Living with Schizophrenia - Series 2 Issue 2, August 31, 2001

By JOHN O'NEIL

Schizophrenia is best known by its active symptoms, like paranoid delusions, but it also has passive ones, like an inability to experience pleasure. A report published last week in The Journal of the American Medical Association suggested that studying the sense of smell could help shed light on some of the symptoms.

Researchers from the University of Iowa Hospitals and Clinics exposed 18 people with schizophrenia and 16 healthy volunteers to a pleasant smell, vanilla, and to an unpleasant smell that Dr. Daniel S. O'Leary, an author of the paper, compared to the odor of moldy socks. An imaging device was used to track blood flow to different areas of the brain, and the subjects were asked to rate each smell.

The groups ranked the unpleasant smell similarly but differed on the pleasant smell. The people with schizophrenia found the vanilla equally intense but half as pleasing as did the healthy volunteers.

The brain images, however, showed big differences in mental processing only with the unpleasant smells. The limbic system, an area linked to smells and basic emotions like fear, was highly active in the healthy people as they smelled the unpleasant odors but was largely unused in the people with schizophrenia. They relied on frontal cortical areas, which are usually reserved for higher level functions like decision-making and distinguishing certain experiences as rewarding.

Dr. O'Leary said he and his co-authors speculated that limbic deficits might be prompting the schizophrenic brain to "hijack" cortical areas to process unpleasant stimuli that could indicate a threat. This misuse of brain circuits could play a role in paranoia and lack of pleasure by creating a habitual association with danger for all kinds of stimuli, they suggested.

Breath Test for Schizophrenia Being Developed [top]

July 18, 2001

By: Janet Hunter

In a doctor's office in the not-too-distant future, the same laser that's in a CD player and a puff of breath will be used to immediately diagnose schizophrenia and a host of other diseases.

When it has done that, the machine will help the physician know how much of a drug to prescribe to treat the disease.

Technology developed by Patrick McCann, a professor of electrical engineering at the University of Oklahoma, uses lasers to measure the amount of a molecule -- carbon disulphide in the case of schizophrenia -- that is known to be present in the breath of people with that particular disease. "Every molecule has a unique fingerprint and by using the laser, we can probe that fingerprint, identify which molecules are there and how many of them are in that sample," Mr. McCann said.

While a breathalyser diagnostic test already exists for asthma, Mr. McCann, president and CEO of the machine's commercial developer, Ekips Technologies, says his invention is superior: It's inexpensive, fast, easy and non-invasive.

The established asthma breathalyser test, for example, uses hazardous gases, requires steroids to be taken and can't be carried out on children younger than five. Asthma, which is marked by an increase in the amount of nitrous oxide in the breath, is the first disease Mr. McCann was able to diagnose with the machine, within the past two months.

He says since his machine doesn't require massive amounts of breath, even infants can be tested with it.

Clinical trials will continue when the first commercial machine is installed in a private medical clinic in Tulsa, Oklahoma, by the end of the year. Each test is expected to cost between $10 and $20 U.S.

Mr. McCann envisions a world where the machine, which is small enough to sit on a tabletop, will be in every doctor's office, clinic and hospital, and will be used routinely to test for a dozen or so diseases.

Tests for lung cancer, breast cancer, renal function, Type 2 diabetes, the monitoring of liver function and drug toxicity are among the technology's other expected applications.

Mr. McCann is particularly interested in using the machine to diagnose schizophrenia and other mental illnesses.

Researchers in Scotland and New York have independently demonstrated that people with schizophrenia have higher levels of carbon disulphide in their breath than those without the disease, Mr. McCann said.

"If it's real, and we intend to show that it is real using our technology, it will be the first biomarker measure that's associated with a mental illness," he said.

"It really will show that schizophrenia is not something that's just in the patient's head, there really is a chemical imbalance, and that's what's causing their hallucinations, that's what's causing their mental health problems."

Since the machine measures the amount of the particular molecule in the breath, repeat tests can easily show whether the drug administered to treat the disease is working.

"We're talking about individualized medicine," Mr. McCann said. "You could use the breath test to monitor the effectiveness of drug treatment and, say if the CS2 level goes down, then you know that drug is doing something to solve the problem, rather than just cover it up."

Earlier research results have been presented at scientific conferences, and Mr. McCann intends to submit the asthma diagnosis test to the journal Optics Letters. Mr. McCann, who did PhD research at the Massachusetts Institute of Technology, has been studying laser diagnostics for 15 years.

Ekips has been spending about $500,000 a year on the machine, a figure that will increase dramatically once the machine goes into production.

The company received money from a private venture capital firm in Oklahoma, and from the U.S. Air Force, which is interested in using the technology to measure pollution and air quality.

