Schizophrenia Mouse Model Should Improve Understanding and Treatment of the Disorder

Scientists have created what appears to be a schizophrenic mouse by reducing the inhibition of brain cells involved in complex reasoning and decisions about appropriate social behavior.

Findings by Medical College of Georgia scientists, published Dec. 28 in the Proceedings of the National Academy of Sciences, elucidate the critical balance between excitation and inhibition of these cells that appears to go awry in schizophrenia. They also provide the first animal model for studying the disabling psychiatric disorder that affects about 1 percent of the population.

"We believe the mouse, which exhibits some of the same aberrant behavior as patients with this disorder, will help identify better therapies," said Dr. Lin Mei, a developmental neurobiologist who directs MCG's Institute of Molecular Medicine and Genetics. "We are doing testing to see if antipsychotic drugs already on the market are effective in treating the mouse."

MCG scientists made the mouse by deleting a candidate gene for schizophrenia, ErbB4, from interneurons, which are brain cells that help shower larger decision-making neurons, called pyramidal cells, with inhibition.

READ MORE @ SCIENCE DAILY

UK study warns against anti-psychotics for dementia

* Most dementia patients given anti-psychotics needlessly

* Report could inform clinical practice around the world

* Global dementia cases seen doubling to 66 mln by 2030

More than 140,000 dementia patients in Britain are given anti-psychotic drugs needlessly and overprescribing of the medicines is linked to an extra 1,800 deaths in elderly people each year, a report said on Thursday.

The government-backed review showed that only around 36,000 of around 180,000 dementia patients prescribed anti-psychotics got any benefit from them -- findings it said could affect clinical practice in dementia across the world.

"Anti-psychotics are used too often in dementia," Sube Banerjee, the report's author and a professor of mental health and ageing at the Institute of Psychiatry at King's College London, said in a statement.

He said use of anti-psychotics drugs for dementia should be cut to a third of current levels in Britain and said his study would "provide international leadership in this complex clinical area."

Alzheimer's Disease International predicted in September that more than 35 million people around the world will suffer from dementia in 2010. That number is expected to almost double every 20 years, to 66 million in 2030 and more than 115 million in 2050. [ID:nN20262573]

READ MORE @ REUTERS

Weight Gain Associated With Antipsychotic Drugs

Young children and adolescents who take the newest generation of antipsychotic medications risk rapid weight gain and metabolic changes that could lead to diabetes, hypertension and other illnesses, according to the biggest study yet of first-time users of the drugs.

The study, to be published Wednesday in The Journal of the American Medical Association, found that 257 young children and adolescents in New York City and on Long Island added 8 to 15 percent to their weight after taking the pills for less than 12 weeks.

The patients, ages 4 to 19, added an average of one to one-and-a-half pounds a week.

“The degree of weight gain is alarming,” said Dr. Wayne K. Goodman, head of a Food and Drug Administration advisory panel on the drugs last summer and chairman of psychiatry at Mount Sinai School of Medicine in Manhattan. “The magnitude is stunning,” he said.

Although the drugs’ influence on weight and metabolism had been previously detected, Dr. Goodman, who was not involved in the study, said the speed and magnitude of the effects found in the study were greater than previously reported — findings he said were made possible by looking exclusively at new patients.

READ MORE @ NY TIMES

Metabolic Side Effects, Cardiovascular Risk Differs Among Antipsychotic Treatments for Schizophrenia: Presented at ECNP

The differences in metabolic side effects and cardiovascular risk resulting from antipsychotics make the initial choice of medication important in controlling long-term effects from treatments used for schizophrenia, researchers said here at the 22nd European College of Neuropsychopharmacology (ECNP) Congress.

W. Wolfgang Fleischhacker, MD, Biological Psychiatry Department, Medical University Innsbruck, Innsbruck, Austria, and colleagues analysed data from the European First Episode Schizophrenia Trial (EUFEST) study to determine the effects of several first- and second-generation antipsychotics on cardiovascular risk factors in patients with or without metabolic syndrome (MS) risk. Results of the study were presented on September 14.

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UPDATE 1-US FDA staff: Schering's antipsychotic works

Schering-Plough Corp's (SGP.N) experimental antipsychotic drug Saphris appears to be effective and as safe as other similar medications, U.S. Food and Drug Administration staff said in a memo released on Tuesday.

