RxPG News : Schizophrenia

Nicotine may be a treatment for some symptoms of schizophrenia

Tue, 11 Jan 2011 17:43:16 PST

( from http://www.rxpgnews.com ) Smoking is a common problem for patients with schizophrenia. The increased tendency of patients diagnosed with this disorder is to not only smoke, but to do so more heavily than the general public. This raises the possibility that nicotine may be acting as a treatment for some symptoms of schizophrenia.

Nicotine acts through two general classes of brain receptors, those with high and low affinity for nicotine. The low affinity class of nicotinic receptors contains the alpha-7 subunit, which is present in reduced numbers in people with schizophrenia.

Two papers published in the January 1st issue of Biological Psychiatry suggest that drugs that stimulate these alpha-7 subunit-containing nicotinic receptors might enhance cortical function and treat cognitive impairments associated with schizophrenia.

In their study of healthy monkeys, Graham Williams and colleagues at Yale University and AstraZeneca found that very low doses of AZD0328, a novel drug that acts as an alpha-7 agonist, produced both acute and persistent improvements in their performance on a spatial working memory task.

"Our work demonstrates that that the neuronal nicotinic alpha-7 receptor plays a critical role in the core cognitive function of working memory, which is a key indicator of outcome in patients with schizophrenia," explained Dr. Williams. "The function of the alpha-7 receptor may account for the ability of a partial agonist to induce long-term beneficial changes for high-order cognition at such low doses."

This influence on cortical function has been exemplified by the work of Jason Tregellas and colleagues. These researchers examined the effects of DMXB-A, a novel alpha-7 partial agonist, on the brain's 'default network' in people with schizophrenia. Function of the default network, which is likely a major contributor to the intrinsic neuronal activity that accounts for 60-80% of the brain's energy use, is different in people with schizophrenia.

Dr. Tregellas summarized their findings: "We found that DMXB-A altered default network activity in people with schizophrenia in a pattern consistent with improved function of the network. We also found that these neuronal differences were related to the genotype of the alpha-7 nicotinic receptor and to drug-related improvements in symptoms."

Together, "these two studies provide additional support for a novel pharmacologic approach to treat cognitive impairments in schizophrenia", observed Dr. John Krystal, Editor of Biological Psychiatry.

People With Schizophrenia Face Increased Risk Of Diabetes - Research

Tue, 31 Mar 2009 14:34:02 PST

( from http://www.rxpgnews.com ) Are people with schizophrenia at an increased risk of developing type-2 diabetes? It would seem so, according to the results of a new study.

Of the 50 people diagnosed with schizophrenia or a related psychotic disorder that participated in the study, eight had either diabetes or an abnormal rate of glucose metabolism, said Brian Kirkpatrick, vice-chairman of the Medical College of Georgia's - Department of Psychiatry and Health Behaviour.

'These findings point toward there being some shared environmental factors or genetic factors between the development of schizophrenia and diabetes,' he said.

Schizophrenia symptoms include memory and attention problems, hallucinations, disorganised thinking and behaviour and delusions. Psychotic symptoms typically start in late adolescence and early adulthood.

People with diabetes cannot produce or properly use insulin, a hormone that converts glucose, starch and other food into energy.

Kirkpatrick and colleagues at the Universities of Barcelona - and Maryland - administered a two-hour oral glucose test to patients who had not yet been placed on anti-psychotic medication.

Catching them before prescriptive treatment was important because researchers already knew that some of the most effective schizophrenia drugs also cause rapid weight gain - a risk factor for type-2 diabetes, according to MGC release.

'We know the medicine causes problems but we wanted to know whether the disease also causes them,' said Kirkpatrick.

Researchers believe that developmental abnormalities they don't yet know about also increase diabetes risk.

Kirkpatrick presented his findings at the International Congress on Schizophrenia Research in San Diego March 28-April 1.

Brain recruiting pattern incorrect in Schizophrenic patients

Wed, 12 Mar 2008 05:38:25 PST

( from http://www.rxpgnews.com ) The enduring memory problems that people with schizophrenia experience may be related to differences in how their brains process information, new research has found.

The Public Library of Science published the report by Vanderbilt University researchers Junghee Lee, Bradley S. Folley, John Gore and Sohee Park in the online journal PLOS One March 12.

“We found that schizophrenic patients use different areas of their brain than healthy individuals do for working memory, which is an active form of short-term memory,” Park said.

“Both groups used their frontal cortex while remembering and forgetting. However, while healthy subjects groups used the right side of this brain area when asked to remember spatial locations, the schizophrenic patients used a wider network in both hemispheres.

“This suggests that while healthy people recruit a specialized and focused network of brain areas for specific memory functions, schizophrenic patients seem to rely on a more diffuse and wider network to achieve the same goal.”

The researchers also found a fundamental difference in the way healthy people and schizophrenic patients made errors. When healthy people forgot, they had no confidence in their response for that trial and the brain areas that were recruited during correct memory trials remained inactive. A more complex picture emerged for schizophrenic patients.

“When healthy people are correct, there is an increased activation of the right frontal cortex. When they forget, there is no such increase. Their brain activation pattern is tightly coupled with their memory performance. Not so with schizophrenic patients,” Park said.

“Schizophrenic patients may encode and remember incorrect information. The brain activation pattern during such error trials indicate that indeed they were remembering something, albeit incorrect,” she continued. “Such coupling of storing incorrect information and feeling confident of one’s response may be one way to think about how delusions get initiated,” Park said.

Researchers have known since the early 1990s that working memory problems are a consistent symptom of schizophrenia. The researchers sought to better understand what is occurring in the brain that may be causing these problems.

“The right hemisphere is usually recruited during spatial information processing but if it is malfunctioning, as it may be in schizophrenia, the left hemisphere may also be recruited,” Park said. “Another possible explanation is that schizophrenic patients may have more difficulty with these tasks, and as a result recruit more brain areas to assist them.”

In the experiment, the subjects were shown a point on a computer screen and told to concentrate upon it. Three identical black circles were then flashed on a gray background, each in a different location. After a short delay, the subjects were shown a probe and told to press one key if the probe matched one of the circles shown earlier and another if it did not. They then were told to press another key ranking on a scale from one to five their confidence in their answer about the probe.

The researchers captured images of brain activity during these tasks using functional magnetic resonance imaging, or fMRI. They repeated the experiment to capture data using another tool, near infrared spectroscopy, or NIRS. NIRS is a new and promising way to study schizophrenia, the researchers believe.

“Many patients exceed the fMRI safety weight limit due to the side effects of their medication. The paranoia and anxiety that are often part of this disorder also make fMRI, which involves entering a tube while laying down, impossible for many patients. Also, individuals with metal implants cannot be scanned,” Park said. “NIRS does not have these problems. As a participant, you sit in an office chair while the experimenter places a plastic ‘probe set’ on your head with a couple of straps. Even babies tolerate it pretty well. Our study demonstrates that NIRS can be used as a viable alternative to fMRI, which means many more people can participate in experiments.”

The researchers chose to publish their work in PLOS One, a relatively new, open access journal, because it is freely available to the public.

“We felt that the fact that anybody can access scientific papers in this journal was a big plus,” Park said. “One normally has to pay for access to journals. Most schizophrenic patients, including the individuals who participated in our study, simply do not have the money to do so. This article is available for free to anyone.”

Schizophrenia Risk Gene DISC1 Plays a Broader Role in the Development of Nervous System

Mon, 10 Sep 2007 04:19:08 PST

( from http://www.rxpgnews.com ) How the gene that has been pegged as a major risk factor for schizophrenia and other mood disorders that affect millions of Americans contributes to these diseases remains unclear. However, the results of a new study by Hopkins researchers and their colleagues, appearing in Cell this week, provide a big clue by showing what this gene does in normal adult brains.

It turns out that this gene, called disc1, makes a protein that serves as a sort of musical conductor for newly made nerve cells in the adult brain, guiding them to their proper locations at the appropriate tempo so they can seamlessly integrate into our complex and intertwined nervous system. If the DISC1 protein doesn’t operate properly, the new nerves go hyper.

"DISC1 plays a broader role in the development of adult nerves than we anticipated," says Hongjun Song, Ph.D., an associate professor at Hopkins’ Institute for Cell Engineering. "Some previous studies hinted that DISC1 is important for nerve migration and extension, but our study in mice suggests it is critical for more than that and may highlight why DISC1 is associated with multiple psychiatric disorders."

"Almost every part of the nerve integration process speeds up," adds fellow author Guo-li Ming, M.D., Ph.D., also an associate professor at ICE. "The new nerves migrate and branch out faster than normal, form connections with neighbors more rapidly, and are even more sensitive to electrical stimulation."

While it may not be obvious why high-speed integration would be detrimental, Song notes that because of the complexity of the brain, timing is critical to ensure that new nerves are prepared to plug into the neural network.

Ming, Song and their collaborators at the National Institutes of Health and UC Davis tracked the abnormal movements of the hyperactive nerve cells by injecting a specially designed virus into a part of a mouse brain known as the hippocampus -a region important for learning and memory and therefore quite relevant to psychiatric disorders. The virus would only infect newly born cells and would both knock down the expression of the disc1 gene and make the nerves glow under a microscope.

Combined with other recent Hopkins research that successfully engineered mouse models that have abnormal DISC1 and can effectively reproduce schizophrenia symptoms such as anxiety, hyperactivity, apathy and altered senses, these current findings teasing out the normal role of this protein may help unravel the causes for this complex disease

Song and Ming add that their studies in the hippocampus - one of the few places where new nerves are made in the adult brain - might answer why symptoms typically first appear in adults despite the genetic basis of many psychiatric illnesses. They plan on continuing their mouse work to try and find those answers.

Chemical maps hint at drug's effects on schizophrenia

Tue, 15 May 2007 19:16:49 PST

( from http://www.rxpgnews.com ) Antipsychotic drugs do most of their work in the brain, but they also leave behind in the bloodstream a trail of hundreds of chemicals that may be used in the future to direct better treatment for schizophrenia and other psychiatric conditions, say Duke University Medical Center researchers.

The study is among the first to use metabolomics -- the measurement of thousands of chemical byproducts of the body's cellular processes -- to look at a psychiatric disease and its response to therapy, according to the researchers.

"Doctors draw blood every day to look at metabolites such glucose and cholesterol and determine whether someone is at risk of diabetes or heart disease," said lead study investigator Rima Kaddurah-Daouk, Ph.D., an associate professor of biological psychiatry. "With metabolomics, we can look at thousands of metabolites to attain a more finely tuned map of an individual's overall health and gain information about how an individual is responding to a particular therapy."

In a report presented Friday, May 18, at the Society of Biological Psychiatry annual meeting, in San Diego, Kaddurah-Daouk said that chemical signatures measured by metabolomics were different for schizophrenia patients than for people without the disease. In patients treated with three different antipsychotic medications, the signatures differed according to which drug was used, giving researchers a tool to explore the metabolic side effects of these and other drugs.

The team's findings also appear in the May 2007 issue of the journal Molecular Psychiatry. The work was funded by the Stanley Medical Research Institute and NARSAD, both national mental health research associations.

Kaddurah-Daouk thinks this technology could lead to earlier diagnosis of schizophrenia. It may also begin to explain what makes some people more susceptible to schizophrenia, and why some people respond better to treatment than others or develop metabolic side effects, she added.

Schizophrenia is a devastating mental illness that is characterized by hallucinations, delusions and changes in outlook and personality. Currently there are no biological markers that can be used to establish a diagnosis or reliably predict response to treatment or how the disease will progress.

Although the prevailing theory has been that schizophrenia is caused by an imbalance in neurotransmitter molecules that help send messages between nerve cells in the brain, scientists recently have begun to investigate whether lipids, small fatty molecules such as cholesterol and triglycerides, also may play a role in the disease and in response to therapy.

The researchers, in collaboration with Lipomics Technologies, measured 300 different lipids in blood drawn from 50 patients with schizophrenia before and after treatment with the atypical antipsychotic drugs olanzapine, risperidone or aripiprazole. Lipomics specializes in diagnostic discovery with an emphasis on lipid metabolism. Atypical antipsychotics, a newer group of prescription medications used to treat psychiatric conditions, have fewer side effects than the older antipsychotics, but several still induce weight gain and diabetes.

Schizophrenic patients were found to have lower levels of the lipids used to make membranes involved in storing and communicating information in the brain. These lipid changes were partially reversed in patients treated with antipsychotic medications, said Joseph McEvoy, M.D., associate professor of biological psychiatry and study co-investigator.

"This technique allows us to identify the specific metabolic changes that are caused by the most commonly used drugs for schizophrenia," McEvoy said.

"This study is extremely important because it is giving us more information about how these drugs work," added Ranga Krishnan, M.D., chairman of psychiatry and senior study investigator. "Now we can begin to develop better medicines that target the specific metabolites important for the disease but not those that could lead to detrimental side effects."

Although some lipids are known to have detrimental effects on human health -- such as high levels of cholesterol that lead to heart disease -- many lipids have positive effects on basic human functions, including communication among all the cells of the body. Scientists are still trying to sort out which of the lipids that are modified in schizophrenia are beneficial and which ones result in metabolic side effects.

"Clearly we need to put forth a major effort to link the changes in the blood to what happens in the brain," Kaddurah-Daouk said. "If we can apply these findings to the mysteries occurring in the brain, then perhaps we can finally unlock the secrets of these devastating diseases."

Kaddurah-Daouk believes that this and other studies that explore metabolism at the global level have the potential to greatly impact medical practice. Future experiments focused on correlating these lipid signatures with the clinical outcomes of patients could yield an important tool for designing the best treatment for each patient, Kaddurah-Daouk said.

Study challenges idea that schizophrenia is distinct in developing and developed regions

Wed, 14 Mar 2007 08:38:10 PST

( from http://www.rxpgnews.com ) Research by the World Health Organization (WHO) has suggested that the course and symptomatic expression of schizophrenia is relatively more benign in developing societies. However, a new study from Current Anthropology challenges this assumption, comparing biological and cultural indicators of schizophrenia in urban, Western societies with study data from the island of Palau, which has one of the highest rates of schizophrenia diagnosis in the world today.

A 1% average worldwide population prevalence of schizophrenia is routinely interpreted in the medical literature as implying a uniform distribution, write Roger J. Sullivan (California State University, Sacramento), John S. Allen (University of Southern California), and Karen L. Nero (University of Canterbury, New Zealand). In this sense, the 1% figure is a myth that conceals considerable variability in actual prevalence between settings.

