Predicting how patients respond to therapy

Brain scans could help doctors choose treatments for people with social anxiety disorder CAMBRIDGE, MA -- A new study led by MIT neuroscientists has found that brain scans of patients with social anxiety disorder can help predict whether they will benefit from cognitive behavioral therapy. Social anxiety is usually treated with either cognitive behavioral therapy or medications. However, it is currently impossible to predict which treatment will work best for a particular patient. The team of researchers from MIT, Boston University (BU) and Massachusetts General Hospital (MGH) found that the effectiveness of therapy could be predicted by measuring patients' brain activity as they looked at photos of faces, before the therapy sessions began. The findings, published this week in the Archives of General Psychiatry, may help doctors choose more effective treatments for social anxiety disorder, which is estimated to affect around 15 million people in the United States. "Our vision is that some of these measures might direct individuals to treatments that are more likely to work for them," says John Gabrieli, the Grover M. Hermann Professor of Brain and Cognitive Sciences at MIT, a member of the McGovern Institute for Brain Research and senior author of the paper. Lead authors of the paper are MIT postdoc Oliver Doehrmann and Satrajit Ghosh, a research scientist in the McGovern Institute. Choosing treatments Sufferers of social anxiety disorder experience intense fear in social situations that interferes with their ability to function in daily life. Cognitive behavioral therapy aims to change the thought and behavior patterns that lead to anxiety. For social anxiety disorder patients, that might include learning to reverse the belief that others are watching or judging them. The new paper is part of a larger study that MGH and BU ran recently on cognitive behavioral therapy for social anxiety, led by Mark Pollack, director of the Center for Anxiety and Traumatic Stress Disorders at MGH, and Stefan Hofmann, director of the Social Anxiety Program at BU. "This was a chance to ask if these brain measures, taken before treatment, would be informative in ways above and beyond what physicians can measure now, and determine who would be responsive to this treatment," Gabrieli says. Currently doctors might choose a treatment based on factors such as ease of taking pills versus going to therapy, the possibility of drug side effects, or what the patient's insurance will cover. "From a science perspective there's very little evidence about which treatment is optimal for a person," Gabrieli says. The researchers used functional magnetic resonance imaging (fMRI) to image the brains of patients before and after treatment. There have been many imaging studies showing brain differences between healthy people and patients with neuropsychiatric disorders, but so far imaging has not been established as a way to predict patients' responses to particular treatments CADC I & II Continuing Education Measuring brain activity In the new study, the researchers measured differences in brain activity as patients looked at images of angry or neutral faces. After 12 weeks of cognitive behavioral therapy, patients' social anxiety levels were tested. The researchers found that patients who had shown a greater difference in activity in high-level visual processing areas during the face-response task showed the most improvement after therapy. Gabrieli says it's unclear why activity in brain regions involved with visual processing would be a good predictor of treatment outcome. One possibility is that patients who benefited more were those whose brains were already adept at segregating different types of experiences, Gabrieli says. The researchers are now planning a follow-up study to investigate whether brain scans can predict differences in response between cognitive behavioral therapy and drug treatment. "Right now, all by itself, we're just giving somebody encouraging or discouraging news about the likely outcome" of therapy, Gabrieli says. "The really valuable thing would be if it turns out to be differentially sensitive to different treatment choices." ### The research was funded by the Poitras Center for Affective Disorders Research and the National Institute of Mental Health. Written by Anne Trafton, MIT News Office

