Genetic Liability for Major Depression Ups Risk of Suicide Attempts

A new study has discovered that a genetic predisposition for major depression also increases an individual’s risk for a suicide attempt. The finding of a shared genetic link between suicide attempt and major depression comes from the largest genome-wide association study (GWAS) to date on suicide attempts.

Researchers at the Icahn School of Medicine at Mount Sinai found that a genetic liability for major depression increases an individual’s risk for suicide attempts regardless of an individual’s mental health diagnosis.

Moreover, suicide attempters with major depressive disorder, bipolar disorder or a schizophrenia diagnosis carry a greater genetic liability for major depression than non-attempters.

Their findings appear in The American Journal of Psychiatry.

Suicide is a worldwide public health problem, with more than 800,000 deaths due to suicide each year. Suicide and suicide attempts take an emotional toll on families and friends of those who died, as well as on attempt survivors.

The Centers for Disease Control and Prevention report that suicide costs the US economy $51 billion per year in medical costs for individuals and families, lost income for families, and lost productivity for employers.

These stark figures highlight the urgent need for improved prevention and treatment, yet progress has been hampered by the lack of reliable methods for predicting suicidality and a poor understanding of its biological etiology.

“Like many psychiatric disorders, suicide attempt is known to have a partially genetic underpinning and genetic studies can provide invaluable insights into the underlying biology,” says Niamh Mullins, PhD, Postdoctoral Fellow in Psychiatric Genomics.

“Through the collective efforts of many researchers, we analyzed the genomes of suicide attempters and non-attempters across three major psychiatric disorders.

Our data showed that suicide attempters with major depressive disorder, bipolar disorder or a schizophrenia diagnosis carry a greater genetic liability for major depression than non-attempters.”

Specifically, the current study compared the genomes of 6,569 suicide attempters and 17,232 non-attempters with major depressive disorder, bipolar disorder, or schizophrenia from the Psychiatric Genomics Consortium, an international collaboration for conducting large-scale genetic studies of psychiatric disorders.

Samples were combined across 46 individual cohorts from Europe, the United States, and Australia. Using polygenic risk scores, which summarize an individual’s genetic liability to a disease based on the results of an independent genetic study, the research team showed that suicide attempters carry an increased genetic liability for depression, regardless of the psychiatric disorder they are affected by.

“These results indicate the existence of a shared genetic etiology between suicide attempt and major depression that is common to suicide attempt in different psychiatric disorders,” says Dr. Mullins.

“Our study is the first consortium-based GWAS on suicide attempt and makes significant progress in increasing numbers by combining samples across clinical cohorts. However, further collaborative efforts to amass samples on an even larger scale will be essential to identify specific genetic variants which play a role in increasing risk of suicide attempt.”

Researchers believe the findings reveal the biological mechanisms underlying suicidality. This knowledge will hopefully lead to the development of new treatments and preventions.

Suicide is a tragic event — learning more about the origin and the innate risk some individuals possess help to reduce its associated burden on patients, families and healthcare systems.

Source: Mount Sinai

Genetic Hotspot May Drive Psychosis in Schizophrenia, Bipolar Disorder

Scientists have identified an epigenetic hotspot which they believe is linked to the dopamine-induced psychosis found in schizophrenia and bipolar disorder.

The findings, published in the journal Nature Communications, may give researchers a fresh path forward for developing more effective treatments and biomarker-based screening strategies.

More than 100 million people worldwide have either schizophrenia or bipolar disorder, which are characterized by periods of hallucinations, delusions and irregular thought processes. They are both linked to an overproduction of the neurotransmitter dopamine, a key regulator of reward-seeking behavior, emotional responses, learning and movement, among other functions.

“We’ve known since the 1970s that the effectiveness of antipsychotic medications is directly related to their ability to block dopamine signaling. However, the exact mechanism that sparks excessive dopamine in the brain and that leads to psychotic symptoms has been unclear,” said Viviane Labrie, PhD, assistant professor at Van Andel Research Institute (VARI) and corresponding author of the study.

“We now have a biological explanation that could help make a real difference for people with these disorders.”