The researchers point to the islands in Micronesia as an example of this variation. Prevalence of schizophrenia ranges from a low of 0.4% in the Marshall Islands to 1.7% in the western Republic of Palau a more than fourfold difference. The expression of schizophrenia in Palau and greater Micronesia is also extraordinarily gendered, with rates of affliction approximately two times higher among males than among females.

Recognizing this high variability in prevalence between populations is important, write the researchers, . . . Genetic perspectives tend to emphasize uniformity in prevalence and symptomatic expression while contextual sociocultural perspectives tend to emphasize variability.

The authors combined quantitative clinical diagnostic tools of symptoms like poor impulse control and eye-tracking with qualitative methods such as patient interviews. Compared to a sample of New Yorkers and other similar studies in New Zealand and Scotland, their findings challenge the idea put forth by the WHO and other research that schizophrenia in developing regions is distinct from and more benign than schizophrenia in developed regions. The researchers also dispute the common assumption that schizophrenia in developing nations is a consequence of development.

These analyses have identified unique aspects of the expression of schizophrenia in Palau, but more striking to us are the similarities that emerge when comparing the Palauan data with research findings in [Western] settings, the authors write.

Indeed, one of the few significant differences between the Palauan sample and the Western sample was the proportion of participants living at home. (Eighty-seven percent of the Palauan participants lived at home.) Notably, extensive kin-based levels of support have been cited by the WHO to explain the supposedly more benign expression of schizophrenia in developing regions.

New details in schizophrenia treatment trial emerge

Thu, 01 Mar 2007 05:52:59 PST

( from http://www.rxpgnews.com ) Two new studies from the Clinical Antipsychotic Trials for Intervention Effectiveness (CATIE) provide more insights into comparing treatment options, and to what extent antipsychotic medications help people with schizophrenia learn social, interpersonal and community living skills. The new studies are published in the March 2007 issue of the American Journal of Psychiatry. CATIE, a $42.6 million, multi-site study, was funded by the National Institutes of Healths National Institute of Mental Health (NIMH).

Comparing Newer Antipsychotic Medications After Older One Fails

Quetiapine, and to some extent olanzapine, may be more effective than risperidone among patients who were originally taking, but had to discontinue, perphenazinean older, first generation antipsychotic medication. However, patient responses varied considerably.

"CATIE continues to fine-tune our understanding of how our arsenal of antipsychotic medications work in real-world settings, but it also is revealing to us what questions we still must address," said NIMH Director Thomas R. Insel, M.D.

Of the 257 patients who were initially randomized to perphenazine in the CATIE study, 192 discontinued the medication for various reasons, including ineffectiveness and intolerable side effects. Among those who discontinued, 114 agreed to be re-randomized to one of three newer antipsychotic medicationsolanzapine, quetiapine or risperidone.

T. Scott Stroup, M.D., MPH, of the University of North Carolina at Chapel Hill, and colleagues compared the effectiveness of the medications by determining how long patients stayed on their assigned medication. Those taking quetiapine stayed on the longestaveraging about ten months before discontinuing. Those taking olanzapine discontinued after an average of about seven months, and those taking risperidone discontinued after an average of four months.

Although the discontinuation results suggest that olanzapine was generally on par with quetiapine, patients taking olanzapine experienced more side effects. While none of those taking quetiapine discontinued use due to weight gain or metabolic side effects, 13 percent of those assigned to olanzapine discontinued it due to weight gain or metabolic problems, and 5 percent of those on risperidone did so.

"These results reinforce the fact that finding the most effective medication for each patient sometimes means trying multiple medications," said Dr. Stroup. "They remind us of the considerable variability in clinical circumstances and of our need to be responsive to an individuals needs and preferences."

Schizophrenia Patients Social and Community Living Skills Improve Modestly While on Antipsychotic Medications

Patients with schizophrenia taking antipsychotic medications experience modest improvements in social, interpersonal and community living (psychosocial) skills, regardless of what antipsychotic medication they are taking.

Improvements in psychosocial skills among patients with schizophrenia have been notoriously difficult to achieve, even when the more disruptive symptoms of the disease can be controlled. "Helping patients with schizophrenia restore their psychosocial functioning remains a challenge," said NIMH Director Thomas R. Insel, M.D. "These CATIE results reinforce the growing understanding that we must do a better job of helping patients get their life skills back on track."

Marvin Swartz, M.D., of Duke University and colleagues evaluated the social and vocational functioning, interpersonal relationships, and psychological well-being of 455 participantsabout one-third of all patients in the CATIE studywho completed an initial evaluation before the study began and were available to provide data after 12 months of treatment. In the first phase of the CATIE study, patients were randomly assigned to take either perphenazinean older, first-generation antipsychotic medicationor one of several newer, second-generation medications (olanzapine, quetiapine, risperidone, or ziprasidone).

The researchers found that those patients who stuck with their initial treatment showed some improvement in their psychosocial functioning, and there were no differences among the medications in making these gains. The results are consistent with previously reported CATIE results (http://www.nimh.nih.gov/healthinformation/catie.cfm) in which few differences were seen among perphenazine and the newer, second-generation antipsychotic medications in effectively reducing symptoms.

The patients who made the greatest gains were the ones with the poorest community living skills at the beginning of the study, but they were also more likely to discontinue treatment early in the process. As noted in previous CATIE reports, many patients discontinued their initial treatments because of intolerable side effects or ineffectiveness.

"Over the long run patients are more likely to function better in the community if they are able to stay on their initial treatment, especially those who are the most impaired," said Dr. Swartz. "More intensive rehabilitative interventions and outreach may help patients stick with their treatment and make greater gains."

Patients who made few gains in community living skills were those with higher-level psychosocial skills at the beginning of the study. Swartz and colleagues posit that patients encountered a "ceiling effect" at which point additional psychosocial skill improvement was unlikely without additional rehabilitative treatment.

"Overall, the findings reiterate the widely held belief that antipsychotic medications alone are not sufficient in helping patients make meaningful gains in real-world functioning," said Dr. Swartz. "Dedicated rehabilitative services that help patients learn to function at work and in social settings are sorely needed."

Abnormalities in eye movements and attention can predict risk of Schizophrenia

Wed, 21 Feb 2007 05:57:56 PST

( from http://www.rxpgnews.com ) A Binghamton University researcher has established a new framework to help determine whether individuals might be at risk for schizophrenia.

In a study published in this month¡¦s Journal of Abnormal Psychology, Mark F. Lenzenweger, a professor of clinical science, neuroscience and cognitive psychology at Binghamton University, State University of New York (SUNY), is the first to have found that abnormalities in eye movements and attention can be used to divide people into two groups in relation to schizophrenia-related risk.

¡§Schizophrenia affects one in every 100 people,¡¨ said Lenzenweger, who considers it the costliest form of mental illness known to humankind. It has a strong genetic component; about 80 percent of what determines schizophrenia is related to genetic influences.

¡§Not only does it impair people¡¦s cognitive, emotional, social and occupational functioning when it¡¦s going in full symptomatic form,¡¨ he said, ¡§it stays with people across the lifespan. Schizophrenia starts early in life, beginning anywhere from 15 to 30, and continues onward. What you have is a person who is impaired, has been removed from the workforce, as well as requires lifelong care and there are immense costs attached to their illness.¡¨

According to Lezenweger, prior studies started with someone who had the illness and then backtracked to find deficits, such as eye tracking and sustained attention problems.

¡§What I said we needed to do was to go into the general population and measure those traits ¡V those neurocognitive processes ¡V and see whether impairment in those processes predicts schizotypic features. So I really turned the whole question on its head,¡¨ said Lezenweger.

The study, funded by a $100,000 Distinguished Investigator Award from the National Alliance for Research on Schizophrenia and Depression, or NARSAD, involved 300 adults drawn from the general population. The findings suggests that the manner in which the eyes can follow a target and how well one can pay attention to a task together help to pinpoint risk factors related to schizophrenia.

¡§I was able to integrate several threads of work that I had been developing over the prior 15 or 20 years,¡¨ he said. ¡§I proposed the study in a way that tied together several methodological and theoretical threads in the way I would want to do it ideally, and they supported it. It was a high-risk funding decision, and I am grateful to NARSAD for getting behind the study.¡¨

Lenzenweger collaborated with Geoff McLachlan at the University of Queensland in Australia and Donald B. Rubin of Harvard University, both leaders in the application of new statistical methods to health-related problems. They applied a technique called finite mixture modeling to separate the research subjects into the two groups.

For years, debate in the field has centered on whether risk for schizophrenia was graded or more binary in nature. Lenzenweger and his colleagues showed that people could be divided into two groups, those at risk and those not at risk.

In the new study, the smaller of the two groups contained individuals who displayed dilute forms of schizophrenia-like symptoms even though they had never had the illness. Study of these people revealed actual schizophrenia in their biological family members, but not other psychiatric illnesses.

¡§What was very exciting for us is that this method allows you to assign a probability to every person in the sample with respect to likelihood of risk for schizophrenia liability,¡¨ Lenzenweger said. ¡§By doing this, one can generate very precise estimates of where individuals fall on the risk dimension.¡¨

A second, mathematically independent model called taxometric analysis generated the same clean partitioning of the two groups, Lenzenweger noted.

Although the risk predictions can be made now, they are not yet ready for clinical applications by practicing therapists. Lenzenweger envisions using the new model as a way to choose schizotypic individuals ¡V people who are at risk for the illness but do not have it ¡V for more intense genomic study. That sort of research may help scientists pinpoint the gene or genes that cause schizophrenia.

¡§The study of schizotypic individuals offers a unique perspective on what might cause the illness,¡¨ Lenzenweger explained. ¡§It provides a clearer window on the likely underpinnings of the illness prior to the devastating impact of the clinical illness.

Possible genetic link to schizophrenia identified

Fri, 09 Feb 2007 02:53:10 PST

( from http://www.rxpgnews.com )

One protein that is crucial for dopamine-mediated neuronal communication in animals is DARPP-32. However, very little is known about the function of this protein in humans.

Several neurological and psychiatric disorders, including schizophrenia, alcoholism, and Parkinsons disease, are associated with changes in the brain that affect the nerves that communicate with each other through the naturally-produced chemical dopamine. One protein that is crucial for dopamine-mediated neuronal communication in animals is DARPP-32. However, very little is known about the function of this protein in humans.

In a study appearing online on February 8 in advance of publication in the March print issue of the Journal of Clinical Investigation, Daniel Weinberger and colleagues from the National Institutes of Health show that the gene that encodes DARPP-32 exhibits genetic variation. One particular variant that increased expression of the mRNA encoding DARPP-32 in the brain was associated with increased performance in a number of cognitive tests, including IQ and memory tests. This variant was also associated with changes in the structure and function of part of the brain known as the neostriatum, as well as changes in the ability of the neostriatum to communicate with the frontal lobe. Importantly, preliminary analysis indicated that this variant was associated with an increased risk of schizophrenia, although further studies will be necessary to confirm this association.

Brain scan may help doctors predict schizophrenia

Thu, 07 Dec 2006 18:48:57 PST

( from http://www.rxpgnews.com ) London, Dec 7 - Brain scans may help doctors predict schizophrenia, a mental disorder that affects one percent of people across the world, says a new study.

Researchers at the University of Edinburgh studied for 10 years 200 people who were at a high risk of developing schizophrenia because two or more family members had already been diagnosed with the illness, the online edition of BBC News said.

The researchers analysed magnetic resonance imaging - scans of 65 of the 200 people, taken on average 18 months apart. They looked specifically for changes in grey matter - brain tissue made principally of neurons that transmit messages and help to store memories.

Eight of the 65 went on to develop schizophrenia an average 2.3 years after the first scan. The scans of each of the eight revealed that they had changes in grey matter that happened before they became unwell.

There is no preventative treatment for schizophrenia because current methods are good only for predicting who won't develop schizophrenia but not who would. An accurate predictive test could help researchers to assess possibilities for prevention in the future, the scientists said.

Key changes take place in the grey matter and tracking these changes over time by scans combined with traditional assessments could help doctors to predict the illness, said the study published in the BioMed Central Medicine journal.

'It needs to be independently replicated before it would make a difference to the thousands of people living with severe mental illness in the UK,' said Jo Loughran, a member of the schizophrenia charity Rethink.

Symptoms usually develop in men in their late teens or early 20s and in women in their 20s and 30s. In rare cases the symptoms, which include hallucinations, delusions, disordered thinking, movement disorders, social withdrawal and cognitive deficits, could also appear in childhood.

Study aims to identify schizophrenics at risk for type 2 diabetes

Tue, 22 Aug 2006 20:16:00 PST

( from http://www.rxpgnews.com ) Dissecting the relationship between schizophrenia and an increased risk of type 2 diabetes has physician-scientists reaching across the Atlantic Ocean.

They are looking at newly diagnosed schizophrenics in an upper-middle-class Spanish community to find whether the disease that causes patients to hear voices and smell, feel and even taste unreal objects also increases their risk of diabetes.

Scientists know the drugs that best control the psychosis increase the risk. We know its the medicine; Im asking whether its the disease as well, says Dr. Brian Kirkpatrick, vice chair of the Medical College of Georgia Department of Psychiatry and Health Behavior and principal investigator on the National Institute of Diabetes & Digestive & Kidney Diseases-funded study.

Dr. Kirkpatrick and colleagues at Hospital Clinic at the University of Barcelona in Spain and the University of Maryland note mounting evidence that developmental problems, resulting from significant maternal stress in the second or early third trimester of pregnancy, may cause schizophrenia and related problems.

The brain has this incredibly complex development where cells are born here and march over here and send communication over here; that goes wrong from the very beginning probably, says Dr. Kirkpatrick of the complex process of laying down normal communication pathways that apparently go awry in about 1 percent of people.

Its kind of a subtle going wrong in the sense that if you look at the brain under a microscope, at first blush, it looks pretty normal, and on MRI (magnetic resonance imaging), it looks pretty normal, but there are subtle differences, he says, and not just in the brain.

Patients can have memory and attention problems, wide palates and subtle abnormalities of their fingertips, ear shape and peripheral nerves in their muscles. Psychotic symptoms typically start in late adolescence or early adulthood. Although psychosis is what we often treat and what tends to be noticeable and dramatic and bring people to medical attention, its just part of the problem, says Dr. Kirkpatrick.

Researchers believe developmental changes also do something that increases the risk of diabetes. Doctors who treat schizophrenics say they see a lot of it. Relative diabetes risk depends on factors including age and which medications patients take, Dr. Kirkpatrick says. One recent study based on data from the Clinical Antipsychotic Trials of Intervention Effectiveness Schizophrenia Trial showed the prevalence rate of metabolic syndrome, a group of risk factors that include abdominal obesity, high lipid and cholesterol blood levels and insulin resistance, is better than 50 percent in women and about 37 percent in men with schizophrenia.

