A symposium sponsored by the National Alliance for Research on Schizophrenia and Depression (NARSAD) in New York City last month celebrated progress in understanding the neuroscience of psychiatric disorder, but served also as a humbling reminder of how little is still known about the complex marvel called the brain.

Paul Greengard, Ph.D., the recipient of the 1996 Lieber Prize for Outstanding Achievement in Schizophrenia Research, made the point at the conclusion of a 20-page paper on how one type of nerve cell functions in the brain. "When one considers that the results summarized here concern just one type of nerve cell in the entire brain, it is clear that the elucidation of the molecular mechanisms by which slow synaptic pathways regulate fast synaptic transmission is going to keep many research groups occupied for many years to come," he writes.

Greengard, the director of the Laboratory of Molecular and Cellular Neuroscience at Rockefeller University in New York, received the $50,000 Lieber Prize for research elucidating the molecular mechanisms by which brain neurons communicate with one another.

David Feifel, M.D., one of several NARSAD "young investigators" honored with research grants totaling $60,000 over two years, is an assistant professor of psychiatry at the University of California at San Diego. He is using his grant to help clarify the role that neuropeptides play in normal and abnormal behavior.

Neuropeptides may prove to be the physiological correlates of what has been called "the mind-body connection," Feifel said. The more than 200 neuropeptides that have been identified in the brain are intimately involved with such activities as perception of pain and bonding behavior. The best-known neuropeptides are the endogenous opiates, naturally occurring analogues of drugs such as morphine and heroin. But the role played by other families of neuropeptides may be equally important and dramatic.

Many neuropeptides are themselves neurotransmitters, while others modulate the actions of other neurotransmitters, he explained. Their actions range from the very simple "to the incredibly complex."

Recent research in rodents suggests that neuropeptides may link emotions and physiological functions together in ways critical to the survival of both individuals and species. For example, mother rats experimentally deprived of a neuropeptide called oxytocin fail to display maternal behavior. But what most intrigues Feifel is that this same chemical helps stimulate the uterine contractions of labor and the production of milk to nurse new pups.

This is an example of "the mind-body connection in a very literal way," said Feifel. "These things exist in both areas and seem to be able to coordinate the functions of the body and the mind."

How and to what extent neuropeptides mediate the perceptions and behaviors of schizophrenia is not well understood, said Feifel. Neuropeptides are "colocalized" with the "classic neurotransmitters" such as serotonin, dopamine, norepinephrine, and others, according to Fiefel. This colocalization means that "they exist in the same nerve terminals and are released in the same synapses. We never knew that was possible before we discovered the neuropeptides," he noted.

The old wisdom, known as "Dale's principle," stated that there was "one nerve terminal, one neurotransmitter," explained Feifel. But within the last two decades, that theory has been discarded. "In fact, colocalization is more the rule than the exception." Scientists are no longer surprised to find as many as three different neurotransmitters or neuropeptide/neurotransmitter combinations at the same site, he noted. This vastly increases the possibilities for various interactions between nerve cells in the brain.

The discovery of colocalization has forced neuroscientists to rethink radically their understanding of the brain, observed Feifel.

In practical terms, it promises to expand greatly the ways in which brain chemistry can be chemically altered by drugs. Today virtually all psychiatric medications target the classical neurotransmitter systems, which exist in only about 1 percent of the brain, said Feifel.

"We haven't even begun to thoroughly exploit brain chemistry," he said. "We're able to do things successfully only with this very, very tiny slice of the pie."

The question is, "How do you go about testing these things?" said Feifel. "You select auspicious candidates, likely to be associated with some kind of mental disorder. Then, the next step is to see what that neuropeptide is doing in that pathway."

For example, three neuropeptides, cholecystokinin (CCK), neurotensin, and somatostatin, modulate the activity of dopamine in the mesolimbic dopaminergic pathway, said Feifel. Knowing that, and conscious of colocalization, the challenge is to create new pharmacotherapies with both greater efficacy and fewer side effects than current drugs.

A "smart treatment strategy" might involve giving a "subtherapeutic dose of a typical antipsychotic, while simultaneously giving a dose of a neuropeptide-targeting drug that potentiates the effects of the conventional antipsychotic selectively in the mesolimbic pathways linked to psychosis," Feifel explained. "This would spare the undesired effects of our conventional antipsychotics on other dopamine systems."

Feifel and colleagues have tested the theory with only limited success in rats, but he remains undaunted and optimistic.

"I am absolutely confident" that drug companies will develop medications designed to exploit the role of neuropeptides in the brain, said Feifel. "It's all a matter of resources. If every drug company focused on neuropeptides, you'd have something in two or three years. There's no reason to think there's anything conceptual that's going to prevent us from having this breakthrough."

Another NARSAD young investigator is Ian Cook, M.D., an assistant professor of psychiatry at the University of California at Los Angeles. His grant is helping him test a relatively inexpensive technique that might be used to tell early in the course of antidepressant therapy who is likely to respond to medication well before any clinical changes become apparent.

What Cook calls his "cordance" method allows clinicians to use an electroencephalogram (EEG) to generate the sort of detailed data on brain activity previously available only by using more costly and cumbersome technologies such as positron emission tomography (PET).

He developed the cordance model when looking at EEG measures of people with Alzheimer's disease or other forms of cerebrovascular dementia, he said.

"EEG machines are not like multimillion-dollar PET machines," he observed. An EEG "would be an affordable and accessible diagnostic tool."

By digitizing the data, he was able to create a "map" that depicts significant parameters of brain function, he explained.

When he compared the cordance maps of depressed people with those of age-matched normal controls, "there were [significant] differences between the areas that showed the highest activity," said Cook. The greatest differences were in the temporal lobes, with depressed subjects displaying much lower activity than normal subjects.

But what Cook found most intriguing was an incidental observation of cordance patterns in depressed people started on antidepressant medications, he said. "If a person's pattern on the cordance map changed within the first week [after receiving medication]," it tended to predict a favorable response to the antidepressant medications "long before" there were any observable signs of clinical improvement.

What is more, the converse was also true, "that failure to have the change in the cordance map was associated with lack of clinical response," he noted.

These anecdotal observations led Cook to design double-blind, placebo trials to test the predictive power of cordance in antidepressant therapy. The trials, using fluoxetine and venlafaxine, are ongoing, and Cook hopes to wind up the studies soon and publish the results sometime next year.

"If the anecdotal observations are borne out with the rigorous study, it will be of great importance to a clinical audience," Cook said.

Readers who are interested in further information about Cook's cordance model and have Internet access may want to visit the Web site .

--R.B.K.

(Psychiatric News, November 1, 1996)