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People with severe mental illness such as schizophrenia or bipolar disorder have a higher risk for substance use, especially cigarette smoking, and protective factors usually associated with lower rates of substance use do not exist in severe mental illness, according to a new study funded by the National Institute on Drug Abuse (NIDA), part of the National Institutes of Health.

Estimates based on past studies suggest that people diagnosed with mood or anxiety disorders are about twice as likely as the general population to also suffer from a substance use disorder. Statistics from the 2012 National Survey on Drug Use and Health indicate close to 8.4 million1 adults in the United States have both a mental and substance use disorder. However, only 7.9 percent of people receive treatment for both conditions, and 53.7 percent receive no treatment at all, the statistics2 indicate.

Studies exploring the link between substance use disorders and other mental illnesses have typically not included people with severe psychotic illnesses.

“Drug use impacts many of the same brain circuits that are disrupted in severe mental disorders such as schizophrenia,” said NIDA Director Dr. Nora D. Volkow. “While we cannot always prove a connection or causality, we do know that certain mental disorders are risk factors for subsequent substance use disorders, and vice versa.”

In the current study, 9,142 people diagnosed with schizophrenia, schizoaffective disorder, or bipolar disorder with psychotic features, and 10,195 controls matched to participants according to geographic region, were selected using the Genomic Psychiatry Cohort3 program. Mental disorder diagnoses were confirmed using the Diagnostic Interview for Psychosis and Affective Disorder (DI-PAD), and controls were screened to verify the absence of schizophrenia or bipolar disorder in themselves or close family members. The DI-PAD was also used for all participants to determine substance use rates.

Compared to controls, people with severe mental illness were about 4 times more likely to be heavy alcohol users (four or more drinks per day); 3.5 times more likely to use marijuana regularly (21 times per year); and 4.6 times more likely to use other drugs at least 10 times in their lives. The greatest increases were seen with tobacco, with patients with severe mental illness 5.1 times more likely to be daily smokers. This is of concern because smoking is the leading cause of preventable death in the United States.

In addition, certain protective factors often associated with belonging to certain racial or ethnic groups – or being female – did not exist in participants with severe mental illness. “In the general population, women have lower substance use rates than men, and Asian-Americans have lower substance use rates than white Americans, but we do not see these differences among people with severe mental illness,” said Dr. Sarah Hartz, from the Washington University School of Medicine in St. Louis and first author on the study. “We also saw that among young people with severe mental illness, the smoking rates were as high as smoking rates in middle-aged adults, despite success in lowering smoking rates for young people in the general population.”

Previous research has shown that people with schizophrenia have a shorter life expectancy than the general population, and chronic cigarette smoking has been suggested as a major contributing factor to higher morbidity and mortality from malignancy as well as cardiovascular and respiratory diseases. These new findings indicate that the rates of substance use in people with severe psychosis may be underestimated, highlighting the need to improve the understanding of the association between substance use and psychotic disorders so that both conditions can be treated effectively.

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A study of 230 patients with bipolar I disorder whose symptoms were severe enough to warrant admission to a Rhode Island psychiatric hospital in 2010 reveals that more than a third were there despite taking four or more psychiatric medications. Including medicines for other conditions, such as cardiometabolic diseases, the average patient came to the hospital taking six different drugs.

The study quantifies a difficult outcome for many patients with this difficult-to-treat disorder, said study lead author Lauren Weinstock of the Alpert Medical School of Brown University and of Butler Hospital, where the patients were admitted: They accrue a high burden of prescriptions each with their own side effects, with often unknown interactions, and with a complexity that can result in not taking the medications as prescribed. This medication burden also includes high overall cost to patients and the healthcare system.

Yet for those patients who’ve needed to come to the hospital, these complex combinations of drugs haven’t proven sufficiently effective, Weinstock said.

The study, published online in the journal Psychiatry Research, also reports the likelihood of a high medication burden was significantly greater for women than men.

“The high rate of complex polypharmacy reflects the enormous challenge of symptom management that we currently face for bipolar disorder,” said Weinstock, an assistant professor of psychiatry and human behavior at Brown. “Without many treatment alternatives, this is where we are as a field. It is important for us to advance science and treatment of bipolar disorder so that this medication burden can be minimized for our patients.”

Weinstock, who studies psychotherapy as a complement to medical treatment at Butler, said she and her colleagues became motivated to quantify the pharmacological burden for those with biploar disorder after witnessing it anecdotally among patients.

