New Drug Developments for Bipolar Mania

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The current “gold standard” for treating bipolar disorder is lithium, but a review of clinical research has found that other drugs may be more effective for acute episodes of mania without the side effects of lithium (“New drug developments for bipolar mania,” Psychiatric Times, Dec. 2012).

Lithium has been associated with negative side effects, including sedation and weight gain, which can impact adherence to the treatment. A meta-analysis of recent clinical findings found lithium to be one of several medications that were more effective than placebo for mania. Another meta-analysis concluded that some of the alternative medications “were significantly more effective than mood stabilizers” in bipolar treatment.

“Because strong evidence exists for the use of lithium . . . as a maintenance treatment for BP, antipsychotics may be increasingly used to treat the acute manic phase of the disorder and mood stabilizers (particularly lithium) may be used for long-term treatment,” the authors suggested.

With research for new mental illness medications in serious decline, identification of what the authors call “novel and more effective treatments” – including the application of existing medications to new situations – is encouraging.

–Treatment Advocacy Center

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Ketamine Cousin Rapidly Lifts Depression Without Side Effects

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.”

–National Institute of Mental Health

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VA, DOD and HHS Partner to Expand Access to Mental Health Services for Veterans, Service Members and Families

The Departments released an interim report outlining progress on this initiative, including: 1) increasing the capacity of the Veterans Crisis Line by 50 percent to help ensure that Veterans in crisis can readily reach help; 2) establishing 15 pilot projects in seven states where VA is working with community-based mental health providers to help Veterans access mental health services in a timely way; 3) increasing VA mental health services capacity through VA hiring of nearly 1,400 mental health providers and over 248 new peer specialists; and 4) implementing a national suicide prevention campaign to connect Veterans and Service Members to mental health services.

Federal Department actions to date include:

Suicide Prevention:  VA and DoD jointly developed and are implementing a national suicide prevention campaign to connect Veterans and Service Members to mental health services.  This year-long effort began Sep. 1, 2012.  The program continues to save lives and link Veterans with effective ongoing mental health services on a daily basis.  As of March 2013, the Veterans Crisis Line (1-800-273-8255, press 1) has received over 814,000 calls, over 94,000 chats, as well as over 7,200 texts, and has helped more than 28,000 Veterans in imminent danger.  VA has also completed the hiring and training of additional staff to increase the capacity of the Veterans Crisis Line that were called for in the Executive Order. In addition, the DoD has initiated a thorough review of its mental health and substance abuse prevention, education and outreach programs informed by the expertise of the Department of Health and Human Services’ Substance Abuse and Mental Health Services Administration.

Enhanced Partnerships Between the VA and Community Providers:  VA worked with HHS to help identify potential local community resources to improve Veterans access to mental health services.  VA has enhanced access to mental health care by establishing 15 VA pilot agreements with clinics in local communities to improve access to mental health service.

Expanded VA Mental Health Staffing:  As of May 7, 2013, VA has hired a total of 1,360 mental health clinical providers towards the goal of 1,600 new mental health professionals outlined in the Executive Order. Additionally, VA has hired 2,036 mental health clinical providers to fill existing vacancies.   VA has also hired nearly 250 new peer specialists in support of the specific goal of 800 peer specialists outlined in the Executive Order.  The interim report indicated that as of Jan. 29, 2013, VA had hired 1,058 mental health clinical providers in support of the specific goal of 1,600 mental health professionals, and over 100 peer specialists in support of the specific goal of 800 peer specialists.

Improved Research and Development: The development of a National Research Action Plan to better understand and develop treatments for post-traumatic stress disorder (PTSD), traumatic brain injury (TBI), and co-occurring conditions; and identify strategies to support collaborative research efforts to address suicide prevention is underway. VA, DoD and HHS and the Department of Education have collaborated and submitted the plan on time. DoD and VA are investing more than $100 million in new research to improve diagnosis and treatment of Traumatic Brain Injury (mTBI) and Post-traumatic Stress Disorder (PTSD).  They have launched two initiatives to establish joint DoD/VA research consortia with academia and industry partnerships to study the chronic effects of mild TBI and PTSD.

Working together, the Departments will continue to expand the public health approach to providing optimal support for the mental health needs of Veterans, Service Members and their families.  They also will continue to provide updates on their work as it progresses.

