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Peter Gochman

National Institutes of Health, Child Psychiatry Branch, Faculty Member

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Papers by Peter Gochman

The catechol o-methyltransferase (COMT) val158met polymorphism modulates the association of serious life events (SLE) and impulsive aggression in female patients with borderline personality disorder (BPD)

Acta Psychiatrica Scandinavica, 2009

We analyzed i) the effects of serious life events (SLE) on impulsive aggression, and ii) modulati... more We analyzed i) the effects of serious life events (SLE) on impulsive aggression, and ii) modulating effects of the COMT Val(158)Met polymorphism on the association between SLEs and impulsive aggression in borderline personality disorder (BPD). One hundred and twelve female BPD patients from Germany were included in this study. Impulsive aggression was assessed by the Buss-Durkee-Hostility Inventory (BDHI). Childhood sexual abuse was associated with lower BDHI sum score (P = 0.003). In COMT Val(158)Val carriers, but not in Val/Met and Met/Met carriers, childhood sexual abuse and the cumulative number of SLEs were associated with lower BDHI sum scores (P &lt; 0.05). This study analyzing a specific gene x environment interaction in female BPD patients suggests an association between SLEs and impulsive aggression, as well as a modulating effect of the COMT Val(158)Val genotype on the relation between SLEs and impulsive aggression.

Psychosis as a dimensional construct: cortical abnormalities associated with schizophrenia spectrum symptoms in siblings of patients with childhood-onset schizophrenia

F1000Research, May 31, 2013

The effect of dopamine receptor blockade on motor behavior in Aplysia californica

Pharmacology, Biochemistry and Behavior, Jul 1, 2001

The mammalian D1- and D2-like receptor blockers SCH-23390 and raclopride were used to block recep... more The mammalian D1- and D2-like receptor blockers SCH-23390 and raclopride were used to block receptors in Aplysia californica, and the effect on reflexes and escape behavior was examined. Four groups of 20 young adults were each injected with SCH-23390, raclopride, SCH-23390+raclopride, or seawater. The drug (0.0125 mg/g of body weight) was injected 2 mm anterior to the parapodia. After the injection of either SCH-23390 or SCH-23390+raclopride, there was a significant increase in parapodia opening (P&lt;.001), siphon withdrawal (P&lt;.05), and galloping following tail pinch (P&lt;.01) compared to raclopride-injected or control animals. The data showed that blockade of receptors by SCH-23390, but not raclopride, produced significant changes in motor behavior in A. californica.

Sleep spindle activity in childhood onset schizophrenia: Diminished and associated with clinical symptoms

Schizophrenia Research, Sep 1, 2020

Neuroimaging studies of childhood onset schizophrenia (COS), a rare yet severe form of schizophre... more Neuroimaging studies of childhood onset schizophrenia (COS), a rare yet severe form of schizophrenia with an onset before the age of 13 years, have shown continuity with adult onset schizophrenia. Previous research in adult patients has shown reduced sleep spindle activity, transient oscillations in the sleep electroencephalogram (EEG) generated through thalamocortical loops. The current study examines sleep spindle activity in patients with COS. Seventeen children and adolescents with COS (16 years ± 6.6) underwent overnight sleep EEG recordings. Sleep spindle activity was compared between patients with COS and age and gender matched controls and correlated with clinical symptom severity. We found pronounced deficits in sleep spindle amplitude, duration, density and frequency in patients with COS (effect size = 0.61 to 1.96; dependent on metric and EEG derivation). Non-rapid eye movement (NREM) sleep EEG power and coherence in the sigma band (11-16 Hz) corresponding to spindle activity were also markedly diminished in patients with COS as compared to controls. Furthermore, the degree of deficit in power and coherence of spindles was strongly associated with clinician rated hallucinations and positive symptoms over widespread cortical regions. Our finding of diminished spindle activity and its association with hallucinations likely reflect dysfunction of the thalamocortical circuits in children and adolescents with COS. Given the relative ease of sleep EEG recordings in vulnerable populations, this study highlights the potential of such recordings to characterize brain function in schizophrenia.

Childhood-onset schizophrenia/autistic disorder and t(1;7) reciprocal translocation: Identification of a BAC contig spanning the translocation breakpoint at 7q21

American journal of medical genetics, 2000

Childhood-onset schizophrenia (COS) is defined by the development of first psychotic symptoms by ... more Childhood-onset schizophrenia (COS) is defined by the development of first psychotic symptoms by age 12. While recruiting patients with COS refractory to conventional treatments for a trial of atypical antipsychotic drugs, we discovered a unique case who has a familial t(1;7)(p22;q21) reciprocal translocation and onset of psychosis at age 9. The patient also has symptoms of autistic disorder, which are usually transient before the first psychotic episode among 40-50% of the childhood schizophrenics but has persisted in him even after the remission of psychosis. Cosegregating with the translocation, among the carriers in the family available for the study, are other significant psychopathologies, including alcohol/drug abuse, severe impulsivity, and paranoid personality and language delay. This case may provide a model for understanding the genetic basis of schizophrenia or autism. Here we report the progress toward characterization of genomic organization across the translocation breakpoint at 7q21. The polymorphic markers, D7S630/D7S492 and D7S2410/D7S646, immediately flanking the breakpoint, may be useful for further confirming the genetic linkage for schizophrenia or autism in this region. Am. J. Med. Genet.

Children and adolescents with psychotic disorder not otherwise specified: A 2- to 8-year follow-up study

Comprehensive Psychiatry, Jul 1, 2001

Although psychotic phenomena in children with disruptive behavior disorders are more common than ... more Although psychotic phenomena in children with disruptive behavior disorders are more common than expected, their prognostic significance is unknown. To examine the outcome of pediatric patients with atypical psychoses, a group of 26 patients with transient psychotic symptoms were evaluated with clinical and structured interviews at the time of initial contact (mean age, 11.6 ؎ 2.7 years) and at follow-up 2 to 8 years later. Measures of functioning and psychopathology were also completed at their initial assessment. Risk factors associated with adult psychotic disorders (familial psychopathology, eyetracking dysfunction in patients and their relatives, obstetrical complications, and premorbid developmental course in the proband) had been obtained at study entry. On follow-up examination (mean age, 15.7 ؎ 3.4 years), 13 patients (50%) met diagnostic criteria for a major axis I disorder: three for schizoaffective disorder, four for bipolar disorder, and six for major depressive disorder. The remaining 13 patients again received a diagnosis of psychotic disorder not otherwise specified (NOS), with most being in remission from their psychotic symptoms. Among this group who had not developed a mood or psychotic disorder, disruptive behavior disorders were exceedingly common at follow-up and were the focus of their treatment. Higher initial levels of psychopathology, lower cognitive abilities, and more developmental motor abnormalities were found in patients with a poor outcome. Obstetrical, educational, and family histories did not differ significantly between the groups. Through systematic diagnostic evaluation, children and adolescents with atypical psychotic disorders can be distinguished from those with schizophrenia, a difference with important treatment and prognostic implications. Further research is needed to delineate the course and outcome of childhood-onset atypical psychoses, but preliminary data indicate improvement in psychotic symptoms in the majority of patients and the development of chronic mood disorders in a substantial subgroup.

