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.

Nearly 20 percent of suicidal youths have guns in their home

Researchers say emergency department doctors should screen all pediatric patients for suicide risk WASHINGTON, DC – Nearly one in five children and teens found to be at risk for suicide report that there are guns in their homes, and 15 percent of those at risk for suicide with guns in the home know how to access both the guns and the bullets, according to a study to be presented Monday, May 6, at the Pediatric Academic Societies (PAS) annual meeting in Washington, DC. Suicide is the second leading cause of death among young people ages 10 to 24 years in the United States, according to Centers for Disease Control and Prevention data. Nearly half of youths who die by suicide use a firearm. Researchers conducted a study to create a suicide risk screening tool that health care professionals in emergency departments (EDs) could use to figure out which youths need further mental health evaluation to keep them from harming themselves. As part of that study, researchers asked youths about access to guns in or around their home and about gun/bullet storage. "For more than 1.5 million adolescents, the ED is their primary point of contact with the health care system, which makes the ED an important place for identifying youth at risk for suicide," said Stephen J. Teach, MD, MPH, FAAP, associate chief in the Division of Emergency Medicine at Children's National Medical Center in Washington, DC, and co-author who will be presenting the study at the PAS meeting. Many clinicians and parents do not know how to ask youth about suicide, so they require screening tools to assist in detection, added study senior author Lisa M. Horowitz, PhD, MPH, staff scientist/pediatric psychologist at the National Institute of Mental Health, National Institutes of Health, Bethesda, Md. "According to our data, when asked their opinion, nearly all of the kids in our study were in favor of suicide screening in the ED. Our study shows that if you ask kids directly about suicide, they will tell you what they are thinking." Study participants included 524 patients ages 10 to 21 who were seen for medical/surgical or psychiatric complaints at one of three pediatric EDs. They were asked to fill out a 17-item questionnaire that the researchers used to develop the Ask Suicide-Screening Questions (ASQ), a four-question screening tool that can be used for all pediatric patients visiting the ED. The ASQ has been validated against a longer more in-depth suicide assessment tool. "While many youths who kill themselves have mental health disorders, up to 40 percent of youths who kill themselves have no known mental illness," said co-author and youth suicide expert Jeffrey A. Bridge, PhD, principal investigator at The Research Institute at Nationwide Children's Hospital and associate professor of pediatrics at The Ohio State University. "Therefore, it is important to screen all children and adolescents for suicide, regardless of the reason they are visiting the ED." Of the patients who completed the screening tools, 151 (29 percent) were found to be at risk for suicide, and 17 percent of them reported guns in or around the home. Of those at risk for suicide and reporting guns in the home, 31 percent knew how to access the guns, 31 percent knew how to access the bullets, and 15 percent knew how to access both the guns and the bullets. "This study highlights the importance of parents understanding the risks of having guns in their homes," said Dr. Bridge. "Being at risk for suicide and having access to firearms is a volatile mix. These conversations need to take place in the ED with families of children at risk for suicide." Suicide Prevention CE Course ### To view the abstract, "Access to Firearms among Patients Screening Positive for Suicide Risk in Pediatric Emergency Departments," go to http://www.pas-meeting.org/2013DC/Abstracts/LB%20Pub%20All%202013.pdf The research was supported by the Intramural Research Program of the National Institute of Mental Health, the National Institutes of Health (Drs. Horowitz & Pao); institutional research funds from the Research Institute at Nationwide Children's Hospital and grant K01 MH-69948 from the National Institute of Mental Health (Dr. Bridge); institutional research funds from the Program for Patient Safety and Quality at Boston Children's Hospital Boston (Dr. Wharff). The Pediatric Academic Societies (PAS) are four individual pediatric organizations that co-sponsor the PAS Annual Meeting – the American Pediatric Society, the Society for Pediatric Research, the Academic Pediatric Association, and the American Academy of Pediatrics. Members of these organizations are pediatricians and other health care providers who are practicing in the research, academic and clinical arenas. The four sponsoring organizations are leaders in the advancement of pediatric research and child advocacy within pediatrics, and all share a common mission of fostering the health and well-being of children worldwide. For more information, visit http://www.pas-meeting.org. Follow news of the PAS meeting on Twitter at http://twitter.com/PedAcadSoc.