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Taming Suspect Gene Reverses Schizophrenia-Like Abnormalities in Mice

NIH-Funded Study Raises Hope for Recovery of Some Adult Patients, Despite Early Damage    

Scientists have reversed behavioral and brain abnormalities in adult mice that resemble some features of schizophrenia by restoring normal expression to a suspect gene that is over-expressed in humans with the illness. Targeting expression of the gene Neuregulin1, which makes a protein important for brain development, may hold promise for treating at least some patients with the brain disorder, say researchers funded by the National Institutes of Health.

Like patients with schizophrenia, adult mice biogenetically-engineered to have higher Neuregulin 1 levels showed reduced activity of the brain messenger chemicals glutamate and GABA. The mice also showed behaviors related to aspects of the human illness. For example, they interacted less with other animals and faltered on thinking tasks.

“The deficits reversed when we normalized Neuregulin 1 expression in animals that had been symptomatic, suggesting that damage which occurred during development is recoverable in adulthood,” explained Lin Mei, M.D., Ph.D., of the Medical College of Georgia at Georgia Regents University, a grantee of NIH’s National Institute of Mental Health (NIMH).

Mei, Dong-Min Yin, Ph.D., Yong-Jun Chen, Ph.D., and colleagues report on their findings May 22, 2013, in the journal Neuron.

“While mouse models can’t really do full justice to a complex brain disorder that impairs our most uniquely human characteristics, this study demonstrates the potential of dissecting the workings of intermediate components of disorders in animals to discover underlying mechanisms and new treatment targets,” said NIMH Director Thomas R. Insel, M.D. “Hopeful news about how an illness process that originates early in development might be reversible in adulthood illustrates the promise of such translational research.”

Schizophrenia is thought to stem from early damage to the developing fetal brain, traceable to a complex mix of genetic and environmental causes. Although genes identified to date account for only a small fraction of cases, evidence has implicated variation in the Neuregulin 1 gene. For example, postmortem studies have found that it is overexpressed in the brain’s thinking hub, or prefrontal cortex, of some people who had schizophrenia. It codes for a chemical messenger that plays a pivotal role in communication between brain cells, as well as in brain development.

Prior to the new study, it was unclear whether damage caused by abnormal prenatal Neuregulin 1 expression might be reversible in adulthood. Nor was it known whether any resulting behavioral and brain deficits must be sustained by continued errant Neuregulin 1 expression in adulthood.

To find out, the researchers engineered laboratory mice to mimic some components of the human illness by over-expressing the Neuregulin 1 gene in the forebrain, comparable to the prefrontal cortex in humans. Increasing Neuregulin 1 expression in adult animals was sufficient to produce behavioral features, such as hyperactivity, social and cognitive impairments, and to hobble neural communications via the messenger chemicals glutamate and GABA.

Unexpectedly, the abnormalities disappeared when the researchers experimentally switched off Neuregulin 1 overexpression in the adult animals. Treatment with clozapine, an antipsychotic medication, also reversed the behavioral abnormalities. The researchers traced the glutamate impairment to an errant enzyme called LIMK1, triggered by the overexpressed Neuregulin 1 – a previously unknown potential pathological mechanism in schizophrenia.

The study results suggest that even if their illness stems from disruptions early in brain development, adult patients whose schizophrenia is rooted in faulty Neuregulin 1 activity might experience a reduction in some of the symptoms following treatments that target overexpression of the protein, say the researchers.

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FDA Investigating Long-Acting Zyprexa Shots After Two Deaths

The Food and Drug Administration says it is investigating the unexplained deaths of two patients in the wake of receiving intramuscular injections of the antipsychotic medication Zyprexa (generic name olanzapine). The patients died three to four days after receiving appropriate doses of Zyprexa Relprevv, which is designed to release slowly into the blood over two to four weeks and provide regular dosing for adults with schizophrenia.

The FDA says the deaths occurred well after the three-to-four-hour window following injection during which patients should be monitored in a physician’s office for a potentially deadly complication called post-injection delirium sedation syndrome (PDSS). Characterized by severe drowsiness, unconsciousness, coma or delirium, PDSS appears to be caused by a rapid buildup of olanzapine in the blood. High doses of olanzapine can cause cardiopulmonary arrest or cardiac arrhythmias, as well as delirium and extreme sedation.

Both deceased patients were found to have “very high olanzapine blood levels after death,” the FDA said. But since their deaths occurred days, not hours, after their injections of Zyprexa Relprevv, their connection to the so-called “depot medication” is uncertain. Clinical trials leading to the approval of the long-acting treatment for schizophrenia saw no deaths in subjects, and found instances of PDSS only in the first several hours following injection.

