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.
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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
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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.
-
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)