The drugmaker, which is expected to be acquired by Merck & Co Inc (MRK.N) later this year, is seeking FDA approval of the drug to treat adults with acute schizophrenia or bipolar disorder.

It has touted Saphris, or asenapine, as one of its five "star" products with the potential to earn more than $1 billion a year.

Although no final conclusion has been made, "we generally are in agreement that the sponsor has provided adequate support to suggest effectiveness for asenapine for the claimed indications," Dr. Thomas Laughren, director of the FDA's Division of Psychiatry Products, wrote in a June 24 memo.

Additionally, the drug's safety profile was "acceptable" and appears to be "qualitatively similar to that observed for other atypical antipsychotic drugs," he wrote.

READ MORE @ REUTERS

Antipsychotic Drugs Associated With High Blood Sugar in Older Adults With Diabetes

Older patients with diabetes who take antipsychotic medications appear to have an increased risk of hospitalization for hyperglycemia (elevated blood glucose level), especially soon after beginning treatment, according to a report in the July 27 issue of Archives of Internal Medicine, one of the JAMA/Archives journals.

An increasing number of older adults are being prescribed antipsychotic drugs for dementia and other conditions, according to background information in the article. However, these medications may be associated with a—including Parkinson’s disease symptoms, stroke and diabetes—in the older population. “The risk of diabetes may be partly related to chronic effects of the weight gain associated with antipsychotic agents,” the authors write. “However, case reports of acute hyperglycemia after the initiation of therapy with these drugs suggest that they may also be associated with acute glycemic [blood glucose level] changes.”

Lorraine L. Lipscombe, M.D., M.Sc., of the Institute for Clinical Evaluative Sciences, University of Toronto and Women’s College Research Institute at Women’s College Hospital, Toronto, Ontario, Canada, and colleagues studied 13,817 individuals age 66 and older (average age 78) with diabetes who began treatment with antipsychotics between April 1, 2002, and March 31, 2006. Each patient who was hospitalized for hyperglycemia during the observation period—through March 31, 2007, an average of two years of follow-up—was considered a case and was matched with up to 10 control patients who were the same age and sex but were not hospitalized over the same time period. The researchers then compared the likelihood of hyperglycemia among those who were currently taking antipsychotic medications to those who had discontinued antipsychotic medications for more than 180 days.

Of the total group of 13,817 patients, 1,515 (11 percent) were hospitalized for hyperglycemia. Those who were currently taking antipsychotic drugs had a higher risk of hospitalization than those who had stopped the medications more than 180 days ago. The risk was highest among those who were just starting antipsychotic drug treatment.

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Delirium in hospitalized adults: Situation critical, no relief available

Every year as many as seven million adults in the United States experience delirium during hospitalization. In a systematic review of the scientific literature on delirium prevention and treatment, investigators from Indiana University School of Medicine, the Regenstrief Institute and Wishard Health Services found that despite the significant health and financial burdens of delirium for hospitalized adults, no effective way to prevent or treat the condition has been identified.

"Having delirium prolongs the length of a hospital stay, increases the risk of post-hospitalization transfer to a nursing home and doubles the risk of death. We need to identify a safe and effective drug to prevent and treat delirium. With our review we are challenging the scientific community to come up with new therapeutic options," said Malaz Boustani, M.D., senior author of the study which appears in the July 2009 issue of the Journal of General Internal Medicine. Dr. Boustani is a Regenstrief Institute investigator and associate professor of medicine at the IU School of Medicine.

Delirium, experienced by a significant number of older patients in surgical and critical care units and over half of older adults who are hospitalized for broken hips, is a state of confusion in which the individual has undergone a sudden alteration of mental status. Delirium is not dementia, but individuals with dementia are more susceptible to developing delirium during hospitalization than individuals without dementia.

The researchers found that only 13 randomized controlled studies on promising drugs for delirium were conducted from January 1966 to October 2008. These studies identified and evaluated 15 drugs including first and second generation antipsychotics, the drugs currently prescribed by most physicians for patients with delirium. The researchers found that neither older agents nor newer, more expensive medications were effective in preventing delirium. The study also found no difference between antipsychotics in treating delirium. To date, there are no U.S. Food and Drug Administration approved drugs to prevent or manage delirium according to Dr. Boustani.