Dr. Kirkpatrick has a chart of weight gain based on drugs used to treat the psychosis that resembles a stairway to disaster. Patients on olanzapine and clozapine, two of the most effective anti-psychotics, gained about 10 pounds within a few weeks. While weight gain is a major risk factor for type 2 diabetes, previous studies have shown the disease also can appear in schizophrenics shortly after they begin treatment and without weight gain.

Studies predating anti-psychotics also have shown schizophrenics have an increased rate of impaired glucose tolerance or insulin resistance, a hallmark of diabetes. Its not 100 percent, it just changes your risk; bad things in utero increase the risk of diabetes and the risk of schizophrenia. It may be they are going to be associated because the same bad things cause both, says Dr. Kirkpatrick.

The bottom line of the study of newly diagnosed schizophrenics is to see whether the disease itself carries an increased risk of diabetes. Researchers are comparing glucose tolerance in these patients to that of healthy people as well as those with untreated depression and those with a recent major crisis. One reason for comparison is that three of the groups should have increased levels of cortisol, a stress hormone that can mimic diabetes by increasing insulin resistance.

Patient enrollment began in 2005 and researchers hope to enroll 82 people in each arm of the study. After initial testing, schizophrenics will receive olanzapine and be followed. Researchers hope to glean measures clinicians can easily use to predict development of insulin resistance with anti-psychotic treatment. Greater insulin resistance prior to treatment may be the measure, Dr. Kirkpatrick says.

The studys catchment area, the Esquerra Eixample neighborhood in Barcelona, was selected because it has a fairly homogenous population and psychiatric researchers can study patients early in the illness. In this case, the Hospital Clinic of the University of Barcelona where most people go, offers the best psychiatric care in the nation, Dr. Kirkpatrick says.

We want to better understand the totality of schizophrenia and we want to increase the risk-benefit ratio of treatment, says Dr. Kirkpatrick. If you come in and I know you are at high risk of diabetes, I am going to suggest that you try one of the medications that has the reduced risk of also causing diabetes.

Effects of ketamine mimic only some of the symptoms of schizophrenia

Wed, 09 Aug 2006 12:37:00 PST

( from http://www.rxpgnews.com ) Ketamine can induce symptoms of referential thinking, but not other symptoms of schizophrenia, according to a new study.

Ketamine is the structural analogue of the drug phencyclidine, now considered too toxic for experimental use in humans. In healthy volunteers, phencyclidine has been reported to induce paranoia, perceptual changes and other symptoms, including disorganisation of thought, negativism, apathy, withdrawal, poverty of speech and catatonia.

The psychosis-inducing effect of ketamine is important evidence supporting the glutamate hypothesis of schizophrenia. This hypothesis, one of the leading neurochemical theories of schizophrenia, is based on the observation that glutamate antagonist drugs like ketamine induce symptoms similar to those of schizophrenia

However, the symptoms the drug produces have not been described systematically. As the effects of ketamine are currently being characterised as a model of schizophrenia, it is important to document its psychopathological effects properly.

In this study, published in the August issue of the British Journal of Psychiatry, ketamine or a placebo was administered by continuous infusion to 15 healthy volunteers on 2 occasions, separated by at least 3 weeks.

While receiving ketamine at a set level, participants were interviewed to measure psychotic and non-psychotic symptoms; speech (for assessment of thought disorder); dissociation (e.g. Do you feel disconnected from your own body?); and also the negative symptoms of schizophrenia.

It was found that ketamine induced a range of perceptual distortions, but not visual or auditory hallucinations. Nearly half the people studied showed abnormal beliefs in the form of referential ideas, or delusions e.g. I feel like a puppetI feel like Im the focus. Everyone is watching me. There were only mild and infrequent ratings of thought disorder.

The authors comment that they were unable to replicate the finding that ketamine causes substantial levels of schizophrenias positive symptoms. Unchanging facial expression and other symptoms of affective flattening, plus another negative symptom, poverty nof speech, were found in over half the sample, where they were usually rated as mild or moderate.

Even so, they say, it is an open question whether ketamine genuinely induces the negative symptoms of schizophrenia, as it is possible that the changes observed were simply manifestations of ketamines general depressant effect on the central nervous system.

In summary, this study suggests that ketamine has a limited psychotomimetic effect, which is most convincing with respect to an ability to induce referential beliefs similar to delusions.

Although ketamine does not reproduce the full picture of schizophrenia, the drug does seem to give rise to some of the symptoms, and it may prove useful in testing theories of specific symptoms such as delusions.

Association between famine and schizophrenia may yield clues about genetic basis

Wed, 02 Aug 2006 11:33:00 PST

( from http://www.rxpgnews.com ) The higher risk of schizophrenia among offspring of expectant mothers living through famine could help us understand the genetic basis for that debilitating mental disorder, a group of researchers argue in a commentary piece in the Aug. 2 issue of JAMA. The finding also supports a theory of medical genetics in which diseases and conditions can be caused by hundreds of different genetic mutations in any number of human genes.

Epidemiologists have studied two major famines in the 20th century: the Dutch Hunger Winter of 1944-45, which was brought about by the Nazi occupation in World War II; and the Chinese famine in 1959-61, a consequence of the failed Great Leap Forward. During both famines, birth rates dropped precipitously. In addition, among children born to women who were pregnant during the famine, the incidence of schizophrenia increased two-fold.

The expectant mothers were not receiving enough folate and other vital micronutrients during the famine, researchers believe, and that deficiency caused new genetic mutations to appear at exceptionally high rates. New mutations in genes related to brain function could lead to development of schizophrenia

"Folate has a major role in genetic processes -- gene transcription and regulation, DNA replication, and the repair of damaged genetic information," explained co-author Dr. Jack McClellan, an associate professor of psychiatry at the University of Washington and medical director of the Child Study and Treatment Center in Tacoma, Wash. "If folate is missing from a mother's diet, that could lead to genetic mutations in the developing fetus."

Nearly three-quarters of the human body's 20,000 or so genes are involved in the development or functioning of the brain in some way, and about one-fourth are specifically brain-related genes -- leaving many possible locations where new genetic mutations would affect the brain. Since schizophrenia has its genesis in the development and distribution of neurons, McClellan said, the areas of the genome related to those processes are probably where researchers will find disease-related mutations.

In addition to urging future research in this area, McClellan and his co-authors, Dr. Ezra Susser of Columbia University and Dr. Mary-Claire King, the American Cancer Society Professor of Medical Genetics and Genome Sciences at the UW, argue that schizophrenia is the latest in a string of disorders showing the nature of inheritance of genetic conditions. The conventional wisdom on psychiatric disorders is that most cases are caused by a handful of common genetic mutations that occur in a small number of genes.

"The problem with that model is that it doesn't correspond to clinical experience," said King. "Studies of families with many complex diseases, like breast cancer, epilepsy, or inherited hearing loss, indicate that many different genetic mutations in many different genes can lead to each disease."

Researchers jokingly refer to this hypothesis as the Anna Karenina model of medical genetics -- each unhealthy family is unhealthy in its own way.

This alterative model of genetics helps explain other aspects of schizophrenia as well. In nearly all populations, the disease has a fairly stable rate of incidence. But in populations with maternal famine, that rate increases significantly. If there are many different possible mutations that could cause schizophrenia, and the number of mutations in a population goes up (due to malnutrition, for example), then one would expect the rate of the disease to rise, as it did during the two famine events.

In addition, schizophrenia can affect the rate of reproduction in people with the condition -- they often have difficulty developing and maintaining relationships with others, so tend to have smaller families and fewer children than other people. If only a small number of common genetic mutations were responsible for schizophrenia, scientists would expect them to become less and less common over time, as people with the condition had fewer children who would carry on those mutations. Instead, the risk of schizophrenia has stayed at about the same level, suggesting that new genetic mutations may crop up periodically to cause the illness anew.

Schizophrenia does run in families, but most people with the condition do not have close relatives with schizophrenia. For many schizophrenia patients, their illness seems to come from out of the blue. This pattern also suggests that new, different mutations appear in different families, McClellan said, and may continue for a few generations before dying out. That could make it hard to determine which genetic mutations cause the disease.

"Normally, if you're looking for what causes an illness, you gather everyone with that illness together and look for mutations they share," said McClellan. "That may be why it has been so hard to find the genetic basis for schizophrenia. The cause may be different from one case to another."

Neuropeptide S (NPS) may help in treating schizophrenia

Mon, 10 Jul 2006 06:18:00 PST

( from http://www.rxpgnews.com ) A small protein in the brain that has only recently been discovered and, paradoxically, induces both profound wakefulness and a less anxious state, may represent a novel target for the treatment of psychotic behavior and schizophrenia, according to new research presented at the 6th International Congress of Neuroendocrinology (ICN 2006) recently.

Neuropeptide S (NPS), so named by Rainer K. Reinscheid, Ph.D., assistant professor, Program in Pharmaceutical Sciences, University of California, Irvine, is produced by a small cluster of cells in the brainstem, yet its specialized receptors are found in several areas of the brain, including those that are associated with the regulation of arousal, sleep and wakefulness, anxiety, appetite, learning and memory. Dr. Reinscheid and his colleagues reported finding the new neuropeptide just last year and described animal studies showing how binding of NPS to its receptors on the surfaces of neurons promotes strong arousal, suppresses all phases of sleep and lessens anxiety in stressful or unfamiliar situations.

Dr. Reinscheid's group reports how NPS also can reduce the biochemical and behavioral symptoms of schizophrenia in an established animal model for this mental illness that affects some 2 million Americans. Animals pretreated with NPS before receiving a drug that normally induces psychotic-like behaviors did not develop the signature behavioral symptoms and neurochemical features of schizophrenia, reported Naoe Okamura, M.D., Ph.D., who is a co-worker of Dr. Reinscheid at the University of California, Irvine.

"Although preliminary, our animal studies indicate the NPS receptor should be explored as a target for the development of novel antipsychotic drugs. Whether molecules activating the NPS system will prove to be better drugs than others used to treat the symptoms of schizophrenia remains to be seen. We still have a very long way to go before proving it can alleviate symptoms in humans as we've seen it do in rodents," said Dr. Reinscheid.

"We've already seen how NPS is unique, being able to modulate both arousal and stress responses. So it could potentially be a target for drugs to treat anxiety and, interestingly, both insomnia and narcolepsy," he added.

The receptor for NPS belongs to a class of those with similar structure called G protein-coupled receptors. Collectively, they have a hand in modulating most every physiological process in the body and brain. Moreover, according to Dr. Reinscheid, about 40 percent of drugs on the market target the function and various actions of these receptors.

Dr. Reinscheid's lab is only beginning to understand how the NPS system works. Thus far, the team's research suggests it acts much like an excitatory neurotransmitter that initiates an impulse by the receiving neuron. Currently, the team is looking at whether natural mutations in the genes of NPS and its receptor might be associated with mental disorders and developing animal models that lack parts of the NPS system in order to better understand its functions.

Neuropeptide S (NPS) may help in treating schizophrenia

Thu, 22 Jun 2006 23:41:00 PST

( from http://www.rxpgnews.com ) A small protein in the brain that has only recently been discovered and, paradoxically, induces both profound wakefulness and a less anxious state, may represent a novel target for the treatment of psychotic behavior and schizophrenia, according to new research presented at the 6th International Congress of Neuroendocrinology (ICN 2006).

Neuropeptide S (NPS), so named by Rainer K. Reinscheid, Ph.D., assistant professor, Program in Pharmaceutical Sciences, University of California, Irvine, is produced by a small cluster of cells in the brainstem, yet its specialized receptors are found in several areas of the brain, including those that are associated with the regulation of arousal, sleep and wakefulness, anxiety, appetite, learning and memory. Dr. Reinscheid and his colleagues reported finding the new neuropeptide just last year and described animal studies showing how binding of NPS to its receptors on the surfaces of neurons promotes strong arousal, suppresses all phases of sleep and lessens anxiety in stressful or unfamiliar situations.

Now, at ICN 2006, Dr. Reinscheid's group reports how NPS also can reduce the biochemical and behavioral symptoms of schizophrenia in an established animal model for this mental illness that affects some 2 million Americans. Animals pretreated with NPS before receiving a drug that normally induces psychotic-like behaviors did not develop the signature behavioral symptoms and neurochemical features of schizophrenia, reported Naoe Okamura, M.D., Ph.D., who is a co-worker of Dr. Reinscheid at the University of California, Irvine.

"Although preliminary, our animal studies indicate the NPS receptor should be explored as a target for the development of novel antipsychotic drugs. Whether molecules activating the NPS system will prove to be better drugs than others used to treat the symptoms of schizophrenia remains to be seen. We still have a very long way to go before proving it can alleviate symptoms in humans as we've seen it do in rodents," said Dr. Reinscheid.

"We've already seen how NPS is unique, being able to modulate both arousal and stress responses. So it could potentially be a target for drugs to treat anxiety and, interestingly, both insomnia and narcolepsy," he added.

The receptor for NPS belongs to a class of those with similar structure called G protein-coupled receptors. Collectively, they have a hand in modulating most every physiological process in the body and brain. Moreover, according to Dr. Reinscheid, about 40 percent of drugs on the market target the function and various actions of these receptors.

Dr. Reinscheid's lab is only beginning to understand how the NPS system works. Thus far, the team's research suggests it acts much like an excitatory neurotransmitter that initiates an impulse by the receiving neuron. Currently, the team is looking at whether natural mutations in the genes of NPS and its receptor might be associated with mental disorders and developing animal models that lack parts of the NPS system in order to better understand its functions.

NMDA receptor hypofunction demonstrated in schizophrenia

Mon, 19 Jun 2006 01:26:00 PST

Hahn and colleagues also studied a second neuron receptor called NMDA, which receives input from the neurotransmitter glutamate. Previous studies at other labs have demonstrated the relationship between erbB4 and NMDA receptor activity and have led researchers to believe that enhanced activity of erbB4 receptors results in a decrease in NMDA receptor activity.

Low levels of NMDA receptor activity are believed to contribute to symptoms of schizophrenia. By stimulating NMDA receptors with glutamate, and measuring the subsequent changes in phosphorylation at the receptor, Penn scientists were able to track an impairment in NMDA receptor activation in the postmortem brain tissue from patients with schizophrenia.

"The fact that our studies of the brains of patients with schizophrenia demonstrate both erbB4 receptor overactivity as well as NMDA underactivity suggests the existence of a relationship between these two receptor groups," explains Hahn. "Altered NRG1-erbB4 signaling may contribute to NMDA receptor hypofunction in schizophrenia." This finding is the first to display NMDA receptor hypofunction in the brains of patients with schizophrenia.

