Schizophrenia.com

I was disappointed to read Dr. Carolyn DeMarco's column promoting high dose vitamin treatments for schizophrenia. At a time of real progress in treatment of schizophrenia, Dr. DeMarco has written about an approach which Dr. Abram Hoffer and others developed in the 1950s, but which by the 1970s was proven to be fruitless. The work of Dr. Hoffer and others is discussed in detail in the American Psychiatric Association Task Force Report, July 1973, which points out methodological flaws in the early work and reviews later studies which failed to show any benefit for such treatments.

In recent years, new medicines, with improved side-effect profiles and techniques to overcome problems with social and occupational functioning, have been well proven advances for the treatment of schizophrenia. Early intervention programs should prevent some of the serious dysfunction of the disease.

Serious illnesses like schizophrenia require proven treatments. Vitamin treatments as "alternative" therapy for schizophrenia should not be recommended.

Researchers at the University of Illinois at Chicago are studying subtle abnormalities in eye movements that may one day be used to diagnose psychiatric disease. Irregularities in how the eyes track a moving object reflect defects in the neural circuitry of the brain and appear to correspond with particular types of mental disorders. Schizophrenic patients, for example, have difficulty keeping their eyes focused on slow-moving objects.

With new technology, these abnormalities can be measured precisely and compared with normal patterns. "Psychiatric illnesses are not well understood neurologically," said John Sweeney, director of the Center for Cognitive Medicine in UIC's department of psychiatry. "Eye movement tests offer a way to investigate abnormalities in the brain that are causing these disturbances."

The goal, Sweeney said, is to develop eye movement tests as a simple, noninvasive tool for diagnosing brain disorders, including schizophrenia, depression and developmental illnesses such as autism. "At present, however, the field is still in its infancy," he said.

Under a $1.2 million grant from the National Institute of Mental Health, Sweeney and his colleagues are testing eye movement patterns in patients diagnosed with psychotic disorders, including schizophrenia, bipolar disorder and depression, in order to begin to validate eye movement abnormalities as markers for different brain diseases.

For these studies, participants undergo a 90-minute series of visual tests in a specially designed laboratory. Seated in a dark room with their heads secured in a chin rest, subjects are shown a pinpoint of light on the opposite wall.

They are asked to focus on the light as it jumps from one spot to another, to anticipate the location of the light after it has disappeared and to follow the light as it glides to the left or right at different speeds. Various tasks are designed to test the function in different parts of the brain controlling cognitive operations and eye movements.

One task, for example, tests short-term memory. Subjects are shown a brief flash of light; after a several-second delay, they are asked to move their eyes to the remembered location. Participants wear infrared spectacles, called scleral-reflection glasses, which are linked to a nearby computer that records small movements of the eyes very precisely.

The measurements are made using software developed in Sweeney's laboratory. Participants also complete similar tasks in an MRI scanner, enabling the researchers to observe the corresponding brain activity directly. With the scanner, the brain regions controlling different types of eye movements are systematically investigated one at a time.

Sweeney and his colleagues, who have been studying eye movement patterns for 20 years, are using their laboratory to document impairments associated with disease and injury and to chart the course of brain and cognitive development from ages 8 to 15.

During that period, the brain undergoes important changes affecting eye movement control. Neurodevelopmental disorders can interfere with this maturation. "Eye movement studies provide a noninvasive way to gain a deeper understanding of the brain dysfunctions at the root of psychiatric illnesses," said Sweeney.

"We are following patients over time to monitor the progression of their disease and determine whether different treatments are improving their brain and cognitive function." With this information Sweeney hopes to develop the tools needed to improve the diagnosis and treatment of psychiatric illnesses. "And in the long-term future," he said, "through our efforts to link eye movement and cognitive abnormalities to their underlying genetic causes, we hope to be able to identify high-risk individuals and someday prevent the onset of some of the most common and severe brain disorders that now overwhelm our mental health treatment services."

Innovative, Multicenter Study Of Schizophrenia Will Follow Disease Traits In Hunt For Genetic Causes

Specific information processing abnormalities and brain-related circuit dysfunction in schizophrenia patients may be the keys to finding the genetic basis of this puzzling, devastating mental illness that affects more than two million Americans and one percent of the world's population.

