The Doctor Weighs In

By Dov Michaeli MD, Ph.D

You never know where investment ideas are going to come from. Jim Cramer, a well known hedge fund manager and now a TV guru found some of his best ideas in trade magazines, like Advertising Age, Gardening—the guy reads everything. But revolutionary scientific development in the business literature? The New York Times Sunday Business section of Feb. 24 had a great article titled “Daring to Think Differently About Schizophrenia”, by Alex Berenson. His science explication is so good that it should be required reading for anybody interested in the subject.

The opening paragraph is a classical description of how paradigm shifts come about:

“Scientists who develop drugs are familiar with disappointment -- brilliant theories that don't pan out or promising compounds derailed by unexpected side effects. They are accustomed to small steps and wrong turns, to failure after failure -- until, in a moment, with hard work, brainpower and a lot of luck, all those little failures turn into one big success.”

In his seminal book “The Structure of Scientific Revolutions” Thomas Kuhn, the scholar of intellectual history, coined the term “paradigm shift” to describe a radical change in the way we view a basic tenet of our world. When examined in depth it is clear that such shifts do not strike with the suddenness of lightning; they are more like the forceful earthquakes that result from the slow buildup of stresses and tensions caused by tectonic shifts of the earth’s plates. There is persistent questioning of the reigning theory, there is accumulating evidence that at first sight doesn’t amount to a challenge of the accepted dogma. And then somebody puts it all together, and a new light is shed on old, entrenched beliefs.

A bit of history

The first schizophrenia medicines were developed accidentally about a half-century ago, when Henri Laborit, a French military surgeon, noticed that an antinausea drug called chlorpromazine helped to control hallucinations in psychotic patients. Chlorpromazine, sold under the brand name Thorazine, blocks the brain's dopamine receptors. That led the way in the 1960s for drug companies to introduce other medicines that worked the same way.

The medicines, called antipsychotics, gave many patients relief from the worst of their hallucinations and delusions. But they also can cause shaking, stiffness and facial tics, and did not help the cognitive problems or the so-called negative symptoms like social withdrawal associated with schizophrenia.

The new paradigm: glutamate

Dr. Darryle D. Schoepp was overseeing early-stage neuroscience research at Eli Lilly & Company and colleagues had just given him the results from a human trial of a new schizophrenia drug that worked differently than all other treatments. From the start, their work had been a long shot. Schizophrenia is notoriously difficult to treat, and Lilly's drug -- known only as LY2140023 -- relied on a promising but unproved theory about how to combat the disorder.

When Dr. Schoepp saw the results, he leapt up in excitement. The drug had reduced schizophrenic symptoms, validating the efforts of hundreds of scientists, inside and outside of Lilly, who had labored together for almost two decades trying to unravel the disorder's biological underpinnings. The results of a Phase 2 clinical trial were published in an article titled "Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial" in Nature Medicine

Dr. Schoepp and other scientists had focused their attention on the way that glutamate, a powerful neurotransmitter, tied together the brain's most complex circuits. Every other schizophrenia drug now on the market aims at a different neurotransmitter, dopamine.

The Lilly results have fueled a wave of pharmaceutical industry research into glutamate. Companies are searching for new treatments, not just for schizophrenia, but also for depression and Alzheimer's disease and other unseen demons of the brain that torment tens of millions of people worldwide .

The commercial aspect of this development notwithstanding, the trial results amounted to a major breakthrough in neuroscience.

Glutamate is a pivotal transmitter in the brain, the crucial link in circuits involved in memory, learning and perception. Too much glutamate leads to seizures and the death of brain cells. Excessive glutamate release is also one of the main reasons that people have brain damage after strokes. Too little glutamate can cause psychosis, coma and death.

Many of us remember the time when the street drug PCP was all the rage. The drug, whose chemical name is phencyclidine, blocks the release of glutamate. Interestingly, people who use PCP often have the hallucinations, delusions, cognitive problems and emotional flatness that are characteristic of schizophrenia. In 1979 it was discovered that it blocked a glutamate receptor, called the NMDA receptor, that is at the center of the transmission of nerve impulses in the brain.

The PCP finding led a few scientists to begin researching glutamate's role in psychosis and other brain disorders. By the early 1990s, they discovered that besides triggering the primary glutamate receptors -- NMDA and AMPA -- glutamate also triggered several other receptors.

They called these newly found receptors ''metabotropic,'' because the receptors modified the amount of glutamate that cells released rather than simply turning circuits on or off. Because glutamate is so central to the brain's activity, directly blocking or triggering the NMDA and AMPA receptors can be very dangerous. The metabotropic receptors appeared to be better targets for drug treatment. During the 1990s, molecular biologists discovered genes for eight metabotropic glutamate receptors, which were located at different places inside nerve cells and had different structures. The finding allowed for the possibility that drug companies could create chemicals to turn them on and off selectively, rather than hitting all of them at once.

And the rest, as they say, is history. Or, history making. The prevailing view that dopamine was central to schizophrenia was supplanted by the glutamate model. And the implication of that is not limited to schizophrenia only; many psychiatric disorders, including bipolar and depression, are now being examined in a new light.

We have traveled a long way from the psychiatric theory of schizophrenia being the result of a child receiving “mixed messages” from his parents, to the subtle disorders of one or more glutamate receptors. A new age of sophisticated and targeted treatment of psychiatric diseases is dawning.