ErbB4 and NMDA receptors are located at the post-synaptic junction, or the chemical receiving end of the neuron. Both, erbB4 and NMDA receptors, are bound to scaffolding proteins called post-synaptic density (PSD), which can bridge receptor groups together and enhance their interactions.

"PSD proteins can act like a raft in the ocean," explains Hahn. "Just as holding onto a raft increases one's chance of survival, by binding onto PSD proteins, NMDA and erbB4 receptors can enhance their activity."

Hahn hypothesizes that schizophrenia may be, in part, caused by the convergence of multiple factors (both genetic and epigenetic) at the PSD, which, in turn, alters the interaction of the molecules in the cellular environment, resulting in the symptoms of schizophrenia. In a continued attempt to understand the differences between the brains of mentally healthy patients and those with schizophrenia, future studies by the research team at Penn will focus on identifying differences in interactive dynamics of proteins in the PSD.

The postmortem brain stimulation method, established in this study, breaks out of the boundaries of previous research using postmortem brain tissue. Postmortem studies have historically focused on snapshot analyses of the brain at the time of death. This new method allows investigation of functional responses of brain tissue to stimulation. "Our hope is that this study will shift our postmortem methodologies from limited comparative studies to a more experimental approach," explains Arnold. "This will allow us to tease apart the molecular complexities that contribute to mental illnesses such as schizophrenia."

Altered NRG1-erbB4 signaling may contribute to NMDA receptor hypofunction in schizophrenia

Fri, 16 Jun 2006 23:59:00 PST

( from http://www.rxpgnews.com ) Researchers at the University of Pennsylvania School of Medicine, in collaboration with scientists at the City University of New York, have identified a striking dysregulation in neuronal receptor activity in the postmortem brain tissue from patients with schizophrenia. By stimulating receptors in the prefrontal cortex, the research team tracked heightened levels of erbB4 receptor activity, as well as decreased NMDA receptor activity in the tissue from patients with schizophrenia. Additionally, they were able to identify a relationship between these two receptor groups, suggesting a mechanism for decreased NMDA receptor function that has long been suspected in schizophrenia. The researchers report their findings in this week's advanced online issue of Nature Medicine.

Schizophrenia, a mental disorder afflicting approximately one percent of the world population, is characterized by a variety of symptoms such as: hallucinations, paranoia, disorganized behavior and the inability to experience pleasure. Previous studies of the brains of patients with schizophrenia suggest altered function in the prefrontal cortex, the brain's organizational center for cognitive function, personality expression, and behavioral control. International, large-scale genetic studies of patients with schizophrenia have pointed researchers to a gene called neuregulin 1 (NRG1), which appears to play a role in determining one's susceptibility to the disease.

Chang-Gyu Hahn, M.D., Ph.D., Assistant Professor of Psychiatry, Steven Arnold, M.D., Associate Professor of Psychiatry and Neurology, and Raquel Gur, M.D., Ph.D., Professor of Psychiatry, and colleagues at Penn, in collaboration with Hoau-Yan Wang, Ph.D., at The City University of New York, took an approach to use NRG1 protein to activate its neuronal receptor, erbB4, to measure the molecular response in postmortem brain tissue.

The binding of NRG1 to erbB4 stimulates neuronal receptor activity by adding phosphate molecules to the site of the receptor. The activation of erbB4, in turn, kicks off a cascade of molecular events within the neuron. When comparing the initial steps of neurochemical activity in postmortem brain tissue of mentally healthy patients to those with schizophrenia, the researchers discovered that NRG1-erbB4 activity was significantly greater in the brains of patients with schizophrenia.

Hahn and colleagues also studied a second neuron receptor called NMDA, which receives input from the neurotransmitter glutamate. Previous studies at other labs have demonstrated the relationship between erbB4 and NMDA receptor activity and have led researchers to believe that enhanced activity of erbB4 receptors results in a decrease in NMDA receptor activity.

Low levels of NMDA receptor activity are believed to contribute to symptoms of schizophrenia. By stimulating NMDA receptors with glutamate, and measuring the subsequent changes in phosphorylation at the receptor, Penn scientists were able to track an impairment in NMDA receptor activation in the postmortem brain tissue from patients with schizophrenia.

"The fact that our studies of the brains of patients with schizophrenia demonstrate both erbB4 receptor overactivity as well as NMDA underactivity suggests the existence of a relationship between these two receptor groups," explains Hahn. "Altered NRG1-erbB4 signaling may contribute to NMDA receptor hypofunction in schizophrenia." This finding is the first to display NMDA receptor hypofunction in the brains of patients with schizophrenia.

ErbB4 and NMDA receptors are located at the post-synaptic junction, or the chemical receiving end of the neuron. Both, erbB4 and NMDA receptors, are bound to scaffolding proteins called post-synaptic density (PSD), which can bridge receptor groups together and enhance their interactions.

"PSD proteins can act like a raft in the ocean," explains Hahn. "Just as holding onto a raft increases one's chance of survival, by binding onto PSD proteins, NMDA and erbB4 receptors can enhance their activity."

Hahn hypothesizes that schizophrenia may be, in part, caused by the convergence of multiple factors (both genetic and epigenetic) at the PSD, which, in turn, alters the interaction of the molecules in the cellular environment, resulting in the symptoms of schizophrenia. In a continued attempt to understand the differences between the brains of mentally healthy patients and those with schizophrenia, future studies by the research team at Penn will focus on identifying differences in interactive dynamics of proteins in the PSD.

The postmortem brain stimulation method, established in this study, breaks out of the boundaries of previous research using postmortem brain tissue. Postmortem studies have historically focused on snapshot analyses of the brain at the time of death. This new method allows investigation of functional responses of brain tissue to stimulation. "Our hope is that this study will shift our postmortem methodologies from limited comparative studies to a more experimental approach," explains Arnold. "This will allow us to tease apart the molecular complexities that contribute to mental illnesses such as schizophrenia."

Transcription factor Elk-1's role in neurodegeneration and schizophrenia

Thu, 08 Jun 2006 06:10:00 PST

( from http://www.rxpgnews.com ) Researchers at the University of Pennsylvania School of Medicine discovered that a protein called Elk-1 interacts with mitochondria, the energy storehouse of a cell, suggesting that this protein - typically active in the nucleus -- could play a role in cell death and mitochondria-related diseases such as neurodegeneration and schizophrenia.

The neuron is a particular type of cell in the brain that is responsible for, among other tasks, learning and memory, cognitive function, and other higher order physiologies. The neuronal cell exhibits a complex structure where fine hair-like structures called dendrites receive signals from other neurons. These signals are transferred to the soma, or body, of the cell and result in neuronal responsiveness to stimulation.

Localization of Elk-1 protein in neuronal dendrites. Elk-1 appears in red. Credit: Lindy Barrett, PhD and Jai Yoon Sul, PhD, University of Pennsylvania School of Medcine, and Nature Methods, June 2006

The researchers found that mRNA (messenger RNA) and protein encoding Elk-1, a transcription factor, were localized in the dendrites of intact rodent neurons. "Transcription factors normally only function in the nucleus and to find a transcription factor in the dendrite is pretty unique," says senior author James Eberwine, Ph.D., professor of pharmacology. "These factors are proteins that bind to DNA and play a role in the regulation of gene expression by promoting transcription. Our lab and others showed that Elk-1 is present in the dendrites of nerve cells." Transcription is the process of translating the DNA code into protein.

Along with Eberwine, co-authors Lindy Barrett, Ph.D., a student from the Eberwine lab who was recently awarded her doctorate in philosophy; Philip Haydon, Ph.D., professor of neuroscience; Jai Yoon Sul, Ph.D., a postdoctoral fellow in the Haydon lab; and colleagues published their findings in the June issue of Nature Methods and a March issue of the Proceedings of the National Academy of Sciences.

In the series of experiments (described in the PNAS study) to discern the nature of Elk-1's role in the dendrite, the investigators first characterized some of the proteins with which Elk-1 interacts, and found that Elk-1 associates with mitochondria proteins. Mitochondria are distributed throughout cells, including in the dendrites, and are important in maintaining the energy stores and regulating viability and death of the cell.

The researchers then overexpressed Elk-1 in rat neurons to see if there was an effect on cell viability. "We thought that through interaction with Elk-1, the mitochondria would be able to regulate cell death," says Eberwine. "By overexpressing Elk-1, we found that we did decrease cell viability, achieving more cell death. Conversely, when we knock-down Elk-1 expression, the survivability of neurons increased, which indicates that Elk-1 plays a role in neuron viability."

Cell-death is a component of a number of psychiatric and neurological diseases such as schizophrenia and those that involve neurodegeneration. For many of these diseases dysfunction of the dendrite is also associated with the disease process. "Therefore, anything that impacts dendrite function might be associated with illness," surmises Eberwine. "The fact that Elk-1 RNA and protein are present in dendrites, and the fact that Elk-1 can modulate cell viability, potentially through the mitochondria, suggests that Elk-1 could play a role in these diseases perhaps through modulation of mitochondrial activity."

Time course of cell death for neurons which have been phototransfected with Elk-1 mRNA. In the first panel (O mins.) the lightning bolts and squares show the region of the dendrite into which the mRNA was phototransfected. By 180 mins clear indications of cell death in a cell soma attached to the phototransfected dendrite is observed (arrow) and by 420 minutes other cell somas attached to phototransfected dendrites are observed to be dying. Other cells whose dendrites are not phototrasfected are observed to be healthy in this image. Credit: Lindy Barrett, PhD and Jai Yoon Sul, PhD, University of Pennsylvania School of Medcine, and Nature Methods, June 2006

To more precisely understand the role of Elk-1 RNA in the dendrite, the researchers developed a method called phototransfection, which was described in their June Nature Methods paper, to focally introduce Elk-1 RNA into the dendrite. In this technique, a laser light beam is used to create small transient pores in the membrane of intact rat nerve cells, into which a known amount of RNA molecules are introduced by diffusion.

The introduction and translation of Elk-1 mRNA in dendrites by phototransfection also elicited cell death whereas introduction and translation of Elk-1 mRNA in the cell soma did not produce cell death. The Elk-1 proteins translated in the dendrites were transported to the nucleus and cell death depended on subsequent transcription. These results compliment and expand upon the PNAS study in which Elk-1's involvement in cell death and association with mitochondria were elucidated.

"This is the first formal proof that RNA can be translated and made into protein in an intact neuronal dendrite," explains Eberwine. "We have seen this with isolated dendrites before, but not in an intact cell."

In the mouse model, Elk-1 mRNA is being made into protein on ribosomes located at the periphery of the nerve cell in the dendrite. Protein is also being made in the cell body, but there may be a difference in the Elk-1 protein made in the cell body. "We speculate that the dendrite's environment comes into play, with kinases and phosphatases that modify the Elk-1 proteins made in the dendrite," explains Eberwine. "We suggest that there's a different phosphorylation signal on the protein made in the dendrite versus in the cell body.

"These studies highlight the importance of the dendritic environment in modifying proteins after they have been made," concludes Eberwine. "There is a clear link between the nucleus and mitochondria via Elk-1, and it's rapid. We don't know exactly what that is, but it's a very interesting signal in terms of neurodegeneration. These data provide intriguing new avenues for research, including determining the role of localized protein synthesis and protein modifications in dendrite-related pathologies, including Fragile X disease, schizophrenia and autism. It is likely that not only are particular proteins going to be important in these diseases, which has been proven by genetics, but also the environment in which they are synthesized."

Schizophrenia limits one's ability to perceive body language

Fri, 19 May 2006 19:50:00 PST

( from http://www.rxpgnews.com ) Understanding the meaning behind a person's posture or body movement comes easily to many people and helps guide how we react to others socially.

But people with schizophrenia, even those who have mild to moderate symptoms and take medications, are not fluent in understanding body language, according to a University of Iowa-led study that included investigators Nirav Bigelow, Ph.D., Sergio Paradiso, M.D., Ph.D., and Nancy C. Andreasen M.D., Ph.D. The results appear in the April 2006 issue of Schizophrenia Research.

Previous studies conducted by Paradiso and Andreasen showed that patients with schizophrenia have trouble deciphering emotion from human facial expressions. However, it was not well understood whether this perception problem extended to other socially relevant clues, said Sergio Paradiso, the study's corresponding author and assistant professor of psychiatry in the UI Roy J. and Lucille A. Carver College of Medicine.

"As we interact with people, we make judgments that we're not consciously aware of," Paradiso said. "If we see a coworker hunched over and don't see his face, we may approach him cautiously because we think something might be wrong and perhaps we can help. We don't see the face, but we glean information from the body language. People with schizophrenia are not as good at extracting this kind of information to guide their social interactions."

The study included 14 people without schizophrenia and 20 people with schizophrenia who were taking medication and had mild to moderate symptoms.

"Unfortunately, standard treatment for schizophrenia does not appear to be capable of improving perception that helps in being social with others," Paradiso said.

The inability to perceive body language also appears unrelated to a person's level of intelligence. "Many people with schizophrenia, including those who are very bright, remain awkward in social situations," Paradiso added.

The study used innovative techniques, selected by the team and implemented by Bigelow and Andreasen, to test the study participants' reactions to human posture and movement. Bigelow, a former UI fellow in psychiatry, is now a clinical neuropsychologist at the Indianapolis Community North Hospital, and Andreasen is the Andrew H. Woods Chair of Psychiatry at the UI.

In one test, participants watched a video of human bodies in motion. The images were manipulated so that no facial features or body shapes could be seen. Instead, only points of light, attached to the joints of the people on the tape, were visible as they moved. Based on the speed and pattern of the bright dots, individuals without schizophrenia and healthy volunteers were asked to determine if the motion depicted joy or sadness, for example. The study found that individuals with schizophrenia could not accurately decipher these emotions.

Study participants also viewed still film clips of complex social scenes in which the actors' faces were erased. The participants then viewed the same clips with the faces reinstated. People with schizophrenia did not improve their performances in identifying the overall mood of the people in the scene.

"The film clip test showed that patients with schizophrenia have problems with both taking advantage of extra information that is conveyed by the human face and with deciphering socially relevant stimuli that are not conveyed by facial expression," Paradiso said.

Whether people with schizophrenia can learn to perceive body posture and other social clues has not been studied in detail. Paradiso said the question is an important one to be examined at a neuroscientific level -- to see whether, with adequate rehabilitation, regions of the brain can take over and support social perception abilities.

"The idea of other circuits taking over the brain for specific mental capacities is not new. There's some degree of redundancy in the brain so that when a specific faculty is affected another part of the brain attempts to take over. It may occur in people who have had a stroke, usually through rehabilitation," he said.