‘Complex polypharmacy’

Graph of results
While 19 percent of bipolar disorder patients in the study were not taking any psychotropic medications, 36 percent were taking three or more meeting the definition of “complex polypharmacy.”
Image credit: Brown University

Weinstock and her co-authors therefore compiled data from patients’ hospital admission records in the calendar year 2010. The only inclusion criteria were being 18 or older, and having a diagnosis of bipolar I disorder at hospital admission and discharge.

“The data aren’t confounded by someone’s active participation in a research study,” Weinstock said. “We wanted to measure what was happening in routine community practice.”

What they found is that when they came to the hospital, patients were taking an average of 3.3 psychotropic drugs and an average of 5.9 drugs overall. Nearly one in five patients weren’t on any psychotropic drugs, but more than half were taking 3 or more and more than a third were taking four or more, meeting the definition of “complex polypharmacy.”

The complex polypharmacy rate of 36 percent is higher than in a few previous studies that looked at bipolar patients, Weinstock said, because those studies did not always include all psychotropic medications, such as the commonly prescribed antianxiety medications.

Weinstock noted that because no clinical trial of bipolar medications has ever tested more than two drugs in combination, prescribing three or four exceeds practices supported by the field.

“By definition that’s not evidence-based treatment,” she said.

No prior studies had looked at the total medication burden, rather than just that of pyschotropics. It’s important to do so, Weinstock said, because cardiometabolic diseases, in particular, are often concurrent with bipolar disorder. Among the 230 patients in the study, for example, about half had such medical problems.

More so for women

Women, the data showed, were 58 percent of the total patients, but 68 percent of those with complex polypharmacy. Women were more likely to be on an antidepressant, antianxiety medication, and on stimulants, all of which which remain somewhat controversial in bipolar disorder treatment, Weinstock said.

The proportion of women taking an antidepressant (43 percent) was nearly twice that of men (23 percent). The significance of the gender disparities in the study endured even after statistically controlling for depressive symptoms in their diagnosis.

“Women weren’t prescribed more medications just because they were more likely to be depressed,” Weinstock said. “This finding raises the question of what other factors may influence higher rates of polypharmacy among female patients, such as patient or provider characteristics.”

But the study does not provide information that could reveal why that is.

Still, combined with other studies and epidemiological data, the study points to a trend that needs improving, Weinstock and her co-authors wrote: “This increased reliance on polypharmacy does not appear to be contributing to decreased rates of illness chronicity or functional impairment in BD.”

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Researchers from Trinity College in Dublin, Ireland, have identified a risk gene mutation for schizophrenia and bipolar disorder that increases chances of developing the conditions by more than 10-fold. The team says they found this mutation is inherited from a distant but common European ancestor.

The international team, led by Prof. Aiden Corvin at Trinity’s School of Medicine, says identifying this genetic mutation provides the medical community with insight into potential risk mechanisms for these disorders, the cause of which is poorly understood.

Results of their study are published in the journal Human Molecular Genetics.

Although treatments are available for schizophrenia and bipolar disorder, and evidence is increasingly suggesting these disorders share common genetic risk factors, the team says response to treatments varies and knowledge of the underlying biology has mostly eluded scientists.

Bipolar disorder affects around 4% of the world’s population, and schizophrenia impacts around 51 million people around the world (about 1% of the world’s population), the team says.

For their research, the investigators analyzed blood samples from over 1,564 Irish people with schizophrenia and 1,748 controls who did not have the disorder. They looked for small structural differences in the genome where material is either duplicated or deleted.

First author of the study Dr. Derek Morris, from the National University of Ireland (NUI), Galway, explains that when replication of a genome takes place, there can be small “editing” problems known as mutations:

“This is how diversity happens in biology and is like a typo in a book; it happens rarely and the context will determine how the ‘word,’ or in our case a protein, is affected.”

Carriers of genetic mutation share common European ancestor

Through their study, the researchers found five patients in which a gene – called Protein-Activated Kinase 7 (PAK7) – was duplicated. This duplication was not found in anyone in the control group, they note.

Diagram of a DNA strand under a magnifying glass
After looking for structural differences in the genomes of European subjects, the researchers found that a rare duplication in the PAK7 gene increased risks of developing schizophrenia or bipolar disorder 10-fold.

After identifying this genetic mutation in Irish people, the team extended their sample to include more than 25,000 people from Europe.

