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Researchers Evaluated Intervention Focusing on Preventive Health and Future Goal Attainment, Not Moral Choices

Teens who received a behavioral intervention centered on abstinence were more likely to delay first sexual contact than teens who received a control intervention focusing on general health promotion, according to an NIMH-funded study. Though differing from federally funded abstinence-only programs, the researchers describe how an abstinence-based intervention may help delay sexual activity among adolescents in the February 2010 issue of the Archives of Pediatrics and Adolescent Medicine.

Background

Sexually active teens face a broad range of potentially negative outcomes related to HIV and other sexually transmitted infections (STIs) and unplanned pregnancies. In particular, African American teens experience these outcomes at much higher rates than their peers.^1,2,3,4

Studies have shown that behavioral interventions can reduce behaviors related to HIV/STI risk. However, U.S. policymakers do not agree on which type of intervention is most appropriate or most effective for use with teens. Many states have adopted abstinence-only programs in their school systems, which not only lack adequate research showing their efficacy, but have been criticized for inclusion of inaccurate information, negative portrayal of sex, and a moralistic tone.

To address this issue, John B. Jemmott, III, Ph.D., of the University of Pennsylvania, and colleagues recruited 662 students in grades 6 and 7 (ages 10—15) from four, public middle schools serving low-income, African American, urban communities. They were randomly assigned to one of five behavioral interventions:

• Abstinence—based-designed to strengthen beliefs supporting abstinence (e.g., prevent pregnancy and STIs, foster attainment of future goals) and increase skills for resisting pressure to have sex. In addition, the intervention providers were expressly instructed not to discredit use of condoms and to correct false beliefs about the effectiveness of condoms in preventing STIs.
• Safer sex—designed to strengthen beliefs supporting condom use and increase skills to negotiate condom use and use condoms properly.
• 12-hour comprehensive—combined the design and aims of the abstinence-based and safer sex interventions.
• 8-hour comprehensive—provided an abbreviated version of the 12-hour comprehensive intervention. This allowed the researchers to assess whether any benefits of the longer comprehensive intervention could be attributed to the students spending more time in the intervention.
• Health promotion—designed to increase knowledge and motivation regarding general healthful behaviors, such as following a balanced diet and discouraging cigarette smoking. This intervention served as the control condition.

All interventions were designed to increase knowledge about HIV and STIs except for the health promotion intervention. Four of the interventions were provided over two 4-hour weekend sessions (eight hours total). The 12-hour comprehensive intervention was provided over three 4-hour weekend sessions. Participants completed questionnaires at the start of the study, immediately after the last intervention session, and every three months afterwards for up to two years.

In addition, the researchers tested an intervention maintenance program. This program, which was tested in half of the participants, consisted of two 3-hour booster sessions given at six weeks and three months after completion of the initial intervention; six issues of a newsletter; and six brief, one-on-one counseling sessions with the original facilitator provided over a 21-month period.

Results of the Study

At the study’s outset, 23.4 percent of the teens reported that they were already sexually active.

At the two-year follow-up, students who received the abstinence-based intervention and had not been sexually active at the study’s outset were significantly less likely to have initiated sexual activity (33 percent) or to have recently had sex (20 percent) compared to the those who received the health promotion intervention; among students in the control group with no prior sexual activity, 49 percent reported first sexual contact and 29 percent recently had sex. None of the other interventions had a significant effect on the initiation of sexual activity when compared to the control condition. The researchers did not compare the four HIV-prevention interventions with each other on any outcome measures.

Students who received either the 8-hour or 12-hour comprehensive intervention were significantly less likely to report having multiple partners (about 9 percent in each group) than those in the control group (14 percent).

The intervention maintenance program modestly enhanced the effectiveness of the abstinence-based and 12-hour comprehensive interventions at reducing multiple partners, but showed no other benefits.

None of the interventions significantly affected consistent condom use.

Significance

According to the researchers, their study shows that a theory-based, abstinence-only intervention may be an effective method for delaying sexual initiation in middle school students who are not already sexually active. They also emphasized that the abstinence-based intervention used in this study was not designed to meet federal criteria for abstinence-only programs. Thus, it is not subject to the criticisms those programs face. Similarly, the results of the abstinence-based intervention cannot be generalized to all abstinence programs or to all populations.

Also of note, the study did not support a common concern about abstinence-only interventions—that they reduce the likelihood of condom use among teens. Similarly, the other behavioral interventions did not increase sexual activity when compared to the control group, a concern expressed by some regarding comprehensive sex education interventions.

The researchers further cautioned that their findings do not suggest that this or other abstinence-based interventions are the best approach for all adolescents. However, the use of evidence-based abstinence interventions may be an effective means of delaying sexual initiation in some communities for whom abstinence is the only acceptable approach to sex education.

What’s Next

Further work is needed to determine whether the interventions assessed in this study are effective for other teen populations and to determine when they affect biological outcomes such as STI or pregnancy rates. Different methods may be more effective in addressing the specific needs of older youth or teens in committed relationships, for example. The researchers also expressed the need for additional studies to identify ways of prolonging the effectiveness of HIV/STI interventions.

Reference

Jemmott JB, Jemmott LS, Fong GT. Efficacy of a Theory-Based Abstinence-Only Intervention over 24 Months: A Randomized Controlled Trial with Young Adolescents. Arch Pediatr Adolesc Med. 2010 Feb;164(2):152-9.

¹ Centers for Disease Control and Prevention. Sexually transmitted disease surveillance 2006. Atlanta, GA: Division of STD Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, November 2007. Downloaded February 22. 2008 at http://www.cdc.gov/std/.

² Centers for Disease Control and Prevention. HIV/AIDS surveillance in adolescents and young adults (through 2005). Atlanta, GA: Division of HIV/AIDS, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, October 23, 2007. Downloaded February 19, 2008 at www.cdc.gov/hiv/topics/surveillance/resources/slides/adolescents/index.htm.

³ Miller WC, Ford CA, Morris M, Handcock MS, Schmitz, JL, Hobbs MM, Cohen MS, Harris KM, Udry JR. Prevalence of chlamydial and gonococcal infections among young adults in the United States. JAMA. 2004;291:2229-2236.

⁴ Ventura SJ, Abma JC, Mosher WD, Henshaw SK. Recent trends in teenage pregnancy in the United States, 1990-2002. Health E-Stats. Hyattsville, MD: National Center for Health Statistics. Released December 2006. Downloaded June 6, 2007 at http://www.csctulsa.org/images/Teen%20Pregnancy%20Trends%201990-2002.pdf

Amidst the background hum of electrical signaling generated by neurons in the brain, scientists have found that local groups of neurons, firing in coordination, sometimes create a signal that is mirrored instantaneously and precisely by other groups of neurons across the brain.  These transient episodes of coherence across different parts of the brain may be an electrical signature of thought and actions.

Background

One of the goals of neuroscience research is to identify how thoughts and actions are encoded in the activity of neurons.  A challenge has been to extract meaningful patterns from the ongoing tumult of electrical activity in the brain.  This global electrical activity is built from the firing of individual neurons.  A single neuron responds to a stimulus in an all or nothing manner—if the stimulus reaches a certain threshold, the neuron “fires” an electrical signal.  Groups of neurons firing in a coordinated way create a local electrical field that is in itself a signal that can vary in pattern.  These local field potentials (LFPs) have been a target of research.

This Study

In this research, Dietmar Plenz and colleagues at NIMH and Duke University pinpointed LFPs in the cortex that surpassed a minimal size threshold, and then searched the rest of the cortex to see what was occurring at the same time.  In each case, they found other answering LFPs across the brain that mimicked each other with high precision: there was no degradation or loss of power (amplitude) in the signal.  Unlike what is observed after dropping a stone in a pond—with wavelets getting smaller farther from the stone—the intensity of the LFPs was the same across the brain.  The investigators call these LFPs coherence potentials.  Although LFPs that occur during these transient episodes of coherence are identical to each other, they are also multidimensional and potentially infinitely diverse, providing a means to encode information.  Most LFPs do not reach the threshold that characterizes a coherence potential but with those that do, propagation of the LFPs across the brain is extraordinarily rapid.  The authors note that the rapid dispersion of such a signal mimics the spread of ideas and behaviors in social networks; a sufficiently provocative idea can spread very swiftly through a population.

Significance

Coherence potentials simultaneously engage groups of neurons in different parts of the brain with diverse functions.  This is consistent with the multi-faceted nature of mental associations and memories—a memory focused on a person or object might conjure various kinds of sensations and thoughts—visual, tactile, auditory, and emotional, for example.

