Posts tagged depression
Posts tagged depression
Lead research Professor Nick Allen from the Melbourne School of Psychological Sciences said, “It is well known that the brain continues to change and remodel itself during adolescence as part of healthy development.”
“In this study, we found that the pattern of development (such as changes in brain structure between ages twelve to sixteen) in several key brain regions differed between depressed and non-depressed adolescents,” Professor Allen said.
The brain regions involved include areas associated with the experience and regulation of emotion, as well as areas associated with learning and memory.
“The findings are an important breakthrough for exploring possible causes of depression in adolescence. They also suggest that both prevention and treatment for depression (even for early signs and symptoms of depression) in adolescence is essential, especially targeting those in the early years of adolescence aged twelve to sixteen,” he said.
“We also observed some differences between males and females. For males, less growth in an area of the brain involved in processing threat and other unexpected events that is a critical part of the brain’s fear circuitry, was associated with depression. On the other hand, for females, greater growth of this area was found to be associated with depression.”
“This is important information because depression becomes much more common amongst girls during adolescence, and these findings tell us about some of the neurobiological factors that might play a role in this gender difference,” he said.
Professor Allen says adolescence is a period during the lifespan where risk for developing depression dramatically increases.
The study examined eighty-six adolescents (41 female) with no history of depressive disorders before age 12 by using a Magnetic Resonance Imaging (MRI) scanner, which allowed researchers to measure the volume of particular brain regions of interest. Participants underwent an MRI scan first at age twelve and again at age sixteen, when rates of depression were beginning to increase. Researchers also conducted detailed interviews with each of the participants at four different time points between age twelve and age eighteen. Thirty participants experienced a first episode of a depressive disorder during the follow-up period.
These findings have recently been published in the American Journal of Psychiatry.
People with multiple sclerosis (MS) might assume that the fatigue they often feel just comes with the territory of their chronic neurological condition.
But a new University of Michigan study suggests that a large proportion of MS patients may have an undiagnosed sleep disorder that is also known to cause fatigue. And that disorder – obstructive sleep apnea – is a treatable condition.
In the latest issue of the Journal of Clinical Sleep Medicine, researchers from the U-M Health System’s Sleep Disorders Center report the results of a study involving 195 patients of the U-M Multiple Sclerosis Center.
In all, 56 percent of the MS patients were found to be at increased risk for obstructive sleep apnea, based on a method of screening for the condition known as the STOP-Bang questionnaire. But most had never received a formal diagnosis of sleep apnea, and less than half of those who had been told they had sleep apnea were using the standard treatment for it.
The authors also found that patients who were more fatigued were more likely to also be at elevated risk for sleep apnea – even after taking into account other factors that might have contributed to feelings of fatigue, such as age, gender, body mass index (BMI), sleep duration, depression, and other nighttime symptoms.
The research is based on patients’ answers from a sleep questionnaire designed by the authors, and four validated instruments designed to assess daytime sleepiness, fatigue severity, insomnia severity and obstructive sleep apnea risk. Medical records also were accessed with patients’ permission, to examine clinical characteristics that may predict fatigue or obstructive sleep apnea risk.
“We were particularly surprised by the difference between the proportion of patients who carried an established diagnosis of obstructive sleep apnea – 21 percent — and the proportion at risk for obstructive sleep apnea based on their STOP-Bang scores, which was 56 percent,” says the study’s lead author, Tiffany Braley, M.D., M.S. “These findings suggest that OSA may be a highly prevalent and yet under-recognized contributor to fatigue in persons with MS.”
Braley, an assistant professor of Neurology and multiple sclerosis specialist at the U-M Medical School, conducted the study in collaboration with professors Ronald Chervin, M.D., M.S., and Benjamin Segal, M.D. Chervin is the Director of U-M Sleep Disorders Center, and Segal directs the U-M MS Center.
Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system that causes inflammation and damage of the brain and spinal cord. In addition to neurological disability, MS patients suffer from a number of chronic symptoms, the most common of which is fatigue. Fatigue is also one of the most disabling symptoms experienced by MS patients.
Braley cautions that the design of this new study does not allow for demonstration of cause and effect – that is, the researchers can’t prove based on survey results that the patients felt more fatigued because they had a high score on a sleep apnea risk survey. But, she says, “the findings should prompt doctors who treat MS patients to consider sleep apnea as a possible contributor to their patients’ fatigue, and recommend appropriate testing and treatment.”
