UCLA researchers develop biomarker for rapid relief of major depression: Brain-wave patterns may predict how effective medication will be

It is a long, slow slog to treat major depression. Many antidepressant medications are available, but no single biomarker or diagnostic test exists to predict which one is right for an individual. As a result, for more than half of all patients, the first drug prescribed doesn't work, and it can take months to figure out what does.

Now, based on the final results of a nationwide study led by UCLA, clinicians may be able to accurately predict within a week whether a particular drug will be effective by using a non-invasive test that takes less than 15 minutes to administer. The test will allow physicians to quickly switch patients to a more effective treatment, if necessary.

The study, called the Biomarkers for Rapid Identification of Treatment Effectiveness in Major Depression, or BRITE-MD, measured changes in brain-wave patterns using quantitative electroencephalography (QEEG), a non-invasive, computerized measurement that recognizes specific alterations in brain-wave activity. These changes precede improvement in mood by many weeks and appear to serve as a biomarker that accurately predicts how effective a given medication will be. The study results appear in two articles published in the September issue of the journal Psychiatry Research.

Nine sites around the country collaborated on the study, which enrolled a total of 375 people who had been diagnosed with major depressive disorder (MDD). Each individual was given a baseline QEEG at the beginning of the trial and then prescribed the antidepressant escitalopram, commonly known as Lexapro, one of a class of drugs known as selective serotonin re-uptake inhibitors that are commonly prescribed for depression. After one week, a second QEEG was taken. The researchers examined a biomarker called the antidepressant treatment response (ATR) index — a specific change in brain-wave patterns from the baseline QEEG.

Subjects were then randomly assigned to continue with escitalopram or were given a different drug. A total of 73 patients who remained on escitalopram were tracked for 49 days to see if their results matched the prediction of the ATR biomarker. The ATR predicted both response and remission with an accuracy rate of 74 percent, much higher than any other method available. The researchers also found that they could predict whether subjects were more likely to respond to a different antidepressant, bupropion, also known as Wellbutrin XL.

"Until now, other than waiting, there has been no reliable method for predicting whether a medication would lead to a good response or remission," said Dr. Andrew Leuchter, professor of psychiatry at the Semel Institute for Neuroscience and Human Behavior at UCLA and lead author of the study. "And that wait can be as long as 14 weeks. So these are very exciting findings for the patient suffering from depression. The BRITE results are a milestone in our efforts to develop clinically useful biomarkers for predicting treatment response in MDD."

Major depressive disorder is a leading cause of disability, costing society in excess of $80 billion annually; approximately two-thirds of these costs reflect the enormous disability associated with the disorder. An estimated 15 million people in the United States experience a depressive episode each year, and nearly 17 percent of adults will experience major depression in their lifetime.

"BRITE study results suggest that the ATR biomarker could potentially provide the greatest clinical benefit for those patients who might be receiving a medication that is unlikely to help them," Leuchter said. "Our results suggest that it may be possible to switch these patients to a more effective treatment quickly. This would help patients and their physicians avoid the frustration, risk and expense of long and ineffective medication trials."

Leuchter noted that research has shown that depression patients who do not get better with a first treatment experience prolonged suffering, are more likely to abandon treatment altogether and may become more resistant to treatment over time.

"So the benefits to the individual and to society are enormous," he said.

An added benefit of the biomarker test, according to Leuchter, is that it is non-invasive, painless and fast — about 15 minutes — and only involves the placement of six electrodes around the forehead and on the earlobes.

Aspect Medical Systems, which developed the ATR biomarker, provided financial support for the study. Aspect also participated in the design and conduct of the study; the collection, management, analysis and interpretation of the data; and the preparation and review of the manuscript. Final approval of the form and content of the manuscript rested with the authors.

Other UCLA authors included Dr. Ian Cook, Dr. Karl S. Burgoyne and Dr. James T. McCracken. Leuchter is chair of Aspect's neuroscience advisory board and has provided scientific consultation to them.

