Posts tagged depression
Posts tagged depression
A new study points to a conceptually novel therapeutic strategy for treating depression. Instead of dampening neuron firing found with stress-induced depression, researchers demonstrated for the first time that further activating these neurons opens a new avenue to mimic and promote natural resilience. The findings were so surprising that the research team thinks it may lead to novel targets for naturally acting antidepressants. Results from the study are published online April 18 in the journal Science.
Researchers from the Icahn School of Medicine at Mount Sinai point out that in mice resilient to social defeat stress (a source of constant stress brought about by losing a dispute or from a hostile interaction), their cation channel currents, which pass positive ions in dopamine neurons, are paradoxically elevated to a much greater extent than those of depressed mice and control mice. This led researchers to experimentally increase the current of cation channels with drugs in susceptible mice, those prone to depression, to see whether it would enhance coping and resilience. They found that such boosting of cation channels in dopamine neurons caused the mice to tolerate the increased stress without succumbing to depression-related symptoms, and unexpectedly the hyperactivity of the dopamine neurons was normalized.
Allyson K. Friedman, PhD, Postdoctoral Fellow in Pharmacology and Systems Therapeutics at the Icahn School of Medicine at Mount Sinai, and the study’s lead author said: “To achieve resiliency when under social stress, the brain must perform a complex balancing act in which negative stress-related changes in the brain actively trigger positive changes. But that can only happen once the negative changes reach a tipping point.”
The research team used optogenetics, a combination of laser optics and gene virus transfer, to control firing activity of the dopamine neurons. When light activation or the drug lamotrigine is given to these neurons, it drives the current and neuron firing higher. But at a certain point, it triggers compensatory mechanisms, normalizes neuron firing, and achieves a kind of homeostatic (or balanced) resilience.
"To our surprise, we found that resilient mice, instead of avoiding deleterious changes in the brain, experience further deleterious changes in response to stress, and use them beneficially," said Ming-Hu Han, PhD, at Icahn School of Medicine at Mount Sinai, who leads the study team as senior author.
Drs. Friedman and Han see this counterintuitive finding as stimulating research in a conceptually novel antidepressant strategy. If a drug could enhance coping and resilience by pushing depressed (or susceptible) individuals past the tipping point, it potentially might have fewer side effects, and work as a more naturally acting antidepressant.
Eric Nestler, MD, PhD, at the Icahn School of Medicine at Mount Sinai praised the study. “In this elegant study, Drs. Friedman and Han and their colleagues reveal a highly novel mechanism that controls an individual’s susceptibility or resilience to chronic social stress. The discoveries have important implications for the development of new treatments for depression and other stress-related disorders.”
Past research has long indicated that depression is a big risk factor for memory loss in aging adults. But it is still unclear exactly how the two issues are related and whether there is potential to slow memory loss by fighting depression.
A preliminary study conducted by researchers from the University of Rochester School of Medicine and Dentistry and the School of Nursing, and published in the 42nd edition of Psychoneuroendocrinology in April, delves more deeply into the relationship between depression and memory loss, and how this connection may depend on levels of insulin-like growth factor, or IGF-1.
Prior research has shown that IGF-1, a hormone that helps bolster growth, is important for preserving memory, especially among older adults.
The collaborative study found that people with lower cognitive ability were more likely to have had higher depressive symptoms if they also had low levels of IGF-1. Reversely, participants with high levels of IGF-1 had no link between depressive symptoms and memory.
Senior author Kathi L. Heffner, Ph.D., assistant professor in the School of Medicine and Dentistry’s Department of Psychiatry, had originally examined possible associations between IGF-1 and memory in a sample of 94 healthy older adults, but couldn’t find strong or consistent evidence.
Heffner then approached the study’s lead author Feng (Vankee) Lin, Ph.D, R.N., assistant professor at the School of Nursing, for input because of her expertise in cognitive aging. Lin is a young nurse researcher whose collaborative work focuses on developing multi-model interventions to slow the progression of cognitive decline in at-risk adults, and reduce their risk of developing dementia and Alzheimer’s disease.
“Vankee spearheaded the idea to examine the role of depressive symptoms in these data, which resulted in the interesting link,” Heffner said.
The association discovered between memory loss, depression and IGF-1 means that IGF-1 could be a very promising factor in protecting memory, Lin said.
