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Can supplementshelp a mutated geneproduce serotonin?

Asked by William Tokarz, Middletown, Connecticut

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My wife has suffered from depression her whole life. Her psychiatrist has performed a blood test and identified a mutated gene that produces serotonin in the brain. Antidepressant drugs provide little help. Are there any supplements that can supply the serotonin that is needed to combat the depression?

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Mental Health Expert Dr. Charles Raison Psychiatrist,
Emory University Medical School

Expert answer

Dear William,

I don't want my answer to sound overly strident, but I have very strong reactions when I hear of physicians making hard and fast treatment decisions based on genetic tests or brain scans. In all fairness, I know many fine psychiatrists who are now incorporating limited genetic testing to guide treatment decisions. Although I think this is premature, it is at least honorable. What really bugs me are docs who are making millions doing various types of brain scans on desperate folk that they offer as definitive diagnostic procedures.

In addition to my clinical background, I spend much of my life as a working scientist. From this perspective, I can assure you that there is not a test in the world that can tell your doctor in any definitive way how to proceed with treatment. There is a way to supplement serotonin, but whether it would benefit your wife is not something that can be known from a blood test.

Your wife's doctor has almost certainly tested her for what is generally known as the long and short forms of the gene for the serotonin transporter, which is a molecule that sucks serotonin back into nerve cells after it has been released as a neurotransmitter. This is the molecule that is targeted by most currently available antidepressants. Starting in the 1990s, studies began to suggest that people with the short form of this gene were more likely to be depressed, anxious or neurotic. However, the studies were very inconsistent, with some finding this effect and others finding no effect, or the opposite -- that is that the long form of the gene conferred depression risk.

Early in this millennium, the mystery appeared to be solved when a very influential study reported that the short form of the serotonin transporter was not a risk factor for depression per se but was a risk factor for depression in response to life stress. If you had the short form and nothing bad happened in your life, the researchers found, you were actually a little less likely to be depressed. But as soon as life stressors happen, folks with the short form have a huge increase in depression, whereas those with the long form appeared to be protected.

It was this study and a few positive replications that got clinicians like your wife's doctor to start checking for the long and short versions of this gene and making all sorts of prognostications when people were found to have the short form. Never mind that any one gene never accounts for more than a tiny fraction of the risk for a person getting depressed, the desire to find an objective test for how to treat depression is so strong on the part of clinicians that common scientific sense often gets tossed overboard.

Well, the story of this serotonin transporter gene has taken an interesting twist in the past several months with the publication of a high-profile paper in the Journal of the American Medical Association.

For this publication, the researchers assembled all the best studies ever done on the serotonin transporter gene and depression and put them together to see whether -- taken as a whole -- the data support the idea that this gene increases the risk for depression in the face of life stress. Amazingly, when all the literature was looked at, the gene was found NOT to be a risk for depression.

I am not telling you all this because I think the recent negative study will be the final answer but only to highlight the fact that depression will never be as simple as one single gene. Similarly, although people thought that genes would tell us which medications to use in which people (a field called pharmacogenomics), this promise remains largely unfulfilled.

Depression is a complex syndrome involving multiple pathways in the brain and body that are likely to vary a little from person to person. Our best studies suggest that even if one takes all of a person's genes into account, genetic contributions to depression are not as strong as environmental ones.

To directly answer your question, there are two strategies for providing the brain with extra serotonin: One is to take tryptophan, and the other is to take 5-hydroxytryptophan. Both of these are raw materials for the synthesis of serotonin in the brain, and some data suggest that they are of benefit to people with depression. Tryptophan is available only by prescription in the United States because of potential health risks.

A final thought: Unless your wife has really tried all the available antidepressants, I would recommend this first; people often say antidepressants don't help when they've only tried a few. Although the odds of responding go down with the more medications a patient has failed, any psychiatrist can tell you plenty of stories of patients who had miracle cures on a medication after failing many others.

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