These findings emerged from recent work that demonstrated that, like other systems in nature, the cortex exists at a critical state between stability and instability.  A characteristic of this state in the brain is the presence of neuronal avalanches—if a stimulus reaches a certain threshold, it will set off cascades of neuronal firing.  This dynamic is analogous to when the slope of a sandpile reaches a point at which adding one more grain will trigger an avalanche.  The adherence of the cortex to this critical state ensures that the brain can respond to a wide range of stimuli, but not lapse into a chaos of excess activity (such as the too-synchronous firing during epilepsy).  Coherence potentials emerge predominantly when the cortex is critical, that is, when it displays neuronal avalanches.  Nudging the cortex away from this point, by inhibiting neuronal signaling with medications for example, disrupts these dynamical patterns.

What’s Next

Coherence potentials were present in cells in culture as well as awake monkeys, a robust demonstration that they occur in the functioning cortex.  Future studies will be aimed at monitoring coherence potentials in the context of behavioral function with the ultimate aim of making a connection between specific coherence potentials and behaviors.

Reference

Thiagarajan, T.C., Lebedev, M.A., Nicolelis, M.A., and Plenz, D. Coherence potentials: loss-less, all-or-none network events in the cortex.  PLoS Biology 2010, doi:10.1371/journal.pbio.1000278.

Increased Risk May Stem From Variation in Gene On/Off Switch

Researchers, for the first time, have pinpointed a genetic hotspot that confers risk for both bipolar disorder and depression. People with either of these mood disorders were significantly more likely to have risk versions of genes at this site than healthy controls. One of the genes, which codes for part of a cell’s machinery that tells genes when to turn on and off, was also found to be over-expressed in the executive hub of bipolar patients’ brains, making it a prime suspect. The results add to mounting evidence that major mental disorders overlap at the molecular level.

“People who carry the risk versions may differ in some dimension of brain development that may increase risk for mood disorders later in life,” explained Francis McMahon, M.D., of the NIMH Mood and Anxiety Disorders Program, who led the study.

McMahon and an international team of investigators, supported, in part by NIMH, report on the findings of their genome-wide meta-analysis online January 17, 2010 in the journal Nature Genetics.

Background

Major mood disorders affect 20 percent of the population and are among the leading causes of disability worldwide. It’s long been known that bipolar disorder and unipolar depression often run together in the same families, hinting at some shared lineage. Yet, until now, no common genes or chromosomal locations had been identified.

McMahon and colleagues analyzed data from five different genome-wide association studies (GWAS) totaling more than 13,600 people, and confirmed their results in 3 additional independent samples totaling 4,677 people.

Findings of This Study

Genetic variations on Chromosome 3 were significantly associated with both mood disorders. The suspect gene, called PBRM1, codes for a protein critical for chromatin remodeling, a key process in regulating gene expression. A neighboring gene is involved in the proliferation of brain stem cells.

The researchers pinpointed a “protective” version of the PBRM1 gene that is carried by 41 percent of healthy controls, but only 38 percent of people with bipolar and unipolar depression. The risk version was found in 62 percent of mood disorder cases and 59 percent of controls. The researchers also showed that PBRM1 is expressed more in the prefrontal cortex of people with bipolar disorder than in controls.

Significance

Since mood disorders likely involve altered gene expression during brain development and in response to stress, PBRM1’s profile makes it a good potential candidate gene. This first genetic evidence of unipolar/bipolar overlap is also the first significant genome-wide association with any psychiatric illness in the Chromosome 3p region.

However, the findings underscore limitations of the GWAS approach, which looks for connections to gene versions that are common in the population. Having one copy of this risk variant increases vulnerability for developing a mood disorder by a modest 15 percent. Why do some people with this variant — and presumably other, yet to be discovered, shared risk genes — develop bipolar disorder while others develop unipolar depression or remain healthy? Environmental influences and epigenetic factors may be involved, suggest the researchers, who note that “genetic association findings so far seem to account for little of the inherited risk for mood disorders.”

“Our results support the growing view that there aren’t common genes with large effects that confer increased risk for mood disorders,” said McMahon. “If there were, in this largest sample to date, we would have found them. The disorders likely involve many genes with small effects — and different genes in different families — complicating the search. Rarer genes with large effects may also exist.”

What’s Next?

Ultimately, findings such as these may lead to identification of common biological pathways that may play a role in both unipolar and bipolar illness and suggest strategies for better treatment, said McMahon. The results add to other evidence of overlap that is spurring a new NIMH initiative to make sense of research findings that don’t fit neatly into current diagnostic categories. See: Genes and Circuitry, Not Just Clinical Observation, to Guide Classification for Research.

Bipolar disorder and unipolar depression often run in the same families, as this pedigree diagram illustrates. The new study is the first to trace both illnesses to a shared chromosomal hotspot.

Source: NIMH Genetics Initiative Bipolar Disorder Consortium

Reference

Meta-analysis of genome-wide association data identifies a risk locus for major mood disorders on 3p21.1.the Bipolar Disorder Genome Study (BiGS) Consortium, McMahon FJ, Akula N, Schulze TG, Muglia P, Tozzi F, Detera-Wadleigh SD, Steele CJ, Breuer R, Strohmaier J, Wendland JR, Mattheisen M, Mühleisen TW, Maier W, Nöthen MM, Cichon S, Farmer A, Vincent JB, Holsboer F, Preisig M, Rietschel M. Nat Genet. 2010 Jan 17. [Epub ahead of print]PMID: 20081856

Samples included in the meta-analysis:

dbGaP National Institute of Mental Health bipolar disorder
Genetic Association Information Network MDD
Wellcome Trust Case Control Consortium
German sample
Systematic Treatment Enhancement Program for Bipolar Disorder

A new NIMH-funded grant aims to increase suicide detection and prevention efforts among patients who present with suicide risk factors in hospital emergency departments.

The Emergency Department Safety Assessment and Follow-up Evaluation (EDSAFE) trial will be coordinated by the Emergency Medicine Network (EMNet), which is based at Massachusetts General Hospital. The team of researchers will be led by Edwin D. Boudreaux, Ph.D., of the University of Massachusetts, Carlos A. Camargo, Jr., M.D., DrPH, of Massachusetts General Hospital and Harvard Medical School, and Ivan Miller, Ph.D., of Butler Hospital in Providence, RI. The project is expected to enroll nearly 1,420 participants over five years.

EDSAFE will be conducted in three phases. The first phase will assess treatment as usual (TAU) for patients. TAU typically consists of evaluating suicidal risk only among those emergency department patients who have psychiatric risk factors such as depression, suicidal thinking or behavior (ideation), or substance abuse. Often these patients are put under observation while at the hospital and are evaluated by a mental health provider. They also may be referred to a mental health professional outside the hospital, but few receive adequate follow-up care after they are discharged. During the second phase, a universal screening process will be tested in which all patients, regardless of whether they exhibit typical risk factors for suicide, will be screened for suicidal ideation. The researchers will compare universal screening with TAU to determine how well each detects suicidal patients.

During the third phase, a more intensive intervention that includes screening, brief counseling, an evaluation by a mental health provider, referral to outpatient care and other components will be implemented. Patients will then receive follow-up phone counseling. The intensive intervention will be compared to TAU and to universal screening.

The study will be conducted at eight sites throughout the nation and is set to begin in June 2010.

More Receive Psychotherapy than Medication; Study Provides New Detail on Disparities

Overall, only about half of Americans diagnosed with major depression in a given year receive treatment for it, and even fewer—about one fifth—receive treatment consistent with current practice guidelines, according to data from nationally representative surveys supported by NIMH. Among the ethnic/racial groups surveyed, African Americans and Mexican Americans had the lowest rates of use of depression care; all groups reported higher use of past-year psychotherapy vs. medication for depression.

Background

Depression is a leading cause of disability in the United States. Past research has found that many people with depression never received treatment, and that the percentage of those receiving treatment varies with ethnicity and race. In order to provide comprehensive and up-to-date information on depression care, with a particular emphasis on minority groups, NIMH’s Collaborative Psychiatric Epidemiology Surveys initiative (CPES) has combined data from three nationally representative studies: the National Survey of American Life, the National Comorbidity Survey-Replication, and the National Latino and Asian American Study.

