Psychiatric Diagnosis; Hyperactive Children; Biological Aspects of Child Psychiatry; Pediatric Psychopharmacology; Obsessive Compulsive Disorder; Childhood Psychoses.

CHILDHOOD ONSET SCHIZOPHRENIA:
    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. A new study of transient cortical electrical stimulation has begun 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 300 medical records have been reviewed from which 320 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 225 were hospitalized for medication free observation.  A total of 112 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; four 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. 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, and our national case finding is being expanded to obtain 120 probands for onging genetic studies (100 TRIOS). 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 (40%) 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.

• Shaw P, Wallace GL, Addington A, Evans A, Rapoport J, Giedd JN. Effects of the Val158Met catechol-O-methyltransferase polymorphism on cortical structure in children and adolescents. Mol Psychiatry. 14(4):348-9. 2009.
• Addington AM, Rapoport JL. The genetics of childhood-onset schizophrenia: when madness strikes the prepubescent. Curr Psychiatry Rep. 11(2):156-61. 2009.
• Rapoport JL, 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. 48:1, 10-18. 2009.
• Gogtay N, Lu A, Leow AD, Klunder AD, Lee AD, Chavez A, Greenstein D, Giedd JN, Toga AW, Rapoport JL, Thompson PM. Three-dimensional brain growth abnormalities in childhood-onset schizophrenia visualized by using tensor-based morphometry. Proc Natl Acad Sci U S A. 14;105(41) 15979-84. Epub. 2008.
• Shaw P, Sharp WS, Morrison M, Eckstrand K, Greenstein DK, Clasen LS, Evans AC, Rapoport JL. Psychostimulant treatment and the developing cortex in attention deficit hyperactivity disorder. Am J Psychiatry. 2009 Jan; 166(1): 58-63. Epub. 15. 2008.
• Greenstein DK, Wolfe S, Gochman P, Rapoport JL, Gogtay N. Remission Status and Cortical Thickness in Childhood-Onset Schizophrenia. J Am Acad Child Adolesc Psychiatry. 2008.