Parental Schizophrenia Spectrum Disorders in Childhood-Onset and Adult-Onset Schizophrenia

American Journal of Psychiatry, Mar 1, 2003

Objective: Childhood onset of "adult" psychiatric disorders may be caused, in part, by more salie... more Objective: Childhood onset of "adult" psychiatric disorders may be caused, in part, by more salient genetic risk. In this study, the rates of schizophrenia spectrum disorders among parents of patients with childhood-onset and adult-onset schizophrenia and parents of community comparison subjects were compared. Method: To assess the presence of axis I and axis II disorders associated with schizophrenia, parents of patients with childhood-onset schizophrenia (95 parents), patients with adult-onset schizophrenia (86 parents), and community comparison subjects (123 parents) were interviewed directly by using semistructured instruments. Information on 19 additional parents (parents of childhood-onset patients, N=2; parents of adult-onset patients, N=11; parents of community comparison subjects, N=6) was obtained by using a family history interview with the same instruments. Transcribed interviews were scored by a rater blind to group membership, and the morbid risks for schizophrenia spectrum disorders in the three groups were compared. Results: Parents of patients with childhood-onset schizophrenia had a significantly higher morbid risk of schizophrenia spectrum disorders (24.74%) than parents of patients with adult-onset schizophrenia (11.35%), and parents of both patient groups had a greater risk of schizophrenia spectrum disorders than did parents of comparison subjects (1.55%). Conclusions: Parents of patients with childhood-onset schizophrenia have a higher rate of schizophrenia spectrum disorders than parents of patients with adultonset illness. This is consistent with the hypothesis that a childhood onset of schizophrenia is due, at least in part, to a greater familial diathesis for the disorder.

Transcriptional signatures of schizophrenia in hiPSC-derived NPCs and neurons are concordant with post-mortem adult brains

Nature Communications, Dec 1, 2017

The power of human induced pluripotent stem cell (hiPSC)-based studies to resolve the smaller eff... more The power of human induced pluripotent stem cell (hiPSC)-based studies to resolve the smaller effects of common variants within the size of cohorts that can be realistically assembled remains uncertain. We identified and accounted for a variety of technical and biological sources of variation in a large case/control schizophrenia (SZ) hiPSC-derived cohort of neural progenitor cells and neurons. Reducing the stochastic effects of the differentiation process by correcting for cell type composition boosted the SZ signal and increased the concordance with post-mortem data sets. We predict a growing convergence between hiPSC and post-mortem studies as both approaches expand to larger cohort sizes. For studies of complex genetic disorders, to maximize the power of hiPSC cohorts currently feasible, in most cases and whenever possible, we recommend expanding the number of individuals even at the expense of the number of replicate hiPSC clones.

Stimulant Drug Treatment in Childhood-Onset Schizophrenia with Comorbid ADHD: An Open-Label Case Series

Journal of Child and Adolescent Psychopharmacology, Sep 1, 2004

The administration of psychostimulants to children with psychotic symptoms is controversial. This... more The administration of psychostimulants to children with psychotic symptoms is controversial. This study reports the stimulant drug response of 5 children, aged 8-15 years, with childhood-onset schizophrenia (COS) and comorbid attention deficit hyperactivity disorder (ADHD). Four COS inpatients were given stimulants for comorbid ADHD after stabilization of psychosis on antipsychotic medication. A fifth COS inpatient received stimulants while still actively psychotic, despite concurrent neuroleptic treatment. Data from the 10-item Brief Conners Teachers Ratings Scale (BCTRS) were examined the week before, and the week after, stimulant addition. A paired t test, conducted using Conners Teachers data from these 4 subjects, indicated significant improvement in ADHD symptoms (p = 0.02). Data obtained from a retrospective chart review indicated no significant worsening of psychosis. The 2 subjects treated with mixed salts of dextroamphetamine sulfate and amphetamine sulfate remained on that medication at 6 months and at the 2-year follow-up. Our results suggest that ADHD comorbid with COS may be safely treated with a stimulant, once the psychosis is stabilized. A systematic investigation of this question may be warranted.

Transcriptional Signatures of Childhood Onset Schizophrenia in Hipsc-Derived NPCS and Neurons Are Concordant with Signatures from Post Mortem Adult Brains

European Neuropsychopharmacology, 2019

value lower than 0.05 after a Bonferroni correction for multiple comparisons and differentially m... more value lower than 0.05 after a Bonferroni correction for multiple comparisons and differentially methylated regions (DMRs) with at least two significant DMPs (FDR) within a 500 bp region. Results: We found 5 DMRs and 16 DMPs comparing controls and FEP, and 14 DMRs and 77 DMPs between FEP before and after treatment. Discussion: To our knowledge, this is the first study to find DMRs in a longitudinal cohort of antipsychotic naïve FEP patients. Collectively, DMRs in the longitudinal comparison seem to be related to the adverse effects and the response to risperidone. Notably, the most associated genomic region in schizophrenia (previously reported by the PGC), the MHC region, is differentially methylated in patients after the treatment, demonstrating an epigenetic modification caused by risperidone in an important schizophrenia genomic region. Identifying the genetic and molecular changes of drug response is one of the first steps through personalized medicine, further studies should replicate these results and aim antipsychotic naive individuals treated with other antipsychotics.

Attenuated resting-state functional connectivity in patients with childhood- and adult-onset schizophrenia, not in their siblings

F1000Research, May 23, 2016

Background: Childhood-onset schizophrenia (COS) is a rare, severe form of the adult-onset disorde... more Background: Childhood-onset schizophrenia (COS) is a rare, severe form of the adult-onset disorder (AOS). Our previous resting-state fMRI study identified attenuated functional connectivity in COS compared with controls. Here, we ask whether COS and AOS patients and their siblings exhibit similar abnormalities of functional connectivity. Methods: A whole-brain, data-driven approach was used to assess resting-state functional connectivity differences in COS (patients/siblings/controls, n: 26/28/33) and AOS (n: 19/28/30). There were no significant differences in age, sex, or head motion across groups in each dataset and as designed, the COS dataset has a significantly lower age than the AOS. Results: Both COS and AOS patients showed decreased functional connectivity relative to controls among a wide set of brain regions (P b 0.05, corrected), but their siblings did not. Decreased connectivity in COS and AOS patients showed no amplitude differences and was not modulated by age-at-onset or medication doses. Cluster analysis revealed that these regions fell into two large-scale networks: one sensorimotor network and one centered on defaultmode network regions, but including higher-order cognitive areas only in COS. Decreased connectivity between these two networks was notable (P b 0.05, corrected) for both patient groups. Conclusions: A shared pattern of attenuated functional connectivity was found in COS and AOS, supporting the continuity of childhood-onset and adult-onset schizophrenia. Connections were altered between sensorimotor areas and default-mode areas in both COS and AOS, suggesting potential abnormalities in processes of self-monitoring and sensory prediction. The absence of substantial dysconnectivity in siblings indicates that attenuation is staterelated.

