Posts tagged psychiatric disorders
Articles and news from the latest research reports.
Life Stressors Trigger Neurological Disorders
When mothers are exposed to trauma, illness, alcohol or other drug abuse, these stressors may activate a single molecular trigger in brain cells that can go awry and activate conditions such as schizophrenia, post-traumatic stress disorder and some forms of autism.
Until now, it has been unclear how much these stressors have impacted the cells of a developing brain. Past studies have shown that when an expectant mother exposes herself to alcohol or drug abuse or she experiences some trauma or illness, her baby may later develop a psychiatric disorder, including some forms of autism or post-traumatic stress disorder, later in life. But the new findings, published online in Neuron, identifies a molecular mechanism in the prenatal brain that may help explain how cells go awry when exposed to certain environmental conditions.
Kazue Hasimoto-Torii, PhD, Principal Investigator of the Center for Neuroscience, Children’s National Health System, and a Scott-Gentle Foundation investigator, is lead author of the paper. Torii was previously at Yale, whose researchers were co-authors in the report. The research was funded primarily through National Institutes of Health grants.
Researchers found that mouse embryos exposed to alcohol, methyl-mercury, or maternal seizures activate a single gene, HSF1, also known as heat shock factor, in cerebral cortex. The HSF1 “plays a crucial role in the response of brain cells to prenatal environmental insults,” the researchers reported. “The gene protects and enables brain cells to survive prenatal assaults. Mice lacking the HSF1 gene showed structural brain abnormalities and were prone to seizures after birth following exposures to very low levels of toxins.”
Even in mice where the HSF1 gene was properly activated to combat environmental insults, the molecular mechanism alone may permanently change how brain cells respond, and may be a reason why someone may be more susceptible to neuropsychiatric disorders later in life.
Innovative work with stem cells also provided findings that supported the theory that stress induces vulnerable cells to malfunction, the researchers reported. For the study, researchers created stem cells from biopsies of people diagnosed with schizophrenia. Stem cells are capable of becoming many different tissue types, including neurons. In the study, genes from the stem cells of those with schizophrenia responded more dramatically when exposed to environmental insults than stem cells from non-schizophrenic individuals.
While it has been generally accepted that exposure to harmful environmental factors increase the susceptibility of the brain to neurological and psychiatric disorders, new types of environmental agents are continuingly added to the mix, requiring evolving studies, Hasimoto-Torii says.
Hashimoto-Torii notes that autism rates have increased substantially and “more people are having these exposures to environmental stressors,” she says. While there have been many studies that have identified singular stressors, such as alcohol, there have not been enough studies to focus on many different environmental factors and their impacts, such as heavy metals as well as alcohol and other toxic exposure, she adds.
Identifying many risk factors helped Hashimoto-Torii and other researchers identify the gene that may be linked to neurological problems. “Different stressors may have different stress responses,” she says. She examined risk factors specifically involving epilepsy, ADHD, autism and schizophrenia. Eventually, it may open the door “to provide therapy in the future to reduce the risk” and protect vulnerable cells.
Smoking’s toll on mentally ill analyzed
Those in the United States with a mental illness diagnosis are much more likely to smoke cigarettes and smoke more heavily, and are less likely to quit smoking than those without mental illness, regardless of their specific diagnosis, a new study by researchers from the Yale School of Medicine shows.
They also found variations in smoking rates and likelihood of quitting among different diagnoses of mental illness. The results are reported in the April issue of the journal Tobacco Control.
Thirty-nine percent of adults with a psychiatric diagnosis smoked compared to 16% without a diagnosis, according to data from the National Epidemiologic Survey on Alcohol and Related Conditions analyzed by researchers. Two out of every three people with drug use disorder smoke, compared to one out of three with social phobia.
“We know that smokers with mental illness are more susceptible to smoking-related disease, and those with mental illness die 25 years earlier than adults without mental illness,” said Sherry McKee, associate professor of psychiatry, and senior author on the study. “Effective smoking cessation treatments are available and we know that smokers with mental illness can quit smoking. We need to address why smokers with mental illness are not being treated for their smoking.”
