Common polygenic variation and risk for childhood-onset schizophrenia.

Childhood-onset schizophrenia (COS) is a rare and severe form of the disorder, with more striking abnormalities with respect to prepsychotic developmental disorders and abnormities in the brain development compared with later-onset schizophrenia. We previously documented that COS patients, compared with their healthy siblings and with adult-onset patients (AOS), carry significantly more rare chromosomal copy number variations, spanning large genomic regions (>100 kb) (Ahn et al. 2014). Here, we interrogated the contribution of common polygenic variation to the genetic susceptibility for schizophrenia. We examined the association between a direct measure of genetic risk of schizophrenia in 130 COS probands and 103 healthy siblings. Using data from the schizophrenia and autism GWAS of the Psychiatric Genomic Consortia, we selected three risk-related sets of single nucleotide polymorphisms from which we conducted polygenic risk score comparisons for COS probands and their healthy siblings. COS probands had higher genetic risk scores of both schizophrenia and autism than their siblings (P<0.05). Given the small sample size, these findings suggest that COS patients have more salient genetic risk than do AOS.

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

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.

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

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=0.017). Moreover, COS probands showed a higher rate than that found in AOS probands (P<0.0001). 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%) (P<0.001) 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.

Neurodevelopmental model of schizophrenia: update 2012.

The neurodevelopmental model of schizophrenia, which posits that the illness is the end state of abnormal neurodevelopmental processes that started years before the illness onset, is widely accepted, and has long been dominant for childhood-onset neuropsychiatric disorders. This selective review updates our 2005 review of recent studies that have impacted, or have the greatest potential to modify or extend, the neurodevelopmental model of schizophrenia. Longitudinal whole-population studies support a dimensional, rather than categorical, concept of psychosis. New studies suggest that placental pathology could be a key measure in future prenatal high-risk studies. Both common and rare genetic variants have proved surprisingly diagnostically nonspecific, and copy number variants (CNVs) associated with schizophrenia are often also associated with autism, epilepsy and intellectual deficiency. Large post-mortem gene expression studies and prospective developmental multi-modal brain imaging studies are providing critical data for future clinical and high-risk developmental brain studies. Whether there can be greater molecular specificity for phenotypic characterization is a subject of current intense study and debate, as is the possibility of neuronal phenotyping using human pluripotent-inducible stem cells. Biological nonspecificity, such as in timing or nature of early brain development, carries the possibility of new targets for broad preventive treatments.

Transcriptome profiling of UPF3B/NMD-deficient lymphoblastoid cells from patients with various forms of intellectual disability.

The nonsense-mediated mRNA decay (NMD) pathway was originally discovered by virtue of its ability to rapidly degrade aberrant mRNAs with premature termination codons. More recently, it was shown that NMD also directly regulates subsets of normal transcripts, suggesting that NMD has roles in normal biological processes. Indeed, several NMD factors have been shown to regulate neurological events (for example, neurogenesis and synaptic plasticity) in numerous vertebrate species. In man, mutations in the NMD factor gene UPF3B, which disrupts a branch of the NMD pathway, cause various forms of intellectual disability (ID). Using Epstein Barr virus-immortalized B cells, also known as lymphoblastoid cell lines (LCLs), from ID patients that have loss-of-function mutations in UPF3B, we investigated the genome-wide consequences of compromised NMD and the role of NMD in neuronal development and function. We found that ~5% of the human transcriptome is impacted in UPF3B patients. The UPF3B paralog, UPF3A, is stabilized in all UPF3B patients, and partially compensates for the loss of UPF3B function. Interestingly, UPF3A protein, but not mRNA, was stabilised in a quantitative manner that inversely correlated with the severity of patients' phenotype. This suggested that the ability to stabilize the UPF3A protein is a crucial modifier of the neurological symptoms due to loss of UPF3B. We also identified ARHGAP24, which encodes a GTPase-activating protein, as a canonical target of NMD, and we provide evidence that deregulation of this gene inhibits axon and dendrite outgrowth and branching. Our results demonstrate that the UPF3B-dependent NMD pathway is a major regulator of the transcriptome and that its targets have important roles in neuronal cells.

