The Mental Health Social Worker

A gene called DISC1, (for “disrupted in schizophrenia”) has been a leading contender among possible genetic causes since it was implicated in schizophrenia in a large Scottish clan two decades ago. The DISC1 gene codes for a protein important for brain development, as well as for mood and memory – functions that are disturbed in schizophrenia. However, until now there have been few clues as to how DISC1 might increase risk for the chronic mental disorder.

A new study suggests how impaired expression of DISC1 might wreak havoc during early critical periods as the developing brain gets wired up. NIMH researchers have discovered that previously unknown shortened forms of the gene were expressed 2.5 times more in the fetal brain than after birth. By contrast, other forms were expressed more evenly across development. The shortened forms were also over-expressed in brains of adults who had schizophrenia.

“These shortened forms may result in a functionally aberrant and truncated protein that is more highly expressed in the brains of people with schizophrenia” explained NIMH’s Dr. Joel Kleinman, who led the research.

Drs. Kleinman, Barbara Lipska, Kenji Nakata, Daniel Weinberger and colleagues, report on their discoveries in postmortem brain tissue online, during the week of August 24, 2009 in the Proceedings of the National Academy of Science (PNAS).

Background

The new findings may help explain the molecular roots of the illness in the Scottish clan, in which more than half of the members developed schizophrenia or other serious mental disorders. Previous studies had traced their disease, in part, to a different aberration, a mismatch called a translocation, in which a chunk of genetic material from one chromosome gets attached to another chromosome. But this has never been seen in other families. A translocation, like the shorter messenger RNA forms, would result in shortened forms of DISC1 protein. So other affected families and the Scottish clan could in fact share a similar illness process, say the researchers.

Results of This Study

The researchers linked several illness-implicated variations in the DISC1 gene to the shorter forms of DISC1 products, called messenger RNAs, that transform the gene into protein. The results suggest that variations in the DISC1 gene boost risk for schizophrenia by producing shortened messenger RNAs that are predominantly expressed during the formative period when the fetal brain is taking shape.

Significance

“Our results cast a new light on apparent failures to replicate findings that have long plagued psychiatric genetics” said Kleinman. “We discovered that different genetic variations can result in the same or similar messenger RNAs and protein. That means that different studies could turn up different variations and still be pointing to the same underlying disease process. So some findings thought to be non-replications may ultimately prove to be replications.”

Since at least a half-dozen genes implicated in schizophrenia by the NIMH group interact with DISC1, the downstream adverse effects of impaired DISC1 on brain systems are likely considerable, said Kleinman.

What’s Next

One of the suspect gene variants associated with a shortened messenger RNAs is detectable in white blood cells, raising the possibility that it could someday be used as a genetic marker for the illness.

NIMH’s Dr. Joel Kleinman explained how the DISC1 gene may increase risk for schizophrenia at a recent NIMH seminar.

Reference

Nakata K, Lipska BL, Hyde TM, Ye T, Fink E, Morita Y, Vakkalanka R, Bareboim M, Sei Y, Weinberger DR, Kleinman JE. DISC1 splice variants are upregulated in schizophrenia and associated with risk polymorphisms. Aug 24, 2009 PNAS.

Washington, DC – Pregnant women with depression face complicated treatment decisions
because of the risks associated with both untreated depression and the use of antidepressants. A new report from The American College of Obstetricians and Gynecologists (ACOG) and the American Psychiatric Association (APA) attempts to help doctors and patients weigh the risks and benefits of various treatment options.

Based on an extensive review of existing research, ACOG and APA offer recommendations for the treatment of women with depression during pregnancy. The report, “The Management of Depression During Pregnancy: A Report from the American Psychiatric Association and The American College of Obstetricians and Gynecologists,” is published in Obstetrics & Gynecology (September 2009) and General Hospital Psychiatry (September/October 2009).

Depression is common during pregnancy—between 14 percent and 23 percent of pregnant women will experience depressive symptoms while pregnant. In 2003, approximately 13 percent of women took an antidepressant at some time during their pregnancy.

“Depression in pregnant women often goes unrecognized and untreated in part because of concerns about the safety of treating women during pregnancy,” said lead author Kimberly Ann Yonkers, MD, Yale University associate professor of psychiatry and obstetrics, gynecology and reproductive sciences. “It is our hope that this will be a resource to clinicians who care for pregnant women who have or are at risk of developing major depressive disorder.”

