Zebrafish study isolates gene related to autism, schizophrenia and obesity

What can a fish tell us about human brain development? Researchers at Duke University Medical Center transplanted a set of human genes into a zebrafish and then used it to identify genes responsible for head size at birth. Researchers at Duke University Medical Center transplanted a set of human genes into a zebrafish and then used it to identify genes responsible for head size at birth. Head size in human babies is a feature that is related to autism, a condition that recent figures have shown to be more common than previously reported, 1 in 88 children in a March 2012 study. Head size is also a feature of other major neurological disorders, such as schizophrenia. "In medical research, we need to dissect events in biology so we can understand the precise mechanisms that give rise to neurodevelopmental traits," said senior author Nicholas Katsanis, Ph.D., Jean and George Brumley Jr., MD, Professor of Developmental Biology, and Professor of Pediatrics and Cell Biology. "We need expert scientists to work side by side with clinicians who see such anatomic and other problems in patients, if we are to effectively solve many of our medical problems." The study was published online in Nature journal on May 16. Katsanis knew that a region on chromosome 16 was one of the largest genetic contributors to autism and schizophrenia, but a conversation at a European medical meeting pointed him to information that changes within that same region of the genome also were related to changes in a newborn's head size. The problem was difficult to address because the region had large deletions and duplications in DNA, which are the most common mutational mechanisms in humans. "Interpretation is harrowingly hard," said Katsanis, who is also director of the Duke Center for Human Disease Modeling. The reason is that a duplication of DNA or missing DNA usually involves several genes. "It is very difficult to go from 'here is a region with many genes, sometimes over 50' to 'these are the genes that are driving this pathology,'" Katsanis said. "There was a light bulb moment," Katsanis said. "The area of the genome we were exploring gave rise to reciprocal (opposite) defects in terms of brain cell growth, so we realized that overexpressing a gene in question might give one phenotype – a smaller head, while shutting down the same gene might yield the other, a larger head." The researchers transplanted a common duplication area of human chromosome 16 known to contain 29 genes into zebrafish embryos and then systematically turned up the activity of each transplanted human gene to find which might cause a small head (microcephaly) in the fish. They then suppressed the same gene set and asked whether any of them caused the reciprocal defect: larger heads (macrocephaly). The researchers knew that deletion of the region that contained these 29 genes occurred in 1.7% of children with autism. It took the team a few months to dissect such a "copy number variant" – an alteration of the genome that results in an abnormal number of one or more sections of chromosomal DNA. "Now we can go from a genetic finding that is dosage-sensitive and start asking reasonable questions about this gene as it pertains to neurocognitive traits, which is a big leap," Katsanis said. Neurocognitive refers to the ability to think, concentrate, reason, remember, process information, learn, understand and speak. Many human conditions have anatomical features that are also related to genetics, he said. "There are major limitations in studying autistic or schizophrenic behavior in zebrafish, but we can measure head size, jaw size, or facial abnormalities." The single gene in question, KCTD13, is responsible for driving head size in zebrafish by regulating the creation and destruction of new neurons (brain cells). This discovery let the team focus on the analogous gene in humans. "This gene contributes to autism cases, and probably is associated with schizophrenia and also childhood obesity," Katsanis said. Once the gene has been uncovered, researchers can examine the protein it produces. "Once you have the protein, you can start asking valuable functional questions and learning what the gene does in the animal or human," Katsanis said. Copy number variants, such as the ones this team found on chromosome 16, are now thought to be one of the most common sources of genetic mutations. Hundreds, if not thousands, of such chromosomal deletions and duplications have been found in patients with a broad range of clinical problems, particularly neurodevelopmental disorders. "Now we may have an efficient tool for dissecting them, which gives us the ability to improve both diagnosis and understanding of disease mechanisms," Katsanis said. The current study suggests that KCTD13 is a major contributor to some cases of autism, but also points to the synergistic action of this gene with two other genes in the region, named MVP and MAPK3, Katsanis said. Other authors include lead author Christelle Golzio, Jason Willer and Edwin Oh of the Duke Center for Human Disease Modeling and Department of Cell Biology; Mike Talkowski, Mei Sun and Jim Guzella from the Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital in Boston; Sebastien Jacquemont, Alexandre Reymond and Jacques Beckmann from the Service de Génétique Médicale, Centre Hospitalier Universitaire Vaudois, in Lausanne, Switzerland; and Yu Taniguchi, Akira Sawa and Atsushi Kamiya from the Department of Psychiatry, Johns Hopkins University School of Medicine in Baltimore. Funding is from a Silvio O. Conte Center grant from the National Institute of Mental Health (NIMH), National Institutes of Health grants, the Simons Foundation, the Autism Consortium of Boston, the Leenaards Foundation Prize, the Swiss National Science Foundation, a National Science Foundation Sinergia grant, an NIMH National Research Service Award, and an academic study award from the University of Lausanne. NIH-related grants: Silvio O. Conte center grant from the National Institute of Mental Health, NIH MH-084018 (AS, AK, and NK), grant MH-091230 (AK), grant HD06286 (JFG) and an NIMH National Research Service Award (F32MH087123) social worker continuing education