Under the Risk Evaluation and Mitigation Strategy (REMS) approved for Zyprexa Relprevv in December 2009, the injections and the three-hour post-injection period of monitoring must take place in a facility certified by the FDA to provide the shots. A long-acting injection can be a particular benefit in treating those with schizophrenia, who frequently fail to take oral medications on the prescribed schedule.

“At this time, the FDA is continuing to evaluate these deaths and will provide an update when more information is available,” the federal drug agency said Tuesday.

by Melissa Healy, Los Angeles Times

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BRAIN Initiative Website

NIH has launched new site as the place for the broader community to discuss the new BRAIN (Brain Research through Advancing Innovative Neurotechnologies) Initiative and provide important feedback regarding the BRAIN Initiative’s scientific agenda. This Initiative, launched by President Obama on April 2, 2013 focuses on accelerating the development and application of innovative new technologies to enable scientists to create a dynamic picture of brain function.

BRAINFEEDBACK.NIH.GOV

Are Multiple Concussions Driving Suicides in the Military?

The U.S. military has faced two epidemics over the last decade of war in Afghanistan and Iraq.

One is suicide. The annual rate of military personnel taking their own lives has doubled to about 20 per 100,000. That translated to a record 324 suicides in the Army last year.

The other is concussion, also known as mild traumatic brain injury, or TBI. The proliferation of roadside bombs has subjected thousands of troops to brain-rattling explosions.

Several studies have suggested a link between the two epidemics — that service members who suffered concussions are at greater risk for suicide.

by Alan Zarembo, Los Angeles Times

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Abnormal Rich Club Organization and Functional Brain Dynamics in Schizophrenia

Importance: The human brain forms a large-scale structural network of regions and interregional pathways. Recent studies have reported the existence of a selective set of highly central and interconnected hub regions that may play a crucial role in the brain’s integrative processes, together forming a central backbone for global brain communication. Abnormal brain connectivity may have a key role in the pathophysiology of schizophrenia.

Objective  To examine the structure of the rich club in schizophrenia and its role in global functional brain dynamics.

Design  Structural diffusion tensor imaging and resting-state functional magnetic resonance imaging were performed in patients with schizophrenia and matched healthy controls.

Results  Rich club organization between high-degree hub nodes was significantly affected in patients, together with a reduced density of rich club connections predominantly comprising the white matter pathways that link the midline frontal, parietal, and insular hub regions. This reduction in rich club density was found to be associated with lower levels of global communication capacity, a relationship that was absent for other white matter pathways. In addition, patients had an increase in the strength of structural connectivity–functional connectivity coupling.

Conclusions  Our findings provide novel biological evidence that schizophrenia is characterized by a selective disruption of brain connectivity among central hub regions of the brain, potentially leading to reduced communication capacity and altered functional brain dynamics.

The human brain is a complex network of structurally and functionally interconnected regions. Studies examining the brain’s underlying network structure are motivated by the notion that brain function is not solely attributable to the properties of individual regions or individual connections but rather emerges from the network organization of the brain as a whole, the human connectome. Conversely, brain dysfunction may result from abnormal wiring of the brain’s network.

The notion that schizophrenia, a severe psychiatric disorder characterized by hallucinations, delusions, loss of initiative, and cognitive dysfunction, may relate to disconnectivity among brain regions has a long history. As cited by Stephan, Wernicke was among the first to suggest that schizophrenia may involve anatomical disruption of association pathways. Bleuler, who coined the term schizophrenia, hypothesized that decoupling of psychological processes might be the primary cause of the disease. Lately, studies using imaging techniques, such as diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI), have reported widespread disconnectivity in patients, in particular reduced integrity of frontal and temporal white matter connections and affected functional coupling of the default mode network.

A few highly connected and central regions, the so-called hub nodes, have a key role in the global topology of the brain’s network. Previous network studies report disruptions in the overall organization of structural connectivity (SC) and functional connectivity (FC) in patients with schizophrenia, together with a less centralized position of some of these hubs in the frontal, temporal, and parietal cortex. However, it remains unknown whether reduced connectivity of hubs constitutes a nonspecific generalized phenomenon involving white matter connectivity to and from all brain regions or whether this disruption disproportionally involves pathways that link highly connected regions. In the healthy brain, hubs have been found to be densely interconnected, together forming a central core or rich club, with rich club connections having a pivotal role in interregional brain communication. We test the hypothesis that disturbed wiring of this central rich club may contribute to the pathophysiology of schizophrenia.