This Study

Scientists at Wayne State University, Detroit, MI; the University of Michigan, Ann Arbor; the University of California, Los Angeles; and the Harvard School of Public Health, Boston, MA, carried out the current study, which reports on data from CPES collected between February 2001 and November 2003 from 15,762 residents 18 years and older. The size of the sample makes it possible to examine health care use in ethnic/racial groups with a new level of detail, distinguishing between groups often surveyed as one population. The investigators were able to break out types of care used, and to assess to what extent the care used was consistent with the American Psychiatric Association (APA) Practice Guidelines for the Treatment of Patients with Major Depressive Disorder. Finally, they examined how factors enabling healthcare access—insurance, education, and household income—influenced rates of care.

A central finding was that overall, 51 percent of all those in the study who met criteria for major depression during the prior year received some kind of treatment for it, with only 21 percent receiving care that was consistent with the APA Guidelines.

Other key study findings addressed disparities, types and quality of care received, and factors that enable access to healthcare.

• Prevalence and severity of major depression was similar among the five studied ethnic/racial groups—Mexican Americans, Puerto Ricans, Caribbean Blacks, African Americans, and non-Latino Whites. However, African Americans and Mexican Americans were least likely to receive any care or care consistent with practice guidelines. Compared with non-Latino Whites for example, of whom 54 percent with depression received care, 40 percent of African Americans and 34 percent of Mexican Americans did. The rate of care for Puerto Ricans was close to that of Whites, 50 percent.
• Across these population groups, psychotherapy was used more frequently than medications (pharmacotherapy). Overall, 34 percent received pharmacotherapy; 45 percent psychotherapy. Psychotherapy was more likely to be consistent with APA guidelines than pharmacotherapy, suggesting that adherence—the extent to which patients completed the recommended therapy—was greater for psychotherapy than pharmacotherapy. The contrast between the rates of Guideline-consistent psychotherapy and pharmacotherapy use was greatest among Caribbean Blacks, African Americans, and Mexican Americans.
• Puerto Ricans had rates of treatment use, and treatment that was consistent with care guidelines, that were similar to, or higher than, non-Latino Whites.
• Differences in factors enabling healthcare access appeared to contribute substantially to disparities in mental healthcare use, particularly for Mexican Americans. When differences in these enabling factors were controlled for statistically—so in effect, the population groups being compared had the same rates of enabling factors—the degree of disparities in use of care by Mexican Americans was reduced. For Caribbean Blacks and African Americans, statistical control of enabling factors reduced disparities in psychotherapy use, but not use of pharmacotherapy.
• Health insurance coverage was associated with a greater likelihood of depression care, but not guideline consistent care. The pattern with education was reversed: education was associated with a greater likelihood of care that was consistent with the APA Guidelines, but not with greater use of care in general.

Significance

This study, with its large sample size and emphasis on minority groups, provides a more nuanced and detailed picture of the care received for major depression among different ethnic/racial groups and of factors that contribute to disparities. Lead author Hector González at Wayne State University said that Mexican-Americans make up over two-thirds of Latinos in the U.S.: “We found in our study that there are some really distinctive differences in mental healthcare use between Mexican Americans and other Latino subgroups that have not been previously reported.” Estimates suggest that Latinos will make up close to one-third of the U.S. population by mid-century; the study findings suggest that Mexican Americans should be a focus of efforts to reduce health disparities to ensure the nation’s health in coming decades.

All groups were more likely to have received psychotherapy than pharmacotherapy. Caribbean Blacks and African Americans were particularly unlikely to receive pharmacotherapy consistent with APA guidelines; enabling factors such as education, health insurance, and income did not explain the lower rates of medication use. The authors note possible reasons for this, including research indicating that perceived discrimination can shape health care seeking. They speculate that the non-immigrant status of Puerto Ricans—and with that, greater predominance of English language use within this group—may be factors in their relatively high rates of health care use.

Findings from this study will inform future research on adherence to various depression therapies, and the factors that shape differences in care among racial/ethnic groups. “Future studies,” say the authors, “should explore the extent to which patients’ subjective experiences of racial bias may affect their access and utilization of mental healthcare.”

Reference

González, H.M., Vega, W.A., Williams, D.R., Tarraf, W., West, B.T., and Neighbors, H.W. Archives of General Psychiatry 2010;67(1):37-4

Gender Gaps Linked to Status of Women, According to New Analysis

WASHINGTON – Girls around the world are not worse at math than boys, even though boys are more confident in their math abilities, and girls from countries where gender equity is more prevalent are more likely to perform better on mathematics assessment tests, according to a new analysis of international research.

“Stereotypes about female inferiority in mathematics are a distinct contrast to the actual scientific data,” said Nicole Else-Quest, PhD, a psychology professor at Villanova University, and lead author of the meta-analysis. “These results show that girls will perform at the same level as the boys when they are given the right educational tools and have visible female role models excelling in mathematics.”

The results are reported in the latest issue of Psychological Bulletin, published by the American Psychological Association. The finding that girls around the world appear to have less confidence in their mathematical abilities could help explain why young girls are less likely than boys to pursue careers in science, technology, engineering and mathematics.

Else-Quest and her fellow researchers examined data from the Trends in International Mathematics and Science Study and the Programme for International Student Assessment, representing 493,495 students ages 14-16 from 69 countries. Both studies’ results were released in 2003, and not all countries participated in both assessments. The TIMSS focuses on basic math knowledge, while the PISA test assesses students’ ability to use their math skills in the real world. The researchers felt these two tests offered a good sampling of students’ math abilities.

While these measures tested different math abilities, there were only small gender differences for each, on average. However, from nation to nation, the size of the gender differences varied a great deal.

The two studies also assessed students’ level of confidence in their math abilities and how important they felt it was to do well in math in order to have a successful career. Despite overall similarities in math skills, boys felt significantly more confident in their abilities than girls did and were more motivated to do well.

The researchers also looked at different measures of women’s education, political involvement, welfare and income in each country. There was some variability among countries when it came to gender differences in math and how it related to the status and welfare of women. For example, if certain countries had more women in research-related positions, the girls in that country were more likely to do better in math and feel more confident of those skills.

‘This meta-analysis shows us that while the quality of instruction and curriculum affects children’s learning, so do the value that schools, teachers and families place on girls’ learning math. Girls are likely to perform as well as boys when they are encouraged to succeed,” said Else-Quest.

Article: “Cross-National Patterns of Gender Differences in Mathematics: A Meta-Analysis,” Nicole M. Else-Quest, PhD, Villanova University; Janet Shibley Hyde, PhD, University of Wisconsin-Madison; Marcia C. Linn, PhD, University of California, Berkeley. Psychological Bulletin, Vol. 136, No. 1.

Contact Dr. Nicole Else-Quest by e-mail or at (610) 519-4758.

Translational Experiments in Rats, Humans Suggest New Medication Target

A study has linked panic disorder to a wayward hormone in a brain circuit that regulates vigilance. While too little of the hormone, called orexin, is known to underlie narcolepsy, the new study suggests that too much of it may lead to panic attacks that afflict 6 million American adults.

“Targeting the brain’s orexin system may hold promise for a new generation of anti-anxiety treatments,” said Thomas R. Insel, M.D., Director of the National Institute of Mental Health (NIMH), part of the National Institutes of Health. “This is a good example of how translational experiments in rats and humans can potentially yield clinical benefits.”

NIMH grantee Anantha Shekhar, M.B., Ph.D., and colleagues at Indiana University and Lund University, report on their findings online Dec. 27, 2009 in the journal Nature Medicine. They showed that blocking orexin gene expression or its receptor prevented panic attack-like responses in rats. The study also revealed that panic disorder patients have excess levels of the hormone.

Background

Orexin, also called hypocretin, is secreted exclusively in a circuit emanating from the brain’s hypothalamus, known to regulate arousal, wakefulness and reward.

Panic attacks can be experimentally-induced by infusing susceptible humans with a normally innocuous salt called sodium lactate. The salt similarly triggers panic-like anxiety behaviors in susceptible rat strains, suggesting that something is altered in their arousal circuit. Since sodium lactate activated orexin-secreting neurons in panic-prone rats but not in control rats, the researchers hypothesized that something might be orexin.

Results of This Study

The investigators first discovered that increased gene expression in orexin-secreting neurons correlated with increases in anxiety-like behavior in panic-prone rats following sodium lactate infusions. Using a technique called RNA interference, they then protected the panic-prone rats from developing anxiety behaviors following the infusions by first injecting them with a genetically-engineered agent that prevented orexin genes from turning on. Blocking orexin receptors with a drug that specifically binds to it also blocked the anxiety like behavior following the infusions. This mirrored effects, seen in both rats and humans, of benzodiazepine medications used to treat panic disorder.