They confirmed that although this duplication is rare, it increases the risks of developing schizophrenia or bipolar disorder more than 10-fold.

Additionally, the team observed that in all cases, the duplications were very similar, suggesting the carriers share a single mutation that was inherited from a common European ancestor long ago.

Prof. Corvin says their findings show how gene discovery can provide new information on devastating disorders that are not well understood.

“Treatment in this area has advanced little in the last 40 years,” he adds. “Making progress in understanding the molecular mechanisms of disease gives me hope that new, effective treatments will emerge as has been the case in other branches of medicine, such as cancer treatment.”

According to the authors, the PAK7 gene family promotes growth and maintenance of brain connections in a pathway that is regulated by a previously known risk gene, called DISC1.

Both DISC1 and PAK7 interact with each other at the synapse level, the researchers say, which suggests that PAK signaling helps maintain synaptic networks – a mechanism that may play a role in development of schizophrenia and bipolar disorder.

Next step: how to reverse duplication interference with brain cell function

Prof. Corvin explains that their study shows the Irish population may be perfect for their gene discovery program, adding that the gene mutation likely came from a Northern European individual over 500 years ago.

“We believe that more is to be found in the Irish population and this will help us to reach a more general understanding about the nature of these disorders,” he says.

Regarding future research, Dr. Morris says:

“In our PAK7 example, about a third of the gene was replicated. For us the next steps will be to understand how this duplication interferes with brain cell function and to test how this might be reversed.”

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To answer the seemingly simple question “Have I been here before?” we must use our memories of previous experiences to determine if our current location is familiar or novel. In a new study published in the Journal of Neuroscience researchers from the RIKEN Brain Science Institute have identified a region of the hippocampus, called CA2, which is sensitive to even small changes in a familiar context. The results provide the first clue to the contributions of CA2 to memory and may help shed light on why this area is often found to be abnormal in the schizophrenic brain.

Change comes in many flavors; if we move to a new country, city or house it is easy to recognize the novelty of the environment, but if we come home to find the furniture rearranged or a new piece of art on the wall, this recognition may be much slower. Scientists believe this is because memory formation requires comparing current information with previous experience and the larger the overlap, the more difficult the distinction. It has long been known that the hippocampus is a region of the brain crucial for this type of memory, however the identification of neurons responsible for this comparison has remained elusive.

In this study Marie Wintzer, Roman Boehringer, Denis Polygalov and Thomas McHugh used genetically modified mice and advanced cell imaging techniques to demonstrate that while the entire hippocampus is capable of detecting large changes in context, the small and often overlooked CA2 region is exquisitely sensitive to small changes.

Mice were familiarized with one context and then placed either in a much different context or back in the original with small alterations, such as several new small objects. By detecting the expression of activity induced genes Wintzer and colleagues were able to demonstrate that just a few new objects in the otherwise unchanged context completely altered the pattern of active cells specifically in CA2. Mice that had been genetically engineered to lack this CA2 response explored the new context much less than their normal siblings.

“CA2 has often been overlooked or simply grouped together with its more prominent neighbors, but these data suggest it’s unique and important for recognizing and reacting to changes in our environments” explains Dr. McHugh, the leader of the study.

Compared to rodents, human CA2 is proportionally larger, but still as mysterious. One intriguing finding has been that early in the onset of schizophrenia and bipolar disorder there is a loss of inhibitory neurons specifically in CA2. In addition to the memory problems that accompany these diseases, patients often exhibit a hyper-sensitivity to changes in environment and routine. This study suggests there may be a functional relationship between this sensitivity and CA2 dysfunction, hinting at a new circuit to target in our attempts to understand the function of both the normal and diseased brain.

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Treatment regimens often evolve without strong scientific evidence of their benefits and drawbacks, particularly in comparison to other drugs or approaches.

Now Duke Medicine is participating in a large national initiative aiming to fill in that missing information.

In separate articles published in the Annals of Internal Medicine, teams led by the Duke Clinical Research Institute detailed the research priorities necessary to address gaps in knowledge about two conditions – bipolar disorder among adolescents and early breast tumors in women.

The two diverse conditions provide similar challenges for patients, doctors and health system administrators: The diagnosis is often not clear-cut, while typical treatments come with a trade-off of benefits and serious side effects.

Collaborating with clinical experts, patients, patient advocates, and other stakeholders, the two Duke-led teams worked to identify and rank the important gaps in knowledge that should be the focus of new research.