The standard treatment for obstructive sleep apnea, called continuous positive airway pressure, or CPAP, involves a machine and mask device that applies a stream of air to the upper airway to keep it open during sleep.
The patients in the study had an average age of 47 and had lived with MS for an average of 10 years. Two-thirds were female, consistent with the prevalence of MS in the U.S., and two-thirds were taking a medication to treat their MS. Three-quarters had the relapsing-remitting form of the disease.
A multicenter research team led by Cedars-Sinai neurologist Nancy Sicotte, MD, an expert in multiple sclerosis and state-of-the-art imaging techniques, used a new, automated technique to identify shrinkage of a mood-regulating brain structure in a large sample of women with MS who also have a certain type of depression.
In the study, women with MS and symptoms of “depressive affect” – such as depressed mood and loss of interest – were found to have reduced size of the right hippocampus. The left hippocampus remained unchanged, and other types of depression – such as vegetative depression, which can bring about extreme fatigue – did not correlate with hippocampal size reduction, according to an article featured on the cover of the January 2014 issue of Human Brain Mapping.
The research supports earlier studies suggesting that the hippocampus may contribute to the high frequency of depression in multiple sclerosis. It also shows that a computerized imaging technique called automated surface mesh modeling can readily detect thickness changes in subregions of the hippocampus. This previously required a labor-intensive manual analysis of MRI images.
Sicotte, the article’s senior author, and others have previously found evidence of tissue loss in the hippocampus, but the changes could only be documented in manual tracings of a series of special high-resolution MRI images. The new approach can use more easily obtainable MRI scans and it automates the brain mapping process.
“Patients with medical disorders – and especially those with inflammatory diseases such as MS – often suffer from depression, which can cause fatigue. But not all fatigue is caused by depression. We believe that while fatigue and depression often co-occur in patients with MS, they may be brought about by different biological mechanisms. Our studies are designed to help us better understand how MS-related depression differs from other types, improve diagnostic imaging systems to make them more widely available and efficient, and create better, more individualized treatments for our patients,” said Sicotte, director of Cedars-Sinai’s Multiple Sclerosis Program and the Neurology Residency Program. She received a $506,000 grant from the National Multiple Sclerosis Society last year to continue this research.
A shock to the system: Electroconvulsive Therapy shows mood disorder-specific therapeutic benefits
The oldest well-established procedure for somatic treatment of unipolar and bipolar disorders, electroconvulsive therapy (ECT) has, at best, a variegated reputation – and not just in its reputation for being a “barbaric” treatment modality (which, as it turns out, it is not). The scientific, clinical, and ethical controversy extends to unanswered questions about its precise mechanism of action – that is, how major electrical discharge over half the brain shows efficacy in recovery from a range of sometimes quite distinct psychological and psychiatric disorders. Recently, however, scientists at Université de Lausanne, Lausanne, Switzerland and Charité University Medicine, Berlin, Germany found local but not general anatomical brain changes following electroconvulsive therapy that are differently distributed in each disease, and are actually the areas believed to be abnormal in each disorder. Since interaction between ECT and specific pathology appears to be therapeutically causal, the researchers state that their results have implications for deep brain stimulation, transcranial magnetic stimulation and other electrically-based brain treatments.
Prof. Bogdan Draganski discussed the paper that he, Dr. Juergen Dukart and their co-authors published in Proceedings of the National Academy of Sciences.
Scientists from the Florida campus of The Scripps Research Institute (TSRI) have described a pair of drug candidates that advance the search for new treatments for pain, addiction and other disorders.
The two new drug scaffolds, described in a recent edition of The Journal of Biological Chemistry, offer researchers novel tools that act on a demonstrated therapeutic target, the kappa opioid receptor (KOR), which is located on nerve cells and plays a role in the release of the neurotransmitter dopamine. While compounds that activate KOR are associated with positive therapeutic effects, they often also recruit a molecule known as βarrestin2 (beta arrestin), which is associated with depressed mood and severely limits any therapeutic potential.
