Category: Schizophrenia

Schizophrenia is a mental disorder that differs between the sexes in terms of age at onset, symptomatology, response to medication, and structural brain abnormalities. Now, a new study from the Université de Montréal shows that there is gender difference between men and women's mental ability — with women performing better than men.

These findings were published recently in Schizophrenia Research.

"We are the first to report sex differences in brain function of schizophrenics," says Université de Montréal professor, Adrianna Mendrek a researcher at the Centre de Recherche Fernand-Seguin, Hospital Louis-H Lafontaine. "We chose to study a task involving mental rotation of a three dimensional image because in healthy men and women, this consistently elicits differences in terms of reaction time and performance accuracy."

Results opposite for control versus schizophrenics

Mendrek and her colleagues compared the brain function of healthy volunteers with schizophrenic patients that were completing the image rotation task by using magnetic resonance imaging (fMRI). Their findings confirmed that healthy men performed better than healthy women in this task, but found that schizophrenic women performed better than schizophrenic men.

"Sex hormones such as testosterone and estrogen may explain these results," says Mendrek. "Findings from our other studies have shown that the testosterone level was positively correlated with activity in healthy men but not in healthy women. And conversely schizophrenic women have been shown to have higher levels of this hormone."

Surprising result: gender differences in "resting" brains

The resting brains of healthy men and women are not the same, according to Mendrek. The area of the brain active while resting (the "default mode network") is more active for women than men. "We are the first group to report sex differences in this network using fMRI," says Mendrek. "The more active resting female brain may explain their reported ability to multi-task and be more introspective than men"

Previous studies have shown that the default network is perturbed in people suffering from depression, Alzheimer's or schizophrenia. In particular, reduced default network activity has been associated with autism, and over-activity is associated with schizophrenia, more specifically with schizophrenia-positive symptoms such as hallucinations and delusions.

This study was funded by the Canadian Institutes of Health Research, the Institute of Gender and Health and the Fonds de la recherché en santé Québec, as well as Hopital Louis-H. Lafontaine Foundation.

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Journal Reference:

1. José A. Jiménez, Adham Mancini-Marïe, Nadia Lakis, Melissa Rinaldi, Adrianna Mendrek. Disturbed sexual dimorphism of brain activation during mental rotation in schizophrenia. Schizophrenia Research, 2010; 122 (1-3): 53 DOI: 10.1016/j.schres.2010.03.011

Estrogen is an elixir for the brain, sharpening mental performance in humans and animals and showing promise as a treatment for disorders of the brain such as Alzheimer's disease and schizophrenia. But long-term estrogen therapy, once prescribed routinely for menopausal women, now is quite controversial because of research showing it increases the risk of cancer, heart disease and stroke.

Northwestern Medicine researchers have discovered how to reap the benefits of estrogen without the risk. Using a special compound, they flipped a switch that mimics the effect of estrogen on cortical brain cells. The scientists also found how estrogen physically works in brain cells to boost mental performance, which had not been known.

When scientists flipped the switch, technically known as activating an estrogen receptor, they witnessed a dramatic increase in the number of connections between brains cells, or neurons. Those connections, called dendritic spines, are tiny bridges that enable the brain cells to talk to each other.

"We created more sites that could allow for more communication between the cells," said lead investigator Deepak Srivastava, research assistant professor in neuroscience at Northwestern University Feinberg School of Medicine. "We are building more bridges so more information can go from one cell to another."

The findings will be presented Nov. 17 at Neuroscience 2010 in San Diego. Peter Penzes, associate professor of physiology and of psychiatry and behavioral sciences at the Feinberg School, is the senior investigator.

Previous research has shown an increase in dendritic spines improves mental performance in animals. In humans, people who have Alzheimer's disease or schizophrenia often have a decrease in these spines.

"We think there is a strong link between the number of dendritic spines and your mental performance," Srivastava said. "A major theory is if you increase the number of spines, it could be a way to treat these significant mental illnesses. "

Northwestern scientists also found strong clues that estrogen can be produced in cortical brain cells. They identified aromatase, a critical protein needed to produce estrogen, to be in precisely the right spot in the brain cell to make more dendritic spines.

"We've found that the machinery needed to make estrogen in these brain cells is near the dendritic spines," Srivastava said. "It's exactly where it's needed. There's a lot of it in the right place at the right time. "

Next, Srivastava said, he wants to further identify the key molecules involved in the dendritic spine production and target them in the same way as the estrogen receptor in order to ultimately be able to treat schizophrenia and other mental disorders.

