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.
All existing antidepressant drugs work in much the same manner. They act on a handful of neurotransmitters -- brain chemicals that pass messages along defined pathways -- that belong to a family called monoamines and circulate in a relatively small portion of the brain.
The most recognized of these neurotransmitters is serotonin, low levels of which have been linked to depression. Drugs such as Prozac and Celexa are aimed at raising serotonin levels available to the brain. The other transmitters targeted by antidepressants are dopamine and norepinephrine. Wellbutrin is an example of an antidepressant that boosts levels of these neurotransmitters but not serotonin.
Scientists first discovered these neurotransmitters affect depression in the 1950s when they found that the tuberculosis drug iproniazid also lifted patients’ moods. The drug blocks an enzyme that converted serotonin, dopamine and norepinephrine into inactive forms, and after some study the drug was marketed for depression. Pharmaceutical companies have developed drugs targeting the trio of neurotransmitters ever since.
Because it is expensive to discover and develop new drugs, it is safer for pharmaceutical companies to stick with known biological targets than to head in risky new directions, said Dr. Carlos Zarate Jr., a researcher at the National Institute of Mental Health. As a result, “we have not made substantial gains in terms of antidepressants,” Zarate said.
But recent studies on ketamine have pushed researchers to change how they think about depression. The anesthetic acts on glutamate, the brain’s most plentiful neurotransmitter, which circulates widely in the brain and hasn’t been linked to depression in the past.
In a small experiment led by Zarate last year, five of 18 people who received a single intravenous dose of ketamine experienced a dramatic lifting of their depression the first day and were still much better a week later. All patients in the experiment had first tried regular antidepressants but did not improve on them, according to the study published last August in the Archives of General Psychiatry.
Similar fast improvements were found in a study of eight patients conducted at Yale Medical School and published in Biological Psychiatry in 2000.
The rapid response was encouraging, Zarate said, suggesting that a faster-acting antidepressant may be possible. Current antidepressants take two to three weeks to begin working, and until recently, “it was just accepted as fact we couldn’t do any better,” he said.
Dr. Gerard Sanacora, director of the depression research program at Yale Medical School, said the results also mean that glutamate may have a more direct role in depression than serotonin and other brain chemicals targeted by current antidepressants.
“The fact that it acts so rapidly means that it is getting closer to the core of depression,” Sanacora said.
In some ways, it’s surprising that researchers studying depression didn’t suspect the role of glutamine, which is an amino acid, in the disorder sooner. Malfunctions in the glutamate system have long been linked to other psychological and neurological disorders, including schizophrenia and Alzheimer’s disease. Glutamate has long been associated with learning and memory.
“It is hard to image anything glutamate is not involved in,” said Sanacora. “It is really what makes the brain run.”
Still, scientists haven’t yet figured out how the glutamate system goes awry in depression.
One theory is that glutamate leaks from brain cells, perhaps in response to chronic emotional stress, and causes changes in key brain structures.
The hippocampus, which processes memory, and the parts of the cortex, where decisions are made, are known to be smaller in depressed people. Perhaps, Zarate said, excess glutamate caused cells in these brain structures to shrivel. High amounts of glutamate are toxic to brain cells and cause the death of some neurons in stroke patients, he noted.
Ketamine is not approved for treating depression and Zarate said it was too soon to give it to patients outside the confines of a clinical trial.
Ketamine can cause hallucinations and confusion and is sometimes abused as a club drug. In fact, he said, all patients who received the drug in his study reported out-of-body hallucinations.
But studying the workings of ketamine in the brain may provide researchers with information that could lead to a new class of fast-acting antidepressants.
Zarate and colleagues reported last month that ketamine blocks a glutamate receptor, called NMDA, on the surface of nerve cells.
As a result, glutamate can’t bind to it anymore and instead binds and activates another receptor, called AMPA. The increased activity of AMPA is what produces ketamine’s mood-elevating effects, Zarate concluded.
Drawing an analogy, he explained: “If you imagine a bifurcated garden hose and you block the left nozzle, you will get a massive amount of water through the right.”
A number of drugs that work on glutamate have been approved as treatments for neurological disorders and are now being tested against depression.
Among them are Forest Laboratories’ Namenda, which is approved to treat Alzheimer’s disease symptoms, and Sanofi-Aventis’ Rilutek, which is used to slow amyotrophic lateral sclerosis, or Lou Gehrig’s disease.
Neither is expected to be a big breakthrough. Namenda is not a powerful blocker of the NMDA receptor and Rilutek doesn’t work very quickly.
Zarate’s group at the National Institute of Mental Health is planning a trial in which depressed patients will receive a dose of ketamine, followed by regular doses of Rilutek, which scientists hope will maintain patients’ recovery.
Other drugs targeting glutamate are on the way, although it could be many years before they reach patients. For example, an experimental Merck & Co. drug that blocks a sub-unit of the NMDA receptor is now in clinical trials.
In May, Pfizer Inc. reported on a study of 30 depressed patients who received an experimental intravenous drug that also blocks that same sub-unit of the NMDA receptor.
The antidepressive effect of the drug, CP-101,606, was similar to that of ketamine, said Dr. Sheldon H. Preskorn, chairman of the department of psychology and behavioral sciences at the University of Kansas School of Medicine-Wichita, who led the study.
Within 24 hours, more than half of the patients in the study had a “bright affect,” were smiling spontaneously and talked more rapidly, Preskorn said. Their about-face was so remarkable “that had I not seen it myself, I would not have believed it,” Preskorn said.
Many questions remain.
No one knows whether depressed patients will tolerate or respond to a second dose of a ketamine-like drug. Patients in trials so far have received only one dose.
In addition, the rapid personality overhauls induced by the drugs have implications for family and social relationships that will need to be addressed, probably through counseling or therapy, Preskorn said.
“The drugs deal with the hardware problem,” he said.
“Once that’s done, we still have to deal with the software issue.”
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The pursuit of happiness
Here are some other drugs under study as possible antidepressants.
*Agomelatine, yohimbine: Works on the sleep-wake cycle.
* Scopolamine: Targets the brain’s cholinergic system.
* Mifepristone, CRF1 antagonists: Lowers levels of the stress hormone cortisol.
* Remicade: Reduces inflammation.
-- Denise Gellene