Rethinking Mental Disorders

An article posted May 20th on Care2.com:

By Kristina Chew

Psychiatric or mental disorders such as schizophrenia, bipolar disorder, depression and psychosis are better understood and treated as 'disorders of the brain' according to an article by Tom Insel, M.D., Director of the National Institute of Mental Health, and Philip Wang, M.D., Deputy Director of NIMH. The article, Rethinking Mental Illness, is published in the May 19th issue of the Journal of the American Medical Association. The authors note that, while there have been many 'insights gained from genetics and neuroscience'---such as twin studies that show high heritability for autism, schizophrenia, and bipolar disorder---such research explains only a 'fraction of the heritability' of mental disorders. (For instance, some182 genes have been identified as linked to eating disorders, and some 100 to autism.) These should rather be seen as 'disorders of brain circuits':

"The genetics of mental illness may really be the genetics of brain development, with different out comes possible, depending on the biological and environmental context."

Other advances in the field of genetics contribute to a reconceptualization of mental disorders. Epigenetics looks at the inherited changes in gene expression caused that are caused by something other than than changes in the underlying DNA sequence; Insel and Wang note that:

"The same twin studies that point to high heritability also demonstrate the limits of genetics: environmental factors must be important for mental disorders......The advent of epigenomics [the study of the factors that control genes], which can detect the molecular effects of experience, may provide a powerful approach for understanding the critical effects of early-life events and environment on adult patterns of behavior."

Further, the authors write that the behavioral and cognitive symptoms that indicate 'mental illness' may actually be the 'late stages' of neurological processes that, if detected at early stages, might be better and more fully treated:

"As a result, interventions, rather than being ameliorative or rehabilitative, could become preemptive or even preventive. But this transformation in diagnosis and treatment, which can be informed by recent progress in cardiovascular disease and cancer, will depend on an intense focus on the genetics and circuitry underlying mental illness to ensure new approaches to detecting risk, validating diagnosis, and developing novel interventions that may be based on alter ing plasticity or retuning circuitry rather than neurotransmitter pharmacology."

As an example, in the past several years, autism has gone from being seen as a psychiatric, and even psychogenic, disorder, to a neurological/neurodevelopmental one, with significant consequences in how autism is conceived of, treated and, too, perceived by the public. Autism was once thought to be caused by bad parenting, by 'refrigerator mothers' who were emotionally withdrawn and 'cold,' and therefore did not 'bond' with their children, who 'withdrew into autism'; the damage wrought to families and individuals by these misconceptions is unmeasurable. Seeing autism as a neurodevelopmental disorder---due, perhaps, to 'abnormalities' in synapses in the brain does change how autistic individuals are see by others.

Similarly, understanding that an eating disorder such as anorexia nervosa is biologically based rather than simply putting the blame on parents, on our society's and culture's equating being thin with success, has significant changes on treatment and, again, understanding, and this can make a huge difference in people's (parents, for sure) lives. Societal factors do play a role, but seeing anorexia as biologically based---a recent study of brain imaging has found neurocircuit dysregulation in anorexics---can have real changes for people's lives and, hopefully, for the ultimate outcomes of those diagnosed with these conditions.

Also see:

NIMH Builds New Framework for Understanding Mental Illness

Image credit

After Abuse, Changes in the Brain

An article published in today's edition of The New York Times:

By Benedict Carey

For years, psychiatrists have known that children who are abused or neglected run a high risk of developing mental problems later in life, from anxiety and depression to substance abuse and suicide.

The connection is not surprising, but it raises a crucial scientific question: Does the abuse cause biological changes that may increase the risk for these problems?

Over the past decade or so, researchers at McGill University in Montreal, led by Michael Meaney [pictured], have shown that affectionate mothering alters the expression of genes in animals, allowing them to dampen their physiological response to stress. These biological buffers are then passed on to the next generation: rodents and nonhuman primates biologically primed to handle stress tend to be more nurturing to their own offspring, Dr. Meaney and other researchers have found.

Now, for the first time, they have direct evidence that the same system is at work in humans. In a study of people who committed suicide published Sunday in the journal Nature Neuroscience, researchers in Montreal report that people who were abused or neglected as children showed genetic alterations that likely made them more biologically sensitive to stress.

The findings help clarify the biology behind the wounds of a difficult childhood and hint at what constitutes resilience in those able to shake off such wounds.

The study “extends the animal work on the regulation of stress to humans in a dramatic way,” Jaak Panksepp, an adjunct professor at Washington State University who was not involved in the research, wrote in an e-mail message.

He added that the study “suggests pathways that have promoted the psychic pain that makes life intolerable,” and continued, “It’s a wonderful example of how the study of animal models of emotional resilience can lead the way to understanding human vicissitudes.”