Over the three-year study period, 22% of smokers with no psychiatric disorders were able to quit smoking, whereas rates of quitting among those with psychiatric disorders were 25% lower. Rates of quitting were lowest among those with dysthymia (10%), agoraphobia (13%), and social phobia (13%). “We also found that individuals with multiple diagnoses had the lowest quit rates,” added Philip Smith, lead author on the study.
This study adds to evidence that smokers with mental illness consume nearly half of all cigarettes in the United States, despite making up a substantially smaller proportion of the population.
Researchers and policymakers are increasingly calling attention to this important public health issue, and this study helps point to a need for interventions and policy that directly help individuals with mental illness quit smoking.
Researchers search for earliest roots of psychiatric disorders
Newborns whose mothers were exposed during pregnancy to any one of a variety of environmental stressors — such as trauma, illness, and alcohol or drug abuse — become susceptible to various psychiatric disorders that frequently arise later in life. However, it has been unclear how these stressors affect the cells of the developing brain prenatally and give rise to conditions such as schizophrenia, post-traumatic stress disorder, and some forms of autism and bipolar disorders.
Now, Yale University researchers have identified a single molecular mechanism in the developing brain that sheds light on how cells may go awry when exposed to a variety of different environmental insults. The findings, to be published in the May 7 issue of the journal Neuron, suggest that different types of stressors prenatally activate a single molecular trigger in brain cells that may make exposed individuals susceptible to late-onset neuropsychiatric disorders.
The researchers found that mouse embryos exposed to alcohol, methyl-mercury, or maternal seizures all activate in the developing brain cells a single gene — HSF1 or heat shock factor — which protects and enables some of the brain cells to survive prenatal insult. Mice lacking the HSF1 gene showed structural brain abnormalities and were prone to seizures after birth, even after exposure to very low levels of the toxins.
In addition, researchers created stem cells — which are capable of becoming many different tissue types, including neurons — from biopsies of individuals diagnosed with schizophrenia. Genes from these “schizophrenic” stem cells responded more dramatically when exposed to environmental insults than stem cells obtained from non-schizophrenic individuals. The findings provide support to the thesis that stress induces vulnerable cells to malfunction.
“It appears that different types of environmental stressors can trigger the same condition if they occur at the same period of prenatal development,” said Yale’s Pasko Rakic, senior author of the study. “Conversely, the same environmental stressor may cause different pathologies, if it occurs at different times during pregnancy.”
Since HSF1 activation can potentially serve as a permanent marker of the stressed/damaged cell, it opens the possibility of identifying these cells in adults in order to explore the pathogenesis of postnatal disorders and how to protect vulnerable cells.
DNA Modifications Measured in Blood Signal Related Changes in the Brain
Research linked to stress in mice confirms blood-brain comparison is valid
Johns Hopkins researchers say they have confirmed suspicions that DNA modifications found in the blood of mice exposed to high levels of stress hormone — and showing signs of anxiety — are directly related to changes found in their brain tissues.
The proof-of-concept study, reported online ahead of print in the June issue of Psychoneuroendocrinology, offers what the research team calls the first evidence that epigenetic changes that alter the way genes function without changing their underlying DNA sequence — and are detectable in blood — mirror alterations in brain tissue linked to underlying psychiatric diseases.
The new study reports only on so-called epigenetic changes to a single stress response gene called FKBP5, which has been implicated in depression, bipolar disorder and post-traumatic stress disorder. But the researchers say they have discovered the same blood and brain matches in dozens more genes, which regulate many important processes in the brain.
“Many human studies rely on the assumption that disease-relevant epigenetic changes that occur in the brain — which is largely inaccessible and difficult to test — also occur in the blood, which is easily accessible,” says study leader Richard S. Lee, Ph.D., an instructor in the Department of Psychiatry and Behavioral Sciences at the Johns Hopkins University School of Medicine. “This research on mice suggests that the blood can legitimately tell us what is going on in the brain, which is something we were just assuming before, and could lead us to better detection and treatment of mental disorders and for a more empirical way to test whether medications are working.”