READ MORE @ EUREKALERT

Paliperidone May Lower Recurrence Risk in Schizophrenia: Presented at APA

Post hoc analyses of a trial of the long-acting antipsychotic drug paliperidone, given by injection, appears to decrease the likelihood of recurrence in schizophrenic patients, according to researchers here at the 162nd Annual Meeting of the American Psychiatric Association (APA).

Larry Alphs, MD, PhD, Ortho-McNeil Janssen Scientific Affairs, Titusville, New Jersey, noted on May 20 that evidence exists to support limiting recurrences in schizophrenia, because brain mass is seen to decrease over time in patients with the disorder.

"The brain deteriorates with each progressive relapse," said Dr. Alphs.

Of the 681 patients tested in the double-blind, open-label trial, 408 were included in the recurrence-prevention phase.

Patients were given a month-long treatment with paliperidone palmitate injection or placebo. Recurrence rates were lower for patients diagnosed <=5 years before the study compared with placebo (20% vs 44%, P = .0025). For those who were diagnosed >5 years before the study, the difference in recurrence was similarly significantly lower with the drug (13% vs 48%, P < .0001).

Paliperidone use was also associated with a longer time to recurrence than placebo for both diagnosis time cohorts (P = .0011 and P < .0001, respectively).

Although what a comparator active antipsychotic drug would have shown in such a study is unknown, Dr. Alphs said that "most [antipsychotic drugs] would do similar things."

READ MORE @ DOCTOR'S GUIDE

Choice of Antipsychotics Influence Metabolic Abnormalities in Patients With Schizophrenia:Presented at APA

A prospective trial comparing 3 antipsychotic drugs revealed that clozapine is most likely to produce metabolic changes that point the way to metabolic syndrome.

However, clozapine was also most likely to control violent behaviour and metabolic consequences were most apparent for African American, researchers stated here at the 162nd Annual Meeting of the American Psychiatric Association (APA).

Menahem Krakowski, MD, New York University, New York, and Nathan Kline Institute, Orangeburg, New York, presented the findings of a randomised, double-blind study on May 20.

The study included 110 inpatients with schizophrenia or schizoaffective disorder who were randomised to receive clozapine (n = 34), olanzapine (n = 31), or haloperidol (n = 28).

At study entry, 93 patients gave blood samples for measuring fasting glucose, cholesterol and triglycerides and had at least 1 more sample collected during the 12 weeks of the study. The patients had a history of physical assaults.

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Fred A. Baughman Jr., MD Announces: Vets' Sudden Cardiac Deaths Are Not Suicides or Overdoses

Fred A. Baughman Jr., MD today announced the results of his research into the "series" of veterans' deaths acknowledged by the Surgeon General of the Army.

Upon reading the May 24, 2008, Charleston (WV) Gazette article "Vets taking Post Traumatic Stress Disorder drugs die in sleep," Baughman began to investigate why these reported deaths were "different." And, why they were likely, the "tip of an iceberg."

Andrew White, Eric Layne, Nicholas Endicott and Derek Johnson were four West Virginia veterans who died in their sleep in early 2008. Baughman's research suggests that they did not commit suicide and did not overdose as suggested by the military. All were diagnosed with PTSD. All seemed "normal" when they went to bed. And, all were on Klonopin (a benzodiazepine), Paxil (an SSRI antidepressant) and Seroquel (an antipsychotic).

On January 15, 2009, the New England Journal of Medicine (Ray et al), reported that antipsychotics double the risk of sudden cardiac death.

On February 7, 2008, Surgeon General Eric B. Schoomaker, said there has been "a series of deaths in Warrior Training Units" -- "often as a consequence of the use of multiple prescription and nonprescription medicines and alcohol ... we all saw the unfortunate death of Heath Ledger, the 'Brokeback Mountain' star, who died from an accidental overdose."

READ MORE @ PR NEWSWIRE

Cardiac Risks Hold Up Approval of Two Antipsychotics

FDA advisors remain skeptical about the safety of two antipsychotics for which regulatory approval is being sought and are especially troubled by potentially fatal cardiac risks.

Despite positive efficacy data from placebo-controlled trials, experts on a Food and Drug Administration (FDA) psychopharmacology advisory committee have reservations about potentially dangerous adverse effects of two antipsychotic medications under regulatory review for approval.

