William Carpenter, M.D., has helped to move the field of schizophrenia
research away from the single disease model to one that focuses on domains of
pathology within a syndrome.
Credit: Vito Sesuknas
During a psychiatry elective at what was then called the Bowman Gray School
of Medicine at Wake Forest University, William Carpenter visited an inpatient
ward where the patients—most of whom had severe depression—were
treated with electroconvulsive therapy (ECT) and sub-coma insulin.
The professor spoke convincingly, describing exactly how ECT worked."
It was all very interesting, and I decided to do a paper on it,"
Carpenter recalled. "When I finished my paper, what I'd found was that
there were at least 50 different theories on how ECT worked.
"I think it was my first taste of the very big difference between
what people purport to know and what they really do know."
That same skepticism and knack for methodological precision would
characterize Carpenter's inquiries for the next 40 years during a career in
which he would challenge the field of psychiatry to examine what it
purports to know about schizophrenia and what it really does
In the process he would question the notion of schizophrenia as a single,
undifferentiated disease and advance the concept of separate domains of
pathology, some of which—especially negative and cognitive
symptoms—have proven crucial to functional outcome.
Along the way he has been a critic of the drug industry's marketing of"
me too" drugs for schizophrenia—drugs that differ little
from their predecessors in terms of efficacy and are sold to a niche market of
patients on the basis of side-effect profiles—and has argued for a new
methodological framework for research and drug discovery.
His work has helped to move the field of schizophrenia research away from
the single-disease model to one that focuses on domains of pathology within a
One fruit of this paradigm shift has been the Measurement and Treatment
Research to Improve Cognition in Schizophrenia (M ATRICS) project, a
neurobiological "Manhattan Project" at NIMH bringing together
industry, academic researchers, and regulatory authorities to foster
development of drugs that target the cognitive impairments of
"Will Carpenter is a towering figure in American psychiatry,"
said past APA President Steven Sharfstein, M.D. "His contributions to
the understanding of the psychopathology of the positive and negative symptoms
of schizophrenia are among the most important in the last 25 years. Patients
and their families are grateful for his work, researchers are grateful for his
mentorship, and clinicians are grateful for his science as it has translated
The North Carolina native's first steps toward medicine and psychiatry were
more fortuitous than providential—so it seemed then. A stellar receiver
on his high school football team, he expected at the time to play college
football and wind up a high school football coach.
But his mother took him to a vocational guidance counselor, who gave him a
standard vocational aptitude test. Carpenter indicated an interest in science
and music, but after the test the counselor told him he had no talent in
music, was naturally lazy and would have to work hard, and should become a
"We immediately set out looking for colleges with a good premed
program," Carpenter said. "I've never looked back."
Recalling the guidance counselor's curiously specific advice, Carpenter
today suspects a mother's providence. "I bet she told him to say
that," he said. "She was smart and wise and cultured and would
have known what was best for me."
Financial circumstances and love of football led him to choose a
school—Wofford College in South Carolina—that offered him a
football scholarship. But despite being wooed by the Baltimore Colts to go
professional, he opted for medical school.
It was during his residency at the University of Rochester under the
chairmanship of John Romano, M.D., that the researcher in Carpenter was
kindled. And it was Romano who inspired him to study schizophrenia.
"John Romano put his personal stamp on all of us," Carpenter
told Psychiatric News. "He was a good, critical thinker who
taught us to be critical of the evidence. At a time when a lot of people were
practicing ideologically based therapeutics, he really emphasized asking, What
is the nature of the evidence?
"He also felt strongly that schizophrenia is the disease that is
central to psychiatry," he continued. "He was very concerned that
our sickest patients were in state hospitals while our best trainees would be
going into private offices. He taught us that there was a moral imperative to
treat the sickest."
Following residency, Carpenter went to work at the National Institute of
Mental Health (NIMH) in the depression unit under William Bunney, M.D., who is
now emeritus professor of psychiatry at the University of California, Irvine.
Later, he joined the International Pilot Study on Schizophrenia of the World
Health Organization (WHO).