The excess sleepiness of narcolepsy, traced a decade ago to loss of orexin-secreting neurons in the arousal circuit, might seem to be an opposite state of a panic attack. However, the researchers demonstrated in rats that such sedation could not account for orexin’s effects on anxiety. Also in rats, they traced orexin neurons to their end target to pinpoint the specific brain site that accounts for the anxiety effects, disentangled from cardio-respiratory components of the panic response.

Finally, by measuring orexin in cerebrospinal fluid of 53 patients, the researchers showed that those with just panic disorder had higher levels of orexin than those with both panic disorder and depression.

Significance

Taken together, these results and other evidence suggest a critical role for an overactive orexin system in producing panic attacks, say the researchers.

What’s Next?

Medications that block the orexin receptor may provide a new therapeutic approach for the treatment of panic disorder, they add.

The research was also supported, in part, by NIH’s National Center for Research Resources.

Reference

A key role for orexin in panic anxiety. Johnson PL, Truitt W, Fitz SD, Kelley PE, Dietrich A, Sanghani S, Traskman-Bendz L, Goddard AW, Brundin, L, Shekhar A. Nature Medicine. Epub 2009 Dec 27.

Wellstone-Domenici Act Goes Into Effect January 1

Contact: Steve Vetzner, (703) 797-2588 or svetzner@mentalhealthamerica.net

ALEXANDRIA, Va. (December 28, 2009) – Mental Health America today called for intensive education efforts to inform the public about the benefits of the new federal mental health parity law (the Paul Wellstone and Pete Domenici Mental Health Parity and Addiction Equity Act ), which becomes fully effective this Friday, January 1.

The law, which Congress passed in October of 2008, broadly outlaws health insurance discrimination against Americans with mental health and substance use conditions in employer-sponsored health plans.

It bans employers and insurers from imposing stricter limits on coverage for mental health and substance use conditions than those set for other medical conditions. The law benefits 82 million Americans covered by self-insured plans and another 31 million in plans that are subject to state regulation. (Fact sheets and background information can be viewed here.)

Mental Health America, which worked for years to pass the law, said public education efforts will ensure Americans are aware of their rights. A recent review of the experience with California’s mental health parity law concluded that public education campaigns are needed to inform individuals about the law and that those efforts could also help reduce the stigma around mental health conditions. It also recommended a system be established to monitor not only cost and coverage issues, but access to and quality of care.

“Parity is a milestone, but given how integral mental health is to overall health we have to raise public awareness,” said David L. Shern, Ph.D., president and CEO of Mental Health America. “With economic problems making it even harder for Americans to afford treatment and driving up rates of depression and family difficulties, the new law is especially important.”

Mental Health America has also urged the three federal departments charged with writing implementing regulations (Labor, Health and Human Services, and Treasury) to reflect the clear Congressional intent of the law. The regulations, which were expected to be published by this fall, are now not likely to be issued until January.

Dr. Shern said employers should embrace parity and recognize the value of providing mental health and substance use care. The findings of at least one recent survey suggest that few employers will drop mental health coverage because of the new law.

“The passage of parity recognized that we have to address mental health and substance use issues with same urgency and on the same level as other medical problems,” he said. “Those who believe parity is costly are making a huge mistake. The real cost is not treating mental health and substance use conditions.”

A number of studies have found that equalizing specialty behavioral health and general medical benefits will not increase total health care expenses at all or will increase them by only a very modest amount. In a landmark report, the National Business Group on Health said the indirect costs associated with mental health and substance use conditions-excess turnover, lost productivity, absenteeism and disability-commonly meet or exceed the direct treatment costs, and have been estimated to be at lest $105 billion annually.

Dr. Shern said the passage of parity has helped elevate the attention paid to mental health and substance use during the health reform debate. Both the House and Senate health reform bills would require that newly issued health plans offer an essential benefits package that includes mental health and substance use services.  A parity requirement would also apply to these new plans.

Only about half of American children and teenagers who have certain mental disorders receive professional services, according to a nationally representative survey funded in part by the National Institute of Mental Health (NIMH). The survey also provides a comprehensive look at the prevalence of common mental disorders.

The results are part of the National Health and Nutrition Examination Survey (NHANES), a collaboration between NIMH and the National Center for Health Statistics of the Centers for Disease Control and Prevention. The survey conducted from 2001 to 2004 had 3,042 participants. These most recent results include data from children and adolescents ages 8 to 15, and were published online ahead of print December 14, 2009, in the journal Pediatrics.

“Data on the prevalence of mental disorders among U.S. youth have been varied, making it difficult to truly understand how many children and teens are affected,” said NIMH Director Thomas R. Insel, M.D. “These data from the NHANES survey can serve as an important baseline as we follow trends of mental disorders in children.”

In the study, the young people were interviewed directly. Parents or caregivers also provided information about their children’s mental health. The researchers tracked six mental disorders—generalized anxiety disorder (GAD), panic disorder, eating disorders (anorexia and bulimia), depression, attention deficit hyperactivity disorder (ADHD) and conduct disorder. The participants were also asked about what treatment, if any, they were receiving.

Overall, 13 percent of respondents met criteria for having at least one of the six mental disorders within the last year. About 1.8 percent of the respondents had more than one disorder, usually a combination of ADHD and conduct disorder. Among the specific disorders,

• 8.6 percent had ADHD, with males more likely than females to have the disorder;
• 3.7 percent had depression, with females more likely than males to have the disorder;
• 2.1 percent had conduct disorder;
• 0.7 percent had an anxiety disorder (GAD or panic disorder);
• 0.1 percent had an eating disorder (anorexia or bulimia).

“With the exception of ADHD, the prevalence rates reported here are generally lower than those reported in other published findings of mental disorders in children, but they are comparable to other studies that employed similar methods and criteria,” said lead author Kathleen Merikangas, Ph.D., of NIMH.

Those of a lower socioeconomic status were more likely to report any disorder, particularly ADHD, while those of a higher socioeconomic status were more likely to report having an anxiety disorder. Mexican-Americans had significantly higher rates of mood disorders than whites or African-Americans, but overall, few ethnic differences in rates of disorders emerged.

Merikangas and colleagues also found that overall, 55 percent of those with a disorder had consulted with a mental health professional, confirming the trend of an increase in service use for childhood mental disorders, especially ADHD. However, only 32 percent of youth with an anxiety disorder sought treatment, a finding consistent with other studies. Moreover, African-Americans and Mexican-Americans were significantly less likely to seek treatment than whites, reiterating the need to identify and remove barriers to treatment for minority youth, noted the researchers.

“Until now, there has been a dearth of reliable data on the magnitude, course and treatment patterns of mental disorders among U.S. youth,” said Dr. Merikangas. “When combined with data from other nationally representative surveys, the data will provide a valuable basis for making decisions about health care for American youth,” she concluded.

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.

The National Institutes of Health (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. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit the NIH website.

ARLINGTON, Va. (Dec. 15, 2009) – A nationwide study found that suicide rates for HIV patients in Switzerland decreased by more than half, after 1996 when the highly active antiretroviral therapy (HAART) was introduced. Despite the dramatic decrease, the suicide rate among HIV-infected individuals still significantly exceeded that of the general population. The study also showed that the majority of HIV patients who died by suicide (62%) had a mental illness diagnosis.

The findings from this nationwide Swiss study by Olivia Keiser, Ph.D., and colleagues from the University of Bern will appear on December 15 at AJP in Advance, the online advance edition of The American Journal of Psychiatry (AJP), the official journal of the American Psychiatric Association.

Keiser et al. found that the reduction in suicide risk after the introduction of retroviral therapy was associated with an increase in CD4 white blood cells, indicating an improvement in HIV disease status. In the pre-HAART era, high suicide rates were driven by disease progression, which at that time could not be prevented.

Although suicide rates have declined, there still remains a serious public health concern that HIV patients are not receiving proper mental health treatment. . Substantial proportions of HIV patients—both before and after antiretroviral therapy was introduced —had not been treated for their mental condition.

“HAART is not a cure,” Keiser explained “Even though the rates of suicide and untreated mental illness in HIV patients have declined, they’re both still high and warrant increases in mental health screening and access to pharmacological and psychological treatment for these patients,”

Data was provided by the Swiss National Cohort and the Swiss HIV Cohort Study, which are funded by the Swiss National Science Foundation. The Swiss HIV Cohort Study is one of the oldest HIV cohort studies worldwide and includes about 40% of all HIV-positive patients in Switzerland and about 70% of all patients with AIDS.

The American Journal of Psychiatry is the oldest continuously published medical specialty journal in the United States and was recently named one of the “Most Influential Journals in Biology & Medicine of the Last 100 Years.” Statements in this press release or the articles in the Journal are not official policy statements of the American Psychiatric Association.