Scientists believe multiple genes cause schizophrenia, but specifically, the genetic basis of this disorder remains somewhat of a mystery. Research has pointed to several chromosomes that harbor likely disease-causing genes, but the search has been unsuccessful for the exact genetic code that causes this devastating, but elusive disorder.

Now, with a $20-million, five-year grant from the National Institute of Mental Health, seven academic research centers in the U.S., led by the University of California, San Diego (UCSD) School of Medicine, are taking a different approach to uncover the genetic causes of schizophrenia. Rather than starting with the broadly defined disorder itself, scientists are beginning with specific physiological markers, or traits, that are characteristic of schizophrenia in both patients and some clinically unaffected, normal family members. These physiological markers - caused by defects in brain circuits - will then be used to identify the complex genetic abnormalities that cause them.

"I believe our research is an important step in furthering our understanding of schizophrenia and then identifying the critical, genetically mediated brain dysfunctions that contribute to the disease," said David Braff, M.D., UCSD professor of psychiatry and director of the seven-center Consortium on the Genetics of Schizophrenia (COGS). "Instead of exploring the genetics of schizophrenia, we're identifying the genetics of different neurological deficits that occur in schizophrenia patients. "

He added that the main research hypothesis is based on the tenants of molecular biology. "If there are several different genetic abnormalities associated with schizophrenia, then each of them would cause a change in a specific protein. We believe that the series of protein changes in this disease is reflected by corresponding discrete functional abnormalities, such as disorganized thought processes," Braff said.

This strategy has been used for gene discovery in other complex medical illnesses. For example, in a form of colon cancer, researchers were able to identify a gene that causes multiple polyp formation, which leads to the cancer, rather than finding a gene for the cancer, itself.

At least six specific schizophrenia traits, called endophenotypes, will be studied in more than 2,000 individuals. UCSD, which is leading the project, will be joined by researchers at Harvard, Mt. Sinai School of Medicine, UCLA, University of Colorado Health Sciences Center, University of Pennsylvania and University of Washington, Seattle. Key to the studies will be the testing of individuals with schizophrenia and their clinically unaffected family members. These family members may have the same liability genes and associated traits, but are normal and don't show clinical signs of the disease. Specifically, the researchers will study cognitive dysfunction and abnormalities in perception and information processing experienced by schizophrenia patients. (See below for descriptions of tests.)

For example, schizophrenia patients, family members and "normal" individuals will be tested for deficits in the ability to inhibit, or "gate" irrelevant stimuli. People are constantly bombarded with a multitude of external and internal stimuli, and most individuals are able to select those stimuli that are most relevant to current activities and goals, while screening out - or gating - irrelevant stimuli. Schizophrenia patients are unable to filter the trivial from essential information and stimuli in everyday sensory input. They, therefore, have troubles navigating in everyday life activities because they are easily distracted, confused, and they become disorganized.

The disordered thinking that is characteristic of schizophrenia may be manifested in some of the more visible features of the disease, such as disorganization of speech and behavior with associated disabilities in work and social relationships.

"Ultimately, the COGS study will lead to a better understanding of the genetic abnormalities associated with these cognitive and information processing dysfunctions in schizophrenia patients," Braff said. "On a longer term basis, this functional genetics approach may lead to a new era of genetically informed treatment options. Thus, medications will be aimed at reversing genetically mediated brain dysfunctions and restoring schizophrenia patients to better levels of social and work function as their symptoms are alleviated."

New dynamic imaging techniques provide a deeper look at Alzheimer's and schizophrenia (excerpt)

By Robert Adler, Globe Correspondent, 5/6/2003

Paul Thompson, the UCLA neuroscientist whose team created these first-ever sequences of a disease engulfing the living human brain, sees [new images they've captured on the disease process of schizophrenia and alzheimers] as a significant step toward earlier diagnosis, more effective treatment, and -- eventually -- prevention or cure of brain-destroying diseases.

