Scripps Research Institute Team Wrests Partial Control of a Memory

News Release

The work advances understanding of how memories form and offers new insight into disorders such as schizophrenia and post traumatic stress disorder

LA JOLLA, CA – March 22, 2012 – Scripps Research Institute scientists and their colleagues have successfully harnessed neurons in mouse brains, allowing them to at least partially control a specific memory. Though just an initial step, the researchers hope such work will eventually lead to better understanding of how memories form in the brain, and possibly even to ways to weaken harmful thoughts for those with conditions such as schizophrenia and post traumatic stress disorder.

The results are reported in the March 23, 2012 issue of the journal Science.

Researchers have known for decades that stimulating various regions of the brain can trigger behaviors and even memories. But understanding the way these brain functions develop and occur normally—effectively how we become who we are—has been a much more complex goal.

“The question we’re ultimately interested in is: How does the activity of the brain represent the world?” said Scripps Research neuroscientist Mark Mayford, who led the new study. “Understanding all this will help us understand what goes wrong in situations where you have inappropriate perceptions. It can also tell us where the brain changes with learning.”

On-Off Switches and a Hybrid Memory

As a first step toward that end, the team set out to manipulate specific memories by inserting two genes into mice. One gene produces receptors that researchers can chemically trigger to activate a neuron. They tied this gene to a natural gene that turns on only in active neurons, such as those involved in a particular memory as it forms, or as the memory is recalled. In other words, this technique allows the researchers to install on-off switches on only the neurons involved in the formation of specific memories.

For the study’s main experiment, the team triggered the “on” switch in neurons active as mice were learning about a new environment, Box A, with distinct colors, smells and textures continuing education for counselors

Next the team placed the mice in a second distinct environment—Box B—after giving them the chemical that would turn on the neurons associated with the memory for Box A. The researchers found the mice behaved as if they were forming a sort of hybrid memory that was part Box A and part Box B. The chemical switch needed to be turned on while the mice were in Box B for them to demonstrate signs of recognition. Alone neither being in Box B nor the chemical switch was effective in producing memory recall.

“We know from studies in both animals and humans that memories are not formed in isolation but are built up over years incorporating previously learned information,” Mayford said. “This study suggests that one way the brain performs this feat is to use the activity pattern of nerve cells from old memories and merge this with the activity produced during a new learning session.”

Future Manipulation of the Past

The team is now making progress toward more precise control that will allow the scientists to turn one memory on and off at will so effectively that a mouse will in fact perceive itself to be in Box A when it’s in Box B.

Once the processes are better understood, Mayford has ideas about how researchers might eventually target the perception process through drug treatment to deal with certain mental diseases such as schizophrenia and post traumatic stress disorder. With such problems, patients’ brains are producing false perceptions or disabling fears. But drug treatments might target the neurons involved when a patient thinks about such fear, to turn off the neurons involved and interfere with the disruptive thought patterns.

In addition to Mayford, other authors of the paper, “Generation of a Synthetic Memory Trace,” are Aleena Garner, Sang Youl Hwang, and Karsten Baumgaertel from Scripps Research, David Rowland and Cliff Kentros from the University of Oregon, Eugene, and Bryan Roth from the University of North Carolina (UNC), Chapel Hill.

This work is supported by the National Institute of Mental Health, the National Institute on Drug Abuse, the California Institute for Regenerative Medicine, and the Michael Hooker Distinguished Chair in Pharmacology at UNC.

About The Scripps Research Institute

The Scripps Research Institute is one of the world's largest independent, non-profit biomedical research organizations. Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neuroscience, and vaccine development, as well as for its insights into autoimmune, cardiovascular, and infectious disease. Headquartered in La Jolla, California, the institute also includes a campus in Jupiter, Florida, where scientists focus on drug discovery and technology development in addition to basic biomedical science. Scripps Research currently employs about 3,000 scientists, staff, postdoctoral fellows, and graduate students on its two campuses. The institute's graduate program, which awards Ph.D. degrees in biology and chemistry, is ranked among the top ten such programs in the nation. For more information, see www.scripps.edu.