Both depression symptoms and the use of antidepressant medications during pregnancy have been associated with negative consequences for the newborn. Infants born to women with depression have increased risk for irritability, less activity and attentiveness, and fewer facial expressions compared with those born to mothers without depression. Depression and its symptoms are also associated with fetal growth change and shorter gestation periods. And while
available research still leaves some questions unanswered, some studies have linked fetal malformations, cardiac defects, pulmonary hypertension, and reduced birth weight to antidepressant use during pregnancy.

Identifying depression in pregnant women can be difficult because its symptoms mimic those associated with pregnancy, such as changes in mood, energy level, appetite, and cognition. Depressed women are more likely to have poor prenatal care and pregnancy complications, such as nausea, vomiting, and preeclampsia, and to use drugs, alcohol, and nicotine.

“Ob-gyns are the front-line physicians for most pregnant women and may be the first to make a diagnosis of depression or to observe depressive symptoms getting worse. In the past, reproductive health practitioners have felt ill equipped to treat these patients because of the lack of available guidance concerning the management of depressed women during pregnancy,” said ACOG President Gerald F. Joseph, Jr, MD. “This joint report bridges the gap by summarizing
current research on various depression treatment methods and can assist clinicians in decisionmaking. Many people—physicians and women alike—will be glad to know that their choices go beyond ‘medication or nothing.’”

According to the report, some patients with mild-to-moderate depression can be treated with psychotherapy (individual or group) alone or in combination with medication. Additionally, the report discusses the need for ongoing consultation between a patient’s ob-gyn and psychiatrist during pregnancy and presents algorithms for treating patients in common scenarios:

Women thinking about getting pregnant

• For women on medication with mild or no symptoms for six months or longer, it may be appropriate to taper and discontinue medication before becoming pregnant.

• Medication discontinuation may not be appropriate in women with a history of severe, recurrent depression (or who have psychosis, bipolar disorder, other psychiatric illness requiring medication, or a history of suicide attempts).

• Women with suicidal or acute psychotic symptoms should be referred to a psychiatrist for aggressive treatment.
Pregnant women currently on medication for depression

• Psychiatrically stable women who prefer to stay on medication may be able to do so after consultation between their psychiatrist and ob-gyn to discuss risks and benefits.

• Women who would like to discontinue medication may attempt medication tapering and discontinuation if they are not experiencing symptoms, depending on their psychiatric history. Women with a history of recurrent depression are at a high risk of relapse if medication is discontinued.

• Women with recurrent depression or who have symptoms despite their medication may benefit from psychotherapy to replace or augment medication.

• Women with severe depression (with suicide attempts, functional incapacitation, or weight loss) should remain on medication. If a patient refuses medication, alternative treatment and monitoring should be in place, preferably before discontinuation.

Pregnant and not currently on medication for depression

• Psychotherapy may be beneficial in women who prefer to avoid antidepressant medication.

• For women who prefer taking medication, risks and benefits of treatment choices should be evaluated and discussed, including factors such as stage of gestation, symptoms, history of depression, and other conditions and circumstances (eg, a smoker, difficulty gaining weight).

All pregnant women

• Regardless of circumstances, a woman with suicidal or psychotic symptoms shouldimmediately see a psychiatrist for treatment.

Background on the report

APA and ACOG convened a work group to critically evaluate and summarize information about the risks associated with depression and antidepressant treatment during pregnancy. The group included clinical research experts within these two medical specialties and a developmental pediatrician.

Researchers reviewed cumulative existing research relating to antidepressant use in pregnancy; however, available research has not yet adequately controlled for other factors that may influence birth outcomes, including maternal illness or problematic health behaviors that can adversely affect pregnancy.