The American Psychiatric Association is a national medical specialty society whose 38,000 physician members specialize in diagnosis, treatment, prevention and research of mental illnesses including substance use disorders. Visit the APA at www.psych.org and www.HealthyMinds.org.

WASHINGTON, DC—Nerve cells transplanted into brain-damaged rats helped them to fully recover their ability to learn and remember, probably by promoting nurturing, protective growth factors, according to a new study.

Building on previous investigation of transplants in the nervous system, this critical study confirms that cell transplants can help the brain to heal itself. Ultimately, it may lead to new therapies to help dementia patients. More generally, scientists can now develop and test new ways to help repair an injured nervous system — whether through new drugs, genetically modified cells, transplanted neural (nerve) and non-neural brain cells, or other means.

The discovery was announced in the December issue of Behavioral Neuroscience, published by the American Psychological Association. The findings, according to the authors, confirm the potential of cell grafts to stimulate the release of growth factors for neurons, regenerate or reorganize a part of the brain, and restore cognitive function, in a process called neural plasticity.

This study focused on the hippocampus, considered to be the seat of learning and memory, whose shrinkage in Alzheimer’s disease causes steadily worsening symptoms. The study’s authors targeted a key player in the hippocampal “learning system,” which includes the hippocampus itself, the subiculum (the major output structure connected to the cortex, the self-aware “thinking” part of the brain), and the adjacent entorhinal cortex.

Previously, these scientists had demonstrated that damage to the subiculum in rats led to deterioration of the hippocampus, and problems with learning. The next question was obvious: Could researchers do the opposite, repair the hippocampus and restore the memory functions?

They sought the answer at India’s National Institute for Mental Health and Neuro Sciences and National Centre for Biological Sciences (Tata Institute for Fundamental Research), both in Bangalore. First, the scientists injected a neuron-destroying chemical into the subiculum area of 48 adult rats.

Next, again using precise micro-injections, the scientists transplanted hippocampal cells that had been taken from newborn transgenic mice and cultured in an incubator into the hippocampi of about half the rats. These special cells had a green fluorescent protein used to “label” and track them after transplantation. (Transgenic mice are bred with a little extra DNA that allows their cells to be grown in glass plates in incubators.)

Two months later, the scientists measured how well both the transplant and non-transplant rats learned and remembered, using two well-established maze tests of spatial learning. The rats given cell transplants had recovered completely: On both mazes, they performed as well as those rats which had not had their subiculums damaged. The rats without transplants did not recover: They had many problems learning their way through the mazes.

After studying behavior, the scientists examined what happened in the brain. Under the microscope, it appeared that the transplanted cells had settled mainly in a sub-area of the hippocampus called the dentate gyrus. There, the transplants appeared to promote the secretion of two types of growth factors, namely brain-derived neurotrophic factor and fibroblast growth factor, which boost the growth and survival of the cells that give rise to neurons. In the hippocampi of rats with cell transplants, the expression of brain-derived growth factor went up threefold.

It is significant that transplants can provide more neural growth factors in the hippocampus, because the formation of new neurons there may be critical for cognitive function.

Neural growth factors, also called neurotrophic factors, hold great promise for treating neurological problems. These specialized chemicals “provide an ideal micro-environment for making new neurons,” said co-author Bindu Kutty, PhD. “They also protect existing brain cells, especially following an injury or other neurological insult.”

Further study is needed, especially to understand the underlying repair mechanism and the apparent starring role of growth factor in brain health. Although the current study shows in the lab that brain-cell transplants can restore function, “more studies along these lines using appropriate animal models are required to find definitive answers about the safety and efficacy of such approaches,” said Kutty. “We are still some way from achieving a new therapy based on these findings.”

Article: “Transplantation of Hippocampal Cell Lines Improves Spatial Learning in Rats with Ventral Subicular Lesions,” J. Rekha, PhD, National Institute of Mental Health and Neuro Sciences (NIMHANS), Deemed University, India; Sridhara Chakravarthy, PhD, National Centre for Biological Sciences, Tata Institute for Fundamental Research (NCBS, TIFR), India; L. R. Veena, master’s student in biotechnology, NIMHANS; People’s Education Society Institute of Technology, India; Vani P. Kalai, master’s student in biotechnology, NIMHANS; Rupam Choudhury, Junior Research Fellow, NCBS, TIFR; Harsha N. Halahalli, PhD student, Phalguni Anand Alladi, PhD, Anandh Dhanushkodi, PhD, and M. Nirmala, PhD student, NIMHANS; Geetha M. Swamilingiah; PhD, NCBS, TIFR; Maulishree Agrahari, PhD, People’s Education Society Institute of Technology, India; T. R. Raju, PhD, NIMHANS; M. M. Panicker, PhD, NCBS, TIFR; Bindu M. Kitty, PhD, NIMHANS; Behavioral Neuroscience, Vol. 123, No. 6.

(Full text of the article is available from the APA Public Affairs Office)

Bindu Kutty can be reached by e-mail or at the following numbers: 091-80-2656 5075 or 091-80-2656 0431 (residence), 091-94-4978 9375 (mobile), or 091-80-2699 5170 (office).

The American Psychological Association, in Washington, D.C., is the largest scientific and professional organization representing psychology in the United States and is the world’s largest association of psychologists. APA’s membership includes more than 150,000 researchers, educators, clinicians, consultants and students. Through its divisions in 54 subfields of psychology and affiliations with 60 state, territorial and Canadian provincial associations, APA works to advance psychology as a science, as a profession and as a means of promoting health, education and human welfare.

Recalling Emotional Memory Opens Window of Opportunity to Re-Write It

Scientists have for the first time selectively blocked a conditioned fear memory in humans with a behavioral manipulation. Participants remained free of the fear memory for at least a year. The research builds on emerging evidence from animal studies that reactivating an emotional memory opens a 6-hour window of opportunity in which a training procedure can alter it.

“Our results suggest a non-pharmacological, naturalistic approach to more effectively manage emotional memories,” said Elizabeth Phelps, Ph.D., of New York University, a grantee of the National Institutes of Health’s National Institute of Mental Health (NIMH).

Phelps and NIMH grantee and NYU colleague Joseph LeDoux, Ph.D., led the research team that reports on their discovery online Dec. 9, 2009 in the journal Nature.

“Inspired by basic science studies in rodents, these new findings in humans hold promise for being translated into improved therapies for the treatment of anxiety disorders, such as post-traumatic stress disorder (PTSD),” said NIMH Director Thomas R. Insel, M.D.

The results add support to the hypothesis that emotional memories are reconsolidated – rendered vulnerable to being modified – each time they are retrieved. That is, reactivating a memory opens what researchers call “reconsolidation window,” a time-limited period when it can be changed.

“This adaptive update mechanism appears to have evolved to allow new information available at the time of retrieval to be incorporated into the brain’s original representation of the memory,” explained Phelps.

Earlier this year, LeDoux and colleagues exploited this potentially clinically important insight to erase a fear memory in rats. They first conditioned rats to fear a tone by pairing it with intermittent shocks. A day later, the rats were re-exposed to the tone, reactivating the fear memory. They then underwent a process to rewrite the fear, called extinction training, in which the tone was repeatedly presented without shocks.

However, the timing of this extinction training proved critical. Fear of the stimulus was erased only in rats trained within a 6-hour reconsolidation window after re-exposure to the feared tone. Fear responses returned in animals trained after the window closed, when the memory had apparently already solidified.

Normally, extinction training suppresses but does not erase the original fear memory. By first reactivating it – sounding the tone – just prior to extinction training, LeDoux and colleagues permanently erased the fear memory. In the new study, Phelps and colleagues similarly conditioned human participants to fear colored squares by intermittently pairing them with mild wrist shocks.

As with the rats, a day later, the memory was first reactivated by re-exposing participants to the feared squares. A measure of nervous system arousal confirmed that they experienced a fear response. Extinction training – repeated trials of exposure to the colored squares without shocks – followed.

Again as in the rats, a day later, the fear response was banished only in human participants who underwent the extinction training soon after the fear reactivation. Those trained after the 6-hour consolidation window remained afraid of the squares – as did a control group that received extinction training without first experiencing reactivation of the fear memory.

In a follow-up experiment to gauge long-term effects a year later, 19 of the original participants received a potent regimen to re-instate the fear: four shocks followed by presentations of the colored squares.

Remarkably, those who had undergone extinction training within the reconsolidation window were largely spared significant effects. By contrast, those whose training had been delayed 6 hours or who hadn’t experienced fear memory reactivation prior to extinction training experienced significant reinstatement of the fear response.