“IGF-1 is currently a hot topic in terms of how it can promote neuroplasticity and slow cognitive decline,” Lin said. “Depression, memory and the IGF-1 receptor are all located in a brain region which regulates a lot of complicated cognitive ability. As circulating IGF-1 can pass through the blood-brain barrier, it may work to influence the brain in a protective way.”
Lin said more data studies are needed of people with depression symptoms and those with Alzheimer’s disease, but this study opens an important door for further research on the significance of IGF-1 levels in both memory loss and depression.
“It really makes a lot of sense to further develop this study,” Lin said. “If this could be a way to simultaneously tackle depression while preventing cognitive decline it could be a simple intervention to implement.”
Heffner said that clinical trials are underway to determine whether IGF-1 could be an effective therapeutic agent to slow or prevent cognitive decline in people at risk.
“Cognitive decline can also increase risk for depressive symptoms, so if IGF-1 protects people from cognitive decline, this may translate to reduced risk for depression as well,” Heffner said.
The first UK study of the use of ketamine intravenous infusions in people with treatment-resistant depression has been carried out in an NHS clinic by researchers at Oxford Health NHS Foundation Trust and the University of Oxford.
'Ketamine is a promising new antidepressant which works in a different way to existing antidepressants. We wanted to see whether it would be safe if given repeatedly, and whether it would be practical in an NHS setting. We especially wanted to check that repeated infusions didn't cause cognitive problems,' explains principal investigator Dr Rupert McShane, a consultant psychiatrist at Oxford Health and a researcher in Oxford University's Department of Psychiatry.
The researchers confirmed that ketamine has a rapid antidepressant effect in some patients with severe depression who have not responded to other treatments. These are patients suffering from severe depression which may have lasted years despite multiple antidepressants and talking therapies. Although many patients relapsed within a day or two, 29% had benefit which lasted at least three weeks and 15% took over two months to relapse.
Ketamine did not cause cognitive or bladder side effects when given on up to six occasions, although some people did experience other side effects such as anxiety during the infusion or being sick. The team have now given over 400 infusions to 45 patients and are exploring ways to maintain the effect. They report their findings in the Journal of Psychopharmacology. The study was funded by National Institute for Health Research (NIHR) Research for Patient Benefit Programme.
A nasal spray that delivers a peptide to treat depression holds promise as a potential alternative therapeutic approach, research from the Centre for Addiction and Mental Health (CAMH) shows.
The study, led by CAMH’s Dr. Fang Liu, is published online in Neuropsychopharmacology.
In a previous study published in Nature Medicine in 2010, Dr. Liu developed a protein peptide that provided a highly targeted approach to treating depression that she hopes will have minimal side effects. The peptide was just as effective in relieving symptoms when compared to a conventional antidepressant in animal testing. However, the peptide had to be injected into the brain. Taken orally, it would not cross the blood-brain barrier in sufficient concentrations.
"Clinically, we needed to find a non-invasive, convenient method to deliver this peptide treatment," says Dr. Liu, Senior Scientist in the Campbell Family Mental Health Research Institute at CAMH. With the support of a Proof of Principle grant from the Canadian Institutes of Health Research (CIHR), Dr. Liu’s team was able to further explore novel delivery methods.
The nasal delivery system, developed by U.S. company Impel NeuroPharma, was shown to deliver the peptide to the right part of the brain. It also relieved depression-like symptoms in animals.
"This study marks the first time a peptide treatment has been delivered through nasal passageways to treat depression," says Dr. Liu, Professor in the University of Toronto’s Department of Psychiatry.
The peptide treatment interferes with the binding of two dopamine receptors – the D1 and D2 receptor complex. Dr. Liu’s team had found that this binding was higher in the brains of people with major depression. Disrupting the binding led to the anti-depressant effects.
The peptide is an entirely new approach to treating depression, which has previously relied on medications that primarily block serotonin or norepinephrine transporters.
Depression, the most common form of mental illness, is one of the leading causes of disability globally. More than 50 per cent of people living with depression do not respond to first-line medication treatment.
"This research brings us one step closer to clinical trials," says Dr. Liu. In ongoing lab research, her team is experimenting to determine if they can make the peptide break down more slowly, and travel more quickly in the brain, to improve its anti-depressant effects.
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.