Genetic 'breakthroughs' in medicine are often nothing of the sort

During the second world war, the physicist Enrico Fermi asked General Leslie Groves of the US Army how many generals might be called "great" and why. Groves replied that any general who won five major battles in a row might be called great, and that about three in every hundred would qualify.

Fermi countered that if opposing forces are roughly equal, the odds are one in two that a general will win one battle, one in four that he will win two battles in a row, one in eight for three battles, one in 16 for four battles, and one in 32 for five battles in a row. "So you are right, General, about three in a hundred. Mathematical probability, not genius."1

There's an analogue of Fermi's "great general": the "great scientific discovery", or at least, as a case study, "the great genetic scientific discovery" as reported in the press. The discovery of genes for a certain behaviour, for schizophrenia, for happiness, always get good press coverage, usually based on publication in a respected scientific journal such as Science or Nature.

The research paper will include a statistic: the probability that the finding could have occurred by chance. The probability will have been sufficiently low that a reviewer for the journal was impressed and therefore recommended publication. Typically this probability or "P-value" will be less than 0.05, or 5%, which means the odds are less than one in 20 that the observed genetic correlation could have occurred by chance.

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'ECG for the mind' could diagnose depression in an hour

An innovative diagnostic technique invented by a Monash University researcher could dramatically fast-track the detection of mental and neurological illnesses.

Monash biomedical engineer Brian Lithgow has developed electrovestibulography which is something akin to an 'ECG for the mind'. Patterns of electrical activity in the brain's vestibular (or balance) system are measured against distinct response patterns found in depression, schizophrenia and other Central Nervous System (CNS) disorders.

The vestibular system is closely connected to the primitive regions of the brain that relate to emotions and behaviour, so Lithgow saw the diagnostic potential of measuring and comparing different patterns of electrovestibular activity.

Working with psychiatry researchers at Monash University's Alfred Psychiatry Research Centre (MAPrc) in Melbourne, Australia, he tested volunteers and found distinct response patterns, or "biomarkers", that distinguished different CNS diseases from each other and from regular electrovestibular activity.

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Novartis Enters Into Agreement for Exclusive US and Canadian Rights to Fanapt(TM), an FDA-Approved Oral Therapy for Schizophrenia

-- Fanapt (iloperidone), an antipsychotic therapy, is indicated in US for the acute treatment of schizophrenia in adults, set for US launch in early 2010

-- Addition of Fanapt will strengthen Novartis psychiatry portfolio and build on history in schizophrenia

-- Schizophrenia is a chronic, severe and disabling psychiatric disorder estimated to affect more than two million adults in the US and nearly 250,000 Canadians

-- Rights to Fanapt acquired from Vanda Pharmaceuticals Inc. for upfront payment of USD 200 million; Vanda eligible for milestones and sales royalties

Novartis Pharma AG has entered into an agreement for exclusive US and Canadian rights to Fanapt(TM) (iloperidone), a new oral medication that is approved by the US Food and Drug Administration (FDA) for the acute treatment of adults with schizophrenia. Novartis plans to launch Fanapt in the US in early 2010.
As part of the agreement with Vanda Pharmaceuticals Inc., Novartis will have exclusive commercialization rights to the oral formulation of this medicine in the US and Canada as well as exclusive rights to develop and commercialize a long-acting injectable (or "depot") formulation of this medicine for these markets.
Schizophrenia is a severe psychiatric disorder that is estimated to affect more than 2 million adults in the US and nearly 250,000 Canadians. Fanapt belongs to a class of medication for schizophrenia known as atypical antipsychotics.

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Statement emphasizes link between severe mental illness, CVD, diabetes

European organizations are calling for improved care and screening for CVD, diabetes in those with mental illnesses.

People with severe mental illnesses, such as schizophrenia, depression and bipolar disorder, die about 10 to 20 years prematurely compared with the general population, and the most common cause of death is cardiovascular disease, experts said at a press conference on Wednesday.

A joint statement issued by the European Association for the Study of Diabetes, European Society of Cardiology and European Psychiatric Association emphasizes the link between mental illness and CVD, with the goal of increasing awareness, improving care and initiating cooperation and screening.

“In addition to having the devastating effects of severe mental illness, people with schizophrenia and bipolar disorder die prematurely,” Richard Holt, MD, PhD, from the University of Southampton, United Kingdom, said during a press conference.

People with mental illness find it much harder to access physical health services, Holt noted. “Rates of screening for both diabetes and CVD are significantly less than in the general population,” he said. “While maybe 20% of cases of diabetes are unknown in the general population, among people with mental illness, as many as 70% are undiagnosed.”

