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 Research & Giving News Article  Top Experts on Childhood Disorders Share Latest Findings The symposium featured outstanding presentations by four nationally renowned research experts on such childhood conditions as mood and anxiety disorders, anorexia and bulimia, autism, and bipolar disorder. It was moderated by Thomas R. Insel, M.D., director of the National Institute of Mental Health (NIMH). As founder of the Center for Behavioral Neuroscience at Emory University and former director of the Yerkes Regional Primate Research Center, in Atlanta, Dr. Insel pioneered the use of selective serotonin reuptake inhibitors (SSRIs) in the treatment of obsessive-compulsive disorder. He has served on NARSAD’s Scientific Council and was a recipient of a NARSAD Distinguished Investigator Award. To highlight the significance of the day’s theme, he opened the proceedings by citing a recently published NIMH study that shows the majority of mental disorders in the country to be disorders of young people. Dr. Daniel S. Pine - Mood and Anxiety Disorders: Among the psychiatric brain and behavior disorders that affect the young, the most widespread are mood and anxiety disorders. Daniel S. Pine, M.D., is chief of the section on development and affective neuroscience and chief of child and adolescent research in the mood and anxiety disorders program at NIMH. He is a current member of the NARSAD Scientific Council and a NARSAD Independent Investigator. He began by stating that between five and 20 percent of children and adolescents suffer major depression at some point in their development. Although relatively rare in young children, its occurrence increases dramatically with puberty, mostly among girls. By contrast, anxiety disorders, which include obsessive-compulsive disorder, post-traumatic stress disorder, and generalized anxiety disorder, appear more frequently in younger children, predominantly prepubescent girls. Anxiety disorders and depression are familial: children born to parents with anxiety have a high rate of anxiety, as do children born to parents with depression. The most important connection between the two conditions, Dr. Pine pointed out, is that anxiety disorders in childhood are probably the best predictors of risk for depression over a lifetime. While anxiety disorders in childhood are common, they are mostly transient. What is not known is what underlies the differences between children with transient anxiety vs. those whose problems will persist. Treatments for depression include SSRI medications, such as fluoxetine (Prozac), and psychotherapy. Recent research has yielded three basic findings: 1) fluoxetine works better than placebo (confirmed in two other studies); 2) cognitive behavior therapy (CBT) by itself is no better than placebo; and 3) therapy combining fluoxetine and CBT is slightly better than fluoxetine alone. The question these findings raise, Dr. Pine said, is whether to give all affected children combination therapy, or start them on fluoxetine alone and wait to see if they respond. Anxiety disorders, also treated with fluoxetine and CBT, tend to respond better than depression and have a much lower relapse rate. To be able to discern who are most at risk for major depression and anxiety disorders, and how best to treat them, will require more precise understanding of the brain circuits and genes involved, Dr. Pine stated. He noted the progress in neuroscience and brain imaging that has pinpointed the amygdala as the key brain structure mediating fear-related behaviors. The application of functional MRI (fMRI) to visualize blood flow in the brain has revealed that in people with depression the amygdala is hypersensitive to fear-inducing stimuli. Dr. Pine and others have been using fMRI to study changes in the developing brain. Comparing children who are not depressed but have a depressed parent and healthy children with no parental depression history, Dr. Pine and his colleagues have determined that when exposed to stimuli, children of depressed parents show dramatically greater increase in activity in the amygdala. These results suggest to him the possibility of developing a test for identifying children at risk. In collaboration with Dr. Nathan Fox of the University of Maryland, Dr. Pine and his group have been looking at activity in another brain area, the striatum, which is involved in reward behavior, to better understand the relationship between behavioral inhibition and depression. Behavioral inhibition is a pattern of fearfulness or wariness that can be detected within the first two years of life and appears to persist. Research aimed at understanding the genetic underpinnings of mood disorders has uncovered variant forms of the gene that codes for the serotonin transporter, the protein target for SSRI medications like fluoxetine. The variant genes correspond to variations in amygdala activity and to risk for depression. But, Dr. Pine added, studies clearly show that neither genes alone nor environmental stressors alone create depression. Its emergence depends on a combination of the two. Dr. B. Timothy Walsh - Eating Disorders While anxiety and depression may be the most pervasive child brain disorders, anorexia nervosa has the highest mortality