Virtual Reality Machine Mimics Hallucinations [top]

The Edmonton Sun August 14, 2001

The public will be invited to hallucinate - drug-free - this week. The Schizophrenia Society, Edmonton Area, will unveil a $40,000 computerized virtual reality machine Thursday that simulates the experience of psychotic hallucination. The device is designed to help the society draw attention to the fact many families are struggling to cope with schizophrenia. Visual and auditory hallucinations are some of the most disturbing symptoms that people with the brain disease experience.

....

Debbie doesn't hear voices any more. But for years, back before her illness was diagnosed, they spoke to her constantly, inside her head. "Sometimes they were angry voices. Sometimes there were a whole bunch of voices." Visitors to Edmonton's Fringe Theatre Festival, which opened last week, got a chance to find out what it's like to hear voices that aren't real and see things that aren't there - just by slipping on a virtual-reality headset. The Schizophrenia Society of Alberta set up a booth to show people virtual hallucinations, mimicking the real illusions symptomatic of the disease. One scenario re-creates a visit to the grocery store. Those who put on the headset will feel themselves walking down aisles, past stocked shelves and the stares of other shoppers, while earphones play those insistent voices. "It's pretty realistic," said Debbie, who asked that her last name not be used. Debbie heard voices once, saw cartoon figures, stepped out of the shower one time and saw words written in the steam on the mirror. None of it was real. After a series of suicide attempts, she was given a diagnosis of schizophrenia 10 years ago and has been taking medication ever since. The hallucinations are gone. She works full-time in the office of the provincial schizophrenia society and part-time as a waitress. "I hope people who try the machine will get a little understanding of what people with schizophrenia go through every day," she said.

By: Bryant Furlow (Bryant Furlow is a science writer based in California)

Even as toddlers, people with schizophrenia tend to be clumsier than normal, and to be slow to talk. When they are eventually diagnosed with the disease years later, they are often found to have a curious brain structure - their ventricles, the fluid-filled cavities, can be up to 30 per cent larger than usual, while the regions of the cortex that deal with memory, language and planning are smaller. Surprisingly, however, their brains have none of the scars or "gliosis" that you would expect to see if those changes had happened during adulthood. Those findings and others have convinced many experts that the brain abnormalities that lead to schizophrenia must come about very early in development, most likely before birth, as the very scaffold of the infant's brain is being built.

And that realisation has reignited interest in a bizarre observation dating back to the 1920s. In Europe and North America, there's a mid-March peak in "schizophrenic births" - babies who grow up to develop schizophrenia. Up to 10 per cent more are born between February and April than in any other three-month period of the year.

That might not sound like a lot, but with an estimated 60 million cases of schizophrenia worldwide, a 10 per cent seasonal increase represents a huge amount of additional suffering. What's more, most studies suggest that season of birth accounts for more cases of schizophrenia than almost any other known risk factor - including a person's genetic heritage. The only risk factor worse than a spring birth is being born in a city.

Solve the riddle of what extra insult is being added during pregnancy to the mishmash of genes and environmental factors, say schizophrenia researchers, and you'll be well on your way to understanding what underpins the disease itself.

Now, an Australian psychiatrist believes he has cracked it. According to John McGrath of the Queensland Centre for Schizophrenia Research in Brisbane, all the evidence suggests that a lack of UV light during pregnancy is the key to the spring peak in schizophrenic births. If his controversial hunch is right, we may one day be able to stop schizophrenia in the womb, before it begins. And we might, just might, be able to do it with nothing more sophisticated than vitamin supplements or a sunlamp.

Long before UV light became a contender, the prime suspect for the spring peak in schizophrenic births was some sort of an infectious agent - perhaps something as common as flu. For March-born babies, the flu season falls squarely in the middle of their mothers' pregnancies, which is just when the main architecture of the brain is being laid down. What's more, major flu pandemics, like the one in 1957, are sometimes followed by spikes in schizophrenic births. The "flu hypothesis" could even explain why proportionally more people with schizophrenia are born in towns than in the country since flu spreads more easily in the hustle of the city.

But, in the biggest study of its type to date, a team led by psychologists Yusef Battle and Stephen Miller of the University of Georgia in Athens examined the health records of nearly three-quarters of a million people born in the state of Georgia between 1948 and 1965. They confirmed the spring peak, but found no relationship between flu infection rates in the population in a given year and the number of schizophrenic births. "We were somewhat surprised not to find a flu effect," admits Miller.

McGrath was not. "Flu is looking very dodgy," he says. "The whole area of seasonality of birth needs a fresh approach."

Take a close look at studies on schizophrenia and the season of birth, says McGrath, and you'd find plenty of other reasons to mistrust the flu hypothesis. For a start, in the northern hemisphere, the precise timing and size of the spring peak varies from year to year, even though the flu season tends not to. And a study from Brazil has found that rainfall is a better predictor of schizophrenic births than the flu season: they peak roughly three months after the rainy season even though it rarely coincides with the flu season.