Thompson, a 31-year-old British emigrant, is unabashedly excited about his team's accomplishments: ''The tools from our group are opening really new windows on what's happening inside the brain.'' They give researchers a powerful way to test new medications and lets doctors diagnose Alzheimer's and other dementias earlier and more accurately. That should give more patients an early start on medications that can at least slow the ravages of these diseases.

Like faces, no two brains are alike. As a result, it's extremely difficult to compare diseased and healthy brains or track changes over time. That's the problem Thompson and his team solved. By morphing ordinary MRI scans onto a standardized brain, they can pool scans from multiple patients without blurring the picture. They can then sequence those standardized images into revealing movies. And, crucially, they can quantify changes with great precision. ''We can code normal human variation,'' he said, ''and still be exquisitely sensitive to abnormal changes.''

As a result, Thompson's group has been able to study diseases such as Alzheimer's and schizophrenia as never before. ''With this kind of imaging, you can see a lava flow of destruction as more and more brain tissue is engulfed,'' Thompson said. ''You can see exactly which areas are losing tissue, when, and how fast.''

Thompson first applied these new tools to schizophrenia....In 2001, Thompson's group produced the first time-lapse images revealing a wave of tissue loss rolling across the brains of schizophrenic children. They utilized high-resolution MRIs of more than 1,000 children scanned every two years since 1992 by Judith Rapoport and colleagues at the National Institute of Mental Health. Thompson's group detected the first flicker of the disease in a small part of the parietal cortex, above and behind the ears.

Over five years, Thompson saw a ''pervasive, unrelenting wave of tissue loss that swept forward like a forest fire,'' eventually engulfing the sides and front of the brain. By 18, the teenagers had lost 25 percent of their gray matter in certain brain areas.

''Seeing that wave of tissue loss in schizophrenia was a huge surprise,'' Thompson said. The pattern matched the drumbeat of schizophrenia's active and passive symptoms -- hallucinations, delusions and bizarre thinking followed by flattened emotions, depression and withdrawal.

The images are disturbing but valuable. They've pushed Thompson toward the theory that schizophrenia is a disrupted version of normal brain development.

Teenagers' brains normally undergo extensive ''pruning'' in which 1 percent of the gray matter disappears every year, more in some areas. Because schizophrenia typically strikes during this process, Thompson sees it as ''an exaggeration or derailment'' of normal pruning -- like a gardener gone wild.

His finding that schizophrenia takes up to seven years to engulf the brain highlights the need for early diagnosis and treatment. It also makes finding drugs that may salvage young people's brains even more vital. ''There is a window of opportunity to step in and oppose the disease,'' he said.

Dynamic brain imaging should also speed up the search for genes that predispose people to specific brain diseases. We know they're there. Siblings and children of schizophrenics have one chance in 10 of developing the disease -- 10 times the average risk. A half-dozen genes already have been linked to Alzheimer's, with more to come. It is much easier to match suspect genes to specific patterns of tissue loss than to shifting, hard-to-measure symptoms.

Thompson's movies can be viewed at http://www.loni.ucla.edu/

Changes in glucose and cholesterol levels in patients with schizophrenia treated with typical or atypical antipsychotics.

(American Journal of Psychiatry)

02/25/2003

Glucose and cholesterol levels increase when schizophrenia patients are treated with most of today's anti-psychotic drugs. Clozapine, olanzapine and haloperidol are associated with increased plasma glucose level, and clozapine and olanzapine with raised cholesterol, report researchers in Orangeburg, New York.

Although mean changes in glucose and cholesterol levels remained within clinically normal ranges, about one patient in seven studied by the researchers developed abnormally high glucose.

The researchers conducted a 14-week randomised, double-blind trial which assessed the effects of clozapine, olanzapine, risperidone and haloperidol on levels of glucose and cholesterol. The study participants were 101 hospital in-patients with schizophrenia or schizoaffective disorder.

American Journal of Psychiatry 2003;160:2:290-296. "Changes in glucose and cholesterol levels in patients with schizophrenia treated with typical or atypical antipsychotics."

Gene May Play a Role in Schizophrenia
Excerpt from story by NICHOLAS WADE, New York Times

The long search for a gene that helps cause schizophrenia may at last be bearing fruit after many false starts and disappointments, scientists are reporting.