rate. B. Timothy Walsh, M.D., is Ruane Professor of Pediatric Psychopharmacology at the College of Physicians and Surgeons of Columbia University and founder of the Eating Disorders Research Unit at New York State Psychiatric Institute. Contrary to what many people think, he stated, anorexia is not a new phenomenon, a product of the current emphasis on being thin and fit, and he showed evidence of its existence dating back centuries. Anorexia usually appears in adolescence and involves a relentless pursuit of thinness and overwhelming fear of becoming fat, leading to dieting to the point of danger. Often, Dr. Walsh said, the fear goes up as weight goes down. Anorexia sufferers are mostly women. Most, but not all, are white and middle-class. About half engage in binge eating, abusing diuretics and laxatives in an attempt to control weight. They exercise and weigh themselves compulsively. They often become socially isolated and depressed, and suicide is a major contributor to the mortality rate. Since the teens are the peak years for the development of bone density, anorexia can have a dramatically negative effect on bone health, setting the stage for later osteoporosis. Over the years, treatments for anorexia have run the gamut from thyroid treatment to hormones to lobotomy, shock treatment, Thorazine, insulin, Elavil, and Prozac, as well as psychoanalysis and behavior therapy. According to Dr. Walsh, the data show conclusively that medicine does not help. Weight gain, while the essential first step in treatment, is not by itself curative, he said, and is difficult to achieve. It takes 4,000 calories above maintenance caloric intake to gain a pound, or a total of 3,500 calories a day to regain two pounds a week. Intensive nursing care can be effective. A method pioneered in 1987 at Maudsley Hospital, in London, has recently been gaining attention as a promising treatment for adolescent anorexia. It involves putting parents in charge of feeding, an idea that runs counter to traditional psychiatric thinking, but has been backed up by at least one further study. For adult anorexia patients, Dr. Walsh’s laboratory and others have shown that CBT and other supportive interventions may be helpful. The good news, Dr. Walsh reported, is that most anorexia patients recover, both psychologically and physically, particularly those who develop the illness in early or middle adolescence and are treated aggressively. The bad news is that five percent per decade die from it. A Swedish study over a 30-plus-year period showed a mortality rate of 25 percent, which other studies have confirmed. The key diagnostic features of bulimia nervosa, the sister disorder to anorexia, is recurrent binge eating followed by self-induced vomiting or laxative abuse. As with anorexia, the majority of patients are women, with illness tending to begin in late adolescence. While physical complications are rare, even for those who binge and vomit five or 10 times a week over several years, serious problems can arise. Additionally, bulimics have a high rate of alcohol and drug abuse. CBT and antidepressant medication appear to be effective treatments. Dr. Walsh said that data from a number of trials, including a study in his laboratory, showed that a daily 60-milligram dose of Prozac works quickly to reduce binge eating, which may be due to Prozac’s short-term effect as an appetite suppressant. Medication and psychotherapy used together, he said, work better than either alone. Dr. Walsh closed by inviting people seeking information to contact him through his Web site, eatingdisordersclinic.org, and said that free treatment is provided as part of the research conducted at Columbia supported by the New York State Psychiatric Institute. Dr. David J. Posey - Autism To emphasize the current critical status of autism, the next subject that was discussed, Dr. Insel cited recent epidemiological research that shows a ten-fold increase in prevalence since the early 1990s, with one child in 166 now having some form of autism spectrum disorder. Treatments, mostly behavioral interventions, are still very much on the frontier. David J. Posey, M.D., M.S., associate professor of psychiatry and chief of the Christian Sarkine Autism Treatment Center at the Indiana University School of Medicine, and twice a recipient of a NARSAD Young Investigator Award, heads a multidisciplinary team that provides treatment for over 600 autistic children. His is one of three NIMH-supported sites in the RUPP autism network (Research Units on Psychopharmacology) focused on developing medication to treat autism. The core symptoms of autism are problems in social communication, attention, and responsiveness. People with autism often have reading and language problems; half of those most severely affected never develop much functional language or it is idiosyncratic or repetitive. Many display other repetitive behaviors like hand-flapping, and ritualistic and compulsive behaviors. They often have narrow or unusual interests. Of the five subtypes of autism spectrum disorder listed in DSM-1V, the most severe is what is generally referred to as autism, Dr. Posey said. Children diagnosed with Asperger’s syndrome have relatively normal language development, with perhaps some peculiarities, but do not