494. A longitudinal MRI study of children and adolescents with atypical psychotic disorders

Biological Psychiatry, Apr 1, 2000

We have previously reported that pediatric OCD patients performed comparably to healthy controls ... more We have previously reported that pediatric OCD patients performed comparably to healthy controls on neuropsychological testing. In fact, OCD patients appeared to actually perform better than controls on an oculomotor delayed response task. The Digit Span subtest of the Weschler Intelligence Scale for Children-Revised, is believed to be associated with striatal circuit functioning, a circuit directly implicated in the pathophysiology of OCD, and may also assess delayed response. Digit Span tests were administered to 40 treatment-naïve pediatric OCD patients (19 males, 21 females) and 29 controls (12 males, 17 females). Scores for Digit Span Forward (repetition of numbers) and Backward (reversal of numbers) were recorded separately; the combined score was recorded as a percentile score. Children with OCD performed significantly better than controls on Digit Span testing, measured as an overall percentile (67.11 Ϯ 31.6 vs. 47.38 Ϯ 33.4, p ϭ 0.015). Female OCD patients did significantly better than female controls on the percentile score (74.93 Ϯ 28.7 vs. 43.64 Ϯ 34.0, p ϭ 0.004), while no significant difference was noted between male OCD patients vs. male controls. In contrast, male OCD patients performed significantly worse than male controls on the Digit Span Forward score only (9.21 Ϯ 2.0 vs. 11.07 Ϯ 1.8, p ϭ 0.007), but not on the Digit Span Backward score. Our results suggest that female OCD patients may perform better on Digit Span testing of delayed response, while males may actually perform worse on the more repetitive Forward component of the Digit Span test. The potential implications of this will be discussed in the poster.

41. Familial schizophrenia spectrum disorders in childhood-and adult-onset schizophrenia

Biological Psychiatry, Apr 1, 2000

using a measure adopted from studies of parkinsonian bradykinesia. There is a general consensus t... more using a measure adopted from studies of parkinsonian bradykinesia. There is a general consensus that parkinsonian bradykinesia stems from an inability to modify, or scale, velocity during movement. In the present study, we hypothesized that a substantial proportion of MD patients would exhibit deficits in velocity scaling. Our measure of velocity scaling quantifies the extent to which a subject programs or scales movement velocity in anticipation of increasing target distance. We studied 54 patients who met DSM-IV criteria for major depression and 26 age and gender comparable healthy comparison subjects. All MD patients were unmedicated at the time of testing. An instrumental measure of wrist movement was developed to quantify several aspects of movement including reaction time (RT), peak velocity (PV), and velocity scaling (VS). Subjects were instructed to flex their wrist when a target box appeared on the computer screen and to reach the target as quickly and as accurately as possible. Results indicated that MD patients exhibited significantly (p Ͻ 0.001) longer mean RT (477 ms) than comparison subjects (391 ms). There was a trend (p ϭ 0.07) for MD patients to have lower scores on the VS measure (2.68 deg/sec/deg) compared with comparison subjects (3.33 d/s/d). 53.7% of the MD patients had VS scores lower than the 95th percentile of the comparison subjects. These findings suggest that MD patients as a group exhibit delayed reaction times. Nevertheless, a significant proportion of MD patients also exhibit disturbances in the programming of movement velocity reflective of a putative dopaminergic disturbance, similar to that seen in parkinsonism.

Hippocampal volume change relates to clinical outcome in childhood-onset schizophrenia

Psychological Medicine, May 4, 2015

Background. Fixed hippocampal volume reductions and shape abnormalities are established findings ... more Background. Fixed hippocampal volume reductions and shape abnormalities are established findings in schizophrenia, but the relationship between hippocampal volume change and clinical outcome has been relatively unexplored in schizophrenia and other psychotic disorders. In light of recent findings correlating hippocampal volume change and clinical outcome in first-episode psychotic adults, we hypothesized that fewer decreases in hippocampal volume would be associated with better functional outcome and fewer psychotic symptoms in our rare and chronically ill population of childhood-onset schizophrenia (COS) patients. Method. We prospectively obtained 114 structural brain magnetic resonance images (MRIs) from 27 COS subjects, each with three or more scans between the ages of 10 and 30 years. Change in hippocampal volume, measured by fit slope and percentage change, was regressed against clinical ratings (Children's Global Assessment Scale, Scale for the Assessment of Positive Symptoms, Scale for the Assessment of Negative Symptoms) at last scan (controlling for sex, time between scans and total intracranial volume). Results. Fewer negative symptoms were associated with less hippocampal volume decrease (fit slope: p = 0.0003, and percentage change: p = 0.005) while positive symptoms were not related to hippocampal change. There was also a relationship between improved clinical global functioning and maintained hippocampal volumes (fit slope: p = 0.025, and percentage change: p = 0.043). Conclusions. These results suggest that abnormal hippocampal development in schizophrenia can be linked to global functioning and negative symptoms. The hippocampus can be considered a potential treatment target for future therapies.

Risk Factors for Neutropenia in Clozapine-Treated Children and Adolescents with Childhood-Onset Schizophrenia

Journal of Child and Adolescent Psychopharmacology, Mar 1, 2013

Objective: The purpose of this study was to retrospectively analyze rates of neutropenia and risk... more Objective: The purpose of this study was to retrospectively analyze rates of neutropenia and risk factors for neutropenia in hospitalized children and adolescents treated with clozapine. Methods: A retrospective chart review was conducted for all patients who received clozapine at any time during a hospitalization at the National Institute of Mental Health (NIMH) between 1990 and 2011. All patients satisfied screening criteria for the NIMH childhood-onset schizophrenia study, including onset of psychosis before the age of 13 years. Absolute neutrophil count (ANC) values recorded during inpatient hospitalization were extracted for 87 eligible patients with a mean age of 13.35-2.46 years at hospitalization and a mean length of stay of 117-43 days. Results: Mild neutropenia only (lowest ANC < 2000/mm 3 but >1500/mm 3) was observed in 27 (31%) patients and moderate neutropenia (any ANC < 1500/mm 3) was observed in 17 (20%) patients. There were no cases of agranulocytosis or severe infection. Significant risk factors for mild neutropenia compared with no hematologic adverse effects (HAEs) were male gender (p = 0.012) and younger age (p < 0.001). Male gender was also a significant risk factor for moderate neutropenia compared with no HAEs (p = 0.003). If a child of African American ethnicity developed neutropenia during hospitalization at all that child was significantly more likely to develop moderate neutropenia than mild neutropenia only (p = 0.017). African American boys had the highest rate of moderate neutropenia at 47%. Sixteen of the 17 patients exhibiting moderate neutropenia were successfully treated with clozapine by the time of discharge; 8 of these 16 required adjunctive lithium carbonate administration to maintain ANC > 2000/mm 3. Conclusions: Our study shows that the rates of neutropenia in clozapine-treated children and adolescents are considerably higher than in the adult population. Younger age, African American ethnicity, and male gender were significant risk factors. These are also risk factors for benign neutropenia in healthy children and adolescents. Despite these high rates of neutropenia, all but one of the patients with neutropenia during hospitalization were successfully discharged on clozapine.