Limitations of existing research include:

• Few studies of antidepressants and birth outcomes assessed the mothers’ psychiatric condition

• Confounding factors that influence birth outcomes (eg, poor prenatal care and drug/alcohol/nicotine use) were often not controlled

• Pregnancy complications (eg, nausea, preeclampsia) occur at a higher rate in depressed than nondepressed women

The report authors are Kimberly A. Yonkers, MD; Katherine L. Wisner, MD, MS; Donna E.
Stewart, MD, FRCPC; Tim F. Oberlander, MD, FRCPC; Diana L. Dell, MD, FACOG, DFAPA; Nada
Stotland, MD, MPH; Susan Ramin, MD, FACOG; Linda Chaudron, MD, MS; and Charles
Lockwood, MD, FACOG.

Making evidence-based mental health services accessible to everyone in a disaster-stricken area would have substantial public health benefits, according to a statistical model developed by NIMH-funded researchers. Rough estimates of cost show such comprehensive care would be within the range of other accepted medical practices. However, given the considerable costs and resources required, further studies are needed to determine whether such broader efforts are advisable and, if so, to what degree. The study was published in the August 2009 issue of the Archives of General Psychiatry.

Background

Research on survivors of Hurricanes Katrina and Rita show that this population continues to face many persistent mental health issues. These issues may at times be worsened by lack of availability or access to proper mental health care services. To help inform future disaster plans, a group of researchers led by Kenneth B. Wells, M.D., MPH, of RAND Corporation and UCLA Semel Institute, Health Services Research Center, developed a model to estimate the costs and outcomes of providing enhanced, evidence-based mental health care in a post-disaster setting.

Starting with a population of around 11 million in the hurricane-affected areas (based on U.S. Census & Area Resources File¹ data), the researchers focused on medium-term mental health response, which starts around seven months post-disaster. They chose this period because fewer strategies have been developed for medium-term response, compared with the immediate post-disaster response (zero to six months), which mainly involves humanitarian efforts such as life-saving care and crisis counseling. Wells and colleagues modeled service use through 24 months post-disaster and measured outcomes up to 30 months out.

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A single-session, online, multimedia intervention effectively reduced risky sexual behaviors among young men who have sex with men, a group at high risk for HIV/AIDS and other sexually transmitted infections. Such low-cost programs may help reverse the steady rise in HIV diagnoses among this population. The study was published online ahead of print on June 5, 2009, in the journal, AIDS and Behavior.

Background

Based on the Information-Motivational-Behavioral Skills (IMB) model for reducing HIV risk,
Kelly M. Carpenter, Ph.D., of Talaria, Inc., and colleagues developed a multimedia, online intervention that aimed to:

• Increase knowledge of risk factors
• Provide skills training for safer sex behaviors
• Increase motivation for behavior change.

The researchers recruited 112 men who have sex with men, ages 18–39. Participants were HIV negative or did not know their status and had engaged in unprotected sex within the preceding three months. All participants completed a 25-minute baseline assessment and then were randomly assigned to the experimental intervention or a control group program. Both the intervention and control program required 1.5–2 hours to complete, though participants had up to a week to finish. Participants were asked to return to the study Web site three months later to complete a 20-minute follow-up questionnaire.

The intervention presented a variety of interactive exercises, multimedia clips, quizzes, and other materials that provided information about safer sex practices and tested participants’ knowledge of HIV risk factors. Those in the control group completed an online stress reduction program that described the effects of stress on the body and health reasons for reducing stress, in addition to leading participants in relaxation exercises, such as deep breathing and guided imagery. The control program did not include any sexual risk reduction information.

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The transition from teen to young adult involves many highly anticipated rites of passage. However, for youths with developmental disorders, coming of age may signal the sudden end of coverage for education and training programs, health insurance, and youth-oriented services. For teens with autism spectrum disorders (ASD) and their families, this transition may be especially difficult. To better understand this issue and how best to address it, NIMH has awarded a five-year grant to Paul T. Shattuck, Ph.D., of the George Warren Brown School of Social Work at Washington University in St. Louis.

With this grant, Dr. Shattuck and his colleagues will pursue a study of socioeconomically and racially diverse adolescents and adults with ASD. The researchers will assess data gathered on 922 people with ASD who participated in the U.S. Department of Education’s (ED) National Longitudinal Transition Study 2. The 10-year ED study included a nationally representative study population of nearly 12,000 youth, ages 13-17 at the start of the study in 2000. In particular, the Shattuck study will focus on:

• Outlining changes in service needs, service use, and health insurance coverage as youths with ASD enter adulthood
• Identifying resources and barriers associated with use of, and continuity in, health care and other services
• Detailing young adult outcomes (such as employment, housing, independent living, health, and community participation) and examining how these may be linked with prior measures of need, service use, resources, and barriers.

