Oct. 1, 2003 — Weight gain, insomnia, sexual dysfunction — these troublesome antidepressant side effects are caused by a genetic variation, a new study shows.

“One of the mysteries at this point is why some people get debilitating [antidepressant] side effects and others don’t,” says lead researcher Greer M. Murphy Jr., MD, PhD, professor of psychiatry and behavioral sciences at Stanford University Medical Center, in a news release.

His study appears in the American Journal of Psychiatry this month.

The eight-week study took place in 18 outpatient clinics across the country. The widely prescribed antidepressants Paxil and Remeron were randomly given to 246 elderly patients suffering from severe depression. Elderly patients were chosen because they are particularly prone to antidepressant side effects.

Dosages were gradually increased to a maximum of 45 mg of Remeron or 40 mg of Paxil. Each week, doctors tracked patients’ depression symptoms.

Researchers also performed DNA blood tests to see which version of a particular gene — called 5HT2a — each patient possessed. This gene is responsible for creating a receptor that reacts with the brain chemical serotonin, which is believed to play a big role in depression.

A variation on this gene could affect the amount of receptors on nerve cells — and therefore affect whether someone experiences antidepressant side effects.

Remeron completely blocks this receptor, so the researchers thought a variation in this gene might not influence antidepressant side effects from Remeron.

However, Paxil does not affect this receptor. Paxil is in a class of antidepressants called selective serotonin reuptake inhibitors (SSRIs), which work by allowing more serotonin to remain in the brain. Because Paxil does not directly interact with serotonin receptors — which means they remain functional — it can lead to antidepressant side effects such as stomach upset, insomnia, and sexual dysfunction.

Indeed, there were differences on the 5HT2a gene. The 46% of patients with one version of the gene — and taking Paxil — were much more likely to quit the drug because of intolerable antidepressant side effects. The Remeron patients had no effect from the gene variation.

Researchers also looked at a liver enzyme called CYP2D6, a key player in the metabolism of many medications including Paxil and Remeron.

Up to 10% of people have a genetic variation for that enzyme that can make a drug metabolize very slowly. This causes the enzyme to build up in the blood and can potentially lead to significant antidepressant side effects.

In this study, however, similar numbers of patients had this CYP2D6 variation — so it was eliminated as a factor in antidepressant side effects.

The researchers say these results demonstrate a major effect of the 5HT2a gene variation in creating adverse antidepressant side effects — but only to Paxil and similar antidepressants, such as Celexa, Lexapro, Prozac, and Zoloft.

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