Next, UI investigators will examine more closely how medication used to treat schizophrenia affects social perception of emotionally laden material and whether different medications have different effects.

Hospitalized schizophrenics are at a higher risk for developing medical/surgical complications

Sun, 19 Mar 2006 02:30:00 PST

( from http://www.rxpgnews.com ) A Johns Hopkins study of more than 1,700 patients with schizophrenia hospitalized for medical or surgical care unrelated to their mental disorder shows they are at least twice as likely as similar patients without schizophrenia to suffer dangerous and expensive adverse events. The adverse events are associated with poor outcomes, including death.
The researchers concluded that decreased quality of care given to patients with schizophrenia may put them at higher risk for serious infections and other complications.

A report on these findings appears in the March issue of the Archives of General Psychiatry.

"The results of our study suggest that having schizophrenia may be a previously unrecognized or under-appreciated contributor to higher likelihood of complications and death for patients admitted to a medical or surgical hospital service," said Gail L. Daumit, M.D., M.H.S., an assistant professor of medicine at The Johns Hopkins University School of Medicine and first author of the report. The primary diagnoses in these cases were conditions that required immediate medical or surgical care.

The Hopkins team, composed of investigators from the School of Medicine and Bloomberg School of Public Health, evaluated patients discharged from Maryland acute care hospitals following medical or surgical treatment in 2001 and 2002. The patients included 1,746 patients who had schizophrenia and 732,210 who did not.

Using a set of standard patient safety indicators, or PSIs, developed by the Agency for Healthcare Research and Quality, the team found that patients with schizophrenia were two and one-half times more likely than non-schizophrenics to have hospital-associated infections; two times more likely to have postoperative respiratory failure or postoperative deep vein blood clots, and two times more likely to suffer post-operative sepsis (overwhelming infections throughout the body caused by toxin-producing bacteria) than patients without schizophrenia.

In addition, patients with schizophrenia who had respiratory failure or sepsis were twice as likely as those without respiratory failure or sepsis to be admitted to the intensive care unit and to die.

The team also found that the median length of hospital stay for patients with schizophrenia and adverse events was at least 10 days longer than the stay of schizophrenics without adverse events; and median hospital charges were at least $20,000 greater in hospitalizations with adverse events.

"Much of this increased risk could be due to variation of quality of care," said Peter Pronovost, M.D., Ph.D., the medical director of the Center for Innovation in Quality Patient Care and a professor in the Department of Anesthesiology/Critical Care Medicine at Johns Hopkins University's School of Medicine.

"We already were aware that individuals with schizophrenia have a high risk of premature mortality, but it wasn't clear until now whether complications during hospitalization were a contributing factor," Daumit said.

Previous studies by others suggest that health care professionals might minimize or misinterpret the medical symptoms of people with schizophrenia and delay diagnosis and treatment of conditions requiring attention, Daumit said. This is especially likely if these patients are hallucinating, behaving aggressively or communicating poorly.

Other factors contributing to poor outcomes may include improper use of restraints, excessive medication dosages and interactions of drugs used to control schizophrenia symptoms with other medications, Daumit noted. Such drug errors can cause over sedation, which in turn could cause respiratory problems, such as pneumonia, she said.

"Further research is needed to evaluate the extent to which having schizophrenia increases the risk for complications and death, and whether they are preventable and responsive to interventions to improve quality of care," Pronovost said. He explained that more information about health care provider and system level factors such as communication between medical specialties and the availability of consultation-liaison psychiatric services would be important to target future quality improvement efforts.

PSIs are designed to help hospitals identify situations that might require further study, according to the Hopkins researchers. AHRQ is part of the U.S. Department of Health and Human Services.

Transcranial magnetic stimulation to curtail auditory hallucinations in schizophrenia

Sun, 12 Mar 2006 03:53:00 PST

( from http://www.rxpgnews.com ) Yale School of Medicine researchers are recruiting patients nationally for a clinical trial using transcranial magnetic stimulation (TMS) to help still the voices that are so troubling to some persons with schizophrenia.

"These hallucinations, which consist of spoken speech that are labeled 'voices' by patients themselves, are often very disabling and resistant to currently available medication therapies," said Ralph Hoffman, M.D., a professor in the Department of Psychiatry and principal investigator of the study.

Hoffman has received a $2.1 million, five-year grant from the National Institute of Mental Health to expand the research to include 90 patients. There are funds to fly patients to New Haven, where they will stay on a research unit during the five-to-eight week period that they are in the clinical trial. TMS generally is painless and is experienced as a knocking sensation. It is administered while persons are awake by positioning an electromagnetic coil on the scalp.

"It appears that stimulating populations of neurons once per second with TMS over many minutes modestly reduces the capacity of these neurons to activate each other," Hoffman said. "As a result, neural populations as a whole become less reactive or excitable. Our study findings suggest that hallucinations can be curtailed using this approach without interfering with normal brain function."

Hoffman recently completed a study testing TMS in different areas of the brain and found that positioning the TMS over what is known as Wernicke's region in the left temporal lobe, and a second region located on the opposite side of the brain, were optimal in reducing these hallucinations. He said these two brain areas, which ordinarily play key roles in perceiving words spoken by other persons, have also been found in other studies to be important in producing hallucinated "voices."

For patients enrolled in the trial, TMS will be administered to these brain areas once per second for 16 minutes daily over a three-week period. One-third of the subjects in the trial will start out receiving a placebo form of TMS. After three weeks, these subjects will also be offered a trial of real TMS. The study will use a magnetic resonance imaging brain scan to precisely position TMS over desired brain regions.

Loss of PRODH and COMT gene activity linked to schizophrenia

Fri, 02 Dec 2005 19:04:00 PST

( from http://www.rxpgnews.com ) Disruption of the normal interaction between the genes PRODH and COMT contributes directly to major symptoms of schizophrenia by upsetting the balance of the brain chemicals glutamate and dopamine, according to a group of investigators that includes a scientist now at St. Jude Children's Research Hospital.

The investigators developed a model of schizophrenia that provides a way to study and understand how the loss of both PRODH and COMT gene activity contributes to the symptoms of schizophrenia.

The insights they gained into the disease with this model are important because the loss of the PRODH gene causes the imbalance in the levels of both glutamate and dopamine; and this imbalance contributes directly to the symptoms of schizophrenia, according to Stanislav Zakharenko, MD, PhD, an assistant member of the Department of Developmental Neurobiology at St. Jude.

The team investigated the roles of PRODH and COMT because these genes are located in the q11 region of human chromosome 22. Previous work by other scientists showed that a mutation in this region--the 22q11 microdeletion--is one of the major risk factors for developing schizophrenia.

The study's findings linked changes seen at the molecular level directly to symptoms of schizophrenia seen in humans, said Zakharenko, who is a co-author of a report on this work that appears in the November 15 issue of Nature Neuroscience. The work was completed by Zakharenko and his colleagues at Columbia University (New York), Rockefeller University (New York) and the University of Utrecht (the Netherlands). Zakharenko is continuing his work on the molecular causes of schizophrenia at St. Jude.

The key finding in the current study was that the models of PRODH deficiency had increased COMT activity in the frontal cortex of the brain. "This might reflect a response to the increased dopamine activity caused by PRODH deficiency," Zakharenko said. "And it shows that when PRODH is lost, the additional loss of COMT due to the 22q11 mutation may worsen the symptoms of schizophrenia by allowing dopamine levels to rise." The prefrontal cortex is the part of the brain involved in complex cognitive functioning (e.g., thinking and reasoning).

In the same issue of Nature Neuroscience, another group of investigators reports that their study of adolescents with the 22q11 deletion showed that low activity of COMT is a risk factor for loss of volume of the part of the brain called the prefrontal cortex; and that this same mutation also puts adolescents at risk for developing psychotic symptoms.

Using their model of schizophrenia, Zakharenko and collegues first discovered that the loss of PRODH function directly causes hyperactivity of nerves that use glutamate to signal other nerves in the brain. Next, they found that disruption of PRODH gene activity causes the upregulation of the COMT gene, which encodes for the enzyme that breaks down dopamine. Upregulation is the increase in the rate at which a gene is decoded so the protein it codes for can be manufactured by the cell.

Prior research had already shown that PRODH makes an enzyme that breaks down proline, an amino acid that mimics the action of glutamate on most nerves in the brain. When PRODH activity is low, proline levels are high, creating an excess of excitatory activity leading to overall hypersensitivity of nerve cells to stimulation that might contribute to some schizophrenia symptoms. "Our model of schizophrenia was particularly useful because it lacked only a part of PRODH gene, so the level of proline rose to approximately that seen in individuals with schizophrenia," Zakharenko said.

Although dopamine and glutamate systems were suspected to contribute separately to the development of schizophrenia, researchers had not found a clear connection between them, according to Zakharenko. However, the present study clearly shows this connection. Specifically, when PRODH activity is low, proline levels are high, and there is excess in dopamine activity, he said. The subsequent increase in COMT compensates for the increased release of this dopamine caused by PRODH deficiency. "This finding shows why loss of COMT activity is linked to symptoms of schizophrenia," Zakharenko said.

The study also showed why patients with schizophrenia who also have the 22q11 microdeletion are especially disadvantaged. "COMT upregulation appears to be a response that brings the level of dopamine signaling back to normal," Zakharenko said. "So patients with the 22q11 microdeletion are unable to compensate for their PRODH deficiency by upregulating COMT."

The team further showed that PRODH deficiency increased the release of glutamate at synapses formed by CA3 and CA1 neurons in the part of the brain called the hippocampus. These synapses are routinely used as models of specific types of brain activity responsible for learning and memory. A synapse is the gap between an incoming nerve and its target cell across that gap. Signals pass from one cell on one side of the gap to another cell on the other side. The increased release of excitatory chemicals glutamate and proline due to PRODH deficiency inhibited the ability of the synapse to undergo a change called long-term potentiation (LTP)--a long-lasting strengthening in the connection between two nerve cells. LTP is an important step in forming memories, and disruption of this process interferes with the ability to store information.

Another study using the PRODH-deficiency model showed that the drug D-amphetamine causes exaggerated movement similar to that caused by amphetamine in humans with schizophrenia, according to the researchers. A PRODH deficiency caused lab models to have problems remembering how to respond to an audible tone in a way that was previously learned.

"These observations showed that lack of regulation of glutamate levels due to loss of PRODH function contributed to learning difficulties similar to those found in schizophrenia," Zakharenko said.

Moreover, the researchers showed that PRODH deficiency caused a reduction in the levels of three proteins that, in combination, are associated with dopamine function in the frontal cortex. Because these proteins cooperate with COMT to regulate the overall dopamine activity, the microdeletion 22q11 is likely to contribute to schizophrenia symptoms by eliminating PRODH. "This finding is further evidence that PRODH and COMT interact to control dopamine levels and further explains why the 22q11 microdeletion is associated with schizophrenia," Zakharenko said.

Finally, the investigators used the drug D-amphetamine to stimulate release of dopamine, while blocking COMT activity with a drug called tolcapone. Blocking COMT activity significantly increased the effect of D-amphetamine in PRODH-deficient models, proving that disruption of COMT disrupts the brain's ability to rein in dopamine activity.

"This genetic model offers a way to make additional predictions about how specific gene defects in addition to PRODH and COMT deletions contribute to the development of schizophrenia in patients with 22q11 microdeletions," said Zakharenko. "Further studies using this model will likely help to answer many more questions about this disease."

Oct-6 protein not a biological marker for schizophrenia

Mon, 24 Oct 2005 14:04:00 PST

( from http://www.rxpgnews.com ) The protein Oct-6 is not a biological marker for schizophrenia. The results of a study published today in the open access journal BMC Psychiatry contradict previous findings and show that Oct-6, a protein involved in neurodevelopment, is normally expressed in the adult brain and cannot be used to identify patients with schizophrenia.

Oct-6 was shown to be expressed in the brain of patients diagnosed with schizophrenia, but not in the brain of healthy individuals, in a study led by Jack Price and published in the July 2002 issue of The American Journal of Psychiatry. Kirenjeet Ubhi and Jack Price, from Kings College London, UK have now replicated Price's original study and extended it. Their findings contradict Price's earlier study.

Events affecting brain development are thought to underlie the occurrence of schizophrenia in later life. Oct-6 plays a crucial role in neurodevelopment, and a genetic variation within the Oct-6 gene has been linked to a subset of patients with schizophrenia and bipolar disorder; therefore, Oct-6 seemed like a good candidate for a biological marker for these disorders.

Ubhi and Price extended Price's original study to include patients with bipolar disorder and major depression it has been suggested that schizophrenia shares a common pathology with these disorders. They analysed post-mortem brain samples from 3 groups of 15 patients. The first group had been diagnosed with schizophrenia, the second group with bipolar disorder and the third group with major depressive disorder. They used 15 brain samples of matched healthy individuals as controls. Oct-6 mRNA and protein expression were determined by in-situ hybridization and immunostaining respectively.

Contrary to their previous results, Ubhi and Price found no difference in Oct-6 protein or mRNA expression between patients and controls.

CATIE study to guide schizophrenia treatment

Tue, 20 Sep 2005 21:47:00 PST

( from http://www.rxpgnews.com ) A large study funded by NIH's National Institute of Mental Health (NIMH) provides, for the first time, detailed information comparing the effectiveness and side effects of five medications both new and older medications that are currently used to treat people with schizophrenia. Overall, the medications were comparably effective but were associated with high rates of discontinuation due to intolerable side effects or failure to adequately control symptoms. Surprisingly, the older, less expensive medication used in the study generally performed as well as the newer medications. The study, which included more than 1,400 people, supplies important new information that will help doctors and patients choose the most appropriate medication according to the patients' individual needs.

"The study has vital public health implications because it provides doctors and patients with much-needed information comparing medication treatment options," said NIMH Director Thomas R. Insel, M.D. "It is the largest, longest, and most comprehensive independent trial ever done to examine existing therapies for this disease."

Schizophrenia, which affects 3.2 million Americans, is a chronic, recurrent mental illness, characterized by hallucinations, delusions, and disordered thinking. The medications used to treat the disorder are called antipsychotics. In the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) trial, researchers directly compared an older medication (perphenazine), available since the 1950s, to four newer medications (olanzapine, quetiapine, risperidone, and ziprasidone), introduced in the 1990s. The purpose of the study was to learn whether there are differences among the newer medications and whether the newer medications hold significant advantages over the older medications; these newer medications known as atypical antipsychotics, cost roughly 10 times as much as the older medications.

