schizo_spring

The making of a mind
21 Jul 01

                                 Schizophrenia can't be cured, but it might be prevented if we
                                 can figure out what's behind one of the biggest risk factors, A
                                 spring birthday. Bryant Furlow reports

                                 IT HITS in early adulthood. At first, the mistrustfulness and
                                 increasingly mercurial outbursts are dismissed by loved ones as a mere
                                 passing youthful "phase". But all too soon comes full-blown psychosis,
                                 that mental schism with reality that is schizophrenia.

                                 Parents watch in horror as their son or daughter lurches into paranoid
                                 delusions, verbal incoherence and hallucinations. It all seems unfairly
                                 sudden. An ambush. In fact, it is a nightmare that has been years in
                                 the making.

                                 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.

                                 "[The] idea would have been dismissed as too outlandish by most
                                 people, if it didn't offer the intriguing possibility of explaining
                                 epidemiological facts that at present, we cannot explain," says Robert
                                 Kendell, a psychiatrist at Edinburgh University. "It's a long shot. But
                                 long shots with high [potential] rewards are worth taking seriously."

                                 And if ever a disease needed a big break, schizophrenia does. Despite
                                 decades of intensive research, a cure for schizophrenia is nowhere
                                 near. True, a third of patients respond well to drugs designed to
                                 alleviate the worst of the symptoms, although even these patients
                                 may still occasionally slip into the overwhelming, incoherent world of
                                 psychosis. But another third of patients respond only moderately well
                                 to drugs, and the rest don't respond at all. For these unlucky people,
                                 holding down a job can be impossible. All too often they end up
                                 homeless, neglected, and estranged from their families.

"We're just desperate to figure this out," says McGrath, "We've got to
find the cause, we've got to focus on prevention."

                                 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.

                                 One study by Alan Brown's team at Columbia University in New York
                                 has even found that pregnant women who catch respiratory infections
                                 during their second trimester-be it bronchitis, flu or tuberculosis-are
                                 more likely to have offspring who develop either schizophrenia or a
                                 number of milder, but related, mental illnesses such as paranoid
                                 personality disorder.

                                 In short, the flu hypothesis had become something of an
                                 epidemiological gospel. So it came as a bit of a surprise when a new
                                 study dealt it a severe blow just two years ago.

                                 Then, 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 NiÑo 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).

                                 "For days, I racked my brains trying to figure out why," says McGrath.
                                 "Whatever [the environmental insult] was, you were getting a bigger
                                 dose of it in the northern hemisphere." A cursory glance at a map of
                                 the world gives one clue-latitude.

                                 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. Besides the fact that
                                 people tend to live closer to the equator on that side of the world,
                                 the southern hemisphere also gets about 15 per cent more UV light
                                 than equivalent latitudes in the north, thanks to a combination of
                                 factors, including the relative lack of pollution and the position of the
                                 Earth relative to the Sun. A lack of UV light could even explain those
                                 bizarre correlations between schizophrenic births, Brazilian rainfall, and
                                 the El NiÑo effect in Queensland: rain means cloud, and cloud soaks
                                 up UV like a sponge.

                                 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.

                                 And it's not just McGrath who finds the UV light hypothesis strangely
                                 compelling. "It's an exciting proposition. He's coming at [the problem]
                                 from a completely new angle," says Jayashri Kulkarni, a psychiatrist at
                                 the Dandenong Psychiatry Research Centre in Melbourne. "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.

                                 Still, the connection between UV light, vitamin D and schizophrenia
                                 would have been relegated to the Annals of Untested Hypotheses had
                                 it not been for some astounding new results from McGrath's lab,
                                 announced this April at an international schizophrenia meeting in
                                 Canada.

                                 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.

                                 What McGrath and Mackay-Sim need to find out now is whether mild
                                 to moderate vitamin D deficiency will also alter brain development in
                                 lab animals. Clearly, in certain circumstances mild vitamin deficiencies
                                 can be disastrous for developing babies-witness folic acid. Children
                                 with spina bifida are rarely born to mothers who have an obvious
                                 deficiency. Nonetheless, folic acid supplements for pregnant women is
                                 one of public health's greatest success stories, slashing the incidence
                                 of the disease in industrialised countries.

                                 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." Brown and his colleagues are now
                                 screening prenatal blood samples banked by hospitals in the US
                                 between 1950 and 1970 for evidence of respiratory infections in
                                 mothers whose babies developed schizophrenia when they grew up.

                                 Meanwhile, McGrath has joined forces with epidemiologist Steve Buka
                                 of Harvard University and paediatric virologist Bob Yolken of Johns
                                 Hopkins University in Baltimore. Together, they plan to search samples
                                 from the same collection for evidence of vitamin D deficiency.

                                 Not only does the solution to a 70-year-old mystery hang on the
                                 results of those two studies, but the hope that schizophrenia, one of
                                 the world's most remorseless mental disorders, may one day be
                                 preventable.