- The Washington Times - Saturday, July 12, 2003

BETTER THAN PROZAC: CREATING THE NEXT GENERATION OF PSYCHIATRIC DRUGS

By Samuel H. Barondes.

Oxford University Press, $32, 240 pages

REVIEWED BY RICHARD RESTAK

More than 100 million people worldwide are takingpsychiatric drugs. Yet “even the best of them are blunt instruments that have a large number of effects on the brain, only some of which can be considered therapeutic,” according to psychiatrist Samuel H. Barondes in his new book “Better Than Prozac.”

In response to the imperfections of presently available drugs, researchers and pharmaceutical companies are vying with each other to create more potent and specific drugs that are free of major side effects. But accomplishing this won’t be easy, judging from past experience.

Historically, the discovery of mind and mood altering drugs largely resulted from hunches, whimsy and just plain luck. Thorazine, the first drug effective for schizophrenia emerged from attempts at synthesizing a sedating antihistamine capable of prolonging the action of general anesthetics. Only serendipitously did psychiatrists stumble on to the fact that the drug also exerted a calming effect on agitated patients.

The chance observation that patients with tuberculosis often became euphoric when treated with iproniazide , inspired psychiatrists to first try it as an antidepressant. The world’s first tranquilizer, Miltown, was originally evaluated as a potential antibacterial agent. After receiving the drug laboratory mice became calmer.

The same response occurred when the drug was given to monkeys and, subsequently, humans. In short, early psychiatric drug development is more suggestive of the methods of the turf accountant than the logician. “Until there is a better understanding of the origins and pathophysiology of mental disorders, we will continue to depend on strokes of luck to find important new psychiatric drugs,” according to Mr. Barondes.

In search of this understanding, researchers are currently concentrating on neurotransmitters (the brain’s chemical messengers), the receptors that accommodate those neurotransmitters, and the genes associated with the various mental disorders. Already there has been impressive progress on all three fronts.

While there are at the moment at least 50 neurotransmitters of interest, most of the research has focused on only a half dozen or so. Nonetheless, antidepressants and antipsychotics are already available whose effectiveness results from manipulations within the brain of neurotransmitter production, release or breakdown. Most notable are the serotonin reuptake inhibitors (the SSRIs) like Prozac and its cousins Zoloft and Paxil.

Research on receptors has spawned a host of drugs that mimic or antagonize the effects of the natural neurotransmitters. For instance, some newer drugs mimic the action of nicotine, which has its own receptor within the brain (one of the reasons why, pace, Mayor Bloomberg, smoking isn’t likely to ever completely disappear no matter how Draconian the measures taken to eliminate it). Antagonist drugs include the opiate antagonists, which can quickly reverse the effect of heroin and precipitate a sudden withdrawal reaction. Other antagonists target the receptors for Valium — like drugs and induce anxiety reactions.

On the genetic front, Mr. Barondes is especially informative. Neuropsychiatric diseases, it’s turning out, are typically caused not by a single gene gone awry but by the combined actions of many genes acting in concert with environmental stresses. Alzheimer’s disease and schizophrenia are good examples of multiple gene disorders. Seemingly identical instances of these illnesses may arise from different genetic origins. Or two patients afflicted with the same disease may share identical genetic susceptibility profiles despite being miles apart in terms of their behavior and disability. This is especially true with schizophrenia.

“For disorders such as schizophrenia, which are influenced by the combined actions of multiple susceptibility genes, the likelihood that different combinations of gene variants may be involved in different patients further complicates the search for each of them.”

As an aid in this search, Mr. Barondes suggests a dimensional rather than a categorical view of mental disorders. Thus depression represents an exaggerated version of the low spirits we all experience on occasion; social phobia an exaggerated form of shyness; anxiety an exaggeration of the tendency to worry and fret unnecessarily. Even a serious mental disorder such as paranoia can be considered — from the dimensional point of view — as an extreme version of normal suspiciousness. Mr. Barondes provides a fascinating example drawn from animal psychiatry that illustrates the power of the dimensional model.

Grooming behavior in mice requires normal functioning of a gene called Hoxb8. Mice lacking this gene are notable for prominent bald patches on their heads. Videotaping the mice over an extended period reveals a distinctive form of obsessive-compulsive behavior: When left to their own devices, the mice engage in repetitive overly vigorous grooming, which includes literally pulling the hair out of their heads!

Researchers believe that the Hoxb8 gene participates in the formation and activity of a nerve cell network associated with normal grooming — an innate and stereotyped form of behavior in the mouse. In normal mice, the Hoxb8 gene contributes to controlling the intensity and duration of grooming. But mice lacking the gene lack normal controls on their grooming behavior, which sounds eerily similar to a condition in humans called trichotillomania, a form of OCD whose essential features include “the recurrent pulling out of one’s own hair that results in noticeable hair loss.”

Mr. Barondes suggests that the Hox8b research in mice may have practical applications in research on OCD and mental illness in general. For one, even though the Hoxb8 gene is only one of a large number of genes that influence the development of brain circuits, work on that gene may open up lines of research that “change our ideas about the nature of mental illness.” Additional knowledge about the genes involved in OCD may provide guidelines for future drugs. “As the brain molecules that are influenced by the Hoxb8 gene are identified, some may become targets for drug development.”

So, is a magic bullet just around the corner that will provide cures for the mental illnesses that plague us? Probably not anytime soon since, as Mr. Barondes points out, simply identifying the biological process that has gone awry as the result of an aberrant chemical is no guarantee that a drug can be found that will correct it. And even if such a drug can be synthesized, its side-effects may be serious enough to preclude its use. Overall, “Beyond Prozac” provides a lively, informative, well-written and authoritative source about likely future developments in the treatment of mental illness.

Richard Restak is a neurologist and neuropsychiatrist who has written on medical ethics, neuroscience and behavior. His books include “The Brain” and “The Mind.”


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