Childhood onset schizophrenia: familial neurocognitive measures

Schizophrenia Research, Nov 1, 2004

Objective: Early onset disorders may have more salient familial/genetic etiology. Neurocognitive ... more Objective: Early onset disorders may have more salient familial/genetic etiology. Neurocognitive deficits which are seen in families of adult onset schizophrenic patients were examined in healthy family members of patients with childhood-onset schizophrenia (COS). Methods: Trail Making Tests (TMT) A and B, Wechsler Intelligence Scale-Revised Digit Span and Vocabulary subtests were administered to 67 parents and 24 siblings of patients with childhood-onset schizophrenia and 114 healthy community controls (CC) comparable in sex, age, and educational level. Results: COS siblings performed significantly more poorly than did controls on Trails Making Test B with a trend for poorer performance evident on Trails Making Test A. COS parents performed more poorly than controls only on Trails Making Test A. Conclusions: Healthy first-degree relatives of COS probands have subtle deficits in tests involving oculomotor/psychomotor speed, working memory and executive function. This provides further support for continuity between COS and later onset schizophrenia and for a familial/genetic factor associated with the illness.

High rate of disease-related copy number variations in childhood onset schizophrenia

Molecular Psychiatry, May 21, 2013

Copy number variants (CNVs) are risk factors in neurodevelopmental disorders, including autism, e... more Copy number variants (CNVs) are risk factors in neurodevelopmental disorders, including autism, epilepsy, intellectual disability (ID) and schizophrenia. Childhood onset schizophrenia (COS), defined as onset before the age of 13 years, is a rare and severe form of the disorder, with more striking array of prepsychotic developmental disorders and abnormalities in brain development. Because of the well-known phenotypic variability associated with pathogenic CNVs, we conducted whole genome genotyping to detect CNVs and then focused on a group of 46 rare CNVs that had well-documented risk for adult onset schizophrenia (AOS), autism, epilepsy and/or ID. We evaluated 126 COS probands, 69 of which also had a healthy full sibling. When COS probands were compared with their matched related controls, significantly more affected individuals carried disease-related CNVs (P ¼ 0.017). Moreover, COS probands showed a higher rate than that found in AOS probands (Po0.0001). A total of 15 (11.9%) subjects exhibited at least one such CNV and four of these subjects (26.7%) had two. Five of 15 (4.0% of the sample) had a 2.5-3 Mb deletion mapping to 22q11.2, a rate higher than that reported for adult onset (0.3-1%) (Po0.001) or autism spectrum disorder and, indeed, the highest rate reported for any clinical population to date. For one COS subject, a duplication found at 22q13.3 had previously only been associated with autism, and for four patients CNVs at 8q11.2, 10q22.3, 16p11.2 and 17q21.3 had only previously been associated with ID. Taken together, these findings support the well-known pleiotropic effects of these CNVs suggesting shared abnormalities early in brain development. Clinically, broad CNV-based population screening is needed to assess their overall clinical burden.

Predictors of two-year follow-up in children and adolescents with schizophrenia

Schizophrenia Research, Mar 1, 2003

GAD1 (2q31.1), which encodes glutamic acid decarboxylase (GAD67), is associated with childhood-onset schizophrenia and cortical gray matter volume loss

Molecular Psychiatry, 2004

Postmortem brain studies have shown deficits in the cortical c-aminobutyric acid (GABA) system in... more Postmortem brain studies have shown deficits in the cortical c-aminobutyric acid (GABA) system in schizophrenic individuals. Expression studies have shown a decrease in the major GABA-synthesizing enzyme (glutamic acid decarboxylase (GAD 67) mRNA levels in neurons in dorsolateral prefrontal cortex in schizophrenics relative to controls. In the present study, SNPs in and around the GAD1 gene, which encodes the protein GAD 67 , were tested on a rare, severely ill group of children and adolescents with childhood-onset schizophrenia (COS) (n ¼ 72), in a family-based association analysis. Compared to adult-onset samples, the COS sample has evidence for more salient familial, and perhaps genetic, risk factors for schizophrenia, as well as evidence for frontal cortical hypofunction, and greater decline in cortical gray matter volume on anatomic brain MRI scans during adolescence. We performed family-based TDT and haplotype association analyses of the clinical phenotype, as well as association analyses with endophenotypes using the QTDT program. Three adjacent SNPs in the 5 0 upstream region of GAD1 showed a positive pairwise association with illness in these families (P ¼ 0.022-0.057). Significant transmission distortion of 4-SNP haplotypes was also observed (P ¼ 0.003-0.008). Quantitative trait TDT analyses showed an intriguing association between several SNPs and increased rate of frontal gray matter loss. These observations, when taken together with the positive results reported recently in two independent adult-onset schizophrenia pedigree samples, suggest that the gene encoding GAD 67 may be a common risk factor for schizophrenia.

High rate of disease-related copy number variations in childhood onset schizophrenia

Molecular Psychiatry, 2013

Copy number variants (CNVs) are risk factors in neurodevelopmental disorders, including autism, e... more Copy number variants (CNVs) are risk factors in neurodevelopmental disorders, including autism, epilepsy, intellectual disability (ID) and schizophrenia. Childhood onset schizophrenia (COS), defined as onset before the age of 13 years, is a rare and severe form of the disorder, with more striking array of prepsychotic developmental disorders and abnormalities in brain development. Because of the well-known phenotypic variability associated with pathogenic CNVs, we conducted whole genome genotyping to detect CNVs and then focused on a group of 46 rare CNVs that had well-documented risk for adult onset schizophrenia (AOS), autism, epilepsy and/or ID. We evaluated 126 COS probands, 69 of which also had a healthy full sibling. When COS probands were compared with their matched related controls, significantly more affected individuals carried disease-related CNVs (P ¼ 0.017). Moreover, COS probands showed a higher rate than that found in AOS probands (Po0.0001). A total of 15 (11.9%) subjects exhibited at least one such CNV and four of these subjects (26.7%) had two. Five of 15 (4.0% of the sample) had a 2.5-3 Mb deletion mapping to 22q11.2, a rate higher than that reported for adult onset (0.3-1%) (Po0.001) or autism spectrum disorder and, indeed, the highest rate reported for any clinical population to date. For one COS subject, a duplication found at 22q13.3 had previously only been associated with autism, and for four patients CNVs at 8q11.2, 10q22.3, 16p11.2 and 17q21.3 had only previously been associated with ID. Taken together, these findings support the well-known pleiotropic effects of these CNVs suggesting shared abnormalities early in brain development. Clinically, broad CNV-based population screening is needed to assess their overall clinical burden.