The FDA held meetings in April to seek the committee's advice on whether sertindole, a second-generation antipsychotic (SGA), should be approved for the treatment of schizophrenia and prevention of suicide in schizophrenia patients, and whether quetiapine XR extended-release tablets should be approved for treating major depressive disorder (MDD) as a monotherapy and as an adjunctive therapy to an antidepressant and for treating generalized anxiety disorder (GAD) as a monotherapy.

READ MORE @ PSYCHIATRIC TIMES

Is The FDA Easing Up? How one company turned a rejection into a thumbs up, and what it could mean for the drug industry as a whole.

After the Food and Drug Administration told Vanda Pharmaceuticals that the company's schizophrenia drug was "not approvable" last July, Wall Street marked the tiny biotech for dead.

The FDA asked for a new clinical trial; Vanda insisted it could change the agency's mind with its existing data. Its shares sank from $4 to 45 cents. A hedge fund, Tang Capital Partners, started a proxy fight to try and get Vanda to liquidate and distribute the proceeds to shareholders.

Then Wednesday night, the FDA announced it was approving the drug, Fanapt, based on data from 3,000 patients. Vanda shares exploded 700% to $8. That's the kind of jackpot that could start getting investors interested in gambling on tiny biotechs again.

But the Vanda story may signal something far more important for investors than just a reminder that biotech stocks can pop: an easier FDA. Both Wyeth ( WYE - news - people ), which is being bought by Pfizer ( PFE - news - people ), and Schering-Plough ( SGP - news - people ), which is being bought by Merck ( MRK - news - people ), were rebuffed last year by the FDA after submitting data for schizophrenia drugs.

READ MORE @ FORBES

Does Antipsychotic Treatment Impact Pediatric Health Care Costs?

Declining health care costs in pediatric patients treated with antipsychotic agents are being offset by the health care costs associated with the development of adverse events related to these medications.

Using retrospective data from South Carolina's Medicaid medical and pharmacy claims between January, 1996 and December, 2005, researchers Jeanette Jerrell, Ph.D., and Roger McIntyre, M.D., identified 4140 children and adolescents prescribed antipsychotic medications, and a random sample of 4500 children not treated with psychotropic medications. Their main outcome measures were total health care costs and emergency, inpatient, and outpatient services use over time, but they included pre-existing medical conditions, receipt of multiple psychotropic medications, and individual risk factor differences for gender, age group, and ethnicity in the analyses.

READ MORE @ MEDICAL NEWS TODAY

Antipsychotic Use in Elders With Alzheimer's Leads to Large Increase in Mortality

There is a large increased long-term risk of mortality in patients with Alzheimer's disease (AD) who are prescribed antipsychotic medication, according to the long-term follow-up results of the Dementia Antipsychotic Withdrawal Trial (DART-AD) published early online and in the February edition of The Lancet Neurology.

While there is evidence of modest short term benefits of antipsychotic treatment for the neuropsychiatric symptoms of AD, there is also clear evidence of an increase in adverse effects. However, all the data regarding mortality so far relate to short term follow-up of 12 weeks or less.

Clive Ballard, MD, Wolfson Centre for Age-Related Diseases, King's College London, London, United Kingdom, and colleagues have provided the first long-term follow-up data for AD patients given antipsychotic drugs.

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Florida Medicaid, Antipsychotics and Small Children

At a time when growing use of atypical antipyschotics in children is under a microscope, Florida’s Medicaid program recently revised rules that makes it possible for doctors to write prescriptions for children of all ages - including those younger than six years old.

Most of these drugs can lead to weight gain and diabetes, and one prominent study found they were no more effective than older meds. Yet the drugs are increasingly prescribed for children, with Medicaid programs in several states reporting rising expenditures for antipsychotics, sometimes to treat ADD or ADHD, which are unapproved uses (look here and here).

In general, the atypical antipsychotics - a newer class that includes AstraZeneca’s Seroquel; Bristol-Myers Squibb’s Abilify; Pfizer’s Geodon; Lilly’s Zyprexa and Johnson & Johnson’s Risperdal - were not approved by the FDA to treat small children, or those younger than 10 years old. Risperdal has been approved for children older than 5 years of age, but only for those with autistic disorder. To be eligible for Medicaid reimbursement, a drug has to be used for a medically accepted indication, which means the drug has to be approved for a specific use or supported by specific compendia (this link indicates the three compendia do not list any use of the atypicals in children younger than 5 years old).