The study also meets a research objective in the Interagency Autism Coordinating Committee’s (IACC) Strategic Plan for Autism Spectrum Disorder Research “to support at least two studies [by 2011] to assess and characterize service access, health, and functional outcomes” among diverse demographic groups. Comprising representatives of federal agencies and members of the public, the IACC coordinates efforts within the U.S. Department of Health and Human Services concerning ASD.

“This study will help us one day answer one of the most pressing issues in treating ASD,” said NIMH Director Thomas R. Insel, M.D. “Bridging the gap in health care, service use, and insurance coverage as these young people leave the school systems and enter adulthood may help prevent lapses in behavioral, social, and occupational skills that they and their families have worked so hard to achieve.”

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Recovery Act Funds Will Support First Phase of Project

The National Institute of Mental Health (NIMH) is launching a large-scale research project to explore whether using early and aggressive treatment, individually targeted and integrating a variety of different therapeutic approaches, will reduce the symptoms and prevent the gradual deterioration of functioning that is characteristic of chronic schizophrenia.

The Recovery After an Initial Schizophrenia Episode (RAISE) project is being funded by NIMH with additional support from the American Recovery and Reinvestment Act (ARRA). RAISE is a model example of how money from the Recovery Act can accelerate science related to public health problems and potentially benefit those citizens most in need.

“This new initiative will help us determine whether intervention that is started early, incorporates diverse treatment and rehabilitation approaches, and is sustained over time, can make it possible for more people with schizophrenia to return successfully to work and school,” said NIMH Director Thomas R. Insel, M.D. “Moreover, the interventions being tested will be designed from the outset to be readily adopted in real-world health care settings and quickly put into practice.”

Despite the availability of moderately effective treatments, such as antipsychotic medications and various psychosocial interventions, people with schizophrenia often do not receive treatment until the disease is already well-established, with recurrent episodes of psychosis, resulting in costly multiple hospitalizations and disabilities that can last for decades. Periods of unemployment, homelessness, and incarceration are common, making schizophrenia a costly disease for individuals, their families, and the community at large.

RAISE will test approaches that involve intervening immediately upon first diagnosis, systematically incorporating the range of options that are now available in a more piecemeal fashion to people with schizophrenia. These options include medications, psychosocial treatments, and rehabilitation, including teaching patients and families how to manage the disease. The hope is that such a coordinated approach tailored to each individual and sustained over time may make lasting differences in the acceptability of treatment and overall function.

Agencies and organizations that play a role in providing health care and other services to people with schizophrenia will have an opportunity to participate in the design of the interventions to be evaluated by RAISE. Federal organizations, including the Substance Abuse and Mental Health Services Administration, the Social Security Administration, the Centers for Medicare and Medicaid Services, the Department of Veterans Affairs, the Walter Reed Army Medical Center, and the National Institute on Drug Abuse, will be involved along with mental health care consumers and family members, private health care providers, additional scientific experts, and state and local agencies. Other agencies may become involved as the project proceeds. Involving these stakeholders will help ensure that, if successful, this evidence-based approach can be disseminated and adopted rapidly, thus significantly speeding the transition between research findings and their use in real-world practice.

Two research groups will work in parallel to develop and test potential intervention approaches. One group will be led by John M. Kane, M.D., of the Zucker Hillside Hospital, Feinstein Institute for Medical Research, Manhasset, N.Y. The second group will be led by Jeffrey Lieberman, M.D., of the Research Foundation for Mental Hygiene, Inc., New York City. The research teams feature national and international collaborations, with treatment to be delivered in up to 30 clinical sites across the United States.

Recovery Act funds will underwrite the initial two phases of the trial, during which the investigators will refine the interventions with input from stakeholders and conduct a feasibility study to demonstrate that each intervention can be fielded in real world community treatment settings and be evaluated in a randomized clinical trial design. With long-term funds committed by NIMH to complete these phases plus a full-scale clinical trial, funding for the study is $40 million.