At the beginning of the study, patients were randomly assigned to receive one of the five medications. Almost three quarters of patients switched from their first medication to a different medication. The patients started on olanzapine were less likely to be hospitalized for a psychotic relapse and tended to stay on the medication longer than patients taking other medications. However, patients on olanzapine also experienced substantially more weight gain and metabolic changes associated with an increased risk of diabetes than those study participants taking the other drugs.

Contrary to expectations, movement side effects (rigidity, stiff movements, tremor, and muscle restlessness) primarily associated with the older medications, were not seen more frequently with perphenazine (the drug used to represent the class of older medications) than with the newer drugs. The older medication was as well tolerated as the newer drugs and was equally effective as three of the newer medications. The advantages of olanzapine in symptom reduction and duration of treatment over the older medication were modest and must be weighed against the increased side effects of olanzapine.

Thus, taken as a whole, the newer medications have no substantial advantage over the older medication used in this study. Several factors, such as adequacy of symptom relief, tolerability of side effects, and treatment cost influence a person's willingness and ability to stay on medication.
"There is considerable variation in the therapeutic and side effects of antipsychotic medications. Doctors and patients must carefully evaluate the tradeoffs between efficacy and side effects in choosing an appropriate medication.

The aim of the CATIE study was to determine which medications provide the best treatment for schizophrenia. Many studies have tested new antipsychotic medications in schizophrenia. By contrast, CATIE compared four of the newer medications to one another, and to an older medication.
For the first time, doctors and people with schizophrenia will have extensive information on antipsychotic medications from a single, large, long-term study directly comparing the drugs to each other.

CATIE greatly enhances the knowledge available to guide treatment choices for people with schizophrenia. CATIE provides new information on the efficacy and side effects of antipsychotic drugs, compared head to head, helping doctors determine the appropriateness of specific medications in individual patients.

All medications included in the study were FDA-approved antipsychotic medications used in the treatment of schizophrenia. Patients were randomly assigned to a medication; study participants and their doctors could not choose which medication to take, and neither the investigators nor the patients knew which antipsychotic a patient was on.

For patients with schizophrenia, staying on medication is critical to controlling symptoms and preventing relapse. Previous studies have shown that antipsychotic treatment is far better than no treatment. Investigators also recorded why a patient stopped a medication: if the medication did not control symptoms, or if the side effects were not tolerable, or if the patient chose to stop treatment for some other reason. Surprisingly, the older, less expensive medication (perphenazine) used in the study generally performed as well as the four newer medications.

The study supplies important new information that will help doctors and patients choose the most appropriate medication according to the patients' individual needs.

At the beginning of the study, patients were randomly assigned to receive one of the five medications. Almost three quarters of patients switched from their first medication to a different medication. The patients started on olanzapine were less likely to be hospitalized for a psychotic relapse and tended to stay on the medication longer than patients taking other medications. Perphenazine (the older medication) equally as effective as the other three newer medications (risperidone, quetiapine, and ziprasidone) and was as well tolerated as the newer drugs. Patients and doctors must carefully evaluate the trade off between effectiveness, side effects, and cost in choosing an appropriate medication.

The pharmaceutical companies donated the study medications and provided advice about the optimal dose for that company's medication.

CAPON and SchizophreniaDoes Size Matter?

Tue, 13 Sep 2005 16:04:00 PST

( from http://www.rxpgnews.com ) Schizophrenia and bipolar disease are complex diseases, with multiple genes and environmental factors thought to be responsible for their manifestation. Many reports have implicated changes in certain regions of the human genome in schizophrenia. An area on Chromosome 1 has been associated with the disease in different studies and populations. Linda Brzustowicz and colleagues had previously described association of several single nucleotide polymorphisms (SNPs) within a gene called CAPON (for carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase) with schizophrenia in a set of Canadian families. A separate study in a Chinese population found an association between schizophrenia and a separate group of SNPs within CAPON. CAPON is an attractive candidate for a schizophrenia gene: CAPON was first identified as a protein binding to neuronal nitric oxide synthase (nNOS), and indirect evidence suggests that it might be linked to the regulation of glutamate neurotransmission. However, so far, no coding sequence mutations in CAPON have been found in patients with schizophrenia.

Brzustowicz and colleagues now report results from a study of CAPON expression in postmortem brain samples from patients with schizophrenia, from patients with bipolar disorder, and from control individuals without psychiatric illness. Initially screening a human fetal brain cDNA library for potential alternative splice forms of CAPON, they found, in addition to the predicted full-length transcript, a shorter isoform that consists of the last two exons of the gene. They also confirmed that both long and short versions of the protein are present in human brain. (The short isoform would still be able to bind nNOS and possibly disrupt its interaction with other proteins.)

The authors then examined CAPON mRNA expression in postmortem brain samples from 35 patients with schizophrenia, from 35 patients with bipolar disorder, and from 35 controls. They looked for transcripts encoding the long and short forms and also compared expression levels (relative to beta-actin) across the diagnostic groups. In the dorsolateral prefrontal cortex (thought to be involved in schizophrenia and the only area for which samples were available), expression levels of the long isoform did not differ between patient and control samples. However, the short isoform was expressed at higher levels in the patients with mental illness than in the controls. They also analyzed DNA from these individuals at three SNPs associated with schizophrenia and found, for each SNP, that the group of individuals who carried one or two copies of the schizophrenia-associated allele had overall higher levels of the short form transcript than those homozygous for the non-associated CAPON allele. They saw no differences in levels of the full-length transcript between the groups with different SNP genotypes.

These are intriguing but preliminary results. Getting reliable results from studies on postmortem samples is extremely difficult because of numerous confounding factors. Brzustowicz and colleagues tried to control for some of them (such as sex of the individual, substance abuse by the individual, and storage time of the sample), but others are impossible to determine or control for. Moreover, this particular collection of samples had only tissue from the dorsolateral prefrontal cortex available for study. Sample preparation was geared toward high-quality RNA for expression studies and not suitable for parallel protein analysis. Future studies, with at least some of them in animal models that allow controlled conditions and experimentation, will need to determine the functions of the long and short isoforms of CAPON and their interaction with other proteins involved in postsynaptic neurotransmission (some of which have also been linked to schizophrenia), and elucidate a possible role for CAPON in psychiatric disorders.

Dopamine and glutamate hypothesis reconciled

Tue, 13 Sep 2005 04:28:00 PST

( from http://www.rxpgnews.com ) Yale School of Medicine researchers published a report this month in the Archives of General Psychiatry that highlights the interplay of two brain signaling systems, glutamate and dopamine, in psychosis and cognitive function.

The study helps resolve a long-standing research debate between the "dopamine hypothesis" and the "glutamate hypothesis" or "PCP Model," said John Krystal, M.D., professor, deputy chair for research in the Department of Psychiatry, and lead author of the study. "Both systems appear to be involved," he said.

The first theory suggests that dopamine neurons are hyperactive in persons with schizophrenia and that effects of the dopamine-releasing drug, amphetamine, can mimic aspects of the illness. The second theory maintains that certain schizophrenia-related deficits in the function of glutamate, the dominant stimulatory transmitter, could be reproduced in healthy people by the administration of drugs such as ketamine, which block the NMDA subtype of glutamate receptors.

The study included 41 healthy subjects who were given amphetamine, ketamine and then saline, in varying sequence. The researchers found the transient psychotic state produced by each drug was similar but not identical and that ketamine produced a more "complete" schizophrenia-like state than amphetamine. They also found that cognitive impairments produced by ketamine, specifically working memory, were reduced by the administration of amphetamine.

"This study lends support to the hypothesis that drugs that facilitate the function of particular dopamine receptors might play a role in treating cognitive impairments associated with schizophrenia," Krystal said.

'Schizophrenia' may not exist

Sat, 10 Sep 2005 15:16:00 PST

( from http://www.rxpgnews.com ) Schizophrenia has been attributed to everything from genetic predisposition, brain chemistry, sufferers' home environment and even cat-borne viruses, but no consistent causal pattern has ever been identified. As a result, treatment outcomes for today's patients are not very different from those of patients treated 100 years ago.

According to Richard Bentall, Professor in Experimental Clinical Psychology at The University of Manchester, the problem is that the psychiatric category 'schizophrenia' falsely groups people with a wide range of problems together.

"Psychiatric diagnoses are based on a set of false assumptions stemming from the 19th century," says Professor Bentall, writer of the highly successful book 'Madness Explained'. "Although deep-seated, these assumptions have very little scientific value, and could actually be detrimental to patients and their treatment options.

"The idea that there is a clear division between 'mad' and 'sane' people, and that distinct psychiatric categories like 'schizophrenic' actually exist, is resulting in the mass-application of treatments which, will benefiting some, are very harmful to others. And because psychiatric patients are seen as having a biological brain illness which affects their rationality, they are not usually allowed a say in the matter."

Although psychiatric drugs and other traditional treatments can be helpful, they are not nearly as effective as is often thought and can have detrimental, even life-threatening side-effects. There is also a significant risk of relapse when treatment is stopped.

"Rather than diagnosing and treating people on the basis of psychiatric categories, which actually contain many people with no symptoms in common, we need to look at each sufferer's symptoms individually from a psychological perspective," says Professor Bentall. "It then becomes relatively easy to understand why they might be happening and how the sufferer can address and cope with them."

Together with colleagues at Manchester, Glasgow, Cambridge and Birmingham, Professor Bentall has recently received a £1.5m grant from the Medical Research Council to research this approach, in which the UK is acknowledged as a world leader. Although sufferers' responses have been very positive however, the availability of psychological treatments for psychiatric difficulties nowhere near matches the incidence of such problems.

"Identifying and addressing the problems the sufferer, rather than the psychiatrist, perceives creates an understanding of each person's condition which is far more scientific, humane and effective than a blanket diagnosis," Professor Bentall asserts. "It also allows us to identify people at risk of psychological breakdown earlier, and keep them out of the traditional cycle of diagnosis and treatment."

Odd behavior and creativity may go hand-in-hand

Wed, 07 Sep 2005 08:13:00 PST

( from http://www.rxpgnews.com ) A quirky or socially awkward approach to life might be the key to becoming a great artist, composer or inventor.

New research in individuals with schizotypal personalitiespeople characterized by odd behavior and language but who are not psychotic or schizophrenicoffers the first neurological evidence that these individuals are more creative than normal or fully schizophrenic people, and rely more heavily on the right sides of their brains than the general population to access their creativity.

Psychologists believe famous creative luminaries, including Vincent Van Gogh, Albert Einstein, Emily Dickinson and Isaac Newton, had schizotypal personalities.

The idea that schizotypes have enhanced creativity has been out there for a long time but no one has investigated the behavioral manifestations and their neural correlates experimentally, Folley said. Our paper is unique because we investigated the creative process experimentally and we also looked at the blood flow in the brain while research subjects were undergoing creative tasks.

Folley and Park conducted two experiments to compare the creative thinking processes of schizotypes, schizophrenics and normal control subjects. In the first experiment, the researchers showed research subjects a variety of household objects and asked them to make up new functions for them. The results showed that the schizotypes were better able to creatively suggest new uses for the objects, while the schizophrenics and average subjects performed similarly to one another.

Thought processes for individuals with schizophrenia are often very disorganized, almost to the point where they cant really be creative because they cannot get all of their thoughts coherent enough to do that, Folley said. Schizotypes, on the other hand, are free from the severe, debilitating symptoms surrounding schizophrenia and also have an enhanced creative ability.

In the second experiment, the three groups again were asked to identify new uses for everyday objects as well as to perform a basic control task while the activity in their prefrontal lobes was monitored using a brain scanning techniques called near-infrared optical spectroscopy. The brain scans showed that all groups used both brain hemispheres for creative tasks, but that the activation of the right hemispheres of the schizotypes was dramatically greater than that of the schizophrenic and average subjects, suggesting a positive benefit of schizotypy.

In the scientific community, the popular idea that creativity exists in the right side of the brain is thought to be ridiculous, because you need both hemispheres of your brain to make novel associations and to perform other creative tasks, Folley said. We found that all three groups, schizotypes, schizophrenics and normal controls, did use both hemispheres when performing creative tasks. But the brain scans of the schizotypes showed a hugely increased activation of the right hemisphere compared to the schizophrenics and the normal controls.

The researchers believe that the results offer support for the idea that schizotypes and other psychoses-prone populations draw on the left and right sides of their brains differently than the average population, and that this bilateral use of the brain for a variety of tasks may be related to their enhanced creativity.

In support of this theory, Folley pointed to research by Swiss neuroscientist Peter Brugger who found that everyday associations, such as recognizing your car key on your keychain, and verbal abilities are controlled by the left hemisphere, and that novel associations, such as finding a new use for a object or navigating a new place, are controlled by the right hemisphere. Brugger hypothesized that schizotypes are better at accessing both hemispheres for novel associations, enabling them to make these associations faster. His theory is supported by research showing that a disproportional number of schizotypes and schizophrenics are neither right nor left hand dominant, but instead use both hands for a variety of tasks, suggesting that they recruit both sides of their brains for a variety of tasks more so than the average person.

The lack of specialization for certain tasks in brain hemispheres could be seen as a liability, but this increased communication between the hemispheres actually could provide added creativity, Folley said.

Hope of early diagnostic tool for schizophrenia and bipolar disorder

Thu, 04 Aug 2005 23:50:00 PST

( from http://www.rxpgnews.com ) Key research from the University of New South Wales (UNSW) could lead to the first early diagnostic tool for schizophrenia and bipolar disorder.
"At the moment we don't have any biological tests for these conditions," said one of the authors, UNSW Associate Professor of Psychiatry, Philip Ward, who is based at Liverpool Hospital's Schizophrenia Research Unit. "Our research could eventually lead to a simple, cost-effective and safe way to distinguish patients with schizophrenia from those suffering bipolar disorder. This is important because a patient can get treatment sooner and hopefully have a better outcome."

Auditory recovery cycle dysfunction in schizophrenia: A study using event-related potentials has just been published in the international journal Psychiatry Research.

"Sixty percent of patients with schizophrenia have auditory hallucinations," said co-author, UNSW PhD candidate Nathan Clunas. "So we decided to look at a particular brain wave-form which measures attention and attention deficits that can be found in these patients."

The researchers recorded the brain waves associated with pairs of sounds in 17 patients with schizophrenia. Subjects heard the sounds through a set of headphones, while performing a visual distraction task. The patients' results were compared with those of a sex and age-matched healthy volunteer group.

"We were looking at what occurs about 100 milliseconds after the sounds were presented," said Nathan Clunas. "The distinctive pattern observed in healthy volunteers was disrupted in patients with schizophrenia.

"These findings may help us understand the problems patients with schizophrenia experience in focussing attention on everyday events," said Nathan Clunas.