Forced exercise may still protect against anxiety and stress, says CU-Boulder study

Being forced to exercise may still help reduce anxiety and depression just as exercising voluntarily does, according to a new study by researchers at the University of Colorado Boulder. Past studies have shown that people who exercise are more protected against stress-related disorders. And scientists know that the perception of control can benefit a person's mental health. But it has been an open question whether a person who feels forced to exercise, eliminating the perception of control, would still reap the anxiety-fighting benefits of the exercise. People who may feel forced to exercise could include high school, college and professional athletes, members of the military or those who have been prescribed an exercise regimen by their doctors, said Benjamin Greenwood, an assistant research professor in CU-Boulder's Department of Integrative Physiology. "If exercise is forced, will it still produce mental health benefits?" Greenwood asked. "It's obvious that forced exercise will still produce peripheral physiological benefits. But will it produce benefits to anxiety and depression?" To seek an answer to the question Greenwood and his colleagues, including Monika Fleshner, a professor in the same department, designed a lab experiment using rats. During a six-week period, some rats remained sedentary, while others exercised by running on a wheel. The rats that exercised were divided into two groups that ran a roughly equal amount of time. One group ran whenever it chose to, while the other group ran on mechanized wheels that rotated according to a predetermined schedule. For the study, the motorized wheels turned on at speeds and for periods of time that mimicked the average pattern of exercise chosen by the rats that voluntarily exercised. After six weeks, the rats were exposed to a laboratory stressor before testing their anxiety levels the following day. The anxiety was quantified by measuring how long the rats froze, a phenomenon similar to a deer in the headlights, when they were put in an environment they had been conditioned to fear. The longer the freezing time, the greater the residual anxiety from being stressed the previous day. For comparison, some rats were also tested for anxiety without being stressed the day before. "Regardless of whether the rats chose to run or were forced to run they were protected against stress and anxiety," said Greenwood, lead author of the study appearing in the European Journal of Neuroscience in February. The sedentary rats froze for longer periods of time than any of the active rats. "The implications are that humans who perceive exercise as being forced — perhaps including those who feel like they have to exercise for health reasons — are maybe still going to get the benefits in terms of reducing anxiety and depression," he said. Anxiety Disorders CE Course ### Other CU-Boulder authors include Katie Spence, Danielle Crevling, Peter Clark and Wendy Craig. All the authors are members of Monika Fleshner's Stress Physiology Laboratory in the Department of Integrative Physiology. The research was funded by the National Institutes of Mental Health and the Defense Advanced Research Projects Agency.

Brain scans might predict future criminal behavior

Low anterior cingulate activity linked to repeat offenses ALBUQUERQUE, NM and DURHAM, NC--A new study conducted by The Mind Research Network in Albuquerque, N.M., shows that neuroimaging data can predict the likelihood of whether a criminal will reoffend following release from prison. The paper, which is to be published in the Proceedings of the National Academy of Sciences, studied impulsive and antisocial behavior and centered on the anterior cingulate cortex (ACC), a portion of the brain that deals with regulating behavior and impulsivity. You can view the paper by clicking here: http://www.pnas.org/cgi/doi/10.1073/pnas.1219302110. The study demonstrated that inmates with relatively low anterior cingulate activity were twice as likely to reoffend than inmates with high-brain activity in this region. "These findings have incredibly significant ramifications for the future of how our society deals with criminal justice and offenders," said Dr. Kent A. Kiehl, who was senior author on the study and is director of mobile imaging at MRN and an associate professor of psychology at the University of New Mexico. "Not only does this study give us a tool to predict which criminals may reoffend and which ones will not reoffend, it also provides a path forward for steering offenders into more effective targeted therapies to reduce the risk of future criminal activity." The study looked at 96 adult male criminal offenders aged 20-52 who volunteered to participate in research studies. This study population was followed over a period of up to four years after inmates were released from prison. "These results point the way toward a promising method of neuroprediction with great practical potential in the legal system," said Dr. Walter Sinnott-Armstrong, Stillman Professor of Practical Ethics in the Philosophy Department and the Kenan Institute for Ethics at Duke University, who collaborated on the study. "Much more work needs to be done, but this line of research could help to make our criminal justice system more effective." The study used the Mind Research Network's Mobile Magnetic Resonance Imaging (MRI) System to collect neuroimaging data as the inmate volunteers completed a series of mental tests. "People who reoffended were much more likely to have lower activity in the anterior cingulate cortices than those who had higher functioning ACCs," Kiehl said. "This means we can see on an MRI a part of the brain that might not be working correctly -- giving us a look into who is more likely to demonstrate impulsive and anti-social behavior that leads to re-arrest." The anterior cingulate cortex of the brain is "associated with error processing, conflict monitoring, response selection, and avoidance learning," according to the paper. People who have this area of the brain damaged have been "shown to produce changes in disinhibition, apathy, and aggressiveness. Indeed, ACC-damaged patients have been classed in the 'acquired psychopathic personality' genre." Kiehl says he is working on developing treatments that increase activity within the ACC to attempt to treat the high-risk offenders. ### The four-year study was supported by grants from the National Institute on Drug Abuse (NIDA), the National Institute of Mental Health (NIMH), and pilot funds by the John D. and Catherine T. MacArthur Foundation Law and Neuroscience Project. The study was conducted in collaboration with the New Mexico Corrections Department. ABOUT THE MIND RESEARCH NETWORK The Mind Research Network (MRN), headquartered in Albuquerque, N.M., is committed to advancing the diagnosis and treatment of mental illness and other brain disorders. MRN is a 501(c)3 non-profit organization consisting of an interdisciplinary association of scientists located at universities, national laboratories and research centers around the world and is focused on imaging technology and its emergence as an integral element of neuroscience investigation. The Mind Research Network is a part of the Lovelace Respiratory Research Institute family of companies Professional Counselor Continuing Education Learn more at http://www.mrn.org

