Veterans' alcohol problems linked to stress on the home front

Returning national guardsmen more likely to turn to alcohol than general public when faced with issues at home, according to new study in the American Journal of Preventive Medicine What do you think of this article? "Ann Arbor, MI, July 31, 2014 — Regardless of traumatic events experienced during deployment, returning National Guard soldiers were more likely to develop a drinking problem if faced with civilian life setbacks, including job loss, legal problems, divorce, and serious financial and legal problems — all commonplace in military families. Results of the study by researchers at Columbia University's Mailman School of Public Health are published online in the American Journal of Preventive Medicine. Alcohol abuse is a major concern for reservists returning home. Nearly 7% of Americans abuse or are dependent on alcohol, but among reserve soldiers returning from deployment, the rate of alcohol abuse is 14%, almost double that of the civilian population. The study looked at a group of 1,095 Ohio National Guard soldiers, who had primarily served in either Iraq or Afghanistan in 2008 and 2009. Over three years, the soldiers were interviewed three times via telephone and were asked about their alcohol use, exposure to deployment-related traumatic events and stressors like land mines, vehicle crashes, taking enemy fire, and witnessing casualties, and any stress related to everyday life since returning from duty. "Guardsmen who return home need help finding jobs, rebuilding their marriages and families, and reintegrating into their communities," says Karestan Koenen, PhD, Professor of Epidemiology at the Mailman School and senior author of the study. "Too many of our warriors fall through the cracks in our system when they return home. This is particularly true of Guardsmen who do not have the same access to services as regular military personnel. We need to support our soldiers on the home front just as we do in the war zone." More than half (60%) of the responding soldiers experienced combat-related trauma, 36% of soldiers experience civilian stressors, and 17% reported being sexually harassed during their most recent deployment. Among the group, 13% reported problems consistent with an alcohol use disorder in the first interview, 7% during the second, and 5% during the third. Alcohol use disorder is defined as alcohol abuse or dependence. The researchers found having at least one civilian stressor or a reported incident of sexual harassment during deployment raised the odds of alcohol use disorders. The effect of the stressors was restricted to cases of new-onset alcohol use disorders, and was not seen among those with a history of problem drinking. In contrast, combat-related traumatic events were only marginally associated with alcohol problems. The study highlights the important role civilian life and the accompanying stress play in cases of alcohol use disorder in the National Guard. "Exposure to the traumatic event itself has an important effect on mental health in the short-term, but what defines long-term mental health problems is having to deal with a lot of daily life difficulties that arise in the aftermath — when soldiers come home," explains lead investigator Magdalena Cerdá, DrPH, MPH, Assistant Professor of Epidemiology, Mailman School of Public Health, Columbia University. "The more traumatic events soldiers are exposed to during and after combat, the more problems they are likely to have in their daily life — in their relationships, in their jobs — when they come home. These problems can in turn aggravate mental health issues, such as problems with alcohol that arise during and after deployment." With high rates of alcohol abuse among soldiers, there is a critical need for targeted interventions to help soldiers handle stressful life events without alcohol, the investigators observe. More than 1.6 million service members have been deployed in support of war efforts Operation Enduring Freedom, Operation Iraqi Freedom, and Operation New Dawn. ### The findings from this study are consistent with two reports the Institute of Medicine released this year, which call attention to the serious mental health issues faced by the military population upon return from Iraq and Afghanistan, and highlight the need for the Department of Defense to develop an evidence base on the effectiveness of prevention and treatment programs targeted at service members and their families. A co-author of the current study, Sandro Galea, MD, DrPH, chair of Epidemiology at the Mailman School, led the Commission that issued one of the reports; Dr. Koenen was a co-author of the same." For more information and free clinical resources on drug/alcohol abuse, please visit Alcoholism and Drug Abuse Counselors Continuing Education

Brain Region Singled Out for Social Memory, Possible Therapeutic Target for Select Brain Disorders

Researchers have found in mice that a formerly obscure region of the hippocampus called CA2 is important for social memory, the ability of an animal to recognize another of the same species. Identifying the role of this region could be useful in understanding and treating disorders characterized by altered social behaviors such as schizophrenia, bipolar disorder, and autism. Funded in part by the National Institute of Mental Health (NIMH), the study was published last month online in Nature. Background The hippocampus is essential for learning and memory—specifically the storage of knowledge of who, what, where, and when. Clues about the hippocampus’s roles emerged from the famous case of patient HM (Henry Molaison), who had most of his hippocampus removed by surgeons in 1953 to cure his epilepsy. HM became unable to form new memories of people he subsequently worked with for years. Most previous studies of how memory is harnessed have focused on the trisynaptic pathway. In this neural circuit, information that is obtained from the entorhinal cortex—the main interface between the hippocampus and the neocortex or the outermostpart of the brain involved in higher functions such as thought or action—proceeds to the dentate gyrus, the front gate of the hippocampus. Granule neurons from the dentate gyrus then shuttle the information to interneurons and pyramidal cells of the CA3 region of the hippocampus, which then sends the information to the CA1 region, the main source of hippocampal output. Absent from this circuit is the CA2 subfield. “Although the CA2 subregion was discovered over 75 years ago, it has received very little attention,” said Steven A. Siegelbaum, Ph.D., lead author of the study. He ascribes two reasons for the inattention: size and location. CA2 has 10 percent the number of neurons of CA1 or CA3, raising questions about its importance. The region is also squeezed between CA1 and CA3, making it difficult to study with traditional approaches of physical or chemical lesions, which lack the precision to selectively target CA2. To circumvent these problems, Siegelbaum, a neuroscience professor at Columbia University and a Howard Hughes Medical Institute Investigator, and Frederick L. Hitti, an M.D.-Ph.D. student, generated a special transgenic mouse in which the CA2 neurons could be selectively inhibited in adult animals. Once these neurons were inactivated, the mice underwent a series of behavioral tests. Results of the Study Normally when a mouse encounters another mouse it does not know, it gives it a “sniff test” and is more interested in this new mouse versus a familiar acquaintance. The CA2-inactive mouse, however, shows no recognition of mice it has seen before and ends up sniffing indiscriminately familiar and novel mice. The mice showed no loss in the ability to discriminate social or non-social odors, such as food buried deeply in its litterbox. Although a pronounced loss of social memory is seen in the CA2-inactive mice, the mice did not experience changes in other hippocampal-specific behaviors such as spatial and contextual memory, and could still distinguish between novel and familiar inanimate objects. Significance “Because several neuropsychiatric disorders are associated with altered social behaviors, our findings raise the possibility that CA2 dysfunction may contribute to these behavioral changes,” said Siegelbaum. Individuals with schizophrenia and bipolar disorder have lowered numbers of CA2 inhibitory neurons. Similarly, individuals with autism have altered signaling of vasopressin, a social behavior hormone that interacts with a specific class of receptors found predominantly in this region. However, the CA2-inactive mice did not display classic symptoms of autism as they had normal levels of sociability, providing evidence that sociability and social memory involve different brain functions. Techniques such as the one detailed here are examples of research tools that the NIH Brain Research through Advancing Innovative Neurotechnologies (BRAIN ) Initiative hopes to build upon to further our understanding of the human brain. What’s Next Siegelbaum’s group hopes to use the same genetic technology to examine whether there are changes in CA2 function in mouse models of psychiatric disorders such as autism and schizophrenia. If so, they plan to screen for drugs that restore normal CA2 function and ask whether this drug treatment helps reverse any behavioral changes seen in the mice. Such research offers the possibility of finding new drug targets and approaches for treating the behavioral changes associated with these disorders Alcoholism and Drug Abuse Counselors Continuing Education Reference Hitti FL, Siegelbaum SA. The Hippocampal CA2 Region is Essential for Social Memory. Nature , published online February 23, 2014. Grant 5F30MH098633-02

