Genome Influences Effects of Antidepressants

By Nancy Touchette
When physicians prescribe a drug to treat a particular disease, chances are good that some patients will respond favorably. But others will not be helped, and a small percentage may even be harmed.

For the most part, doctors have not been able to predict who will be helped and who will be hurt by a particular medication. This has been especially true in the field of mental illness and among patients with clinical depression.

“One of the biggest questions in psychiatry is ‘Why do some people respond to a particular drug while others don't?'” says Greer M. Murphy Jr., a psychiatrist and neuroscientist at Stanford University School of Medicine in California . “It's really a guessing game.”

Now, a growing number of researchers worldwide are searching the human genome for subtle differences in genes that might explain why people respond so differently to the same drug.

The hope is that doctors will one day routinely use a person's genetic profile when selecting medications. To make that happen, researchers are starting to develop genetic information that can predict who will benefit from a drug—and who will develop side effects.

In a recent clinical trial to test the effects of drugs to treat depression in 342 elderly patients, Murphy and his colleagues identified two different genes that seem to correlate with whether different antidepressants hurt or help.

The researchers reported in the American Journal of Psychiatry that one gene variation seemed to predict whether a patient would develop intolerable side effects while taking the antidepressant Paxil, which is the brand name of paroxetine.

People with a single mutation in both copies of a gene called HTR2A were three times more likely to experience side effects than those without the mutation. The side effects were so bad in some people that they stopped taking the drug.

The HTR2A gene makes a protein that binds to the brain chemical serotonin, which has been implicated in depression. Paxil works by influencing the levels of serotonin in the brain.

People taking antidepressants commonly experience side effects, including insomnia, dizziness, sexual dysfunction and agitation. This can be especially dangerous to elderly patients.

“A young person who gets dizzy may just ask their doctor to switch to a different drug,” says Murphy. “But an older person who gets dizzy may fall down and break their hip. So it's important to identify who will experience an adverse effect.”

In a second report involving the same patients, Murphy and his colleagues looked at variations in a second gene, called Apolipoprotein E. Patients with the “ApoE 4” variant had a better response to the drug mirtzapine, which is also called Remeron, than to Paxil, compared to those without the mutation.

For people with this variant, Remeron alleviated symptoms of depression sooner and more completely than did Paxil. Those without the variant showed no difference in their response to the drugs.

Like many in the field, the researchers believe that genetic markers may be useful in predicting the outcomes of antidepressant treatment in all patients, not just in the elderly.

Murphy cautions that more studies are needed to develop a clinically useful picture of how people with different gene variants respond to different drugs.

Nevertheless, Bruce G. Pollock, a psychiatrist at the University of Pittsburgh, is encouraged by the studies.

“These are very interesting results,” says Pollock. “But Murphy has just scratched the surface. There is enormous potential for tailoring a person's therapy to avoid side effects and increase the speed of response.”

* * *

Murphy, G.M. et al. Pharmacogenetics of Antidepressant Medication Intolerance. Am J Psychiatry 160, 1830-1835 (October 2003).

Murphy, G.M. et al. The Apolipoprotein E 4 allele and antidepressant efficacy in cognitively intact elderly depressed patients. Biol. Psychiatry 54, 665-673 (2003).

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