Schizophrenia Update, September 26, 2003 Issue

Schizophrenia and Manic Depression share gene flaw

Schizophrenia and manic depression could have similar genetic causes, researchers suggest. The flaw appears to lie in genes which affect how the central nervous system develops. Researchers from the University of Cambridge say the findings are surprising because the conditions are so different. Schizophrenia and manic depression, or bipolar disorder, affect around 2% of the population.

The researchers looked at genes associated with the formation of the myelin sheath which covers and protects nerves and enables the efficient conduction of electrical impulses through the nervous system. The genes were either linked to the development of oligodendrocyte cells, which make up the sheath tissue, or the development of the myelin itself. The team looked at mRNA, which carries the genetic code, to look at how effectively the genes were expressed in the different groups.

They found these genes were less active in people with schizophrenia and bipolar disorder, and there were also faults in how the remaining genes were expressed. Similar changes were seen in the brains of people with both conditions. Treatment Dr Sabine Bahn, who led the research, published in The Lancet, said: "We believe that our results provide strong evidence for oligodendrocyte and myelin dysfunction in schizophrenia and bipolar disorder. "The high degree of correlation between the expression changes in schizophrenia and bipolar disorder provide compelling evidence for common pathophysiological pathways that may govern the disease phenotypes of schizophrenia and bipolar disorder."

Writing in the journal, Dr Kenneth Davis of the Mount Sinai School of Medicine, New York, USA, said: "The observation that at least some myelin-related gene- expression deficits are common between individuals with schizophrenia and bipolar disorder is intriguing because schizophrenia and bipolar disorder have different symptom profiles and require treatment based on quite different neurotransmitter systems."

Psychiatric illness 'can be halted in childhood' Source of Excerpt: Daily Telegraph Date: 16/07/2003

Up to half of all adult mental disorders could be prevented if doctors tackled childhood psychiatric and behavioural problems, according to a study published yesterday in the Archives of General Psychiatry. A team of scientists studied 1,000 New Zealanders for 15 years from the age of 11, and observed that the majority of adults who have a psychiatric disorder had been diagnosed with a psychiatric disorder in childhood. Adult anxiety and schizophrenia-type disorders were preceded by a broad array of juvenile disorders. Based on the findings, the report calls for GPs to do more to screen for anxiety, depression, hyperactivity and conduct/oppositional defiant disorder in children.

Schizophrenia drug claims questioned. Scientists have raised concerns that claims about the benefits of a new generation of drugs for conditions such as schizophrenia may have been exaggerated.

Not only are the new antipsychotic drugs - known as atypicals - thought to be more effective, they have also been associated with fewer side effects. However, a new study has questioned whether they are actually as relatively side effect free as was thought. The drugs, which include risperidone, quetiapine, clozapine and olanzapine, have been approved for use by the NHS by the National Institute for Clinical Excellence (NICE). However, they are very expensive, and campaigners are concerned that they have only been made available to a small minority of patients who would benefit.

The latest study has examined concerns that the drugs' reputation for being side effect free is unjustified - largely because initial trials compared them with a particularly potent older generation drug called haloperidol. ] A team from Zucker Hillside Hospital in New York lead by Dr Stefan Leucht carried out a comprehensive review of data from 31 studies which involved 2,320 patients. Of the new generation drugs, only clozapine was associated with fewer neurological side-effects and higher efficacy than low-potency conventional drugs.

And as a group, new-generation drugs were only moderately more efficacious than low-potency conventional antipsychotics. Dr Leucht said: "If these findings are confirmed by future studies, there would be a good argument for the use of appropriately dosed conventional drugs - such as chlorpromazine - for patients with schizophrenia in settings where new-generation drugs are not generally affordable."

Marjorie Wallace, chief executive of mental health charity SANE, expressed concern that the benefits of the newer drugs was being questioned. She said: "All drugs, if they are to be effective, will have side effects, but our experience is that for the majority the side effects of the newer drugs are more tolerable, people are more willing to take them and they are therefore more effective. "In a significant number of cases (by no means everyone) atypical drugs can transform lives in a way in which the older drugs have failed."

Paul Corry, of the charity Rethink, said much more research was needed before a switch away from the newer drugs could be seriously considered. "People generally prefer the new atypical antipsychotics because they are associated with fewer and less severe side effects. "All medicines have side-effects of some kind. They tend to be most severe when, as is often the case with medicines for treating psychosis, they are prescribed without the full involvement of the person taking them or above recommended dosage levels."

The research is published in The Lancet medical journal.