The catechol o-methyltransferase (COMT) val158met polymorphism modulates the association of serious life events (SLE) and impulsive aggression in female patients with borderline personality disorder (BPD)

Acta Psychiatrica Scandinavica, 2009

We analyzed i) the effects of serious life events (SLE) on impulsive aggression, and ii) modulati... more We analyzed i) the effects of serious life events (SLE) on impulsive aggression, and ii) modulating effects of the COMT Val(158)Met polymorphism on the association between SLEs and impulsive aggression in borderline personality disorder (BPD). One hundred and twelve female BPD patients from Germany were included in this study. Impulsive aggression was assessed by the Buss-Durkee-Hostility Inventory (BDHI). Childhood sexual abuse was associated with lower BDHI sum score (P = 0.003). In COMT Val(158)Val carriers, but not in Val/Met and Met/Met carriers, childhood sexual abuse and the cumulative number of SLEs were associated with lower BDHI sum scores (P &lt; 0.05). This study analyzing a specific gene x environment interaction in female BPD patients suggests an association between SLEs and impulsive aggression, as well as a modulating effect of the COMT Val(158)Val genotype on the relation between SLEs and impulsive aggression.

Psychosis as a dimensional construct: cortical abnormalities associated with schizophrenia spectrum symptoms in siblings of patients with childhood-onset schizophrenia

F1000Research, May 31, 2013

The effect of dopamine receptor blockade on motor behavior in Aplysia californica

Pharmacology, Biochemistry and Behavior, Jul 1, 2001

The mammalian D1- and D2-like receptor blockers SCH-23390 and raclopride were used to block recep... more The mammalian D1- and D2-like receptor blockers SCH-23390 and raclopride were used to block receptors in Aplysia californica, and the effect on reflexes and escape behavior was examined. Four groups of 20 young adults were each injected with SCH-23390, raclopride, SCH-23390+raclopride, or seawater. The drug (0.0125 mg/g of body weight) was injected 2 mm anterior to the parapodia. After the injection of either SCH-23390 or SCH-23390+raclopride, there was a significant increase in parapodia opening (P&lt;.001), siphon withdrawal (P&lt;.05), and galloping following tail pinch (P&lt;.01) compared to raclopride-injected or control animals. The data showed that blockade of receptors by SCH-23390, but not raclopride, produced significant changes in motor behavior in A. californica.

Sleep spindle activity in childhood onset schizophrenia: Diminished and associated with clinical symptoms

Schizophrenia Research, Sep 1, 2020

Neuroimaging studies of childhood onset schizophrenia (COS), a rare yet severe form of schizophre... more Neuroimaging studies of childhood onset schizophrenia (COS), a rare yet severe form of schizophrenia with an onset before the age of 13 years, have shown continuity with adult onset schizophrenia. Previous research in adult patients has shown reduced sleep spindle activity, transient oscillations in the sleep electroencephalogram (EEG) generated through thalamocortical loops. The current study examines sleep spindle activity in patients with COS. Seventeen children and adolescents with COS (16 years ± 6.6) underwent overnight sleep EEG recordings. Sleep spindle activity was compared between patients with COS and age and gender matched controls and correlated with clinical symptom severity. We found pronounced deficits in sleep spindle amplitude, duration, density and frequency in patients with COS (effect size = 0.61 to 1.96; dependent on metric and EEG derivation). Non-rapid eye movement (NREM) sleep EEG power and coherence in the sigma band (11-16 Hz) corresponding to spindle activity were also markedly diminished in patients with COS as compared to controls. Furthermore, the degree of deficit in power and coherence of spindles was strongly associated with clinician rated hallucinations and positive symptoms over widespread cortical regions. Our finding of diminished spindle activity and its association with hallucinations likely reflect dysfunction of the thalamocortical circuits in children and adolescents with COS. Given the relative ease of sleep EEG recordings in vulnerable populations, this study highlights the potential of such recordings to characterize brain function in schizophrenia.

Childhood-onset schizophrenia/autistic disorder and t(1;7) reciprocal translocation: Identification of a BAC contig spanning the translocation breakpoint at 7q21

American journal of medical genetics, 2000

Childhood-onset schizophrenia (COS) is defined by the development of first psychotic symptoms by ... more Childhood-onset schizophrenia (COS) is defined by the development of first psychotic symptoms by age 12. While recruiting patients with COS refractory to conventional treatments for a trial of atypical antipsychotic drugs, we discovered a unique case who has a familial t(1;7)(p22;q21) reciprocal translocation and onset of psychosis at age 9. The patient also has symptoms of autistic disorder, which are usually transient before the first psychotic episode among 40-50% of the childhood schizophrenics but has persisted in him even after the remission of psychosis. Cosegregating with the translocation, among the carriers in the family available for the study, are other significant psychopathologies, including alcohol/drug abuse, severe impulsivity, and paranoid personality and language delay. This case may provide a model for understanding the genetic basis of schizophrenia or autism. Here we report the progress toward characterization of genomic organization across the translocation breakpoint at 7q21. The polymorphic markers, D7S630/D7S492 and D7S2410/D7S646, immediately flanking the breakpoint, may be useful for further confirming the genetic linkage for schizophrenia or autism in this region. Am. J. Med. Genet.

Children and adolescents with psychotic disorder not otherwise specified: A 2- to 8-year follow-up study

Comprehensive Psychiatry, Jul 1, 2001

Although psychotic phenomena in children with disruptive behavior disorders are more common than ... more Although psychotic phenomena in children with disruptive behavior disorders are more common than expected, their prognostic significance is unknown. To examine the outcome of pediatric patients with atypical psychoses, a group of 26 patients with transient psychotic symptoms were evaluated with clinical and structured interviews at the time of initial contact (mean age, 11.6 ؎ 2.7 years) and at follow-up 2 to 8 years later. Measures of functioning and psychopathology were also completed at their initial assessment. Risk factors associated with adult psychotic disorders (familial psychopathology, eyetracking dysfunction in patients and their relatives, obstetrical complications, and premorbid developmental course in the proband) had been obtained at study entry. On follow-up examination (mean age, 15.7 ؎ 3.4 years), 13 patients (50%) met diagnostic criteria for a major axis I disorder: three for schizoaffective disorder, four for bipolar disorder, and six for major depressive disorder. The remaining 13 patients again received a diagnosis of psychotic disorder not otherwise specified (NOS), with most being in remission from their psychotic symptoms. Among this group who had not developed a mood or psychotic disorder, disruptive behavior disorders were exceedingly common at follow-up and were the focus of their treatment. Higher initial levels of psychopathology, lower cognitive abilities, and more developmental motor abnormalities were found in patients with a poor outcome. Obstetrical, educational, and family histories did not differ significantly between the groups. Through systematic diagnostic evaluation, children and adolescents with atypical psychotic disorders can be distinguished from those with schizophrenia, a difference with important treatment and prognostic implications. Further research is needed to delineate the course and outcome of childhood-onset atypical psychoses, but preliminary data indicate improvement in psychotic symptoms in the majority of patients and the development of chronic mood disorders in a substantial subgroup.

