Brain, Gene Discoveries Drive New Concept of Mental Illness

It's time to fundamentally rethink mental illness, said National Institute of Mental Health (NIMH) Director Thomas Insel, M.D.

Credit: Mark Moran

Delivering the Frontiers of Science Lecture at APA's 2011 annual meeting in Honolulu, Insel described an emerging concept of mental illnesses as disorders of brain circuits caused by developmental processes shaped through a complex interplay of genetics and experience.

That model will in time upend the existing conceptual model of psychiatric practice in which diagnosis is made by observation of manifest symptoms, detection of illness is late, prediction of illness is poor, etiology is largely unknown, and treatment is trial and error.

Insel said psychiatric research today promises to produce a true science of the brain based on three core principles (see Points to Remember):

• Mental disorders are brain disorders.

• Mental disorders are developmental disorders.

• Mental disorders result from complex genetic risk plus experiential factors.

What is emerging today is a picture of mental illness as the result of a pathophysiological chain from genes to cells to distributive systems within the brain, based on a patient's unique genetic variation.

One of the most surprising findings from the Human Genome Project has been that psychiatric disorders, unlike common medical illnesses, appear to be the result of extremely rare, but highly penetrant—or potent—genetic variations. And these variations are not associated with any specific illness, but with a variety of phenotypes recognized as mental disorders, Insel said.

For any individual, the rare mutation may take a different developmental pathway that affects multiple complex brain circuits, resulting in the anomalous thoughts, feelings, and behaviors that have been categorized in today's diagnostic system.

As an example of how the new integrated science of the brain is changing the understanding of mental illness, Insel presented research, published in the November 2007 Proceedings of the National Academy of Science in which computational neuroanatomic techniques were used to estimate cortical thickness in children with and without attention-deficit/hyperactivity disorder (ADHD).

What the researchers found was that children with ADHD had a marked delay in cortical maturation and that the delay was most prominent in prefrontal regions important for control of cognitive processes including attention and motor planning.

"We call it ADHD because of the observable deficits in behavior and cognition," Insel said. "But this science looks like it is a disorder of cortical maturation. Imagine if we said everyone who had a myocardial infarction had a ‘chest pain’ disorder.

"In general, for brain disorders, behavior and cognition are the last to change," Insel said. "If mental illnesses are brain disorders and are developmental, and if we only allow ourselves to base our diagnoses and treatments on manifest signs and symptoms, it means we are getting into the game in the ninth inning."

In the same way, Insel said a diagnosis of schizophrenia is typically made when a patient has an acute psychotic break. "That's like diagnosing coronary artery disease when a person has a heart attack," he said. "The challenge for us is to move upstream, ideally using genetic risk factors to identify who is at highest risk.

"Rethinking mental illness means changing the emphasis so that you make sure the worst outcomes don't happen," he said. "We need to ask the question, How does variation in the genome lead to changes in particular neuronal circuits, which in turn bias the way an individual deals with emotional regulation?"

With a true science of mental illness—from genes, to cells, to brain circuits, to behavior—psychiatrists will be able to better predict who is likely to develop a mental disorder and to intervene earlier.

"Once that happens," he said, "we will be in a different world."

Insel's "Director's Blog" is posted at <www.nimh.nih.gov/about/director/index.shtml>.