For the study, the Johns Hopkins team worked with mice with a rodent version of Cushing’s disease, which is marked by the overproduction and release of cortisol, the primary stress hormone also called glucocorticoid. For four weeks, the mice were given different doses of stress hormones in their drinking water to assess epigenetic changes to FKBP5. The researchers took blood samples weekly to measure the changes and then dissected the brains at the end of the month to study what changes were occurring in the hippocampus as a result of glucocorticoid exposure. The hippocampus, in both mice and humans, is vital to memory formation, information storage and organizational abilities.
The measurements showed that the more stress hormones the mice got, the greater the epigenetic changes in the blood and brain tissue, although the scientists say the brain changes occurred in a different part of the gene than expected. This was what made finding the blood-brain connection very challenging, Lee says.
Also, the more stress hormone, the more RNA from the FKBP5 gene was expressed in the blood and brain, and the greater the association with depression. However, it was the underlying epigenetic changes that proved to be more robust. This is important, because while RNA levels may return to normal after stress hormone levels decrease or change due to small fluctuations in hormone levels, epigenetic changes persist, reflect overall stress hormone exposure and predict how much RNA will be made when stress hormone levels increase.
The team of researchers used an epigenetic assay previously developed in their laboratory that requires just one drop of blood to accurately assess overall exposure to stress hormone over 30 days. Elevated levels of stress hormone exposure are considered a risk factor for mental illness in humans and other mammals.
(Source: hopkinsmedicine.org)
Schizophrenia: What’s in my head?
When she’s experiencing hallucinations, artist Sue Morgan feels compelled to draw; to ‘get it out of her head’. Sue was diagnosed with schizophrenia about 20 years ago. The drawing is therapeutic, but it’s also Sue’s way of expressing the complex and sometimes frightening secret world in her head. In this film Sue meets Sukhi Shergill, a clinician and researcher at the Institute of Psychiatry in London. He’s also making pictures, but using MRI to peer inside the brains of schizophrenia patients.
Read more about schizophrenia
Mapping brain circuitry
Common psychiatric disorders, such as anxiety and addiction, likely result from changes in brain circuitry. Understanding structural and functional brain connections – and how they change in psychiatric disorders – could lead to novel preventive and therapeutic strategies.
The bed nucleus of the stria terminalis (BNST) has been linked to both anxiety and addiction, but its circuitry in humans has not been described. Jennifer Blackford, Ph.D., assistant professor of Psychiatry, and colleagues used two neuroimaging methods – diffusion tensor imaging and functional MRI – to identify patterns of connectivity between the BNST and other brain regions in healthy individuals. The BNST showed connections to multiple subcortical brain regions, including limbic, thalamic and basal ganglia structures, which matched reported connections in rodents. The researchers also identified two novel BNST connections: to the temporal pole and to the paracingulate gyrus.
The findings, reported in NeuroImage, provide a map of BNST neurocircuitry and lay the foundation for future studies of the circuits that mediate anxiety and addiction.
(Source: news.vanderbilt.edu)
Alcohol, tobacco, drug use far higher in severely mentally ill
In the largest ever assessment of substance use among people with severe psychiatric illness, researchers at Washington University School of Medicine in St. Louis and the University of Southern California have found that rates of smoking, drinking and drug use are significantly higher among those who have psychotic disorders than among those in the general population.
The study is published online in the journal JAMA Psychiatry.
The finding is of particular concern because individuals with severe mental illness are more likely to die younger than people without severe psychiatric disorders.
“These patients tend to pass away much younger, with estimates ranging from 12 to 25 years earlier than individuals in the general population,” said first author Sarah M. Hartz, MD, PhD, assistant professor of psychiatry at Washington University. “They don’t die from drug overdoses or commit suicide — the kinds of things you might suspect in severe psychiatric illness. They die from heart disease and cancer, problems caused by chronic alcohol and tobacco use.”
The study analyzed smoking, drinking and drug use in nearly 20,000 people. That included 9,142 psychiatric patients diagnosed with schizophrenia, bipolar disorder or schizoaffective disorder — an illness characterized by psychotic symptoms such as hallucinations and delusions, and mood disorders such as depression.
The investigators also assessed nicotine use, heavy drinking, heavy marijuana use and recreational drug use in more than 10,000 healthy people without mental illness.