Heavy marijuana users have abnormal brain structure and poor memory

Drug abuse appears to foster brain changes that resemble schizophrenia CHICAGO --- Teens who were heavy marijuana users -- smoking it daily for about three years -- had abnormal changes in their brain structures related to working memory and performed poorly on memory tasks, reports a new Northwestern Medicine® study. A poor working memory predicts poor academic performance and everyday functioning. The brain abnormalities and memory problems were observed during the individuals' early twenties, two years after they stopped smoking marijuana, which could indicate the long-term effects of chronic use. Memory-related structures in their brains appeared to shrink and collapse inward, possibly reflecting a decrease in neurons. The study also shows the marijuana-related brain abnormalities are correlated with a poor working memory performance and look similar to schizophrenia-related brain abnormalities. Over the past decade, Northwestern scientists, along with scientists at other institutions, have shown that changes in brain structure may lead to changes in the way the brain functions. This is the first study to target key brain regions in the deep subcortical gray matter of chronic marijuana users with structural MRI and to correlate abnormalities in these regions with an impaired working memory. Working memory is the ability to remember and process information in the moment and -- if needed -- transfer it to long-term memory. Previous studies have evaluated the effects of marijuana on the cortex, and few have directly compared chronic marijuana use in otherwise healthy individuals and individuals with schizophrenia. The younger the individuals were when they started chronically using marijuana, the more abnormally their brain regions were shaped, the study reports. The findings suggest that these regions related to memory may be more susceptible to the effects of the drug if abuse starts at an earlier age. "The study links the chronic use of marijuana to these concerning brain abnormalities that appear to last for at least a few years after people stop using it," said lead study author Matthew Smith, an assistant research professor in psychiatry and behavioral sciences at Northwestern University Feinberg School of Medicine. "With the movement to decriminalize marijuana, we need more research to understand its effect on the brain." Alcoholism and Drug Abuse Counselors Continuing Education The paper will be published Dec. 16 in the journal Schizophrenia Bulletin. In the U.S., marijuana is the most commonly used illicit drug and young adults have the highest -- and growing -- prevalence of use. Decriminalization of the drug may lead to greater use. Because the study results examined one point in time, a longitudinal study is needed to definitively show if marijuana is responsible for the brain changes and memory impairment. It is possible that the abnormal brain structures reveal a pre-existing vulnerability to marijuana abuse. But evidence that the younger a subject started using the drug the greater his brain abnormality indicates marijuana may be the cause, Smith said. The groups in the study started using marijuana daily between 16 to 17 years of age for about three years. At the time of the study, they had been marijuana free for about two years. A total of 97 subjects participated, including matched groups of healthy controls, subjects with a marijuana use disorder, schizophrenia subjects with no history of substance use disorders, and schizophrenia subjects with a marijuana use disorder. The subjects who used marijuana did not abuse any other drugs. Few studies have examined marijuana's effect on the deep regions in the brain -- the 'subcortical gray matter' below the noodle-shaped cortex. The study also is unique in that it looked at the shapes of the striatum, globus pallidus and thalamus, structures in the subcortex that are critical for motivation and working memory. The Marijuana and Schizophrenia Connection Chronic use of marijuana may contribute to changes in brain structure that are associated with having schizophrenia, the Northwestern research shows. Of the 15 marijuana smokers who had schizophrenia in the study, 90 percent started heavily using the drug before they developed the mental disorder. Marijuana abuse has been linked to developing schizophrenia in prior research. "The abuse of popular street drugs, such as marijuana, may have dangerous implications for young people who are developing or have developed mental disorders," said co-senior study author John Csernansky, M.D., chair of psychiatry and behavioral sciences at Northwestern University Feinberg School of Medicine and Northwestern Memorial Hospital. "This paper is among the first to reveal that the use of marijuana may contribute to the changes in brain structure that have been associated with having schizophrenia." Chronic marijuana use could augment the underlying disease process associated with schizophrenia, Smith noted. "If someone has a family history of schizophrenia, they are increasing their risk of developing schizophrenia if they abuse marijuana," he said. While chronic marijuana smokers and chronic marijuana smokers with schizophrenia both had brain changes related to the drug, subjects with the mental disorder had greater deterioration in the thalamus. That structure is the communication hub of the brain and is critical for learning, memory and communications between brain regions. The brain regions examined in this study also affect motivation, which is already notably impaired in people with schizophrenia. "A tremendous amount of addiction research has focused on brain regions traditionally connected with reward/aversion function, and thus motivation," noted co-senior study author Hans Breiter, M.D., professor of psychiatry and behavioral sciences and director of the Warren Wright Adolescent Center at Feinberg and Northwestern Memorial. "This study very nicely extends the set of regions of concern to include those involved with working memory and higher level cognitive functions necessary for how well you organize your life and can work in society." "If you have schizophrenia and you frequently smoke marijuana, you may be at an increased risk for poor working memory, which predicts your everyday functioning," Smith said. ### The research was supported by grants R01 MH056584 and P50 MH071616 from the National Institute of Mental Health and grants P20 DA026002 and RO1 DA027804 from National Institute of Drug Abuse, all of the National Institutes of Health.