It was at WHO, as co-chief collaborating investigator in the Washington
Field Research Center, that he and colleagues John Bartko, M.D., and John
Strauss, M.D., published multiple papers on the signs and symptoms of
schizophrenia, laying the groundwork for future research on separate domains
In a paper in the winter 1974 Schizophrenia Bulletin,"
Speculations on the Processes That Underlie Schizophrenic Signs and
Symptoms," they posited the existence of three subdomains of disease
consisting of positive symptoms, negative symptoms, and disorders of
relationship. The paper was the third in a series of seminal papers on the
"If... schizophrenia is a concept involving several processes,
perhaps three major ones, it will be important to test the validity of these
processes by providing more information about whether they have separate
etiologies, outcomes, and treatment requirements," the authors concluded
It was also during his early training that Carpenter was exposed to a 1964
publication by John Platt in Science titled "Strong
Inference," which stated that the greatest advances in science derive
from hypothesis-falsifying experiments—that is, experiments that are
designed to exclude, or falsify, one or more hypotheses and then are
replicated to winnow out remaining hypotheses.
It is in this way, Platt said, that researchers continually force
progressive changes and refinements in theory. And it is a process, some would
say, that is exactly the opposite of the way much research on schizophrenia,
especially drug discovery research, has been conducted.
Fifty years of pharmaceutical-funded clinical trials tweaking existing
molecules have tended to confirm the dopamine hypothesis. A theory that offers
little real insight into the nature of the disease process, it rests on the
observation that antipsychotic medications treat the positive psychotic
symptoms of schizophrenia by acting on the dopamine system. The result has
been the long line of "me too" drugs, and Carpenter has been a
vocal critic of the process.
In a debate about the relative merits of first- and second-generation
antipsychotics (SGAs) at APA's 2005 annual meeting, he cited a host of
methodological flaws in studies purporting to show the superiority of SGAs:
use of patients who had failed on first-generation drugs; the use of"
last observation carried forward" analysis to compensate for
treatment drop-out and boost efficacy reporting; and the comparison of SGAs
against very high doses of haloperidol (Psychiatric News, July 1,
"No one has a right to be surprised about the CATIE findings,"
he told Psychiatric News more recently. "It's been easy to make
drugs look good by comparing them to Haldol at the wrong dose." (CATIE
is the acronym for Clinical Antipsychotic Trials of Intervention
He added, "Almost everyone now believes the dopamine-blocking drugs
treat some aspects of the disease and don't treat others. These other features
are very important to functional outcome and require a different discovery
pattern for creating new therapeutics that has been crystallized in the
In 1977 Carpenter became director of the Maryland Psychiatric Research
Center (MPRC), one of the nation's premier psychiatric research institutions.
Located on the campus of a state mental hospital, the Spring Grove Hospital in
Catonsville, Md., MPRC is uniquely situated to translate basic and clinical
research to the bedside.
"Being on that campus, we have a natural connection between basic
science and the clinical side," Carpenter said. "It's an intimate
relationship that was designed for doing translational research even before
that term was coined."
He laments the never-ending challenge of recruiting patients for research
and the chronic problem of funding. The center is a joint program of the
University of Maryland and the state's Mental Hygiene Administration, with
most of its budget, until last year, coming from the state.
Now, the budget allocation has shifted to the university. With just 10
percent of the center's funding in hard money, the rest comes from grants and
contracts—mostly from NIMH and the National Institute on Drug Abuse.
Carpenter also worries about the increasing costs associated with
"The costs of doing business keep going up along with the amount of
time and effort required to know how to deal effectively with requirements of
review boards," Carpenter said. "There is an increasing demand for
demonstrating compliance with ever-expanding requirements that are often put
in place without regard to benefit-risk analysis or evidence that they are
advancing the safety of research subjects."
But MPRC is also well placed to pursue the lines of research that Carpenter
believes are the future of schizophrenia research—lines that he helped
to establish over a 40-year career: hypothesis-falsifying experiments aimed at
drug discovery for separate domains of pathology, especially cognitive and
With a scientific consensus forming around the signs and symptoms of a
prodromal phase of schizophrenia, Carpenter foresees the possibility of
therapeutic interventions long before the first acute psychosis.
"If people put the resources into developing drugs for negative
symptoms, cognition, and other unique features of the disease, it is bound to
pay off," he said. "Suppose between ages 5 and 10 a child with a
genetic predisposition for schizophrenia loses five IQ points. If we had safe,
effective drugs for cognition, we would be justified in intervening early in
"Imagine if we could keep that child from losing those five points.
It becomes a lot easier to imagine a robust effect on long-term outcome by
intervening for those traits that appear years before psychosis, regardless of
whether or not it actually prevents psychosis." ▪