The research team discovered a cluster of epigenetic marks that pumps up dopamine production while simultaneously scrambling the brain’s synapses, the information hubs that transmit rapid-fire neural messages responsible for healthy function. The result is a catastrophic shake-up of the brain’s organization and chemical balance that fuels symptoms of psychosis.

“What we’re seeing is a one-two punch — the brain is being flooded with too much dopamine and at the same time it is losing these critical neural connections,” Labrie said.

“Like many other neurological disorders, schizophrenia and bipolar disorder often have early, or prodromal, phases that begin years before obvious symptoms. It is our hope that our findings may lead to new biomarkers to screen for risk, which would then allow for earlier intervention.”

For the study, the researchers analyzed DNA derived from brain cells of individuals with either schizophrenia or bipolar disorder and compared them to healthy controls. Their analyses revealed a cluster of epigenetic marks in an enhancer at a gene called IGF2, a critical regulator of synaptic development.

Enhancers are stretches of DNA that help activate genes and can be major players in the development of diseases in the brain and other tissues.

This enhancer also controls the activity of a nearby gene called tyrosine hydroxylase, which produces an enzyme that keeps dopamine in check. When the enhancer is epigenetically switched on, production of dopamine becomes dysregulated, resulting in too much of the chemical in the brain.

Any molecular changes at this site may explain why psychosis brought on by dopamine frequently is accompanied by a disruption of brain synapses, a devastating double-hit that promotes symptoms.

The study controlled for genetic factors, sex, ethnicity, treatment history and lifestyle influences such as smoking, and the results were validated in experimental models of the disease.

“We used cutting-edge computational strategies to understand the events occurring in brain cells that underlie psychiatric disorders,” said Shraddha Pai, PhD, a postdoctoral fellow at University of Toronto and the study’s first author. “Our results were strengthened by additional studies in disease models. This comprehensive approach lends weight to our findings, which we believe will propel additional groundbreaking investigations into this enhancer at the IGF2 gene.”

Source: Van Andel Research Institute

Brain Study Hunts ‘Fingerprints’ of Severe Mental Disorders

In a new study, researchers took a “birds-eye view” into the brain to examine how its large-scale systems interact with one another, in order to gain a better understanding of the causes and symptoms of severe mental disorders including bipolar disorder, schizophrenia and depression.

The findings, published in the Proceedings of the National Academy of Sciences, shed new light on the similarities and differences in these three mental illnesses.

Lead researcher Justin T. Baker, M.D., Ph.D., scientific director of the McLean Institute for Technology in Psychiatry explains that the work is based on connectomics, the concept of “measuring all connections in the brain at the same time.”

“For most studies, illnesses are studied in isolation, but evidence strongly suggests that distinct psychiatric diagnoses are not separated by clear neurobiological boundaries,” said Baker.

“The approach we’ve taken is to look at the whole brain so you can see not only how individual systems like the visual system and motor system are functioning, but how higher order systems like cognitive systems are functioning in the brain to see if there are correlations.”

For the study, researchers from McLean Hospital in Massachusetts and Yale University looked at functional magnetic resonance imaging (fMRI) data from more than 1,000 individuals, including patients who had been diagnosed with bipolar disorder, schizophrenia and depression.

Information was collected through rest scans, in which participants were asked to simply lie in a scanner with their eyes open, allowing researchers to capture data about spontaneous fluctuations in the brain.

This approach allowed for “brain fingerprinting” to address “what changes in the brain are shared across illnesses and what aspects might be specific to different illnesses,” said Baker. “This work points to evidence at a high level that there are very pronounced changes in the brain that could start to serve as an objective biomarker.”

The findings are significant, said Baker, as there are no objective measures of psychiatric illnesses that can verify a patient’s reports regarding their symptoms.

Previous research suggests there is a significant genetic risk for schizophrenia and bipolar disorder and that these conditions affect certain parts of the brain. But this study highlights how one system is affected or disrupted as a function of how severe the illness is, irrespective of whether it is psychosis or depression.

The researchers plan to build on this work through studies into the functioning of large-scale brain systems related to OCD and trauma and longer-term investigations.

“We want to see if there is a fingerprint for different conditions and then use that information and apply it to the individual,” said Baker. “We are conducting studies that follow individuals over time to look at the brain to see how symptoms are changing.