Common functional polymorphisms of DISC1 and cortical maturation in typically developing children and adolescents.

Disrupted-in-schizophrenia-1 (DISC1), contains two common non-synonymous single-nucleotide polymorphisms (SNPs)--Leu607Phe and Ser704Cys--that modulate (i) facets of DISC1 molecular functioning important for cortical development, (ii) fronto-temporal cortical anatomy in adults and (iii) risk for diverse psychiatric phenotypes that often emerge during childhood and adolescence, and are associated with altered fronto-temporal cortical development. It remains unknown, however, if Leu607Phe and Ser704Cys influence cortical maturation before adulthood, and whether each SNP shows unique or overlapping effects. Therefore, we related genotype at Leu607Phe and Ser704Cys to cortical thickness (CT) in 255 typically developing individuals aged 9-22 years on whom 598 magnetic resonance imaging brain scans had been acquired longitudinally. Rate of cortical thinning varied with DISC1 genotype. Specifically, the rate of cortical thinning was attenuated in Phe-carrier compared with Leu-homozygous groups (in bilateral superior frontal and left angular gyri) and accelerated in Ser-homozygous compared with Cys-carrier groups (in left anterior cingulate and temporal cortices). Both SNPs additively predicted fixed differences in right lateral temporal CT, which were maximal between Phe-carrier/Ser-homozygous (thinnest) vs Leu-homozygous/Cys-carrier (thickest) groups. Leu607Phe and Ser704Cys genotype interacted to predict the rate of cortical thinning in right orbitofrontal, middle temporal and superior parietal cortices, wherein a significantly reduced rate of CT loss was observed in Phe-carrier/Cys-carrier participants only. Our findings argue for further examination of Leu607Phe and Ser704Cys interactions at a molecular level, and suggest that these SNPs might operate (in concert with other genetic and environmental factors) to shape risk for diverse phenotypes by impacting on the early maturation of fronto-temporal cortices.

Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia.

Autism spectrum disorder (ASD) and schizophrenia (SCZ) are two common neurodevelopmental syndromes that result from the combined effects of environmental and genetic factors. We set out to test the hypothesis that rare variants in many different genes, including de novo variants, could predispose to these conditions in a fraction of cases. In addition, for both disorders, males are either more significantly or more severely affected than females, which may be explained in part by X-linked genetic factors. Therefore, we directly sequenced 111 X-linked synaptic genes in individuals with ASD (n = 142; 122 males and 20 females) or SCZ (n = 143; 95 males and 48 females). We identified >200 non-synonymous variants, with an excess of rare damaging variants, which suggest the presence of disease-causing mutations. Truncating mutations in genes encoding the calcium-related protein IL1RAPL1 (already described in Piton et al. Hum Mol Genet 2008) and the monoamine degradation enzyme monoamine oxidase B were found in ASD and SCZ, respectively. Moreover, several promising non-synonymous rare variants were identified in genes encoding proteins involved in regulation of neurite outgrowth and other various synaptic functions (MECP2, TM4SF2/TSPAN7, PPP1R3F, PSMD10, MCF2, SLITRK2, GPRASP2, and OPHN1).

Attention-deficit/hyperactivity disorder is characterized by a delay in cortical maturation.