Mental stress + heart disease: Stronger presence in women under 50

Patients with recent heart attack tested with public speaking task Researchers have found that women younger than 50 with a recent heart attack are more likely to experience restricted blood flow to the heart (myocardial ischemia) in response to psychological stress. The finding may partly explain why younger women who are hospitalized after a heart attack face a greater risk of complications and dying, compared to men of the same age. The results are scheduled to be presented Wednesday, Nov. 20 at the American Heart Association Scientific Sessions meeting in Dallas. Researchers at Emory University have been studying the responses of patients who recently had a heart attack to exercise stress and mental stress, in the form of public speaking on an emotional topic. They have found that women age 50 and below are more likely to experience mental stress-induced ischemia, compared to men of the same age (52 percent compared to 25 percent). The MIMS (Myocardial Infarction and Mental Stress) study included 49 men and 49 women, age-matched pairs who all had a heart attack in the last six months. Their ages ranged from 38 to 59. Among study participants older than 50, there were no significant sex differences in mental stress-induced ischemia;, however, men older than 50 had a rate of exercise-induced ischemia that was twice as high as women of a similar age. "This is the first study to examine the cardiovascular effects of psychological stress as a possible mechanism for the greater mortality after myocardial infarction among younger women," says study leader Viola Vaccarino, MD, PhD, professor and chair of the Department of Epidemiology, Rollins School of Public Health. "We saw a dramatic difference in mental stress-induced ischemia specifically in younger women. In addition, when ischemia was graded in a continuous way, we saw that it was twice as severe among the younger women." Women who experience a heart attack before age 50 are relatively rare, suggesting that perhaps those who do simply have more severe heart disease. However, even when investigators adjusted for different rates of traditional heart disease risk factors such as smoking and diabetes, the disparity remained. In fact, women tended to have less severe coronary artery disease, measured by examining the degree of blockage in their coronary arteries. One possible explanation the Emory investigators considered was a higher burden of psychosocial stress, Vaccarino says. In the study, the younger women were more often poor, of minority race, with a history of sexual abuse and with higher levels of depressive symptoms. "Yet if we look at the statistics, factors such as poverty, race and depression do not explain the difference," she says. "Yes, women have more stressors. But our data show that women also may be more vulnerable to the effects of mental stress on the heart." "This could be an added stimulus to the medical community to pay more attention to the emotional factors in cardiac patients. We are now taking a closer look at potential physiological factors that account for the additional susceptibility in younger women." Emory researchers working with Vaccarino have identified two areas where there are specific differences in younger women who had a recent heart attack: inflammation and heart rate variability, a measure of the responsiveness of the autonomic nervous system. Low heart rate variability has been previously linked to greater heart disease risk. The inflammation data is being presented in a poster by postdoctoral researcher Cherie Rooks, PhD on Sunday, Nov. 17 and the heart rate variability data in a poster by assistant professor Amit Shah, MD on Tuesday, Nov. 19. Interleukin-6 is a marker of inflammation that goes up and down quickly depending on someone's environmental exposures including mental stress, even in healthy individuals. In the MIMS study, women age 50 and below had much higher levels of IL-6 in their blood, compared to age-matched men, both before the mental stress test and afterwards. Women and men older than 50 had similar levels of IL-6. Heart rate goes up in response to physical or psychological stress, but the beats also become more evenly spaced. Heart rate variability is a measure of how much moment-to-moment fluctuation is present; higher heart rate variability is a marker of a more flexible, and thus healthier, autonomic system. In the MIMS study, younger women had their heart rate variability dip more in response to stress, compared to men the same age. This is additional evidence that young women after a heart attack may be more vulnerable to the adverse effects of psychological stress on the heart. Vaccarino and her colleagues are continuing to investigate mental stress-induced ischemia, including how it affects mortality and complication rates, in a second phase of the MIMS study at Emory, which will include a larger sample with patient follow-up Alcoholism and Drug Abuse Counselors Continuing Education ### How the study was conducted The mental stress test part of the study was a public speaking task involving an emotional topic. Participants were asked to imagine a real-life stressful situation, such as a close relative been mistreated in a nursing home. They had to quickly prepare a speech and deliver it in front of a video camera and an audience wearing white coats, while their blood pressure and other vital signs were monitored. Immediately afterwards, cardiac imaging was performed to assess blood flow within the heart via SPECT (single photon emission computed tomography). On a separate day, study participants performed a standard exercise test on a treadmill; a few were unable to exercise at a high heart rate and had to have a "pharmacological" stress test with a drug that dilates coronary arteries. The research was supported by the National Heart Lung and Blood Institute and the National Institute for Mental Health (R21HL093665, R21HL093665-01A1S1, R01 HL109413, K24HL077506, and K24 MH076955).

OHSU Vollum Institute research gives new insight into how antidepressants work in the brain

Vollum Institute scientist publishes two papers on neurotransmission in today’s edition of Nature Research from Oregon Health & Science University's Vollum Institute, published in the current issue of Nature, is giving scientists a never-before-seen view of how nerve cells communicate with each other. That new view can give scientists a better understanding of how antidepressants work in the human brain — and could lead to the development of better antidepressants with few or no side effects. The article in today’s edition of Nature came from the lab of Eric Gouaux, Ph.D., a senior scientist at OHSU's Vollum Institute and a Howard Hughes Medical Institute Investigator. The article describes research that gives a better view of the structural biology of a protein that controls communication between nerve cells. The view is obtained through special structural and biochemical methods Gouaux uses to investigate these neural proteins. The Nature article focuses on the structure of the dopamine transporter, which helps regulate dopamine levels in the brain. Dopamine is an essential neurotransmitter for the human body's central nervous system; abnormal levels of dopamine are present in a range of neurological disorders, including Parkinson's disease, drug addiction, depression and schizophrenia. Along with dopamine, the neurotransmitters noradrenaline and serotonin are transported by related transporters, which can be studied with greater accuracy based on the dopamine transporter structure. The Gouaux lab's more detailed view of the dopamine transporter structure better reveals how antidepressants act on the transporters and thus do their work Alcoholism and Drug Abuse Counselors Continuing Education The more detailed view could help scientists and pharmaceutical companies develop drugs that do a much better job of targeting what they're trying to target — and not create side effects caused by a broader blast at the brain proteins. "By learning as much as possible about the structure of the transporter and its complexes with antidepressants, we have laid the foundation for the design of new molecules with better therapeutic profiles and, hopefully, with fewer deleterious side effects," said Gouaux. Gouaux's latest dopamine transporter research is also important because it was done using the molecule from fruit flies, a dopamine transporter that is much more similar to those in humans than the bacteria models that previous studies had used. The dopamine transporter article was one of two articles Gouaux had published in today’s edition of Nature. The other article also dealt with a modified amino acid transporter that mimics the mammalian neurotransmitter transporter proteins targeted by antidepressants. It gives new insights into the pharmacology of four different classes of widely used antidepressants that act on certain transporter proteins, including transporters for dopamine, serotonin and noradrenaline. The second paper in part was validated by findings of the first paper — in how an antidepressant bound itself to a specific transporter. "What we ended up finding with this research was complementary and mutually reinforcing with the other work — so that was really important," Gouaux said. "And it told us a great deal about how these transporters work and how they interact with the antidepressant molecules." Gouaux's discoveries over the years in neurotransmission have established him as one of the top investigators in his field. His research has important implications for understanding the mechanisms of not just antidepressants, but also drugs used for the treatment of a wide range of psychiatric and neurological diseases. Gouaux's co-authors on the dopamine transporter paper were both members of his lab; Aravind Penmatsa, Ph.D., and Kevin Wang, Ph.D. Gouaux's co-authors on the second Nature paper were also members or former members of his lab: Hui Wang, Ph.D.; April Goehring, Ph.D.; Kevin Wang, Aravind Penmatsa and Ryan Ressler, Ph.D. Both papers were funded by the American Heart Association, the National Institute of Mental Health, (1F32MH093120 and 5R37MH070039) and the Howard Hughes Medical Institute. About the OHSU Vollum Institute The Vollum Institute is a privately endowed research institute at OHSU and is dedicated to basic research that will lead to new treatments for neurological and psychiatric diseases. Vollum scientists have transformed the field of neuroscience and, in particular, have been pioneers in the study of cellular signaling, neuronal development, gene regulation and the neurobiology of disease. About OHSU Oregon Health & Science University is a nationally prominent research university and Oregon’s only public academic health center. It serves patients throughout the region with a Level 1 trauma center and nationally recognized Doernbecher Children’s Hospital. OHSU operates dental, medical, nursing and pharmacy schools that rank high both in research funding and in meeting the university’s social mission. OHSU’s Knight Cancer Institute helped pioneer personalized medicine through a discovery that identified how to shut down cells that enable cancer to grow without harming healthy ones. OHSU Brain Institute scientists are nationally recognized for discoveries that have led to a better understanding of Alzheimer’s disease and new treatments for Parkinson’s disease, multiple sclerosis and stroke. OHSU’s Casey Eye Institute is a global leader in ophthalmic imaging, and in clinical trials related to eye disease.

