Interview With A Researcher: Chief of Child Psychiatry at the NIMH Shares Insight

From The Quarterly, Spring 2013

Learning how genes predispose, even if they don’t determine



Over the last decade of her distinguished career in studying the genetics of brain and behavior disorders, Judith L. Rapoport, M.D., has focused on a group of children who are very sick, and whose sickness is very rare. These children, who are under the age of 13, have developed what is termed childhood-onset schizophrenia.  



While their illness is uncommon, Dr. Rapoport and her colleagues at the Child Psychiatry Branch of the National Institute of Mental Health (NIMH), of which she is Chief, have learned some intriguing facts about its causation. These shed important new light on the relationship between events at the beginning of life and the subsequent emergence of schizophrenia and other serious disorders such as bipolar disorder, psychotic depression, even epilepsy.



Dr. Rapoport, whose devotion to the Brain & Behavior Research Foundation is reflected in her longtime volunteer service on the organization’s Scientific Council, co-discovered the role of rare genetic mutations in schizophrenia. These gene irregularities, called copy-number variants (or CNVs), are extra copies or missing copies of genes, and, though rare, are seen much more often in people with schizophrenia, compared with healthy people.



Might CNVs serve as diagnostic markers, which have long been sought for schizophrenia and other psychiatric disorders? Not yet, Dr. Rapoport explains. It turns out that some healthy siblings of children and adults with schizophrenia also have some of the illness-linked CNVs. Also, some CNVs have been shown to be inherited from parents who do not have schizophrenia. So it’s not yet clear how or how much having disease-associated CNVs increases one’s risk for actually getting sick.



While the causal relation of both rare CNVs and much more commonly seen mutations to the development of brain and behavior disorders isn’t yet clear, Dr. Rapoport and colleagues have recognized that they are “non-specific” for schizophrenia. That is, mutations seen more frequently in people with schizophrenia are sometimes also seen in people with other diagnoses, particularly autism, but also intellectual disability and even epilepsy. This is promising for the development of future treatments: “The fact that these mutations are non-specific means that if and when we figure out how to counteract them, they may have benefits for patients across several illnesses, by attacking pathology common to all of them,” says Dr. Rapoport.



Tracking brain development “trajectories”



There is other encouraging news, Dr. Rapoport says. In her group’s effort to closely analyze a set of 3,000 cases of childhood-onset behavioral and mental illness, they have learned a great deal about pathologies affecting a broad array of disorders whose causes can be traced at least partly to abnormal brain development trajectories. The right and left halves of the human brain develop at different rates. As Dr. Rapoport and others have discovered, abnormal timing of developmental events in the growth and maturation of various key brain regions appears to generate pathologies that later lead to schizophrenia, psychosis, attention-deficit hyperactivity disorder (ADHD) and likely other illnesses. Such developmental abnormalities can, for instance, affect the size or volume of brain structures such as the critical cerebral cortex, the seat of higher cognitive functions.



More good news: “One truly significant discovery has been that in ADHD, we and others have found that while a big portion of hyperactive kids have abnormally slow development of their frontal lobes, say at age 7 or 8, by the time they’re 15, about half of them will be so much better, whether or not they have had treatment.” In other words, it may be that for some, a glitch in timing corrects itself.



This makes it very clear to Dr. Rapoport what she and her colleagues need to focus on. “We’re really interested in developing diagnostics and treatments for the children who aren’t going to grow out of these timing disturbances.” Meantime, certain common genetic risks for major psychiatric illness can already be detected through prenatal screening, using specialized “gene chips” like those co-developed at Baylor University, Dr. Rapoport notes. These are designed to compare the genetic profile of the fetus with major known gene mutations. Prenatal Chromosomal Microarray Analysis (Prenatal CMA), for instance, is a diagnostic test that can detect genetic abnormalities in a fetus.



Offering advice for parents



Dr. Rapoport offers this advice to parents with a child who has either been diagnosed with a psychiatric disorder or whose behavior has raised warning flags. First, she suggests talking to a trustworthy pediatrician.



“They can make referrals and often have a good sense of what type of problem your child may be having. There are different things you would do if you felt it was just developmental delay, or a very focused behavioral problem.”



It also makes sense, she says, for parents to contact their local medical school to find someone in the child psychiatry department. “I am a very strong believer in psychiatric diagnoses, made by skilled clinicians. They can give parents a reasonable prediction, based on the doctor’s experience, of what sort of treatment can help; what kinds of problems one might anticipate developing within the family structure; what the child’s prognosis might be; what the chances are of outgrowing the symptoms and which treatments are likely to be the most useful.”

Judith L. Rapoport, M.D.

Chief, Child Psychiatry Branch

National Institute of Mental Health

2002 Brain & Behavior Research Foundation Ruane Prize for Outstanding Achievement in Child and Adolescent Psychiatric Research

2009 NARSAD Distinguished Investigator Grantee

Scientific Council Member