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The future of schizophrenia

Press conference at the 22nd Congress of the European College of Neuropsychopharmacology, Sept. 14, 2009, Istanbul, Turkey

Schizophrenia is a major public health problem. Affecting almost 1% of the world's population, it takes an enormous economic and social toll in addition to the distress, dysfunction, disability and mortality for those afflicted with this disease. Elements of the disease are present from birth, other aspects emerge during developmental years, and the illness becomes fully expressed in early adulthood with long-lasting implications for most patients.

Schizophrenia, which is seen as the paradigmatic psychiatric illness, presents different symptoms in multiple domains, whereby positive and negative phenomena can be separated (Falkai et al., 2005): Positive (psychotic) symptoms in a broader sense include delusions or delusional ideation, hallucinations, disturbance of association, catatonic symptoms, agitations as well as feelings of alien influence and suspiciousness. Negative symptoms include restricted range and intensity of emotional expression, limited thought and speech productivity, social withdrawal, and reduced initiation of goal-directed behaviour. These negative components are typically characterised as affective flattening, alogia, diminished drive, anhedonia and avolition. Furthermore, schizophrenia is associated with cognitive impairment, disorganised speech and behaviour, as well as poor attention. The primary advance in pharmacological treatment of schizophrenia was in 1952 with the introduction of dopamine antagonist antipsychotic drugs.

Paradigm shift in schizophrenia research: from single-disease entity to the paradigm of multiple domains

A century of work has been based on designs that conceptualise schizophrenia as a single disease entity, despite recognition that schizophrenia must have scientific status of a syndrome in the absence of proof of a single disease process (Carpenter et al., 1999). The implications are profound. Research based on the presumption that a single disease is present has produced weak findings that frequently fail confirmation in replication studies. The heterogeneity of patients receiving this diagnosis is substantial. Causal and neuropathological findings valid for some patients will not be found in others. Illness manifestations vary substantially between patients, and symptomatic components of illness are only weakly related to each other within individuals.

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Brain Defect Implicated In Early Schizophrenia

In the first functional magnetic resonance imaging (fMRI) study of its kind, neurologists and psychiatrists at Columbia University have identified an area of the brain involved in the earliest stages of schizophrenia and related psychotic disorders.

Activity in this specific region of the hippocampus may help predict the onset of the disease, offering opportunities for earlier diagnosis and for the development of drugs for schizophrenia prevention.

Details of the findings were published in the September 7, 2009, issue of Archives of General Psychiatry.

In the study, the researchers scanned the brains of 18 high-risk individuals with "prodromal" symptoms, and followed them for two years. Of those individuals who went on to develop first-episode psychotic disorders such as schizophrenia, 70 percent had unusually high activity in this region of the hippocampus, known as the CA1 subfield.

SCIENCE DAILY

Iloperidone Approved as “Second-Generation” Benefits Debated

The FDA recently approved iloperidone (Fanapt, Vanda Pharmaceuticals) for the treatment of schizophrenia, reversing a July 2008 determination that the New Drug Application (NDA) was “not approvable.” An FDA spokesperson explained in an interview in Forbes (May 8), “Vanda provided the FDA with additional data and arguments that led us to reinterpret results of several of their studies.”

The favorable judgment culminated a circuitous product development path. The compound had been developed by Hoechst Marion Roussel, but the rights were sold to Titan Pharmaceuticals in 1997, and then to Novartis in 1998, before Vanda Pharmaceuticals acquired them in 2004. Vanda succeeded in garnering regulatory approval, in large part by redesigning the clinical trials supporting the NDA.

Rather than comparing the efficacy of iloperidone with risperidone and haloperidol, which had not previously favored iloperidone, the new trials compared iloperidone with placebo and used ziprasidone as an active control. In this design, the active agents were shown to have comparable efficacy in improving symptoms measured on the 30-item Positive and Negative Syndrome Scale (PANSS) and were both statistically superior to placebo.

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Schering-Plough Gets FDA Approval for Saphris

Schering-Plough Corp.'s new drug for schizophrenia and bipolar disorder, Saphris, has been approved by the Food and Drug Administration.

The pill, taken twice a day, is the first mind-altering medication to get simultaneous approval for treating both conditions, but it will face significant competition in a crowded market.

For now, it is only specifically approved for short-term use for acute problems, such as when patients have a psychotic episode. However, the drug's label, or detailed package insert, recommends patients responding well to Saphris should continue on it.

Kenilworth, N.J.-based Schering-Plough has completed some studies and is finishing up others on the long-term safety and effectiveness of the drug, spokesman Robert Consalvo said Friday. The company plans to eventually seek official approval for ''maintenance treatment.''

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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.