Using neuroimaging data in a group of 48 patients and 45 healthy controls, we examined potentially abnormal connectivity of the brain’s rich club and the relationship of a disruption of this communication backbone to (reduced) levels of global communication capacity and changed functional dynamics in the brain networks of patients. An independently acquired data set of patients and controls (41 patients and 51 controls) was used to replicate possible findings.

Martijn P. van den Heuvel, PhD; Olaf Sporns, PhD; Guusje Collin, MD; Thomas Scheewe, PhD; René C. W. Mandl, PhD; Wiepke Cahn, MD, PhD; Joaquín Goñi, PhD; Hilleke E. Hulshoff Pol, PhD; René S. Kahn, MD, PhD

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People With Behavioral Health Conditions Are More Likely to Smoke. Psychologists Are Among Those Working to Understand Why and Helping Them Quit

For people with mental illnesses, just staying alive can be challenging: People with serious mental illness treated in the public health system die a startling 25 years earlier than those without mental illness, according to a 2006 article in Preventing Chronic Disease. The problem hasn’t improved in the years since, Morris notes, and all too often, smoking is part of that mortal equation.

Tobacco-related illnesses including cancer, heart disease and lung disease are among the most common causes of death in this population. And Americans with mental illnesses have a 70 percent greater likelihood of smoking than the general population, according to new findings from researchers at the Centers for Disease Control and Prevention (Morbidity and Mortality Weekly Report, Feb. 8). People with mental illnesses also smoke more often than smokers without mental illness, says Tim McAfee, MD, director of the CDC’s Office on Smoking and Health and a co-author of the report. “We can’t just ignore this population.”

In some cases, people with mental illness may be using tobacco to mask symptoms or medication side effects, McAfee says. Some might also be more affected by nicotine withdrawal. “People with panic attacks, for instance, may have a harder time quitting because the symptoms of withdrawal — such as increased heart rate — can trigger an attack,” he says.

Quitting smoking does not impair mental health recovery. On the contrary, tobacco use is associated with greater depressive symptoms, a greater likelihood of psychiatric hospitalization and an increase in suicidal behavior. Abstaining from cigarettes, on the other hand, can help people with other addictions maintain sobriety, as Prochaska reported in 2010 in Drug and Alcohol Dependence. And despite some misconceptions, mental health patients can stop smoking; studies have shown that people with depression, schizophrenia and post-traumatic stress disorder can quit without impairing their mental health recovery, Prochaska says. She works with smokers with a full range of psychiatric disorders, recruited from acute inpatient settings. Using a combination of motivational approaches, cognitive-behavioral therapy and nicotine-replacement medications, she says, “we’re seeing quit rates comparable to those you see in the general population.”

Not only can mental health patients quit, says Morris, many of them would very much like to. “If you ask them, people with behavioral health conditions want to quit at the same rate as the general population, but we were not giving them the same resources and affording them the same opportunities to change,” he says. “At the bottom line, this is a patients’ rights issue.”

By Kirsten Weir, American Psychological Association (APA)

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Avatars Ease Voices for Schizophrenia Patients

Use of an avatar can help treat patients with schizophrenia who hear voices, a UK study suggests.

The trial, published in the British Journal of Psychiatry, focused on patients who had not responded to medication.

Using customised computer software, the patients created avatars to match the voices they had been hearing.

After up to six therapy sessions most patients said their voice had improved. Three said it had stopped entirely.

The study was led by psychiatrist emeritus professor Julian Leff, who spoke to patients through their on-screen avatars in therapy sessions. Gradually he coached patients to stand up to their voices.

The avatar gradually changes to saying, ‘all right I’ll leave you alone’”

“I encourage the patient saying, ‘you mustn’t put up with this, you must tell the avatar that what he or she is saying is nonsense, you don’t believe these things, he or she must go away, leave you alone, you don’t need this kind of torment’,” said Prof Leff.

“The avatar gradually changes to saying, ‘all right I’ll leave you alone, I can see I’ve made your life a misery, how can I help you?’ And then begins to encourage them to do things that would actually improve their life.”

By the end of their treatment, patients reported that they heard the voices less often and that they were less distressed by them. Levels of depression and suicidal thoughts also decreased, a particularly relevant outcome-measure in a patient group where one in 10 will attempt suicide.

by Lorna Stewart, BBC

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