usually have cognitive problems or mental retardation. Childhood disintegrative disorder is a rare, late-onset form in which the child develops normally until the age of four or five, then shows a loss of skills that finally leads to autism. Also rare, occurring primarily in girls, is Rett’s disorder, for which, fortunately, there is a genetic test. Last is pervasive developmental disorder, which does not fully meet the criteria for autism or for the other disorders in the spectrum. In the epidemiological study cited by Dr. Insel, which was conducted in Britain, 10,000 preschoolers were screened for autism. Pervasive developmental disorder turned out to be the most common form. The rate of full-blown autism was around 1 in 500. Asperger’s was less common, which Dr. Posey thinks might be an underestimation since it is often not recognized until children are older than were those in the test group. Childhood disintegrative disorder was relatively rare. The cause of autism remains unknown. What is known, Dr. Posey said, is that it is about four times more common in boys and has a genetic base. Recent studies are beginning to reveal problems with brain growth and abnormalities in task-processing in specific brain areas, and problems in serotonin transmission. There are no FDA-approved treatments for autism. Fifteen years ago, first-generation antipsychotics, principally haloperidol, were prescribed for some of the disruptive behaviors of the disorder. It was effective in reducing some symptoms, but caused a high rate of tardive dyskinesia, an impairment in the ability to control movements. Nowadays, Dr. Posey said, he and his colleagues frequently turn to atypical antipsychotics. In a pilot study by Dr. Christopher McDougal, at Indiana, risperidone given to adult patients helped to counter a variety of symptoms, including aggression, irritability, anxiety, depression, and repetitive behavior; and was well tolerated. More recently, risperidone was chosen as the first drug to be used by the RUPP network in a large-scale, placebo-controlled study with of children with autism. The 101 children in the risperidone study displayed classic autism behaviors, such as high levels of irritability, aggression, and self-injury. After eight weeks, those who responded to the drug entered a continuation phase at the end of which, Dr. Posey reported, the rate of improvement in reduction of irritability was 70 percent. The children also showed definite improvement with regard to repetitive behavior; some improvement of hyperactivity, attention, and compliance; and slight improvement with regard to social withdrawal and repetitive speech. Risperidone also helped with sensory motor behaviors like hand-flapping, and with mood reactions and sensory overstimulation. It did not appear to help with social relatedness or language usage. Since risperidone carries significant side effects, Dr. Posey’s laboratory conducted tests, after six months, to see whether treatment could be suspended. Within two weeks off the drug, the patients showed dramatic increases in negative symptoms. The major side effect of risperidone is abnormal weight gain, which levels off after time, but remains above normal. Another study is examining the effects of risperidone on the hormone prolactin. Elevated prolactin levels are known to cause a variety of problems, including breast enlargement in males as well as females. The test group was comprised of prepubescent boys. After eight weeks, Dr. Posey said, the boys showed a four-fold increase in their prolactin levels. After 18 months, their levels remained elevated, but only twice the normal level. None of the boys showed breast enlargement. Dr. Posey reported that among other second-generation antipsychotics being studied, his group recently published promising results with five patients treated with aripiprazole, which was recently released. Dr. McDougal has now initiated a double-blind, placebo-controlled study of this drug with autistic children. Hyperactivity is a major problem affecting half of children with autism spectrum disorders, but there has been little consensus as to the most effective treatment. To address this problem, the RUPP network is focusing on the drug methyphenidate, or Ritalin. In a study with children aged 5 to 14, the researchers found differing responses; some children doing better on low doses, others on higher doses. When doses were individualized, the beneficial effect was significant, but 18 percent of those treated with the drug became more irritable, and had to be dropped from the study. Dr. Posey’s group has recently completed a pilot study with, atomoxetine, or Strattera, to target hyperactivity. For 16 of the children, or three-quarters of the group, the drug seemed to work reasonably well. There are currently no clearly effective drugs for the social and language impairments of autism, Dr. Posey stated. Fenfluramine and naltrexone have been tried without much success, but Dr. Posey believes that a host of other drugs on the market deserve further study. A few years ago, SSRIs were the treatment of choice despite the lack of any placebo-controlled studies in children. Some open-label studies have suggested that SSRIs do help, but without placebo-controlled studies, Dr. Posey said, it is hard