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Friendly-to-a-Fault, Yet Tense: Personality Traits Traced in Brain

Scans Reveal How Genes Alter Circuit Hub to Shape Temperament – NIH Study

A personality profile marked by overly gregarious yet anxious behavior is rooted in abnormal development of a circuit hub buried deep in the front center of the brain, say scientists at the National Institutes of Health. They used three different types of brain imaging to pinpoint the suspect brain area in people with Williams syndrome, a rare genetic disorder characterized by these behaviors. Matching the scans to scores on a personality rating scale revealed that the more an individual with Williams syndrome showed these personality/temperament traits, the more abnormalities there were in the brain structure, called the insula CADC I & II Continuing Education

“Scans of the brain’s tissue composition, wiring, and activity produced converging evidence of genetically-caused abnormalities in the structure and function of the front part of the insula and in its connectivity to other brain areas in the circuit,” explained Karen Berman, M.D., of the NIH’s National Institute of Mental Health (NIMH).

Berman, Drs. Mbemda Jabbi, Shane Kippenhan, and colleagues, report on their imaging study in Williams syndrome online in the journal Proceedings of the National Academy of Sciences.

“This line of research offers insight into how genes help to shape brain circuitry that regulates complex behaviors – such as the way a person responds to others – and thus holds promise for unraveling brain mechanisms in other disorders of social behavior,” said NIMH Director Thomas R. Insel, M.D.

Williams syndrome is caused by the deletion of some 28 genes, many involved in brain development and behavior, in a particular section of chromosome 7. Among deficits characteristic of the syndrome are a lack of visual-spatial ability – such as is required to assemble a puzzle – and a tendency to be overly-friendly with people, while overly anxious about non-social matters, such as spiders or heights. Many people with the disorder are also mentally challenged and learning disabled, but some have normal IQs.

Previous imaging studies by the NIMH researchers found abnormal tracts of the neuronal fibers that conduct long-distance communications between brain regions -- likely resulting from neurons migrating to the wrong destinations during early development.

Evidence suggests that genes influence our temperament and the development of mental disorders via effects on brain circuits that regulate behavior. Yet direct demonstration of this in humans has proven elusive. Since the genetic basis of Williams syndrome is well known, it offers a unique opportunity to explore such effects with neuroimaging, reasoned the researchers.

Although the insula had not previously been studied in such detail in the disorder, it was known to be related to brain circuitry and certain behaviors, such as empathy, which is also highly prominent in the disorder. Berman and colleagues hypothesized that the insula’s anatomy, function and connectivity would predict patients’ scores for Williams syndrome-associated traits on personality rating scales. Fourteen intellectually normal Williams syndrome participants and 23 healthy controls participated in the study.

Magnetic resonance imaging (MRI) revealed that patients had decreased gray matter – the brain’s working tissue – in the bottom front of the insula, which integrates mood and thinking. By contrast, they had increased gray matter in the top front part of the insula, which has been linked to social/emotional processes.

Diffusion tensor imaging, which by detecting the flow of water in nerve fibers can identify and measure the connections between brain areas, showed reduced white matter – the brain’s long-distance wiring – between thinking and emotion hubs.

Tracking radioactively-tagged water in order to measure brain blood flow at rest, via positron emission tomography (PET), exposed activity aberrations consistent with the MRI abnormalities. The PET scans also revealed altered functional coupling between the front of the insula and key structures involved in thinking, mood and fear processing. These structural and functional abnormalities in the front of the insula correlated with the Williams syndrome personality profile.

“Our findings illustrate how brain systems translate genetic vulnerability into behavioral traits,” explained Berman.

The severity of abnormalities in insula (red structure near bottom of brain) gray matter volume (left) and brain activity (right) predicted the extent of aberrant personality traits in Williams syndrome patients – as reflected in their scores (red dots) on personality rating scales (WSPP).

Source: Karen Berman, M.D., NIMH Clinical Brain Disorders Branch


Long distance connections, white matter, between the insula and other parts of the brain are aberrant in Williams syndrome. Neuronal fibers of normal controls (left) extend further than those of Williams syndrome patients (right). Picture shows diffusion tensor imaging data from each patient superimposed on anatomical MRI of the median patient.

Source: Karen Berman, M.D., NIMH Clinical Brain Disorders Branch


Reference:

The Williams syndrome chromosome 7q11.23 hemideletion confers hypersocial, anxious personality coupled with altered insula structure and function. Jabbi M, Kippenhan JS, Kohn P, Marenco S, Mervis CB, Morris CA, Meyer-Lindenberg A, Berman KF. Proc Natl Acad Sci U S A. 2012 Mar 12. [Epub ahead of print] PMID: 22411788

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The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit the NIMH website.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit the NIH website.

