Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Stanford research finds gene variations that alter antidepressant side effects

30.09.2003


Researchers at Stanford University Medical Center have identified a genetic marker that can explain why some people experience side effects to common antidepressants while others do not. They also found that a key liver enzyme involved in breaking down these antidepressants surprisingly played no role in the development of side effects nor in how well the drugs worked. The findings may lead to fewer side effects for patients undergoing antidepressant drug therapy.



"Antidepressants are among the most widely prescribed medications in the world," said lead author Greer Murphy Jr., MD, PhD, associate professor of psychiatry and behavioral sciences. "One of the mysteries at this point is why some people get debilitating side effects and others don’t."

To start solving the mystery, Murphy and Alan Schatzberg, MD, the Kenneth T. Norris Jr. Professor of Psychiatry and Behavioral Sciences, wanted to find differences among patients in the function of proteins - and the genes that encode those proteins - that could account for the varied response to drug treatment. Their findings appear in the October issue of the American Journal of Psychiatry.


Good candidate proteins for studying an antidepressant response include the receptors that the drug interacts with in the brain and the enzymes in the liver that metabolize the drugs. Murphy and Schatzberg chose one of each for their research. In what Murphy said is the only double-blind randomized prospective psychiatric genetic study of its kind, the researchers analyzed DNA samples from 246 depressed patients who were randomly assigned either paroxetine (marketed as Paxil) or mirtazapine (marketed as Remeron) for eight weeks.

All of the patients studied in 18 U.S. outpatient clinics were 65 years of age or older. Side effects are particularly relevant in this age group, Murphy said. Older people, for example, are more susceptible to injury from a fall caused by dizziness, which can be a side effect of some antidepressant drugs. "Being able to pick the best drug would be a huge advantage when you are dealing with older people," he said.

The two antidepressants work in completely different ways, though both affect serotonin, a neurotransmitter that binds to specific receptors found abundantly in the brain and peripheral nervous system. Serotonin has many effects, including mood control, but it also affects the gastrointestinal tract, the sleep-wake cycle and levels of alertness.

The researchers looked at one type of serotonin receptor called 5HT2a, thought to be involved in causing antidepressant side effects. Mirtazapine completely blocks this receptor, so the researchers predicted that variation in the 5HT2a gene would not influence mirtazapine side effects. Paroxetine, on the other hand, is a selective serotonin re-uptake inhibitor, or SSRI, which works by allowing more serotonin to remain in the brain. Paroxetine does not directly interact with serotonin receptors, so they remain functional, which can lead to unwanted side effects such as stomach upset, dizziness, insomnia, agitation and sexual dysfunction.

One variation of the 5HT2a gene, based on a single nucleotide change in the DNA sequence, is thought to affect the amount of the receptor on nerve cells. When the researchers compared the version of this gene that a patient had to his or her experience taking the drug, the differences due to gene variation were striking. People with the one version of the gene were much more likely to discontinue therapy due to intolerable side effects when compared to the two other versions (46 percent vs. 16 percent).

In the mirtazapine patients, there was no effect due to the serotonin receptor gene variation, as predicted. The ability of both drugs to work as an antidepressant was unrelated to what version of this gene a patient had.

To explore a different hypothesis - that drug response is directly affected by how efficiently the liver metabolizes the drug - they chose a particular liver enzyme called CYP2D6, a key player in the metabolism of many medications, including paroxetine and mirtazapine. Most people have a normal level of this enzyme, but 7 to 10 percent have a variation in the gene for the enzyme that makes it work very slowly, causing the drug to build up in the blood, potentially leading to significant side effects. Another 3 to 4 percent have genetic changes that cause excessive enzyme activity, resulting in the drug breaking down rapidly, perhaps before it has had a chance to work.

Many in the medical field have assumed that genetic variation in this enzyme is responsible for the side effects a patient experiences. "I can’t tell you how often this hypothesis is stated," said Murphy. "Whole marketing campaigns have been built on whether or not a drug interacted with this enzyme."

