Researchers Look Beyond Serotonin For Next Antidepressant Advance
Dennis Charney, M.D.: “Depression is a systemic disease—it affects the entire body, and that is why it is so serious.”
“Depression is a systemic disease—it affects the entire body, and that is why it is so serious,” Charney told attendees of the National Alliance for Research on Schizophrenia and Depression (NARSAD) “Mind Matters” symposium in New York City in January.
Charney pointed out that depression has long been known to be a risk factor in the development of coronary disease and can even increase the risk of death from a heart attack (Psychiatric News, November 16, 2001).
For instance, in a study of 2,847 subjects as part of the Amsterdam Longitudinal Aging Study undertaken by Brenda Penninx, Ph.D., and colleagues, it was found that people with major depression were about four times more likely to die of cardiac disease than people without that diagnosis. The study was published in the March 2001 issue of Archives of General Psychiatry.
Other studies have found a link between complications stemming from types I and II diabetes and symptoms of depression. “If one gets depressed and has diabetes,” said Charney, “it is well known that insulin is not as effective at controlling the disease.”
Now there is preliminary evidence that when depressive symptoms lift, glycemic control improves in people with diabetes. Patrick Lustman, Ph.D., a researcher at Washington University in St. Louis, specializes in research on depression and diabetes.
In 1997 Lustman conducted a study of 35 patients with diabetes and depression and 44 with diabetes but not depression. He found that the improvement in depressed patients given nortriptyline was associated with a clinically significant 1.2 percent reduction in glycated hemoglobin—an aggregate measure of blood sugar—over a 120-day period.
Charney also mentioned a study published by Lustman in 2000 that tested a different antidepressant on people with diabetes. “Treatment of diabetic patients with fluoxetine revealed a trend toward better glycemic control.”
Researchers have also found that depression may have adverse effects on bone density, according to Charney. For instance, one study conducted in Germany in 1994 by Ulrich Schweiger, M.D., found that bone density at the lumbar spine was 15 percent lower for a sample of 80 people with major depression than in nondepressed control subjects. A follow-up study conducted with the same people four years later found that bone loss over a period of at least two years was 10 percent to 15 percent greater in those with a diagnosis of major depression.
There is also anecdotal evidence showing that depression is associated with a worsening of the condition of patients with cancer, Alzheimer’s disease, and Parkinson’s disease, according to Charney.
New Treatments on Horizon
Twenty years after the advent of selective serotonin reuptake inhibitors (SSRI), researchers are investigating new classes of antidepressants that would target compounds in the brain other than serotonin for faster and more effective antidepressant effects, according to Charney.
“We don’t want to discover ‘me too’ medications at this point.” he said. “Our current treatments are not curative. Although the antidepressants available now are better than placebo, they don’t prevent relapse enough.”
One such chemical that would be targeted by new medications is corticotropin-releasing hormone (CRH), which is a brain neuropeptide. Researcher Charles Nemeroff, M.D., of Emory University discovered in 1984 that increased levels of the peptide are found in the cerebrospinal fluid of some people with depression, and Charney, along with colleagues at Yale, found increases in CRH in patients with posttraumatic stress disorder in 1997.
Discoveries such as these led companies to develop compounds that would block the function of CRH by antagonizing its binding to its receptor. One such compound developed by Neurocrine Biosciences was licensed to Janssen Pharmaceutica. The compound was found in a German study to decrease symptoms of depression, according to Charney, but was discontinued because it was also associated with an elevation of liver enzymes. However, drug companies such as Bristol-Myers Squibb, Pfizer, and Janssen are developing other CRH antagonists to fight depression.
Charney said that cortisol, a primary corticotropin released when CRH levels increase, has been found to be elevated in people with psychotic depression. He said that “increased cortisol levels may also be related to medical problems such as reduced sensitivity to insulin, osteoporosis, and increased coronary vascular risk.”
Research has also found that high levels of the stress hormone may cause a chronic stress reaction that underlies the symptoms of psychotic depression, such as hallucinations, sleep disturbances, and memory problems. However, researchers are unsure of what happens when cortisol levels are abnormally low, as could happen when CRH is blocked. Dosing of CRH antagonists is especially difficult because of the need to bring cortisol levels down to a normal range while not decreasing them below normal.
Two years ago researchers at Stanford University tested the effects of RU-486, or mifepristone, on a sample of 30 patients with psychotic depression. The FDA approved the cortisol-blocking drug in 2000 to function as an emergency contraceptive and, in higher doses, to terminate pregnancy.
Charney said that the investigators found that within just a week, depressive symptoms decreased by 42 percent, and psychotic symptoms decreased by 63 percent in the sample of 30 patients.
“These results are very promising,” said Charney, who added that Corcept Therapeutics Inc., a small biotechnology company based in California, is sponsoring a drug trial using mifepristone at 20 sites across the country to further investigate its effect on psychotic depression.
Antidepressants and New Cells
Evidence is now emerging that contradicts what doctors and scientists have been claiming for years—that there is no new cell growth in the adult brain. “We were taught in medical school that, in general, once you were an adult, the brain was fixed,” said Charney.
New experiments have shown, however, that if an adult animal is physically active, new cells are created in the animal’s brain and that fewer new cells are produced when an animal is under stress.
The most exciting news, however, may be that antidepressant drugs play an important role in cell genesis. “Antidepressants can enhance the creation of new cells in the hippocampus of adult animals,” said Charney.
He cited the work of Ronald Duman, Ph.D., a professor of psychiatry at Yale. Duman found that adult rats given fluoxetine had evidence of cell proliferation in the dentate gyrus.
Findings such as this, noted Charney, have “led our field to focus on the effects of stress and depression on brain structure” and whether researchers should develop new compounds that “increase neurogenesis and neuroplasticity in the brain.” ▪
