Why does an anti-depressant work for some people, but not others?

October 13, 2000

TORONTO, ONT. -- A Toronto neurologist has found an important clue in the brain that may explain why some people respond better to an anti-depressant than others. The discovery is an important step in the development of more effective and faster-acting treatments for depression.

The clinical study, to be published in the October 15th, 2000 issue of the international journal Biological Psychiatry, looked at why there is often a delay of several weeks before an anti-depressant starts to make a person feel better AND what has to change in the brain over time in order to get well.

It's the first study to zone in on the 'timing' of changes taking place in brain regions during drug treatment. It's also the first to identify brain areas that appear to be critical to illness remission in that they behave like a "switcher" in a railway yard -- deciding what track a train will take.

Dr. Helen Mayberg, with her colleagues Drs. Steven Brannan, Janet Tekell and Arturo Silva, conducted the study at the Research Imaging Centre, a specialized research facility at The University of Texas Health Science Centre at San Antonio. Dr. Mayberg is now with Toronto's Rotman Research Institute at Baycrest Centre for Geriatric Care.

In the double blind study, 15 male veterans diagnosed with severe depression at a San Antonio hospital were given either a standard dose of the anti-depressant fluoxetine (trade name Prozac), or a placebo. Of the 10 who received Prozac, all showed a similar pattern of brain changes at the end of the first week of treatment, but none felt any better. By the end of six weeks of treatment, only four of the men were responding well to treatment and feeling better.

Using positron emission tomography -- which constructs computerized multi-colored images showing where maximum activity (glucose metabolism) is occurring in the brain -- the research team identified 'distinct differences' in the change pattern in brains of responders compared to non-responders on Prozac.

Both groups showed changes in ventral limbic sites associated with emotion (mood) AND dorsal cortical regions thought to mediate reason and cognition -- a relationship that was first identified by Dr. Mayberg in a landmark study in the American Journal of Psychiatry last year.

But in this study of veterans who did and did not respond to Prozac, the researchers identified a more widespread chain of events kicking in across a system of brain regions from one week to six weeks -- and only in the responders! This chain of events was not limited to the limbic and cortical sites. The cingulate, an area associated with emotional processing, and the hippocampus, an additional limbic region associated with memory and modulating stress, showed signs of "switching off" -- or decreased metabolism -- as the depression went into remission. Failure of these two regions to switch off was seen in those patients not responding to Prozac.

"We know anti-depressants work, but we don't know why they don't work for everyone," says Dr. Mayberg, an internationally-renowned neurologist who specializes in depression.

"Now that we have identified a distinct chain of events in the brains of people who respond well to a specific anti-depressant, we can start to investigate if the same is true for other anti-depressant medications as well as non-drug therapies. We can also use this knowledge as a basis for investigating new strategies, including more aggressive treatments, that induce or manipulate this chain reaction for all patients earlier in their treatment."

Dr. Mayberg likened the anti-depressant's effect on brain regions to "recalibrating" the system to bring it into a healthy balance once again.

"It's not as simple as adding Prozac or any other anti-depressant drug to the tank and depression will go into remission," she says. "There is a whole set of changes that need to happen in the brain to set a path for recovery."

At the Rotman Research Institute in Toronto, Dr. Mayberg is continuing her research in understanding the neurobiology of depression. Funding for this study was provided by the National Institutes of Mental Health, the National Alliance for Research in Schizophrenia and Depression, and Eli Lilly and Company.

Baycrest Centre for Geriatric Care

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