There is controversy over the nature of the disturbance in brain development that underpins attention-deficit/hyperactivity disorder (ADHD). In particular, it is unclear whether the disorder results from a delay in brain maturation or whether it represents a complete deviation from the template of typical development. Using computational neuroanatomic techniques, we estimated cortical thickness at >40,000 cerebral points from 824 magnetic resonance scans acquired prospectively on 223 children with ADHD and 223 typically developing controls. With this sample size, we could define the growth trajectory of each cortical point, delineating a phase of childhood increase followed by adolescent decrease in cortical thickness (a quadratic growth model). From these trajectories, the age of attaining peak cortical thickness was derived and used as an index of cortical maturation. We found maturation to progress in a similar manner regionally in both children with and without ADHD, with primary sensory areas attaining peak cortical thickness before polymodal, high-order association areas. However, there was a marked delay in ADHD in attaining peak thickness throughout most of the cerebrum: the median age by which 50% of the cortical points attained peak thickness for this group was 10.5 years (SE 0.01), which was significantly later than the median age of 7.5 years (SE 0.02) for typically developing controls (log rank test chi(1)(2) = 5,609, P < 1.0 x 10(-20)). The delay was most prominent in prefrontal regions important for control of cognitive processes including attention and motor planning. Neuroanatomic documentation of a delay in regional cortical maturation in ADHD has not been previously reported.

Dextroamphetamine: cognitive and behavioral effects in normal prepubertal boys.

The behavioral, cognitive, and electrophysiological effect of a single dose of dextroamphetamine (0.5 milligram per kilogram of body weight) or placebo was examined in 14 normal prepubertal boys (mean age, 10 years 11 months) in a double-blind study. When amphetamine was given, the group showed a marked decrease in motor activity and reaction time and improved performance on cognitive tests. The similarity of the response observed in normal children to that reported in children with "hyperactivity" or minimal brain dysfunction casts doubt on pathophysiological models of minimal brain dysfunction which assume that children with this syndrome have a clinically specific or "paradoxical" response to stimulants.

Structural maturation of neural pathways in children and adolescents: in vivo study.

Structural maturation of fiber tracts in the human brain, including an increase in the diameter and myelination of axons, may play a role in cognitive development during childhood and adolescence. A computational analysis of structural magnetic resonance images obtained in 111 children and adolescents revealed age-related increases in white matter density in fiber tracts constituting putative corticospinal and frontotemporal pathways. The maturation of the corticospinal tract was bilateral, whereas that of the frontotemporal pathway was found predominantly in the left (speech-dominant) hemisphere. These findings provide evidence for a gradual maturation, during late childhood and adolescence, of fiber pathways presumably supporting motor and speech functions.

Segmental uniparental isodisomy on 5q32-qter in a patient with childhood-onset schizophrenia.

Schizophrenia is a severe mental disorder affecting approximately 1% of the world's population. Although the aetiology of schizophrenia is complex and multifactorial, with estimated heritabilities as high as 80%, genetic factors are the most compelling. Childhood-onset schizophrenia (COS), defined as onset of schizophrenia before the age of 13 years, is a rare and malignant form of the illness that may have more salient genetic influence. The first known case of paternal segmental uniparental isodisomy (iUPD) on 5q32-qter in a patient with COS is described, which adds to the previously known high rates of chromosomal abnormalities reported in this sample. iUPD is a rare genetic condition in which the offspring receives two chromosomal homologues from one parent. Segmental UPD is defined as UPD on a portion of a chromosome with biparental inheritance seen in the rest of the homologous pair. Complications owing to this abnormality may arise from malfunctioning imprinted genes or homozygosity of recessive disease-causing mutations. This aberration became apparent during whole-genomic screening of a COS cohort and is of particular interest because 5q has been implicated in schizophrenia by several genomewide linkage studies and positive gene associations. This report, therefore, presents more evidence that schizophrenia susceptibility gene, or genes, may be found on distal 5q.

Drug treatment of canine acral lick. An animal model of obsessive-compulsive disorder.

Canine acral lick dermatitis is a naturally occurring disorder in which excessive licking of paws or flank can produce ulcers and infection that require medical treatment. Forty-two dogs with severe chronic canine acral lick dermatitis were treated in three double-blind crossover comparisons of clomipramine hydrochloride/desipramine hydrochloride, fluoxetine hydrochloride/fenfluramine hydrochloride, and sertraline hydrochloride/placebo. The serotonin uptake blocking drugs were clinically effective, while the other drugs were not. Based on phenomenology and pharmacological response, we propose canine acral lick dermatitis as an animal model of obsessive-compulsive disorder.