In a similar experiment, the researchers also confirmed that the fear memory was blocked only for the specific colored square for which fear memory was reactivated prior to extinction training. The effect did not generalize to a differently colored square associated with the shocks. This indicated that memory re-writing during reconsolidation is highly specific and that prior reactivation with the specific stimuli is critical.

“Timing may have a more important role in the control of fear than previously appreciated,” Phelps suggested. “Our memory reflects our last retrieval of it rather than an exact account of the original event.”

Evidence suggests that the behavioral manipulation may work through the same molecular mechanisms as experimental medications under study for quelling traumatic emotional memories.

“Using a more natural intervention that captures the adaptive purpose of reconsolidation allows a safe and easily implemented way to prevent the return of fear,” suggest the investigators.

References

Preventing the return of fear in humans using reconsolidation update mechanisms. Schiller D, Monfils MH, Raio CM, Johnson DC, LeDoux JE, Phelps EA. Nature. 2009 December 9.

Extinction-reconsolidation boundaries: key to persistent attenuation of fear memories. Monfils MH, Cowansage KK, Klann E, LeDoux JE. Science. 2009 May 15;324(5929):951-5. Epub 2009 Apr 2.PMID: 19342552

Children with poor reading skills who underwent an intensive, six-month training program to improve their reading ability showed increased connectivity in a particular brain region, in addition to making significant gains in reading, according to a study funded in part by the National Institute of Mental Health (NIMH). The study was published in the Dec. 10, 2009, issue of Neuron.

“We have known that behavioral training can enhance brain function.” said NIMH Director Thomas R. Insel, M.D. “The exciting breakthrough here is detecting changes in brain connectivity with behavioral treatment. This finding with reading deficits suggests an exciting new approach to be tested in the treatment of mental disorders, which increasingly appear to be due to problems in specific brain circuits.”

For the study, Timothy Keller, Ph.D., and Marcel Just, Ph.D., both of Carnegie Mellon University, randomly assigned 35 poor readers ages 8-12, to an intensive, remedial reading program, and 12 to a control group that received normal classroom instruction. For comparison, the researchers also included 25 children of similar age who were rated as average or above-average readers by their teachers. The average readers also received only normal classroom instruction.

Four remedial reading programs were offered, but few differences in reading improvements were seen among them. As such, results for participants in these programs were evaluated as a group. All of the programs were given over a six month schooling period, for five days a week in 50-minute sessions (100 hours total), with three students per teacher. The focus of these programs was improving readers’ ability to decode unfamiliar words.

Using a technology called diffusion tensor imaging (DTI), the researchers were able to measure structural properties of the children’s white matter, the insulation-clad fibers that provide efficient communication in the central nervous system. Specifically, DTI shows the movement of water molecules through white matter, reflecting the quality of white matter connections. The better the connection, the more the water molecules move in the same direction, providing a higher “bandwidth” for information transfer between brain regions.

At the outset of the study, poor readers showed lower quality white matter than average readers in a brain region called the anterior left centrum semiovale. Six months later, at the completion of the intensive training, the poor readers showed significant increases in the quality of this region. Children who did not receive the training did not show this increase, suggesting that the changes seen in the remedial training group were not due to natural maturation of the brain.

In an effort to further pinpoint the mechanism underlying this change, the researchers deduced that a process called myelination may be key. Myelin is akin to electrical insulation, allowing for more rapid and efficient communication between nerve cells in the brain. However, the directional association between brain changes and reading improvements remains unclear—whether intensive training brings about increased myelination that results in improved word decoding skills, or whether improved word decoding skills leads to changes in reading habits that result in greater myelination.

“Our findings support not only the positive effects of remediation and rehabilitation for reading disabilities, but may also lead to improved treatments for a range of developmental conditions related to brain connectivity, such as autism,” noted Just.

Source: Timothy Keller, Ph.D.; Marcel Just, Ph.D.

Left brain image shows the area of lower quality white matter (blue area) among poor readers relative to good readers at the beginning of the study.

Center brain image shows the area where the white matter quality increased (red/yellow area) among poor readers who received the remedial reading instruction.

Right brain image shows that following the instruction, there were no differences between the poor and average readers with respect to the quality of their white matter.

Reference

Keller TA, Just MA. Altering cortical connectivity: Remediation-induced changes in the white matter of poor readers. Neuron.

Depressed teens who report low levels of impairment related to drug or alcohol use tended to respond better to depression treatment than depressed teens with higher levels substance-related impairment, according to an analysis of data from the NIMH-funded Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) study. However, it is unclear whether less substance-related impairment allowed for better response to depression treatment, or if better treatment response led to less substance-related impairment. The study was published in the December 2009 issue of the Journal of the American Academy of Child and Adolescent Psychiatry.

Background

Substance use is more common among teens with depression than among those without depression. Researchers have also found that depression can inhibit teens’ response to treatment of substance abuse, and substance abuse is associated with a poorer response to treatment of depression. Still, few trials have examined how coexisting depression and substance use among teens may affect treatment outcomes for both.

In the TORDIA study, 334 teens who did not respond to a type of antidepressant called a selective serotonin reuptake inhibitor (SSRI) before the trial were randomly assigned to one of four treatments for 12 weeks:

• Switch to another SSRI
• Switch to venlafaxine (Effexor), a different type of antidepressant
• Switch to another SSRI and add cognitive behavioral therapy (CBT), a type of psychotherapy
• Switch to venlafaxine and add CBT

Results of the trial were previously reported in February 2008. They showed that teens who received combination therapy, with either type of antidepressant, were more likely to improve than those on medication alone.

In this new analysis, Benjamin Goldstein, M.D., of the University of Toronto, and colleagues examined TORDIA data to determine the relationship, if any, between substance use, major depression and response to depression treatment. Substance use was defined as using alcohol or drugs without meeting criteria for having a full-blown substance abuse disorder. Teens who were diagnosed with a substance abuse disorder were excluded from the TORDIA study.

Results of the Study

Substance use was fairly common among TORDIA participants. At baseline, about 28 percent reported experimenting with drugs or alcohol. Those who showed more substance -related impairment were older, felt more hopeless, had greater family conflict, developed depression at an earlier age, were more likely to have a history of physical or sexual abuse, and were more likely to have coexisting oppositional defiant disorder (ODD) or conduct disorder (CD). Substance-related impairment included certain attitudes and behaviors such as craving the substance, feeling hooked on it, accidentally hurting oneself or others while using it, and other similar effects.

Participants with low levels of substance use and substance-related impairment throughout the study tended to respond better to depression treatment than those who showed persistently high or increasing levels of substance-related impairment. There were no significant differences in rates of substance use and impairment among the treatment groups.

Significance

This study is one of the first to examine the association between substance use and depression treatment among depressed teens. The findings are consistent with other studies that found depression severity to be associated with a history of physical or sexual abuse, coexisting ODD or CD, and substance-related impairment. However, the direction of the association is uncertain. The data could not determine whether low substance-related impairment facilitates improvement in depression symptoms, or whether improvement in depressed mood leads to a decrease in substance-related impairment.

What’s Next

The authors caution that the study does not provide definitive conclusions about depression treatment and substance use. However, they do suggest that clinicians treating teens for depression screen for signs of substance use and address those issues as well, even if the teen does not meet criteria for a full-blown substance abuse disorder.

Reference

Goldstein BI, Shamseddeen W, Spirito A, Emslie G, Clarke G, Wagner KD, Asarnow JR, Vitiello B, Ryan N, Birmaher B, Mayes T, Onorato M, Zelazny J, Brent D. Substance use and the treatment of resistant depression in adolescents. Journal of the American Academy of Child and Adolescent Psychiatry. 2009 Dec. 48(12):1182-1192.

Children with autism who receive a high intensity developmental behavioral intervention starting by age 18-30 months show major improvements in IQ, language, adaptive behavior, and severity of their diagnosis, according to an NIMH-funded study.

Background

Current guidelines by the American Academy of Pediatrics recommend screening children for autism spectrum disorder (ASD) by age 18 months. However, no randomized clinical trials of intensive interventions for this age group had been conducted.

To address this gap, Geraldine Dawson, Ph.D., who was at the University of Washington at the time of the study, and colleagues randomly assigned 48 children, ages 18-30 months, to one of two intervention groups:

• Early Start Denver Model (ESDM), a comprehensive, developmental behavioral intervention designed for toddlers with ASD as young as 12 months old. ESDM combines aspects of applied behavioral analysis (ABA) with developmental and relationship-based approaches.
• Assess and Monitor (A/M), the comparison group intervention in which parents received recommendations on ASD interventions for their children, as well as referrals to local community providers of the interventions. A/M represents typical community-based care.