Nick Brandon, head of psychiatry at Pfizer Inc., whose group collaborated with the Penzes lab for this work, added, "We are very excited by the emerging data in this area. There is a great deal of literature and precedent for a role of estrogen and estrogen signaling in major mental illnesses. This adds to our understanding of the specific neuronal functions. As we understand the effects of these specific estrogen receptor beta compounds in preclinical models, we are discovering effects on specific neuronal functions, which could be relevant for the treatment of cognitive disorders, depression and schizophrenia. "

The research was supported by the National Institutes of Health, the American Heart Association and the National Alliance for Research into Schizophrenia and Depression.

The potential for harmful side effects associated with anti-psychotic medications for treating schizophrenia is a frustration for mental-health professionals who must balance this with the positive benefits of drugs. For example, the issue of the antipsychotic drug ziprasidone lengthening the QTc interval, a possible indicator of life-threatening heart arrhythmias, has demanded much attention among clinicians since the drug was introduced in 2001.

Ziprasidone (marketed as Geodon and Zeldox by Pfizer Inc.) was the fifth second-generation anti-psychotic to gain Food and Drug Administration (FDA) approval. These second-generation drugs have been thought to be associated with a lower risk of suicides, better functional capacity, and an improved quality of life for people with schizophrenia. (It is well known that patients with schizophrenia suffer an overall increased risk of death.) But questions remained as to whether the modest QTc prolongation caused by ziprasidone would translate into increased mortality for the patients using it.

A study published online this month in the American Journal of Psychiatry in advance of print publication in February 2011 showed no difference in nonsuicide mortality between people taking ziprasidone and another second-generation anti-psychotic in real-world use.

Because the number of patients exposed to ziprasidone at the time of marketing authorization was too small to allow for estimation of QTc-related effects on mortality, and because such studies would not reflect real-world prescribing practices, the Ziprasidone Observational Study of Cardiac Outcomes (ZODIAC) was initiated to provide safety assurance for the use of the drug. ZODIAC was a post-approval commitment by the drug's manufacturer, Pfizer, Inc., to the FDA.

ZODIAC is an international, multimember, randomized trial designed to examine the risks of nonsuicidal mortality and hospitalization associated with ziprasidone and olanzapine, another second-generation anti-psychotic approved by the FDA for the treatment of schizophrenia and bipolar disorder. Brian Strom, MD, director of the Center for Clinical Epidemiology and Biostatistics at the University of Pennsylvania School of Medicine, chaired the steering committee that designed and directed the ZODIAC study. Strom is also chair of the Department of Biostatistics and Epidemiology and Vice Dean for Institutional Affairs in the School of Medicine.

Olanzapine (marketed as Zyprexa and other brands names by Eli Lilly and Comp.) was selected for comparison in the study because it was not linked to QTc prolongation in the literature or in a controlled pharmacokinetic study of several agents compared with ziprasidone. The main objective of ZODIAC was to evaluate nonsuicide mortality, which limited the study's ability to provide data on drug efficacy.

ZODIAC, an open-label, randomized trial, enrolled over 18,000 patients with schizophrenia in 18 countries. The primary outcome measure was nonsuicide mortality in the year after initiation of treatment. Patients were randomly assigned to receive treatment with either ziprasidone or olanzapine and followed for one year by unblinded investigators providing usual care. A physician-administered questionnaire was used to collect baseline demographic information, medical and psychiatric history, and concomitant medication use. Follow-up information on hospitalizations and emergency department visits, patients' vital status, and current antipsychotic drug status was also collected.

A total of 205 deaths occurred overall in the study population. Despite the known risk of QTc prolongation with ziprasidone treatment, the findings did not show that ziprasidone is associated with an elevated risk of nonsuicidal mortality relative to olanzapine in real-world use. However the study was not designed to examine the risk of rare cardiac events associated with lengthening of the QTc interval.

"We could not disprove that the drug caused abnormal heart rhythms, but that was not the goal of the study," says Strom. "Our goal was to determine whether there was a difference in risk of nonsuicide death, and there was not."