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Schizophrenia Drug Limits May Have Led to Deaths (Update1)

Restrictions on the use of the antipsychotic medicine clozapine may have led to thousands of additional deaths in schizophrenia patients around the world, a study published in The Lancet medical journal found.

Researchers examined data from patients taking the six most frequently used antipsychotic drugs and found that clozapine was associated with the lowest death rate compared with use of the older medicine perphenazine. Clozapine was linked to a 26 percent reduction in mortality according to the study, led by Jari Tiihonen at the University of Kuopio in Finland.

Doctors can prescribe clozapine, first developed by Switzerland’s Novartis AG, only after two unsuccessful trials with other antipsychotics because it has been linked with agranulocytosis, a condition causing a severe decrease in white blood cells and problems such as fevers, fatigue and bleeding sores, Tiihonen said. Patients taking clozapine need weekly blood monitoring for six months followed by monthly testing to look for signs of the disorder, he said.

“Our results raise the issue of whether clozapine should be used as a first-line treatment, because it seems to be the safest antipsychotic in terms of mortality and it is also the most effective,” Tiihonen and colleagues wrote in the study. “However, clozapine is inexpensive, and hence it’s unprofitable for the pharmaceutical industry to market compared with other second-generation antipsychotic drugs.”

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Schizophrenia genetically linked to other psychiatric disorders

A huge international study has discovered the first common genetic mutations involved in schizophrenia. The results show that schizophrenia shares some genetic links with other psychiatric problems, including bipolar disorder.

Three research consortia analysed the DNA of 15,000 people with schizophrenia and 50,000 health control subjects, to find differences between those with and without the disease. Their findings are published in Nature, the journal

Schizophrenia, which affects about 1 per cent of adults, tends to run in families. This tripartite study has uncovered a vast array of genetic variation that is estimated to account for about a third of the disease's total heritability.

"Each individual gene has a small effect, raising the [risk] of schizophrenia from 1 per cent to 1.2 per cent at most," said David Collier, of the Institute of Psychiatry, London.

While the findings do not provide any astonishing revelations, the international collaboration has been a "spectacular success", according to Dr Collier. It will lead soon to a better understanding of the biology of schizophrenia, though new diagnostic tests and treatments lie further in the future.

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Hoopla, and Disappointment, in Schizophrenia Research

The journal Nature held a big press conference in London Wednesday, at the World Conference of Science Journalists, to unveil three large studies of the genetics of schizophrenia. Press releases from five American and European institutions celebrated the findings, one using epithets like “landmark,” “major step forward,” and “real scientific breakthrough.” It was the kind of hoopla you’d expect for an actual scientific advance.

It seems to me the reports represent more of a historic defeat, a Pearl Harbor of schizophrenia research.

The defeat points solely to the daunting nature of the adversary, not to any failing on the part of the researchers, who were using the most advanced tools available. Still, who is helped by dressing up a severely disappointing setback as a “major step forward”?

The principal news from the three studies is that schizophrenia is caused by a very large number of errant genes, not a manageable and meaningful handful.

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FDA Reverses Earlier Decision, Approves Schizophrenia Drug

The new antipsychotic medication has pharmacological and clinical profiles similar to those of other second-generation drugs on the market and appears to carry comparable risks.

After being turned down by the Food and Drug Administration (FDA) almost a year ago, iloperidone has gained approval for the acute treatment of schizophrenia in adult patients.

Iloperidone is a second-generation antipsychotic (SGA) medication mixed antagonism for dopamine D2 and serotonin 5HT2A receptors and is owned by Vanda Pharmaceuticals.

In two randomized, placebo-controlled, phase-3 trials in patients with schizophrenia, iloperidone was found more efficacious than placebo in reducing schizophrenia symptoms among study subjects.

In one trial, 604 patients with schizophrenia received iloperidone 24 mg/day, placebo, or ziprasidone for four weeks, with patients on iloperidone showing significant benefits in Positive and Negative Syndrome Scale total scores compared with placebo. In the other trial, involving 706 patients, iloperidone was compared with placebo and risperidone. After six weeks, the drug was superior to placebo in the reduction of total score on the Brief Psychiatric Rating Scale. The company did not release any data on how iloperidone compared with either ziprasidone or risperidone on efficacy indicators.

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Antipsychotic drugs appear to work in kids: FDA staff

Three antipsychotic drugs appear to work in children and teens but their risks must be weighed as the makers seek to promote them for younger patients, the head of the U.S. Food and Drug Administration's psychiatric division said in a memo released on Friday.

The FDA has yet to make a final decision on whether to approve drugs made by AstraZeneca, Pfizer and Eli Lilly and Co for children and teens with schizophrenia or bipolar disorder.

An FDA panel is to meet next week to give recommendations on the companies' bid to promote the drugs for children and teenagers with schizophrenia or bipolar disorder.

