By David Cyranoski

Evidence that prescription drugs shrink patients' brains would, one might think, suggest only one course of action: stop prescribing them. But the matter turns out to be much more complicated, according to research published February 7 in Archives of General Psychiatry on the effects of antipsychotic drugs in people with schizophrenia.

In the past 15 years, research has indicated that people with schizophrenia have smaller cerebral volumes than the general population, and that this reduction is particularly large in 'grey-matter' structures, which contain the cell bodies of neurons. For instance, one meta-analysis points to 5-7 percent reductions in the size of the amygdala, hippocampus and parahippocampus, which are all involved in memory storage and retrieval.

But scientists have debated whether the decrease is caused by the disease alone, or whether powerful antipsychotic drugs also have a role. According to the latest findings, the more antipsychotics patients receive, the more likely they are to have a decreased amount of grey matter.

The research was led by Beng Choon Ho, a psychiatrist and neuroscientist at the University of Iowa in Iowa City. His team used magnetic resonance imaging (MRI) to scan the brains of 211 patients, administering on average 3 scans per patient over a 7.2-year period. They found that treatment length and the type and dose of antipsychotic drugs taken were both relatively good predictors of total brain volume change. Use of antipsychotics explained 6.6 percent of the change in total brain volume and 1.7 percent of the change in total grey-matter volume.

The study developed from a previous work in which Ho's team analyzed the contribution of a genetic variation to grey-matter volume reduction. In the latest work, the researchers looked again at those results and added data from more patients. This time, they examined the contribution from the dose of antipsychotics prescribed. They found that the greatest reduction came in those who had been recently diagnosed--and so would have just started taking the medications. "We did not expect to see this," says Ho.

Ho says that the effect is "small but significant." He adds, "We have been looking at the data for five years. We've been very careful to get it right because of the potential implications."

Missing control

The scale of the study is impressive, says Andreas Meyer-Lindenberg, a neuroscientist at the University of Heidelberg in Mannheim, Germany. "It's by far the largest sample studied longitudinally. And there was a great follow-up and retention rate," he says. Stefan Borgwardt, a neuropsychiatrist at the University of Basel, Switzerland, says that the study "will definitely have a great impact, not only on the field of schizophrenia research but also on clinical practice".

Animal studies support the link. David Lewis, a neuroscientist and psychiatrist at the University of Pittsburgh, found that healthy non-human primates, given doses of antipsychotics similar to those given to humans, showed brain volume reductions of around 10 percent, mostly attributable to loss of the glial cells that support and protect neurons.

But Lewis, who has written an editorial to accompany Ho's study, warns that his own, Ho's and other studies are "convergent but still circumstantial." It is impossible to distinguish the effect of the disease from that of the drug, he says, because "both are changing over time."

Ho acknowledges that his study is marred by the lack of a placebo control group--for ethical reasons, patients cannot be deprived of the medications they need--and the lack of "within individual" studies in which the same patient either uses or does not uses the drugs. "It's not the ideal study design, but as good as we could ever get with something like this," says Ho.

Meyer-Lindenberg warns against over-interpreting MRI data, which can be affected by confounding factors including lifestyle, smoking and socioeconomic differences. "Although it does address them as far as possible statistically, this study cannot exclude them," he says. Meyer-Lindberg himself published a study last year showing that antipsychotics cause quickly reversible changes in brain volume that do not reflect permanent loss of neurons (see "Antipsychotic deflates the brain").

Bigger and better

The idea that decreased brain volumes are necessarily bad is also controversial. Borgwardt says that small cerebral volumes are generally thought to lead to worse brain function, and some studies show that the greater the decrease, the worse the illness outcome. Antipsychotics have long been known to have side effects--notably uncontrolled tremors (parkinsonism) and restless leg syndrome (akathisia)--that might be explained by reduction in brain volume.

But decreasing brain volume could also be responsible for the beneficial effects of the drugs. Lewis points out that the reduction is greatest in patients who stay on the drugs the longest--meaning, presumably, that they are getting the best benefit and suffering relatively few side effects.

In the brains of adolescents, volume loss has been shown to reflect maturation through the elimination of superfluous synapses, says Meyer-Lindenberg.

Borgwardt has begun to scan the brains of people at high risk of developing schizophrenia and track the cerebral volume of those who go on to be treated, a strategy that, on a larger scale, could help to clarify the controversy. An alternative route could be to study people with depression and bipolar disorder, says Lewis. Comparing changes in the brain volume of such patients who use antipsychotics with those that do not would help to tease out the relative contribution of the drugs.

In the meantime, Ho's study and others should strengthen doctors' commitments to use antipsychotic drugs sparingly, say all the researchers contacted by Nature. "We stated as clearly as possible that we are not advocating that people stop taking medications. A large body of evidence shows the drugs relieve symptoms and prevent relapse," says Ho. "But this will reinforce what I have always tried to do with my patients--work with them in finding the lowest effective dose."