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Journal Reference:

1. B. L. Strom, S. M. Eng, G. Faich, R. F. Reynolds, R. B. D'Agostino, J. Ruskin, J. M. Kane. Comparative Mortality Associated With Ziprasidone and Olanzapine in Real-World Use Among 18,154 Patients With Schizophrenia: The Ziprasidone Observational Study of Cardiac Outcomes (ZODIAC). American Journal of Psychiatry, 2010; DOI: 10.1176/appi.ajp.2010.08040484

Working to change the behaviour of family members may be an effective treatment for people with schizophrenia, according to a new Cochrane systematic review. The researchers reviewed the most up-to-date evidence on the subject and found that patients whose families received the interventions were less likely to relapse.

It has long been known that people who have schizophrenia are more likely to relapse if they come from families where they experience high levels of criticism, hostility and over involvement. New psychosocial interventions that aim to reduce levels of these potentially negative emotions are now widely used, although their effectiveness has not been proved.

The researchers reviewed data from 53 trials involving a total of 4,708 patients. Interventions lasted from six weeks to three years and involved a range of psychosocial techniques aimed at reducing stress and levels of expressed emotions, and helping family members to solve patient problems. Patients in control groups were given standard care, including their usual drug treatments. Patients were assessed using a wide variety of different scales for general and mental health, social functioning, behaviour and quality of life.

The main benefit of family interventions was a decrease in relapses. Results from 32 of the trials showed that for every seven patients whose relatives were given family interventions, one benefited compared to control groups. Family interventions also significantly reduced hospital admissions over a year, improved patients' social functioning and encouraged them to stick to drug treatment regimes.

"Prevention of relapse is a cornerstone of psychiatric care," said lead researcher Fiona Pharoah of Oxford and Buckinghamshire Mental Health NHS Foundation Trust, UK. "If high quality family services are available, mental health professionals and managers may feel that family interventions are a worthwhile investment of time and effort for schizophrenic patients." However, the numbers of patients that would need to be treated in order to see a benefit may deter policy makers from investing in family interventions.

Co-author John Rathbone, of the Health Economics and Decision Science department at the University of Sheffield, points out that there are still differences of opinion about the evidence base for family interventions in schizophrenia. "We still need a better designed large study to settle arguments about this widely used therapy," he said. "Some of the important data within the studies that were reviewed were poorly reported and patients might have reason to feel let down by the research community in these cases."

Researchers have uncovered a prominent genetic risk factor for autism spectrum disorders and schizophrenia. The study, published by Cell Press on Nov. 4 in the American Journal of Human Genetics, reports a small genomic deletion in patients with these neurological conditions. The region includes a gene in which mutations cause a kidney disease (renal cysts and diabetes syndrome, RCAD).

ASDs include a range of neurodevelopmental conditions that are being diagnosed at an increasing rate. The Center for Disease Control and Prevention estimates that ASD currently affects 1 in 110 people. The prevalence of schizophrenia, with a diagnostic rate of 1 in 100 to 1 in 20, is similar. ASD and schizophrenia affect males more often than females, and both are thought to have a strong and overlapping genetic component.

"The genetic overlap between ASD and schizophrenia, both of which have a high heritability, has been the focus of several recent studies; however, no single specific genetic cause accounts for more than 1%-2% of cases," says Dr. Daniel Moreno-De-Luca, the lead author of the study.

Dr. Moreno-De-Luca and colleagues analyzed genomic DNA from more than 23,000 patients with ASD, developmental delay, or schizophrenia. They were looking for DNA duplications or deletions referred to as copy-number variants (CNV). Remarkably, they found the same deletion on chromosome 17 in 24 separate patients. This CNV was absent in 52,448 controls, making the finding statistically significant.

"We calculate the risk for this combined sample (ASD and schizophrenia) to be at least 13.58, and probably much higher," says Dr. David H. Ledbetter of Emory University. An odds ratio of 13.58 means that someone with this deletion is 13.58 times more likely to develop ASD or schizophrenia than is someone lacking this CNV.

The gene highlighted in this study is one of 15 contained within the deletion. Mutations in HNF1B have been associated with RCAD, and a number of the studied ASD patients were found to have a family history of kidney disease and/or diabetes. Conversely, RCAD patients often present with neurodevelopmental disorders.

"The phenotypic spectrum of patients with the 17q12 deletion is consistent with a gene syndrome that extends beyond RCAD," says Dr. Moreno-De-Luca. "We have uncovered a recurrent pathogenic CNV that confers a very high risk for ASD, schizophrenia, and neorodevelopmental disorders."

These data suggest that one or more of the 15 genes are critical for neorocognitive development.