An errant gene first implicated among schizophrenic patients in Iceland has now turned up in a survey of Scottish patients, too, giving a clear confirmation of the earlier result.

The gene may be involved in remodeling the connections that brain cells make with one another, called synapses. Many of the Icelandic and Scottish patients have the same variant pattern in the gene, supporting the idea that when the gene does not work as designed, wrongly formed nerve-to-nerve wiring accumulates in the brain, giving rise to schizophrenia.

Not all schizophrenics carry the variant and many people carry it without a problem, an expected pattern in diseases caused by several genes. But in both populations, inheriting the variant form of the gene appears to double the risk of schizophrenia.

The finding, if correct, would bolster the strategy followed by Decode Genetics, a company based in Reykjavik that is using the Icelandic population to search for the genetic roots of common diseases like cancer, diabetes, heart disease and Parkinson's. The schizophrenia-related gene is one of the first it has found.

Dr. Kari Stefansson, a former Harvard neuropathologist who is the company's chief executive, said Decode and its partner, the drug company Roche, were developing new drugs to counteract the aberrant gene's effects but could not say when any would be ready for clinical testing.

A defect in neuregulin-1, he suggested, might lead to an accumulation of wrongly formed synapses, accounting for the progressive nature of the disease. It might also explain why environmental factors as well as heredity contribute to schizophrenia, as shown by the fact that if one identical twin has the disease the other has only a 30 to 50 percent chance of developing it.

Dr. Stefansson said he had a considerable emotional investment in the disease because his elder brother has schizophrenia.

The variation discovered by Decode Genetics is a set of seven genetic differences that spans the beginning of the neuregulin gene, which is located on the eighth of the 23 pairs of human chromosomes. Dr. Stefansson said he guessed that the seven changes might in some unexplained way be altering the amount of protein the gene could produce. ...

Dr. Kendler said the progress with the two genes "induces a bit more optimism in a field that has had some difficult times."

Research may lead to better schizophrenia drugs
July, 6 2003 20:29 , Source: MIT Press Release

The study, reported this week in the early online edition of the Proceedings of the National Academy of Sciences, may lead to the first genetically targeted drugs for the disease, which affects 1 percent of the population worldwide.

Nobel laureate Susumu Tonegawa, director of the Picower Center for Learning and Memory at MIT and a Howard Hughes Medical Institute investigator, found that genetically engineered mice lacking the brain protein calcineurin exhibit a number of behavioral abnormalities shared by schizophrenic patients.

In a related study with researchers at Rockefeller University in New York, MIT scientists show that variation in a human calcineurin gene also is associated with schizophrenia. Calcineurin--part of a biochemical pathway in the brain linked to receptors for two brain chemicals, NMDA and dopamine--plays a significant role in the central nervous system.

This is the first study that uses animals who demonstrate an array of symptoms observed in schizophrenic patients to identify specific genes that predispose people to the disease.

MICE AND MEMORY

Tonegawa creates tools to explore the genetic underpinnings of the molecular mechanism for memory. Genetically engineered mice who are missing the brain enzyme calcineurin were previously shown to have an impairment in short-term, day-to-day memory formation, known as working memory. This kind of memory also is impaired in schizophrenia patients.

Further testing of these mice by Picower Center research scientist Tsuyoshi Miyakawa revealed that they also have attention deficits, aberrant social behavior and several other abnormalities characteristic of schizophrenia.

Picower Center research scientist David Gerber then collaborated with Rockefeller's Maria Karayiorgou to examine calcineurin genes in DNA samples from schizophrenic patients and their immediate relatives. The researchers found an association between a particular calcineurin gene and schizophrenia.

"This is an intriguing series of findings," Tonegawa said. "The combination of evidence from the genetically altered mice, together with the human gene studies, create a strong argument to link calcineurin with schizophrenia."

A SEARCH FOR DRUGS

Alterations in multiple genes are believed to predispose people to schizophrenia. Tonegawa suspects that many of these genes may turn out to be components of the calcineurin pathway or to directly interact with the calcineurin pathway.