The Semel Institute for Neuroscience and Human Behavior is an interdisciplinary research and education institute devoted to the understanding of complex human behavior, including the genetic, biological, behavioral and sociocultural underpinnings of normal behavior and the causes and consequences of neuropsychiatric disorders. In addition to conducting fundamental research, institute faculty seek to develop effective treatments for neurological and psychiatric disorders, improve access to mental health services and shape national health policy regarding neuropsychiatric disorders.


Release link :

http://newsroom.ucla.edu/portal/ucla/ucla-researchers-develop-biomarker-101338.aspx

Fall forum at UT Southwestern will focus on genetic causes of Alzheimer's

Dr. Allen Roses, director of Duke University’s Deane Drug Discovery Institute, will discuss research aimed at reducing the risk of Alzheimer’s disease in people most susceptible to it at a Fall Public Forum on Sept. 23 at UT Southwestern Medical Center.

In 1992 Dr. Roses discovered a gene responsible for about half of inherited Alzheimer’s cases, and recently found that another gene interacts with it to further increase a person’s risk. In concert, these genes may account for most of the inherited form of the disease’s genetic effect.

The 7 p.m. forum, presented by The Friends of the Alzheimer’s Disease Center at
UT Southwestern, will be held in the Simmons/Hamon Biomedical Research Buildings on the North Campus. Complimentary valet parking is available, but because seating is limited, attendance should be confirmed by calling the medical center’s Office of Development at 214-648-2344.

“Dr. Roses is truly a great physician-scientist and one of the most important Alzheimer’s disease researchers in the world today,” said Dr. Roger Rosenberg, director of the Alzheimer’s Disease Center. “He discovered 17 years ago the most important genetic risk for developing Alzheimer’s disease and continues to investigate other genes that increase the risk for AD.”

Alzheimer’s disease is predicted to rise to 12 million cases in the U.S. by 2030. Inherited cases of Alzheimer’s represent a fraction of the cases, but they are more severe and start at an earlier age.

Dr. Roses’ recent work defines another gene that plays a major role in the development of Alzheimer’s. His studies may account for 85 percent to 90 percent of the genetic effects.

The Friends of the Alzheimer’s Disease Center was established in 1996 to provide financial support for Alzheimer’s research at UT Southwestern. All of the group’s membership contributions go directly to support Alzheimer’s research at the medical center.

Since its founding, the group has raised more than $600,000 for grants to researchers.


Release link :

http://www.utsouthwestern.edu/utsw/cda/dept353744/files/546701.html

Plastic surgeons should be part of disaster relief planning, response

When a terrorist bomb explodes, a tornado rips through a town, a hurricane devastates a region, or wildfires ravage homes and businesses, plastic surgeons are not typically atop the list of emergency responders.

But they should be, UT Southwestern Medical Center plastic surgeons and disaster experts recommend in the September issue of Plastic and Reconstructive Surgery.

Including plastic surgeons in disaster-relief efforts could improve long-term outcomes for victims of catastrophes, particularly in medical cases that might involve physical scarring and nerve damage, but which can be made worse by lack of quick attention.

“Plastic surgeons are often being overlooked in disaster-planning efforts, particularly in developing medical-team responders,” said Dr. Rod Rohrich, chairman of plastic surgery at
UT Southwestern and the study’s senior author. “Plastic surgeons, particularly those based at academic medical centers and/or major trauma centers, are far more engaged in complex reconstruction procedures on a day-to-day basis than cosmetic surgeons. We are intimately involved in preventing and treating face and tissue scarring, treating burns, and handling sensitive nerve-related injuries, some of which can be best served by having plastic surgeons on the scene or at least near the front lines where disaster victims are being evacuated.”

Examining the on-site evidence of several disasters, the authors identified four pivotal areas in trauma care where plastic surgeons have added expertise:

• soft tissue trauma;
• upper and lower extremity trauma;
• facial trauma; and
• burn management.

The authors suggest that plastic surgeons should be among those who help plan for medical responses prior to disasters, as well part of the responders working in conjunction with traditional surgical responders, such as trauma and orthopaedic surgeons.

