Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


Stanford research finds gene variations that alter antidepressant side effects


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

Mitzi Baker | EurekAlert!
Further information:

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: Space observation with radar to secure Germany's space infrastructure

Satellites in near-Earth orbit are at risk due to the steady increase in space debris. But their mission in the areas of telecommunications, navigation or weather forecasts is essential for society. Fraunhofer FHR therefore develops radar-based systems which allow the detection, tracking and cataloging of even the smallest particles of debris. Satellite operators who have access to our data are in a better position to plan evasive maneuvers and prevent destructive collisions. From April, 25-29 2018, Fraunhofer FHR and its partners will exhibit the complementary radar systems TIRA and GESTRA as well as the latest radar techniques for space observation across three stands at the ILA Berlin.

The "traffic situation" in space is very tense: the Earth is currently being orbited not only by countless satellites but also by a large volume of space...

Im Focus: Researchers Discover New Anti-Cancer Protein

An international team of researchers has discovered a new anti-cancer protein. The protein, called LHPP, prevents the uncontrolled proliferation of cancer cells in the liver. The researchers led by Prof. Michael N. Hall from the Biozentrum, University of Basel, report in “Nature” that LHPP can also serve as a biomarker for the diagnosis and prognosis of liver cancer.

The incidence of liver cancer, also known as hepatocellular carcinoma, is steadily increasing. In the last twenty years, the number of cases has almost doubled...

Im Focus: Researchers at Fraunhofer monitor re-entry of Chinese space station Tiangong-1

In just a few weeks from now, the Chinese space station Tiangong-1 will re-enter the Earth's atmosphere where it will to a large extent burn up. It is possible that some debris will reach the Earth's surface. Tiangong-1 is orbiting the Earth uncontrolled at a speed of approx. 29,000 km/h.Currently the prognosis relating to the time of impact currently lies within a window of several days. The scientists at Fraunhofer FHR have already been monitoring Tiangong-1 for a number of weeks with their TIRA system, one of the most powerful space observation radars in the world, with a view to supporting the German Space Situational Awareness Center and the ESA with their re-entry forecasts.

Following the loss of radio contact with Tiangong-1 in 2016 and due to the low orbital height, it is now inevitable that the Chinese space station will...

Im Focus: Alliance „OLED Licht Forum“ – Key partner for OLED lighting solutions

Fraunhofer Institute for Organic Electronics, Electron Beam and Plasma Technology FEP, provider of research and development services for OLED lighting solutions, announces the founding of the “OLED Licht Forum” and presents latest OLED design and lighting solutions during light+building, from March 18th – 23rd, 2018 in Frankfurt a.M./Germany, at booth no. F91 in Hall 4.0.

They are united in their passion for OLED (organic light emitting diodes) lighting with all of its unique facets and application possibilities. Thus experts in...

Im Focus: Mars' oceans formed early, possibly aided by massive volcanic eruptions

Oceans formed before Tharsis and evolved together, shaping climate history of Mars

A new scenario seeking to explain how Mars' putative oceans came and went over the last 4 billion years implies that the oceans formed several hundred million...

All Focus news of the innovation-report >>>



Industry & Economy
Event News

New solar solutions for sustainable buildings and cities

23.03.2018 | Event News

Virtual reality conference comes to Reutlingen

19.03.2018 | Event News

Ultrafast Wireless and Chip Design at the DATE Conference in Dresden

16.03.2018 | Event News

Latest News

For graphite pellets, just add elbow grease

23.03.2018 | Materials Sciences

Unique communication strategy discovered in stem cell pathway controlling plant growth

23.03.2018 | Agricultural and Forestry Science

Sharpening the X-ray view of the nanocosm

23.03.2018 | Physics and Astronomy

Science & Research
Overview of more VideoLinks >>>