Health Science Center research explores antidepressants’ early effects November 2004 by Will Sansom "Bill’s" experience exemplified the conundrum doctors face when treating depressed patients. The 47-year-old former factory worker had hit the skids in a big way, and by the time he saw a doctor, Bill was clinically depressed and mentally fragile. Life was not worth living, he said. His psychiatrist prescribed a selective serotonin re-uptake inhibitor, or SSRI, one of three classes of antidepressant medications available today to treat depression. Bill could not expect to feel better overnight, the doctor said, but in eight to 12 weeks he would feel more like the man who had married his high school sweetheart and already put one of his children through college. Tragically, Bill could not see the promise. Just 10 days after he sat in the doctor’s office, he left a note to his wife and put a bullet through his head. Life was not worth living, he wrote.  Video on File Depression affects 1 in 10 Americans each year. See the video to learn how antidepressants affect activity in the brain.

That’s why a research program under way in the Health Science Center’s departments of pharmacology and psychiatry is so important. The program, supported by the National Institute of Mental Health and the U.S. Department of Veterans Affairs, could lead to development of new medications that not only work faster but provide more complete recovery than current antidepressants.

The researchers, who include Alan Frazer, Ph.D., professor and chairman of the department of pharmacology, and David Morilak, Ph.D., associate professor of pharmacology, are monitoring changes that occur in rat brains during the first weeks of antidepressant activity. "We implant mini-pumps that maintain a steady level of antidepressant medication in approximately the same effective dose range that people treated with antidepressants receive," Dr. Morilak said.

Antidepressants affect the activity of chemicals called neurotransmitters, in particular serotonin and norepinephrine. These chemicals, which are released and reabsorbed by nerve cells constantly, serve as "relay runners" moving information in the brain. Antidepressants’ effects vary, but generally they work by blocking the re-entry of serotonin and/or norepinephrine back into the nerves from which they were released, resulting in elevated serotonin and norepinephrine in the brain and improving the flow of information that the nerves produce.

By inserting transmitter-sensing probes into targeted regions of rat brains, Drs. Frazer and Morilak hope to learn a great deal more about the action of antidepressants. How do they work in human patients? Why are behavioral improvements not seen for several weeks? What happens when therapy is withdrawn?

Dr. Frazer, and his collaborator, Saloua Benmansour, Ph.D., use a technique called in vivo voltammetry to measure the speed of serotonin re-uptake into cells. Through a probe with an electrode at the tip, they inject serotonin into a brain command center called the hippocampus. Next they send a slight amount of voltage through the electrode, jostling the adjacent serotonin, which peaks around the tip. They measure the peak and how quickly it clears, and also how SSRIs such as Prozac modify the clearance.

"We believe chemical changes in the brain precede outward behavioral improvements," Dr. Frazer said. "Our data say there are effects caused by SSRIs that do not occur immediately but rather take about two weeks to occur." One of those effects appears to be loss of a transporter that enables serotonin to re-enter cells. Cataloging such effects is precisely what could lead to more effective medications.

Dr. Morilak uses a technique called microdialysis to measure the amount of norepinephrine in a brain region called the medial prefrontal cortex, an area important to attention, emotion and decision making. He implants a probe containing artificial cerebral spinal fluid into the rat brain and extracts norepinephrine molecules through tiny pores in the probe membrane. The process is similar to kidney dialysis but on a smaller scale.

The point of Dr. Morilak’s experiment is to note dramatic increases or decreases in norepinephrine over the course of antidepressant treatment. "The key is to find out what takes time in treatment and to speed that up," Dr. Morilak said. Manipulating serotonin and norepinephrine may be like resetting the thermostat in a house. "What we think we’re doing with chronic drug treatment is changing the set point for these neurotransmitter systems, which is somehow beneficial to people with depression and other mood disorders," Dr. Morilak said.

In rats or humans, the endpoints of antidepressant treatment are observable improvements in behavior. In one experiment, rats are exposed to a harmless electric shock from a post at one end of their cages. A layer of wood shavings lines the bottom of the cages. After the shock, the animals actively bury the post under the bedding, an adaptive behavioral response to anxiety. Dr.Morilak evaluates subtle changes in the burying behavior at specific points in time, with the goal of matching these changes against serotonin and/or norepinephrine levels at the same points in time.

In the department of psychiatry, researchers are monitoring changes in the behavior of depressed human patients during the first weeks after initiation of antidepressant treatment. The clinical studies, carried out by Dr. Frazer in collaboration with Charles Bowden, M.D., and Martin Katz, M.D., professors of psychiatry, indicate that patients who demonstrate early behavioral improvement (within two weeks of the start of therapy) are the ones who go on to have a good response with longer treatment (six weeks or more). "These findings show that it is possible to detect clinical changes in behavior earlier than previously thought and that these early changes predict what’s to come," Dr. Frazer said. "If this is confirmed, it could have important implications for changing treatment in non-responsive patients earlier than is currently the case, which could be useful, given the ever-present risk of suicide in such patients."

The clinical group found that desipramine, an antidepressant that works on the norepinephrine system, helped patients by increasing their activity level, whereas paroxetine, a drug that affects serotonin function, had its earliest effects on improving anxiety in the patients. These changes were observable within the first week or two of treatment. By contrast, patients who responded to treatment with a placebo, an inactive agent, did not show any consistent patterns of early behavioral change.

The human behavioral studies, overlaid on the rat behavioral studies and the information obtained from the rat brain probes, should generate emerging patterns of how antidepressants alter neurotransmitter levels and affect surface behaviors. Such refinements one day might keep the Bills of the world from going over the edge.

"Anything that can provide doctors and patients more information will be of great value," said Dr. Bowden, who holds the Nancy Ullman Karren Chair in Psychiatry. "The issue is, can we look at early treatment and say, ‘Are we on the right path?’ It’s like driving down the wrong street to get to your destination, finding out early and making the necessary course correction."

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