Daily or Severe Tantrums May Point to Mental Health Issues

Most young children lose their temper sometimes, but daily tantrums or tantrums with severe behaviors, such as aggressive or destructive tantrums, are unusual and could signal a larger problem, according to an NIMH-funded study published online August 3, 2012, in a special issue of the Journal of Child Psychology and Psychiatry. Background Distinguishing “normal” misbehaviors of early childhood from clinically worrisome problems can be challenging for pediatricians, parents, and others who work with young children. To address this issue, Lauren Wakschlag, Ph.D., of Northwestern University, Margaret Briggs-Gowan, Ph.D., of University of Connecticut Health Center, and their colleagues examined temper loss among preschoolers as a spectrum of behaviors ranging from mild or normal to “problem indicators” that may be signs of a greater, underlying mental health issue. For this study, the researchers developed the Multidimensional Assessment of Preschool Disruptive Behavior (MAP-DB) questionnaire. Rather than merely asking whether a child had tantrums or not, the MAP-DB assesses the frequency, quality, and severity of behaviors related to temper tantrums and the extent of a child’s anger management skills over the past month. Parents of almost 1,500 preschoolers, ages 3-5, took part in the study. Results of the Study The researchers found that more than 80 percent of preschoolers had one or more tantrums in the past month. However, less than 10 percent had tantrums every day. Also, normal temper loss behaviors showed similar patterns and could be reliably distinguished from problem indicators. For example, over a one month period, tantrums typically occurred: when preschoolers were frustrated, angry, or upset (61 percent) during daily routines, such as bedtime, mealtime, or getting dressed (58 percent) with their parents (56 percent). In contrast, it was less typical for preschoolers to have a tantrum: with an adult who was not their parent, such as a babysitter or teacher (36 percent) during which they broke or destroyed things (28 percent) “out of the blue,” or for which parents could not discern a reason (26 percent) that lasted an unusually long time (26 percent) during which they hit, bit, or kicked someone else (24 percent). Significance The findings provide early evidence that studying behaviors as a spectrum may provide new insights into how mental disorders develop and better target early diagnosis, prevention, and treatment. “Our goal was to provide a standard method that would take the guesswork out of ‘when to worry’ about young children’s behavior and to provide a more developmentally sensitive way of characterizing the emergence of mental health problems, moving away from traditional approaches emphasizing extreme clinical distinctions to a dimensional approach that charts a progression from normal to abnormal,” said Wakschlag. What’s Next Further research is needed to confirm and evaluate the effectiveness of the MAP-DB questionnaire in identifying the point at which very young children would benefit from more specialized mental health screening and treatment. Changes in behavior as the child ages and whether problematic behaviors in early childhood lead to greater mental health issues later in life are also important areas for future study MHC Continuing Education Reference Wakschlag et al. Defining the developmental parameters of temper loss in early childhood: Implications for developmental psychopathology. Journal of Child Psychology and Psychiatry. In press. Related Funding: R01MH082830, R01MH090301

Male mice exposed to chronic social stress have anxious female offspring

BOSTON (August 22, 2012) —A study in mice conducted by researchers at Tufts University School of Medicine (TUSM) suggests that a woman's risk of anxiety and dysfunctional social behavior may depend on the experiences of her parents, particularly fathers, when they were young. The study, published online in Biological Psychiatry, suggests that stress caused by chronic social instability during youth contributes to epigenetic changes in sperm cells that can lead to psychiatric disorders in female offspring across multiple generations. "The long-term effects of stress can be pernicious. We first found that adolescent mice exposed to chronic social instability, where the cage composition of mice is constantly changing, exhibited anxious behavior and poor social interactions through adulthood. These changes were especially prominent in female mice," said first author Lorena Saavedra-Rodríguez, Ph.D., postdoctoral fellow in the Larry Feig laboratory at Tufts University School of Medicine (TUSM). The researchers then studied the offspring of these previously-stressed mice and observed that again female, but not male, offspring exhibited elevated anxiety and poor social interactions. Notably, even though the stressed males did not express any of these altered behaviors, they passed on these behaviors to their female offspring after being mated to non-stressed females. Moreover, the male offspring passed on these behaviors to yet another generation of female offspring LSW Continuing Education "We are presently searching for biochemical changes in the sperm of stressed fathers that could account for this newly appreciated form of inheritance" said senior author Larry A. Feig, Ph.D., professor of biochemistry at Tufts University School of Medicine and member of the biochemistry and neuroscience program faculties at the Sackler School of Graduate Biomedical Sciences at Tufts University. "Hopefully, this work will stimulate efforts to determine whether similar phenomena occur in humans." ### This research was supported by award numbers AA019317 from the National Institute on Alcohol Abuse and Alcoholism, and MH083324 from the National Institute of Mental Health, both part of the National Institutes of Health (NIH). The research was also supported by award number NS047243 from National Institute of Neurological Disorders and Stroke (NIH) to the Tufts Center for Neuroscience Research. Saavedra-Rodríguez L, Feig LA. Biological Psychiatry. "Chronic Social Instability Induces Anxiety and Defective Social Interactions Across Generations." Available online August 20, 2012. http://dx.doi.org/10.1016/j.biopsych.2012.06.035 About Tufts University School of Medicine and the Sackler School of Graduate Biomedical Sciences Tufts University School of Medicine and the Sackler School of Graduate Biomedical Sciences at Tufts University are international leaders in innovative medical education and advanced research. The School of Medicine and the Sackler School are renowned for excellence in education in general medicine, biomedical sciences, special combined degree programs in business, health management, public health, bioengineering and international relations, as well as basic and clinical research at the cellular and molecular level. Ranked among the top in the nation, the School of Medicine is affiliated with six major teaching hospitals and more than 30 health care facilities. Tufts University School of Medicine and the Sackler School undertake research that is consistently rated among the highest in the nation for its effect on the advancement of medical science.

