EDINBURGH (EGMN) – Mounting evidence suggests that antipsychotic agents might cause significant shrinkage of brain volume – and therein lies a dilemma for psychiatrists.

“I think this may be the big controversy for the future in psychosis,” Dr. Robin M. Murray predicted at the International Congress of the Royal College of Psychiatrists.

This is an issue psychiatrists will want to keep abreast of, he stressed. They need to start thinking about how they’re going to explain it to their patients.

“Is it the case that we can resolve hallucinations and delusions, but one of the consequences may be that we induce shrinkage in grey matter? Is having less grey matter significant? Should we just not worry about it? I suspect that once our patients learn about this, they may be even more resistant to the idea of taking antipsychotics than they are at present,” said Dr. Murray, professor of psychiatry at the Institute of Psychiatry, King’s College London.

He noted that antipsychotic-related brain shrinkage was raised as a hot-button issue a couple of years ago in a New York Times interview with Dr. Nancy C. Andreasen, professor of psychiatry and director of the neuroimaging research center at the University of Iowa, Iowa City. She mentioned in the wide-ranging interview that her 18-year ongoing longitudinal brain imaging study shows that people with schizophrenia are losing brain tissue at a greater rate than are healthy controls, and that the more antipsychotic drugs they’ve been given, the more brain tissue they’ve lost. Some patients, she said, are losing brain tissue at a rate of 1% per year, year after year.

“What exactly do these drugs do? They block basal ganglia activity. The prefrontal cortex doesn’t get the input it needs and is being shut down by drugs. That reduces the psychotic symptoms. It also causes the prefrontal cortex to slowly atrophy,” Dr. Andreasen explained.

She added in the interview that she had refrained from publishing these findings for several years – to this day she still hasn’t done so, Dr. Murray noted – because of concern that the data might be misused.

“My biggest fear is that people who need these drugs will stop taking them,” she told the Times.

But others have published preclinical data suggesting the brain shrinkage problem is real, Dr. Murray said. He pointed to a study in monkeys conducted by researchers at the University of Pittsburgh.

The researchers gave macaque monkeys oral haloperidol, olanzapine, or placebo for 17-27 months, with blood levels of the antipsychotic agents similar to those attained in schizophrenia patients on treatment. The result was an 8%-11% reduction in mean fresh brain weights and volumes in both drug-treated groups, compared with the control animals. The differences were greatest in the frontal and parietal regions, but were present across all the major brain regions (Neuropsychopharmacology 2005;30:1649-61).

More recently, investigators at University College London conducted a systematic review of published brain MRI studies on the effects of antipsychotic agents on brain volume. They found 14 of 26 longitudinal studies showed a reduction in global brain or grey-matter volume and/or increased ventricular or CSF volume during drug treatment. They concluded that this evidence points to the possibility that antipsychotic drugs might contribute to some of the abnormalities customarily attributed to schizophrenia (Psychol. Med. 2010 Jan. 20 [doi: 10.1017/S0033291709992297]).

Even more recently, researchers at the National Institutes of Health in Bethesda, Md., and the University of Heidelberg (Germany) gave normal volunteers a single dose of haloperidol and documented shrinkage of striatal volume within 1-2 hours, using multimodal pharmaconeuroimaging. This shrinkage was reversed by 24 hours as the drug wore off.

“But this was after just one dose,” Dr. Murray commented.

In addition to the short-term structural changes, the investigators found that motor circuits between the striatum and other regions of the brain were disturbed for hours after a single exposure to the antipsychotic agent (Nat. Neurosci. 2010 June 6 [doi: doi:10.1038/nn.2572]).

“I think that this brain shrinkage is going to be an important issue,” Dr. Murray reiterated.

He declared having no financial conflicts.