The researchers are currently analysing the results of patients with bipolar disorder, to see whether different patterns of response to sounds are seen in these patients.

"Depending on the final results in the bipolar group, we may be on the way to developing a biological test," said Professor Ward.

Quetiapine effective in reducing aggression & violent behaviour in schizophrenia

Mon, 20 Jun 2005 16:01:00 PST

( from http://www.rxpgnews.com ) A new study, published today in the journal Human Psychopharmacology: Clinical and Experimental,1 shows that the atypical antipsychotic SEROQUEL (quetiapine), may be an effective treatment option for patients with schizophrenia who exhibit aggressive behaviour during psychotic episodes.

In the study, patients who received SEROQUEL demonstrated significantly greater improvements in symptoms of aggression and hostility compared to patients receiving placebo (p less than 0.01 P less than 0.01 on Brief Psychiatric Rating Scale (BPRS) alternative hostility cluster score, one of three parameters derived from the BPRS to measure hostility symptoms in the study. ).

"Aggressive behaviour is a significant problem in patients with schizophrenia and has severe negative consequences for the patient, families, carers and the therapeutic community as a whole" commented Professor Celso Arango, from the Hospital General Universitario Gregorio Maranon, Madrid, Spain, and study author. "It is important that patients who are experiencing aggressive symptoms are prescribed a therapy which not only treats these symptoms but which they also find acceptable, in terms of its tolerability, so that they adhere to the prescribed treatment" continued Professor Arango. "In both respects, SEROQUEL holds advantages for both patient and clinician, making it a powerful treatment option for these distressing and challenging symptoms."

SEROQUEL has been shown to provide first line efficacy together with trusted tolerability in treatment of schizophrenia during three randomised, double-blind, placebo-controlled studies.2, 3, 4 The study published today, an analysis of pooled data from these three pivotal trials, included a total of 389 patients who exhibited aggressive behaviour at study entry. The results show that patients who received SEROQUEL demonstrated significantly greater improvements in symptoms of aggression and hostility, compared with patients taking placebo, across all three efficacy parameters used in the study.** In addition, the analysis showed that these improvements in hostility were highly correlated with improvements seen in patients' positive symptoms (characterised by delusions, an inability to think clearly and hallucinations).1

Although the vast majority of patients with schizophrenia are not violent, much of the stigma associated with the condition is linked to the public perception that patients are inherently violent or aggressive. Historically, first generation antipsychotics have been the mainstay of treatment for treating aggressive or violent patients, however severe side effects limit their benefit.1 Therefore, research in this field, particularly as regards the benefits of newer atypical antipsychotics such as SEROQUEL in reducing such violent behaviour, is of great importance to patients and their families.

SEROQUEL has been licensed for the treatment of schizophrenia since 1997 and is available in 82 countries for the treatment of this condition. SEROQUEL is also licensed in 63 countries for the treatment of mania associated with bipolar disorder, including the US, Canada and several European countries. To date, over 8 million people have been treated with SEROQUEL worldwide.

Schizophrenia is less prevalent than textbook figures

Tue, 31 May 2005 19:02:00 PST

( from http://www.rxpgnews.com ) Schizophrenia is a devastating mental illness and a major contributor to the global burden of disease, but how many people are actually suffering from the disease worldwide? John McGrath and colleagues from the University of Queensland have conducted the most comprehensive analysis on the topic and now report their findings in the May issue of the international open-access journal PLoS Medicine.

The researchers have done what is called a systematic review of the medical literature, which turned out a few surprises. And knowing about prevalence--defined as the number of people suffering from the disease at a given time or within a time interval--of such an important disease is crucial to health policy strategies.

They found that schizophrenia is more common in developed than in poorer countries but overall less common than previously thought. Across countries, immigrants have higher rates of the disease than native-born individuals.

The scientists have analyzed a total of 1,721 estimates from 188 studies covering 46 countries and calculated the following median prevalence estimates: 4.6 per 1,000 for point prevalence (defined as prevalence during any interval of less than a month), 3.3 for period prevalence (defined as prevalence during a period from 1 to 12 months), 4.0 for lifetime prevalence (the proportion of individuals in the population who have ever manifested the disease and who are alive on a given day), and 7.2 for lifetime morbid risk (which attempts to include the entire lifetime of a birth cohort, both past and future, and includes those deceased at the time of the survey).

The point prevalence numbers are consistent with key policy documents, but the 0.5% estimate for lifetime prevalence given in many textbooks is a significant overestimate. "This," the authors suggest, "is another example where the research community needs to review their belief systems in the face of data." Another often quoted statistic, namely that "schizophrenia affects about one in a hundred" most sensibly refers to lifetime morbid risk data. Here as well, the systematic analysis suggests that the reality is somewhat lower, and the authors suggest that "if we wish to provide the general public with a measure of the likelihood that individuals will develop schizophrenia during their lifetime, then a more accurate statement would be that about seven to eight individuals per 1,000 will be affected."

However, the analysis makes clear that "many people with schizophrenia have persisting symptoms, despite the best mix of interventions we can offer." It has been estimated that current interventions can at most reduce 25% of disease burden. Thus, the authors conclude that "this is a powerful argument for investing in applied and basic research."

Quetiapine Improves Cognitive Function in Schizophrenia - Study

Tue, 24 May 2005 12:18:00 PST

( from http://www.rxpgnews.com ) Data presented today, drawn from an 8-week, double-blind, flexible-dose, parallel study of 673 schizophrenia patients randomized to treatment with SEROQUEL (mean modal dose of 525 mg/day) or risperidone (mean modal dose of 5.2 mg/day), analyzed the cognitive benefits of both medications. Cognitive assessments including memory, verbal fluency and executive function, as well as a social skills performance-based measure, were conducted at baseline and at endpoints. Data showed that both SEROQUEL and risperidone were associated with overall improvements in cognitive functioning versus baseline, with no significant differences between the treatment groups.

This study, which was presented at the annual meeting of the American Psychiatric Association (APA), showed that SEROQUEL and risperidone improved overall cognitive function and social skills performance in this patient population.1 In addition, an analysis of a large health claims database showed that patients with schizophrenia taking atypical antipsychotics, including SEROQUEL, exhibited greater treatment compliance than those taking conventional antipsychotic treatments.2

SEROQUEL currently is approved for the treatment of acute manic episodes associated with bipolar I disorder and for the treatment of schizophrenia.

"Cognitive function and treatment compliance are important components to the successful, long-term management of schizophrenia. Specifically, patients who take medications that are effective and well tolerated, and who stick to that treatment, are more likely to manage their illness successfully," said Philip Harvey, Ph.D., Department of Psychiatry, Mount Sinai School of Medicine. "The results of these studies reconfirm the tolerability of SEROQUEL, as measured by treatment adherence, and its ability to improve cognitive function in patients with schizophrenia."

For patients with schizophrenia, cognitive functioning often is impaired, which can be a significant barrier to long-term recovery.1 To date, few studies have directly compared atypical antipsychotics for the treatment of cognitive function.1

"Deficits in social functioning are a major barrier to recovery in schizophrenia," added Dr. Harvey. "The results of this study show that SEROQUEL at an appropriate dose has a beneficial effect on social competence even at 8 weeks, with part of this improvement associated with improvements in memory and speed of cognitive processing."

In an analysis of a large health claims database, also presented today, that studied 7,216 antipsychotic monotherapy treatment episodes in patients with schizophrenia, several atypical antipsychotics (SEROQUEL, risperidone, olanzapine, and ziprasidone) and conventional antipsychotics (haloperidol, perphenazine, thioridazine, and thiothixene) were compared with respect to treatment compliance and duration of treatment.

-- Data showed that patients in the atypical antipsychotic group experienced greater treatment compliance than patients in the conventional antipsychotic group.2

"In serious mental illnesses such as schizophrenia, treatment compliance is crucial to the overall management of the condition," said Kitty Rajagopalan, Ph.D., Director, Health Economics and Outcomes Research, AstraZeneca Pharmaceuticals LP. "Effective treatments such as SEROQUEL, when taken persistently, help ensure improved patient outcomes."

Schizophrenia is a serious brain disorder with symptoms including distorted perceptions of reality, hallucinations and delusions, confused thinking, and flat or blunted emotions.3 The first signs of schizophrenia typically emerge in the teenage years or early twenties.3 Almost 2.2 million Americans - or 8 out of every 1,000 people - suffer from schizophrenia.4 Medications are important in the management of symptoms.5 Approximately 70 percent of patients with schizophrenia clearly improve when treated with antipsychotic drugs,4 which are classified into two categories -- "typical" and "atypical" antipsychotics.4

SEROQUEL is indicated for the treatment of acute manic episodes associated with bipolar I disorder, as either monotherapy or adjunct therapy with lithium or divalproex, and the treatment of schizophrenia. Patients should be periodically reassessed to determine the need for continued treatment.

AstraZeneca received notice on April 11, 2005, of the US Food and Drug Administration (FDA) request that the product labeling for all atypical antipsychotics, including SEROQUEL, be updated to include a boxed warning noting the increased risk of mortality in elderly patients with dementia-related psychosis taking these drugs, compared to patients taking placebo. The FDA proposed boxed warning also notes that these drugs are not approved for treatment of elderly patients with dementia-related psychosis.

Prescribing should be consistent with the need to minimize the risk of tardive dyskinesia. A rare condition referred to as neuroleptic malignant syndrome has been reported with this class of medications, including SEROQUEL.

Hyperglycemia, in some cases extreme and associated with ketoacidosis, hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics, including SEROQUEL. Patients starting treatment with atypical antipsychotics who have or are at risk for diabetes should undergo fasting blood glucose testing at the beginning of and during treatment. Patients who develop symptoms of hyperglycemia should also undergo fasting blood glucose testing.

Precautions include the risk of seizures, orthostatic hypotension and cataract development.

The most commonly observed adverse events associated with the use of SEROQUEL in clinical trials were somnolence, dry mouth, dizziness, constipation, asthenia, abdominal pain, postural hypotension, pharyngitis, SGPT increase, dyspepsia, and weight gain.

1 Harvey P.D., Brecher M, Sweitzer D, et al. Improvements in cognitive functioning for patients with schizophrenia after treatment with Seroquel or Risperidone. Annual Meeting of the American Psychiatric Association, 2005, Atlanta, Georgia, poster 244.

2 Rajagopalan K, Gianfrancesco F. Treatment compliance and persistence among patients with schizophrenia: atypical versus typical antipsychotics. Annual Meeting of the American Psychiatric Association, 2005, Atlanta, Georgia, poster 188.

3 National Alliance for the Mentally Ill: About Mental Illness/Schizophrenia fact sheet. Reviewed by Daniel Weinberger, M.D.: October 2003

4 Torrey Fuller E. Surviving Schizophrenia: A Manual for Families, Consumers, and Providers: Fourth Edition. New York: HarperCollins, 2001.

5 Miller, Rachel and Susan E. Mason. Diagnosis Schizophrenia: A Comprehensive Resource. New York: Columbia University Press, 2002.

For full prescribing information for SEROQUEL, please visit the Web site http://www.seroquel.com.

Maternal Exposure to Parasitic Infection may Increase Schizophrenia Risk

Tue, 17 May 2005 18:48:00 PST

( from http://www.rxpgnews.com ) A study published last month in the American Journal of Psychiatry suggests an association between maternal exposure to toxoplasmosis and increased risk for developing schizophrenia in adult children. The study, which evaluated archived blood samples from pregnant women who participated in a large birth cohort called the Child Health and Development Study (CHDS) from 19591967, was conducted by researchers at the New York State Psychiatric Institute and the Department of Epidemiology at the Mailman School of Public Health at Columbia University, in collaboration with the Kaiser Permanente Medical Care Plan, Northern California Region.

Toxoplasmosis is a parasitic infection that can develop from eating undercooked meat and unwashed fruits and vegetables, drinking contaminated water, or not washing one's hands after gardening or changing cat litter boxes. Researchers found a potential link between high maternal toxoplasmosis gondii antibody titers and development of schizophrenia spectrum disorders in the adult offspring. No association was found for moderate antibody titers. While active toxoplasmosis infection is known to adversely affect fetal brain development, this is the first suggestion of a possible association between an elevated maternal antibody to toxoplasmosis and the risk of schizophrenia.

"These findings underscore the value of prenatal serologic samples to document how maternal infectious disease exposures affect the development of adult disorders over time," said Alan Brown, MD, lead author and associate professor of clinical psychiatry and epidemiology at the New York State Psychiatric Institute, Columbia University and Mailman School of Public Health. Since publication of this study, another group presented similar findings at a recent scientific conference. Their study, based in Denmark, also suggests a potential link between elevated levels of maternal toxoplasmosis gondii antibody and increased risk for schizophrenia among adult offspring. Dr. Brown noted, "While it's as good an idea as ever to wash hands before eating and to cook meat thoroughly, these studies are too preliminary to lead to new public health recommendations."

The risk of schizophrenia spectrum disorders in the general population is about one percent. The increase related to high toxoplasma antibody suggested by the Columbia study would add another one to two percent to this risk.

"Evidence from this and previous studies leads us to consider that the increased risk for schizophrenia may not stem from exposure to a specific infectious disease, but from a mechanism secondary to infection, such as inflammation," said Ezra Susser, MD, DrPH, Anna Cheskis Gelman and Murray Charles Gelman Professor and chair of the Department of Epidemiology at the Mailman School of Public Health. Dr. Susser is also senior investigator of the Prenatal Determinants of Schizophrenia (PDS) study, and head of Epidemiology of Brain Disorders at the New York State Psychiatric Institute. He added, "The current findings, while intriguing, must be replicated in a larger sample before we can conclude that elevated toxoplasma antibody in a pregnant woman could predispose her unborn child to develop schizophrenia later in life."

The PDS study is based in the Child Health and Development Study (CHDS) cohort initiated by Jacob Yerushalmy at the University of California, Berkeley, in 1959, in collaboration with Kaiser Permanente Medical Care Plan in Northern California (KPNC). The goal of the CHDS was to examine influences on outcomes of pregnancy and childhood health and development. The CHDS recruited nearly every pregnant woman under obstetric care from the Kaiser Foundation Health Plan (KFHP) in Alameda County, California. The 19,044 offspring of these women born between 1959 and 1967 were automatically enrolled in KFHP. In addition to collecting and storing blood sera samples, the CHDS study collected extensive data on the prenatal period, and conducted maternal interviews on family health history, maternal and paternal health habits, and maternal and paternal socio-demographic information. In 1997- 1999, the research team used electronic databases to identify adult CHDS offspring that might have developed schizophrenia during the period between January 1, 1981 and December 31, 1997. These individuals were invited to participate in a diagnostic interview, and those who participated and were confirmed to have schizophrenia or disorders in the schizophrenia spectrum, were then compared with carefully matched individuals from the CHDS who did not develop these disorders.