“We’re trying to go from the snapshot view of these biomarkers to something that is much more dynamic and captures changes and nuances.”

Source: McLean Hospital

Growing Up Poor May Double Risk of Future Psychosis

Growing up in a poor urban neighborhood more than doubles the average person’s risk of developing a psychosis-spectrum disorder by middle adulthood, according to a new study led by researchers from the University of California (UC) Davis and Concordia University in Canada.

The results of the research, which followed nearly 4,000 Québec families for more than 30 years, suggest that interventions through social policies and neighborhood improvements could prevent future debilitating illnesses as well as the societal and personal costs associated with them, said the study’s authors.

“One important message to take from this study is that the stresses and chronic day-to-day challenges of living in under-resourced or impoverished communities can undermine the well-being of individuals whether they seem to have a vulnerability or not,” said Dr. Paul D. Hastings, professor in the Department of Psychology at UC Davis and the lead author of the paper.

He explains that although heredity is a major factor in predicting schizophrenia, bipolar disorder and other disorders involving psychoses, the new findings show clear evidence that environmental factors experienced in childhood also affect future mental health.

The study is published in the journal Development and Psychopathology.

The origins of the Concordia Longitudinal Research Project date back to the 1970s, when the initial researchers sought to test existing theories on the roles of early adversity and children’s social traits on the development of psychiatric disorders.

The study followed families living in low-income urban communities in French-speaking parts of Montréal, Québec, comprising, in the end, nearly 11,000 individuals. Peer reports of behavior at school were used to assess children’s aggression, withdrawal and likability.

Beginning in the mid 2000s, researchers began analyzing the previous three decades of individual medical records as well as census data on neighborhood economic conditions. On average, the children were around 10 years old at the beginning of the study and were followed until they were 40. Meanwhile, their parents aged from their late 30s into their late 60s.

Residents of Québec receive government-funded health care, and the researchers were able to analyze numerically coded records of the subject families in order to identify psychiatric diagnoses. Since the researchers were able to identify parental diagnoses in the study, their analyses were able to predict the children’s future prevalence of psychiatric disorders above and beyond what would result from heredity, Hastings said.

The findings show that more than 6 percent of the children in the study had developed schizophrenia, bipolar disorder with psychosis, or other psychosis-spectrum disorders by middle-adulthood. Those who grew up in the most economically disadvantaged neighborhoods had the greatest likelihood of developing schizophrenia or bipolar disorder.

In addition, childhood social behaviors were strong predictors of psychotic illnesses. In particular, children who were evaluated by their peers as both highly aggressive and highly withdrawn were likely to develop psychosis-spectrum disorders if they also grew up in more impoverished neighborhoods.

The findings suggest that interventions with young children who exhibit these complex patterns of antisocial behavior could lead to better outcomes.

“Once psychosis spectrum disorders take hold they are difficult to treat. It is kind of like ALS (amyotrophic lateral sclerosis) and similar illnesses,” said Hastings.

“Disorders like schizophrenia really become chronic diseases that require constant care, management, and maintenance. Reducing them by improving neighborhood conditions for all families in economically disadvantaged communities, and working directly with the families of children showing risky profiles of behavior, could improve the quality of people’s lives and markedly reduce health care costs.”

Source: University of California- Davis


Altered Neuron Growth May Be Why Some Depressed People Don’t Respond to SSRIs

Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed medication for major depressive disorder (MDD), yet scientists still do not understand why they don’t work in nearly 30 percent of patients.

A new study by researchers at the Salk Institute in La Jolla, California, discovered differences in growth patterns of neurons of SSRI-resistant patients. Published in Molecular Psychiatry, the study has implications for depression, as well as other psychiatric conditions, such as bipolar disorder and schizophrenia that likely also involve abnormalities of the serotonin system in the brain, according to the researchers.

“With each new study, we move closer to a fuller understanding of the complex neural circuitry underlying neuropsychiatric diseases, including major depression,” said Salk Professor Rusty Gage, the study’s senior author, president of the Institute, and the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Disease.

“This paper, along with another we recently published, not only provides insights into this common treatment, but also suggests that other drugs, such as serotonergic antagonists, could be additional options for some patients.”