Excerpt from BBC NEWS:

Experts See Mind's Voices in New Light By ERICA GOODE, Excerpt from New York Times: May 6, 2003

It was just one voice at first, loud and male, coming from the ceiling, saying, "Hi, John," calling him by name as if they were buddies. But after a while, the voice, which he came to know as the "evil genius," urged him to steal other people's brain cells and told him that he had a cancerous tumor in his head.

Eventually, other voices joined in, maybe 50 of them, male and female, yelling "as loud as humans with megaphones," John recalled, from the moment he awoke in the morning until he fell asleep at night, cursing or ordering him to kill himself or, once, when he picked up a ringing telephone, screaming in chorus, "You're guilty! You're guilty!"

"It was utter despair," John said. "I felt scared. They were always around."

Auditory hallucinations are a hallmark of schizophrenia: 50 percent to 75 percent of the 2.8 million Americans who suffer from the illness hear voices that are not there. Like John, whose schizophrenia was diagnosed in 1981 and who spoke on the condition that he not be identified, many people with schizophrenia spend years pursued by verbal tormentors as relentless as the furies of Greek mythology. Suicide is sometimes the result, death seeming the only escape from unending harassment.

Yet psychiatrists who study schizophrenia have traditionally shown little interest in the voices their patients hear, often dismissing them as simply a byproduct of the illness, "crazy talk" not worthy of study.

Recently, however, a small group of scientists has begun studying auditory hallucinations more intensively. Aided by new brain imaging techniques, they have begun tracking such hallucinations back to abnormalities in the brain, finding that certain brain regions "light up" on brain scans when patients are actively hallucinating. And the experts are listening far more carefully to what patients say about their hallucinatory experiences.

The research has led to new theories of what may cause such bizarre alterations in perception and has spawned at least one promising new treatment: the delivery of low-frequency magnetic pulses to areas identified by the brain scans seems to quiet, at least temporarily, the voices of patients who have not found relief through standard treatment with antipsychotic medications.

Ultimately, the researchers say, knowing more about what causes auditory hallucinations may help them understand more broadly the mechanisms that underlie schizophrenia and other psychotic illness.

"These are critical, core experiences that really constitute what having schizophrenia is all about," said Dr. Ralph Hoffman, a psychiatrist at Yale who is studying the magnetic stimulation treatment, called transcranial magnetic stimulation or T.M.S.

In research described in a recent issue of Archives of General Psychiatry, Dr. Hoffman and his colleagues found that schizophrenic patients who received 132 minutes of the magnetic stimulation over 9 days showed a significant reduction in auditory hallucinations compared with control subjects given a dummy treatment. Half of the subjects in the study experienced a return of their symptoms within 12 weeks, though in some cases, the hallucinations remained at bay for up to a year. All the patients were also taking antipsychotic medication.

Schizophrenic patients describe voices that not only talk to them but talk about them, haranguing, insulting and sometimes provoking them to hurt themselves or to perform other actions. In many cases, the hallucinations become more intense when the patient is under stress.

In a study of 200 patients with schizophrenia and other psychotic illnesses, Dr. David L. Copolov, director of the Mental Health Research Institute of Victoria in Melbourne, Australia, and his colleagues found that 74 percent said they heard voices more than once a day. More than 80 percent described the voices as "very real," rather than "dreamlike" or "imaginary," and 34 percent experienced the voices as coming from outside their heads (38 percent said they came from both inside and outside their heads and 28 percent from inside only).

A small minority of the patients said the voices they heard were always or almost always supportive and positive in tone. But more than 70 percent described them as always or almost always negative. Dr. Hoffman of Yale said some of his research subjects heard voices intermittently, but others heard them continuously, the only respite coming when they slept. One patient who committed suicide described her voices as "a constant state of mental rape," Dr. Hoffman said.

Nicole Gilbert, 37, received a diagnosis of schizophrenia in 1985. For years, she said, she could not read anything because her voices "would tell me that it was about me." "They would say things to try to make me believe that I was Jesus," she recalled.

"Then they would torture me and say: `We're just joking. You're so stupid, how could you believe this?' "

Ms. Gilbert, who is much recovered and is now a case manager at a mental health agency in California, said the voices seemed so real that she could not believe it when her friends told her she was hallucinating.

The findings of studies using brain scanning techniques like positron emission tomography (PET) or functional magnetic resonance imaging (M.R.I.) underscore how persuasive auditory hallucinations are to those who experience them. When patients are hallucinating, areas of the brain involved with auditory perception, speech, emotion and memory show increased blood flow, indicating greater nerve cell activity.