"Once we better understand exactly which genes are involved, we will know how proteins are affected, and we can set up a test to screen large numbers of compounds to identify ones that have desired effects on the activity of these proteins," Tonegawa said. "This can potentially lead to the discovery of new kinds of drugs for psychiatric conditions such as schizophrenia."

In addition to Gerber, Miyakawa, Karayiorgou and Tonegawa, co-authors include Joseph A. Gogos of Columbia University, and Diana Hall and Sandra Demars of Rockefeller University. Authors on the mouse study include research specialist Lorene M. Leiter and Hongkui Zeng of MIT, and Raul R. Gainetdinov, Tatyana D. Sotnikova and Marc G. Caron of Duke University.

The study on the human genes associated with schizophrenia susceptibility was funded by the Picower Foundation, the National Institutes of Health, the Howard Hughes Medical Institute, the Otsuka Maryland Research Institute, the McKnight Endowment Fund for Neuroscience, the EJLB Foundation and the New York City Council Speaker's Fund.

The study on the genetically altered schizophrenic mice was funded by the Picower Foundation, the National Institutes of Health, the Howard Hughes Medical Institute, RIKEN and NARSAD.

Leading Drugs for Psychosis Come Under New Scrutiny
Excerpt from Story by ERICA GOODE, New York Times

They were billed as near wonder drugs, much safer and more effective in treating schizophrenia than anything that had come before.

There were remarkable stories of recovery. And the new generation of antipsychotic drugs, called atypicals, seemed to have few of the side effects commonly seen with high doses of older medications for psychosis.

The drugs appeared so successful that doctors began prescribing them for other things, not only for other psychotic illnesses, like manic depression, but also for Alzheimer's, personality disorders and nonpsychotic depression, and for conduct disorder and severe aggression in children. Sales of the drugs soared. More than 15 million prescriptions were written last year for the two leading drugs alone, Zyprexa and Risperdal, industry figures show.

But 14 years after the first of the drugs entered the market, researchers are questioning whether they are quite as miraculous - or benign - as originally advertised.

The first round of antipsychotics had such unpleasant side effects, like dry mouth, stiffness and trembling, that people often just stopped using them. The atypicals are considered by many patients to be more tolerable, and many experts believe they are better than older drugs in treating some aspects of psychosis.

But studies suggest that their superiority is at best modest, specific to certain symptoms and variable from drug to drug. Also, there is increasing suspicion that they may cause serious side effects, notably diabetes, in some cases leading to death.

The issue of risks has become more pressing as the drugs are prescribed for children and for adults with milder conditions. And the states, which pay enormous sums for the atypicals in caring for the severely mentally ill, are questioning whether the benefits of the new drugs are worth their costs.

The drugs, experts say, have now reached a turning point where benefits must be balanced by side effects and cost.

National sales of antipsychotics reached $6.4 billion in 2002, making them the fourth-highest-selling class of drugs, behind cholesterol-lowering drugs, ulcer drugs and antidepressants, said IMS Health, a company that tracks drug sales. According to NDCHealth, another company that tracks the industry, in 2002, more than 7.4 million prescriptions were written for Zyprexa and more than 7.6 million for Risperdal.

Many doctors and patients prefer the drugs to the older medications. Bretta M., 34, a Brooklyn woman, for example, said that the Zyprexa she takes is an improvement over Haldol, an old-generation drug that she said made her feel "like a zombie."

But the drugs have hardly proved to be a panacea, experts say, and some are more effective and less likely to cause the side effects of older medications than others.

"There has been what I see as a kind of myth-making," said Dr. William Carpenter, a professor of psychiatry and pharmacology at the University of Maryland and the director of the Maryland Psychiatric Research Center. "It's like: `The new generation of drugs is safe, patients like them and they're more effective.' "

"Patients probably do like them a little bit more," Dr. Carpenter said, and therefore might be slightly more likely to keep taking their medication. "But we still have plenty of trouble with the new-generation drugs."

Like other experts, Dr. Carpenter believes that the atypicals have an edge over the older drugs in some areas. He and others said they seem better at easing the emotional blunting, withdrawal and depression often seen in schizophrenia.