A walk in the park gives mental boost to people with depression

Study suggests nature walks improve cognitive abilities for people with clinical depression Toronto, CANADA – A walk in the park may have psychological benefits for people suffering from depression. In one of the first studies to examine the effect of nature walks on cognition and mood in people with major depression, researchers in Canada and the U.S. have found promising evidence that a walk in the park may provide some cognitive benefits. The study was led by Marc Berman, a post-doctoral fellow at Baycrest's Rotman Research Institute in Toronto, with partners from the University of Michigan and Stanford University. It is published online this week, ahead of print publication, in the Journal of Affective Disorders. "Our study showed that participants with clinical depression demonstrated improved memory performance after a walk in nature, compared to a walk in a busy urban environment," said Dr. Berman, who cautioned that such walks are not a replacement for existing and well-validated treatments for clinical depression, such as psychotherapy and drug treatment. "Walking in nature may act to supplement or enhance existing treatments for clinical depression, but more research is needed to understand just how effective nature walks can be to help improve psychological functioning," he said. Dr. Berman's research is part of a cognitive science field known as Attention Restoration Theory (ART) which proposes that people concentrate better after spending time in nature or looking at scenes of nature. The reason, according to ART, is that people interacting with peaceful nature settings aren't bombarded with external distractions that relentlessly tax their working memory and attention systems. In nature settings, the brain can relax and enter a state of contemplativeness that helps to restore or refresh those cognitive capacities. In a research paper he published in 2008 in Psychological Science, Dr. Berman showed that adults who were not diagnosed with any illness received a mental boost after an hour-long walk in a woodland park – improving their performance on memory and attention tests by 20 percent – compared to an hour-long stroll in a noisy urban environment. The findings were reported by The Wall Street Journal, The Boston Globe, The New York Times, and in the Pulitzer Prize finalist book by Nicholas Carr, The Shallows: What the internet is doing to our brains. In this latest study, Dr. Berman and his research team explored whether a nature walk would provide similar cognitive benefits, and also improve mood for people with clinical depression. Given that individuals with depression are characterized by high levels of rumination and negative thinking, the researchers were skeptical at the outset of the study that a solitary walk in the park would provide any benefit at all and may end up worsening memory and exacerbating depressed mood. For the study, 20 individuals were recruited from the University of Michigan and surrounding Ann Arbor area; all had a diagnosis of clinical depression. The 12 females and eight males (average age 26) participated in a two-part experiment that involved walking in a quiet nature setting and in a noisy urban setting. Prior to the walks, participants completed baseline testing to determine their cognitive and mood status. Before beginning a walk, the participants were asked to think about an unresolved, painful autobiographical experience. They were then randomly assigned to go for an hour-long walk in the Ann Arbor Arboretum (woodland park) or traffic heavy portions of downtown Ann Arbor. They followed a prescribed route and wore a GPS watch to ensure compliance. After completing their walk, they completed a series of mental tests to measure their attention and short-term/working memory and were re-asssessed for mood. A week later the participants repeated the entire procedure, walking in the location that was not visited in the first session. Participants exhibited a 16 percent increase in attention and working memory after the nature walk relative to the urban walk. Interestingly, interacting with nature did not alleviate depressive mood to any noticeable degree over urban walks, as negative mood decreased and positive mood increased after both walks to a significant and equal extent. Dr. Berman says this suggests that separate brain mechanisms may underlie the cognitive and mood changes of interacting with nature CADC I & II Continuing Education ### The study was supported by a grant from the National Institute of Mental Health and a private grant from the TKF Foundation. At Baycrest's Rotman Research Institute, Marc Berman's research explores the brain mechanisms involved in controlling thoughts, feeling and behaviors, and how to improve those abilities. Prior to joining Baycrest in 2011, Dr. Berman received his Ph.D. in Cognitive Neuroscience and Industrial and Operations Engineering at the University of Michigan.