In August 2004, the researchers determined in the same cohort that prenatal exposure to influenza may increase the risk for schizophrenia years later. Both of these findings are part of the larger team PDS study, which examines prenatal infection, nutrition, chemical exposure, paternal age, and a range of other prenatal factors that influence schizophrenia risk.

Olanzapine prevents Brain Loss in Schizophrenia

Tue, 05 Apr 2005 17:06:00 PST

( from http://www.rxpgnews.com ) A new brain imaging study of recently diagnosed schizophrenia patients has found, for the first time, that the loss of gray matter typically experienced by patients can be prevented by one of the new atypical antipsychotic drugs, olanzapine, but not by haloperidol, an older, conventional drug. The study, published in today's Archives of General Psychiatry, also confirmed previous studies that show patients who experience less brain loss do better clinically.

"This is a really big breakthrough," says the study's leader, Jeffrey Lieberman, M.D., director of the New York State Psychiatric Institute and chairman of psychiatry at Columbia University Medical Center. "The drugs we have for schizophrenia can't cure people who've been sick for years, but this study shows that the newer atypical drugs, if started early, can prevent the illness from progressing. If our findings are confirmed, one could argue that we should treat new patients with atypical drugs like olanzapine rather than older conventional medications such as haloperidol and chlorpromazine."

Gray matter contains the bulk of the brains cell's and the billions of connections among the cells. Loss of gray matter in patients with schizophrenia has been linked to social withdrawal and progressive deterioration in cognition and emotion--which are among the least responsive symptoms to medications.

To see if antipsychotic drugs could slow the initial brain changes in new patients, Dr. Lieberman and colleagues at 14 sites in North America and Europe measured brain volume and cognitive changes in 263 first-episode schizophrenia patients and 58 non-schizophrenic volunteers over a two-year period. Half of the patients received the atypical antipsychotic olanzapine and the other half took the conventional antipsychotic haloperidol. Dr. Lieberman initiated the study when he was professor of psychiatry at the University of North Carolina, which also coordinated the research.

The study found that, on average, haloperidol-treated patients lost about two percent of their gray matter, or about 12 cubic centimeters. No changes were detected in the olanzapine-treated patients and the normal volunteers. Patients who lost gray matter, particularly in the frontal lobe of the brain, also had greater problems with cognitive functioning, as measured by tests of verbal fluency, verbal learning and memory.

Schizophrenia has always been known as a disease that causes progressive worsening of symptoms and deterioration in function, but only in the last 10 years have researchers found that the brains of schizophrenics are also progressively deteriorating.

"People used to think that the deterioration was inevitable, but now we're thinking that if you can prevent the acute episodes of psychosis in schizophrenia you can actually stop the loss of gray matter," Dr. Lieberman says.

"It also gives us hope that we will be able to completely forestall the disease in the future by intervening before psychosis even begins," Dr. Lieberman adds. "In three to five years, we should have ways to identify which adolescents will become schizophrenic, and we can then begin to test the preventative power of treatments."

Images of brain activity may hold clues to the onset of schizophrenia

Thu, 17 Mar 2005 19:10:00 PST

( from http://www.rxpgnews.com ) Images of brain activity may hold clues to the onset of schizophrenia in people at high risk for the disease, according to a study headed by psychiatry researchers at the University of North Carolina at Chapel Hill School of Medicine.

A decline in function in the prefrontal cortex, the "executive" or front part of the brain, is present in high-risk individuals experiencing early symptoms of schizophrenia and may reflect biological changes that precede the onset of diagnosable illness, the study indicates.

Identifying such changes prior to disease onset also may prove useful in determining vulnerability to schizophrenia onset, particularly in those at high risk for the disease, the researchers said.

"We know that individuals who experience symptoms that occur before the disease becomes full-blown demonstrate impaired performance in tasks requiring executive function, attention and working memory, but the neurobiological bases of this remains unclear," said Dr. Aysenil Belger, the study's senior author.

"In looking at the brain activity of high-risk people while they performed some of these tasks, we hoped to identify a neurobiological marker of vulnerability to disease onset, a tool we might use to help assess their risk of developing psychotic symptoms," Belger said. "If such a tool became established, perhaps we could intervene early on in some way to improve whatever pathology it showed."

Belger is an associate professor of psychiatry in UNC's School of Medicine and of psychology in UNC's College of Arts and Sciences.

The study involved functional magnetic resonance imaging, or fMRI. Unlike standard MRI scans that show anatomical structures in black and white, fMRI offers digitally enhanced color images of brain function, depicting localized changes in blood flow and oxygenation.

When particular regions of the brain increase their neural activity in association with various actions or thought processes, they emit enhanced blood oxygen level dependent signals. The signals can be localized in the brain and translated into digital images that portray neural activity level as a ratio of oxygenated to de-oxygenated hemoglobin, the iron-containing pigment in red blood cells. Researchers then can quantify these signals to generate maps of various brain functions.

Fifty-two study participants were divided into four groups: "ultra-high-risk," where participants experience symptoms but the illness is not full-blown; early schizophrenia, where participants have had the illness less than five years; chronic schizophrenia, where participants have had the illness for more than five years; and healthy age-matched "controls," for comparison.

Those at ultra-high-risk had been pre-screened for schizophrenia symptoms, revealing that some were showing early emotional, affective and cognitive symptoms such as the blunting of emotion, poor personal relationships, poor hygiene, emotional detachment and false beliefs.

While undergoing fMRI scans, all participants responded to an executive decision test - so-called because decision making and task-appropriate response selection are required - displayed on a computer screen. This test, developed by the study team, requires push-button responses to certain colored squares, circles and objects from everyday life. Each visual cue is presented at a fraction of a second against a white background, and participants must ignore an auditory tone sounded when each cue is presented.

"Of particular interest was the neural activity generated by a series of infrequent circles that were designated as 'target' events, which participants were instructed to detect and respond to as quickly as possible by pressing a button," Belger said.

"Accurate and fast performance on this test requires both the maintenance of attention and vigilance, as well as the ability to rapidly discriminate between target events and other non-target distracters, such as the colored squares and objects."

The scanner mapped participants' neural activity in specific brain areas before, during and after the presentation of the visual target events.

"Our goal was to see if the high-risk individuals showed normal brain activity during these executive tasks or whether or not they showed some of the pathology of individuals who already have schizophrenia," Belger said.

The researchers found that when the healthy people make these types of detections and decisions, they activate frontal and mid-brain regions. Chronic schizophrenia patients showed a significant drop in activation of these regions, "thus it appears that they fail to engage these frontal regions," said Belger.

"And we found that the high-risk group and early, or first-episode, schizophrenia group are somewhere in between: It looks like these deficits begin even before they are diagnosed and treated. It suggests that this area of the brain that's important for executive decision-making processes is already altered before disease onset."

The preliminary study represents a "first pass" at determining feasibility of the tool to map tiny differences between patients and controls, Belger said.

"We need to show that the tool is reliable and that, indeed, it's detecting something in the population that it's not detecting in healthy individuals," she added.

"This is also a cross-sectional study, a comparison between groups. It's not longitudinal, as we did not study the same individuals over time. Still, the findings are intriguing; they are suggestive. We still need to know how they actually correlate with schizophrenia onset."

Nicotine could have a beneficial effect on the symptoms of schizophrenia

Thu, 03 Mar 2005 18:05:00 PST

( from http://www.rxpgnews.com ) A new study has suggested that nicotine could have a beneficial effect on the symptoms of schizophrenia among mildly dependent smokers. However, people with schizophrenia who have high nicotine dependence are more likely to be readmitted to hospital and have a poor outcome.

Published in the March issue of the British Journal of Psychiatry, the study set out to explore the hypothesis that smoking is a form of 'self-medication' for people with schizophrenia.

Worldwide, schizophrenia is associated with a higher rate of smoking than that observed in the general population, or among those with other severe mental illnesses.

Although it has been suggested that smoking may have a beneficial effect on either schizophrenic symptoms, or on the side effects of antipsychotics drugs, research so far has been hampered by confounding factors, such as medication, or alcohol and drug use.

The study was carried out in two community mental health centres in Granada in Spain. 250 patients diagnosed with schizophrenia were classified into three categories: highly dependent smokers, mildly dependent smokers and non-smokers.

'Positive' symptoms of schizophrenia (e.g. delusions and hallucinations) and 'negative' symptoms (e.g. withdrawal and depression), and the number of admissions to hospital, were compared between the three groups.

69% of the patients studied were current smokers. It was found that high total and positive symptom levels were less frequent in mildly dependent smokers than in non-smokers or in highly dependent smokers. This finding supports the self-medication hypothesis for these symptoms in this group of patients.

Negative symptoms were not significantly associated with nicotine dependence, however, and so the self-medication hypothesis is not borne out in this respect.

Highly dependent smokers had the highest proportion of hospital admissions compared with mildly dependent smokers and non-smokers.

The authors of the study comment that the findings do not generally support the self-medication hypothesis, but rather suggest a complex interaction between nicotine dependence and the symptoms of schizophrenia.

If there is any beneficial effect of nicotine, it may be restricted to mildly dependent smokers, and particularly to those on low dosages of typical antipsychotics who are sensitive to the side effects of these older types of drug.

Schizophrenia can be predicted years before development

Fri, 07 Jan 2005 04:42:00 PST

( from http://www.rxpgnews.com ) It is possible to predict with some accuracy which people in a high-risk group who will (and will not) develop schizophrenia, some years before the development of the psychosis. The latest publication from the Edinburgh High-Risk Study, which appears in the January 2005 issue of the British Journal of Psychiatry, has shown that among people at increased genetic risk of schizophrenia, a state of vulnerability will occur in many more individuals than will actually develop the disorder.

Simple behavioural measures of e.g. social withdrawal or odd behaviour, and 'schizotypal' thinking ('sometimes I get a weird feeling that I am not really here') provide the best evidence for distinguishing high-risk individuals who will develop schizophrenia from those who will not.

The purpose of the Edinburgh High-Risk Study, which began in 1994, is to determine what distinguishes high-risk individuals who go on to develop schizophrenia from those who do not, and to compare relevant factors in affected and unaffected high-risk people with matched controls.

A high-risk sample was recruited of 163 young adults aged 16-24 with two relatives with schizophrenia. The control groups were made up of young people who were well, and individuals in the first episode of schizophrenia who did not have a family risk of the disorder.

In this study the high-risk group and 36 controls were examined. Baseline measures were compared between those who did develop schizophrenia, a well control group, a well high-risk group and high-risk participants with partial or isolated psychotic symptoms.

Of those at high risk, 20 developed schizophrenia within 2.5 years. Just over half of those who fell ill were in the 'psychotic or possibly psychotic symptoms' group on entry to the study. However, many of the high-risk group who did not fall ill were just as symptomatic on entry as any of those who did.

The filmed records of interviews from this study show that such symptoms often appear to have been associated with little distress or functional impairment. They may be short-lived and followed by years in which they do not occur at all.

Those who developed schizophrenia differed from those who did not on social anxiety, withdrawal and other 'schizotypal' features, all of which were best assessed by simple behavioural and cognitive measures. Other measures, particularly in terms of neuropsychology, were also predictive, especially assessments of episodic memory (which are suggestive of temporal lobe dysfunction).

The authors of the study comment that the findings are consistent with the view that schizophrenia is primarily a disorder of temporal lobe structure and function that develops slowly over several years. The exact nature of the change that pushes an individual into psychosis is not yet clear, but continuing studies, particularly of functional brain imaging, may reveal this.

Painkillers during pregnancy increase risk of schizophrenia by four times

Tue, 02 Nov 2004 15:17:00 PST

( from http://www.rxpgnews.com ) Children born to mothers who took analgesics in the second three months of pregnancy run a more than four-fold greater risk of developing schizophrenia, a new study from Denmark has found.

Published in the November issue of the British Journal of Psychiatry, the study set out to shed light on the hypothesis that prenatal exposure to analgesics may affect the development of the nervous system of the foetus, leading to an increased risk of schizophrenia in adulthood.

The researchers analysed data from the Copenhagen Perinatal Cohort, which consists of 9125 individuals delivered by 8949 pregnant women between October 1959 and December 1961. A total of 8400 infants survived the first month after birth.

Information on exposure to analgesics and psychiatric hospitalisation was available for 7999 people from the Perinatal Cohort. It was found that the prevalence of exposure to analgesics at any time during the first trimester was 0.9%; during the second trimester 1.8%; and during the third, 2.0%.

A total of 116 cases of schizophrenia were identified. For the first trimester, the risk was only significant for the third month, and was not significant for the third trimester. However, the incidence of schizophrenia in both males and females in the analgesic exposure group during the second trimester was more than four times higher than in the non-exposure group during that period.

The association was slightly stronger in females than males. Importantly, it was independent of maternal schizophrenia, which was the strongest risk factor for schizophrenia in this study.

Other known risk factors, such as parental history of schizophrenia, second-trimester viral infections, treatment with other drugs, pregnancy complications, parental social status and parental age were all taken into account. The link between prenatal exposure to analgesics and schizophrenia was found to be independent of all these risk factors.

The authors comment that during the second trimester of pregnancy a part of the brain called the cortical subplate reaches its peak of development. This may be a period when the immature foetal brain is particularly sensitive to a range of environmental influences.

It was previously found from data from the Copenhagen Perinatal Cohort that the risk of having malformed children was over twice as high in mothers who took analgesics during pregnancy. This discovery is of potential relevance to theories on causal factors in schizophrenia, as well.

A large number of physical defects, such as cleft palate, large or small distance between tear ducts and adherent earlobes have been linked to schizophrenia-spectrum disorders in a sample of the Copenhagen Perinatal Cohort.

The researchers also found that taking psychiatric medications during the second trimester was associated with intake of analgesics during the same period. Taking both these medications could be associated with increased levels of psychiatric problems and/or a tendency to consult a physician more often.

However, it would have required a larger cohort study and the collection of additional prenatal and perinatal data to disentangle effects of prenatal exposure to analgesic drugs from the effects of the somatic and psychosomatic conditions prompting their use.

The authors of the study caution that as only 6.9% of all the cohort members with schizophrenia had been exposed to analgesics in the second trimester, this research needs to be replicated before prenatal exposure to analgesics can be added to the list of demonstrated risk factors for schizophrenia.

Reference:
Holger J, Sorensen E L, Mortensen L, Reinisch J M and Mednick S A (2004) Association between prenatal exposure to analgesics and risk of schizophrenia. British Journal of Psychiatry, 185, 366-371.

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