Genetics Open Door to More Effective Depression Treatment
> 6/20/2007 10:16:03 AM

An article appearing yesterday in the New York Times described the frustration that a physician feels for having to rely on trial-and-error to find the right depression treatment medication for each patient. The author, Dr. Richard Friedman, relates the first-hand experience of stumbling through three months of different, useless drugs for one patient until finally finding success with Prozac. He doesn’t cite his shrewd deductions or professional experience for the success. Rather, he admits that the right drug was only found because his patient mentioned that her father had been helped by Prozac.

This similar reaction of relatives to medication suggests that a genetic analysis can predict an individual's reaction to a drug. This assumption is at the heart of a burgeoning new medical field--pharmacogenomics. Pharmacogenomics seeks to fit the right drug to the right person so that adverse effects can be avoided and positive effects fully exploited. The National Center for Biotechnology Information, a fervent supporter of pharmacogenomics, argues for the extreme need for tailored drugs by pointing to a JAMA study finding 100,000 adverse drug reaction deaths in America in one year.

In the field of mental health, several drugs have in recent years been stuck with blackbox warnings because a small percentage of patients have adverse reactions. There is emerging evidence that the suicidal ideation that occurs in a small percentage of patients could be genetically predicted. Dr. Roy Perlis published a study earlier this month suggesting a link between variation in the CREB1 gene and suicidal thoughts among male patients. If the at-risk patients can be identified, doctors can prescribe antidepressants to those who need them without fear of terrible consequences.

The idea that genetic differences can put some patients at risk may seem more intuitive than the idea that there will be differing levels of benefit from a drug, but a detailed examination of depression treatment may elucidate the matter. A large percentage of patients will not respond to the first depression drug they are given, sometimes taking, as Dr. Friedman's did, several tries before the right prescription can be found. Most antidepressants also take 4-6 weeks before results begin to manifest (or fail to), making this selection process a time-consuming and difficult one. So it is heartening news that researchers have recently been able to finger specific genetic variants as the potential culprits for the failure rate. The journal Science published a study by Dr. Francis Lee showing that the introduction of a flawed gene for brain-derived neurotrophic factor could render ineffective S.S.R.I , a depression treatment that relies on the increase of this protein. Another study in the Pharmacogenomics Journal found that the DAT1 polymorphism was associated with a substandard reaction to a large range of depression drugs. The National Institute of Mental Health was so impressed by this string of findings  that it offered a $3 million grant for any project designed to further investigate variable drug responses. The UCSF Today reports that Dr. Steven Hamilton's team, which won the grant, has already tentatively identified dozens of new genes that seem to affect depression drug reaction.

The hope is that eventually doctors will be able to take a DNA sample and then adjust their prescription for all known complicating factors. Once the process of gene sequencing becomes cheaper, or new methods of identifying genetic factors emerge, finding the appropriate depression treatment medication will not have to involve so much guesswork.

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