Children in the ESDM group were provided 20 hours per week of therapy from study clinicians, while their parents received related training to use ESDM strategies for at least five additional hours per week during their daily activities. Parents of all study participants were also free to receive other community services they thought appropriate.

All children in the study had been diagnosed with autism or a milder form of ASD called pervasive developmental disorder not otherwise specified (PDD-NOS). They were assessed yearly for two years or until the child turned four years old, whichever was longer.

Results of the Study

By the first- year assessment, children in the ESDM group gained 15.4 IQ points on average, while children in the A/M group gained an average of 4.4 points.

Over the two-year study period, children in the ESDM group consistently improved on measures of communication skills. They also showed improvements in motor skills, daily living skills, and other adaptive behaviors.

While children in the ESDM group were significantly delayed in their adaptive behaviors compared to typically developing children, they showed similar rates of improvement. In contrast, children in the A/M group fell further and further behind over time.

By the end of the study, more children who had received ESDM received improved diagnoses than children in the A/M group—seven children initially diagnosed with autistic disorder had their diagnosis change to PDD-NOS after receiving ESDM (30 percent), compared to only one child in the A/M group (5 percent).

Significance

According to the researchers, this is the first randomized controlled trial to study a potentially useful intensive intervention for very young children with ASD.

The study’s findings suggest that ESDM can help children with ASD achieve better outcomes in terms of IQ, language, and behavioral skills, and in severity of their ASD diagnosis, than if they receive community-based care. Compared to research on other, similar interventions, this study showed greater differences between groups, suggesting that ESDM, delivered at a very young age, may be more effective than other approaches. The researchers noted that parents’ use of ESDM strategies at home may have been key to this intervention’s effectiveness.

What’s Next

The University of Washington research team has been funded through the NIH Autism Centers of Excellence (ACE) program to follow this study’s participants to determine whether the effects of ESDM can be sustained over time. In addition, Dr. Sally Rogers, Ph.D., a co-author on the study and co-developer with Dr. Dawson of the ESDM model, is leading a multi-site, randomized clinical trial of ESDM, also funded through the NIH ACE program. With a larger sample size, the investigators hope to better understand factors that predict level of response to the ESDM intervention.

Reference

Dawson G, Rogers S, Munson J, Smith M, Winter J, Greenson J, Donaldson A, Varley J. Randomized, Controlled Trial of an Intervention for Toddlers With Autism: The Early Start Denver Model. Pediatrics. 2009 Nov 30. [Epub ahead of print] PubMed PMID: 19948568.

Alcoholic ‘energy’ drinks could raise risks from intoxication

WASHINGTON, DC—People who drink may want to know that coffee won’t sober them up, according to new laboratory research. Instead, a cup of coffee may make it harder for people to realize they’re drunk.

What’s more, popular caffeinated “alcohol-energy” drinks don’t neutralize alcohol intoxication, suggest the findings from a mouse study reported in the journal Behavioral Neuroscience, which is published by the American Psychological Association.

“The myth about coffee’s sobering powers is particularly important to debunk because the co-use of caffeine and alcohol could actually lead to poor decisions with disastrous outcomes,” said co-author Thomas Gould, PhD, of Temple University, in extending the research to what it means for humans.

“People who have consumed only alcohol, who feel tired and intoxicated, may be more likely to acknowledge that they are drunk,” he added. “Conversely, people who have consumed both alcohol and caffeine may feel awake and competent enough to handle potentially harmful situations, such as driving while intoxicated or placing themselves in dangerous social situations.”

In the laboratory, caffeine made mice more alert but did not reverse the learning problems caused by alcohol, including their ability to avoid things they should have known could hurt them, according to the study.

Scientists gave groups of young adult mice various doses, both separately and together, of caffeine and of ethanol (pure alcohol) at levels known to induce intoxication. The doses of caffeine were the equivalent of one up to six or eight cups of coffee for humans. Control mice were given saline solution.

Gould and co-author Danielle Gulick, PhD, then tested three key aspects of behavior: the ability to learn which part of a maze to avoid after exposure to a bright light or loud sound; anxiety, reflected by time spent exploring the maze’s open areas; and general locomotion.

Ethanol, as expected, increased locomotion and reduced anxiety and learning in proportion to the dose given. In other words, intoxicated animals were more relaxed and moved around more but learned significantly less well than control mice to avoid the part of the maze with the unpleasant stimuli.

By itself, caffeine increased anxiety and reduced both learning and locomotion. Compared to the control animals, mice given caffeine were significantly more inhibited, less mobile and less savvy about avoiding the unpleasant stimuli.

When the drugs were given together, ethanol blocked caffeine’s ability to make the mice more anxious. Conversely, caffeine did not reverse ethanol’s negative effect on learning. As a result, alcohol calmed the caffeine jitters, leaving an animal more relaxed but less able to avoid threats – a combination that the authors speculated could make people more likely to believe they are not drunk or not impaired enough to have problems functioning.

“The alcohol-energy drink combinations have skyrocketed in popularity,” Gould noted. He cited other evidence that these drinks produce deficits in general cognitive ability and raise the odds of alcohol-related problems such as drunken-driving citations, sexual misconduct, and needing medical assistance.

“The bottom line is that, despite the appeal of being able to stay up all night and drink, all evidence points to serious risks associated with caffeine-alcohol combinations,” he concluded.

The Food and Drug Administration is looking into the safety and legality of combination alcohol-caffeine beverages. In November, it sent letters to 30 manufacturers asking for evidence that such drinks are safe and legal under FDA regulations. To date, the FDA has only approved caffeine as an additive in soft drinks at concentrations less than 200 parts per million and has not approved adding caffeine at any level to alcoholic beverages. Under the Federal Food, Drug and Cosmetic Act, a substance added intentionally to food (such as caffeine in alcoholic beverages) is deemed unsafe and is unlawful unless its particular use has been approved by FDA regulation or is generally recognized as safe.

Article: “Effects of Ethanol and Caffeine on Behavior in C57BL/6 Mice in the Plus-Maze Discriminative Avoidance Task,” Danielle Gulick, PhD, and Thomas J. Gould, PhD, Temple University; Behavioral Neuroscience, Vol. 123, No. 6.

(Full text of the article is available from the APA Public Affairs Office)

Thomas Gould can be reached by e-mail or at (215) 204-7495.

The American Psychological Association, in Washington, D.C., is the largest scientific and professional organization representing psychology in the United States and is the world’s largest association of psychologists. APA’s membership includes more than 150,000 researchers, educators, clinicians, consultants and students. Through its divisions in 54 subfields of psychology and affiliations with 60 state, territorial and Canadian provincial associations, APA works to advance psychology as a science, as a profession and as a means of promoting health, education and human welfare.

Epigenetic Mark in Blood Could Serve as Biomarker for Disorder

For the first time, inherited disruption of gene expression in a brain system for social behavior has been implicated in autism. NIMH grantee Margaret Pericak-Vance, Ph.D., at the University of Miami and Simon Gregory, Ph.D., at Duke University, and a multinational team of researchers found evidence for such epigenetic effects on the gene for the oxytocin receptor –– part of a brain system that mediates social behaviors disturbed in autism. The findings suggest a potential genetic biomarker for the disorder.

The researchers report on their findings online October 22, 2009 in BMC Medicine.

Background

Environmentally-influenced and heritable chemical tags called epigenetic marks regulate the mix of proteins needed to build each tissue of the body. These alterations do not change a person’s DNA, or genetic blueprint. However, epigenetic changes that occur from the moment sperm meets egg can alter when and where genes get turned on.

Researchers are testing oxytocin as a possible treatment for social behavior disturbances in autism. Oxytocin is a hormone produced in the brain, which works through the oxytocin receptor. Previous studies had hinted at oxytocin receptor abnormalities in autism, but not at an epigenetic mechanism.

The researchers first used high-tech, genome-wide techniques to search for deletions or duplications of genes in 119 people with autism from families that had multiple children with the disorder and 54 healthy controls. They then searched in brain tissue and blood samples from affected and unaffected individuals for a common type of epigenetic mark created by methylation. In this process, molecules called methyl groups attach to DNA in response to an environmental trigger, preventing a gene’s expression.