In the study, scientists at McGill and the Singapore Institute for Clinical Sciences compared the brains of 12 people who had committed suicide and who had had difficult childhoods with 12 people who had committed suicide and who had not suffered abuse or neglect as children.

The scientists determined the nature of the subjects’ upbringing by doing extensive interviews with next of kin, as well as investigating medical records. The brains are preserved at Douglas Hospital in Montreal as part of the Quebec Suicide Brain Bank, a program founded by McGill researchers to promote suicide studies that receives brain donations from around the province.

When people are under stress, the hormone cortisol circulates widely, putting the body on high alert. One way the brain reduces this physical anxiety is to make receptors on brain cells that help clear the cortisol, inhibiting the distress and protecting neurons from extended exposure to the hormone, which can be damaging.

The researchers found that the genes that code for these receptors were about 40 percent less active in people who had been abused as children than in those who had not. The scientists found the same striking differences between the abused group and the brains of 12 control subjects, who had not been abused and who died from causes other than suicide. “It is good evidence that the same systems are at work in humans that we have seen in other animals,” said Patrick McGowan, a postdoctoral fellow in Dr. Meaney’s lab at McGill and the lead author of the study.

His co-authors, along with Dr. Meaney, were Aya Sasaki, Ana C. D’Alessio, Sergiy Dymov, Benoît Labonté and Moshe Szyf, all of McGill, and Dr. Gustavo Turecki, a McGill researcher who leads the Brain Bank.

Because of individual differences in the genetic machinery that regulates stress response, experts say, many people manage their distress despite awful childhoods. Others may find solace in other people, which helps them regulate the inevitable pain of living a full life.

“The bottom line is that this is a terrific line of work, but there is a very long way to go either to understand the effects of early experience or the causes of mental disorders,” Dr. Steven Hyman, a professor of neurobiology at Harvard, wrote in an e-mail message.

Posting of this article is for the purposes of research into suicide.

Also see:

Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse

Childhood trauma has life-long effects on genes and the brain

Image and photograph courtesy of the Douglas Mental Health University Institute.

$9.8 Million Grant to Map “Epigenome” of Schizophrenia

A November 21st press release from Johns Hopkins Medicine:

Researchers at the Johns Hopkins University School of Medicine and four other academic medical centers have been awarded a $9.8 million grant from the National Institutes of Mental Health to pin down inherited changes that occur outside a cell’s DNA sequence in people with schizophrenia. Unlike changes or mutations in the DNA sequence itself, epigenetic marks or alterations can be affected by a lifetime of exposure to the environment in which cells operate.

“A comprehensive understanding of a disease’s epigenome can provide hidden and valuable clues to the role of diet, chemicals, infections and behaviors in genetic predisposition to diseases,” says Andrew Feinberg [pictured], M.D., professor of medicine and director of Hopkins’ Center for Epigenetics in its Institute of Basic Biomedical Sciences. Because a significant indicator of epigenetic change is our body chemistry’s addition of so-called methyl groups to DNA at specific sites, the research will focus on identifying changes in “methylated” sites in the epigenome that are associated with schizophrenia.

The research team is comprised of scientists at Hopkins, University of Pennsylvania, University of Alabama at Birmingham, University of Pittsburgh, and University of California San Diego. "The NIMH is very excited about funding this team of world-class scientists to look into epigenetic factors as possible causes for schizophrenia," says Thomas Lehner Ph.D., M.P.H., chief of the genomics research branch and the associate director of the division of neuroscience and basic behavioral science at the National Institute of Mental Health.

“Many researchers have identified genetic alterations associated with schizophrenia, but so far they do not account for a large proportion of schizophrenia patients,” says Feinberg, who is leading the multi-institutional effort. “Our work can identify differences in methylation patterns seen in blood samples or brain tissue samples from patients with and without schizophrenia to fill out the whole picture of both epigenetic and genetic contributions to this disabling disorder.”

The scientists will take advantage of DNA samples from the National Institutes of Mental Health genetics repository. They will analyze the methylation patterns at nearly ten thousand sites throughout the genomes of several thousand samples and controls, choose the 50 most prominent sites, and map the locations of the methylation marks to identify and analyze the activity of nearby genes.

“These studies will provide the first comprehensive evaluation of the epigenetics of schizophrenia and allow for unprecedented integration of genetic and environmental information about schizophrenia,” says Feinberg.

Because epigenetic changes — unlike nuclear DNA changes — are potentially reversible, “these studies may also lead to exciting new avenues for schizophrenia therapy,” Feinberg notes.

Stephen Desiderio, M.D., Ph.D., director of the Institute for Basic Biomedical Sciences at Hopkins, says the collaborative nature of the epigenome investigation “promises to add quickly and richly to the growing body of knowledge about schizophrenia,” which affects an estimated 2 million adults in the United States alone.