Perceived racism may impact black Americans' mental health

For black American adults, perceived racism may cause mental health symptoms similar to trauma and could lead to some physical health disparities between blacks and other populations in the United States, according to a new study published by the American Psychological Association (APA). While previous studies have found links between racism and mental health, this is the first meta-analysis on the subject focusing exclusively on black American adults, according to the study published online in APA's Journal of Counseling Psychology. "We focused on black American adults because this is a population that has reported, on average, more incidents of racism than other racial minority groups and because of the potential links between racism and not only mental health, but physical health as well," said lead author Alex Pieterse, PhD, of the University at Albany, State University of New York. Researchers examined 66 studies comprising 18,140 black adults in the United States. To be included in the analysis, a study must have been published in a peer-reviewed journal or dissertation between 1996 and 2011; include a specific analysis of mental health indicators associated with racism; and focus specifically on black American adults in the United States. Black Americans' psychological responses to racism are very similar to common responses to trauma, such as somatization, which is psychological distress expressed as physical pain; interpersonal sensitivity; and anxiety, according to the study. Individuals who said they experienced more and very stressful racism were more likely to report mental distress, the authors said. While the researchers did not collect data on the impacts on physical health, they cite other studies to point out that perceived racism may also affect black Americans' physical health. "The relationship between perceived racism and self-reported depression and anxiety is quite robust, providing a reminder that experiences of racism may play an important role in the health disparities phenomenon," Pieterse said. "For example, African-Americans have higher rates of hypertension, a serious condition that has been associated with stress and depression." The authors recommended that therapists assess racism experiences as part of standard procedure when treating black Americans, and that future studies focus on how discrimination is perceived in specific settings, such as work, online or in school MFT Ceus