The authors examined responses reported in disaster events ranging from devastating earthquakes in Turkey and the London Underground bombings to the Sept. 11 attacks on the East Coast and found a substantial volume of overall cases involving plastic surgery-related issues.

In the case of the London bombings in 2005, facial fractures affected 18 percent of patients. In the Turkey earthquake in 1999, more than 13 percent of hospital beds were occupied by patients needing plastic surgery. In New York City, only 26 percent of burn victims were correctly triaged first to a burn center, despite there being an adequate number of dedicated burn beds in the area.

“Not only should such expert plastic surgeons become part of the disaster preparation team and actual response to applicable incidents, but their training curricula should now also include formal courses in disaster life support and incident command system management,” said Dr. Paul Pepe, chief of emergency medicine at UT Southwestern and an international expert in disaster management. “In essence, both disaster managers and plastic surgery program directors need to foster the contributions of this previously overlooked resource for dealing with catastrophic events.”

Soft tissue injuries, for example, are the most common acute injury from casualties resulting from a blast or explosion and can be treated by other specialties, according to the article. Early intervention by plastic surgeons, however, could help avert problems such as long-term scarring or wound healing and closure, and could be more cost effective.

“Plastic surgeons routinely deal with facial healing, facial fractures, tissue damage and related territory, making access to the expertise of a plastic surgeon invaluable,” Dr. Rohrich said.

Plastic surgeons also bring expertise in tissue viability, amputation and microcirculation issues that can affect whether limbs are preserved, the authors said. Similarly, plastic surgeons have routine experience with burn care that could be invaluable in the case of radiation, biological or fire disasters, as well as help in triaging patients. While other surgical specialists have degrees of expertise in such areas, having direct access to plastic surgeons would be an important asset to disaster medical relief teams.

“As many disciplines gather together to partner in disaster response and preparation, the plastic surgeons should be seen as pivotal members, let alone additional assets, for the medical casualty care team,” the study’s authors concluded.

Visit www.utsouthwestern.org/plasticsurgery to learn more about UT Southwestern’s clinical services in plastic surgery. Visit www.utsouthwestern.org/emergency to learn about clinical services in emergency medicine at UT Southwestern.

Release link :

http://www.utsouthwestern.edu/utsw/cda/dept353744/files/547658.html

Link between depression, early stages of chronic kidney disease found by researchers

One in five patients with chronic kidney disease is depressed, even before beginning long-term dialysis therapy or developing end-stage renal disease, UT Southwestern Medical Center researchers have found.

The study, based on a pool of 272 participants, is the first to examine the rate of depression among these patients using the Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM IV), which is considered the gold-standard in evaluating depression.

“Because patients in the early stages of chronic kidney disease are at increased risk for clinical depression, we as nephrologists should consider screening our patients for depression in clinic,” said Dr. Susan Hedayati, assistant professor of internal medicine at UT Southwestern and a staff nephrologist at the Dallas Veterans Affairs Medical Center. She is the lead author of the study, available online and in the current issue of the American Journal of Kidney Diseases.


Previous research has shown that depression rates in the general community are 2 percent to 4 percent; among diabetes patients, 11 percent; among congestive heart failure patients, 14 percent; and among coronary artery disease after heart attack patients, 16 percent.

“Chronic kidney disease patient depression numbers may be higher due to the presence of the same simultaneously occurring conditions that resulted in progressive kidney disease, such as diabetes and atherosclerotic vascular disease,” Dr. Hedayati said. “Alternatively, patients such as diabetics, who are depressed, may develop progressive kidney disease because of non-adherence to medications and physicians’ advice.”

Earlier estimates of depression among chronic kidney disease patients were based on self-report depression scales that can emphasize symptoms such as lack of appetite, weight loss and fatigue. Such symptoms can overlap with other medical conditions, so
UT Southwestern researchers took a novel approach.