“Depending on the study’s outcome, RAISE could help set the stage for a paradigm shift in the way schizophrenia is treated in the United States. The ultimate goal of the initiative is to eliminate the chronic form of schizophrenia that is so costly and devastating to the individual, family members, and society as a whole,” said Robert Heinssen, Ph.D., acting director of the NIMH Division of Services and Intervention Research and project officer for RAISE. “This Recovery Act-supported project will hire and help train many mental health researchers and care providers for a project that is likely to help some of our most vulnerable citizens lead more productive and satisfying lives.”

NIMH is using Recovery Act funds to carry out objectives identified in its Strategic Plan. Among these objectives is to develop new and better interventions that incorporate the diverse needs and circumstances of people with mental illnesses and to strengthen the public health impact of NIMH-supported research.

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What is going on in teenagers’ brains as their drive for peer approval begins to eclipse their family affiliations? Brain scans of teens sizing each other up reveal an emotion circuit activating more in girls as they grow older, but not in boys. The study by Daniel Pine, M.D., of the National Institute of Mental Health (NIMH), part of National Institutes of Health, and colleagues, shows how emotion circuitry diverges in the male and female brain during a developmental stage in which girls are at increased risk for developing mood and anxiety disorders.

“During this time of heightened sensitivity to interpersonal stress and peers’ perceptions, girls are becoming increasingly preoccupied with how individual peers view them, while boys tend to become more focused on their status within group pecking orders,” explained Pine. “However, in the study, the prospect of interacting with peers activated brain circuitry involved in approaching others, rather than circuitry responsible for withdrawal and fear, which is associated with anxiety and depression.”

Pine, Amanda Guyer, Ph.D., Eric Nelson, Ph.D., and colleagues at NIMH and Georgia State University, report on one of the first studies to reveal the workings of the teen brain in a simulated real-world social interaction, in the July, 2009 issue of the Journal Child Development.

Thirty-four psychiatrically healthy males and females, aged 9 to 17, were ostensibly participating in a study of teenagers’ communications via Internet chat rooms. They were told that after an fMRI (functional magnetic resonance imaging) scan, which visualizes brain activity, they would chat online with another teen from a collaborating study site. Each participant was asked to rate his or her interest in communicating with each of 40 teens presented on a computer screen, so they could be matched with a high interest participant (see picture below).

Two weeks later, the teens viewed the same faces while in an fMRI scanner. But this time they were asked to instead rate how interested they surmised each of the other prospective chatters would be in interacting with them.

Only after they exited the scanner did they learn that, in fact, the faces were of actors, not study participants, and that there would be no Internet chat. The scenario was intended to keep the teens engaged –– maintain a high level of anticipation/motivation –– during the tasks. This helped to ensure that the scanner would detect contrasts in brain circuit responses to high interest versus low interest peers.

Although the faces were selected by the researchers for their happy expressions, their attractiveness was random, so that they appeared to be a mix of typical peers encountered by teens.

As expected, the teen participants deemed the same faces they initially chose as high interest to be the peers most interested in interacting with them. Older participants tended to choose more faces of the opposite sex than younger ones. When they appraised anticipated interest from peers of high interest compared with low interest, older females showed more brain activity than younger females in circuitry that processes social emotion.

“This developmental shift suggested a change in socio-emotional calculus from avoidance to approach,” noted Pine. The circuit is made up of the nucleus accumbens (reward and motivation), hypothalamus (hormonal activation), hippocampus (social memory) and insula (visceral/subjective feelings).

By contrast, males showed little change in the activity of most of these circuit areas with age, except for a decrease in activation of the insula. This may reflect a waning of interpersonal emotional ties over time in teenage males, as they shift their interest to groups, suggest Pine and colleagues.

“In females, absence of activation in areas associated with mood and anxiety disorders, such as the amygdala, suggests that emotional responses to peers may be driven more by a brain network related to approach than to one related to fear and withdrawal,” said Pine. “This reflects resilience to psychosocial stress among healthy female adolescents during this vulnerable period.”

Nodes of a brain circuit for social emotion and approach behavior activated more in teenage girls than in boys with age. Functional MRI data (red) superimposed on anatomical MRI images.