The effects of discrimination could last a lifetime

Increased levels of depression as a result of discrimination could contribute to low birth weight babies Given the well-documented relationship between low birth weight and the increased risk of health problems throughout one’s lifespan, it is vital to reduce any potential contributors to low birth weight. A new study by Valerie Earnshaw and her colleagues from Yale University sheds light on one possible causal factor. Their findings, published online in Springer's journal, the Annals of Behavioral Medicine, suggest that chronic, everyday instances of discrimination against pregnant, urban women of color may play a significant role in contributing to low birth weight babies. Twice as many black women give birth to low birth weight babies than white or Latina women in the U.S. Reasons for this disparity are, as yet, unclear. But initial evidence suggests a link may exist between discrimination experienced while pregnant and the incidence of low birth weight. In addition, experiences of discrimination have also been linked to depression, which causes physiological changes that can have a negative effect on a pregnancy CADCA Continuing Education Earnshaw and her colleagues interviewed 420, 14- to 21-year-old black and Latina women at 14 community health centers and hospitals in New York, during the second and third trimesters of their pregnancies, and at six and 12 months after their babies had been born. They measured their reported experiences of discrimination. They also measured their depressive symptoms, pregnancy distress and pregnancy symptoms. Levels of everyday discrimination reported were generally low. However, the impact of discrimination was the same in all the participants regardless of age, ethnicity or type of discrimination reported. Women reporting greater levels of discrimination were more prone to depressive symptoms, and ultimately went on to have babies with lower birth weights than those reporting lower levels of discrimination. This has implications for healthcare providers who work with pregnant teens and young women during the pre-natal period, while they have the opportunity to try and reduce the potential impacts discrimination on the pregnancy. The authors conclude that "Given the associations between birth weight and health across the life span, it is critical to reduce discrimination directed at urban youth of color so that all children are able to begin life with greater promise for health. In doing so, we have the possibility to eliminate disparities not only in birth weight, but in health outcomes across the lifespan." Data for this study came from the Centering Pregnancy Plus project, funded by the National Institute of Mental Health, and conducted in collaboration with Clinical Directors’ Network and the Centering Healthcare Institute. References 1. Earnshaw VA, Rosenthal L, Lewis JB, Stasko EC, Tobin JN, Lewis TT, Reid AE and Ickovics JR (2012). Maternal experiences with everyday discrimination and infant birth weight: a test of the mediators and moderators among young, urban women of color. Annals of Behavioral Medicine; DOI 10.1007/s12160-012-9404-3

