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 A promising target for kidney fibrosis
21.04.2017 | Brigham and Women's Hospital

nachricht Stem cell transplants: activating signal paths may protect from graft-versus-host disease
20.04.2017 | Technische Universität München

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: Making lightweight construction suitable for series production

More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.

Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...

Im Focus: Wonder material? Novel nanotube structure strengthens thin films for flexible electronics

Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.

"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...

Im Focus: Deep inside Galaxy M87

The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.

Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...

Im Focus: A Quantum Low Pass for Photons

Physicists in Garching observe novel quantum effect that limits the number of emitted photons.

The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...

Im Focus: Microprocessors based on a layer of just three atoms

Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.

Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Expert meeting “Health Business Connect” will connect international medical technology companies

20.04.2017 | Event News

Wenn der Computer das Gehirn austrickst

18.04.2017 | Event News

7th International Conference on Crystalline Silicon Photovoltaics in Freiburg on April 3-5, 2017

03.04.2017 | Event News

 
Latest News

NASA's Fermi catches gamma-ray flashes from tropical storms

25.04.2017 | Physics and Astronomy

Researchers invent process to make sustainable rubber, plastics

25.04.2017 | Materials Sciences

Transfecting cells gently – the LZH presents a GNOME prototype at the Labvolution 2017

25.04.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>