The researchers found that 30 percent of those with severe psychiatric illness engaged in binge drinking, defined as drinking four servings of alcohol at one time. In comparison, the rate of binge drinking in the general population is 8 percent.
Among those with mental illness, more than 75 percent were regular smokers. This compares with 33 percent of those in the control group who smoked regularly. There were similar findings with heavy marijuana use: 50 percent of people with psychotic disorders used marijuana regularly, versus 18 percent in the general population. Half of those with mental illness also used other illicit drugs, while the rate of recreational drug use in the general population is 12 percent.
“I take care of a lot of patients with severe mental illness, many of whom are sick enough that they are on disability,” said Hartz. “And it’s always surprising when I encounter a patient who doesn’t smoke or hasn’t used drugs or had alcohol problems.”
Hartz said another striking finding from the study is that once a person develops a psychotic illness, protective factors such as race and gender don’t have their typical influence.
Previous research indicates that Hispanics and Asians tend to have lower rates of substance abuse than European Americans. The same is true for women, who tend to smoke, drink and use illicit drugs less often than men.
“We see protective effects in these subpopulations,” Hartz explained. “But once a person has a severe mental illness, that seems to trump everything.”
That’s particularly true, she said, with smoking. During the last few decades, smoking rates have declined in the general population. People over age 50 are much more likely than younger people to have been regular smokers at some point in their lives. For example, about 40 percent of those over 50 used to smoke regularly. Among those under 30, fewer than 20 percent have been regular smokers. But among the mentally ill, the smoking rate is more than 75 percent, regardless of the patient’s age.
“With public health efforts, we’ve effectively cut smoking rates in half in healthy people, but in the severely mentally ill, we haven’t made a dent at all,” she said.
Until recently, smoking was permitted in most psychiatric hospitals and mental wards. Hartz believes that many psychiatrists decided that their sickest patients had enough problems without having to worry about quitting smoking, too. There also were concerns about potential dangers from using nicotine-replacement therapy, while continuing to smoke since smoking is so prevalent among the mentally ill. Recent studies, however, have found those concerns were overblown.
The question, she said, is whether being more aggressive in trying to curb nicotine, alcohol and substance use in patients with severe psychiatric illness can lengthen their lives. Hartz believes health professionals who treat the mentally ill need to do a better job of trying to get them to stop smoking, drinking and using drugs.
“Some studies have shown that although we psychiatrists know that smoking, drinking and substance use are major problems among the mentally ill, we often don’t ask our patients about those things,” she said. “We can do better, but we also need to develop new strategies because many interventions to reduce smoking, drinking and drug use that have worked in other patient populations don’t seem to be very effective in these psychiatric patients.”
(Source: news.wustl.edu)
Rats! Humans and rodents face their errors
What happens when the brain recognizes an error? A new study shows that the brains of humans and rats adapt in a similar way to errors by using low-frequency brainwaves in the medial frontal cortex to synchronize neurons in the motor cortex. The finding could be important in studies of “adaptive control” like obsessive compulsive disorder, ADHD, and Parkinson’s.
People and rats may think alike when they’ve made a mistake and are trying to adjust their thinking.
That’s the conclusion of a study published online Oct. 20 in Nature Neuroscience that tracked specific similarities in how human and rodent subjects adapted to errors as they performed a simple time estimation task. When members of either species made a mistake in the trials, electrode recordings showed that they employed low-frequency brainwaves in the medial frontal cortex (MFC) of the brain to synchronize neurons in their motor cortex. That action correlated with subsequent performance improvements on the task.
“These findings suggest that neuronal activity in the MFC encodes information that is involved in monitoring performance and could influence the control of response adjustments by the motor cortex,” wrote the authors, who performed the research at Brown University and Yale University.
The importance of the findings extends beyond a basic understanding of cognition, because they suggest that rat models could be a useful analog for humans in studies of how such “adaptive control” neural mechanics are compromised in psychiatric diseases.