Parental Schizophrenia Spectrum Disorders in Childhood-Onset and Adult-Onset Schizophrenia

American Journal of Psychiatry, Mar 1, 2003

Objective: Childhood onset of "adult" psychiatric disorders may be caused, in part, by more salie... more Objective: Childhood onset of "adult" psychiatric disorders may be caused, in part, by more salient genetic risk. In this study, the rates of schizophrenia spectrum disorders among parents of patients with childhood-onset and adult-onset schizophrenia and parents of community comparison subjects were compared. Method: To assess the presence of axis I and axis II disorders associated with schizophrenia, parents of patients with childhood-onset schizophrenia (95 parents), patients with adult-onset schizophrenia (86 parents), and community comparison subjects (123 parents) were interviewed directly by using semistructured instruments. Information on 19 additional parents (parents of childhood-onset patients, N=2; parents of adult-onset patients, N=11; parents of community comparison subjects, N=6) was obtained by using a family history interview with the same instruments. Transcribed interviews were scored by a rater blind to group membership, and the morbid risks for schizophrenia spectrum disorders in the three groups were compared. Results: Parents of patients with childhood-onset schizophrenia had a significantly higher morbid risk of schizophrenia spectrum disorders (24.74%) than parents of patients with adult-onset schizophrenia (11.35%), and parents of both patient groups had a greater risk of schizophrenia spectrum disorders than did parents of comparison subjects (1.55%). Conclusions: Parents of patients with childhood-onset schizophrenia have a higher rate of schizophrenia spectrum disorders than parents of patients with adultonset illness. This is consistent with the hypothesis that a childhood onset of schizophrenia is due, at least in part, to a greater familial diathesis for the disorder.

Transcriptional signatures of schizophrenia in hiPSC-derived NPCs and neurons are concordant with post-mortem adult brains

Nature Communications, Dec 1, 2017

The power of human induced pluripotent stem cell (hiPSC)-based studies to resolve the smaller eff... more The power of human induced pluripotent stem cell (hiPSC)-based studies to resolve the smaller effects of common variants within the size of cohorts that can be realistically assembled remains uncertain. We identified and accounted for a variety of technical and biological sources of variation in a large case/control schizophrenia (SZ) hiPSC-derived cohort of neural progenitor cells and neurons. Reducing the stochastic effects of the differentiation process by correcting for cell type composition boosted the SZ signal and increased the concordance with post-mortem data sets. We predict a growing convergence between hiPSC and post-mortem studies as both approaches expand to larger cohort sizes. For studies of complex genetic disorders, to maximize the power of hiPSC cohorts currently feasible, in most cases and whenever possible, we recommend expanding the number of individuals even at the expense of the number of replicate hiPSC clones.

Stimulant Drug Treatment in Childhood-Onset Schizophrenia with Comorbid ADHD: An Open-Label Case Series

Journal of Child and Adolescent Psychopharmacology, Sep 1, 2004

The administration of psychostimulants to children with psychotic symptoms is controversial. This... more The administration of psychostimulants to children with psychotic symptoms is controversial. This study reports the stimulant drug response of 5 children, aged 8-15 years, with childhood-onset schizophrenia (COS) and comorbid attention deficit hyperactivity disorder (ADHD). Four COS inpatients were given stimulants for comorbid ADHD after stabilization of psychosis on antipsychotic medication. A fifth COS inpatient received stimulants while still actively psychotic, despite concurrent neuroleptic treatment. Data from the 10-item Brief Conners Teachers Ratings Scale (BCTRS) were examined the week before, and the week after, stimulant addition. A paired t test, conducted using Conners Teachers data from these 4 subjects, indicated significant improvement in ADHD symptoms (p = 0.02). Data obtained from a retrospective chart review indicated no significant worsening of psychosis. The 2 subjects treated with mixed salts of dextroamphetamine sulfate and amphetamine sulfate remained on that medication at 6 months and at the 2-year follow-up. Our results suggest that ADHD comorbid with COS may be safely treated with a stimulant, once the psychosis is stabilized. A systematic investigation of this question may be warranted.

Transcriptional Signatures of Childhood Onset Schizophrenia in Hipsc-Derived NPCS and Neurons Are Concordant with Signatures from Post Mortem Adult Brains

European Neuropsychopharmacology, 2019

value lower than 0.05 after a Bonferroni correction for multiple comparisons and differentially m... more value lower than 0.05 after a Bonferroni correction for multiple comparisons and differentially methylated regions (DMRs) with at least two significant DMPs (FDR) within a 500 bp region. Results: We found 5 DMRs and 16 DMPs comparing controls and FEP, and 14 DMRs and 77 DMPs between FEP before and after treatment. Discussion: To our knowledge, this is the first study to find DMRs in a longitudinal cohort of antipsychotic naïve FEP patients. Collectively, DMRs in the longitudinal comparison seem to be related to the adverse effects and the response to risperidone. Notably, the most associated genomic region in schizophrenia (previously reported by the PGC), the MHC region, is differentially methylated in patients after the treatment, demonstrating an epigenetic modification caused by risperidone in an important schizophrenia genomic region. Identifying the genetic and molecular changes of drug response is one of the first steps through personalized medicine, further studies should replicate these results and aim antipsychotic naive individuals treated with other antipsychotics.

Attenuated resting-state functional connectivity in patients with childhood- and adult-onset schizophrenia, not in their siblings

F1000Research, May 23, 2016

Background: Childhood-onset schizophrenia (COS) is a rare, severe form of the adult-onset disorde... more Background: Childhood-onset schizophrenia (COS) is a rare, severe form of the adult-onset disorder (AOS). Our previous resting-state fMRI study identified attenuated functional connectivity in COS compared with controls. Here, we ask whether COS and AOS patients and their siblings exhibit similar abnormalities of functional connectivity. Methods: A whole-brain, data-driven approach was used to assess resting-state functional connectivity differences in COS (patients/siblings/controls, n: 26/28/33) and AOS (n: 19/28/30). There were no significant differences in age, sex, or head motion across groups in each dataset and as designed, the COS dataset has a significantly lower age than the AOS. Results: Both COS and AOS patients showed decreased functional connectivity relative to controls among a wide set of brain regions (P b 0.05, corrected), but their siblings did not. Decreased connectivity in COS and AOS patients showed no amplitude differences and was not modulated by age-at-onset or medication doses. Cluster analysis revealed that these regions fell into two large-scale networks: one sensorimotor network and one centered on defaultmode network regions, but including higher-order cognitive areas only in COS. Decreased connectivity between these two networks was notable (P b 0.05, corrected) for both patient groups. Conclusions: A shared pattern of attenuated functional connectivity was found in COS and AOS, supporting the continuity of childhood-onset and adult-onset schizophrenia. Connections were altered between sensorimotor areas and default-mode areas in both COS and AOS, suggesting potential abnormalities in processes of self-monitoring and sensory prediction. The absence of substantial dysconnectivity in siblings indicates that attenuation is staterelated.

