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Experimental Medication Kicks Depression in Hours

Current antidepressants usually take four to eight weeks to exert their effects. In a preliminary new study, a single intravenous dose of ketamine, a medication usually used in higher doses as an anesthetic, brought symptom relief to people with treatment-resistant depression in as little as two hours.

Ketamine blocks a brain protein called the N-methyl-D-aspartic acid (NMDA) receptor. NMDA receptors are critical for receiving the signals of glutamate, a brain chemical that several emerging lines of evidence suggest plays a role in mood disorders. Agents that block the NMDA receptor reduce depression-like behaviors in animals, and a preliminary study in humans showed that ketamine had a rapid antidepressant effect .

Researchers at NIH's National Institute of Mental Health set out to further explore ketamine's potential to treat human depression. They randomly assigned 18 treatment-resistant, depressed patients to receive either a single intravenous dose of ketamine or a placebo (an inactive compound). One week later, the participants were given the opposite treatment, unless the beneficial effects of the first treatment were still evident. This "crossover" study design strengthens the validity of the results.

In the August issue of the Archives of General Psychiatry, the researchers report that depression improved within one day in 71% of the patients who received ketamine, with 29% of these becoming nearly symptom-free. Over a third of the patients who received ketamine still showed benefits a week later. In contrast, those receiving a placebo infusion showed no improvement. None of the patients had serious side effects.

Scientists think the reason that current antidepressant medications take weeks to work is that they act on targets close to the beginning of a series of biochemical reactions regulating mood. The medications' effects have to trickle down through the rest of the system, which takes time. Ketamine's target, the NMDA receptor, may be closer to the end of this series of reactions.

"This may be a key to developing medications that eliminate the weeks or months patients have to wait for antidepressant treatments to kick in," lead researcher Dr. Carlos A. Zarate Jr. said.

Ketamine, while important for research, is unlikely to become a widely-used clinical treatment for depression because of its potential side effects, including hallucinations and euphoria, at higher doses. Nevertheless, scientists say this research could point the way toward development of a new class of faster- and -longer-acting medications. The research team is now zeroing in on other areas of the glutamate system. Learning which components of the system are affected by compounds such as ketamine may help scientists understand how and why depression occurs and point the way to more precise targets for new diagnostic tests and medications.