Researchers pursue red flag for schizophrenia relapse

AUGUSTA, Ga. – Blood levels of a protein that helps regulate inflammation may also serve as a red flag for relapse in some schizophrenia patients, researchers said. "There are no good, objective measures of treatment efficacy or indicators for relapse," said Dr. Brian Miller, a psychiatrist specializing in schizophrenia at the Medical College of Georgia at Georgia Health Sciences University. Researchers hope monitoring levels of interleukin-6 can fill that gap for a population in which more than half of patients don't take their medications as prescribed, often because of side effects. The relapse rate is about 80 percent within two years in patients who don't take their medication properly and about half that in those who do, according to the National Institute of Mental Health LSW Continuing Education "We hope the upshot of our studies will lead to new treatment approaches and strategies for care," Miller said, including the kind of personalized, multi-drug therapies that are becoming the standard for controlling other chronic conditions such as diabetes and hypertension. "We want to attack the disease from as many directions as possible." To get a better handle on how IL-6 levels correspond to disease status, they are looking at levels in blood samples taken multiple times over several years in 305 patients enrolled in a study comparing injectable to oral medication. They also are taking one-time measurements in 80 healthy controls and comparing those to levels in 240 patients who are acutely ill, stable outpatients or stable outpatients who smoke marijuana, a drug commonly abused by patients. While many previous studies have excluded drug abusers, marijuana may increase inflammation, so they want to explore the relationship between IL-6 levels and its use, Miller said. Miller received a five-year, $920,000 National Institute of Mental Health Mentored Patient-Oriented Research Career Development Award to measure IL-6 levels as a potential indicator of how well treatment is working to control disease in these vulnerable patients and whether they are headed to relapse. Amazingly the contributions of "immune disturbances" to schizophrenia have been debated for about 100 years yet anti-inflammatory drugs aren't routinely given to patients in addition to their antipsychotic medication, Miller said. Part of the problem is physicians still have no idea what percentage of patients with this very heterogeneous disease have evidence of increased inflammation. In fact, no two patients have the exact constellation of symptoms considered disease hallmarks, such as hallucinations, delusions, disorganized speech and thinking, he said. But mounting evidence suggests inflammation's impact in schizophrenia. A British study of 50 patients experiencing their first episode of schizophrenic behavior found a handful had indicators of an immune response to their brains, called autoantibodies, and no other conditions, such as a brain infection, to explain them. What amounts to a chronic low-grade flu has been found in some patients and rare immune system disorders such as Sjögren's syndrome, which attacks moisture-producing glands resulting in dry eyes and mouth, also tend to be more common in schizophrenics. Additionally, a handful of clinical trials has shown – not surprisingly – that patients with the highest levels of pro-inflammatory factors had the best response to anti-inflammatory drugs. "It's likely we are talking about a subset of people with this illness who would be most likely to respond to anti-inflammatory therapy – in addition to standard anti-psychotics – so part of our work is to begin to piece out who those people are (and whether) they have a particular clinical picture," Miller said. "Even being able to predict relapse or improve therapy in 25 percent of patients would be a tremendous advance," he said, noting that the vast majority of schizophrenia drugs work essentially by the same mechanism. Once patients can be identified, ideally with a blood test of their IL-6 levels, the next questions are which drugs to use and for how long. Miller's primary mentor for the studies is Dr. Andrew Mellor, a molecular geneticist and immunologist who leads the Cancer Immunology, Inflammation Tolerance Program at the GHSU Cancer Center. Mellor also is Bradley-Turner & Georgia Research Alliance Eminent Scholar in Molecular Immunogenetics. Co-secondary mentors are schizophrenia experts Dr. Peter F. Buckley, Dean of the Medical College of Georgia at GHSU, and Dr. Mark Rapaport, Chair of the Department of Psychiatry and Behavioral Sciences at Emory University School of Medicine. Schizophrenia affects about 1 percent of the population, or some 2.4 million American adults. Hallucinations are a disease hallmark: patients hear voices and can even see, touch and taste things that are not real. They can become depressed, reclusive and suicidal and have an increased risk of cardiovascular and other health conditions. Patients die on average15-20 years younger than the general population. Miller, a recipient of the 2011 National Alliance on Mental Illness Exemplary Psychiatrist Award, said he felt a calling to psychiatry and specifically schizophrenia as a medical student at The Ohio State University. "The patients are wonderful and their stories are fascinating," he said, noting that the field is "wide open" to improve their care. ###