Possible Causes of Sudden Onset OCD in Kids Broadened

NIH Immune-Based Treatment Study Underway

Criteria for a broadened syndrome of acute onset obsessive compulsive disorder (OCD) have been proposed by a National Institutes of Health scientist and her colleagues. The syndrome, Pediatric Acute-onset Neuropsychiatric Syndrome (PANS), includes children and teens that suddenly develop on-again/off-again OCD symptoms or abnormal eating behaviors, along with other psychiatric symptoms – without any known cause nursing ceus

PANS expands on Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcus (PANDAS), which is limited to a subset of cases traceable to an autoimmune process triggered by a strep infection. A clinical trial testing an immune-based treatment for PANDAS is currently underway at NIH and Yale University (see below).

“Parents will describe children with PANS as overcome by a ‘ferocious’ onset of obsessive thoughts, compulsive rituals and overwhelming fears,” said Susan Swedo, M.D., of the NIH’s National Institute of Mental Health (NIMH), who first characterized PANDAS two decades ago. “Clinicians should consider PANS when children or adolescents present with such acute-onset of OCD or eating restrictions in the absence of a clear link to strep.”

Swedo, James Leckman, M.D., of Yale University, and Noel Rose, M.D., Ph.D. of Johns Hopkins University, propose working criteria for PANS in February 2012 in the open source journal Pediatrics & Therapeutics.

“As the field moves toward agreement on this broadened syndrome, affected youth will be more likely to receive appropriate care, regardless of whether they are seen by a neurologist, pediatrician or child psychiatrist,” said NIMH Director Thomas R. Insel, M.D.

Differing causes sharing a “common presentation”

The PANS criteria grew out of a PANDAS workshop convened at NIH in July 2010, by the NIMH Pediatric and Developmental Neuroscience Branch, which Swedo heads. It brought together a broad range of researchers, clinicians and advocates. The participants considered all cases of acute-onset OCD, regardless of potential cause.

Clinicians reported that evaluations of more than 400 youth diagnosed with PANDAS confirmed that affected boys outnumbered girls 2:1, with psychiatric symptoms, always including OCD, usually beginning before 8 years.

Although debate continues about the fine points, the field is now of one mind on the core concept of “acute and dramatic” onset of a constellation of psychiatric symptoms. There is also broad agreement on the need for a “centralized registry” that will enable the research community to analyze evidence from studies that will eventually pinpoint causes and treatments. Such a registry is currently under development by members of the International Obsessive Compulsive Foundation (IOCDF).

Since a diagnosis of PANS implies no specific cause, clinicians will have to evaluate and treat each affected youth on a case-by-case basis.

“PANS will likely turn out to include a number of related disorders with different causes that share a common presentation,” explained Swedo.

The authors propose that a patient must meet 3 diagnostic criteria for a diagnosis of PANS:
1.Abrupt, dramatic onset of OCD or anorexia.
2.Concurrent presence of at least two additional neuropsychiatric symptoms with similarly severe and acute onset. These include: anxiety; mood swings and depression; aggression, irritability and oppositional behaviors; developmental regression; sudden deterioration in school performance or learning abilities; sensory and motor abnormalities; somatic signs and symptoms.
3.Symptoms are unexplainable by a known neurologic or medical disorder.

Among the wide range of accompanying symptoms, children may appear terror stricken or suffer extreme separation anxiety, shift from laughter to tears for no apparent reason, or regress to temper tantrums, “baby talk” or bedwetting. In some cases, their handwriting and other fine motor skills worsen dramatically. Leckman’s team at the Yale Child Study Center is in the process of developing assessment tools for diagnosing the syndrome.

PANDAS treatment study targets errant antibodies

Meanwhile, Swedo, Leckman, and Madeleine Cunningham of the University of Oklahoma, and colleagues, are collaborating on a new, multi-site placebo-controlled study, testing the effectiveness of intravenous immunoglobulin (IVIG) for reducing OCD symptoms in children with PANDAS.

Previous human and animal research suggested mechanisms by which strep-triggered antibodies mistakenly attack specific brain circuitry, resulting in obsessional thoughts and compulsive behaviors.

