Many researchers are finding new ways to use drugs already available for treating depression.

According to the Food and Drug Administration, it takes an average of eight years to develop a new drug; drug companies say it can take 15. For every 5,000 new compounds that make it into preclinical testing, only five enter human trials. The costs can be astronomical. Because pharmaceutical companies are loath to invest in a therapy that may never succeed—a particular obstacle in neurology, which includes very rare diseases—many researchers are finding new ways to use drugs already available. The approach is faster, cheaper, and often remarkably effective, says Robert Baughman, associate director for technology and development at the National Institute for Neurological Disorders and Stroke. “From a combination of clinical observation and understanding of brain biochemistry, we often find that a drug’s activity in one disorder will predict its usefulness in a seemingly unrelated condition,” Baughman says. The anti-epileptic drug pregabalin, for example, has proven quite effective at treating neuropathic pain. This intense, chronic pain is common in diabetes, AIDS, and spinal cord injury. It results from nerve damage, when cells continue to transmit pain messages indefinitely, and does not respond to conventional analgesics. Reporting in the November 2006 Neurology, Philip Siddall and colleagues at the University of Sydney, Australia, found that patients with neuropathic pain caused by spinal cord injury reported a significant decrease in pain when given pregabalin twice a day for twelve weeks; patients also reported better sleep and less anxiety. Another anticonvulsant, gabapentin, has proved useful at treating post-herpetic neuralgia, or shingles (an intensely painful viral infection of sensory nerves), and the neuropathic pain associated with diabetes. Baughman notes that anticonvulsants have the advantage of achieving their primary task quickly. “If a drug is meant to stop a seizure, you know right away if it works or not,” he says. “Then you have a rationale for testing it in a condition that responds more slowly, such as chronic pain.” Fast-Acting Antidepressant Two existing drugs have shown dramatic results in relieving depression. In the August 2006 Archives of General Psychiatry, researchers led by Carlos Zarate, Jr., of the National Institute of Mental Health reported that ketamine, an anesthetic, improved the mood of patients with major depression in as little as two hours. The subjects had tried at least two conventional treatment regimens, usually more, without success, and their current depression had lasted up to several years. After receiving a single low dose of ketamine directly into the bloodstream, many patients noticed a lessening of symptoms within the hour. Seventy percent showed a response after 24 hours, as measured by their having reported a 50 percent reduction in scores on several measures of depression. “Our patients said they felt a lifting of the heaviness that had engulfed them, as well as relief from suicidal thoughts and guilt,” says study author Husseini Manji of NIMH. About 30 percent achieved “remission,” meaning that they had almost no symptoms; at the end of the weeklong study period, most patients still felt better. These results are in stark contrast to currently available antidepressants, such as the selective serotonin reuptake inhibitors (SSRIs), which take from three to eight weeks to work, if they work at all. SSRIs are thought to trigger a complex chain of biochemical events that ultimately improves mood. Previous studies have suggested that toward the end of this process, specific receptors for the neurotransmitter glutamate, dubbed NMDA receptors, become involved. Because ketamine targets the NMDA receptors, Manji and colleagues suspect that its actions bypass many of the earlier steps initiated by the SSRIs, thus relieving depression more quickly. The report confirms a similar result reported in the February 2000 Biological Psychiatry, from a trial of eight patients. An investigator in both studies, Dennis Charney, now at Mount Sinai Medical Center in New York, recalls his surprise at the initial findings. “The purpose of the 2000 study was to see if NMDA receptor signaling was abnormal in patients with depression,” Charney says. “We used ketamine more as a probe—we didn’t expect it to be such an effective treatment.” Serendipity played a role when another drug, a sedative known as scopolamine, also proved to be a fast-acting antidepressant. Scopolamine targets receptors for the neurotransmitter acetylcholine, which is out of balance in depression. Because acetylcholine plays a role in memory, and memory problems and lack of focus are common complaints in depression, Maura Furey and Wayne Drevets of NIMH explored whether scopolamine could improve memory in patients with depression. Subjects with depression or bipolar disorder were given three separate infusions of scopolamine and asked to perform memory tests. Though effects on memory were mixed, the patients reported a marked improvement in mood beginning three to four days after the first treatment. “We thought that tweaking the acetylcholine system would help with cognitive symptoms,” Furey says. “We were quite surprised to find that scopolamine had such a powerful effect on mood.” Their findings were published in the October 2006 Archives of General Psychiatry. Because about a third of depressed patients do not respond to any treatment, approaching the disorder from a different angle makes sense, Manji says. He notes that such patients may have abnormalities unrelated to serotonin. “You can inhibit serotonin reuptake all you want, but if that’s not where the problem is, it won’t help,” he says.

NMDA, receptor, antidepressant, depression, scopolamine, acetylcholine, medication, treatment