“Compounds that act at kappa receptors may provide a means for treating addiction and for treating pain; however, there is the potential for the development of depression or dysphoria associated with this receptor target,” said Laura Bohn, a TSRI associate professor who led the study. “There is evidence that the negative feelings caused by kappa receptor drugs may be, in part, due to receptor actions through proteins called beta arrestins. Developing compounds that activate the receptors without recruiting beta arrestin function may serve as a means to improve the therapeutic potential and limit side effects.”
The new compounds are called “biased agonists,” activating the receptor without engaging the beta arrestins.
Research Associate Lei Zhou, first author of the study with Research Associate Kimberly M. Lovell, added, “The importance of these biased agonists is that we can manipulate the activation of one particular signaling cascade that produces analgesia, but not the other one that could lead to dysphoria or depression.”
The researchers note that the avoidance of depression is particularly important in addiction treatment, where depressed mood can play a role in relapse.
The two drug candidates also have a high affinity and selectivity for KOR over other opioid receptors and are able to pass through the blood-brain barrier. Given these promising attributes, the scientists plan to continue developing the compounds.
The World health Organization calls depression “the leading cause of disability worldwide,” causing more years of disability than cancer, HIV/AIDS, and cardiovascular and respiratory diseases combined. In any given year, 5-7% of the world’s population experiences a major depressive episode, and one in six people will at some point suffer from the disease.
Despite recent progress in understanding depression, scientists still don’t understand the biological mechanisms behind it well enough to deliver effective prevention and therapy. One possible reason is that almost all research focuses on the brain’s neurons, while the involvement of other brain cells has not been thoroughly examined.
Now researchers at the Hebrew University of Jerusalem have shown that changes in one type of non-neuronal brain cells, called microglia, underlie the depressive symptoms brought on by exposure to chronic stress. In experiments with animals, the researchers were able to demonstrate that compounds that alter the functioning of microglia can serve as novel and efficient antidepressant drugs.
The findings were published in Molecular Psychiatry, the premier scientific journal in psychiatry and one of the leading journals in medicine and the neurosciences.
The research was conducted by Prof. Raz Yirmiya, director of the Hebrew University’s Psychoneuroimmunology Laboratory, and his doctoral student Tirzah Kreisel, together with researchers at Prof. Yirmiya’s laboratory and at the University of Colorado in Boulder, USA.
The researchers examined the involvement of microglia brain cells in the development of depression following chronic exposure to stress. Comprising roughly 10% of brain cells, microglia are the representatives of the immune system in the brain; but recent studies have shown that these cells are also involved in physiological processes not directly related to infection and injury, including the response to stress.
The researchers mimicked chronic unpredictable stress in humans — a leading causes of depression — by exposing mice to repeated, unpredictable stressful conditions over a period of 5 weeks. The mice developed behavioral and neurological symptoms mirroring those seen in depressed humans, including a reduction in pleasurable activity and in social interaction, as well as reduced generation of new brain cells (neurogenesis) — an important biological marker of depression.
The researchers found that during the first week of stress exposure, microglia cells undergo a phase of proliferation and activation, reflected by increased size and production of specific inflammatory molecules, after which some microglia begin to die. Following the 5 weeks of stress exposure, this phenomenon led to a reduction in the number of microglia, and to a degenerated appearance of some microglia cells, particularly in a specific region of the brain involved in responding to stress.
When the researchers blocked the initial stress-induced activation of microglia with drugs or genetic manipulation, they were able to stop the subsequent microglia cell death and decline, as well as the depressive symptoms and suppressed neurogenesis. However, these treatments were not effective in “depressed” mice, which were already exposed to the 5-weeks stress period and therefore had lower number of microglia. Based on these findings, the investigators treated the “depressed” mice with drugs that stimulated the microglia and increased their number to a normal level.
Prof. Yirmiya said, “We were able to demonstrate that such microglia-stimulating drugs served as effective and fast-acting antidepressants, producing complete recovery of the depressive-like behavioral symptoms, as well as increasing the neurogenesis to normal levels within a few days of treatment. In addition to the clinical importance of these results, our findings provide the first direct evidence that in addition to neurons, disturbances in the functioning of brain microglia cells have a role in causing psychopathology in general, and depression in particular. This suggests new avenues for drug research, in which microglia stimulators could serve as fast-acting antidepressants in some forms of depressive and stress-related conditions.”
The Hebrew University’s technology transfer company, Yissum, has applied for a patent for the treatment of some forms of depression by several specific microglia-stimulating drugs.
