Psychiatry is still awaiting the "disruptive innovations" in
scientific research that have helped to reconceptualize disease in other areas
of medicine, said Thomas Insel, M.D., director of the National Institute of
Mental Health (NIMH), at APA's 2008 annual meeting in Washington, D.C., in
The study of genomic variation and its role in leading to changes in
complex brain circuitry, recognition of the longitudinal and developmental
nature of disorders, and the discovery of biomarkers linked to a more precise
understanding of the pathophysiology of disease are the tools of a
21st-century science promising to transform the treatment of mental
Insel said those same tools have been applied in other areas of medicine to
reconceptualize the nature of disease and to reduce mortality dramatically for
people with such disorders as cardiovascular disease and cancer.
In contrast, the diagnosis and treatment of mental illness, he said, have
been stuck in a 20th-century model.
NIMH Director Thomas Insel, M.D.: "Genes code for proteins that
play out in particular brain areas at particular times to change the way brain
circuitry develops. It's all about variation and how it plays out at each of
Credit: Mark Moran
"By comparison, when one looks at mental illness, I think it's fair
to say that unlike the rest of medicine we are locked into diagnosis by
observation, we make our diagnoses late in the [trajectory of disease], and
our ability to predict disease is not very good," Insel said. "We
don't know much about the causes of the disorders we treat, and treatment is
largely by trial and error."
Nonetheless, progress is being made. He outlined a number of areas in which
psychiatric research is moving slowly in the direction of new strategies of
scientific discovery—what Insel called "disruptive
innovations"—that will provide a radically altered understanding
of the nature of mental illness.
These include recent research showing that the conditions psychiatrists
treat are disorders of complex brain circuitry; that they typically begin
years before they come to the attention of a clinician; and that they are the
result of multiple genetic variations, each of which may confer a degree of
risk over time until the balance is tipped toward disease.
He cited, for instance, research from the intramural program at NIMH using
structural imaging to compare brain changes in healthy children with those of
children with a variety of neuropsychiatric illnesses. In one study, the
brains of children between 7 and 12 years of age with and without ADHD were
studied at two-year intervals over several years. The children with ADHD were
found to have marked thinning of cortical areas.
The study, "Attention-Deficit/Hyperactivity Disorder Is Characterized
By a Delay in Cortical Maturation," was published in the December 7,
2007, Proceedings of the National Academy of Sciences. An abstract of
the article is posted at<www.pnas.org/cgi/content/short/104/49/19649>.
"It turns out that children with ADHD are about three years behind
[their healthy counterparts] in cortical maturation," Insel said."
This tells us that this disorder that we have defined on the basis of
cognitive and behavioral manifestations is a brain disease, a disease of
"Looking at it in this way raises all sorts of new questions,"
he continued. "What causes the delay in maturation? Do medications that
reduce the behavioral and cognitive aspects have any impact on this
maturation? So now we have an opportunity to think about this disorder in a
way that is very different from where we have been."
But Insel cautioned that to say that psychiatric illnesses are brain
disorders is not to equate them with neurological disorders, which typically
stem from lesions in a particular part of the brain. Rather, it appears that
complex social behavior—including the abnormal behavior, feelings, and
cognition that are typically called mental illness—is related to
abnormal development of interrelated networks, or circuits, in the brain.
"Neurology deals primarily with focal lesions, places where you can
find dead cells," he said. "Psychiatry is going to deal with
circuit problems. You might use as an analogy the difference between studying
myocardial infarction versus studying left bundle branch block. Both of them
can kill you, but only one of them is going to give you gross pathology in the
way that we think about when we think about neurological illness."
He highlighted work by Helen Mayberg, M.D., of Emory University, showing
that the so-called Brodmann's area 25 of the brain, located under the corpus
collosum, may be central in depression. Area 25 appears to be decreased in
volume and increased in metabolic activity among people who are depressed;
moreover, there appears to be a reduction in metabolic activity among people
who receive antidepressant medication or cognitive-behavioral therapy
(Psychiatric News, June 20).
But he stressed that decreased volume in area 25 should not be thought of
as a focal lesion that is the cause of all depression; rather, it appears to
be a conduit for serotonin and other neurochemicals known to be associated
with depression and negative rumination.
"It would be a mistake to think of this as the 'home of
depression,'" Insel said. "It is important to remember that this
is a circuit, a gateway for many of the fibers [associated with
Moreover, many psychiatric disorders are developmental, beginning many
years before they typically come to clinical attention, said Insel."
They start early in life, but we tend to make the diagnosis many years
after the onset," Insel said. "It is almost a truism that
psychiatric diagnosis is made so late that it is unlikely we will be able to
get the full recovery that we would like."
Insel cited research showing that adolescents with the APOE4 gene for
Alzheimer's have decreased volume in critical areas of the cortex and show
subtle deficits in cognition, decades before they would ever show symptoms of
That kind of predictive capability is now being developed, slowly, for
schizophrenia. "We still think of schizophrenia as psychosis," he
said. "But that is the worst outcome of a very long developmental
process that we are unable to detect until one of these very severe events,
when it is most difficult to get the kind of full recovery and remission you
He said research on the schizophrenia prodrome—the preclinical period
that precedes an acute psychotic break—has shown that adolescents with a
family history of schizophrenia along with functional deficits and other
anomalous symptoms can be predicted with 80 percent accuracy to convert to
Finally, Insel said, the deepening understanding of genomic variation and
how it affects normal or abnormal development of brain circuits in different
ways at different periods over time will help push psychiatric diagnosis and
treatment into 21st-century medicine.
"One thing we won't get is a code for diagnosis," Insel said."
These are variations that contribute small amounts of risk; each
variation may contribute 2 or 3 percent risk."
At some point the balance of risk and protective factors tips toward
disease. But he cautioned that it would be a mistake to think that research
will identify specific genes that cause schizophrenia.
"Genes code for proteins that play out in particular brain areas at
particular times to change the way brain circuitry develops. It's all about
variation and how it plays out at each of these levels."
Ultimately, a 21st-century neuropsychiatry in which the true
pathophysiology of mental illness is understood—from genes to neurons to
brain circuits and systems to behavior—will yield a new individualized
"We need a different kind of science to tailor treatments and allow
clinicians to choose from many different options... that are personalized and
preemptive," Insel said. "That is where we are going to get the
biggest impact." ▪