From May 2005 to November 2006, researchers invited patients at the Dallas VA Medical Center who were visiting the clinic for chronic kidney disease appointments to join the study. Patients who agreed to participate then underwent a structured clinical interview to determine if they had a current major depressive episode, based on the DSM IV definition of major depressive disorder.

Fifty-seven patients, or 21 percent, were found to be depressed. The mean age of depressed patients was about 65; two were women; and nearly 56 percent were white. All patients were veterans.

The researchers also found that diabetic patients were twice as likely to be depressed as those without diabetes; 63 percent of patients had at least three other medical conditions; and 41 percent had at least four other diseases.

Twenty-six million people in America have chronic kidney disease and millions more are at increased risk, according to the National Kidney Foundation. If treatment does not begin early, the condition progresses to end-stage renal disease. At that point, a patient’s kidneys have failed to the point where dialysis — a filtering of toxic chemicals in the blood and removing fluid to help control blood pressure — or a kidney transplant is needed.

According to the U.S. Renal Data System Annual Report, expenditures for end-stage renal disease patients totaled $15.5 billion, which is approximately 6 percent of the entire Medicare budget, and are projected to consume $28 billion by 2010.

Dr. Hedayati is now conducting the Chronic Kidney Disease Antidepressant Sertraline Trial (CAST) to determine whether antidepressant medication would be tolerated in kidney-disease patients and whether such treatment can improve depression.

Other UT Southwestern researchers involved in this study were Dr. Abu Minhajuddin, assistant professor of clinical sciences; Dr. Robert Toto, professor of internal medicine and clinical sciences; and Dr. David Morris, assistant professor of psychiatry. Also involved in the study was Dr. A. John Rush, a former professor of clinical sciences and psychiatry at
UT Southwestern, now vice dean of Duke-NUS Graduate Medical School Singapore.

The study was funded by the Veterans Integrated Service Network 17, Veterans Affairs North Texas Health Care System Research Corporation, the National Institutes of Health and the UT Southwestern O’Brien Kidney Research Core Center.

Visit www.utsouthwestern.org/kidneys to learn more about clinical services at
UT Southwestern for kidney diseases. Visit www.utsouthwestern.org/mentalhealth to learn more about UT Southwestern’s clinical services in psychiatry.


Release link :

http://www.utsouthwestern.edu/utsw/cda/dept353744/files/547326.html

Ice cream may target the brain before your hips, UT Southwestern study suggests

Blame your brain for sabotaging your efforts to get back on track after splurging on an extra scoop of ice cream or that second burger during Friday night's football game.

Findings from a new UT Southwestern Medical Center study suggest that fat from certain foods we eat makes its way to the brain. Once there, the fat molecules cause the brain to send messages to the body's cells, warning them to ignore the appetite-suppressing signals from leptin and insulin, hormones involved in weight regulation.

The researchers also found that one particular type of fat – palmitic acid – is particularly effective at instigating this mechanism.

"Normally, our body is primed to say when we've had enough, but that doesn't always happen when we're eating something good," said Dr. Deborah Clegg, assistant professor of internal medicine at UT Southwestern and senior author of the rodent study appearing in the September issue of The Journal of Clinical Investigation.

"What we've shown in this study is that someone's entire brain chemistry can change in a very short period of time. Our findings suggest that when you eat something high in fat, your brain gets 'hit' with the fatty acids, and you become resistant to insulin and leptin," Dr. Clegg said. "Since you're not being told by the brain to stop eating, you overeat."

Dr. Clegg said that in the animals, the effect lasts about three days, potentially explaining why many people who splurge on Friday or Saturday say they're hungrier than normal on Monday.

Though scientists have known that eating a high-fat diet can cause insulin resistance, little has been known about the mechanism that triggers this resistance or whether specific types of fat are more likely to cause increased insulin resistance. Dr. Clegg said she suspected the brain might play a role because it incorporates some of the fat we eat – whether it is from healthy oils or the not-so-healthy saturated fat found in butter and beef – into its structure.