Doctors can already prescribe the medications for children, but FDA approval would allow the manufacturers to market them more widely.

The drugs, known as atypical antipsychotics, are widely used to treat various psychiatric conditions but have come under scrutiny for links to weight gain.

"We generally are in agreement that the sponsors have provided adequate support to suggest effectiveness," FDA's Thomas Laughren wrote in the memo released on Friday.

He added that the safety of the drugs in children appeared "to be qualitatively similar to those observed with these drugs in adult patients."

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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."

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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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A New Way Of Thinking For Schizophrenia Treatment

The effectiveness of psychiatric drugs varies considerably in individuals being treated for depression or schizophrenia. These drugs act on serotonin, a neurotransmitter (chemical messenger) central to the regulation of moods. Scientists from Oxford and Belfast have discovered more about emotional processing and genetic variations that will help to inform treatment strategies.

The long-held view that serotonin levels are low in people with depression has been challenged by Philip Cowen, professor of psychopharmacology at Oxford University. "We asked what evidence is there that the action is abnormal and this stimulated new thinking about how anti-depressants work," he said at the British Neuroscience Association meeting in Liverpool today (21 April).

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FDA Review Questions Cardiac, Suicide Risks for Investigational Antipsychotic

Investigational antipsychotic drug sertindole (Serdolect) is effective at treating schizophrenia, but it may lead to sudden cardiac death, according to an FDA review.

The agency released its review in advance of Tuesday's meeting of the Psychopharmacologic Drugs Advisory Committee, which will decide if the drug's cardiovascular risk is an obstacle to FDA approval.

The advisory panel will also consider the sponsor's suicide prevention claim, and whether to recommend to the FDA that the drug is safe and effective. The vote will effectively amount to a recommendation of approval or denial.

Sertindole is already used in other countries to treat schizophrenia.

According to the FDA review, led by psychiatrist Phillip Kronstein, M.D., sertindole is effective in treating schizophrenia, but concerns remain about the drug's potential to prolong the heart's QT interval, which can lead to sudden cardiac death. That same cardiac risk has been seen in other antipsychotic drugs similar to sertindole.

Sertindole is a so-called atypical antipsychotic drug, Its specific mechanism appears to be to inhibit spontaneously active dopamine neurons in the mesolimbic ventral tegmental area without affecting dopamine neurons in the substantial nigra compacta.

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Schizophrenia - Novel Treatment May Provide Relief

A compound that naturally occurs in the brain and other areas of the body may be a promising new treatment for the most severe and disruptive symptoms of schizophrenia, according to researchers from Durham Veterans Affairs Medical Center and Duke University Medical Center.

Researchers conducted a pilot study that suggests the neurosteroid pregnenolone targets symptoms of schizophrenia for which no treatment options are available. The findings are published online in journal Neuropsychopharmacology.

While antipsychotic medications can help reduce hallucinations and delusions associated with schizophrenia for some patients, the other two categories of symptoms often continue to significantly disable patients -- negative symptoms, such as apathy, lack of emotion and poor social functioning, and cognitive symptoms, which include memory impairment and difficulty concentrating and completing tasks.

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Bitter Pill

Created to treat schizophrenia, Zyprexa wound up being used on misbehaving kids. How the pharmaceutical industry turned a flawed and dangerous drug into a $16 billion bonanza

In June 1992, not long after the place closed down, a Harvard-trained psychologist named Sergio Pirrotta walked out of Danvers State Hospital for the last time. The psychiatric facility, at this late date, was a baggy old thing, rectangled into a field just north of Boston; whole wings were barely occupied, and vandals had already begun to rip out the mantelpieces and furniture. The hospital had been slowly, incrementally shutting down for a decade, and the patients that remained were the hardest cases, mostly schizophrenics and those with disorders too dense and weird to classify. But now, as Pirrotta took a walk around the campus, even those patients were gone: released into the larger world to fend for themselves or bused to hospitals where the staffs had little psychiatric training.

Pirrotta had come to Danvers in the mid-1970s to rehabilitate children whom the courts had declared insane. Back then the place was overpopulated, the halls packed with madmen who would wander around smoking cigarettes, leering and lunging at the kids. In those days, the drugs used to treat mental illness were crude and ugly things. Thorazine was the best, and it made you into a ghouled and lifeless ogre — your face seized up involuntarily, you kept shuffling around, you were an emotional drone. But gradually the medications got a little bit better, the pharmacology more precise. First there was haloperidol, similar to Thorazine but with less-vivid side effects. Then clozapine, which had at first seemed a wonder drug, before it turned out to trigger a potentially fatal immune deficiency in two cases out of a hundred.

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