Source: NIMH Emotion and Development Branch

Teenage participants were first asked to rate their interest in peers with whom they might communicate in an internet chat room (left). Two weeks later, while in a brain scanner, they were asked to rate how interested the same peers were in interacting with them (right).

Source: NIMH Emotion and Development Branch

Reference

Probing the neural correlates of anticipated peer evaluation in adolescence. Guyer AE, McClure-Tone EB, Shiffrin ND, Pine DS, Nelson EE. July 2009, Child Development.

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Chromosomal Hotspot of Immunity/Gene Expression Regulation Implicated

A trio of genome-wide studies – collectively the largest to date – has pinpointed a vast array of genetic variation that cumulatively may account for at least one third of the genetic risk for schizophrenia. One of the studies traced schizophrenia and bipolar disorder, in part, to the same chromosomal neighborhoods.

“These new results recommend a fresh look at our diagnostic categories,” said Thomas R. Insel, M.D., director of the National Institute of Mental Health (NIMH), part of the National Institutes of Health. “If some of the same genetic risks underlie schizophrenia and bipolar disorder, perhaps these disorders originate from some common vulnerability in brain development.”

Three schizophrenia genetics research consortia, each funded in part by NIMH, report separately on their genome-wide association studies online July 1, 2009, in the journal Nature. However, the SGENE, International Schizophrenia (ISC) and Molecular Genetics of Schizophrenia (MGS) consortia shared their results – making possible meta-analyses of a combined sample totaling 8,014 cases and 19,090 controls.

All three studies implicate an area of Chromosome 6 (6p22.1), which is known to harbor genes involved in immunity and controlling how and when genes turn on and off. This hotspot of association might help to explain how environmental factors affect risk for schizophrenia. For example, there are hints of autoimmune involvement in schizophrenia, such as evidence that offspring of mothers with influenza while pregnant have a higher risk of developing the illness.

“Our study was unique in employing a new way of detecting the molecular signatures of genetic variations with very small effects on potential schizophrenia risk,” explained Pamela Sklar, M.D., Ph.D., of Harvard University and the Stanley Center for Psychiatric Research, who co-led the ISC team with Harvard’s Shaun Purcell, Ph.D.

“Individually, these common variants’ effects do not all rise to statistical significance, but cumulatively they play a major role, accounting for at least one third – and probably much more – of disease risk,” said Purcell.

Among sites showing the strongest associations with schizophrenia was a suspect area on Chromosome 22 and more than 450 variations in the suspect area on Chromosome 6. Statistical simulations confirmed that the findings could not have been accounted for by a handful of common gene variants with large effect or just rare variants. This involvement of many common gene variants suggests that schizophrenia in different people might ultimately be traceable to distinct disease processes, say the researchers.

“There was substantial overlap in the genetic risk for schizophrenia and bipolar disorder that was specific to mental disorders,” added Sklar. “We saw no association between the suspect gene variants and half a dozen common non-psychiatric disorders.”

Still, most of the genetic contribution to schizophrenia, which is estimated to be at least 70 percent heritable, remains unknown.

“Until this discovery, we could explain just a few percent of this contribution; now we have more than 30 percent accounted for,” said Thomas Lehner, Ph.D., MPH, chief of NIMH’s Genomics Research Branch. “The new findings tell us that many of these secrets have been hidden in complex neural networks, providing hints about where to look for the still elusive – and substantial – remaining genetic contribution.”

The MGS consortium pinpointed an association between schizophrenia and genes in the Chromosome 6 region that code for cellular components that control when genes turn on and off. For example, one of the strongest associations was seen in the vicinity of genes for proteins called histones that slap a molecular clamp on a gene’s turning on in response to the environment. Genetically rooted variation in the functioning of such regulatory mechanisms could help to explain the environmental component repeatedly implicated in schizophrenia risk.

The MGS study also found an association between schizophrenia and a genetic variation on Chromosome 1 (1p22.1) which has been implicated in multiple sclerosis, an autoimmune disorder.

“Our study results spotlight the importance not only of genes, but also the little-known DNA sequences between genes that control their expression,” said Pablo Gejman, M.D., of the NorthShore University HealthSystem Research Institute, of Evanston, ILL, who led the MGS consortium team. “Advances in biotechnology, statistics, population genetics, and psychiatry, in combination with the ability to recruit large samples, made the new findings possible.”