Studies have indicated that they are better at preventing relapse and that they carry a lower risk of the most pernicious side effect of older drugs: tardive dyskinesia, a disorder that causes repetitive movements - chewing motions, lip-smacking and contortions of the arms and legs - that sometimes persisted even after the drugs were stopped.

The drugs may help with problems in memory, decision-making and other mental functions that can keep schizophrenia patients from working, but this is still debated.

"I think the new-generation drugs have shown advantages," said Dr. John Kane, the chairman of psychiatry at Zucker Hillside Hospital in Queens and an expert on schizophrenia. "They may not be consistent across every study or every drug, but when you take them in their totality, they are meaningful."

But determining how much more effective the drugs are is not easy. As in all areas of medicine, many studies, including those that appear in peer-reviewed journals, are financed by drug companies. Others are financed by government insurers.

Complicating matters further, many studies are small and they use a variety of methodologies, making comparison difficult.

Analyses that examine the findings from many studies have come up with mixed results. For example, in a presentation at a schizophrenia meeting last month, Dr. John Davis, a professor of psychiatry at the University of Illinois at Chicago, reported on an analysis of 124 studies comparing newer and older drugs. Ten atypical antipsychotics were included, some of them available only in Europe. Five of the newer drugs, including two not on the market here, were moderately more effective in treating psychotic symptoms than the conventional treatments, the analysis found. Of those sold here, Clozaril was the most effective, followed by Risperdal and Zyprexa. Four of the drugs, however, offered no advantage, and one drug, sold only in Europe, was actually worse. Dr. Davis said he received no financing from pharmaceutical companies for his research.

But a 2000 analysis, by Dr. John Geddes, a psychiatrist at the University of Oxford, created a stir by finding no difference in effectiveness between the two classes of drugs. The study, financed by the British government and published in the British Medical Journal, examined 52 studies comparing atypicals and older drugs.

Some patient-advocacy groups have criticized the study as biased toward the lower-cost, older-generation drugs.

In a telephone interview, Dr. Geddes said that, like other clinicians, he had seen patients improve remarkably on the newer medications. "But I remember over the last 20 years I had quite a lot of people who did really well on the older ones, too," he said.

Part of what gave the older drugs a bad reputation, Dr. Geddes contends, was that in the past they were given in very high doses that may have made them less effective and increased side effects. Too, he said, many atypicals "were quite new, and it's not good to go spraying around new drugs without knowing about the long-term effects."

In a report this month in The Lancet, the medical journal, Dr. Stefan Leucht, a research associate at Zucker Hillside Hospital, and his colleagues found that although most atypicals produced fewer Parkinson's-like side effects than high-potency older drugs like Haldol, when compared with older drugs of lower potency, some of the new drugs were just as likely to cause the side effects.

The analysis indicated that only Clozaril and, by a hair, Zyprexa had fewer of the side effects than the conventional antipsychotics, while the other drugs, including Risperdal, showed no fewer side effects.

Dr. Leucht cautioned that the number of studies examined in the analysis was small and that the findings needed confirmation through further research.

Joel Yates of Brooklyn, 53, who has schizo-affective disorder, said he took Haldol at low doses for 15 years and had no bad side effects. Three months ago, Mr. Yates's doctor, concerned about the risk of tardive dyskinesia, switched him to Abilify, a new atypical.

But Regina Moran, a spokeswoman for Novartis, the maker of Clozaril, said that the atypicals had made a large difference for many patients and their families. Before the drugs, she said, "there were many, many schizophrenic patients who never left the back wards of mental institutions."

Some experts hope that a large study comparing atypical and traditional antipsychotics, underwritten by the National Institute of Mental Health and directed by Dr. Lieberman, will help resolve the issue when its results come out next year.

Even less is known about how the drugs affect children. Psychiatrists say they are helpful and necessary for children who suffer from psychosis or who demonstrate severe aggression. But there is so far little data on their effectiveness or safety, though pharmaceutical companies are now beginning to study the drugs in children and adolescents.

Old antipsychotic drugs were notorious for their side effects, not only tardive dyskinesia but the dull-eyed stare and stiff-legged walk that became known in the back wards of state hospitals as the Thorazine shuffle.