“With this rat model of adaptive control, we are now able to examine whether novel drugs or other treatment procedures boost the integrity of this system,” said James Cavanagh, co-lead author of the paper who was at Brown when the research was done and has since become assistant professor of psychology at the University of New Mexico. “This may have clear translational potential for treating psychiatric diseases such as obsessive compulsive disorder, depression, attention deficit hyperactivity disorder, Parkinson’s disease and schizophrenia.”
To conduct the study, the researchers measured external brainwaves of human and rodent subjects after both erroneous and accurate performance on the time estimation task. They also measured the activity of individual neurons in the MFC and motor cortex of the rats in both post-error and post-correct circumstances.
The scientists also gave the rats a drug that blocked activity of the MFC. What they saw in those rats compared to rats who didn’t get the drug, was that the low-frequency waves did not occur in the motor cortex, neurons there did not fire coherently and the rats did not alter their subsequent behavior on the task.
Although the researchers were able to study the cognitive mechanisms in the rats in more detail than in humans, the direct parallels they saw in the neural mechanics of adaptive control were significant.
“Low-frequency oscillations facilitate synchronization among brain networks for representing and exerting adaptive control, including top-down regulation of behavior in the mammalian brain,” they wrote.
What Is the Brain Telling Us About the Diagnoses of Schizophrenia and Bipolar Disorder?
We live in the most exciting and unsettling period in the history of psychiatry since Freud started talking about sex in public.
On the one hand, the American Psychiatric Association has introduced the fifth iteration of the psychiatric diagnostic manual, DSM-V, representing the current best effort of the brightest clinical minds in psychiatry to categorize the enormously complex pattern of human emotional, cognitive, and behavioral problems. On the other hand, in new and profound ways, neuroscience and genetics research in psychiatry are yielding insights that challenge the traditional diagnostic schema that have long been at the core of the field.
“Our current diagnostic system, DSM-V represents a very reasonable attempt to classify patients by their symptoms. Symptoms are an extremely important part of all medical diagnoses, but imagine how limited we would be if we categorized all forms of pneumonia as ‘coughing disease,” commented Dr. John Krystal, Editor of Biological Psychiatry.
A paper by Sabin Khadka and colleagues that appears in the September 15th issue of Biological Psychiatry advances the discussion of one of these roiling psychiatric diagnostic dilemmas.
One of the core hypotheses is that schizophrenia and bipolar disorder are distinct scientific entities. Emil Kraepelin, credited by many as the father of modern scientific psychiatry, was the first to draw a distinction between dementia praecox (schizophrenia) and manic depression (bipolar disorder) in the late 19th century based on the behavioral profiles of these syndromes. Yet, patients within each diagnosis can have a wide variation of symptoms, some symptoms appear to be in common across these diagnoses, and antipsychotic medications used to treat schizophrenia are very commonly prescribed to patients with bipolar disorder.
But at the level of brain circuit function, do schizophrenia and bipolar differ primarily by degree or are there clear categorical differences? To answer this question, researchers from a large collaborative project called BSNIP looked at a large sample of patients diagnosed with schizophrenia or bipolar disorder, their healthy relatives, and healthy people without a family history of psychiatric disorder.
They used a specialized analysis technique to evaluate the data from their multi-site study, which revealed abnormalities within seven different brain networks. Generally speaking, they found that schizophrenia and bipolar disorder showed similar disturbances in cortical circuit function. When differences emerged between these two disorders, it was usually because schizophrenia appeared to be a more severe disease. In other words, individuals with schizophrenia had abnormalities that were larger or affected more brain regions. Their healthy relatives showed subtle alterations that fell between the healthy comparison group and the patient groups.
The authors highlight the possibility that there is a continuous spectrum of circuit dysfunction, spanning from individuals without any familial association with schizophrenia or bipolar to patients carrying these diagnoses. “These findings might serve as useful biological markers of psychotic illnesses in general,” said Khadka.
Krystal agreed, adding, “It is evident that neither our genomes nor our brains have read DSM-V in that there are links across disorders that we had not previously imagined. These links suggest that new ways of organizing patients will emerge once we understand both the genetics and neural circuitry of psychiatric disorders sufficiently.”