Alcoholism and Drug Abuse Counselors Continuing Education

Alcoholism and Drug Abuse Counselors Continuing Education (CADC CEUs, CPS CEUS, CCS CEUs, CADCA CEUs) Aspira Continuing Education is a California Association of Alcoholism and Drug Abuse Counselors-Approved Continuing Education Provider (ACEPTM) and offers CAADAC-approved clock hours for events that meet CAADAC requirements. The ACEP solely is responsible for all aspects of the program. (Provider # 2C-09-123-0811). Aspira Continuing Education offers online CE courses for the various certifications provided by CAADAC. Such as CADC I, CADC II, CPS, CCS and CADCA. View our Board Approvals and Accreditations page for provider numbers. Click here for: CAADAC Website View Aspira’s CE courses to see the variety options you have to satisfy your CAADAC requirements. View Aspira's CEU Pricing page to see how to pay for Aspira's CE courses. View Aspira's CEU Offers page to see the latest offers and discounts available. Also, see how to earn free CEUs. **CADC I & II Continuing Education For your information, here is an excerpt from the CAADAC website: “Certified Alcohol and Drug Counselor (CADC I & II) Requirements: •Meet all requirements of the CADCA formerly (RADI) •Provide documentation of 4,000 hours or two (2) years full-time supervised work experience as an alcohol and drug counselor (supervised by at least a CADC-II) •Pass IC&RC Case Presentation Method of Oral Review Examination (see manual for additional information and requirements) •Submit appropriate fees Download the CADC I & II Manual and Handbook now! CADC I/II Manual CADC I/II Handbook Click here for: CADC I & II Certification Requirements Aspira Continuing Education is an approved CE Provider for CAADAC licensees. Some of the online courses Aspira offers can be used toward necessary CE requirements others can be used toward Professional Development requirements. View the table on each course description page to see if that particular course is approved for Certified Alcohol and Drug Counselors CADC I & II. If the course is indicated as approved for CAADAC professionals, then that course can be applied toward CE requirements. If not, then that course can be applied toward Professional Development requirements. View our CE Courses today! View Aspira's CEU Pricing page to see how to pay for Aspira's CE courses. View Aspira's CEU Offers page to see the latest offers and discounts available. Also, see how to earn free CEUs. View our Board Approvals and Accreditations page for provider numbers.

Ketamine Cousin Rapidly Lifts Depression Without Side Effects

Neurons in a subsection of the adult rat hippocampus are stained with a monoclonal antibody (yellow) that enhances learning and memory. A portion of this antibody is where GLYX-13 came from. Source: Dr. Joseph Moskal, Ph.D., Northwestern University GLYX-13, a molecular cousin to ketamine, induces similar antidepressant results without the street drug side effects, reported a study funded by the National Institute of Mental Health (NIMH) that was published last month in Neuropsychopharmacology. Background Major depression affects about 10 percent of the adult population and is the second leading cause of disability in U.S. adults, according to the World Health Organization. Despite the availability of several different classes of antidepressant drugs such as selective serotonin reuptake inhibitors (SSRIs), 30 to 40 percent of adults are unresponsive to these medications. Moreover, SSRIs typically take weeks to work, which increases the risk for suicide. Enter NMDA (N-methyl-D-aspartate) receptor modulators. In the 1970s, researchers linked the receptors to learning and memory. Biotech and pharmaceutical companies in the 1980s attempted to apply chemical blockers to these receptors as a means to prevent stroke. But blocking these receptors led to the opposite effect—--the rise of cardiovascular disease. Research in the field dampened until a glutamate receptor antagonist already approved for anesthesia, and known on the streets as “Special K”, ketamine, made headlines in the early 2000s. Human clinical studies demonstrated that ketamine can ward off major and bipolar depressive symptoms within 2 hours of administration and last for several days. Ketamine is fraught with serious side effects including excessive sleepiness, hallucinations, and substance abuse behavior. “Ketamine lit the field back up,“ said Joseph Moskal, Ph.D., a molecular neurobiologist at Northwestern University and senior study author. “Our drug, GLYX-13, is very different. It does not block the receptor ion channel, which may account for why it doesn’t have the same side effects.” Moskal’s journey with GLYX-13 came about from his earlier days as a Senior Staff Fellow in NIMH’s Intramural Research Program. While at NIMH, he created specific molecules, monoclonal antibodies, to use as new probes to understand pathways of learning and memory. Some of the antibodies he created were for NMDA receptors. When he moved to Northwestern University, Moskal converted the antibodies to small protein molecules. Comprised of only four amino acids, GLYX-13 is one of these molecules. Previous electrophysiological and conditioning studies had suggested that GLYX-13, unlike ketamine, enhanced memory and learning in rats, particularly in the brain’s memory hub or hippocampus. GLYX-13 also produced analgesic effects. Using several rat behavioral and molecular experiments, Moskal’s research team tested four compounds: GLYX-13, an inactive, “scrambled” version of GLYX-13 that had its amino acids rearranged, ketamine, and the SSRI fluoxetine. Results of the Study GLYX-13 and ketamine produced rapid acting (1 hour) and long-lasting (24 hour) antidepressant-like effects in the rats. Fluoxetine, an SSRI that typically takes from 2–4 weeks to show efficacy in humans, did not produce a rapid antidepressant effect in this study. As expected, the scrambled GLYX-13 showed no antidepressant-like effects at all. The researchers observed none of the aforementioned side effects of ketamine in the GLYX-13–treated rats. Protein studies indicated an increase in the hippocampus of the NMDA receptor NR2B and a receptor for the chemical messenger glutamate called AMPA. Electrophysiology studies in this brain region showed that GLYX-13 and ketamine promoted long-lasting signal transmission in neurons, known as long-term potentiation/synaptic plasticity. This phenomenon is essential in learning and memory. The researchers propose how GLYX-13 works: GLYX-13 triggers NR2B receptor activation that leads to intracellular calcium influx and the expression of AMPA, which then is responsible for increased communication between neurons. These results are consistent with data from a recent Phase 2 clinical trial, in which a single administration of GLYX-13 produced statistically significant reductions in depression scores in patients who had failed treatment with current antidepressants. The reductions were evident within 24 hours and persisted for an average of 7 days. After a single dose of GLYX-13, the drug’s antidepressant efficacy nearly doubled that seen with most conventional antidepressants after 4–6 weeks of dosing. GLYX-13 was well tolerated and it did not produce any of the schizophrenia-like effects associated with other NMDA receptor modulating agents. Significance NMDA receptors need a molecule each of the amino acid chemical messengers glutamate and glycine to become activated. Moskal speculates that GLYX-13 either directly binds to the glycine site on the NMDA receptor or indirectly modulates how glycine works with the receptor. Resulting activation of more NMDA and AMPA receptors leads to an increase in memory, learning—and antidepressant effects. By contrast, ketamine only blocks the NMDA receptor, but also increases the activity of the AMPA receptor. Knowledge of these mechanisms could lead to the development of more effective antidepressants. What’s Next GLYX-13 is now being tested in a Phase 2 repeated dose antidepressant trial, where Moskal and his colleagues at Naurex, Inc., a biotechnology company he founded, hope to find in humans the optimal dosing for the drug. They also want to see if this molecule, and others like it, regulate other NMDA receptor subtypes—there are over 20 of them—and whether it will work on other disorders, such as schizophrenia, attention-deficit hyperactivity disorder, and autism. “One could call NMDA modulators such as GLYX-13 ‘comeback kids,’” said Moskal. “A toolkit that I developed in 1983 is now setting the stage in 2013 for the development of possible new therapeutics that may provide individuals suffering from depression with a valuable new treatment option.” Alcoholism and Drug Abuse Counselors Continuing Education Reference Burgdorf J, Zhang X-l, Nicholson KL, Balster RL, Leander JD, Stanton PK, Gross AL, Kroes RA, Moskal JR. GLYX-13, a NMDA Receptor Glycine-Site Functional Partial Agonist, Induces Antidepressant-Like Effects Without Ketamine-Like Side Effects. Neuropsychopharmacology, April 2013. 38:729–742.