The enzyme has at least 40 genetic variations, but to their surprise, the researchers found that the variation did not alter treatment outcome or side effects. Murphy emphasized that this study, like all genetic association studies, will need to be replicated, and the results may not apply to other antidepressants. The researchers will further analyze the data they have from this study, looking at more genes to see how they relate to antidepressant efficacy and side effect frequency. "We have many other markers in the pipeline in other candidate genes that we are exploring and so we feel like this is just sort of the first stab," said Murphy.


Funding for this study was provided by Organon Pharmaceuticals, Inc., the manufacturer of Remeron; the National Association for Research on Schizophrenia and Depression; The Nancy Pritzker Network and the Department of Veterans Affairs Sierra Pacific Mental Illness Research, Education and Clinical Center.


Stanford University Medical Center integrates research, medical education and patient care at its three institutions - Stanford University School of Medicine, Stanford Hospital & Clinics and Lucile Packard Children’s Hospital at Stanford. For more information, please visit the Web site of the medical center’s Office of Communication & Public Affairs at http://mednews.stanford.edu.

Mitzi Baker | EurekAlert!
Further information:
http://mednews.stanford.edu

More articles from Health and Medicine:

nachricht 'Exciting' discovery on path to develop new type of vaccine to treat global viruses
18.09.2017 | University of Southampton

nachricht A new approach to high insulin levels
18.09.2017 | Schweizerischer Nationalfonds SNF

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Ultrafast snapshots of relaxing electrons in solids

Using ultrafast flashes of laser and x-ray radiation, scientists at the Max Planck Institute of Quantum Optics (Garching, Germany) took snapshots of the briefest electron motion inside a solid material to date. The electron motion lasted only 750 billionths of the billionth of a second before it fainted, setting a new record of human capability to capture ultrafast processes inside solids!

When x-rays shine onto solid materials or large molecules, an electron is pushed away from its original place near the nucleus of the atom, leaving a hole...

Im Focus: Quantum Sensors Decipher Magnetic Ordering in a New Semiconducting Material

For the first time, physicists have successfully imaged spiral magnetic ordering in a multiferroic material. These materials are considered highly promising candidates for future data storage media. The researchers were able to prove their findings using unique quantum sensors that were developed at Basel University and that can analyze electromagnetic fields on the nanometer scale. The results – obtained by scientists from the University of Basel’s Department of Physics, the Swiss Nanoscience Institute, the University of Montpellier and several laboratories from University Paris-Saclay – were recently published in the journal Nature.

Multiferroics are materials that simultaneously react to electric and magnetic fields. These two properties are rarely found together, and their combined...

Im Focus: Fast, convenient & standardized: New lab innovation for automated tissue engineering & drug

MBM ScienceBridge GmbH successfully negotiated a license agreement between University Medical Center Göttingen (UMG) and the biotech company Tissue Systems Holding GmbH about commercial use of a multi-well tissue plate for automated and reliable tissue engineering & drug testing.

MBM ScienceBridge GmbH successfully negotiated a license agreement between University Medical Center Göttingen (UMG) and the biotech company Tissue Systems...

Im Focus: Silencing bacteria

HZI researchers pave the way for new agents that render hospital pathogens mute

Pathogenic bacteria are becoming resistant to common antibiotics to an ever increasing degree. One of the most difficult germs is Pseudomonas aeruginosa, a...

Im Focus: Artificial Enzymes for Hydrogen Conversion

Scientists from the MPI for Chemical Energy Conversion report in the first issue of the new journal JOULE.

Cell Press has just released the first issue of Joule, a new journal dedicated to sustainable energy research. In this issue James Birrell, Olaf Rüdiger,...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

“Lasers in Composites Symposium” in Aachen – from Science to Application

19.09.2017 | Event News

I-ESA 2018 – Call for Papers

12.09.2017 | Event News

EMBO at Basel Life, a new conference on current and emerging life science research

06.09.2017 | Event News

 
Latest News

“Lasers in Composites Symposium” in Aachen – from Science to Application

19.09.2017 | Event News

New quantum phenomena in graphene superlattices

19.09.2017 | Physics and Astronomy

A simple additive to improve film quality

19.09.2017 | Power and Electrical Engineering

VideoLinks
B2B-VideoLinks
More VideoLinks >>>