Aiming patient-focused research efforts and dollars at such clinical uncertainties is the mission of a national initiative called the Patient-Centered Outcomes Research Institute (PCORI), which was established three years ago under the Affordable Care Act. Using funds from the insurance mandate, PCORI is working to improve the quality of research, speed it into clinical practice, and assure that it answers the most pressing questions and concerns of patients.

In the case of bipolar disorder among adolescents and young adults, the Duke researchers noted that establishing this diagnosis is particularly complex, and the condition can be difficult to distinguish from other behavioral disorders, including attention deficit hyperactivity disorder. Yet the use of antipsychotic drugs for this condition has increased dramatically over the past two decades, and carries with it a high risk of weight gain, diabetes and other problems.

“This is clearly an important area of clinical uncertainty that will benefit from more research,” said Matthew J. Crowley, M.D., assistant professor of medicine in the Division of Endocrinology, Diabetes and Metabolism at Duke and lead author of the study addressing research priorities for adolescents with bipolar disorder.

Likewise with ductal carcinoma in situ – tiny breast lesions detected via mammography – considerable uncertainty has evolved over whether to treat the condition as cancer. Many of the lesions may never progress to life-threatening invasive cancer, while treatment plans call for mastectomy, lumpectomy and radiation.

“We don’t have a good handle on how to distinguish between the cases that will develop into invasive cancers, and those that are harmless,” said Jennifer Gierisch, Ph.D., assistant professor of medicine in the Division of General Internal Medicine at Duke and lead author of the breast cancer paper. “There is a lot of uncertainty about what a diagnosis means and how to proceed around a diagnosis. Our goal is to identify research priorities to address these questions and reduce the uncertainty for both patients and doctors.”

Members of the Duke Clinical Research Institute have been key players in the PCORI initiative, led by Robert Califf, M.D., who is a co-principal investigator of PCORI’s national clinical research network. The group will amass, coordinate and manage the database of medical information that researchers can use to learn how well treatments work.

PCORI has also funded research at Duke, including the work of the two teams that identified research priorities in bipolar disorder and breast cancer. PCORI has provided additional funding for other Duke Clinical Research Institute members to:
◾ Track the effectiveness of stroke treatments, particularly among older people, women and minority patients;
◾ Determine the benefits and risks of different stroke rehabilitation services after hospitalizations;
◾ Develop and expand a network of patients, advocates and doctors around pediatric arthritis and other rheumatic diseases;
◾ Study the effectiveness of treatments for aortic heart valve disease, comparing “real-world” outcomes for two different methods of valve replacement;
◾ Compare the results of randomized trials, which are considered the gold standard, against observational studies.

“We are pleased to be able to contribute to such an important national enterprise,” Califf said. “Patients deserve to know the comparative risks and benefits of treatment alternatives, and PCORI is providing the focus to provide this critical knowledge.”

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Bipolar disorder is characterized by dramatic changes in mood, energy and activity levels that impact a person’s ability to carry out everyday tasks. The exact cause of the condition is unknown. But now, researchers are one step closer to finding out with the discovery of two new genetic regions that are connected to the disease.

The international research team, led by investigators from Germany and Switzerland, recently published their findings in the journal Nature Communications.

Although the cause of bipolar disorder is unclear, researchers do know that genetic factors play a large part.

“There is no one gene that has a significant effect on the development of bipolar disorder,” says Dr. Markus M. Nöthen, of the University of Bonn Hospital in Germany.

“Many different genes are evidently involved and these genes work together with environmental factors in a complex way.”

For their study, the researchers obtained genetic data from 2,226 patients with bipolar disorder and 5,028 individuals without the condition. This data was merged with existing data sets and analyzed.

This led to the comparison of genetic material from 9,747 bipolar patients with that of 14,728 healthy individuals – the largest investigation of the genetic foundations of bipolar disorder to date, according to the researchers.

The team says that the search for genes involved in bipolar disorder is like “looking for a needle in a haystack.” Dr. Sven Cichon, of the University of Basel Hospital in Switzerland, explains that individual genes make contributions to the disease that are so small, it is difficult to identify them.

However, comparing the DNA of large numbers of bipolar patients with the DNA of large numbers of healthy individuals makes this process easier, as differences between the two groups can be confirmed statistically.

Five risk regions found, two newly discovered

Using their large data collection, the investigators analyzed around 2.3 million different genetic regions, first in the bipolar patients, then in the healthy controls.