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Journal Reference:

1. Daniel Moreno-De-Luca , Jennifer G. Mulle , Erin B. Kaminsky , Stephan J. Sanders , Scott M. Myers , Margaret P. Adam , Amy T. Pakula , Nancy J. Eisenhauer , Kim Uhas , LuAnn Weik , Lisa Guy , Melanie E. Care , Chantal F. Morel , Charlotte Boni , Bonnie Anne Salbert , Ashadeep Chandrareddy , Laurie A. Demmer , Eva W.C. Chow , Urvashi Surti , Swaroop Aradhya , Diane L. Pickering , Denae M. Golden , Warren G. Sanger , Emily Aston , Arthur R. Brothman , Troy J. Gliem , Erik C. Thorland , Todd Ackley , Ram Iyer , Shuwen Huang , John C. Barber , John A. Crolla , Stephen T. Warren , Christa L. Martin and David H. Ledbetter. Deletion 17q12 Is a Recurrent Copy Number Variant that Confers High Risk of Autism and Schizophrenia. American Journal of Human Genetics, 2010; DOI: 10.1016/j.ajhg.2010.10.004

 An Australian study suggests that children who are sexually abused, especially if it involves penetration, appear to be at higher risk for developing schizophrenia and other psychotic disorders, according to a report in the November issue of Archives of General Psychiatry, one of the JAMA/Archives journals.

Previous studies have established that abused children are more likely to develop depression, anxiety, substance abuse, borderline personality disorders, posttraumatic stress disorder and suicidal behavior, according to background information in the article. "The possibility of a link between childhood sexual abuse and later psychotic disorders, however, remains unresolved despite the claims of some that a causal link has been established to schizophrenia," the authors write

Margaret C. Cutajar, D.Psych., M.A.P.S., of Monash University, Victoria, Australia, and colleagues linked data from police and medical examinations of sexual abuse cases to a statewide register of psychiatric cases. Rates of psychiatric disorders among 2,759 individuals who had been sexually abused when younger than age 16 were compared with those among 4,938 individuals in a comparison group drawn from electoral records.

Over a 30-year period, individuals who had experienced childhood sexual abuse had significantly higher rates than those in the comparison group of psychosis overall (2.8 percent vs. 1.4 percent) and schizophrenia disorders (1.9 percent vs. 0.7 percent). Participants experienced abuse at an average age of 10.2, and 1,732 (63 percent) of cases involved penetration of a bodily orifice by a penis, finger or other object. Those exposed to this type of abuse had higher rates of psychosis (3.4 percent) and schizophrenia (2.4 percent).

"The risks of subsequently developing a schizophrenic syndrome were greatest in victims subjected to penetrative abuse in the peripubertal and postpubertal years from 12 to 16 years and among those abused by more than one perpetrator," the authors write. "Children raped in early adolescence by more than one perpetrator had a risk of developing psychotic syndromes 15 times greater than for the general population."

The results establish childhood sexual abuse as a risk factor for psychotic illness, but do not necessarily translate into abuse causing or increasing the risk of developing such a disease, the authors note. Many cases of childhood sexual abuse never come to light, and the overall population of abused children maybe significantly different from those whose abuse is detected by officials.

"Establishing that severe childhood sexual abuse is a risk factor for schizophrenia does have important clinical implications irrespective of questions of causality and irrespective of whether those whose abuse is revealed are typical," the authors conclude. "Children who come to attention following childhood sexual abuse involving penetration, particularly in the peripubertal and postpubertal period, should receive ongoing clinical and social support in the knowledge that they are at greater risk of developing a psychotic illness."

"Such treatment in our opinion should focus on improving their current functioning and adaptation to the demands of the transition from adolescent to adult roles rather than primarily on the abuse experience itself. Such an approach should benefit all victims, irrespective of whether they have the potential to develop a psychotic illness."

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Journal Reference:

1. M. C. Cutajar, P. E. Mullen, J. R. P. Ogloff, S. D. Thomas, D. L. Wells, J. Spataro. Schizophrenia and Other Psychotic Disorders in a Cohort of Sexually Abused Children. Archives of General Psychiatry, 2010; 67 (11): 1114 DOI: 10.1001/archgenpsychiatry.2010.147

Researchers at the University of Copenhagen have succeeded in creating a model of the way the brain releases dopamine, an important chemical involved in transmitting signals between nerve cells. The model, the product of an interdisciplinary collaboration, will be an important tool in helping scientists understand how we learn and how the brain perceives reward and punishment. It is hoped that the model can be used to understand drug addiction and in the treatment of schizophrenia.