“Strep bacteria has evolved a kind of camouflage to evade detection by the immune system,” Swedo explained. “It does this by displaying molecules on its cell wall that look nearly identical to molecules found in different tissues of the body, including the brain. Eventually, the immune system gets wise to this ‘molecular mimicry,’ recognizes strep as foreign, and produces antibodies against it; but because of the similarities, the antibodies sometimes react not only with the strep, but also with the mimicked molecules in the human host. Such cross-reactive ‘anti-brain’ antibodies can cause OCD, tics, and the other neuropsychiatric symptoms of PANDAS.”

IVIG, a medication derived from normal antibodies, neutralizes such harmful antibodies, restoring normal immune function. It is used to treat other autoimmune illnesses and showed promise in a pilot study with PANDAS patients.

“We predict that IVIG will have striking benefits for OCD and other psychiatric symptoms, and will prove most effective for children who show high levels of anti-brain antibodies when they enter the study,” said Swedo.

Prospective study participants are first screened by phone by investigators at the NIH or the Yale Child Study Center. Those who meet eligibility requirements are then randomized to receive either active IVIG or a placebo procedure during a brief inpatient stay at the NIH Clinical Center. The researchers remain blind to which children received the active medication; after 6 weeks of placebo control, they give any children whose symptoms fail to improve the option to receive open-label active treatment.

In addition to assaying for antibodies that attack brain cells, the researchers use magnetic resonance imaging to see if the treatment reduces inflammation in an area of the brain known as the basal ganglia, which is thought to be the target of the errant antibodies. They also analyze levels of immune system chemical messengers (cytokines) in cerebrospinal fluid and blood – with an eye to identifying biomarkers of disease activity and potential predictors of treatment response.

The study was launched with support from the NIH Clinical Center’s Bench to Bedside program, which encourages such intramural-extramural collaborations in translational science.


Children with PANS and PANDAS sometimes experience sudden loss of fine motor skills.
Source: Susan Swedo, M.D., NIMH Pediatric and Developmental Neuroscience Branch

Reference:

Swedo, SE, Leckman JF, Rose, NR. From Research Subgroup to Clinical Syndrome: Modifying the PANDAS criteria to describe PANS (Pediatric Acute-onset Neuropsychiatric Syndrome). Feb 2012, Pediatrics & Therapeutics.

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The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit the NIMH website.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit the NIH website.

Linked Brain Centers Mature in Sync

Imaging Reveals Underlying Unity Between Brain Structure and Development

Long-term neuroimaging studies show for the first time that areas of the brain that are wired together structurally and functionally also tend to mature in tandem over the course of development. The finding adds a new dimension to a picture that is emerging of how structure, function, and development of the brain are intertwined ceus for mfts

Background

Studies of brain development have shown that growth across the brain is not steady and uniform; some areas mature more quickly than others. These studies to date have not, however, examined whether areas of the brain that are linked functionally also develop in a coordinated way. It’s a challenging question because the developmental changes in brain anatomy that can be detected by neuroimaging unfold very slowly. Also, tempos of anatomical change differ from person to person, so comparing brain dimensions in different individuals at the same age can be misleading. The only way to approach this question is to track patterns of growth in the same individuals over many years.

This Study

To address this question, Armin Raznahan and colleagues at NIMH took advantage of a dataset that is unique in the world, consisting of records of brain growth measured by magnetic resonance imaging (MRI) of individuals from childhood to young adulthood. They studied changes in thickness of the outer layer of the brain, the cortex. In order to look for correlated anatomical change in connected parts of the brain, these investigators used records of cortical thickness from 108 individuals from ages 9 to 22. They focused on a well-defined and documented brain circuit: the default mode network or DMN. The DMN, a network identified by functional brain imaging, consists of nodes, or centers, in the brain that are active when someone’s mind is at rest, but quiet when the mind is focused on a task. In addition to tracking growth in the DMN, the NIMH investigators also looked at patterns of growth on the right and left side of the brain. There are extensive neuronal connections between the right and left hemispheres of the brain. Activation tends to be symmetrical and simultaneous within analogous parts on either side of the brain.

Results showed that there was a marked correlation in the rates of cortical thickness change between different points within the DMN when compared with the average correlation among thousands of other points across the brain. A similar pattern was seen among points in a second “task positive” network that is active while someone is carrying out goal-directed tasks; rates of change in cortical thickness within this second network also showed a pattern of coordinated maturing. Parts of the cortex involved in the integration and processing of incoming information and responses—the association cortex—were most likely to show correlated anatomical change with broad areas of the cortex. Similar correlations in change were not seen among parts of the cortex involved primarily in sensory input.