Imaging Biomarker Predicts Response to Rapid Antidepressant

Signals Dysfunction in Brain System Targeted by Scopolamine – NIH Study A telltale boost of activity at the back of the brain while processing emotional information predicted whether depressed patients would respond to an experimental rapid-acting antidepressant, a National Institutes of Health study has found. NIMH’s Dr. Maura Furey talks about scopolamine research “We have discovered a potential neuroimaging biomarker that may eventually help to personalize treatment selection by revealing brain-based differences between patients,” explained Maura Furey, Ph.D., of NIH’s National Institute of Mental Health (NIMH). Furey, NIMH’s Carlos Zarate, M.D., and colleagues, reported on their functional magnetic resonance imaging (fMRI) study of a pre-treatment biomarker for the antidepressant response to scopolamine, Jan. 30, 2013, online in JAMA Psychiatry. Scopolamine, better known as a treatment for motion sickness, has been under study since Furey and colleagues discovered its fast-acting antidepressant properties in 2006. Unlike ketamine, scopolamine works through the brain’s acetylcholine chemical messenger system. The NIMH team’s research has demonstrated that by blocking receptors for acetylcholine on neurons, scopolamine can lift depression in many patients within a few days; conventional antidepressants typically take weeks to work. But not all patients respond, spurring interest in a predictive biomarker Alcoholism and Drug Abuse Counselors Continuing Education The acetylcholine system plays a pivotal role in working memory, holding information in mind temporarily, but appears to act by influencing the processing of information rather than through memory. Imaging studies suggest that visual working memory performance can be enhanced by modulating acetylcholine-induced activity in the brain’s visual processing area, called the visual cortex, when processing information that is important to the task. Since working memory performance can predict response to conventional antidepressants and ketamine, Furey and colleagues turned to a working memory task and imaging visual cortex activity as potential tools to identify a biomarker for scopolamine response. Depressed patients have a well-known tendency to process and remember negative emotional information. The researchers propose that this bias stems from dysregulated acetylcholine systems in some patients. They reasoned that such patients would show aberrant visual cortex activity in response to negative emotional features of a working memory task. They also expected to find that patients with more dysfunctional acetylcholine systems would respond better to scopolamine treatment. Before receiving scopolamine, participants performed a working memory task while their brain activity was monitored via fMRI. For some trials, it required that they pay attention to, and remember, the emotional expression (sad, happy, etc.) of faces flashing on a computer monitor. For other trials, they had to pay attention to only the identity, or non-emotional feature, of the faces. After scanning, and over the following several weeks, 15 patients with depression and 21 healthy participants randomly received infusions of a placebo (salt solution) and/or scopolamine. Mood changes were monitored with depression rating scales. Overall, scopolamine treatment reduced depression symptoms by 63 percent, with 11 of the patients showing a significant clinical response. The strength of this response correlated significantly with visual cortex activity during key phases of the working memory task – while participants were paying attention to the emotional content of the faces. There was no such correlation for trials when they attended to the identity of the faces. The findings suggest that acetylcholine system activity drives visual cortex activity that predicts treatment response – and that differences seen between depressed patients and controls may be traceable to acetylcholine dysfunction. Overall, patients showed lower visual cortex activity than controls during the emotion phase of the task. Patients showing activity levels most dissimilar to controls experienced the greatest antidepressant response to scopolamine treatment. Visual cortex activity in patients who didn’t respond to scopolamine more closely resembled that of controls. As hypothesized, the pretreatment level of visual cortex activity appears to reflect the extent of patients’ acetylcholine system dysfunction and to predict their response to the experimental medication, say the researchers. Preliminary evidence suggests that such visual cortex activity in response to emotional stimuli may also apply to other treatments and may prove to be a shared biomarker of rapid antidepressant response, according to Furey. The level of increased activity in left and right visual cortex (blue), while attending to emotional faces in a working memory task, predicted depressed patients’ responsiveness to the experimental antidepressant scopolamine. View from the back of the brain shows fMRI data superimposed on anatomical MRI scan data. Source: Maura Furey, Ph.D., NIMH Experimental Therapeutics and Pathophysiology Branch Working memory task: Over several trials, participants were required to attend to either the identity (non-emotional feature) or the emotion of a face, remember it during a 9 second delay, and match the feature to a subsequent face. Neural activity in the visual cortex elicited by the emotion trials predicted a patient’s subsequent responsiveness to scopolamine treatment. Source: Maura Furey, Ph.D., NIMH Experimental Therapeutics and Pathophysiology Branch References Potential of Pretreatment Neural Activity in the Visual Cortex During Emotional Processing to Predict Treatment Response to Scopolamine in Major Depressive Disorder. Furey ML, Drevets WC, Hoffman EM, Frankel E, Speer AM, Zarate CA. JAMA Psychiatry. 2013 Jan 30:1-11. doi: 10.1001/2013.jamapsychiatry.60. [Epub ahead of print] PMID:23364679 Cholinergic Modulation of Cognition and Emotion in Mood Disorders ### 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.

Many Teens Considering Suicide Do Not Receive Specialized Mental Health Care

HomeScience NewsScience News from 2012Science Update • October 12, 2012

Many Teens Considering Suicide Do Not Receive Specialized Mental Health Care

Source: iStockPhotoMost adolescents who are considering suicide or who have attempted suicide do not receive specialized mental health services, according to an analysis published online August 15, 2012, in Psychiatric Services, a journal of the American Psychiatric Association.

Background

National survey data from the Centers for Disease Control and Prevention (CDC) notes that approximately 14 percent of high school students seriously consider suicide each year, 11 percent have a suicide plan, and 6 percent attempt suicide. Other research has suggested that less than half of teens who attempt suicide received mental health services in the year prior to their attempt.Kathleen Merikangas, Ph.D., of NIMH and colleagues analyzed data from the National Comorbidity Survey-Adolescent Supplement (NCS-A), a nationally representative, face-to-face survey of more than 10,000 teens ages 13 to 18. They asked teens whether they had any suicidal thoughts, plans, or actions (ideation) over a one-year period prior to the survey. They also completed a structured diagnostic interview regarding the full range of mental disorders including mood, anxiety, eating and anxiety disorders and whether they had received treatment for emotional or behavioral problems in the past 12 months. Respondents were asked to differentiate between receiving care from a mental health specialist such as a social worker, psychiatrist or other mental health professional, and receiving care from a general service provider, such as a primary care physician.