"These people are not just crazy; they're telling you what their brains are telling them," said Dr. David Silbersweig, an associate professor of psychiatry at Weill Medical College of Cornell University who has studied hallucinations with brain-imaging. Still, studies so far have come up with differing patterns of brain activation. For example, both Dr. Hoffman's group and a team led by Dr. Philip McGuire, a professor at the Institute of Psychiatry in London, found heightened activity in Broca's area, a region of the frontal lobe involved with speech perception and processing. But Broca's area was not identified in Dr. Silbersweig's research or in a study by Dr. Copolov that will be published soon. The precise areas of the brain's temporal and parietal lobes that show activity during hallucinations also differ from study to study.

The discrepancies are difficult to interpret and reflect the imprecision of even advanced technology in capturing highly complex brain processes. The data are further clouded because the high costs of scans limit the size of most studies.

But the disparity in the findings has also led to different theories about how hallucinations arise.

Schizophrenia typically strikes in adolescence or early adulthood. Extensive research over the last few decades has indicated that the brains of people with the illness differ in significant ways from those of healthy people.

Experts agree that schizophrenia stems from a combination of genetic predisposition and unknown environmental influences. What everyone who studies hallucinations agrees on is that schizophrenic patients misperceive signals generated inside the brain.

But scientists are still debating what is being misinterpreted and how this occurs. Dr. Copolov, for example, suggests that the "voices" patients hear are really fragments of auditory memories "that come to consciousness fused with emotional content" and are then incorrectly evaluated as originating from an outside source.

The fact that in some studies the hippocampus and other brain structures known to be involved in memory retrieval are active during hallucinations is consistent with this theory, Dr. Copolov said. Other researchers, including Dr. McGuire of the London institute, have argued that what is misperceived is internal speech - the running dialogue most people engage in while thinking. In schizophrenia, in this view, a mechanism that normally distinguishes between internal and external speech breaks down.

Dr. Judith Ford, an associate professor of psychiatry at Stanford, and Dr. Daniel Mathalon, an assistant professor of psychiatry at Yale, have proposed that the brain's auditory cortex may play a role in this failure to identify speech correctly as internal or external. In studies, they recorded electrical activity in the auditory cortices of schizophrenic patients and healthy control subjects. In the control group, the auditory cortex showed a dampening of activity in response to internal speech, they found. But this inhibition was lacking in schizophrenic patients.

"When you and I have these thoughts," Dr. Ford said, "we are inhibiting the response of our auditory cortex, saying, `Don't pay attention to this; it's me, talking.' But the schizophrenic patients do not inhibit the response the way normal healthy people do."

Dr. Hoffman has a slightly different theory. In schizophrenia, he suggests, a loss of gray matter may intensify the link between Broca's area, involved in speech production, and Wernicke's area, responsible for speech perception.

In the normal course of affairs, Dr. Hoffman said, Wernicke's area receives information from a variety of nearby brain areas and distant structures like Broca's. But in schizophrenic patients, who in imaging studies show a loss of gray matter in the superior temporal lobe containing Wernicke's, the signals sent from more local regions may be knocked out or greatly decreased. If so, Dr. Hoffman suggests, the signals coming from Broca's may then become more salient, bombarding Wernicke's area with internally generated words and phrases that are in some way interpreted by Wernicke's as external speech.

Dr. Hoffman noted that transcranial magnetic stimulation applied to Wernicke's area appeared to suppress hallucinations in some schizophrenics. "My view is that in schizophrenia it is not just inner speech or an acoustic memory that is misinterpreted," Dr. Hoffman said. Instead, he said, patients "are actually having perceptual experiences that have the same clarity and vividness of external speech."

Dr. Hoffman's research team is now using M.R.I. scanning with each research subject to determine which brain regions are active when the subject is hallucinating, and then delivering stimulation to that area.

But whatever the research on magnetic stimulation yields, it is already helping some of the 25 percent of hallucinating patients whose voices are not stopped by antipsychotic drugs.

"Just stimulating in a single site appears to have a significant impact," Dr. Hoffman said.

Other experts call the results impressive.

In the treatment, an electromagnetic coil shaped like a Figure 8 is held to the patient's head. The coil produces a quarter-size magnetic field that is then rapidly turned on and off, inducing an electrical field in the cerebral cortex's gray matter. Scientists do not know exactly how the treatment works, but they believe it dampens the reactivity of neurons, an effect that is then passed on to other connected brain regions.

Unlike electroshock therapy, long used for severe depression, transcranial magnetic stimulation does not induce seizures at the levels used in the studies and has a far more selective effect on the brain. Nor does the treatment appear to have the serious side effects, like memory loss, of electroshock therapy.