In the brain, dopamine is involved in a number of processes that control the way we behave. If an action results in the substance being released, we are more likely to repeat the action. This applies to actions such as eating, sexual intercourse or winning a competition. However, the same also holds true when individuals take harmful narcotics. Scientists believe that mental illnesses such as schizophrenia can be linked to dopamine imbalances.

Learning signal

If an action leads to a better response than expected, the brain will temporarily release more dopamine. If the response is worse than expected, the brain momentarily stops releasing dopamine. This mechanism is responsible for our tendency to repeat actions that have given us a high level of dopamine, and to avoid those that result in lower dopamine levels.

"That's why many see dopamine as a learning signal," according to post doctorate Jakob Kisbye Dreyer of the Department of Neuroscience and Pharmacology, the Faculty of Health Sciences, who was involved with the module's creation.

"Others have argued that it is impossible for the dopamine system to react quickly enough to be a part of our learning process. It can take a split second to learn something, but a cell that releases dopamine works slowly. If you look at a lighthouse that flashes at a slow frequency, you might not notice right away that the light was turned off. Likewise, the arguments against dopamine as an aid to learning have focused on the slow feedback time when you experience something bad, and that it is too slow for the brain to make a connection. Our model shows that the collective signal from many cells provides a rapid enough reaction to influence learning."

Mathematic approach to the brain

One of the biggest challenges faced by neurologists is that it is difficult to study active brains in living humans.

"Theoretical neuroscience can easily become very complicated," Dreyer says. "If we try to come up with complete explanations of the way the brain works, we get models that are so complex that they are difficult to test." The dopamine model's predictions, created as part of a unique collaborative effort among physicists, mathematicians and neurobiologists, are supported by observations made in animal models.

"Different branches of natural science have surprisingly different ways of thinking," Dreyer says. "Our work — and our model — is only possible because even though I am a physicist, I have been able to conduct research at the Department of Neuroscience and Pharmacology at the University of Copenhagen. As soon as we are certain that the model is correct, we can begin applying it to dopamine-related illnesses such as drug addiction and schizophrenia."

Publication

The team's dopamine model will be described in the cover article of the Oct. 20 issue of the Journal of Neuroscience. The article was written by Jakob Dreyer, Rune Berg and Jørn Hounsgaard, all of the Department of Neuroscience and Pharmacology, together with Kjartan Herrik of Lundbeck's Department of Neurophysiology.

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Journal Reference:

1. Jakob K. Dreyer, Kjartan F. Herrik, Rune W. Berg, and Jørn D. Hounsgaard. Influence of Phasic and Tonic Dopamine Release on Receptor Activation. Journal of Neuroscience, 2010; 30: 14273-14283 DOI: 10.1523/JNEUROSCI.1894-10.2010

UCLA scientists have discovered that exposing fetal neurons to higher than normal levels of a common immune protein leads to abnormal brain development in mice.

Published Oct. 14 in the online Journal of Neuroimmunology, the finding may provide new insights into factors contributing to human neurological disorders like schizophrenia and autism.

The researchers studied a protein called major histocompatibility complex, or MHC. The protein plays a dual role in the body: It helps the immune system to identify infected cells, and it enables neurons to make the right connections with each other in the brain.

"When neurons sense infection or damage to the brain, they produce more MHC," said Daniel Kaufman, professor of molecular and medical pharmacology at the David Geffen School of Medicine at UCLA. "We wanted to explore whether higher levels of MHC affect how the brain develops."

Kaufman and his colleagues studied the development of mice whose neurons were genetically engineered to produce more MHC than normal.

Focusing on two key regions of the brain, the researchers looked at neurons that process vision and neurons involved in learning and memory. Next, the team compared these cells with their counterparts in normal mice.

What the scientists saw confirmed their hunch.

"The mice whose neurons produced extra MHC showed subtle changes in the connections between those neurons and other neurons in both brain regions," Kaufman said.

The UCLA finding could be of relevance in unraveling the origins of schizophrenia and autism, he noted.

"Infections in pregnant women have been associated with slightly higher risks for schizophrenia and autism in their children," he said. "Subtle changes in brain development due to excess MHC may explain this relationship."

Kaufman noted that female mice that contract infections during pregnancy also often give birth to offspring with behavioral abnormalities similar to autism and schizophrenia.

