Functional MRI speeds psych drug development

Drug manufacturers are increasingly relying on functional MRI to help assess the efficacy of psychiatric drugs.

The imaging technique 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 in October 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 Dr. 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. Most research projects are conceptually flawed, and some psychiatric drugs that do make it through may fail once on the market, Hargreaves said.

"We have to get better at picking the concept and picking the molecule. It is a sobering thought that most of the projects we run in industry are conceptually flawed," he 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, according to Dr. Edward Bullmore, a professor of psychiatry at Addenbrookes Hospital in Cambridge.

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

"You can see different effects on fMRI signals of other drugs-antipsychotics, benzodiazepines-every major class of psychotropic drugs has been studied with fMRI. All show a change in brain activation," he 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 a lower capacity for activation in the left amygdala, ventral striatum, and frontoparietal cortex. They also demonstrated 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. The 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 a lot more consolidation of the 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 the expected rise in incidence of conditions such as 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 could help industry take advantage of these developments, Bullmore said. Unlike PET, MRI does not involve a radiation dose and is therefore more practical for pharmacological studies, which often require repeated scanning.

In the case of antidepressants, preliminary research is promising, but drug companies want a study that shows functional changes in healthy volunteers or people with transient depression. They are also interested in seeing 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, and, as a result, patients are hard to find and trials are expensive and difficult to conduct.

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