Results of the study

The survey revealed that, within the past year, 3.6 percent of adolescents had suicidal thoughts, but did not make a specific plan or suicide attempt. In addition, 0.6 percent reported having a plan, and 1.9 percent reported having made a suicide attempt within the past year.Suicidal behavior among youth was not only associated with major depression, but also with a range of other mental health problems including eating, anxiety, substance use and behavior disorders, as well as physical health problems. Between 50 and 75 percent of those teens who reported having suicidal ideation had recent contact with a service provider. However, most only had three or fewer visits, suggesting that treatment tends to be terminated prematurely. Moreover, most teens with suicidal ideation did not receive specialized mental health care.

Significance

The results of this study suggest that depression and other mood disorders are not the only pathways to suicide. They also highlight the importance of integrating risk assessment for suicide into routine physical and mental health care for teens. Even if adolescents are in treatment, they should continue to be monitored for suicidal ideation and behaviors, the researchers concluded.

Reference

Husky M, Olfson M, He J, Nock M, Swanson S, Merikangas K. Twelve-month suicidal symptoms and use of services among adolescents: results from the National Comorbidity Survey. Psychiatric Services in Advance, Aug 15, 2012. 

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Ready for Your Close-Up?

Caltech study shows that the distance at which facial photos are taken influences perception PASADENA, Calif.—As the saying goes, "A picture is worth a thousand words." For people in certain professions—acting, modeling, and even politics—this phrase rings particularly true. Previous studies have examined how our social judgments of pictures of people are influenced by factors such as whether the person is smiling or frowning, but until now one factor has never been investigated: the distance between the photographer and the subject. According to a new study by researchers at the California Institute of Technology (Caltech), this turns out to make a difference—close-up photo subjects, the study found, are judged to look less trustworthy, less competent, and less attractive. The new finding is described in this week's issue of the open-access journal PLoS One. Pietro Perona, the Allen E. Puckett Professor of Electrical Engineering at Caltech, came up with the initial idea for the study. Perona, an art history enthusiast, suspected that Renaissance portrait paintings often featured subtle geometric warping of faces to make the viewer feel closer or more distant to a subject. Perona wondered if the same sort of warping might affect photographic portraits—with a similar effect on their viewers—so he collaborated with Ralph Adolphs, Bren Professor of Psychology and Neuroscience and professor of biology, and CNS graduate student Ronnie Bryan (PhD '12) to gather opinions on 36 photographs representing two different images of 18 individuals. One of each pair of images was taken at close range and the second at a distance of about seven feet. "It turns out that faces photographed quite close-up are geometrically warped, compared to photos taken at a larger distance," explains Bryan. "Of course, the close picture would also normally be larger, higher resolution and have different lighting—but we controlled for all of that in our study. What you're left with is a warping effect that is so subtle that nobody in our study actually noticed it. Nonetheless, it's a perceptual clue that influenced their judgments." That subtle distance warping, however, had a big effect: close-up photos made people look less trustworthy, according to study participants. The close-up photo subjects were also judged to look less attractive and competent. "This was a surprising, and surprisingly reliable, effect," says Adolphs. "We went through a bunch of experiments, some testing people in the lab, and some even over the Internet; we asked participants to rate trustworthiness of faces, and in some experiments we asked them to invest real money in unfamiliar people whose faces they saw as a direct measure of how much they trusted them." Alcoholism and Drug Abuse Counselors Continuing Education Across all of the studies, the researchers saw the same effect, Adolphs says: in photos taken from a distance of around two feet, a person looked untrustworthy, compared to photos taken seven feet away. These two distances were chosen by the researchers because one is within, and the other outside of, personal space—which on average is about three to four feet from the body. In some of the studies, the researchers digitally warped images of faces taken at a distance to artificially manipulate how trustworthy they would appear. "Once you know the relation between the distance warp and the trustworthiness judgment, you could manipulate photos of faces and change the perceived trustworthiness,'' notes Perona. He says that the group is now planning to build on these findings, using machine-vision techniques—technologies that can automatically analyze data in images. For example, one application would be for a computer program to have the ability to evaluate any face image in a magazine or on the Internet and to estimate the distance at which the photo was taken. "The work might also allow us to estimate the perceived trustworthiness of a particular face image," says Perona. "You could imagine that many people would be interested in such applications—particularly in the political arena." The study, "Perspective Distortion from Interpersonal Distance Is an Implicit Visual Cue for Social Judgments of Faces," was funded by grants from the National Institute of Mental Health and from the Gordon and Betty Moore Foundation. Written by Katie Neith

Studying sex differences in autism focus of $15 million NIH award to Yale center

The reasons why autism spectrum disorders are almost five times more common among boys than among girls may soon be revealed, thanks to a five-year, $15 million National Institutes of Health (NIH) grant awarded to Yale School of Medicine for the Autism Centers of Excellence (ACE) research program. Led by principal investigator Kevin Pelphrey of Yale Child Study Center, the Yale ACE award is part of a $100 million National Institutes of Health grant to nine institutions investigating sex differences in autism spectrum disorders, or ASD, as well as studying ASD and limited speech. Pelphrey and a collaborative team of researchers from Yale, UCLA, Harvard, and the University of Washington, will investigate the poorly understood nature of autism in females. The team will study an unprecedented number of girls with autism and will focus on genes, brain function, and behavior throughout childhood and adolescence. The objectives are to identify causes of autism and develop novel treatments.

ASDs are complex developmental disorders that affect how a person behaves, interacts with others, communicates, and learns. According to the Centers for Disease Control and Prevention, ASD affects approximately 1 in 88 children in the United States. "This award represents an innovative collaboration among three laboratories at Yale led by Drs. Matthew State, James McPartland, and myself," said Pelphrey, the Harris Associate Professor in the Child Study Center, and associate professor of psychology, and director of the Child Neuroscience Laboratory. "It is my hope that this award will invigorate research in autism at Yale and allow us to maintain our outstanding history of cutting edge work in this field." Alcoholism and Drug Abuse Counselors Continuing Education ### NIH created the ACE Program in 2007 to launch an intense and coordinated research program into the causes of ASD and to find new treatments. The program supports large collaborative efforts to advance the broad research goals. The program expanded this year to examine such issues as children and adults who have limited or no speech, possible links between ASD and other genetic syndromes, potential treatments, and the possible reasons why ASDs are more common among boys than girls, according to Alice Kay of the Intellectual and Developmental Disabilities Branch at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), one of five institutes funding the ACE program. In addition to the NICHD, the NIH institutes that support the ACE program are the National Institute on Deafness and Other Communication Disorders, the National Institute of Environmental Health Sciences, the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke. The eight other researchers to receive ACE funding hail from the following institutions: University of California, Emory University, Boston University, University of North Carolina at Chapel Hill, Mount Sinai School of Medicine, and Harvard Medical School. *Research reported here was supported by the National Institute Of Mental Health (NIMH) of the National Institutes of Health under Award Number R01MH100028.