"We suspect that infection stimulates the mother's immune system to produce molecules that act like distress signals — they circulate through her blood and then enter the developing brain of the fetus," he said. "There, they alert neurons to make more MHC, which our study shows can lead to altered neuronal circuitry."

"This finding gives us greater insight into the role that MHC plays in the nervous system and may enhance our understanding of the factors that can contribute to neuropsychiatric disorders like autism and schizophrenia," Kaufman said.

The study was supported by funding from the National Institute of Neurological Disorders and Stroke. Kaufman's co-authors included Zhongqi-Phyllis Wu, Lorraine Washburn, Tina Bilousova, Maia Boudzinskaia, Nathalie Escande-Beillard, Jyes Querubin, Hoa Dang, Cui-Wei Xie and Jide Tian, all of UCLA.

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Journal Reference:

1. Zhongqi-Phyllis Wu, Lorraine Washburn, Tina V. Bilousova, Maia Boudzinskaia, Nathalie Escande-Beillard, Jyes Querubin, Hoa Dang, Cui-Wei Xie, Jide Tian, Daniel L. Kaufman. Enhanced neuronal expression of major histocompatibility complex class I leads to aberrations in neurodevelopment and neurorepair. Journal of Neuroimmunology, 2010; DOI: 10.1016/j.jneuroim.2010.09.009

A new class of compounds identified by researchers at Emory University School of Medicine could be developed into drugs for the treatment of schizophrenia. The compounds enhance signaling by molecules in the brain called NMDA receptors, which scientists believe are functioning at low levels in people with schizophrenia.

Led by Stephen Traynelis, PhD, professor of pharmacology, a team of Emory researchers sifted through thousands of chemicals and found one, called CIQ, which could selectively enhance the function of certain NMDA receptors without affecting others.

The results were published Oct. 5, 2010 by the journal Nature Communications.

The first author of the paper is Praseeda Mullasseril, PhD. The research was a collaboration with Dennis Liotta, PhD, professor of chemistry, and his colleagues.

Doctors now treat schizophrenia with a variety of antipsychotic drugs, but these can have several long-term side effects. The rationale for treating schizophrenia via NMDA receptors comes from the observation that when healthy people take the drugs ketamine or phencyclidine (PCP or angel dust), they temporarily experience the symptoms of schizophrenia, such as hallucinations, disorganized thoughts and flattened emotions.

"There is room for improvement in therapeutic treatment of schizophrenia," Traynelis says. "Exploration of alternative targets, such as the NMDA receptor, could potentially lead to expanded treatment options and improved outcomes for patients with schizophrenia."

Ketamine and phencyclidine both interfere with NMDA receptors. This has led scientists to the idea that pushing in the opposite direction chemically — enhancing rather than blocking NMDA receptors — may help relieve schizophrenia's symptoms.

NMDA receptors act as gates that let electrical charges flow into neurons when enough of the neurotransmitter glutamate is present. They are essential for receiving signals in the brain connected with sensory perception, learning and memory.

NMDA receptors come in several forms. When assembled, they have two parts: one that stays the same throughout the brain, called NR1, and one that comes in four different varieties (NR2A, B, C and D) of varying prominence, depending on the region of the brain being examined.

Only a few known drugs can selectively target NMDA receptors comprised of different NR2 subunits. Traynelis' team was looking for chemicals that would only enhance function by the NR2C and NR2D forms. Previous studies have suggested that enhancement of these subunits may help people with schizophrenia.

"Enhancing NMDA receptor function might compensate for some of the deficits seen in patients with schizophrenia," he says. "Because NMDA receptors play a number of important roles in the brain, we sought to target only those subunits that have been suggested to potentially improve symptoms in patients with schizophrenia."

The team discovered a compound called CIQ that makes it easier for NMDA receptor gates to open, although it doesn't act alone; it still needs glutamate and glycine to bind to the NMDA receptor before CIQ can exert its actions. The scientists also discovered that the parts of the NR2C and NR2D NMDA receptors that are CIQ-sensitive are distinct from those regions of NMDA receptors known to interact with other known drugs.

"CIQ appears to act at a new, physically distinct site on the receptor that could offer an opportunity to manipulate receptor function in a variety of ways," Traynelis says.