Fast facts about bipolar disorder

•Biopolar disorder affects around 5.7 million adults in the US every year.
•Onset of the disorder usually occurs in late teens or early adult years.
•Children who have a parent or sibling with bipolar disorder are much more likely to develop the illness.

Subsequent evaluation of these regions revealed five risk regions on DNA that are associated with bipolar disorder.

Three of these regions – ANK3, ODZ4 and TRANK1 – have been described in previous studies, although the researchers note that they were statistically better confirmed in this study.

But the other two risk regions – ADCY2 on chromosome five and so-called MIR2113-POU3F2 on chromosome six – were newly discovered.

The research team says the ADCY2 region is of particular interest, as it codes an enzyme that plays a part in sending signals to nerve cells.

“This fits very well with observations that the signal transfer in certain regions of the brain is impaired in patients with bipolar disorder,” explains Dr. Nöthen.

The research team concludes that their findings – particularly the discovery of the ADCY2 risk region – provide new insight into the biological mechanisms involved in the development of bipolar disorder.

Dr. Nöthen adds:

“Only when we know the biological foundations of this disease can we also identify starting points for new therapies.”

Last year, Medical News Today reported on a study detailing new brain scans that measure blood flow, which could diagnose bipolar disorder in its early stages and differentiate it from depression.

Written by Honor Whiteman

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First on top of the world and then in the depths of despair – this is what the extreme mood changes for people with bipolar disorder are like. Under the direction of scientists from the University of Bonn Hospital, the Central Institute of Mental Health of Mannheim and the University of Basel Hospital, an international collaboration of researchers discovered two new gene regions which are connected with the prevalent disease. In addition, they were able to confirm three additional suspect genes. In this unparalleled worldwide study, the scientists are utilizing unprecedented numbers of patients. The results are now being published in the renowned journal “Nature Communications”.

Throughout the course of their lives, about one percent of the population suffers from bipolar disorder, also known as manic-depressive disorder. The patients undergo a veritable rollercoaster of emotions: During extreme shifts, they experience manic phases with delusions of grandeur, increased drive and a decreased need for sleep as well as depressive episodes with a severely depressed mood to the point of suicidal thoughts. The causes of the disease are not yet fully understood, however in addition to psychosocial triggers, genetic factors play a large role. “There is no one gene that has a significant effect on the development of bipolar disorder,” says Prof. Dr. Markus M. Nöthen, Director of the Institute of Human Genetics of the University of Bonn Hospital. “Many different genes are evidently involved and these genes work together with environmental factors in a complex way.”

Scale of the investigation is unparalleled worldwide

In recent years, scientists at the Institute of Human Genetics were already involved in decoding several genes associated with bipolar disorder. The researchers working with Prof. Dr. Marcella Rietschel from the Central Institute of Mental Health of Mannheim, Prof. Dr. Markus M. Nöthen from the University of Bonn Hospital and Prof. Dr. Sven Cichon from the University of Basel Hospital are now using unprecedented numbers of patients in an international research collaboration: New genetic data from 2266 patients with manic-depressive disorder and 5028 control persons were obtained, merged with existing data sets and analyzed together. In total, data on the genetic material of 9747 patients were compared with data from 14,278 healthy persons. “The investigation of the genetic foundations of bipolar disorder on this scale is unique worldwide to date,” says Prof. Rietschel from the Central Institute of Mental Health of Mannheim.

The search for genes involved in manic-depressive disorder is like looking for a needle in a haystack. “The contributions of individual genes are so minor that they normally cannot be identified in the ‘background noise’ of genetic differences,” explains Prof. Cichon from the University of Basel Hospital. Only when the DNA from very large numbers of patients with bipolar disorder are compared to the genetic material from an equally large number of healthy persons can differences be confirmed statistically. Such suspect regions which indicate a disease are known by scientists as candidate genes.

Two new gene regions discovered and three known gene regions confirmed

Using automated analysis methods, the researchers recorded about 2.3 million different regions in the genetic material of patients and comparators, respectively. The subsequent evaluation using biostatistical methods revealed a total of five risk regions on the DNA associated with bipolar disorder. Two of these regions were newly discovered: The gene “ADCY2” on chromosome five and the so-called “MIR2113-POU3F2” region on chromosome six. The risk regions “ANK3”, “ODZ4” and “TRANK1” have already been described in prior studies. “These gene regions were, however, statistically better confirmed in our current investigation – the connection with bipolar disorder has now become even clearer,” says Prof. Nöthen.