(Image: ALAMY)
5 Disorders Share Genetic Risk Factors, Study Finds
The psychiatric illnesses seem very different — schizophrenia, bipolar disorder, autism, major depression and attention deficit hyperactivity disorder. Yet they share several genetic glitches that can nudge the brain along a path to mental illness, researchers report. Which disease, if any, develops is thought to depend on other genetic or environmental factors.
Their study, published online Wednesday in the Lancet, was based on an examination of genetic data from more than 60,000 people worldwide. Its authors say it is the largest genetic study yet of psychiatric disorders. The findings strengthen an emerging view of mental illness that aims to make diagnoses based on the genetic aberrations underlying diseases instead of on the disease symptoms.
Two of the aberrations discovered in the new study were in genes used in a major signaling system in the brain, giving clues to processes that might go awry and suggestions of how to treat the diseases.
“What we identified here is probably just the tip of an iceberg,” said Dr. Jordan Smoller, lead author of the paper and a professor of psychiatry at Harvard Medical School and Massachusetts General Hospital. “As these studies grow we expect to find additional genes that might overlap.”
The new study does not mean that the of psychiatric disorders are simple. Researchers say there seem to be hundreds of genes involved and the gene variations discovered in the new study confer only a small risk of psychiatric disease.
Steven McCarroll, director of genetics for the Stanley Center for Psychiatric Research at the Broad Institute of Harvard and M.I.T., said it was significant that the researchers had found common genetic factors that pointed to a specific signaling system.
“It is very important that these were not just random hits on the dartboard of the genome,” said Dr. McCarroll, who was not involved in the new study.
The work began in 2007 when a large group of researchers began investigating genetic data generated by studies in 19 countries and including 33,332 people with psychiatric illnesses and 27,888 people free of the illnesses for comparison. The researchers studied scans of people’s DNA, looking for variations in any of several million places along the long stretch of genetic material containing three billion DNA letters. The question: Did people with psychiatric illnesses tend to have a distinctive DNA pattern in any of those locations?
Researchers had already seen some clues of overlapping genetic effects in identical . One twin might have schizophrenia while the other had bipolar disorder. About six years ago, around the time the new study began, researchers had examined the genes of a few rare families in which psychiatric disorders seemed especially prevalent. They found a few unusual disruptions of chromosomes that were linked to psychiatric illnesses. But what surprised them was that while one person with the aberration might get one disorder, a relative with the same mutation got a different one.
Jonathan Sebat, chief of the Beyster Center for Molecular Genomics of Neuropsychiatric Diseases at the University of California, San Diego, and one of the discoverers of this effect, said that work on these rare genetic aberrations had opened his eyes. “Two different diagnoses can have the same genetic risk factor,” he said.
In fact, the new paper reports, distinguishing psychiatric diseases by their symptoms has long been difficult. Autism, for example, was once called childhood schizophrenia. It was not until the 1970s that autism was distinguished as a separate disorder.
But Dr. Sebat, who did not work on the new study, said that until now it was not clear whether the rare families he and others had studied were an exception or whether they were pointing to a rule about multiple disorders arising from a single genetic glitch.
“No one had systematically looked at the common variations,” in DNA, he said. “We didn’t know if this was particularly true for rare mutations or if it would be true for all genetic risk.” The new study, he said, “shows all genetic risk is of this nature.”
The new study found four DNA regions that conferred a small risk of psychiatric disorders. For two of them, it is not clear what genes are involved or what they do, Dr. Smoller said. The other two, though, involve genes that are part of channels, which are used when neurons send signals in the brain.
“The calcium channel findings suggest that perhaps — and this is a big if — treatments to affect calcium channel functioning might have effects across a range of disorders,” Dr. Smoller said.
There are drugs on the market that block calcium channels — they are used to treat — and researchers had already postulated that they might be useful for bipolar disorder even before the current findings.
One investigator, Dr. Roy Perlis of Massachusetts General Hospital, just completed a small study of a calcium channel blocker in 10 people with bipolar disorder and is about to expand it to a large randomized clinical trial. He also wants to study the drug in people with schizophrenia, in light of the new findings. He cautions, though, that people should not rush out to take a calcium channel blocker on their own.
“We need to be sure it is safe and we need to be sure it works,” Dr. Perlis said.