494. A longitudinal MRI study of children and adolescents with atypical psychotic disorders

Biological Psychiatry, Apr 1, 2000

We have previously reported that pediatric OCD patients performed comparably to healthy controls ... more We have previously reported that pediatric OCD patients performed comparably to healthy controls on neuropsychological testing. In fact, OCD patients appeared to actually perform better than controls on an oculomotor delayed response task. The Digit Span subtest of the Weschler Intelligence Scale for Children-Revised, is believed to be associated with striatal circuit functioning, a circuit directly implicated in the pathophysiology of OCD, and may also assess delayed response. Digit Span tests were administered to 40 treatment-naïve pediatric OCD patients (19 males, 21 females) and 29 controls (12 males, 17 females). Scores for Digit Span Forward (repetition of numbers) and Backward (reversal of numbers) were recorded separately; the combined score was recorded as a percentile score. Children with OCD performed significantly better than controls on Digit Span testing, measured as an overall percentile (67.11 Ϯ 31.6 vs. 47.38 Ϯ 33.4, p ϭ 0.015). Female OCD patients did significantly better than female controls on the percentile score (74.93 Ϯ 28.7 vs. 43.64 Ϯ 34.0, p ϭ 0.004), while no significant difference was noted between male OCD patients vs. male controls. In contrast, male OCD patients performed significantly worse than male controls on the Digit Span Forward score only (9.21 Ϯ 2.0 vs. 11.07 Ϯ 1.8, p ϭ 0.007), but not on the Digit Span Backward score. Our results suggest that female OCD patients may perform better on Digit Span testing of delayed response, while males may actually perform worse on the more repetitive Forward component of the Digit Span test. The potential implications of this will be discussed in the poster.

41. Familial schizophrenia spectrum disorders in childhood-and adult-onset schizophrenia

Biological Psychiatry, Apr 1, 2000

using a measure adopted from studies of parkinsonian bradykinesia. There is a general consensus t... more using a measure adopted from studies of parkinsonian bradykinesia. There is a general consensus that parkinsonian bradykinesia stems from an inability to modify, or scale, velocity during movement. In the present study, we hypothesized that a substantial proportion of MD patients would exhibit deficits in velocity scaling. Our measure of velocity scaling quantifies the extent to which a subject programs or scales movement velocity in anticipation of increasing target distance. We studied 54 patients who met DSM-IV criteria for major depression and 26 age and gender comparable healthy comparison subjects. All MD patients were unmedicated at the time of testing. An instrumental measure of wrist movement was developed to quantify several aspects of movement including reaction time (RT), peak velocity (PV), and velocity scaling (VS). Subjects were instructed to flex their wrist when a target box appeared on the computer screen and to reach the target as quickly and as accurately as possible. Results indicated that MD patients exhibited significantly (p Ͻ 0.001) longer mean RT (477 ms) than comparison subjects (391 ms). There was a trend (p ϭ 0.07) for MD patients to have lower scores on the VS measure (2.68 deg/sec/deg) compared with comparison subjects (3.33 d/s/d). 53.7% of the MD patients had VS scores lower than the 95th percentile of the comparison subjects. These findings suggest that MD patients as a group exhibit delayed reaction times. Nevertheless, a significant proportion of MD patients also exhibit disturbances in the programming of movement velocity reflective of a putative dopaminergic disturbance, similar to that seen in parkinsonism.

Hippocampal volume change relates to clinical outcome in childhood-onset schizophrenia

Psychological Medicine, May 4, 2015

Background. Fixed hippocampal volume reductions and shape abnormalities are established findings ... more Background. Fixed hippocampal volume reductions and shape abnormalities are established findings in schizophrenia, but the relationship between hippocampal volume change and clinical outcome has been relatively unexplored in schizophrenia and other psychotic disorders. In light of recent findings correlating hippocampal volume change and clinical outcome in first-episode psychotic adults, we hypothesized that fewer decreases in hippocampal volume would be associated with better functional outcome and fewer psychotic symptoms in our rare and chronically ill population of childhood-onset schizophrenia (COS) patients. Method. We prospectively obtained 114 structural brain magnetic resonance images (MRIs) from 27 COS subjects, each with three or more scans between the ages of 10 and 30 years. Change in hippocampal volume, measured by fit slope and percentage change, was regressed against clinical ratings (Children's Global Assessment Scale, Scale for the Assessment of Positive Symptoms, Scale for the Assessment of Negative Symptoms) at last scan (controlling for sex, time between scans and total intracranial volume). Results. Fewer negative symptoms were associated with less hippocampal volume decrease (fit slope: p = 0.0003, and percentage change: p = 0.005) while positive symptoms were not related to hippocampal change. There was also a relationship between improved clinical global functioning and maintained hippocampal volumes (fit slope: p = 0.025, and percentage change: p = 0.043). Conclusions. These results suggest that abnormal hippocampal development in schizophrenia can be linked to global functioning and negative symptoms. The hippocampus can be considered a potential treatment target for future therapies.

Risk Factors for Neutropenia in Clozapine-Treated Children and Adolescents with Childhood-Onset Schizophrenia

Journal of Child and Adolescent Psychopharmacology, Mar 1, 2013

Objective: The purpose of this study was to retrospectively analyze rates of neutropenia and risk... more Objective: The purpose of this study was to retrospectively analyze rates of neutropenia and risk factors for neutropenia in hospitalized children and adolescents treated with clozapine. Methods: A retrospective chart review was conducted for all patients who received clozapine at any time during a hospitalization at the National Institute of Mental Health (NIMH) between 1990 and 2011. All patients satisfied screening criteria for the NIMH childhood-onset schizophrenia study, including onset of psychosis before the age of 13 years. Absolute neutrophil count (ANC) values recorded during inpatient hospitalization were extracted for 87 eligible patients with a mean age of 13.35-2.46 years at hospitalization and a mean length of stay of 117-43 days. Results: Mild neutropenia only (lowest ANC < 2000/mm 3 but >1500/mm 3) was observed in 27 (31%) patients and moderate neutropenia (any ANC < 1500/mm 3) was observed in 17 (20%) patients. There were no cases of agranulocytosis or severe infection. Significant risk factors for mild neutropenia compared with no hematologic adverse effects (HAEs) were male gender (p = 0.012) and younger age (p < 0.001). Male gender was also a significant risk factor for moderate neutropenia compared with no HAEs (p = 0.003). If a child of African American ethnicity developed neutropenia during hospitalization at all that child was significantly more likely to develop moderate neutropenia than mild neutropenia only (p = 0.017). African American boys had the highest rate of moderate neutropenia at 47%. Sixteen of the 17 patients exhibiting moderate neutropenia were successfully treated with clozapine by the time of discharge; 8 of these 16 required adjunctive lithium carbonate administration to maintain ANC > 2000/mm 3. Conclusions: Our study shows that the rates of neutropenia in clozapine-treated children and adolescents are considerably higher than in the adult population. Younger age, African American ethnicity, and male gender were significant risk factors. These are also risk factors for benign neutropenia in healthy children and adolescents. Despite these high rates of neutropenia, all but one of the patients with neutropenia during hospitalization were successfully discharged on clozapine.

