chemicals

Eli Lilly and Co.'s experimental schizophrenia drug, which may replace its top-selling Zyprexa, was just as effective without causing patients to gain weight, according to a study.

Unlike other schizophrenia medicines on the market, the new compound doesn't target dopamine, a chemical that functions within the brain's reward system. It affects glutamate, involved in learning and memory. The study showed the new drug candidate to be as effective as Zyprexa in reducing symptoms such as hallucinations and social withdrawal.

The new drug candidate, dubbed LY2140023, would be the first for the disorder affecting glutamates, a company official said. Zyprexa, with $4.3 billion in 2006 sales, now faces competition from less expensive copies in Canada and Germany, the Indianapolis-based company said on June 8. The drug's U.S. patent expires in 2011.

``Discovering an antipsychotic drug that doesn't work through dopamine is the holy grail of drug development,'' said Gerald Marek, Lilly's chief scientific officer of psychiatric disorders, in an Aug. 30 telephone interview. ``It looks like we've hit upon a target that will ultimately do this.''

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Headway in developing a faster-acting antidepressant

The key might be provided by studying the effect that ketamine, an anesthetic, has on a neurotransmitter.

After years of little progress, scientists are making headway in the search for a better, faster-acting antidepressant. Experiments with an anesthetic called ketamine have yielded important clues about the biology of depression, leading scientists to attack the mood disorder in new ways.

Improved treatments are sorely needed. Depression affects about one in 10 adult Americans each year, while current drugs work in only 50% to 60% of patients, can cause sexual problems and take weeks to work. They also carry a small risk of suicidal thoughts and behaviors in adolescents and young adults.

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