Studies seek better understanding and treatment of depression

AUGUSTA, Ga. – Connecting the dots between two molecules whose levels are decreased in depression and increased by current antidepressants could yield new therapies, researchers say. Serotonin is a neurotransmitter that enables brain cells to communicate and brain-derived neurotropic factor, or BDNF, is a brain-nourishing molecule that also aids connectivity. Popular antidepressants such as Prozac, developed to increase levels of serotonin, have recently been found to also increase BDNF levels, said Dr. Anilkumar Pillai, neuroscientist at the Medical College of Georgia at Georgia Health Sciences University. "We don't know how the molecule, serotonin, which is well-studied in depression, regulates BDNF signaling," Pillai said. He's principal investigator on a five year, $1.5 million grant from the National Institute of Mental Health to help him make the connection He suspects a critical piece is the protein transglutaminase 2, or TG2, expressed by brain cells and most other cell types. TG2 plays a role in natural serotonin recycling and potentially is a factor in the serotonin deficiency associated with depression. It also may help explain why levels of serotonin and BDNF seem to rise and fall in sync, Pillai said. TG2 coverts serotonin to Rac1, a protein that helps rejuvenate BDNF receptors, which typically sit on the surface of brain cells but must periodically move inside to reinvigorate. Depression appears to upset the balance of these complex, critical inner workings. Pillai hypothesizes that the high levels he has found in depression, likely result in too much serotonin conversion leaving too little of the neurotransmitter to properly support brain cell communication. Instead, more Rac1 is produced but – inexplicably – its degradation also increases ultimately decreasing BDNF signaling as well. Pillai has seen the unfortunate chain of events play out in an animal model with increased levels of TG2 and clear signs of depression. "If you can fix problems with the receptor, you should be able to reverse depressive symptoms in these mice," he said One of the many questions he wants to answer is whether existing antidepressants impact TG2. To help clarify the role of the impaired BDNF receptors, Pillai also wants to know whether giving BDNF to the depressed animal model improves depression. He's using a viral particle to directly activate the BDNF receptor. And he's also giving the TG2 inhibitor cysteamine to an animal model developed by administering stress hormones. He recently published in the journal PLoS ONE findings that the inhibitor appears effective in normalizing depressive behavior and BDNF levels in that model. Mental stress is a major factor in numerous psychiatric disorders including depression, schizophrenia and anxiety, he noted. Some antidepressants, such as Prozac, were designed to interfere with a natural recycling of serotonin called reuptake so more serotonin is available where needed to enable cell communication. Pillai said it's not yet clear if serotonin reuptake is the same thing as its conversion to Rac-1. "We need to learn more about how all these pieces fit to ultimately design new therapies for depression and related psychiatric disorders," he said. Dr. Alvin V. Terry Jr., MCG pharmacologist, is co-investigator on the studies MHC continuing education Major depressive disorder is the leading cause of disability in Americans age 15-44, affects about 14.8 million adults and is more prevalent in women, according to the National Institute of Mental Health. ###

