Evidence of progressive abnormal brain development in schizophrenia has emerged from the first longitudinal brain imaging study ever conducted in adolescents for any illness. MRI (magnetic resonance imaging) scans revealed ventricles (fluid-filled cavities in the middle of the brain) enlarging between ages 14 and 16 in teens with a rare, severe, childhood onset form of the disorder, report Judith Rapoport, M.D., and colleagues of the National Institute of Mental Health, in the October issue of the Archives of General Psychiatry.
Also in this issue, NIMH's Theodore Zahn, Ph.D., Rapoport and colleagues report that the same adolescents, all of whom had experienced psychosis prior to age 12, showed autonomic nervous system abnormalities characteristic of adult schizophrenia. "These and other studies add to mounting evidence that the childhood and adult forms are the same illness," said Rapoport, Chief of the NIMH Child Psychiatry Branch. "Understanding what's happening in these young people during this period of highly volatile brain development may provide clues about risk factors and neurodevelopmental abnormalities involved in the much more common adult onset schizophrenia. Adults with the disorder may well have experienced the same kind of abnormal brain changes during their teens."
Affecting about 1 percent of adults, but only about .005 percent of children, schizophrenia is the most chronic and disabling mental illness. It typically begins as a psychotic episode in young adulthood, with devastating hallucinations, delusions, social withdrawal, blunted emotionality and loss of social and personal care skills. A new generation of antipsychotic medications, such as clozapine, has helped many patients manage their symptoms with fewer side effects.
In the MRI study, the researchers compared scans of 16 ill teenagers participating in a clozapine trial with those of 24 age-matched controls. At the initial scan, the youths with schizophrenia tended to show enlarged ventricles, reduced total cerebral volume, and other structural anomalies. After two years, a series of re-scans revealed "highly significant" increases in the size of ventricles among those with schizophrenia. The controls showed no significant changes.
Although adult schizophrenia patients tend to have enlarged ventricles, evidence for progressive brain changes in adults has been more equivocal. Absent signs of an ongoing illness process, one prevailing theory has held that schizophrenia likely stems from damage caused by a prenatal event -- such as a viral infection in the womb, or some other environmental insult to the developing brain -- that interacts with normal brain development and life stresses, in genetically vulnerable individuals, to produce the disorder in young adulthood. While not one of its original tenets, the findings of progressive brain changes in adolescence are not inconsistent with this "neurodevelopmental" hypothesis, say the researchers.
Unlike in adults, schizophrenia usually emerges gradually in children, and is often preceded by developmental disturbances, such as lags in motor and speech development. Adolescents in the study who had histories of such autistic-like behavior tended to show greater ventricular enlargement. Childhood onset schizophrenia also tends to be harder to treat and to have a worse prognosis than the adult onset form. However, in a series of studies over the past few years, Rapoport's group has shown that affected children share with adults a similar pattern of brain structure abnormalities and physiological features. For example, in the study led by Zahn, the researchers report that the ill children had skin conductance and heart rate anomalies similar to those seen in affected adults.
In interpreting the imaging findings, Rapoport and colleagues suggest that the scans captured changes in the brain during a critical period in development when it is "uniquely sensitive" to effects of the illness. It's unlikely that the ventricles would continue enlarging at such a high rate, "as that would produce improbably large ventricular volume later in life," they note. Also, the "possibility that clozapine treatment accelerates adolescent brain change can not be ruled out," they add. The 16 affected adolescents in the study were the first to be re-scanned from a total of 30 patients in the clozapine trial. Their MRI scans were compared with scans from an ongoing NIMH study designed to provide data on normal brain development during childhood and adolescence.
"The study of childhood onset cases presents a unique approach to schizophrenia," said Rapoport. "If we can understand what turns on the illness in these rare cases, it may provide clues about how to turn it off for others."
Also participating in the studies were: Drs. Jay Giedd, Sanji Kumra, Leslie Jacobsen, and Amy Smith, Paul Lee, Jean Nelson and Susan Hamburger of NIMH; and Dr. Charles Gordon, University of Maryland; Dr. Kathleen McKenna, Northwestern University; and Dr. Jean Frazier, Harvard University.
NIMH is a component of the National Institutes of Health, an agency of the U.S. Department of Health and Human Services.