Functional MRI speeds development of psychiatric drugs

Drug manufacturers are increasingly relying on functional MRI to help assess the efficacy of psychiatric drugs. It could potentially save millions of dollars and help speed effective drugs to the marketplace, according to speakers at the Horizon Seminar "Imaging and Healthcare: The Future" held last month in Cambridge, U.K.

A technique that could spot the winners and losers among hundreds of psychiatric drug compound contenders would have great clinical and commercial value, said Richard Hargreaves, vice president of imaging at Merck Research Laboratories in West Point, PA.

Moving a psychiatric drug through development stages and complex trials to regulatory approval can cost from $500 million to $800 million over several years. Most research projects are conceptually flawed, and some psychiatric drugs that do make it through to the market may fail at great expense, Hargreaves said.

"We have to get better at picking the concept and picking the molecule," Hargreaves said. "If we are going to choose a target, we are likely to choose the wrong one. If we choose the wrong one, we need to fail quickly and cheaply, so we have dollars left in the pot."

The body of evidence for fMRI in pharmacological studies is small, said Dr. Edward Bullmore, a professor of psychiatry at Addenbrookes Hospital in Cambridge.

Bullmore reviewed the literature and found only about 50 studies done in the field. But trial activity has been growing rapidly (Trends in Pharmacological Sciences 2004;25[7]:366-374), and studies show fMRI could help predict treatment response and identify new compounds for drug development.

"You can see different effects on fMRI signals of other drugs - antipsychotics, benzodiazepines. Every major class of pychotropic drugs has been studied with fMRI. All show a change in brain activation," Bullmore said.

In a trial funded by pharmaceutical manufacturer GlaxoSmithKline, researchers examined patients with severe depression, correlating changes in facial expression with functional brain changes over the course of eight weeks of antidepressant use (Arch Gen Psychiatry 2004;61:877-889).

Depressed patients had lower capacity for activation in the left amygdala, ventral striatum, and frontoparietal cortex and a negatively correlated increase of dynamic range in the prefrontal cortex.

Patients who improved on the course of antidepressants showed a reduction of dynamic range in the pregenual cingulate cortex, ventral striatum, and cerebellum. Researchers concluded that fMRI may be a useful indicator of antidepressant treatment response.

"Drug discovery data are promising in terms of future clinical and commercial applications," Bullmore said. "But there needs to be more consolidation of early academic results, and the technique must be road-tested quite comprehensively before you could have real-life application."

Demand for drugs to treat diseases of the central nervous system is likely to grow in the future, given the aging population and expected rise in incidence of conditions like Alzheimer's disease. CNS drugs have become better tolerated and patient compliance has improved over the last 25 years, but the range of treatments has not expanded greatly.

Functional MRI is one tool that could help industry take advantage of these developments, Bullmore said. Unlike PET, MRI does not involve radiation and is therefore more practical for pharmacological studies, which tend to require considerable repeat scanning.

Preliminary research of antidepressants is promising, but drug companies want a study showing functional changes in healthy volunteers or people with transient depression and the application of this information to predict therapeutic effects in very sick people.

Drugs currently must be tested in a large number of treatment-naive patients with certifiable severe depression. As a result, patients are hard to find and trials are expensive and difficult to conduct.

If fMRI proves effective, the technique would change the way clinicians manage patients and drug companies manage the drug development process, Bullmore said.

For more information from the Diagnostic Imaging archives:

Feds fail to stop fMRI marketing studies

Functional MRI moves into clinical service

NIH funds first nationwide imaging network of patients with schizophrenia

MR links depression with biology