Such problems are less frequent in the newer generation of drugs, but they are not unheard of. If researchers agree on anything, it is that the new medications have side effects of their own, some serious.

Most disturbing are cases of diabetes, Type II and Type I, and hyperglycemia that have been reported in adults and some children taking atypical antipsychotics. A study presented yesterday at the psychiatric meetings by Dr. P. Murali Doraiswamy, chief of the division of biological psychiatry at Duke University, and his colleagues raises the possibility that some newer drugs may also be linked to pancreatitis.

Excessive weight gain is common on some atypicals, and may be linked to cases of diabetes: Some patients have reported gaining up to 65 pounds. Some developed diabetes or glucose abnormalities after gaining weight. Others already had the disease and grew worse while taking the drugs. Still others fell ill quickly after starting an atypical and got better once the drug was stopped. For some, the illness was fatal.

Many experts suspect that the drugs are somehow causing or bringing out diabetes and that some drugs may do so more than others. But they are not yet certain that this is the case. Nor do they know how big the problem is. The number of reported cases so far is relatively small, given the many millions of people who have taken the drugs. More than 12 million people have taken Zyprexa alone, according to Eli Lilly.

Complicating matters further, diabetes is common and increasing in the general population. And some studies of patients in the 1940's suggest that diabetes may be higher in people with schizophrenia even without antipsychotic medication.

But the cases are worrisome because it took many years for psychiatrists to recognize that the older drugs were causing tardive dyskinesia.

In three studies, researchers led by Dr. Elizabeth A. Koller examined cases of diabetes in patients taking Clozaril, Zyprexa or Risperdal in an eight-year period. The drugs had 384 reported cases, 289 cases and 132 cases, respectively. On Clozaril, 25 patients died; on Zyprexa, 28; and on Risperdal, 5. The patients who developed diabetes tended to be young and male. The data were gathered from reports filed with the F.D.A. and from medical journals.

The researchers cautioned that reporting of adverse drug reactions to the F.D.A. is voluntary on the part of doctors, making it hard to know whether the higher numbers for some drugs truly reflect differences in relative risk. The agency says the reports it receives represent perhaps 10 percent of the actual number of adverse reactions.

Another study found higher rates of diabetes for patients on Clozaril, Zyprexa and Seroquel but not Risperdal.

In their study of Zyprexa, published last year in the journal Pharmacotherapy, Dr. Koller, an endocrinologist then working at the F.D.A., and Dr. Doraiswamy concluded that the number of cases, the timing of the illnesses and the relatively young ages of the patients who fell ill "suggest a causal relationship" between the drug and the development or worsening of diabetes. Also suggestive, they wrote, was that many patients improved when the drug was stopped.

Marni Lemons, a spokeswoman for Eli Lilly, which has been served with five lawsuits involving patients who developed diabetes while on Zyprexa, said the company did not believe its product was causing diabetes. "This is not an issue for a specific drug, but for this patient population," she said.

Ms. Moran, the Novartis spokeswoman, said, "At this time, there is no evidence suggesting" that diabetes is more common or more serious in patients on Clozaril than "outside the context of Clozaril treatment."

The issue is far from settled, and more than 20 papers on the topic will are being presented at the psychiatric meetings.

The F.D.A. is also looking closely at the diabetes issues. A spokeswoman said the agency is waiting for the findings of a large analysis by the Veterans Administration, to be completed this year, before deciding whether to require warning labels on some or all of the atypicals. Some drugs already carry such labels in Japan or Europe, including Zyprexa and Seroquel.

However, psychiatrists say patients taking antipsychotic drugs should be monitored on a regular basis for glucose abnormalities.

Eventually, Dr. Geddes said, the two classes of antipsychotic medication may come down to a tradeoff of side effects: The risk of tardive dyskinesia posed by the older drugs versus the risk of diabetes.

"It's not up to me to say, is it?" Dr. Geddes asked. "It's up to the patient to say."

Of the billions of dollars spent each year on antipsychotic drugs, a large part comes from government insurance programs.

