Judith Rapoport, M.D.
NIH Distinguished Investigator
Child Psychiatry Branch
Building 10, Room 3N202
10 Center Drive
Bethesda, MD 20892
Schizophrenia is one of the most devastating and costly mental illnesses. Clinical studies across all of medicine show that early onset illness is often more severe, and with stronger biological and genetic factors. Since 1990, the NIMH has been recruiting patients with onset of schizophrenia before age 13. Major goals are to study brain development during childhood and adolescence in early onset schizophrenia patients. Preliminary genetic studies show association with a number of schizophrenia risk genes such as GAD and NRG1, supporting continuity with the adult disorder. In addition, abnormal brain developmental trajectories in patients and their full healthy siblings are seen in relation to risk alleles for these genes. Treatment studies have shown the unique benefit of clozapine for treatment resistant patients. New study of intranasal oxytocin and transient cortical electrical stimulation (TDCS) are underway for control of selected symptoms.
Children and adolescents meeting DSM-IV criteria for schizophrenia are being recruited nationally for a study of the phenomenology, neurobiology and pharmacologic response of childhood onset schizophrenia. Over 500 medical records have been reviewed from which 380 patients and their families, appearing to meet DSM-IV criteria for schizophrenia with onset of psychosis prior to age 12, were screened in person. Of these 234 were hospitalized for medication free observation. A total of 126 received the diagnosis of schizophrenia at NIMH screening. A large number of children are receiving the diagnosis of schizophrenia improperly resulting in inappropriate treatment, even at academic centers. Our findings to date indicate continuity between childhood onset and later onset schizophrenia, with evidence that childhood onset schizophrenia may result from a more severe neurodevelopment lesion. Family/genetic data indicate three cases (5%) have familial schizophrenia, not higher than seen with adult cases; one subject had a 1:7 balanced chromosomal translocation; five subjects had a microdeletion at 22q11; one had uniparental isodisomy at 5q; two had 45x0 (Turners Syndrome); one had trisomy X. Three of 45 full siblings are mentally retarded with two of these meeting criteria for autism.
COS Probands show greater premorbid developmental delays for motor and language than seen for the later onset disorder. Autonomic and eye tracking measures parallel those of adult schizophrenia. Brain MRI abnormalities ultimately resemble those of adult onset schizophrenia but with more striking and consistent progression during adolescence. This progressive loss appears specific to schizophrenia and not due to medication. A double-blind comparison of olanzapine and clozapine shows superiority of clozapine for those responding to medication. Several lines of evidence indicate greater genetic loading for these cases. Genetic data to date indicate significant association with four risk genes for schizophrenia, even with this limited sample size. Ongoing whole genomic screening studies show evidence for increased (12%) rate for rare copy number variants (CNVs) that interrupt genes. This high rate may be related to early age of onset and to early developmental brain abnormalities rather than to schizophrenia. Skin biopsies are being obtained over the next three years on selected subjects for transformation to pluripotent stem cells for further physiological study in a collaborative study with Dr. Ricardo Dolmetsch (Stanford University). One thousand genes related to synaptic development are being sequenced in a collaborative study with Dr. Guy Rouleau, University of Montreal.
Judith L. Rapoport M.D. is Chief of the Child Psychiatry Branch NIMH. She is a graduate of Harvard Medical School, and did her clinical and research training at the Massachusetts Mental Health Center (Boston), Children's Hospital (DC), and the Karolinska Hospital (Stockholm). Her research has focused on diagnosis in child psychiatry, Attention Deficit Hyperactivity Disorder and Obsessive Compulsive Disorder. Over the past decade, her group has been studying the clinical phenomenology, neurobiology and treatment of Childhood Onset Schizophrenia. She is an author or coauthor of over 300 scientific papers, a member of the Institute of Medicine, and a Fellow of the American Academy of Arts and Sciences.
Zalesky A, Pantelis C, Cropley V, Fornito A, Cocchi L, McAdams H, Clasen L, Greenstein D, Rapoport JL, Gogtay N. Delayed Development of Brain Connectivity in Adolescents With Schizophrenia and Their Unaffected Siblings. JAMA Psychiatry. 2015;72(9):900-8.
Rapoport J, Chavez A, Greenstein D, Addington A, Gogtay N. Autism spectrum disorders and childhood-onset schizophrenia: clinical and biological contributions to a relation revisited. J Am Acad Child Adolesc Psychiatry. 2009;48(1):10-8.
Watsky RE, Ludovici Pollard K, Greenstein D, Shora L, Dillard-Broadnax D, Gochman P, Clasen LS, Berman RA, Rapoport JL, Gogtay N, Ordóñez AE. Severity of Cortical Thinning Correlates With Schizophrenia Spectrum Symptoms. J Am Acad Child Adolesc Psychiatry. 2016;55(2):130-6.
Berman RA, Gotts SJ, McAdams HM, Greenstein D, Lalonde F, Clasen L, Watsky RE, Shora L, Ordonez AE, Raznahan A, Martin A, Gogtay N, Rapoport J. Disrupted sensorimotor and social-cognitive networks underlie symptoms in childhood-onset schizophrenia. Brain. 2016;139(Pt 1):276-91.
Vértes PE, Alexander-Bloch AF, Gogtay N, Giedd JN, Rapoport JL, Bullmore ET. Simple models of human brain functional networks. Proc Natl Acad Sci U S A. 2012;109(15):5868-73.