A team of researchers working in the Netherlands has found that partial selective memory deletion can be achieved using Electroconvulsive Therapy (ECT). In their paper published in the journal Nature Neuroscience, the team describes a memory experiment they conducted with the assistance of severely depressed people who had already consented to undergoing ECT and found that such treatment could be used to at least partially erase memories of a specified event.
Scientists have known since 1968 (thanks to experiments conducted by psychologist Donald Lewis) that applying a shock to the brain of a rat can cause it to forget something unpleasant it had remembered. Subsequent experiments have found that memories can be blunted using repetitive type therapies or by injecting drugs such as propranolol into the brain. The one element all such findings have in common is that they must be applied during a time when a person is attempting to recall a certain event. Scientists hope that such research may lead to new ways to treat PTSD and other memory related mental ailments. In this new effort the researchers explored the idea of erasing specific memories using ECT.
Currently, people with severe depression who don’t respond to any other type of treatment are offered ECT as a last resort. It has a remarkably good success rate (approximately 86 percent rate of remission) but causes some degree of memory loss. In the Netherlands study, the team enlisted the assistance of 39 such patients who had already agreed to undergo ECT. Instead of receiving just the standard treatment, however, the volunteers were asked to watch two slide shows (along with narration) —both of which contained unsettling content. A week later the participants were divided into three groups—two to get the shock treatment and one to serve as a control group—all were asked to remember and describe one of the traumatic events described in the slide shows. Afterwards, one of the groups was given ECT and then the next day was asked to recount both stores. The other non-control group was given ECT and then were asked right afterwards to recount the unpleasant stories. The control group was asked to try to recount both stories as well.
In comparing the results between the groups, the researchers found that the first group that had been quizzed a day after receiving ECT had difficulty recalling the first story, which they had recounted prior to ECT, but remembered most of second. The second group that received ECT were able to recall both stories equally well, and the third—the control group—were able to remember both stories better than either of the groups that had received ECT.
The experiment suggests that it is possible to selectively erase short term memory in a controlled environment. Much more research will have to be conducted to determine if it would work in real world situations.
TAU researchers discover gene that may predict human responses to specific antidepressants
Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed antidepressants, but they don’t work for everyone. What’s more, patients must often try several different SSRI medications, each with a different set of side effects, before finding one that is effective. It takes three to four weeks to see if a particular antidepressant drug works. Meanwhile, patients and their families continue to suffer.
Now researchers at Tel Aviv University have discovered a gene that may reveal whether people are likely to respond well to SSRI antidepressants, both generally and in specific formulations. The new biomarker, once it is validated in clinical trials, could be used to create a genetic test, allowing doctors to provide personalized treatment for depression.
Doctoral students Keren Oved and Ayelet Morag led the research under the guidance of Dr. David Gurwitz of the Department of Molecular Genetics and Biochemistry at TAU’s Sackler Faculty of Medicine and Dr. Noam Shomron of the Department of Cell and Developmental Biology at TAU’s Sackler Faculty of Medicine and Sagol School of Neuroscience. Sackler faculty members Prof. Moshe Rehavi of the Department of Physiology and Pharmacology and Dr. Metsada Pasmnik-Chor of the Bioinformatics Unit were coauthors of the study, published in Translational Psychiatry.
"SSRIs only work for about 60 percent of people with depression," said Dr. Gurwitz. "A drug from other families of antidepressants could be effective for some of the others. We are working to move the treatment of depression from a trial-and-error approach to a best-fit, personalized regimen."
Good news for the depressed
More than 20 million Americans each year suffer from disabling depression that requires clinical intervention. SSRIs such as Prozac, Zoloft, and Celexa are the newest and the most popular medications for treatment. They are thought to work by blocking the reabsorption of the neurotransmitter serotonin in the brain, leaving more of it available to help brain cells send and receive chemical signals, thereby boosting mood. It is not currently known why some people respond to SSRIs better than others.
To find genes that may be behind the brain’s responsiveness to SSRIs, the TAU researchers first applied the SSRI Paroxetine — brand name Paxil — to 80 sets of cells, or “cell lines,” from the National Laboratory for the Genetics of Israeli Populations, a biobank of genetic information about Israeli citizens located at TAU’s Sackler Faculty of Medicine and directed by Dr. Gurwitz. The TAU researchers then analyzed and compared the RNA profiles of the most and least responsive cell lines. A gene called CHL1 was produced at lower levels in the most responsive cell lines and at higher levels in the least responsive cell lines. Using a simple genetic test, doctors could one day use CHL1 as a biomarker to determine whether or not to prescribe SSRIs.