"CIQ is not a drug or clinical candidate," he adds. "Rather, it marks the beginning of a process that involves fine tuning the structure to build potent, selective, and well-tolerated compounds. Later, these can be evaluated in clinical trials to determine whether the strategy of enhancing NMDA receptor signaling does indeed improve the lives of patients with schizophrenia. In addition, compounds emerging from this optimization process could become useful tools for dissecting NMDA receptor contributions to cognition, learning, memory, as well as other diseases."

The research was supported by the National Institute for Neurological Diseases and Stroke, the Lundbeck Foundation, the Villum Kann Rasmussen Foundation, the Michael J. Fox Foundation, Emory University Research Committee, Georgia Tech & Emory Center for Regenerative Medicine, the Atlanta Clinical and Translational Science Institute, and a research grant to Emory from Pfizer.

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Journal Reference:

1. Praseeda Mullasseril, Kasper B. Hansen, Katie M. Vance, Kevin K. Ogden, Hongjie Yuan, Natalie L. Kurtkaya, Rose Santangelo, Anna G. Orr, Phuong Le, Kimberly M. Vellano, Dennis C. Liotta, Stephen F. Traynelis. A subunit-selective potentiator of NR2C- and NR2D-containing NMDA receptors. Nature Communications, 2010; 1 (7): 1 DOI: 10.1038/ncomms1085

New research has linked psychosis with an abnormal relationship between two signalling chemicals in the brain. The findings, published in tomorrow's edition of the journal Biological Psychiatry, suggest a new approach to preventing psychotic symptoms, which could lead to better drugs for schizophrenia.

Schizophrenia is one of the most common severe mental health conditions. Sufferers experience symptoms of psychosis — an inability to distinguish between reality and imagination — such as hallucinations and delusions. The condition tends to begin in the late teens or twenties, and usually persists for the rest of the sufferer's life.

Brain chemicals called neurotransmitters carry signals from one nerve cell to another. Research has linked schizophrenia with abnormally high levels of a neurotransmitter called dopamine in a region of the brain called the striatum. Drugs currently used to treat schizophrenia block the effects of dopamine in the brain. These drugs are not effective for all patients, and can have serious side effects.

The new pilot research, funded by the Medical Research Council (MRC), provides evidence that high levels of dopamine in people with psychotic symptoms occur as a consequence of changes in another brain chemical, glutamate. Glutamate-releasing cells in a brain region called the hippocampus connect to the striatum and influence the activity of dopamine-releasing cells. Drugs that interfere with glutamate signals in the brain might therefore be able to prevent psychotic symptoms in people with schizophrenia.

"Schizophrenia is a devastating illness that destroys the lives of people who are afflicted and those around them," said Dr James Stone of the Department of Medicine at Imperial College London, first author of the study. "At the moment, the drugs we have just aren't adequate. They don't help everybody, and they don't stop some of the most debilitating symptoms."

The researchers carried out brain scans on 16 people with an at-risk mental state for psychosis and 12 healthy volunteers, to measure the levels of glutamate and dopamine. In people with early signs of psychotic symptoms, there was a negative correlation between glutamate levels in the hippocampus and dopamine levels in the striatum area. There was a particularly marked correlation in the subjects who went on to develop psychosis later. There was no correlation in the healthy subjects.

"In healthy volunteers, there's no clear relationship between glutamate and dopamine, but in people with early signs of psychosis, we see this abnormal relationship," Dr Stone said. "This suggests that the signalling pathway between the hippocampus and the striatum is dysfunctional, and we might be able to treat this by targeting the glutamate system. If drugs that act on glutamate signalling can prevent psychotic symptoms, it would mean a real shift in the way that people are treated for schizophrenia.

"The next step will be to see if these results are confirmed in a larger group of people. There are already a number of promising drug candidates that interfere with glutamate signalling, so hopefully in a few years we'll be able to start testing new treatments for people with schizophrenia."

Professor Chris Kennard, chair of the MRC Neuroscience and Mental Health Board, said:

"Studies like these are helping to unravel the complex mechanisms of psychiatric illness and bring us a step closer to more effective, targeted drugs for patients with schizophrenia. The MRC funds research like this in order to bring scientific findings from the lab bench to patient bedside, more quickly. If we can develop new drugs that prevent psychotic symptoms, it would mean a real benefit for patients with schizophrenia."

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Journal Reference:

1. Stone. Altered Relationship Between Hippocampal Glutamate Levels and Striatal Dopamine Function in Subjects at Ultra High Risk of Psychosis. Biological Psychiatry, 2010; 68 (7): 599 DOI: 10.1016/j.biopsych.2010.05.034