Based on this suspicion, her team attempted to isolate the effects of fat on the animals' brains. Researchers did this by exposing the animals to fat in different ways: by injecting various types of fat directly into the brain, infusing fat through the carotid artery or feeding the animals through a stomach tube three times a day. The animals received the same amount of calories and fat; only the type of fat differed. The types included palmitic acid, monounsaturated fatty acid and oleic acid.

Palmitic acid is a common saturated fatty acid occurring in foods such as butter, cheese, milk and beef. Oleic acid, on the other hand, is one of the most common unsaturated fatty acids. Olive and grapeseed oils are rich in oleic acid.

"We found that the palmitic acid specifically reduced the ability of leptin and insulin to activate their intracellular signaling cascades," Dr. Clegg said. "The oleic fat did not do this. The action was very specific to palmitic acid, which is very high in foods that are rich in saturated-fat."

Dr. Clegg said that even though the findings are in animals, they reinforce the common dietary recommendation that individuals limit their saturated fat intake. "It causes you to eat more," she said.

The other key finding, she said, is that this mechanism is triggered in the brain – long before there might be signs of obesity anywhere else in the body.

The next step, Dr. Clegg said, is to determine how long it takes to reverse completely the effects of short-term exposure to high-fat food.

Release link :

http://www.utsouthwestern.edu/utsw/cda/dept353744/files/548055.html

World-first swine-flu vaccine trial reveals one dose provides 'strong immune response'

Results from the first swine-flu vaccine trials taking place in Leicester reveal a strong immune response after just one dose.

The pilot study, run by the University of Leicester and Leicester Hospitals, was trialled with 100 healthy volunteers, aged between 18 and 50.

Dr Iain Stephenson, who led the trial at the Leicester Royal Infirmary, said: “The clinical trial of Novartis MF59-adjuvanted cell-based A (H1N1) vaccine indicates that the “swine flu” vaccine elicits a strong immune response and is well-tolerated.

“Results showed that the serum antibody responses were highest among subjects who received two doses of vaccine, however a single vaccine dose also induced responses associated with protection against influenza.

“The findings showed that it is possible to induce protective antibody against A(H1N1) infection within two weeks of administration of a single low-dose adjuvanted vaccine.”

Non-adjuvanted formulations were not evaluated in this part of the study and will be evaluated shortly

The trial evaluated the tolerability and immunogenicity of the vaccine, and tested different schedules of vaccination, in terms of time between vaccinations. The vaccine schedule was one or two doses of 7.5μg MF-59 adjuvanted surface-antigen A/California/2009 vaccine derived from cell-culture.

Dr. Stephenson, of the Department of Infection, Immunity and Inflammation at the University of Leicester is a clinical senior lecturer at the University, and a consultant in infectious diseases at the University Hospitals of Leicester NHS Trust. He said: “The aim of the trial was to find out how many doses and what type of vaccine is needed to give protection. These initial results should help to plan vaccination campaigns in the autumn, including doses and timings. We concluded that the MF59-adjuvanted A(H1N1) vaccine of low antigen content was well tolerated and generated antibody responses associated with protection against influenza, even after a single dose.”

“The results suggest that one vaccine dose may be sufficient to protect against the A(H1N1) swine flu, rather than two. Larger trials are already underway around the world. Timings on when the vaccine will be available to governments will depend on the results of these clinical trials, and approvals by regulatory authorities’’

The research found the vaccine is well tolerated with pain at the injection site the most frequent adverse event.

Additional pivotal trials with both cell culture and traditional egg based vaccines under way around the world that will include more than 6000 adults and children.

Previous research had indicated that two doses of the vaccine would be needed against swine flu. You can access earlier stories here:

http://www2.le.ac.uk/ebulletin/news/press-releases/2000-2009/2009/08/nparticle.2009-08-11.3248230936

You can view the press release from Novartis here:

http://www.novartis.com/newsroom/media-releases/en/2009/1339223.shtml


Release link :

http://www2.le.ac.uk/ebulletin/news/press-releases/2000-2009/2009/09/nparticle.2009-09-03.6831410081