The SGENE consortium study pinpointed a site of variation in the suspect Chromosome 6 region that could implicate processes related to immunity and infection. It also found significant evidence of association with variation on Chromosomes 11 and 18 that could help account for the thinking and memory deficits of schizophrenia.

The new findings could eventually lead to multi-gene signatures or biomarkers for severe mental disorders. As more is learned about the implicated gene pathways, it may be possible to sort out what’s shared by, or unique to, schizophrenia and bipolar disorder, the researchers say.

Schizophrenia and bipolar disorder share genetic roots that appear to be specific to serious mental disorders, and are not shared by non-psychiatric illnesses. Bars representing different study samples show that the same genetic variations that account for risk in both mental disorders account for virtually none of the risk for coronary artery disease (CAD), Crohn’s disease (CD), hypertension (HT), rheumatoid arthritis (RA), or Type 1 (T1D) or Type 2 (T2D) diabetes.

Source: Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Harvard University.

References

Jianxin S, et al. Common variants on chromosome 6p22.1 are associated with schizophrenia. July 1, 2009, Nature

Stefansson H, et al. Common variants conferring risk of schizophrenia. July 1, 2009, Nature

Purcell SM, et al. Common polygenic variation contributes to risk of schizophrenia that overlaps with bipolar disorder. July 1, 2009, Nature

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Rarity Makes Definitive Assessment Elusive

A study examining stimulant use among children and adolescents found an association between stimulants and sudden unexplained death in youth with no evidence of pre-existing heart disease. The finding draws attention to the potential risks of stimulant medication, according to the study’s authors; an accompanying editorial notes that the rarity of sudden unexplained death and the lack of long-term data on the effectiveness of these medications for reducing other health risks make a full benefit/risk assessment difficult.

Background

Stimulant medications are widely used to treat children with attention deficit hyperactivity disorder (ADHD). The medications help reduce hyperactivity and impulsivity and improve the ability of affected children to focus and learn. Research has shown that stimulants can also have effects on the cardiovascular system, for example, raising blood pressure and heart rate. There have also been reports of sudden deaths in children receiving the medications, prompting the U.S. Food and Drug Administration (FDA) to direct drug manufacturers to inform consumers of possible risks of stimulant medications in children and adolescents with known pre-existing heart problems. In order to assess the association between stimulants and risk of death in young people, the National Institute of Mental Health and the FDA jointly funded a study looking at records of children and adolescents who died suddenly and unexpectedly.

This Study

Madelyn Gould, Ph.D., and colleagues at Columbia University College of Physicians & Surgeons and the New York State Psychiatric Institute identified 564 children and adolescents who had died suddenly for unexplained reasons. These youth had no known structural heart defects or other co-existing physical disorders known or suspected to be associated with sudden death. Each of these young people was then matched with a comparison young person who had also died suddenly, but in a motor vehicle accident. Information from family, medical, and autopsy records were systematically reviewed. The results revealed that stimulants were used by 10 of the young people whose deaths were unexplained and by 2 who died in crashes. (The stimulant found in each case was methylphenidate [Ritalin]. This study examined deaths that occurred between 1985 and 1996, before mixed amphetamine preparations [Adderall] became commonly used).

Because sudden death is extremely rare in childhood, randomized controlled studies—the ideal approach to studying health effects in populations—cannot be conducted to investigate such events. The authors employed a case-control design in which child or adolescent with the condition of interest—in this case sudden unexplained death—was matched with someone who died suddenly as a passenger in a motor vehicle accident. Using this approach, the authors were able to control for many relevant factors other than those being studied, such as asthma and other conditions associated with sudden death, although it was not possible to control for all potentially confounding factors.

Significance

According to the authors, the results of this study draw attention to concerns that stimulant medications increase the risk of sudden unexplained death in children and adolescents. The accompanying editorial, by coauthors Benedetto Vitiello, M.D. and Kenneth Towbin, M.D., both at NIMH, points out that the study, though rigorous in its approach, could not provide information on whether ADHD itself could increase the risk of sudden death, given its association with high-risk behaviors such as substance abuse.