Correlations in anatomical change were also apparent between analogous centers on the right and left side of the brain, paralleling the symmetry in activation of these areas. Finally, the investigators looked at an area of the cortex (the frontopolar cortex) for which previous work had shown differences in the rate of maturation between males and females. This study found the same difference between males and females in maturation rate in this area. In addition, there were differences between the sexes in the degree to which thickness change in this area showed coordination with that of other areas of the cortex.

The coloring in this MRI scan reflects the extent to which changes in various areas of the maturing cortex correlate with similar changes over time in the default mode network, a network in the brain that is active when a person is at rest. Red indicates the highest degree of correlation—blue is the lowest. (Colors indicate correlation with one “node” within the default mode network, indicated by a circle in the image.)

Source: Armin Raznahan, Child Psychiatry Branch, National Institute of Mental Health


Significance

Neuroscientists are increasingly viewing the brain in terms of the development and function of neural circuits. According to Dr. Raznahan, this approach represents a sea change compared to the earlier emphasis on studying individual brain areas. In addition to the work reported here, recent studies of gene expression (activity) patterns in the brain suggest that genes that have roles in laying down connections between functionally related areas are also especially active during development.

In a high percentage of cases of mental disorders, the first symptoms emerge during youth; this is one piece of evidence that mental illnesses are disorders of development. Research on the relationships between brain connectedness and structural maturation can help provide a basis for future studies of how disruptions in the laying down of neural circuits in the brain during development can shape the structure and function of the adult brain and set the stage for mental illness. The authors point out in their paper that disorders that disrupt functional connections might also alter structural brain development. Comparing how development unfolds in individuals with and without disorders of mental health can offer clues to causes and targets for therapies. Finally, the findings on sex differences reported here can lend insight into the types of behavior seen during adolescence, especially risk-taking.

Reference

Raznahan, A., Lerch, J.P., Lee, N., Greenstein, D., Wallace, G., Stockman, M., Clasen, L., Shaw, P., and Giedd, J. Patterns of coordinated anatomical change in human cortical development: a longitudinal neuroimaging study of maturational coupling. Neuron. 2011 Dec 8;72(5):873-84.

Computer-Based Treatment Eases Anxiety Symptoms in Children

Small Clinical Trial Supports Larger Scale Testing

A computer-based training method that teaches a person with anxiety to shift attention away from threatening images reduced symptoms of anxiety in a small clinical trial in children with the condition. The results of this first randomized clinical trial of the therapy in children with anxiety suggest that the approach warrants more extensive testing as a promising therapy.

Background

As many as a quarter of 13- to 18-year-olds have met the criteria for an anxiety disorder at some point. Currently available treatments—including cognitive behavioral therapy and medication—relieve symptoms of anxiety in about 70 percent of children treated. Most children with clinical anxiety do not receive treatment, partly because of difficulties in access to care, including distance and financial resources. Scientists are searching for additional approaches, including therapies that do not involve medication with its associated side effects counselor ceus

A treatment called attention bias modification (ABM) has emerged from the observation that people with anxiety unconsciously pay more attention than others to anything that seems threatening. One way of detecting such a bias is a dot probe test. In the test, people view a computer screen on which angry and neutral faces are flashed briefly, adjacent to each other. After the faces disappear, a test image of dots appears where either one or the other face was, and the person has to respond by pushing a button. People with anxiety consistently respond more quickly to dots that appear where the angry face was located.

ABM presents patients with an exercise similar to the dot probe test, but the dots always appear where the neutral face was, and thus consistently draw the attention of the participant to this non-threatening image. A recent meta-analyses of ABM in adults by some of the same investigators who carried out this work suggested its potential as a treatment.

This Study

Researchers at Tel Aviv University (TAU) in Israel carried out a clinical trial on ABM as an outcome of a three-year collaboration with scientists at the National Institute of Mental Health and the University of Maryland, College Park, Maryland. Yair Bar-Haim of TAU led the study, which appears in the American Journal of Psychiatry. The study enrolled 40 children, 8 to 14 years old, who had sought help for anxiety. For children receiving ABM, after faces appeared on a screen, two dots appeared on the screen; children had to determine whether the dots were side by side, or one above the other. In every case, dots appeared only where the neutral face had been. There were also two control groups: in the first, dots appeared equally frequently where angry and neutral faces appeared; in the second, the only faces that appeared throughout were neutral, so the dots always appeared in the location of a neutral face. The object of the second control group was to help confirm that any therapeutic effect was from the ABM training, and not from desensitizing the children to threatening faces. Children in the study were randomly assigned to receive treatment, or to be in one of two control groups. All children had four training sessions over 4 weeks, with 480 dot-probe trials per session.

