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For a decade, scientists have been trying to explain why a single dose of the drug ketamine manages to do what typical antidepressants don't: Lift symptoms of chronic depression within hours, rather than weeks, in treatment-resistant patients.
Now, researchers at the Yale School of Medicine, which was involved in discovering the original link between ketamine and relief from depression, have mapped the pathway that allows the pediatric anesthetic to regenerate synaptic connections between brain cells damaged by stress and depression, according to a review of scientific research published in the Oct. 5 issue of the journal Science.
"The rapid therapeutic response of ketamine in treatment-resistant patients is the biggest breakthrough in depression research in a half-century," said Ronald Duman, a professor of psychiatry and neurobiology at Yale and the paper's co-author.
"We used to think of the brain as this hard-wired part of the body that developed a certain (immutable) way. . . but what we realize now is that it's not. The connections are very plastic," he said. "Even though depression and stress are associated with a loss of those connections, these are reversible conditions. And that's a hopeful discovery."
In reviewing research on ketamine, Duman and Dr. George K. Aghajanian, professor of psychiatry at Yale, postulate that depression is caused by disruption of homeostatic mechanisms that control the plasticity of synapses, resulting in a loss of synapse connections in the brain's mood and emotional circuitry.
Ketamine works on the glutamate pathway in the brain -- a different type of neurotransmitter system than targeted by current antidepressants, which can take months to improve symptoms and do not work at all for one in three patients.
"The widely prescribed serotonin selective reuptake inhibitors (SSRIs), derived from drugs developed more than 50 years ago, take weeks to months to produce a therapeutic response," the Yale researchers said. SSRIs target only monoamines, which are modulatory transmitters that don't produce "a robust impact on synaptic transmission" or a release of BDNF, a protein that supports the growth of neurons and synapses.
Agents such as ketamine "produce more profound effects on fast excitatory glutamate transmission" and increase BDNF release, to cause long-term changes in synaptic connections, Duman said.
Understanding how ketamine works in the brain could lead to development of an entirely new class of antidepressants, offering relief for millions of people suffering from chronic depression, Duman said. He noted that ketamine itself has limitations, however, including that it may cause short-term symptoms of psychosis and is prone to abuse as the party drug "Special K."
"Because of the potential side effects and abuse potential, it's unlikely ketamine itself will be a widespread treatment," Duman said. But he said growing evidence of its effectiveness is leading clinicians at Yale-New Haven Hospital and the Connecticut Mental Health Center to consider using it more widely, in a hospital setting, in cases of severe treatment-resistant depression and suicidal behavior. Many patients begin feeling the effects within two hours of an IV administration.
Duman said he was hopeful that understanding the mechanisms underlying the actions of ketamine would lead to new targets for drug development. Ketamine, which is sold as a generic and under the brand names Ketalar and Ketaject by Pfizer, already is the subject of multiple trials. Efforts so far to develop drugs that replicate its effects have produced some promising results, but none acts as quickly as ketamine, Duman said.
At Yale, Aghajanian and other researchers have found that combining a lower dose of ketamine with lithium appears to have similar effects, in rodents, as a higher dose of ketamine. The research team is now planning to conduct trials on the combination in humans.
In their research, Duman and others have shown that in a series of steps, ketamine triggers release of neurotransmitter glutamate, which in turn stimulates growth of synapses. Although the glutamate burst is brief, it triggers a one- to two-week change in the synaptic connections damaged by chronic stress.
"Eventually these conditions do relapse. It's not clear why," Duman said. Subsequent dosing appears to be effective, but needs further study, he said.
Ketamine caught the attention of psychiatrists more than a decade ago, when researchers at the Connecticut Mental Health Center, including Dr. John Krystal, chair of the department of psychiatry at Yale, discovered that the drug, in low doses, appeared to give patients quick relief from depression. Dr. Dennis Charney, formerly at Yale and now dean of Mt. Sinai School of Medicine, helped launch clinical trials of ketamine at the National Institute of Mental Health that showed 70 percent of patients with treatment-resistant depression experienced rapid symptom relief with a single intravenous dose of ketamine.
Charney is now investigating the use of ketamine in treating core symptoms of post-traumatic stress disorder (PTSD), a debilitating anxiety disorder that afflicts thousands of combat veterans returning from Iraq and Afghanistan.
Duman said Yale has "a lot of work going on" in further understanding the magic of ketamine.
"This work started in Connecticut and will continue in Connecticut -- for a long time to come," he said.
This story was reported under a partnership with the Connecticut Health I-Team (www.c-hit.org).