Brain imaging can predict how intelligent you are, study finds

'Global Brain Connectivity' explains 10 percent of variance in individual intelligence When it comes to intelligence, what factors distinguish the brains of the exceptionally smart from those of average humans? As science has long suspected, overall brain size matters somewhat, accounting for about 6.7 percent of individual variation in intelligence. More recent research has pinpointed the brain's lateral prefrontal cortex, a region just behind the temple, as a critical hub for high-level mental processing, with activity levels there predicting another 5 percent of variation in individual intelligence. Now, new research from Washington University in St. Louis suggests that another 10 percent of individual differences in intelligence can be explained by the strength of neural pathways connecting the left lateral prefrontal cortex to the rest of the brain. Published in the Journal of Neuroscience, the findings establish "global brain connectivity" as a new approach for understanding human intelligence. "Our research shows that connectivity with a particular part of the prefrontal cortex can predict how intelligent someone is," suggests lead author Michael W. Cole, PhD, a postdoctoral research fellow in cognitive neuroscience at Washington University. The study is the first to provide compelling evidence that neural connections between the lateral prefrontal cortex and the rest of the brain make a unique and powerful contribution to the cognitive processing underlying human intelligence, says Cole, whose research focuses on discovering the cognitive and neural mechanisms that make human behavior uniquely flexible and intelligent. "This study suggests that part of what it means to be intelligent is having a lateral prefrontal cortex that does its job well; and part of what that means is that it can effectively communicate with the rest of the brain," says study co-author Todd Braver, PhD, professor of psychology in Arts & Sciences and of neuroscience and radiology in the School of Medicine. Braver is a co-director of the Cognitive Control and Psychopathology Lab at Washington University, in which the research was conducted. One possible explanation of the findings, the research team suggests, is that the lateral prefrontal region is a "flexible hub" that uses its extensive brain-wide connectivity to monitor and influence other brain regions in a goal-directed manner. "There is evidence that the lateral prefrontal cortex is the brain region that 'remembers' (maintains) the goals and instructions that help you keep doing what is needed when you're working on a task," Cole says. "So it makes sense that having this region communicating effectively with other regions (the 'perceivers' and 'doers' of the brain) would help you to accomplish tasks intelligently." While other regions of the brain make their own special contribution to cognitive processing, it is the lateral prefrontal cortex that helps coordinate these processes and maintain focus on the task at hand, in much the same way that the conductor of a symphony monitors and tweaks the real-time performance of an orchestra. "We're suggesting that the lateral prefrontal cortex functions like a feedback control system that is used often in engineering, that it helps implement cognitive control (which supports fluid intelligence), and that it doesn't do this alone," Cole says. The findings are based on an analysis of functional magnetic resonance brain images captured as study participants rested passively and also when they were engaged in a series of mentally challenging tasks associated with fluid intelligence, such as indicating whether a currently displayed image was the same as one displayed three images ago. Previous findings relating lateral prefrontal cortex activity to challenging task performance were supported. Connectivity was then assessed while participants rested, and their performance on additional tests of fluid intelligence and cognitive control collected outside the brain scanner was associated with the estimated connectivity. Results indicate that levels of global brain connectivity with a part of the left lateral prefrontal cortex serve as a strong predictor of both fluid intelligence and cognitive control abilities. Although much remains to be learned about how these neural connections contribute to fluid intelligence, new models of brain function suggested by this research could have important implications for the future understanding — and perhaps augmentation — of human intelligence. The findings also may offer new avenues for understanding how breakdowns in global brain connectivity contribute to the profound cognitive control deficits seen in schizophrenia and other mental illnesses, Cole suggests. Alcoholism and Drug Abuse Counselors Continuing Education ### Other co-authors include Tal Yarkoni, PhD, a postdoctoral fellow in the Department of Psychology and Neuroscience at the University of Colorado at Boulder; Grega Repovs, PhD, professor of psychology at the University of Ljubljana, Slovenia; and Alan Anticevic, an associate research scientist in psychiatry at Yale University School of Medicine. Funding from the National Institute of Mental Health supported the study (National Institutes of Health grants MH66088, NR012081, MH66078, MH66078-06A1W1, and 1K99MH096801).

Phase III trial of dapivirine ring begins in Africa: New HIV prevention approach for women