Although the trial was small, there was a “reasonably robust” decrease in the severity of anxiety, according to the authors. Following ABM, both the number and severity of symptoms were reduced.

Significance

An important feature of ABM, says NIMH author Daniel Pine, is that it addresses the fundamental neurological function underlying anxiety: attention. Changes in attention happen very quickly—in milliseconds. “We know from neuroscience that if you want to change behaviors that happen very quickly, you have to practice. You can’t just tell someone how to drive, or throw a ball. You have to practice,” says Pine.

Longitudinal studies that follow children into adulthood suggest that most chronic mood and anxiety disorders in adults begin as high levels of anxiety in children. In fact, childhood anxiety is as important in predicting adult depression as it is for adult anxiety. The ability to influence attention biases early in development might provide a powerful means of prevention for both of these disorders later in life. The approach requires no medication and in practical terms, the computer-based nature of ABM lends itself to large-scale dissemination, in a medium children are comfortable with. Larger-scale trials will be able to provide more information on the efficacy of the treatment in children and how it works to reduce symptoms of anxiety.

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Reference

Eldar, S., Apter, A., Lotan, D., Perez-Edgar, K., Naim, R, Fox, N.A., Pine, D.S., and Bar-Haim, Y. American Journal of Psychiatry. 2012 Feb 1;169(2):213-30.

NIH-funded study defines treatment window for HIV-positive children infected at birth

HIV-positive children older than 1 year who were treated after showing moderate HIV-related symptoms did not experience greater cognitive or behavior problems compared to peers treated when signs of their infection were still mild, according to a study funded by the National Institutes of Health. But both groups of HIV-positive children lagged behind HIV-negative children in these areas, suggesting that the first year of life may present a critical treatment window for minimizing impairments in brain development due to HIV ceus for social workers

“Especially in children, we must always weigh the benefits of early treatment for HIV infection against the risks, which can range from long-term toxicity or drug resistance to scarcity of the supply of medications in regions with limited health care resources,” noted Thomas R. Insel, M.D., director of the National Institute of Mental Health (NIMH), part of NIH. “Knowing the parameters of appropriate care can assist providers in making difficult treatment decisions for this vulnerable population.”

As part of the NIH-funded Pediatric Randomized Early vs. Deferred Initiation in Cambodia and Thailand (PREDICT) trial, researchers assessed 284 HIV-positive children ages 1-12 who had mildly weakened immune systems but no severe symptoms of HIV infection. The children were randomly assigned to receive treatment immediately or to have treatment deferred until they began to show moderate signs of HIV-related illness.

At follow-up almost 3 years later, very few children in either group had progressed to AIDS. Children who received deferred treatment performed as well as those treated immediately on tests measuring intelligence, memory, and hand-eye coordination. However, both groups scored lower on these tests and had more behavior problems than HIV-negative children who took part in the PREDICT study. Though the study did not assess the children’s actual educational needs, the difference in test scores would place many HIV-positive children at a lower functional level than their HIV-negative peers, indicating they may need additional resources or special schooling.

“These findings suggest that the window of opportunity for avoiding neurocognitive deficits by treating HIV infection may only occur earlier, in infancy,” noted Pim Brouwers, Ph.D., who oversees NIMH-funded research on HIV/AIDS among children and adolescents and also served as a co-investigator on neurodevelopmental outcomes of the PREDICT study.

The results of the PREDICT study were presented at the 19th Conference on Retroviruses and Opportunistic Infections at the Washington State Convention Center in Seattle. The PREDICT study was sponsored by the National Institute of Allergy and Infectious Diseases, with further neurological analysis of the study participants supported by NIMH and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, all parts of NIH.

The ClinicalTrials.gov identifier for the PREDICT study is NCT00234091.

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The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit the NIMH website.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit the NIH website.