The researchers are particularly interested in the newly discovered gene region “ADCY2”. It codes an enzyme which is involved in the conduction of signals into nerve cells. “This fits very well with observations that the signal transfer in certain regions of the brain is impaired in patients with bipolar disorder,” explains the human geneticist of the University of Bonn Hospital. With their search for genetic regions, the scientists are gradually clarifying the causes of manic-depressive disorder. “Only when we know the biological foundations of this disease can be also identify starting points for new therapies,” says Prof. Nöthen.

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Lithium, one of the oldest and most widely used drugs to treat neuropsychiatric illnesses, such as bipolar disorder, has a serious drawback – toxicity. In a continued effort to find a safer form of lithium, researchers at the University of South Florida (USF) have discovered that lithium salicylate, an alternative salt form, might be the answer.

The researchers found that oral lithium salicylate produced steady lithium levels up to 48 hours in rats without the toxic spike associated with the rapid absorption of current FDA-approved lithium carbonate. They concluded that lithium salicylate could be more effective than lithium carbonate, yet without accompanying risks of toxicity, a potentially important development in the next generation of lithium therapeutics.

Their study results appeared in a recent issue of RSC Advances, the journal of the Royal Society of Chemistry.

While lithium carbonate has been very effective for the treatment of mania in bipolar disorder, and credited for reducing suicides in depressive phases of the disease, patients who take lithium carbonate are often noncompliant because of adverse effects, including hand tremor, diarrhea, vomiting, weight gain and decreased thyroid function. New drugs that are as effective as lithium carbonate, but without toxicity, have not been forthcoming.

“Despite its narrow therapeutic window and the emergence of proprietary alternatives, U.S. FDA-approved lithium therapeutics are still regarded as the ‘gold standard’ for the treatment of the manic phase of bipolar disorder,” said study lead author Adam J. Smith, PhD, a neuroscientist at the Center of Excellence for Aging and Brain Repair, Department of Neurosurgery, at USF Health.

“Our previous research suggested that re-engineering lithium therapeutics by crystal engineering might produce better performance with reduced toxicities.”

Crystal engineering is the design and synthesis of molecular solid crystal structures with desired properties using intermolecular interactions, Smith said.

For their latest study published in RSC Advances, the researchers tested two previously untested salts of lithium – salicylate and lactate – both of which are structurally different from lithium carbonate. In laboratory rats, they found that lithium salicylate and lithium lactate exhibited “profoundly different pharmacokinetics” when compared to the FDA-approved and widely used lithium carbonate. Pharmacokinetics is the way the body absorbs, distributes and gets rid of a drug.

“To our knowledge, this is the first pharmacokinetic study of lithium salicylate and lithium lactate in laboratory animals,” Smith said.

The findings support earlier suggestions that an ideal lithium preparation would be one that would both “flatten” high blood level peaks and also slow declining blood concentrations, the researchers report.

“This is exactly the pharmacokinetic profile produced by lithium salicylate in our study,” said senior author Doug Shytle, PhD, also of the Center of Excellence for Aging and Brain Repair at USF Health. “Remarkably, lithium salicylate produced elevated levels of lithium in the blood and brain 48 hours after the dose, but without the sharp peaks that contribute to the toxicity problems of lithium in the currently used form.”

That 48-hour window, the researchers said, represents a critical difference between lithium salicylate and current FDA-approved lithium therapeutics. If these preclinical results hold true in humans, this would allow for a less frequent dosing regimen and possibly fewer troublesome side effects that plague conventional lithium therapy.

“Psychiatry has long struggled with the fact that, while lithium is highly effective for treating bipolar disorder, the narrow therapeutic window and side effect profile often makes lithium both difficult and sometimes dangerous to work with clinically,” said Todd Gould, MD, of the Department of Psychiatry at the University of Maryland, an expert in the mechanisms of lithium and the neurobiology of bipolar disorder.

“The pharmacokinetic data by Dr. Smith and colleagues suggests that lithium salts other than the commonly used lithium carbonate may have a broader therapeutic window and potentially fewer side effects. Studies in humans will be needed to confirm safety and demonstrate that the pharmacokinetic profile observed in rats is similarly observed in humans.”