Findings of This Study

The researchers found a deletion in the oxytocin receptor gene in a person with autism and his mother, who had obsessive compulsive disorder (OCD). OCD shares with autism symptoms of repetitive behaviors. Oxytocin receptor genes were similarly silenced –– but by methylation — in a sibling with autism who lacked the deletion. That is, two separate mechanisms of gene expression regulation resulted in the same outcome — loss of oxytocin receptor expression — in the same family.

Following up in blood cells and temporal cortex brain tissue of people with autism, the researchers pinpointed higher levels of methylation — about 70 percent vs. the normal 40 percent –– at an epigenomic site known to regulate the oxytocin receptor. They also found decreased expression of the receptor in the temporal cortex tissue, an area previously linked to autism.

Significance

Excess methylation of the oxytocin receptor could render people with autism less sensitive to the social hormone’s effects. Gene expression most likely became altered in very early gestation (between fertilization and implantation), suggest the researchers. This could increase vulnerability of the oxytocin receptor gene to environmental insults during the first few weeks of pregnancy, they say. The results suggest that such epigenetic misregulation of the oxytocin receptor gene may be an important factor in the development of autism.

What’s Next?

Since evidence of excess methylation of the oxytocin receptor gene in temporal cortex was also found in blood cells, the researchers suggest that the blood measure may be a marker, more generally, of the methylation status of the temporal cortex. So measuring the methylation status of the oxytocin receptor in blood could potentially serve as a biomarker for autism that might be used in conjunction with traditional diagnostic criteria. Drugs that target methylation might also hold promise for treatment.

Reference

Genomic and epigenetic evidence for oxytocin receptor deficiency in autism. Gregory SG, Connelly JJ, Towers AJ, Johnson J, Biscocho D, Markunas CA, Lintas C, Abramson RK, Wright HH, Ellis P, Langford CF, Worley G, Delong GR, Murphy SK, Cuccaro ML, Persico A, Pericak-Vance MA. BMC Med. 2009 Oct 22;7(1):62. [Epub ahead of print]PMID: 19845972.

Deleting one type of neurotransmitter receptor in a specific population of brain cells can induce schizophrenia-like behavior in mice, but only when the receptor is deleted early in development, according to a study by NIMH intramural scientists. The work provides strong support for previous observations implicating these receptors in psychosis; further, the mice provide a model of how psychotic symptoms can arise from a disruption in neuronal development, consistent with observations of how schizophrenia emerges in humans.

Background

Glutamate is the brain’s chief excitatory signaling molecule, or neurotransmitter, lowering the threshold at which neurons will fire and send a signal to adjacent neurons. Past studies have shown that drugs that shut down a specific type of receptor for glutamate—the NMDA receptor (NMDAR)—cause psychotic symptoms that resemble schizophrenia. That observation has led to a theory that psychosis in schizophrenia can be traced to reduced NMDAR function. Past work has also implicated a specific population of cells—interneurons—in schizophrenia. Interneurons function as integrating connectors between other neurons. Signaling by interneurons characteristically involves the inhibitory neurotransmitter GABA, which, contrary to glutamate, acts to slow the pace of neuronal activity.

This Study

To explore whether reduced NMDAR function in interneurons could cause psychosis, scientists in NIMH’s intramural program, led by Dr. Kazu Nakazawa, used a technique that allowed them to create mouse lines in which an essential subunit of the NMDA receptor was deleted (“knocked out”), but only in interneurons in areas of the brain (the cortex and hippocampus) that are thought to be particular targets of reduced NMDAR function. The method they used allowed them to create mouse lines in which they could vary the timing of the deletion: in one mouse line, the deletion was evident early in postnatal development; in the other, the deletion took place after the mice had reached adulthood.

By four weeks of age, a time period that corresponds roughly to infancy in humans, NMDA receptors were knocked out in one of the mouse lines. After a delay of several weeks, testing showed a number of types of behaviors analogous to schizophrenia in humans. As in humans, there was a latency, or prodromal period, before signs of abnormal behavior became apparent.

In tests of exploratory behavior, the knockout mice showed signs of hyper-reactivity and increased anxiety. They also showed reduced appetite for sweet solutions and deficits in nesting and mating, all signs that parallel the negative symptoms seen in schizophrenia: a lack of pleasure in everyday activities, and a reduced ability to plan and carry out tasks. Social and working memory were also affected in the mice. In another parallel to human schizophrenia, symptoms showed up earlier in mice that had been raised for several weeks in isolation, a form of social stress. Finally, no symptoms appeared in mice in which the NMDA receptors were knocked out after 12 weeks.

Significance

In this study, reduced function of NMDA receptors in a specific population of cells was sufficient to cause symptoms resembling schizophrenia in humans, providing the first direct evidence that these cell receptors are central in the origin of psychosis. The fact that the symptoms developed over time, and only when the receptors were deleted in younger mice, also depicts a process consistent with the view of schizophrenia as a disease in which a failure in one type of neuronal signaling throws off the normal formation of neuronal connections (synapses) and leads to disease.

What’s Next

This knockout mouse provides a model for exploring the role of NMDA receptors in schizophrenia. Future studies will address what could cause reduced NMDAR function in people with schizophrenia; how disrupted regulation of this receptor causes symptoms and how stress exacerbates them; and how currently-used medications work to alleviate symptoms. Ultimately, understanding these processes will provide the basis for developing new, targeted medications.

A provocative aspect of these results is that deleting the receptor in adult mice failed to cause symptoms, a surprise given the fact that drugs with an analogous effect on the receptor cause symptoms in adult humans and animals. A question for future research is whether the drugs that target NMDA receptors also have broader actions that explain their ability to cause psychosis. In addition, the study found that deleting a receptor for glutamate—which is excitatory—resulted in increased, not decreased, activity of neurons in the cortex. The explanation may be related to regulation by glutamate of interneuron activity, which is in turn GABA-based and inhibitory.

Reference

Belforte, J.E., Zsiros, V., Sklar, E.R., Jiang, Z., Yu, G., Li, Y., Quinlan, E.M. and Nakazawa, K. Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes. Nature Neuroscience published online 11/15/2009; doi: 10.1038/nn.2447

Other Subtypes May Affect Disease Outcomes Too

In a study of HIV-related cognitive impairment in Uganda, people with HIV subtype D were more likely than those with the other subtypes to have HIV-associated dementia (HAD), according to NIMH-funded researchers. This study, published in the September 1, 2009, issue of Clinical Infectious Diseases, is the first to show that HIV subtype may affect a person’s risk for developing HAD.

Background

HIV-associated dementia is a common symptom of advanced HIV infection, affecting a person’s central nervous system and cognitive skills. While the subtype of HIV has been shown to affect the progression of HIV to AIDS, the effect on HAD risk has been unknown.

To explore this relationship, Ned Sacktor, M.D., of Johns Hopkins Bayview Medical Center, and colleagues conducted a study in Uganda of 60 people at risk of developing HAD. The wide variety of HIV subtypes in Uganda and other sub-Saharan countries, along with studies suggesting a relatively high prevalence of HAD and other HIV-related neurological complications in these regions, makes them ideal locations for studying the effects of HIV subtypes on various disease outcomes.

All participants in Sacktor’s study had advanced HIV infection but had not previously received highly active antiretroviral treatment (HAART), the current standard of care for HIV. The researchers assessed participants’ neurological, neuropsychological, and functional status, as well as their HIV subtype.

Results of the Study

Of the 60 study participants:

• 33 were infected with subtype A
• 2 were infected with subtype C
• 9 were infected with subtype D
• 16 were infected with a subtype that had characteristics of both subtype A and subtype D.

Participants with HIV subtype D were more likely to have HAD (89 percent with dementia) than those with subtype A (24 percent with dementia). The two other HIV subtypes observed in the study did not show a significant association with HAD.

Significance

The results suggest that among people with advanced HIV infection, those with subtype D are more likely to have HAD than those with other subtypes. According to the researchers, these findings are the first to show that HIV subtypes may play a role in causing HAD.

What’s Next

More studies are needed to confirm whether the relationship between HIV subtype D and increased HAD risk exists among the broader HIV-infected community, instead of just those who had not previously received HAART. Additional research should also focus on how subtype D may lead to increased risk of HAD, and whether other subtypes may also influence risk for this and other HIV-related neurological complications.

Reference

Sacktor N, Nakasujja N, Skolasky RL, Rezapour M, Robertson K, Musisi S, Katabira E, Ronald A, Clifford DB, Laeyendecker O, Quinn TC. HIV subtype D is associated with dementia, compared with subtype A, in immunosuppressed individuals at risk of cognitive impairment in Kampala, Uganda. Clin Infect Dis. 2009 Sep 1;49(5):780-6. PubMed PMID: 19622045.