READ MORE @ PHARMALOT

FDA Panel Slams Rising Antipsychotic Use In Kids

After a steady stream of reports that antipsychotics are increasingly prescribed to children, often for unapproved uses, such as treating attention deficit disorders (back story), an FDA advisory committee yesterday chastised the FDA for not doing more to discourage such prescribing.

For instance, more than 389,000 youngsters last year were given Johnson & Johnson’s Risperdal, and 240,000 were 12 or younger, The New York Times writes. Often, the drug was prescribed to treat attention deficit disorders, but Risperdal is not approved for that use and its risks - weight gain, metabolic disorders and possibly permanent muscular tics - aren’t justified, panel members said.

“This committee is frustrated,” Leon Dure, a pediatric neurologist from the University of Alabama School of Medicine and panel member, told the meeting. “And we need to find a way to accommodate this concern of ours.”

However, Tom Laughren, director of the FDA’s division of psychiatry products, told the panel that the agency could do little to fix the problem and, instead, pointed the finger at medical specialty societies, which he insisted must do a better job educating doctors about side effects.

READ MORE @ PHARMALOT

Side-Effects of Antipsychotics

A new federally funded study will examine ways to control the metabolic side effects associated with the use of the newer atypical antipsychotic medications in children with schizophrenia or bipolar disorder.

The use of atypical antipsychotic medications to treat children and adolescents with schizophrenia or bipolar disorder is relatively common, but the side effects associated with them are troubling.

The recent NIMH-funded Treatment of Early Onset Schizophrenia Study (TEOSS) found that two atypical medications were associated with more metabolic side effects than an older generation antipsychotic.

The new grant will test ways in which the metabolic side effects, such as weight gain, insulin sensitivity and other factors that can lead to type 2 diabetes and heart disease, may be controlled or reduced.

READ MORE @ PSYCHCENTRAL

Psychiatrist And Neuroscientist Says Antipsychotics Cause Brain Shrinkage

I've been writing about the dirtiest little secret of antipsychotics for some time now, namely that they cause brain shrinkage in some (I'm assuming it's not all) patients and animal studies, so it was rather bracing yesterday to read this New York Times interview with Nancy Andreasen, a neuroscientist and psychiatrist at the University of Iowa who does nervous system research on people diagnosed with schizophrenia with MRIs.

READ MORE @ FURIOUS SEASONS

Antipsychotic drug 'stroke risk'

More people than previously thought could be at higher risk of having a stroke caused by their antipsychotic drugs, say UK scientists.

Previous research suggested only some types of the drug increased the risk, particularly for people with dementia.

However a study published in the British Medical Journal says all forms of antipsychotics boost the risk, in all patients.

A mental health charity said patients on the drugs must be closely monitored.

Antipsychotic drugs are generally used to control psychotic symptoms in patients with disorders such as schizophrenia, and some severe forms of depression.

They are also thought to be widely used to control symptoms of dementia such as aggression, leading to accusations they were being used unnecessarily as a "chemical cosh" in some circumstances.

READ MORE @ BBC

Looking beyond the drug receptor for clues to drug effectiveness

Antipsychotic drugs that are widely used to treat schizophrenia and other problems may not work as scientists have assumed, according to findings from Duke University Medical Center researchers that could lead to changes in how these drugs are developed and prescribed.

Scientists have known that all antipsychotic drugs target the D2 receptor inside cells. New tests developed at Duke reveal that the biochemical pathways linked to this receptor – the pathways along which the drugs deliver their therapeutic effects – may function differently than previously understood.

The Duke team developed specialized tests and studied two main pathways that stem from the receptor. The first is the G-protein-dependent signaling pathway, and the other is the beta arrestin pathway.

Most antipsychotic drugs in use today were developed to target the G-protein signaling that occurs at the receptor. Only recently, beta-arrestin, a protein known as an "off-switch" for G-protein receptors, has been shown to also play a role in directing other cellular activities.

The tests uncovered surprising results. "Our work showed that all nine antipsychotic drugs we examined uniformly and more potently block the beta-arrestin pathway downstream of the D2 dopamine receptor," said Bernard Masri, Ph.D., lead author and postdoctoral researcher in the Duke Department of Cell Biology.

READ MORE @ EUREKALERT