Antidepressant-suicide link in youths absent in new analysis

Drugs also found effective in reducing suicidal behavior in adults, elderly

In 2004, concerns about antidepressant drugs increasing suicidal thoughts and behaviors in young patients prompted the FDA to issue a rare "black box warning." Now, a new analysis of clinical trial data finds that treatment with the antidepressant fluoxetine did not increase — or decrease — suicidality in children compared to placebo treatment.

An analysis built on data from 41 trials and more than 9,000 patients also found that two different popular antidepressant drugs were effective at reducing suicidal behavior and depressive symptoms in adult and geriatric patients. The findings are published online Feb. 6 in the journal Archives of General Psychiatry Alcoholism and Drug Abuse Counselors Continuing Education


The failure to replicate the link between antidepressants and suicide should reassure doctors about prescribing these drugs to depressed patients, said first author Robert Gibbons, PhD, professor of medicine, health studies, and psychiatry at the University of Chicago Medicine.

"The key finding here, when we re-analyze all the patient-level longitudinal records in these studies, is that antidepressants neither increase nor decrease suicidal thoughts or behavior in children," Gibbons said.

The FDA decision on the black box warning was based on retrospective data from 25 clinical trials of newer antidepressant medications, including the serotonin reuptake inhibitor drug fluoxetine, marketed as Prozac or Sarafem. A meta-analysis combining adverse event data (primarily based on self reports of suicidal thoughts) from the trials revealed a small, but significant, increase in suicidal thoughts and behavior in children and young adults up to the age of 25.

For the new analysis, Gibbons and colleagues from the University of Illinois at Chicago, the University of Miami and Columbia University obtained individual-level, longitudinal clinical trial data — some of it unpublished — from pharmaceutical producers and a large National Institute of Mental Health collaborative study of fluoxetine and venlafaxine. The data included weekly screening of each trial subject for depression and suicidal thoughts, allowing researchers to compare the effect of drug or placebo over time on these measures.

In the analysis of the adult and geriatric trials testing fluoxetine or venlafaxine, both antidepressants were found effective in reducing suicide risk and depression symptoms. These two effects were also found to be statistically associated, suggesting that the drugs reduced suicidality by alleviating depression. Therefore, Gibbons said, effective treatment of major depressive disorder is important for a patient's safety.

"Basically, the results say that the mechanism by which the antidepressants affect suicide rates is by decreasing depression," Gibbons said. "It follows that if a treatment is not working for an individual, the risk for suicidal behavior and perhaps worse remains high."

To analyze the effects of antidepressants in children, the researchers used four trials of fluoxetine, which until recently was the only antidepressant approved for pediatric use. Once again, a reduction in depressive symptoms was observed in the drug-treated population compared to placebo. However, no significant change in suicide risk was detected between the two patient groups.

"I think that this paper supports the general idea that the effects of antidepressants in kids and adults are not really the same, since we don't see anything but beneficial effects of antidepressants in adults and geriatrics," Gibbons said. "In kids, we don't see a harmful effect, but we do see a disassociation between the beneficial effects on depression and the potential beneficial effect on suicide."

"This raises continued questions about what's going on in children," he continued. "Maybe children think about suicide in part because of depression, but also maybe due to other reasons not related to depression that are not affected by antidepressants."

Gibbons, who sat on the Food and Drug Administration panel that considered placing the black box warning on antidepressants, said he hoped the new results would reassure clinicians about the safety of the drugs. Previous research by his group found that the addition of the warning significantly reduced antidepressant prescriptions to both children and adults and correlated with a spike in suicide rates.

"I hope that the warnings will not prevent depressed children and adults from getting treatment for depression," Gibbons said. "The greatest cause of suicide is untreated or undiagnosed depression. It's very important that this condition be recognized and appropriately treated and not discarded because doctors are afraid to be sued."


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The paper, "Suicidal Thoughts and Behavior with Antidepressant Treatment," will be published online February 6th by Archives of General Psychiatry. In addition to Gibbons, authors include C. Hendricks Brown of the University of Miami, Kwan Hur of the University of Chicago, John M. Davis of the University of Illinois at Chicago, and J. John Mann of Columbia University. Funding for the research was provided by the National Institute of Mental Health and the Agency for Healthcare Research and Quality.

For more news from the University of Chicago Medical Center, follow us on Twitter at @UChicagoMed, or visit our Facebook page at facebook.com/UChicagoMed, our research blog at sciencelife.uchospitals.edu, or our newsroom at uchospitals.edu/news.