Healing Trauma’s Invisible Wounds

Mental Health Month Raises Awareness of Trauma and Impact on Children, Families, Communities; New Approaches to Treatment “Healing Trauma’s Invisible Wounds” ALEXANDRIA, Va. (April 23, 2012)—For May is Mental Health Month, Mental Health America is raising awareness of trauma, the devastating impact it has on physical, emotional, and mental well-being, and how therapeutic techniques based in neuroscience can mitigate these effects and create dramatic changes in people’s lives. “As a society, we are just beginning to deal with trauma—bringing it out of the shadows, finding new ways of healing its wounds, and casting off the shame that prevents trauma survivors from seeking help,” said David Shern, Ph.D., president and CEO of Mental Health America. “Most people think that “trauma” refers only to physical trauma that occurs as a result of a car accident or assault. But it’s much more than that.” Trauma includes: ■ Interpersonal violence – such as abuse, rape, domestic violence, and bullying; ■ Social violence — such as war, terrorism, and living under oppressive political regimes; ■ Natural disasters and accidents — such as hurricanes, floods, earthquakes, tornadoes, and auto crashes; ■ Serving in combat; ■ Chronic social stressors – such as racism, sexism, poverty, humiliation and cultural dislocation; ■ Childhood trauma—including physical, emotional and sexual abuse; emotional and physical neglect; a parent who’s an alcoholic or addicted to other drugs; a mother who’s been battered; a family member in prison or diagnosed with mental illness; and a loss of a parent through divorce or abandonment Dr. Shern said trauma has tremendous human and societal costs. Trauma is the leading cause of the death of children in this country. The effect of trauma on productive life years lost exceeds that of any other disease. The economic cost of 50 million injuries in the year 2000, alone, was $406 billion. This includes estimates of $80 billion in medical care costs, and $326 billion in productivity losses. And the predicted cost to the health care system from interpersonal violence and abuse ranges between $333 billion and $750 billion annually, or nearly 17 to 37.5 percent of total health care expenditures. When children or adults respond to traumas with fear, horror and/or helplessness, the extreme stress is toxic to their brains and bodies, and overwhelms their ability to cope, Dr. Shern said. “While many people who experience a traumatic event are able to move on with their lives without lasting negative effects, others may have more difficulty managing their responses to trauma.” Unresolved trauma can manifest in many ways, including anxiety disorders, panic attacks, intrusive memories (flashbacks), obsessive-compulsive behaviors, Post-Traumatic Stress Disorder, addictions, self-injury and a variety of physical symptoms. Trauma increases health-risk behaviors such as overeating, smoking, drinking and risky sex. Trauma survivors can become perpetrators themselves. Dr. Shern said unaddressed trauma can significantly increase the risk of mental and substance use disorders, suicide, chronic physical ailments, as well as premature death. The Adverse Childhood Experiences (ACE) Study, one of the largest investigations ever conducted to assess associations between childhood maltreatment and later-life health and well-being, demonstrated that trauma and other adverse experiences are associated with lifelong problems in behavioral health and general health. Until recently, trauma survivors were largely unrecognized by the formal treatment system. The costs of trauma and its aftermath to victims and society were not well documented. Inadvertently, treatment systems may have frequently re-traumatized individuals and failed to understand the impact of traumatic experiences on general and mental health. But that is changing. Researchers have learned how trauma changes the brain and alters behavior. A movement for trauma-informed care has emerged to ensure that trauma is recognized and treated and that survivors are not re-victimized when they seek care. Complementing these changes are programs to promote healthy development of children and healthy behaviors in families, schools and communities that reduce the likelihood of trauma. “It is critical that these efforts strengthened and we heal the invisible wounds of trauma,” Dr. Shern said. “They are crucial to promoting the healthy development of children and families.” For more than 50 years, Mental Health America and its affiliates around the country have led the observance of May is Mental Health Month by reaching millions of people through the media, local events and screenings. This unified effort includes educational messages about mental health and substance use conditions and the importance of mental health ceus for counselors Mental Health America (www.mentalhealthamerica.net) is the nation’s largest and oldest community-based network dedicated to helping all Americans achieve wellness by living mentally healthier lives. With our more than 300 affiliates across the country, we touch the lives of millions—Advocating for changes in mental health and wellness policy; Educating the public & providing critical information; and delivering urgently needed mental health and wellness Programs and Services.