The editorial went on to note that while randomized prospective studies are not practical—given the large numbers of subjects needed to detect such rare events—additional case/control studies would still be informative. In addition, research to improve screening methods for heart conditions that raise the risk of sudden death is essential.

Finally, the editorial notes that “1) sudden unexplained death is a rare event, 2) this is only the first such study, 3) it relies on small numbers, and 4) it is not possible to quantify the risk beyond estimating that it is very small.”

Reference

Gould, M.S., Walsh, T., Munfakh, J.L., Kleinman, M., Duan, N., Olfson, M., Greenhill, L, and Cooper, T. Sudden death and use of stimulant medications in youth. American Journal of Psychiatry AIA:1-10, 2009.

Vitiello, B. and Towbin, K. Stimulant treatment of ADHD and risk of sudden death in children. American Journal of Psychiatry AIA:1-10, 2009.

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Cognitive Prevention Program Trumps Usual Care in “Real World” Trial

At-risk teens exposed to a program that teaches them to counteract their unrealistic and overly negative thoughts experienced significantly less depression than their peers who received usual care, NIMH-funded researchers have found. However, the cognitive behavioral prevention program failed to similarly help adolescents prone to the mood disorder if their parents were currently depressed.

NIMH grantee Judy Garber, Ph.D., of Vanderbilt University, and colleagues, report on the findings of their multi-site clinical trial in the June 3, 2009 issue of the Journal of the American Medical Association.

Background

Only a fourth of depressed youth receive any treatment and at least 20 percent develop a chronic, difficult-to-treat form of the illness. Having a history of the illness substantially increases risk for depression, which soars two to three times among children of depressed parents. An initial study had supported the efficacy of a cognitive behavioral prevention program in reducing risk in such depression-prone teens, but it was unknown whether this would hold up across diverse “real world” settings.

To find out, Garber and Drs. David Brent, the University of Pittsburgh, William Beardslee, Boston Children’s Hospital and Judge Baker Children’s Center, and Gregory Clarke, Kaiser Permanente Center for Health Research in Portland, OR, randomly assigned 316 at-risk adolescents (aged 13-17) to either the cognitive behavioral program or usual care.

Teens in the cognitive behavioral program received eight weekly 90-minute group cognitive behavioral sessions. Masters or doctoral-level therapists helped them learn to restructure dysfunctional thinking patterns and practice problem solving skills. This was followed by six monthly continuation sessions in which they reviewed the cognitive and problem-solving skills and also learned relaxation, assertiveness and behavioral activation techniques.

Teens in the usual care condition as well as those in the cognitive behavior program were allowed to begin or continue with any mental health or other healthcare services available in their communities.

Results of This Study

Over a 9-month follow-up period, the rate of depression in the cognitive behavioral program group was 11 percent lower than for those in the usual care condition — 21.4 percent vs. 32.7 percent. Adolescents in the prevention program also self-reported lower levels of depression symptoms than those in usual care. Among teens whose parents were not depressed at the beginning of the study, the program was more effective in preventing onset of depression than usual care — 11.7 percent vs. 40.5 percent. However, this advantage did not hold for youth in the cognitive behavioral program if they had a parent who was depressed at the start of the study. Such teens had significantly higher rates of depression than those without a currently depressed parent.

Significance

The results demonstrate that the prevention program can be effectively delivered in a variety of “real world” settings, say the researchers.

“For every 9 adolescents who received the cognitive intervention, we would expect to prevent one from developing a depressive episode,” explained Garber. “This is comparable to what is seen with treatment response to medication.”

Moreover, preventing recurrence of a depressive episode may arguably bring even greater benefits than treating an episode after it has already produced other negative consequences. This suggests that the program may be useful for maintaining recovery, once achieved, she noted.

What’s Next?

“Our results also underscore the link between changes in parent and youth depression. Future investigations might explore combining or sequencing parental depression and prevention programs for at-risk teens.”

Reference

Prevention of depression in at-risk adolescents: a randomized controlled trial. Garber J, Clarke GN, Weersing VR, Beardslee WR, Brent DA, Gladstone TR, DeBar LL, Lynch FL, D’Angelo E, Hollon SD, Shamseddeen W, Iyengar S. JAMA. 2009 Jun 3;301(21):2215-24.PMID: 19491183