"We want to end up with a blood test that will allow us to tell a patient which drug is best for him," said Oved. "We are at the early stages, working on the cellular level. Next comes testing on animals and people."
Rethinking how antidepressants work
The TAU researchers also wanted to understand why CHL1 levels might predict responsiveness to SSRIs. To this end, they applied Paroxetine to human cell lines for three weeks — the time it takes for a clinical response to SSRIs. They found that Paroxetine caused increased production of the gene ITGB3 — whose protein product is thought to interact with CHL1 to promote the development of new neurons and synapses. The result is the repair of dysfunctional signaling in brain regions controlling mood, which may explain the action of SSRI antidepressants.
This explanation differs from the conventional theory that SSRIs directly relieve depression by inhibiting the reabsorption of the neurotransmitter serotonin in the brain. Dr. Shomron adds that the new explanation resolves the longstanding mystery as to why it takes at least three weeks for SSRIs to ease the symptoms of depression when they begin inhibiting reabsorption after a couple days — the development of neurons and synapses takes weeks, not days.
The TAU researchers are working to confirm their findings on the molecular level and with animal models. Adva Hadar, a master’s student in Dr. Gurwitz’s lab, is using the same approach to find biomarkers for the personalized treatment of Alzheimer’s disease.
One of the smallest parts of the brain is getting a second look after new research suggests it plays a crucial role in decision making.
A University of British Columbia study published today in Nature Neuroscience says the lateral habenula, a region of the brain linked to depression and avoidance behaviours, has been largely misunderstood and may be integral in cost-benefit decisions.
“These findings clarify the brain processes involved in the important decisions that we make on a daily basis, from choosing between job offers to deciding which house or car to buy,” says Prof. Stan Floresco of UBC’s Dept. of Psychology and Brain Research Centre (BRC). “It also suggests that the scientific community has misunderstood the true functioning of this mysterious, but important, region of the brain.”
In the study, scientists trained lab rats to choose between a consistent small reward (one food pellet) or a potentially larger reward (four food pellets) that appeared sporadically. Like humans, the rats tended to choose larger rewards when costs—in this case, the amount of time they had to wait before receiving food–were low and preferred smaller rewards when such risks were higher.
Previous studies suggest that turning off the lateral habenula would cause rats to choose the larger, riskier reward more often, but that was not the case. Instead, the rats selected either option at random, no longer showing the ability to choose the best option for them.
The findings have important implications for depression treatment. “Deep brain stimulation – which is thought to inactivate the lateral habenula — has been reported to improve depressive symptoms in humans,” Floresco says. “But our findings suggest these improvements may not be because patients feel happier. They may simply no longer care as much about what is making them feel depressed.”
Floresco, who conducted the study with PhD candidate Colin Stopper, says more investigation is needed to understand the complete brain functions involved in cost-benefit decision processes and related behaviour. A greater understanding of decision-making processes is also crucial, they say, because many psychiatric disorders, such as schizophrenia, stimulant abuse and depression, are associated with impairments in these processes.
The lateral habenula is considered one of the oldest regions of the brain, evolution-wise, the researchers say.
Research released today reveals new mechanisms and areas of the brain associated with anxiety and depression, presenting possible targets to understand and treat these debilitating mental illnesses. The findings were presented at Neuroscience 2013, the annual meeting of the Society for Neuroscience and the world’s largest source of emerging news about brain science and health.
More than 350 million people worldwide suffer from clinical depression and between 5 and 25 percent of adults suffer from generalized anxiety, according to the World Health Organization. The resulting emotional and financial costs to people, families, and society are significant. Further, antidepressants are not always effective and often cause severe side effects.
Today’s new findings show that:
Other recent findings discussed show that:
“Today’s findings represent our rapidly growing understanding of the individual molecules and brain circuits that may contribute to depression and anxiety,” said press conference moderator Lisa Monteggia, PhD, of the University of Texas Southwestern Medical Center, an expert on mechanisms of antidepressant action. “These exciting discoveries represent the potential for significant changes in how we diagnose and treat these illnesses that touch millions.”