Dr. Joseph Parks, the medical director of Missouri's Department of Mental Health, said that his state spent $104 million, or 11.6 percent of the total Medicaid payout, on three atypical antipsychotics, Zyprexa, Risperdal and Seroquel, between April 2002 and March 2003. The three drugs topped the list in dollar volume of all drugs covered by the state Medicaid program, including cancer, H.I.V. and heart medications.

"They are good medications," said Dr. Parks, who is also the president of the National Association of State Mental Health Directors' medical directors' council, "and they seriously help a lot of people. I would not want to give up any of them."

But for the price of treating one person with Zyprexa at $303 for a month's prescription, he said, or two on Risperdal, at $159 per month, the state could treat 8 or 10 people with Haldol at $35 per month.

Ohio, a larger state, spent $174 million on antipsychotic medications in 2002, close to $145 million of that on the atypical drugs, said Dennis Evans, a spokesman for the state's Medicaid program.

Yesterday, researchers at the psychiatric meetings presented a study of the cost effectiveness of Zyprexa in treating patients at 17 Veterans Affairs medical centers. The study, led by Dr. Robert Rosenheck, a professor of psychiatry and public health at Yale and the director of the Department of Veterans Affairs Northeast Program Evaluation Center, found that Zyprexa cost the V.A. $3,000 to $9,000 more per patient, with no benefit to symptoms, Parkinson's-like side effects or overall quality of life.

Zyprexa was less likely to produce the physical restlessness called akisthesia, the study found, and was associated with slightly better memory and motor skills. The study was financed by Eli Lilly.

Advocacy groups like the National Mental Health Association worry that the price difference in the drug classes might cause some states, pressed by shrinking budgets, to include only some atypicals in their formularies or even to eliminate them altogether.

Because different drugs work for different people, said Jennifer Bright, the association's senior policy director for health care reform, forcing people to choose from two or three medications increases the chances that none will work, and increases the risk of hospitalization or other, higher cost care.

Whatever the final verdict on the atypicals, many experts believe what is really needed is new and better drugs.

Meanwhile, few psychiatrists - and perhaps even fewer patients - would want to lose any of the newer generation of antipsychotics now on the market. But how they are used and how much value they add, experts say, is ultimately a question for society.

Risperdal (Risperidone) Quick Dissolve Tablets Launched In US
TITUSVILLE, NJ -- May 6, 2003 -- A new, fast-dissolving form of the schizophrenia medication Risperdal® (risperidone) is launching this week. Risperdal M-TAB(tm) dissolves in seconds when placed on the tongue. Risperdal, marketed by Janssen Pharmaceutica Products, L.P., is the most widely prescribed antipsychotic medication in the United States.

"Many individuals can't, won't or just would prefer not to swallow pills. Having an option like Risperdal M-Tab will be useful in helping to ensure patients are able to take their medication regularly," said Dilip Jeste, MD, professor of psychiatry and neurosciences and chief of the Division of Geriatric Psychiatry at the University of California, San Diego (UCSD).

Atypical antipsychotic medications are the most commonly prescribed treatments for schizophrenia -- a disease that affects 2 million Americans and includes symptoms such as agitation, depression, anxiety, delusions, social withdrawal and a diminished capacity for organized thought.

Delivery Technology
Risperdal M-Tab tablets are produced using freeze-drying technology, creating highly porous tablets that rapidly disintegrate upon contact with saliva. The coral-colored, peppermint-flavored tablets will be available in 0.5 mg, 1 mg and 2 mg doses and are bioequivalent to comparable dosages of the original-formulation tablets.

In clinical trials, Risperdal was generally well tolerated. However, as with all other psychotropic medications, Risperdal is associated with side effects. In two controlled trials involving individuals with schizophrenia or schizoaffective disorder, adverse events with an incidence of 5 percent or greater in at least one of the Risperdal groups and that occurred at a rate that was at least twice that of placebo were anxiety, drowsiness, extrapyramidal symptoms (uncontrolled tremors and muscle stiffness), dizziness, constipation, nausea, dyspepsia (upset stomach), rhinitis (runny nose), rash and tachycardia (rapid heart beat). For more information, refer to the full prescribing information for Risperdal or visit http://www.risperdal.com.