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 cytogenetic abnormalities and/or rare copy number variants (CNVs) that interrupt genes. This high rate of chromosome abnormalities 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 all childhood schizophrenia subjects for transformation to pluripotent stem cells for further physiological study in a collaborative study with Dr. Ricardo Dolmetsch (Stanford University). All known genes are being sequenced in a collaborative study with Dr. Guy Rouleau, University of Montreal. Children and adolescents meeting DSM-IV criteria for schizophrenia are being obtained through vigorous national recruiting for a study of the phenomenology, neurobiology and pharmacologic response of childhood onset schizophrenia. Over 3000 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 inappropriately 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 skills and language development, than seen for the later onset disorder. Autonomic and eye tracking measures parallel these 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 show superiority of clozapine for these medications for non-responders. Several lines of evidence indicate greater genetic loading for these cases and our national case finding is being expanded to obtain 120 probands for ongoing genetic studies (including complete parent-child trios).

Project Start
Project End
Budget Start
Budget End
Support Year
19
Fiscal Year
2009
Total Cost
$1,776,974
Indirect Cost
Name
U.S. National Institute of Mental Health
Department
Type
DUNS #
City
State
Country
Zip Code
Watsky, Rebecca E; Gotts, Stephen J; Berman, Rebecca A et al. (2018) Attenuated resting-state functional connectivity in patients with childhood- and adult-onset schizophrenia. Schizophr Res :
Xu, J; Hartley, B J; Kurup, P et al. (2018) Inhibition of STEP61 ameliorates deficits in mouse and hiPSC-based schizophrenia models. Mol Psychiatry 23:271-281
Zhou, Dale; Liu, Siyuan; Zhou, Xueping et al. (2018) 7 T MRI reveals hippocampal structural abnormalities associated with memory intrusions in childhood-onset schizophrenia. Schizophr Res 202:431-432
Ordóñez, Anna E; Luscher, Zoe I; Gogtay, Nitin (2016) Neuroimaging findings from childhood onset schizophrenia patients and their non-psychotic siblings. Schizophr Res 173:124-131
Kasoff, Lauren I; Ahn, Kwangmi; Gochman, Peter et al. (2016) Strong Treatment Response and High Maintenance Rates of Clozapine in Childhood-Onset Schizophrenia. J Child Adolesc Psychopharmacol 26:428-35
Ambalavanan, Amirthagowri; Girard, Simon L; Ahn, Kwangmi et al. (2016) De novo variants in sporadic cases of childhood onset schizophrenia. Eur J Hum Genet 24:944-8
Ordóñez, Anna E; Loeb, Frances F; Zhou, Xueping et al. (2016) Lack of Gender-Related Differences in Childhood-Onset Schizophrenia. J Am Acad Child Adolesc Psychiatry 55:792-9
Watsky, Rebecca E; Pollard, Katharine Ludovici; Greenstein, Deanna et al. (2016) Severity of Cortical Thinning Correlates With Schizophrenia Spectrum Symptoms. J Am Acad Child Adolesc Psychiatry 55:130-136
Topol, Aaron; Zhu, Shijia; Hartley, Brigham J et al. (2016) Dysregulation of miRNA-9 in a Subset of Schizophrenia Patient-Derived Neural Progenitor Cells. Cell Rep 15:1024-1036
Berman, Rebecca A; Gotts, Stephen J; McAdams, Harrison M et al. (2016) Disrupted sensorimotor and social-cognitive networks underlie symptoms in childhood-onset schizophrenia. Brain 139:276-91

Showing the most recent 10 out of 66 publications