Researchers at UNMC are conducting unique basic and clinical studies to investigate the pharmacological treatment of depression.

Working from the Psychopharmacology Research Center, the investigators are seeking to understand how antidepressant drugs work and are evaluating the clinical efficacy and safety of new compounds.

The investigators are Shelton Hendricks, Ph.D., professor of psychiatry, Donald Johnson, Ph.D., associate professor, pathology/microbiology, William Burke, M.D., professor of psychiatry and director of the division of geriatric psychiatry, and Steven Wengel, M.D., assistant professor of psychiatry

They have proposed a three-year, double-blind, placebo-controlled study that will involve 60 patients with major depressive disorder who will be given paroxetine (Paxil), a specific serotonin reuptake inhibitor (SSRI) drug, or a placebo. The study also will use in vitro methods to try to identify the mechanisms by which SSRIs and similar compounds affect natural killer cell cytolytic activity (NKCA).

"NK cells are large granular lymphocytes that comprise about 5 percent of the circulating blood lymphocytes in the human body. They are capable of spontaneously killing tumor or viral infected cells," Dr. Johnson said.

"They are considered to be an important cellular component in the defense against viral diseases and may play a role in the immunosurveillance against cancer and the spread of cancer," he said.

In a pilot study of depressed geriatric patients, the investigators at UNMC were able to demonstrate a reliable elevation in NKCA when these patients were treated with a serotonin reuptake inhibitor, Zoloft. A second study of depressed outpatients partially replicated the previous reports of enhanced NKCA with the treatment of depression. At UNMC, those depressed patients who exhibited low NKCA at the beginning of treatment showed increased NKCA with treatment of their depression with a similar drug, Prozac.

In a parallel series of in vitro studies conducted with graduate students Matt Frank and Julie Wieseler, evidence has accumulated suggesting the effects observed on immune function with the treatment of depression may not reflect the effects of antidepressant drugs on the brain or emotional state, but rather the result these drugs are having directly on the immune system.

"Our theory is that the medication is affecting lymphocytes. We want to learn more about how this is happening and how the immune system affects the brain," Dr. Hendricks said.

In their study, they will measure the NKCA levels of the participants at the beginning to establish a baseline and then throughout the following 12 weeks of treatment with a placebo or 20 mg. of paroxetine. Clinical responses to the drug will be evaluated to determine any association between changes in clinical symptoms and changes in NK levels.

A second part of their study will involve a comparison of mononuclear cells from depressed patients treated with paroxetine or placebos and normal volunteers. The cells will be incubated in vitro with SSRIs, high-affinity serotonin (5-hydroxytryptamine [5-HT]) transporters and related compounds, Dr. Johnson said. They also will test the hypothesis that SSRIs act to block receptor uptake of 5-HT through transporters located on platelets, resulting in an increase of NK cell cytotoxicity.

"It’s possible to improve the immune system by giving antidepressant drugs. Many drugs that boost the immune system, such as cytokines and interferons, are powerful, but they can have dangerous side effects," Dr. Johnson said.

"Understanding more about the immune system and substances that can boost it without side effects would be especially helpful for a person who is already in a stressed situation, such as an elderly person with a disease or a person with AIDS," he said.

This research also could be useful for transplant patients who are at increased risk of developing lymphomas and other cancers after years of taking immune suppressant drugs, Dr. Johnson said.

"If antidepressant drugs can enhance the NK cells without hindering the graft, it could help the immune system fight off viruses, cancer and other diseases," he said.

The Psychopharmacology Research Center, which is involved in investigating depression and the immune function, also conducts contract clinical trials for development of new psychiatric medications.

In one study, expected to begin in November, Dr. Burke and colleagues will be part of a two-year, national 20-site clinical trial to test the use of a susbtance P antagnoist as a new way of treating depression.