Runaway Vigilance Hormone Linked to Panic Attacks

Translational Experiments in Rats, Humans Suggest New Medication Target A study has linked panic disorder to a wayward hormone in a brain circuit that regulates vigilance. While too little of the hormone, called orexin, is known to underlie narcolepsy, the new study suggests that too much of it may lead to panic attacks that afflict 6 million American adults. "Targeting the brain's orexin system may hold promise for a new generation of anti-anxiety treatments," said Thomas R. Insel, M.D., Director of the National Institute of Mental Health (NIMH), part of the National Institutes of Health. "This is a good example of how translational experiments in rats and humans can potentially yield clinical benefits." NIMH grantee Anantha Shekhar, M.B., Ph.D., and colleagues at Indiana University and Lund University, report on their findings online Dec. 27, 2009 in the journal Nature Medicine. They showed that blocking orexin gene expression or its receptor prevented panic attack-like responses in rats. The study also revealed that panic disorder patients have excess levels of the hormone Alcoholism and Drug Abuse Counselors Continuing Education Background Orexin, also called hypocretin, is secreted exclusively in a circuit emanating from the brain's hypothalamus, known to regulate arousal, wakefulness and reward. Panic attacks can be experimentally-induced by infusing susceptible humans with a normally innocuous salt called sodium lactate. The salt similarly triggers panic-like anxiety behaviors in susceptible rat strains, suggesting that something is altered in their arousal circuit. Since sodium lactate activated orexin-secreting neurons in panic-prone rats but not in control rats, the researchers hypothesized that something might be orexin. Results of This Study The investigators first discovered that increased gene expression in orexin-secreting neurons correlated with increases in anxiety-like behavior in panic-prone rats following sodium lactate infusions. Using a technique called RNA interference, they then protected the panic-prone rats from developing anxiety behaviors following the infusions by first injecting them with a genetically-engineered agent that prevented orexin genes from turning on. Blocking orexin receptors with a drug that specifically binds to it also blocked the anxiety like behavior following the infusions. This mirrored effects, seen in both rats and humans, of benzodiazepine medications used to treat panic disorder. The excess sleepiness of narcolepsy, traced a decade ago to loss of orexin-secreting neurons in the arousal circuit, might seem to be an opposite state of a panic attack. However, the researchers demonstrated in rats that such sedation could not account for orexin's effects on anxiety. Also in rats, they traced orexin neurons to their end target to pinpoint the specific brain site that accounts for the anxiety effects, disentangled from cardio-respiratory components of the panic response. Finally, by measuring orexin in cerebrospinal fluid of 53 patients, the researchers showed that those with just panic disorder had higher levels of orexin than those with both panic disorder and depression. Significance Taken together, these results and other evidence suggest a critical role for an overactive orexin system in producing panic attacks, say the researchers. What's Next? Medications that block the orexin receptor may provide a new therapeutic approach for the treatment of panic disorder, they add. The research was also supported, in part, by NIH's National Center for Research Resources. Reference A key role for orexin in panic anxiety. Johnson PL, Truitt W, Fitz SD, Kelley PE, Dietrich A, Sanghani S, Traskman-Bendz L, Goddard AW, Brundin, L, Shekhar A. Nature Medicine.

Effects on Personality May Be Mechanism of Antidepressant Effectiveness

Results of a study of antidepressant treatment for major depression suggest that changes in personality traits seen in patients taking the drug paroxetine (Paxil) may not be the result of the medication’s lifting of mood but may instead be a direct effect of this class of drugs and part of the mechanism by which they relieve depression ceus for social workers Background People with a high level of the personality trait neuroticism—characterized by a tendency to experience negative emotions and moodiness—are more likely than others to develop depression. Neuroticism is one of five personality traits that psychologists use as an organizing scheme for understanding personality: the other four traits are extraversion, openness, conscientiousness, and agreeableness. People who take anti-depressants report lower levels of neuroticism and increased extroversion, in addition to a lifting of depression. The assumption has been that these changes in personality measures were the result, not the cause, of a lifting of depression. Studies in twins suggest that to a large degree the same genetic factors underlie both neuroticism and depression risk. Research also suggests that the neurotransmitter serotonin plays a role in the expression of both neuroticism and extraversion. The class of anti-depressant drugs to which paroxetine belongs—the selective serotonin reuptake inhibitors (SSRIs)—increase the neurotransmitter’s availability in the brain. This Study To test the relationship between SSRIs and personality, investigator Tony Tang and colleagues at Northwestern University, Evanston, IL, the University of Pennsylvania in Philadelphia, and Vanderbilt University in Nashville, TN, randomly assigned patients with major depressive disorder (MDD) to receive paroxetine (120 patients), placebo (60 patients), or cognitive therapy (60 patients). After 8 weeks, medication and cognitive therapy (CT) each proved more effective than placebo in reducing depression. In addition, measures of neuroticism (based on standard surveys) in the groups receiving medication or cognitive therapy dropped, while extraversion scores rose. The changes were striking; while patients receiving placebo also reported small changes in both traits, the changes in patients on paroxetine were four to eight times as large. Patients receiving paroxetine had much greater changes in personality traits than patients receiving placebo even when the degree of improvement in depression was the same. This suggested that the effects on personality traits were not the result of the drug’s lifting of depression. After accounting for decreases in depression in patients receiving CT, the improvement in extraversion, but not neuroticism, remained significant. In further comparison of paroxetine with placebo, patients who had initially taken placebo were given the option after 8 weeks to take paroxetine. During the placebo phase, there were small changes in neuroticism and extraversion; much greater changes occurred after 8 weeks on paroxetine. Finally, those patients on paroxetine with the greatest degree of change in neuroticism (but not extraversion) were least likely to relapse to depression; the degree of changes in personality in those receiving CT did not affect the chances of relapse. Significance While the neurochemical effects of SSRIs are known, how those changes act to reduce depression is not clear. These results contradict the prevailing assumption that changes seen in personality traits in patients taking SSRIs are a result of the drugs’ effects on depression. SSRIs may alter personality directly—and thus lift depression—or may act on a third factor that underlies both. CT may alter personality by a different path. Continued research on how these treatments work can provide a clearer understanding of the mechanism of action of SSRIs and how treatment can be best used to reduce depression and minimize relapse. Reference Tang, T.Z., DeRubeis, R.J., Hollon, S.D., Amsterdam, J., Shelton, R., and Schalet, B. Personality change during depression treatment. Archives of General Psychiatry 2009 Dec;66(12):1322-30.