Fat-free See-through Brain Bares All

Method Enables 3-D Analysis of Fine Structure and Connections – NIH-funded Study Slicing optional. Scientists can now study the brain’s finer workings, while preserving its 3-D structure and integrity of its circuitry and other biological machinery. A breakthrough method, called CLARITY, developed by National Institutes of Health-funded researchers, opens the intact postmortem brain to chemical, genetic and optical analyses that previously could only be performed using thin slices of tissue. By replacing fat that normally holds the brain’s working components in place with a clear gel, they made its normally opaque and impenetrable tissue see-through and permeable. This made it possible to image an intact mouse brain in high resolution down to the level of cells and molecules. The technique was even used successfully to study a human brain. “CLARITY has the potential to unmask fine details of brains from people with brain disorders without losing larger-scale circuit perspective,” said NIH Director Francis S. Collins, M.D., Ph.D., whose NIH Director’s Transformative Research Award Program helped to fund the research, along with a grant from the National Institute of Mental Health NIMH. “CLARITY will help support integrative understanding of large-scale, intact biological systems, explained Karl Deisseroth, M.D., Ph.D., of Stanford University in California. “It provides access to subcellular proteins and molecules, while preserving the continuity of intact neuronal structures such as long-range circuit projections, local circuit wiring and cellular spatial relationships.” Deisseroth, Kwanghun Chung, Ph.D., and other Stanford colleagues report on their findings April 10, 2013 in the journal Nature. “This feat of chemical engineering promises to transform the way we study the brain’s anatomy and how disease changes it,” said NIMH Director Thomas R. Insel, M.D. “No longer will the in-depth study of our most important three-dimensional organ be constrained by two-dimensional methods.” Until now, researchers seeking to understand the brain’s fine structure and connections have been faced with tradeoffs. To gain access to deeply buried structures and achieve high enough resolution to study cells, molecules and genes, they had to cut brain tissue into extremely thin sections (each a fraction of a millimeter thick), deforming it. Loss of an intact brain also makes it difficult to relate such micro-level findings to more macro-level information about wiring and circuitry, which cuts across slices. In tackling this challenge, the researchers saw opportunity in the fact that the fats, or lipids, that physically support the brain’s working components, such as neurons and their connections, also block chemical probes and the passage of light. So replacing the lipids with something clear and permeable – that would also hold everything else in place – might make it possible to perform the same tests in an intact brain that previously could only be done with brain tissue slices. Deisseroth’s team infused into brain a high-tech cocktail, including a plastic-like material and formaldehyde. When heated, it formed a transparent, porous gel that biochemically integrated with, and physically supported, the brain’s working tissue – while excluding the lipids, which were safely removed via an electrochemical process. The result was a brain transformed for optimal accessibility. They called the new method Clear Lipid-exchanged Anatomically Rigid Imaging/immunostaining-compatible Tissue Hydrogel – CLARITY, for short. Using CLARITY, the researchers imaged the entire brain of a mouse that had been genetically engineered to express a fluorescent protein. A conventional microscope revealed glowing details, such as proteins embedded in cell membranes and individual nerve fibers, while an electron microscope resolved even ultra-fine structures, such as synapses, the connections between neurons. In a series of experiments using CLARITY in mouse brain, the researchers demonstrated that, for the first time, standard immune- and genetics-based tests can be performed repeatedly in the same intact brain. Tracer molecules, such as antibodies, can be readily delivered for staining tissue – or removed – leaving brain tissue undisturbed. The researchers found that CLARITY outperformed conventional methods across a range of previously problematic technical challenges. When they used CLARITY to analyze a post-mortem human brain of a person who had autism, even though it had been hardening in formaldehyde for six years, they were able to trace individual nerve fibers, neuronal cell bodies and their extensions. Free continuing education course material at Aspira Continuing Education Online Courses