Then there are McGrath's own studies. In Queensland, there's a peak in schizophrenic births every three or four years. Those peaks don't coincide with big flu outbreaks, but they do seem to occur at the same frequency at which the El Nino weather system periodically casts a temporary gloom over the Sunshine State. And while proponents of the flu hypothesis tend to assume that the seasonal pattern of births is the same the world over, it isn't. For sure, some studies have found a seasonal effect in southern hemisphere countries like Australia and South Africa, but others have not. When McGrath and Joy Welham, a psychologist and epidemiologist who also works at the Queensland Centre for Schizophrenia Research, pooled all the data, they found no overall seasonal variation in schizophrenic births in the southern hemisphere - even though all the countries in the study did have an annual flu season ("Schizophrenia Research", vol 35, p 237).

In the southern hemisphere, people tend to live closer to the equator than in the northern hemisphere. "To reach the latitudes inhabited by northern Europeans," says McGrath, "you have to go to the southern tip of South America." When McGrath and Welham pooled data from 170,000 people with schizophrenia living in the northern hemisphere, the seasonal peak in schizophrenic births grew bigger the further north they went.

Taken with the other curious epidemiological observations, "that just screams out to us that it has something to do with ultraviolet light", says McGrath. At higher latitudes UV light has to travel further through the atmosphere before it hits the Earth - in other words, the changes in UV light mirror the way the spring birth peak varies with latitude. Differences in UV light could explain the lack of a seasonal birth effect in the southern hemisphere, says McGrath.

The next question was how a lack of UV light could so alter the course of a baby's development that years later she would develop a disease as devastating as schizophrenia. Besides giving you a tan, UV light has another major impact on the body - it converts a cholesterol-like molecule in the skin to vitamin D.

At first glance, vitamin D, best know for its role in building healthy bones, seems like a feeble candidate for triggering a brain disease. But the circumstantial evidence compelled McGrath to take a second look. It turns out that a surprisingly large number of women are deficient in vitamin D - about 12 per cent among 20 to 39-year-olds, according to a large US survey. What's more, harking back to that urban birth risk factor for schizophrenia, city women are more likely to be vitamin D deficient than their country cousins. Finally, Afro-Caribbean immigrants to England and Surinamese immigrants to Holland have between three and four times the number of schizophrenic births than other populations in the same areas - and because of their dark skin, they are more likely to run low on vitamin D.

"Vitamin D is low in winter, low in cities, and low in dark-skinned migrants to northern climates," says McGrath. "If McGrath's theory is true," adds Kendell, "it would explain these epidemiological facts that currently have no plausible explanation."

Still, that's a big "if". For the theory to be correct, vitamin D would have to play some key role in early brain development. Here the evidence starts to thin out. What is known is that in the developing brain, receptors for vitamin D pack the areas where cells are multiplying, including parts that are wrongly wired in schizophrenia. And although nobody knows exactly what vitamin D might be doing there, there are more than a few tantalising hints that it's something to do with brain development.

In a lab flask, vitamin D prods glial cells - the brain's support cells - into making nerve growth factor. NGF plays a pivotal role in shaping the developing brain. Then there's the growing evidence that vitamin D and vitamin A get together in the cell's nucleus to turn genes on and off - a process that is key to the development of any tissue.

When McGrath and developmental neurobiologist Alan Mackay-Sim from Griffith University in Brisbane deprived pregnant rats of UV light or vitamin D in their food, the brains of their offspring contained less NGF than normal. What's more, they looked suspiciously like the brains of people with schizophrenia: the baby rats had enlarged ventricles. "We were shocked that the effect was so large," says McGrath.

McGrath is quick to point out the rats were far more deficient in vitamin D than the vast majority of pregnant women, and that not all the abnormalities in the rodent brains mirror what you find in schizophrenia. Still the study made a point: vitamin D is crucial for normal brain development.

The causes of schizophrenia are probably more complex than those underlying neural tube defects like spina bifida. Nonetheless, McGrath's dream is that vitamin D supplements for pregnant women or even sunlamps will one day slash the incidence of schizophrenia, just as folic acid has driven down spina bifida cases. However, too much vitamin D can cause birth defects, so McGrath cautions pregnant women not to take supplements until such a treatment has been shown to be effective and the safe dose has been worked out.

But although the rat study provides the most promising support to date for the idea that a lack of UV light and vitamin D in pregnancy may predispose a fetus to schizophrenia, the flu hypothesis hasn't yet bitten the dust - far from it. "The vitamin D hypothesis is not incompatible with the infection hypothesis," says Brown. "Each could theoretically explain a certain proportion of schizophrenia cases."

Further reading: "The impact of low prenatal vitamin D on brain development: using an animal model to examine the vitamin D hypothesis of schizophrenia" by John McGrath and others, "Schizophrenia Research", vol 49, p 48 (2001)

"Climate, geography and the search for candidate nongenetic risk factors for schizophrenia" by Joy Welham and others, "International Journal of Mental Health", vol 29, p 79 (2000).
"Schizophrenia and season of birth in a tropical region: relationship to rainfall" by Erick de Messias and others, "Schizophrenia Research", vol 48, p 227 (2001)