Teens Who Recover from Hard-to-treat Depression Still at Risk for Relapse

Teens with hard-to-treat depression who reach remission after 24 weeks of treatment are still at a significant risk for relapse, according to long-term, follow-up data from an NIMH-funded study published online ahead of print November 16, 2010, in the Journal of Clinical Psychiatry. The long-term data reiterate the need for aggressive treatment decisions for teens with stubborn depression continuing education for social workers Background In the Treatment of Resistant Depression in Adolescents (TORDIA) study, teens whose depression had not improved after an initial course of selective serotonin reuptake inhibitor (SSRI) antidepressant treatment were randomly assigned to one of four interventions for 12 weeks: Switch to another SSRI-paroxetine (Paxil), citalopram (Celexa) or fluoxetine (Prozac) Switch to a different SSRI plus cognitive behavioral therapy (CBT), a type of psychotherapy that emphasizes problem-solving and behavior change Switch to venlafaxine (Effexor), a different type of antidepressant called a serotonin and norepinephrine reuptake inhibitor (SNRI) Switch to venlafaxine plus CBT As reported in May 2010, nearly 40 percent of those who completed 24 weeks of treatment achieved remission, regardless of the treatment to which they had initially been assigned. However, those who achieved remission were more likely to have responded to treatment early—during the first 12 weeks. After 24 weeks of treatment, the participants were discharged from the study and urged to continue care within their community. They were then asked to return for an assessment at 72 weeks. Results of the Study Of the 334 original TORDIA participants, about 61 percent had reached remission by week 72. Symptoms of depression steadily decreased after the initial 24 weeks of treatment. But at 72 weeks, many participants still reported having residual symptoms of depression, such as irritability, fatigue and low self-esteem. Those with more severe depression at baseline were less likely to reach remission. Those who responded early to treatment—within the first six weeks of treatment—were more likely to reach remission. Initial treatment assignment during the study did not appear to influence the remission rate or time to remission. However, of the 130 participants who had remitted by week 24, 25 percent had relapsed by week 72. Ethnic minorities tended to have a higher risk for relapse than whites. Significance Because more than one-third of the teens did not recover and the relapse rate was high, the authors conclude that more effective interventions early in the treatment process are needed. In addition, the higher risk of relapse for ethnic minorities suggests that cultural factors may influence the long-term course of depression and recovery, but it is unclear what those factors may be. What's Next The findings indicate that new methods are needed to accurately identify those who may not respond early in treatment so that patients unlikely to reach remission using a particular treatment may be offered alternative treatments earlier in the process. More data is needed, however, to be able to predict who might be more likely to remit and who may not. Reference Vitiello B, Emslie G, Clarke G, Wagner K, Asarnow JR, Keller M, Birmaher B, Ryan N, Kennard B, Mayes T, DeBar L, Lynch F, Dickerson J, Strober M, Suddath R, McCraken JT, Spirito A, Onorato M, Zelazny J, Porta G, Iyengar S, Brent D. Long-term outcome of adolescent depression initially resistant to SSRI treatment. Journal of Clinical Psychiatry.