Autism Risk Unrelated to Total Vaccine Exposure in Early Childhood

A child’s risk for developing an autism spectrum disorder (ASD) is not increased by receiving “too many vaccines too soon,” according to a new study published in The Journal of Pediatrics. Although previous scientific evidence has shown that vaccines do not cause autism, more than 1 in 10 parents refuse or delay vaccinations for their young children. A main safety concern of these parents is the number of vaccines administered, both on a single day and over the course of a child’s first 2 years of life. In the first study of its kind, researchers from the CDC and Abt Associates, Inc. compared vaccine records for over 1000 children born from 1994–1999, some of whom were later diagnosed with ASD. The researchers calculated the total number of vaccine antigens each child received between birth and age 2, as well as the maximum number of antigens each child received on a single day. The study found that the total number of vaccine antigens received was the same between children with ASD and those without ASD. Additionally, antigen number was also found to be unrelated to the development of two sub-categories of ASD—autistic disorder and ASD with regression LCSW Continuing Education The researchers concluded, “The possibility that immunological stimulation from vaccines during the first 1 or 2 years of life could be related to the development of ASD is not well-supported by what is known about the neurobiology of ASDs.”

NIH Study Shows People with Serious Mental Illnesses Can Lose Weight

People with serious mental illnesses such as schizophrenia, bipolar disorder and major depression can lose weight and keep it off through a modified lifestyle intervention program, a National Institute of Mental Health (NIMH)-funded study reported online today in The New England Journal of Medicine. Over 80 percent of people with serious mental illnesses are overweight or obese, which contributes to them dying at three times the rate of the overall population. They succumb mostly to the same things the rest of the population experiences—cardiovascular disease, diabetes and cancer. Although antipsychotic medications increase appetite and cause weight gain in these patients, it is not the only culprit. Like the general population, sedentary lifestyle and poor diet also play a part. Lifestyle modifications such as diet and exercise should work for these patients, yet they are often left out of weight loss studies. “People with serious mental illnesses are commonly excluded from studies to help them help themselves about their weight,” said Gail L. Daumit, M.D., of Johns Hopkins University, Baltimore, and the study’s lead author. “We’re showing that serious mentally ill patients can make successful, sustained changes with proper interventions.” This study could usher in new forms of weight loss treatment for people with serious mental illness. “Until now, obesity among those with serious mental illnesses has not received adequate attention,” said NIMH Director Thomas R. Insel, M.D. “People with serious mental illnesses need more attention to their physical health. This study provides convincing evidence these individuals can make substantial lifestyle changes and therefore should suffer fewer medical complications as they age.” Other factors that preclude people with serious mental illnesses from losing weight include memory impairments or residual psychiatric symptoms that impede learning and adopting new behaviors such as counting calories. Socioeconomics are also a factor as many can’t afford or can’t get to physical activity programs like fitness gyms. Some patients additionally suffer from social phobia or have poor social interactions, and are simply afraid to work out in a public area. Daumit’s group attempted to solve these issues by bringing the gyms and nutritionists to places most of these patients frequent—psychiatric rehabilitation outpatient programs. Under the trial name ACHIEVE, the researchers randomized 291 participants in 10 rehab centers around Maryland to receive the usual care, consisting of nutrition and physical activity information, or six months of intensive intervention consisting of exercise classes three times a week along with individual or group weight loss classes once a week. Both groups were followed for an additional year, during which the weight loss classes of the intervention arm tapered down but the exercise classes remained constant. The intervention arm included goals such as reducing caloric intake by avoiding sugar-sweetened beverages and junk food; eating five servings of fruits and vegetables daily; choosing smaller portions and healthy snacks; and moderate intensity aerobic exercise. Participants in the specially tailored weight loss program lost seven pounds more than the controls—and continued to lose weight and did not regain, despite the reduced frequency of classes and counseling sessions. In contrast, the general population tends to experience peak weight loss in the first six months and then rebound and gain part or all of their weight back. On average, each participant was on three psychotropic medications, with half on lithium or mood stabilizers, all known to cause weight gain. But no matter what they were on, they lost the weight. “We’re showing behavioral interventions work regardless of what they’re taking,” Daumit said. Her group is now looking for ways to spread the program. VIDEO Project Achieve is the first weight loss clinical trial to include people with serious mental illnesses. Reference Effects of a behavioral weight loss intervention in persons with serious mental illness. Daumit GL, Dickerson FB, Wang N-Y, Dalcin A, Jerome GJ, Anderson CAM, Young DR, Frick KD, Yu A, Gennusa III JV, Oefinger M, Crum RM, Charleston J, Casagrande SS, Guallar E, Goldberg RW, Campbell LM, Appel LJ. NEJM, March 21, 2013 Professional Counselor Continuing Education Grant number: MH080964 ### 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.