In spite of these drawbacks, I spent many happy hours designing front-engine cars, repairing the neighbors’ televisions, and—for a short but bloody few weeks—dissecting the rabbits caught eating our raspberry plants. The taste for killing passed almost immediately, but not the taste for inspecting the component parts of organisms and machines. During my school years, I struck bargains with several lab partners willing to do the killing if I would do the dissecting.

Around the same time, the discovery of Lloyd Castle Douglas’s Doctor Hudson’s Secret Journal combined with an uneasy adolescence to produce an enduring fascination with the brain. My head, limbs, and emotions had apparently lost all connection. Testosterone ruled, and I needed to know why. Yet even at thirteen, Douglas’s divide between mind and brain struck me as pragmatic but not terribly interesting, with the result that his neurosurgeon hero gripped my imagination more spiritually than scientifically.

I began reading everything I could about psychology. Almost all the books in the local library dated from the nineteenth century. The words went through my eyes slowly and confusedly. Still I persevered.

I read about Mesmerism, hypnotism, and Freud. Skinner was just beginning to filter down to the public, but the approach seemed simplistic. I found the popular Fifty-Minute Hour intriguing, but not the way I saw my future. My interest was piqued, but I concluded that psychodynamics—psychiatry’s enchantment at the time—had become overextended in its effort to explain all of humanity. I found the tales of heavy-handed Freudianism emanating from the University of Chicago’s Orthogenic School disturbing (although I later met a graduate who had benefited dramatically from his stay there). At any rate, sitting passive and still has never been my strong suit. Some attention deficit disorder is mixed in with my dyslexia.

In my late teens I read about the reticular activating system and slightly later about REM sleep’s connection to dreams. When it came time for college I chose the University of Michigan because of its size. I figured that I could manage the multiple-choice exams then used to test classes of a thousand or more students at a time.

Unfortunately, Michigan had just started an honors program, and I was encouraged to join. To my chagrin classes were small and essays were required. I managed to thread a painful course through this minefield for two years, but the time was coming when I was to be judged solely on my non-existent writing skills.

Ironically, it was the competitive Johns Hopkins School of Medicine that came to my rescue. I applied for the school’s new medical program for students with only two years of college and the next Fall was off to Baltimore. To reduce medical students’ temptation to cut their own—and each other’s—throats, Hopkins did not reveal our grades unless major remedial attention was needed. To this day, among a backdrop of students who were universally able and mature, I am not sure whether or not they knew that I could not spell, punctuate, or produce even half-literate compositions.

After internship, and a residency in psychiatry at Harvard’s Massachusetts Mental Health Center (a real torture, endured amidst the most literate and verbal group of people I have ever known), I made my way to the National Institutes of Health, where I have had the great fortune to spend my professional career. I have always thought that one of our chief goals at the NIH is to take on challenges that others, hemmed in by grant requirements and promotion committees, cannot. The NIH is also the best place in the world for those of us who have never given up Tinker Toys.

During my career I have focused on schizophrenia, which—though little understood—continues to cause untold suffering lifelong. My investigation into the course and roots of schizophrenia led me into research on sleep and imaging, psychopharmacology, biochemistry, neuroplasticity, economics, and epidemiology.

Which brings us to the topic of "Neuroleptics and the natural course of schizophrenia," (Schizophrenia Bulletin 17[2]: 325-51, 1991). Ten years ago, most psychopharmacologic texts stated that neuroleptics or antipsychotic medications never cure schizophrenia. For unlike the foreign invaders responsible for most infections that can be knocked out with a magic bullet, schizophrenia was seen as a chronic disease that follows an immutable course.

Yet as a clinician I had seen a few patients who—treated very early in their illness—went on for many years thereafter without further symptoms. It is of course impossible to be sure if, without intervention, these individuals would have gone on to become schizophrenic. But if the effect was supported by more than anecdotal data, the stakes were high enough to justify testing the notion more formally.

The article "Neuroleptics and the natural course of schizophrenia" grew out of my search for evidence that early intervention can change the course of schizophrenia. With some digging I found about twenty studies—none of them designed for the purpose—whose data could be reanalyzed to test this hypothesis.

Could antipsychotic medication given early decrease the long-term morbidity—and even reduce the incidence of schizophrenia? I concluded that a number of studies could be interpreted as pointing in a positive direction. And a number of publications since 1991, although not always citing statistically significant results, point in the same direction. No studies indicate that early intervention makes schizophrenia worse. But the unevenness of the results indicates that the effect in any case is relatively weak.

Several years ago researchers in many parts of the world began designing studies to test whether or not early intervention reduces long-term morbidity. These studies should begin to provide answers to a number of related questions. What kind of patients benefit from early intervention, if in fact there are such patients? At what point can at-risk individuals be identified? Just how much benefit can be expected? What are the treatment requirements needed to gain a benefit? What are the economic and other costs of early intervention—including potential stigmatization and treatment side effects? And even if chronicity cannot be lessened, can early intervention lower the risk of suicide, substance abuse, and other problems that develop early on in the disease? I believe that early intervention will almost certainly convey sufficient benefit in these latter areas to force a change in public health practices.

The conclusion that early intervention with antipsychotic medications decreases long-term morbidity would also give rise to a host of new ethical dilemmas. When does one stop treating patients who have had good responses to treatment? Can placebos be justified in clinical trials? How do possible benefits from early intervention affect issues of informed consent by patients and families participating in scientific studies? What should we tell patients and their families, who should tell them, and how should they be told? How can we make sure that patients and families understand what we are telling them?

There is an assumption that if early intervention does change the course of schizophrenia for some patients, it does so by altering some mechanism in the brain. If this is correct, what is the result of provocative stimulation of individuals with schizophrenia or who are pre-schizophrenic? Such studies are often designed to stimulate some aspect of schizophrenia briefly in order to understand vulnerability better, or the basic processes that take place during psychosis. Does such stimulation—which has been used a great deal in psychiatric research—itself produce changes in the brain similar to the putative changes produced by the illness?

Throughout my career I have never expected to understand schizophrenia. But it is my hope and belief that investigations into early intervention’s effect on the course of schizophrenia will sharpen our thinking about ethical dilemmas such as these and may help a few people cope with the disease’s terrible effects.

Richard Jed Wyatt, MD
Chief, Neuropsychiatry Branch
NIMH-NIH
Bethesda MD USA