USF researchers continue to pursue a safer, more effective lithium therapy, and expect to soon conduct the experiments required to support early clinical trials.

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New research suggests that a commonly used mood-stabilizing drug – valproic acid – could help reduce the risk of developing head and neck cancer.

The research team, led by Dr. Johann Christoph Brandes of the Atlanta Veterans Medical Center and Emory University in Atlanta, GA, recently published their findings in the journal Cancer.

Valproic acid (VPA) is a medication used to treat epilepsy and manic-depressive illness, such as bipolar disorder.

However, the medication is able to block histone acetyl transferases (HATs) – enzymes that control gene expression by altering DNA structure. This is a process that occurs in the early stages of many cancers, including lung, bladder, prostate, and head and neck cancers.

Therefore, the researchers investigated whether VPA has the potential to be used as an anticancer agent.

The team analyzed information from the National Veterans Affairs (VA) Medical SAS data set linked to the VA Central Cancer Registry. This involved 439,628 veterans, of which 26,911 were taking VPA for bipolar disorder, post-traumatic stress disorder, migraine and seizures.

‘VPA could prevent 16,000 new cases of head and neck cancer’

Results of the analysis revealed that individuals who had been using VPA for at least 1 year had a 34% lower risk of developing head and neck cancer, compared with those who did not use the medication.

Headache migraine
Researchers say VPA – a drug used to treat migraines, seizures and manic-depressive illness – may be effective in reducing the risk of head and neck cancer.

The researchers found that the risk reduction for head and neck cancer was most pronounced in individuals who took VPA for at least 3 years.

However, the team notes that they were not able to determine the optimal duration for which VPA should be taken because the number of patients in the study with longer exposure was limited.

Furthermore, the investigators found that higher doses of VPA were associated with a greater reduction in head and neck cancer risk. But again, the team was unable to determine the optimal dosage.

According to the National Cancer Institute, head and neck cancers account for approximately 3% of all cancers in the US and mainly occur in people aged over 50. At least 75% of all head and neck cancers are caused by tobacco and alcohol use.

Dr. Brandes says that a 34% risk reduction in head and neck cancer with VPA use equates to around 16,000 new cases and between 3,000 and 4,000 deaths being prevented in the US alone.

He says:

“Head and neck cancer is an important global health crisis, and low-cost and low-toxicity prevention strategies like VPA use have a high potential impact on pain, suffering, costs, and mortality associated with this disease.”

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It is unclear what causes bipolar disorder – a condition characterized by dramatic changes in mood. But researchers from the University of Michigan Medical School have created the first stem cell model for bipolar disorder, which they say could uncover the origins of the condition and open the door to new treatments.

The research team recently published their study in the journal Translational Psychiatry.

To reach their findings, the investigators obtained skin samples from people with bipolar disorder, alongside skin samples from individuals without the condition.

By exposing small samples of skin cells to carefully controlled conditions, the researchers turned them into induced pluripotent stem cells (iPSCs). These are stem cells that have the potential to be turned into any other type of cell. The team then turned the iPSCs into neurons.

They measured gene expression of the iPSCs and then re-evaluated gene expression once the stem cells became neurons.

From this, the team found significant differences between the stem cells taken from bipolar patients and those taken from individuals without the condition.

Bipolar patients ‘express more genes for calcium signaling’

Stem cell lines
The stem cell lines were made from the skin of bipolar patients.
Image credit: University of Michigan Medical School

The researchers found that the neurons from bipolar patients expressed more genes for membrane receptors and ion channels than the neurons from non-bipolar patients – particularly genes for receptors and channels involved in sending and receiving calcium signals between cells.

Since calcium signals play a significant role in neuron development and function, the investigators say their findings suggest that genetic differences in early brain development may contribute to the development of bipolar and other mental health conditions later in life.

When the researchers exposed the neurons to lithium – a chemical that bipolar patients often use to regulate their mood – signaling patterns changed.

The researchers explain that lithium changes how calcium signals are sent and received, so these new cell lines will allow them to determine the mechanisms behind this in cells specific to bipolar patients.

The team also found that the neurons from bipolar patients were “addressed” differently during development than those from non-bipolar patients, meaning signaling could be misdirected. They say this could affect brain development.

Furthermore, the researchers found differences in microRNA expression – small RNA fragments that play an important role in “reading” genes – in the cells of bipolar patients. The teams says this discovery supports the idea that bipolar disorder develops from a “combination of genetic vulnerabilities.”

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