The most common side effect, Dr. Hoffman said, is mild contractions of the scalp that some patients find uncomfortable. Also, in contrast to electroshock, patients receiving the magnetic stimulation remain awake, unsedated, through it. John, who participated in Dr. Hoffman's research last summer, said the procedure did not bother him. "This thing kind of taps on your head every second and it's not intrusive," John said. He said his voices got "smaller and not as loud" after treatment, but they did not go away entirely, and the improvement lasted only six months.

Without a full cure in sight, John said he has developing his own tactics for fighting the hallucinations, which persist despite the medications he takes. He talks back to them in his head, he said, and criticizes them when they criticize him. Between his own efforts and the treatments, John has made much progress. He now attends school, has his own apartment, goes out with friends and has a girlfriend. "I wanted to try to make the voices my friends, but I found out later that that is not realistic," John said. "I was kicked around by them for a long time. Now, if they start bothering me, I just kick them around instead."

Survey Finds U.S. Has High Rate Of Mental Illness, Low Rate Of Treatment Compared To Other Countries BOSTON, MA -- Source: Harvard Medical School Date: 2003-05-07.

The United States has a higher prevalence and lower treatment rate of serious mental illness than a number of other developed countries, according to a study published in a special edition on international health care in the May/June issue of the policy journal Health Affairs.

Treatment was also to be more strongly related to the ability to pay and less to need for care in the United States than the other countries. The study analyzed data from community surveys with more than 22,000 respondents in Canada, Chile, Germany, the Netherlands, and the United States. All these countries, except the United States, have universal health insurance.

Despite differences in treatment, researchers found remarkably similar high proportions of the population with mental disorders (17 to 29 percent), early age of onset (mostly in childhood through the early adult years), high rates of chronic mental illness, and high levels of adverse effects on jobs, marriages, and other aspects of life, said corresponding author Ronald Kessler, professor of health care policy at Harvard Medical School's Department of Health Care Policy.

"The consistency of these patterns across a wide variety of countries is striking," Kessler said. "Issue number one is that we can't wait as long as we do to get young people into treatment. Issue number two is that we have to do a better job of making sure patients are treated with the best available therapies once we manage to get them into treatment."

In all countries, young, poorly educated males with serious mental disorders are the least likely to receive treatment. The report suggests that school-based interventions in low-income school districts may help reach these young men to prevent progression from mild to more serious disorders. Early intervention is uncommon but important, according to the report.

"People with mild mental disorders, if left untreated, have a significant risk of future serious outcomes, such as attempted suicide, hospitalization, and work disability," the authors write.

"Most people with serious mental disorders have conditions that start in childhood or adolescence, but do not get treatment until adulthood," Kessler said. "The problems are usually quite serious by the time they go for professional help. In many cases, these people have dug themselves into quite a hole before getting treatment that would be difficult for even the most emotionally secure person to overcome, such as teen childbearing, school failure, violent relationships, and drug problems.

We can't wait as long as we currently do to get these kids into treatment." People with more serious disorders were more likely to receive treatment, but between one-third and two-thirds of people with serious disorders in the five countries reported receiving no treatment.

No matter how mild or serious the mental disorder, people were more likely to receive treatment if they were older (except for Chile), educated, and female. Kessler said he and his co-authors were also struck by the inadequate treatments in this country.

"This involves both medical care that fails to conform with accepted treatment guidelines, such as a homeopathic dose of a psychopharmacological medication prescribed by a family doctor, or care in some other sector of the treatment system, such as self-help or religious counseling, that has not been shown to be effective in treatment clinically significant mental disorders."

The instrument used to assess mental illness in the surveys, the Composite International Diagnostic Interview (CIDI), was developed in 1990 by the World Health Organization (WHO). Kessler conducted one of the first major CIDI surveys, a nationally representative general population survey of the United States.

When he became the chair of the WHO CIDI Advisory Committee in the late 1990s, Kessler established a data pooling project for cross-national comparative studies that led to this paper. "The first generation of CIDI surveys focused on diagnoses, but did not have good information on severity, which can vary enormously," Kessler said. Severity estimates in this paper are rough.

Kessler is one of two coprincipal investigators of an expanded survey, called the WHO World Mental Health survey initiative, which is being carried out in 28 countries with a combined sample size of more than 200,000 respondents. Analyses of the new surveys are beginning this year, Kessler said. Source:

Glaxo Wins FDA Approval For New Version of Wellbutrin -- GlaxoSmithKline PLC said Friday that U.S. regulators approved Wellbutrin XL, a new version of a GSK antidepressant whose earlier forms have been threatened by generic competition. The U.S. Food and Drug Administration approved Wellbutrin XL for treatment of major depressive disorder in patients aged 18 or over.



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