to tell whether the improvement that may occur is actually due to the treatment. In other areas, Dr. Posey reported that there has been some research using cholinergic agents, such as those used for Alzheimer’s disease, to treat autism. One placebo-controlled study with donepezil appeared to produce some improvements in autistic children, and there are ongoing trials with other anticholinesterase inhibitors. Also, glutamatergic drugs have been receiving some attention for neuropsychiatric disorders. Lamotrigine, or Lamictal, an anticonvulsant that decreases glutamate, produced no significant effects with autism, but a placebo-controlled test with Amantine, an NMDA antagonist (NMDA is a receptor that glutamate binds to), showed some improvement in autistic children with regard to hyperactivity and inappropriate speech. Dr. Posey has recently published a pilot study of D-cycloserine, an NMDA partial agonist, which elicited some improvement in social withdrawal, and he is now conducting a controlled trial with it. Since it is unlikely that one drug will prove effective for all symptoms of autism, Dr. Posey stated that other studies will be looking into treatments with a combination of drugs. Meanwhile, the RUPP psychosocial intervention network is conducting a controlled trial that combines parent training and behavior therapy with risperidone treatment. Dr. Ellen Leibenluft - Bipolar Disorder Dr. Insel introduced the final subject on the afternoon’s agenda, pediatric bipolar disorder, as perhaps the most controversial in terms of pathophysiology and diagnosis: the point of contention is whether it is the same illness as adult bipolar disorder. The speaker, Ellen Leibenluft, M.D., chief of the unit on affective disorders of the pediatrics and developmental neuropsychiatry branch in the NIMH mood and anxiety program, has worked with both adult and child patients. Whatever the anomalies among children diagnosed as bipolar, she stated, what is clear is the seriousness of the impairment it causes. A recent study found that 77 percent of these children have suicidal ideation and 35 percent have made a suicide attempt; and they are symptomatic 60 percent of the time despite state-of-the-art treatment. With classic adult bipolar disorder, patients experience episodes of mania and of depression. With the manic episodes characteristically come euphoria, grandiosity, a decreased need or desire for sleep, increased goal-directed activity. With children, irritability is probably the single most common reason they are brought for psychiatric assessment. The question, Dr. Leibenluft says, is whether to diagnose as manic those children who show severe, chronic irritability with ADHD-like symptoms. To try to answer this question, she and her colleagues recruited a group of children with classic bipolar symptoms and a group with controversial symptoms, whom they labeled SMD, for severe mood dysregulation. The average age in both groups was 12, with more boys than girls. All had been ill for some time, were frequently hospitalized, and were on medication. Comparing these SMD children with data from an earlier epidemiological survey, Dr. Leibenluft and her group determined that in the range of psychiatric illnesses, the symptoms they had designated SMD were relatively common. Also, the children in the survey who showed SMD traits at age 10 or 11 were, by age 18, at risk for depression at a rate 10 times higher than non-SMD children. Another study showed that chronic irritability at age 14 predicted depression at three times the normal rate by age 22. The data was not sufficient to determine if these children would become classically bipolar. Dr. Leibenluft and her group have been devising ways to compare what happens in the brains of bipolar and SMD children. One device they are using is a computer game in which the children are made to experience frustration. Dr. Leibenluft reported that the frustrated bipolar children did not stay on task; they displayed what is called adverse attention emotion reaction. The SMD children displayed as much frustration as the bipolar children, but measurements of activity in their parietal lobes looked like those of normal controls and not like those of the bipolar children. Like Dr. Pine in his studies of children with depression and anxiety disorders, Dr. Leibenluft is also looking at the amygdala. She and her team have found that bipolar-diagnosed children responded to neutral stimulation with more emotion (negative) than controls and with greater amygdala activity. The need for more effective treatment for these children is pressing; protocols based on adult data work poorly. Dr. Leibenluft cited a recent study of 255 children diagnosed as bipolar. Although 97 percent were receiving medication, 66 percent had to be hospitalized and 35 percent had psychosis and other psychiatric problems, principally anxiety disorder and ADHD. Dr. Leibenluft is currently serving on a committee that is working toward developing treatment guidelines and is compiling data on ongoing drug studies. She is optimistic that these efforts, combined with information being gathered concerning brain activity in these children, will lead to better, earlier diagnosis and treatment. |
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