Girls with ADHD more prone to self-injury, suicide as they enter adulthood

Visible symptoms can go undercover, UC Berkeley psychologists find Girls with Attention Deficit Hyperactivity Disorder (ADHD) – and their families – often look forward to the likely decline in visible symptoms such as fidgety or disruptive behavior as they mature into young women. However, new findings from UC Berkeley caution that, as they enter adulthood, girls with histories of ADHD are more prone to internalize their struggles and feelings of failure – a development that can manifest itself in self-injury and even attempted suicide LPC continuing education "Like boys with ADHD, girls continue to have problems with academic achievement and relationships, and need special services as they enter early adulthood," said Stephen Hinshaw, UC Berkeley professor of psychology and lead author of a study that reports after 10 years on the largest-ever sample of girls whose ADHD was first diagnosed in childhood. "Our findings of extremely high rates of cutting and other forms of self-injury, along with suicide attempts, show us that the long-term consequences of ADHD females are profound," he added. The study is published today (Tuesday, August 14) in the Journal of Consulting and Clinical Psychology. Its results are consistent with earlier findings by the UC Berkeley team that, as girls with ADHD grow older, they show fewer visible symptoms of the disorder, but continue to suffer in hidden ways. The findings challenge assumptions that girls can "outgrow" ADHD, and underscore the need for long-term monitoring and treatment of the disorder, Hinshaw said. The longitudinal study, which began when the girls were ages 6 to 12, is funded by grants from the National Institute of Mental Health. Since 1997, Hinshaw and his team have tracked a racially and socio-economically diverse group of girls with ADHD in the San Francisco Bay Area through early childhood summer camps, adolescence and now early adulthood. In addition to this new study, many others have been published by the team about the girls every five years. In the United States, more than 5 million children ages 3-17 – approximately one in 11 – have been diagnosed with ADHD, according to the Centers for Disease Control and Prevention. ADHD is characterized by poor concentration, distractibility, hyperactivity, impulsiveness and other symptoms that are inappropriate for the child's age. Evidence-based treatment includes stimulant medications and various forms of behavior therapy. The new UC Berkeley study, assessing the girls 10 years after it began, examined 140 of them, ages 17-24, comparing their behavioral, emotional and academic development to that of a demographically similar group of 88 girls without ADHD. It also gauged the symptoms of two major ADHD subtypes: Those who entered the study with poor attention alone versus those who had a combination of inattention plus high rates of hyperactivity and impulsivity. The study's major finding was that the group with combined inattention and hyperactivity-impulsivity during childhood was by far the most likely to manifest self-injury and suicide attempts in early adulthood. In fact, the study pointed out, more than half of the members of this subgroup were reported to have engaged in self-injurious behavior, and more than one-fifth had attempted suicide, Hinshaw said. "A key question is why, by young adulthood, young women with ADHD would show a markedly high risk for self-harm … Impulse control problems appear to be a central factor," the study said. In the first study on this group, published in 2002, the 6- to- 12-year old girls attended five-week camps where they were closely monitored as they partook in art and drama classes and outdoor activities. Those taking ADHD medication volunteered to go off the drug treatment for much of the summer camp study. The counselors and staff observing all the participants did not know which of them had been diagnosed with ADHD. That study found that girls with ADHD were more likely to struggle academically and to be rejected by their peers, compared to the comparison peer group. The five-year follow-up study, when the girls were 12 to 17 and experiencing early to mid-adolescence, found that the fidgety and impulsive symptoms tended to subside in the early teen years, but that the learning gap between girls with ADHD and their non-ADHD peers had widened, and eating disorders and substance abuse had surfaced. For the latest study, in which 95 percent of the original sample of girls participated, the researchers conducted intensive interviews with the subjects and their families. Those interviews include personal reports on behaviors such as self-harm and suicide attempts, drug use, eating habits and driving behavior. Researchers also measured key cognitive functions such as executive planning skills, which include goal-setting and monitoring, planning and keeping on task despite distractions. While many girls in the study showed improvement in ADHD symptoms during the 10-year period, certain problems persisted and new ones emerged, suggesting that careful monitoring and treatment are essential, Hinshaw said. "The overarching conclusion is that ADHD in girls portends continuing problems, through early adulthood," the study concluded. "Our findings argue for the clinical impact of ADHD in female samples, the public health importance of this condition on girls and women, and the need for ongoing examination of underlying mechanisms, especially regarding the high risk of self-harm in young adulthood." That said, Hinshaw added, "ADHD is a treatable condition, as long as interventions are monitored carefully and pursued over a number of years." ### In addition to Hinshaw, authors and researchers of the study are Elizabeth Owens, Christine Zalecki, Emily Schrodek and Erika Swanson at UC Berkeley; Suzanne Perrigue Huggins at the University of Maryland and Adriana Montenegro-Nevado at Palo Alto University