The cause of depression is still unknown, but scientists believe the disease is partly linked to the serotonergic circuit in the brain, the researcher explains. This is largely because SSRIs, which increase levels of the neurotransmitter serotonin at neuron connections, help alleviate the symptoms of many people diagnosed with depression.

However, the mechanism of why some people respond to SSRIs, while others do not, remains a mystery.

Solving that mystery has been challenging because it requires studying the 300,000 neurons that use the neurotransmitter serotonin for communication within a brain of 100 billion total neurons, researchers point out. One way scientists have recently overcome this obstacle is to generate these serotonergic neurons in the lab.

The team’s previous study published in Molecular Psychiatry showed that SSRI non-responders had increased receptors for serotonin, which made the neurons hyperactive in response to serotonin. In the new study, researchers wanted to examine SSRI non-responders from a different angle.

“We wanted to know if serotonin biochemistry, gene expression, and circuitry were altered in SSRI non-responders compared to responders using serotonergic neurons derived from MDD patients,” said Dr. Krishna Vadodaria, a Salk staff scientist and first author of the new paper. “Using neurons derived from actual MDD patients provides a novel representation of how SSRI responders compare to non-responders.”

From a large-scale clinical study of 800 MDD patients, the researchers selected the most extreme cases of SSRI response — patients who drastically improved when taking SSRIs and patients who saw no effect.

The researchers took skin samples from these patients and reprogrammed the cells into induced pluripotent stem cells (iPSCs) to create serotonergic neurons they could study.

The scientists examined serotonin targets in patient serotonergic neurons, including the enzyme that makes serotonin, the protein that transports it, and the enzyme that breaks it down, but found no differences in biochemistry interactions between groups. Instead, the researchers observed a difference in how the neurons responded based on their shape.

Neurons from SSRI non-responders had longer neuron projections than responders, the researchers discovered.

Abnormal features could lead to too much neuronal communication in some areas of the brain and not enough in other parts, altering communication within the serotonergic circuitry and explaining why SSRIs do not always work to treat MDD, the researchers explain.

“These results contribute to a new way of examining, understanding, and addressing depression,” Gage said.

Source: The Salk Institute

Photo: These are human serotonergic neuron projections (red) and cell bodies (green). Credit: Salk Institute.

Unhealthy Diet Linked to Poor Mental Health

A new study adds to the mounting evidence that an unhealthy diet is tied to poor mental health, regardless of personal characteristics such as gender, education, age, marital status and income level.

The findings, published in the International Journal of Food Sciences and Nutrition, show that California adults who consumed a large amount of unhealthy food were more likely to report symptoms of either moderate or severe psychological distress compared to those who ate a healthier diet.

Lead author Jim E. Banta, PhD, MPH, associate professor at Loma Linda University School of Public Health, says the findings are similar to those of other studies around the world revealing a link between mental illness and unhealthy diet choices.

Increased sugar consumption has been shown to be linked to bipolar disorder, for example, while fried foods or foods that contain high amounts of sugar and processed grains have been linked with depression.

“This and other studies like it could have big implications for treatments in behavorial medicine,” Banta said. “Perhaps the time has come for us to take a closer look at the role of diet in mental health, because it could be that healthy diet choices contribute to mental health. More research is needed before we can answer definitively, but the evidence seems to be pointing in that direction.”

Banta warns that the study does not prove a causal link between unhealthy food and poor mental health. Still, he said the findings build upon previous work and could impact future research and treatment approaches.

In the study, the research team looked at data from more than 240,000 telephone surveys conducted between 2005 and 2015 as part of the multi-year California Health Interview Survey (CHIS).

The CHIS dataset includes extensive information about socio-demographics, health status and health behaviors and was developed to provide statewide approximations for regions within California and for various ethnic groups. The findings show that nearly 17 percent of California adults are likely to suffer from mental illness: 13.2 percent with moderate psychological distress and 3.7 percent with severe psychological distress.

The paper states that the team’s findings provide “additional evidence that public policy and clinical practice should more explicitly aim to improve diet quality among those struggling with mental health.”

It also stated that “dietary interventions for people with mental illness should especially target young adults, those with less than 12 years of education, and obese individuals.”

Source: Loma Linda University Adventist Health Sciences Center