Childhood onset schizophrenia: familial neurocognitive measures

Schizophrenia Research, Nov 1, 2004

Objective: Early onset disorders may have more salient familial/genetic etiology. Neurocognitive ... more Objective: Early onset disorders may have more salient familial/genetic etiology. Neurocognitive deficits which are seen in families of adult onset schizophrenic patients were examined in healthy family members of patients with childhood-onset schizophrenia (COS). Methods: Trail Making Tests (TMT) A and B, Wechsler Intelligence Scale-Revised Digit Span and Vocabulary subtests were administered to 67 parents and 24 siblings of patients with childhood-onset schizophrenia and 114 healthy community controls (CC) comparable in sex, age, and educational level. Results: COS siblings performed significantly more poorly than did controls on Trails Making Test B with a trend for poorer performance evident on Trails Making Test A. COS parents performed more poorly than controls only on Trails Making Test A. Conclusions: Healthy first-degree relatives of COS probands have subtle deficits in tests involving oculomotor/psychomotor speed, working memory and executive function. This provides further support for continuity between COS and later onset schizophrenia and for a familial/genetic factor associated with the illness.

High rate of disease-related copy number variations in childhood onset schizophrenia

Molecular Psychiatry, May 21, 2013

Copy number variants (CNVs) are risk factors in neurodevelopmental disorders, including autism, e... more Copy number variants (CNVs) are risk factors in neurodevelopmental disorders, including autism, epilepsy, intellectual disability (ID) and schizophrenia. Childhood onset schizophrenia (COS), defined as onset before the age of 13 years, is a rare and severe form of the disorder, with more striking array of prepsychotic developmental disorders and abnormalities in brain development. Because of the well-known phenotypic variability associated with pathogenic CNVs, we conducted whole genome genotyping to detect CNVs and then focused on a group of 46 rare CNVs that had well-documented risk for adult onset schizophrenia (AOS), autism, epilepsy and/or ID. We evaluated 126 COS probands, 69 of which also had a healthy full sibling. When COS probands were compared with their matched related controls, significantly more affected individuals carried disease-related CNVs (P ¼ 0.017). Moreover, COS probands showed a higher rate than that found in AOS probands (Po0.0001). A total of 15 (11.9%) subjects exhibited at least one such CNV and four of these subjects (26.7%) had two. Five of 15 (4.0% of the sample) had a 2.5-3 Mb deletion mapping to 22q11.2, a rate higher than that reported for adult onset (0.3-1%) (Po0.001) or autism spectrum disorder and, indeed, the highest rate reported for any clinical population to date. For one COS subject, a duplication found at 22q13.3 had previously only been associated with autism, and for four patients CNVs at 8q11.2, 10q22.3, 16p11.2 and 17q21.3 had only previously been associated with ID. Taken together, these findings support the well-known pleiotropic effects of these CNVs suggesting shared abnormalities early in brain development. Clinically, broad CNV-based population screening is needed to assess their overall clinical burden.

Predictors of two-year follow-up in children and adolescents with schizophrenia

Schizophrenia Research, Mar 1, 2003

GAD1 (2q31.1), which encodes glutamic acid decarboxylase (GAD67), is associated with childhood-onset schizophrenia and cortical gray matter volume loss

Molecular Psychiatry, 2004

Postmortem brain studies have shown deficits in the cortical c-aminobutyric acid (GABA) system in... more Postmortem brain studies have shown deficits in the cortical c-aminobutyric acid (GABA) system in schizophrenic individuals. Expression studies have shown a decrease in the major GABA-synthesizing enzyme (glutamic acid decarboxylase (GAD 67) mRNA levels in neurons in dorsolateral prefrontal cortex in schizophrenics relative to controls. In the present study, SNPs in and around the GAD1 gene, which encodes the protein GAD 67 , were tested on a rare, severely ill group of children and adolescents with childhood-onset schizophrenia (COS) (n ¼ 72), in a family-based association analysis. Compared to adult-onset samples, the COS sample has evidence for more salient familial, and perhaps genetic, risk factors for schizophrenia, as well as evidence for frontal cortical hypofunction, and greater decline in cortical gray matter volume on anatomic brain MRI scans during adolescence. We performed family-based TDT and haplotype association analyses of the clinical phenotype, as well as association analyses with endophenotypes using the QTDT program. Three adjacent SNPs in the 5 0 upstream region of GAD1 showed a positive pairwise association with illness in these families (P ¼ 0.022-0.057). Significant transmission distortion of 4-SNP haplotypes was also observed (P ¼ 0.003-0.008). Quantitative trait TDT analyses showed an intriguing association between several SNPs and increased rate of frontal gray matter loss. These observations, when taken together with the positive results reported recently in two independent adult-onset schizophrenia pedigree samples, suggest that the gene encoding GAD 67 may be a common risk factor for schizophrenia.

High rate of disease-related copy number variations in childhood onset schizophrenia

Molecular Psychiatry, 2013

Copy number variants (CNVs) are risk factors in neurodevelopmental disorders, including autism, e... more Copy number variants (CNVs) are risk factors in neurodevelopmental disorders, including autism, epilepsy, intellectual disability (ID) and schizophrenia. Childhood onset schizophrenia (COS), defined as onset before the age of 13 years, is a rare and severe form of the disorder, with more striking array of prepsychotic developmental disorders and abnormalities in brain development. Because of the well-known phenotypic variability associated with pathogenic CNVs, we conducted whole genome genotyping to detect CNVs and then focused on a group of 46 rare CNVs that had well-documented risk for adult onset schizophrenia (AOS), autism, epilepsy and/or ID. We evaluated 126 COS probands, 69 of which also had a healthy full sibling. When COS probands were compared with their matched related controls, significantly more affected individuals carried disease-related CNVs (P ¼ 0.017). Moreover, COS probands showed a higher rate than that found in AOS probands (Po0.0001). A total of 15 (11.9%) subjects exhibited at least one such CNV and four of these subjects (26.7%) had two. Five of 15 (4.0% of the sample) had a 2.5-3 Mb deletion mapping to 22q11.2, a rate higher than that reported for adult onset (0.3-1%) (Po0.001) or autism spectrum disorder and, indeed, the highest rate reported for any clinical population to date. For one COS subject, a duplication found at 22q13.3 had previously only been associated with autism, and for four patients CNVs at 8q11.2, 10q22.3, 16p11.2 and 17q21.3 had only previously been associated with ID. Taken together, these findings support the well-known pleiotropic effects of these CNVs suggesting shared abnormalities early in brain development. Clinically, broad CNV-based population screening is needed to assess their overall clinical burden.