It came to John as he stood with a gun in his hand yelling at some teen-agers partying near his house. This man wasn't him.
"The next day a friend of mine said, `John, you need to get some help,'^" said John, 56, who asked that his full name be concealed. After months of wildly different moods, from being irritable and stubborn with his wife to feeling so worthless he contemplated suicide, John admitted he needed help.
He was able to get on some anti-depression medicine that evened out his moods and helped him feel better about himself. But 20-30 percent of depressed people don't respond to medications like Prozac for reasons that have so far eluded researchers.
"That's a good news-bad news situation," said Jeffrey Rausch, vice chairman of the Department of Psychiatry at Medical College of Georgia. While it shows that most people do respond to the medications, "if you're one of the 20-30 percent of people who don't respond, it can be very discouraging, and often even disabling."
A study at MCG hopes to unlock part of that mystery by combining Prozac with a second medicine that works on a receptor in the brain that may be slowing down the firing of brain cells and limiting the production of serotonin. Low levels of serotonin, a key neurotransmitter in the brain, have been linked to depression. Prozac works by preventing nerve cells that fire and release serotonin from taking it back into the cell again, keeping levels of serotonin high in the synapse, the critical communication gap between the nerve cells.
But even with Prozac, two very similar patients might respond very differently, leading researchers like Dr. Rausch to look for a biological difference between the two patients. His study is focused on the serotonin 1A receptor, one of several receptors on nerve cells that help regulate nerve cell firing based on serotonin levels surrounding the nerve cells.
"It is the governor on how fast the serotonin brain cells will fire and release their serotonin," Dr. Rausch said. When there is a lot of serotonin outside, as when Prozac is working, the receptor compensates by telling the cell to slow down its firing. In his study, Dr. Rausch hopes to discover whether some of the people who have not responded to drugs such as Prozac may have an overly sensitive serotonin 1A receptor.
The study will use a second drug, Pindolol, that blocks the action of the serotonin 1A receptor, to see if it will keep the nerve cells firing steadily and therefore allow the anti-depression drugs to work, Dr. Rausch said.
"We're stimulating the system by inhibiting the inhibitor," Dr. Rausch said.
The patient has to have been on the medication for two months with no measurable decrease in their depression before they are considered drug resistant, Dr. Rausch said. The study also seeks to find a way to get a quicker response to anti-depressants, Dr. Rausch said. Depression affects about 15 million people a year, and switching medicines sometimes works for those who don't respond to one particular drug, Dr. Rausch said. But most have been through a number of different medications before coming to the study, and only seem to respond once the second medicine is added.
Jim, 48, knows all about that. Though first diagnosed with depression in 1986, "I don't ever remember being real well," said Jim, who also asked that his last name not be used. "I've always had to struggle to get through," said the computer technician. "No motivation, no ambition, that kind of thing. Always very cynical, looking at the dark side of things."
At least three times, he tried to take his own life through drug overdoses, once ironically with the anti-depressants that didn't work for him. After his last attempt in April 1997, he was institutionalized, given therapy and new medications, but none of it worked.
"I came out in worse shape than when I went in," Jim said. And while initially hopeful that drugs could help him when he first was diagnosed, he had given up.
"I've had 10 or 12 anti-depressants and none of them seemed to help," he said. Then he saw a notice about Dr. Rausch's study and signed up. He began to notice his world changing.
"My appetite improved, I started sleeping better," he said. "I used to have to practically force myself to go anywhere but I started to just get up and do it. I started enjoying my work, which I didn't use to do."
As the dosage increased, his symptoms seemed to get better and better, he said. Though no longer on the study, he is still on the dual medication and has something he never thought he'd have: hope.
"I have a lot of hope this can keep me going," he said.
Patients who have not responded to anti-depressive medication or physicians with such patients can call (706) 721-7835 to see if they qualify for the study.
Depression affects an estimated 15 million people in the United States alone, with a cost of up to $30 billion in lost productivity and treatment. Symptoms of depression include:
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