On the Web:
www.hopkinsmedicine.org/ibbs/research/epigenetics

Media Contacts:
Audrey Huang; 410-614-5105; audrey@jhmi.edu
Maryalice Yakutchik; 443-287-2251; myakutc1@jhmi.edu

Photograph of Dr. Feinberg courtesy of Johns Hopkins Medicine.

Suicide linked to brain changes

Posted today by BBC News:

The brains of people who commit suicide are chemically different to those who die from other causes, a Canadian study has suggested.

To read the entire article, click here.

Also see:

GABAA Receptor Promoter Hypermethylation in Suicide Brain: Implications for the Involvement of Epigenetic Processes

Study finds genomic changes in the brains of people who commit suicide

Suicide's genetic key discovered

Thanks go to John Devlin for bringing this article to my attention.

Suicide's genetic key discovered

From the July 31st edition of The Globe and Mail:

By Carly Weeks

Canadian researchers may have discovered the underlying cause that leads some people to commit suicide or suffer major depression, a finding that could revolutionize how mental disorders are treated.

After examining the brains of people who committed suicide, a team of scientists discovered an abundance of protein affecting a particular gene that controls anxiety and stress compared with the brains of people who had died of heart attacks or other natural causes.

The study is part of the burgeoning field of epigenetics that examines how genes are regulated, or turned on and off.

"It's a really new avenue of research," said Michael Poulter, lead researcher and professor in the physiology and pharmacology department at the University of Western Ontario.

"There's only a few people around the world that are doing it."

In this study, researchers found that people who committed suicide had elevated levels of a specific protein.

They believe the abundance of the protein alters or modifies a gene that normally helps people cope with stress. As a result of the change, the gene shuts down and malfunctions, inhibiting the individual's ability to handle stress and cope with anxiety.

The researchers, whose findings were published in this month's Biological Psychiatry journal, aren't sure why some people have higher levels of the protein. But Dr. Poulter believes it is somehow linked to stressful life events and how people may cope with them in different ways.

To read the entire article, click here.

Thanks go to John Devlin for bringing this article to my attention.

Epigenetic Changes Discovered in Major Psychosis: New clues for uncovering the mysteries of mental illness

For Immediate Release – March 11, 2008 (TORONTO): Scientists have discovered epigenetic changes (i.e. chemical changes to a gene that do not alter the DNA sequence) in individuals with schizophrenia and bipolar disorder. This is the first epigenome-wide investigation in psychiatric research, and this groundbreaking data may be a significant step on the journey to fully understanding major psychosis.

Dr. Arturas Petronis, senior scientist in the Krembil Family Epigenetic Laboratory at the Centre for Addiction and Mental Health (CAMH), and his team studied 12,000 locations on the genome using an epigenomic profiling technology developed at CAMH. Approximately one in every two hundred of these genes showed an epigenetic difference in the brains of psychiatric patients. Significantly, these changes were noted on genes involved in neurotransmission (the exchange of chemical messages within the brain), brain development, and other processes linked to disease origins.

Dr. Petronis explains that these epigenetic changes may be the missing link in understanding what causes an illness. “The DNA sequence of genes for someone with an illness like schizophrenia and a for someone without a mental illness often look the same; there are no visible changes that explain the cause of a disease. But we now have tools that show us changes in the second code, the epigenetic code, which may give us some very important clues for uncovering the mysteries of major psychosis and other complex non-Mendelian illnesses.”

This proof-of-principle study is the first demonstration of what CAMH epigeneticists have hypothesized for the last 10 years. “Until now, we only had theories that epigenetic changes were important to understanding what causes major psychosis,” explains Dr. Petronis. “Now we have the tools and expertise to support our theories and we can look at conducting larger studies, which will hopefully give us an even better understanding of psychiatric illnesses. And once we understand the primary molecular causes of an illness, we can advance diagnosis and treatment approaches, and possibly even prevent illness.”

The Krembil Family Epigenetics Laboratory is the only psychiatric epigenetics laboratory in North America, one of the few programs in North America that is exploring this field.

Visit Epigenomic Profiling Reveals DNA-Methylation Changes Associated with Major Psychosis for more information on this study in the American Journal of Human Genetics.

To arrange interviews please contact Michael Torres, Media Relations, CAMH at (416) 595-6015.

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The Centre for Addiction and Mental Health (CAMH) is Canada's largest mental health and addiction teaching hospital, as well as one of the world's leading research centres in the area of addiction and mental health. CAMH combines clinical care, research, education, policy development, prevention and health promotion to transform the lives of people affected by mental health and addiction issues.

CAMH is fully affiliated with the University of Toronto, and is a Pan American Health Organization/World Health Organization Collaborating Centre.