WASHINGTON, D.C., July 24, 2012 – A large clinical trial testing the long-term safety and effectiveness of a new approach for preventing HIV in women – a vaginal ring used once a month – is now underway in Africa, researchers announced today at the XIX International AIDS Conference (AIDS 2012)Alcoholism and Drug Abuse Counselors Continuing Education ASPIRE – A Study to Prevent Infection with a Ring for Extended Use – is a Phase III trial evaluating a vaginal ring that contains dapivirine, a potent antiretroviral (ARV) drug originally developed to treat HIV. The ring slowly releases dapivirine to cells inside the vagina throughout the one-month period that it's worn, potentially giving women discreet, long-acting protection against HIV transmitted through sex. Nearly 3,500 women in Africa will take part in ASPIRE, which is being led by the Microbicide Trials Network (MTN) and funded by the National Institute of Allergy and Infectious Diseases and the National Institute of Mental Health, which are part of the U.S. National Institutes of Health. The Makerere University-Johns Hopkins University Research HIV Clinical Trial Unit in Kampala, Uganda this week began screening women interested in joining the study. A second site, the Emavundleni Research Center at the Desmond Tutu HIV Foundation, University of Cape Town, South Africa, should be ready to screen potential participants next week. The MTN hopes to conduct ASPIRE at a total of 17 sites in Malawi, Uganda, South Africa, Zambia and Zimbabwe. A second trial, The Ring Study, is being conducted in parallel with ASPIRE. The Ring Study is being led by the International Partnership for Microbicides (IPM), which developed the dapivirine ring, and will involve about 1,650 women. IPM has already enrolled more nearly 400 participants at trial sites in South Africa since the study launched in April. The Ring Study will also be conducted in Rwanda and is expected to start there in August. The two sister studies are the first effectiveness trials of a vaginal ring for HIV prevention. Vaginal rings, which are flexible products that fit comfortably high up inside the vagina and are seldom felt by either partner during sex, are already used in many countries as a way to deliver hormonal contraception. ASPIRE and The Ring Study are also the first large-scale prevention trials involving an ARV other than tenofovir or a tenofovir combination. For this reason, and because it is used for a month at a time, the dapivirine ring is seen as an alternative to tenofovir gel used daily or at the time of sex, and oral pre-exposure prophylaxis (PrEP), which involves the use of a daily ARV tablet – tenofovir or Truvada (tenofovir plus emtricitabine). "As a field, we must continue to develop new strategies for HIV prevention. No single approach will be right for every person. In the same way there is a range of effective choices when it comes to birth control, women must have multiple effective options for HIV prevention," explained Jared Baeten, M.D., Ph.D., of the University of Washington in Seattle, who is leading ASPIRE with Thesla Palanee, Ph.D., of the Wits Reproductive Health and HIV Institute (WRHI) in Johannesburg, South Africa. "The most effective HIV prevention product can only work if it's used consistently. The recent PrEP and microbicide studies have taught us that using a product every day can be challenging for many people. A sustained delivery product like a vaginal ring can release an antiretroviral drug in the vagina over an entire month following a single insertion. We think this will be an attractive option for many women, and we hope that women in ASPIRE will like the ring and use it consistently," added Sharon Hillier, Ph.D., principal investigator of the MTN, which is based at the University of Pittsburgh School of Medicine and Magee-Womens Research Institute. ASPIRE is designed to enroll approximately 3,476 HIV-negative women between the ages of 18 and 45 who will be randomly assigned to use either the dapivirine ring or a placebo ring that looks the same but contains no active drug. Participants will be instructed how to insert and remove the ring, which they will replace every four weeks over the course of the one to two years they are in the study. All participants will receive ongoing HIV risk reduction counseling, condoms and diagnosis and treatment of sexually transmitted infections (STIs). The results of ASPIRE, which are expected late 2014 or early 2015, together with results of The Ring Study, as well as smaller, supporting studies, will form the basis of an application that IPM plans to submit to regulatory authorities seeking approval of the dapivirine ring for widespread use. "Through IPM's partnership with MTN and NIH, we are able to conduct two pivotal studies in parallel and get the answers we need quickly," said Zeda Rosenberg, Sc.D., chief executive officer of IPM, a nonprofit product development partnership based in Silver Spring, Md. "Regulators usually require results of two large-scale Phase III trials, along with data from other supporting studies, to approve a product for use. This unique collaboration aims to help us make dapivirine ring available as quickly as possible to women in developing countries if it is proven effective and safe for long-term use." Of the more than 34 million people living with HIV, half are women; and women account for 59 percent of adults with HIV in sub-Saharan Africa, where unprotected heterosexual intercourse is the primary driver of the epidemic. Young women are especially vulnerable; women ages 15 to 24 are up to five times more likely to become infected with HIV than young men. Efforts to promote abstinence, monogamy and the use of male condoms have not been enough to stop the HIV epidemic nor are these practical methods in many settings. IPM is developing dapivirine for use as a microbicide through a royalty-free licensing agreement with Janssen R&D Ireland (previously Tibotec Pharmaceuticals), one of the Janssen pharmaceutical companies of Johnson & Johnson. Dapivirine, also known as TMC-120, belongs to a class of ARVs called non-nucleoside reverse transcriptase inhibitors (NNRTIs) that bind to and disable HIV's reverse transcriptase enzyme, a protein that HIV needs to make copies of itself. In addition to the Uganda and Cape Town, South Africa sites, ASPIRE will be conducted at the following MTN-affiliated trial sites, pending all necessary approvals: In Malawi – the University of North Carolina Clinical Research Site in Lilongwe and the College of Medicine-Johns Hopkins University Research Project at Queen Elizabeth Central Hospital in Blantyre; in South Africa – the Medical Research Council of South Africa in KwaZulu-Natal (seven sites), the eThekwini site for the Centre for the AIDS Programme in Research in South Africa (CAPRISA) in Durban; WRHI in Johannesburg; in Zambia – the Centre for Infectious Diseases Research in Zambia in Lusaka; and, in Zimbabwe – the University of Zimbabwe-University of California, San Francisco HIV Prevention Trials Unit in Harare (three sites). ### More information about ASPIRE is available at http://www.mtnstopshiv.org/news/studies/mtn020 and about The Ring Study at http://www.ipmglobal.org/the-ring-study. About the Microbicide Trials Network The Microbicide Trials Network (MTN) is an HIV/AIDS clinical trials network established in 2006 by the National Institute of Allergy and Infectious Diseases with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health, all components of the U.S. National Institutes of Health. Based at Magee-Womens Research Institute and the University of Pittsburgh, the MTN brings together international investigators and community and industry partners who are devoted to preventing or reducing the sexual transmission of HIV through the development and evaluation of products applied topically to mucosal surfaces or administered orally.

Runaway Vigilance Hormone Linked to Panic Attacks

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 Alcoholism and Drug Abuse Counselors Continuing Education 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.

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."


###


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.

Preference for Moving Shapes vs. People Linked to Autism in Babies

A 1-minute video showing computer screensavers next to videos of dancing children may prove to be a simple, inexpensive screening tool for autism spectrum disorders (ASD) in toddlers. According to an NIMH-funded study, infants as young as 14 months old who had autism spent more time looking at the moving shapes than social images, in contrast to typically developing children and those who had delays but not autism. The study was published online, September 6, 2010, in the Archives of General Psychiatry. Alcoholism and Drug Abuse Counselors Continuing Education


Background
Among the hallmark signs of ASD are repetitive behaviors, which may include persistent and intense preoccupation with objects. For example, a child with ASD may fixate on moving objects or parts of objects, like the moving blade of a fan or spinning tires on a car. Whether this behavior could predict or identify ASD in very young children had not previously been studied.

About the study
To study this phenomenon, Karen Pierce, Ph.D., at the University of California San Diego School of Medicine, and colleagues enrolled 110 toddlers, ages 14-42 months. Of this group, 37 had ASD, 22 were developmentally delayed (DD) but did not have ASD, and 51 had typical development (TD).

The toddlers viewed a 1-minute video showing geometric patterns on one side—basically a computer screensaver—and children exercising, dancing, or otherwise in action on the other side. Using eye tracking technology, the researchers measured how long the toddlers looked at each type of movement and how many times they switched from looking at one type or part of an image to another.

Results
In this study, 40 percent of toddlers with ASD spent significantly more time fixating on moving geometric patterns compared with 9.9 percent in the DD group and 1.9 percent of TD children. The other 60 percent of toddlers with ASD performed similarly to their DD and TD peers, showing a preference for social movement. If a toddler spent more than 69 percent of the time fixating on geometric patterns, ASD could be predicted 100 percent of the time.

While viewing the video, DD and TD children tended to let their eyes wander, changing their focus from one part of an image to another. Among toddlers with ASD, however, those who preferred geometric patterns showed significantly less eye movement when viewing geometric patterns, gazing at only a few parts of an image for extended periods of time. These children also showed significantly more frequent eye movement than DD or TD toddlers when viewing social movement.

A subsample of 41 toddlers were re-tested an average of 8 months later. The researchers found that the toddlers' preferences generally stayed the same between the original study and the follow-up.

Significance
The results suggest that assessing infants' visual preference for geometric vs. social movement, including the amount of time they spend staring at moving geometric patterns, is an inexpensive and easy-to-conduct screening method for ASD.

"What an infant prefers to look at when given a choice between two images may turn out to be a more clearly observable indicator of autism risk than how he or she looks at a single image," Pierce said.

That most of the toddlers with ASD in this study responded in the same way as DD and TD children came as a surprise to the researchers. They suggest that differing patterns of brain activity may underlie toddlers' preference for geometric or social movement. Brain imaging studies would help to confirm whether subgroups of ASD can be distinguished by brain activity patterns.

What's Next
According to the researchers, this screening tool may also be useful in identifying babies who would benefit from further developmental evaluation or even early treatment. The findings also provide new lines of inquiry regarding the role of various brain regions involved in processing social cues and shifting attention in the development of ASD.

Sample "social" image (left) and "geometric" image (right) from Pierce's eye tracking study. Forty percent of babies later diagnosed as having autism preferred to look at the moving geometric images, in contrast to just 2 percent of typically developing babies.

Source: Karen Pierce, Ph.D., UC San Diego

Reference
Pierce K, Conant D, Hazin R, Stoner R, Desmond J. A Preference for Geometric Patterns Early in Life is a Risk Factor for Autism. Arch Gen Psychiatry. 2010 Sep 6. [Epub ahead of print]