Thought, language, communication, and affective flattening in autistic adults.

Subtypes of thought disorder and affective flattening were examined in 14 adults with clear DSM-III diagnoses of infantile autism or autism, residual state, using videotaped psychiatric interviews and objective rating scales. Schizophrenic, manic, and normal subjects constituted contrast groups. Autistic adults, most of whom were high functioning, showed a high incidence and severity of poverty of speech, poverty of content of speech, perseveration, and affective flattening. They showed significantly less derailment, illogicality, and other features of "positive thought disorder" than either the schizophrenic or manic group, but they did not differ from schizophrenics on any affective flattening variable.

Behavioral effects of caffeine in children. Relationship between dietary choice and effects of caffeine challenge.

From a survey of 24-hour caffeine intake of 798 grade-school children (mean age, 10.3 years), 19 "high consumers" (reported intake of 500 mg/day or more) and a matched group of 19 "low consumers" were recruited for a double-blind, placebo-controlled, caffeine challenge study. Children received 5 mg/kg of caffeine twice a day or placebo for two weeks each, using a crossover design. While not receiving caffeine, high consumers had higher scores on an anxiety questionnaire and tended to have lower autonomic arousal (less frequent spontaneous skin conductance response and lower skin conductance level). While receiving caffeine, low consumers were perceived by their parents as more emotional, inattentive, and restless, while high consumers were not rated as changed. These differences cannot be attributed to tolerance, withdrawal, or subject selection, and suggest a possible physiological basis in children for dietary caffeine preference.

Fenfluramine and dextroamphetamine treatment of childhood hyperactivity. Clinical and biochemical findings.

Twenty boys (mean age, 9 +/- 2 years) with attention deficit disorder with hyperactivity received three weeks each of dextroamphetamine sulfate (0.5 mg/kg/d), fenfluramine hydrochloride (0.6 mg/kg/d increased to 2.0 mg/kg/d), and placebo in a double-blind, random-order, crossover design. Half the boys also met criteria for conduct disorder. Dextroamphetamine produced immediate and marked improvement in disruptive, overactive behaviors. Fenfluramine had no effect on any behavioral measure at either the low or high dosage. Both drugs decreased levels of urinary norepinephrine, 3-methoxy-4-hydroxyphenylglycol (MHPG), and vanillylmandelic acid. Fenfluramine, however, also produced a significant decrease in plasma MHPG levels and a larger decrease in urinary norepinephrine levels. It reduced urinary epinephrine levels as well, an effect opposite to that of dextroamphetamine. These findings suggest that different mechanisms of action are involved in the ability of the two drugs to reduce levels of MHPG and vanillylmandelic acid. Fenfluramine increased plasma prolactin levels and decreased platelet serotonin levels. Despite the structural similarity of the two drugs, some common overall effects on catecholamine metabolism, and similar effects on weight, fenfluramine had none of the motor activity or therapeutic effects of dextroamphetamine.

Treatment of hyperactive children with monoamine oxidase inhibitors. I. Clinical efficacy.

Fourteen boys (mean age, 9.2 +/- 1.5 years) with Attention Deficit Disorder (ADD) With Hyperactivity were treated with dextroamphetamine sulfate or a monoamine oxidase inhibitor (MAOI) (six received clorgyline, eight received tranylcypromine sulfate) for four weeks each in a double-blind, cross-over study that included a two-week placebo washout between active drug periods. The MAOIs had immediate, clinically significant benefit and were clinically indistinguishable from dextroamphetamine. Most children responded to both stimulant and MAOI. These findings of equivalent efficacy of MAOIs in ADD are in contrast to our previous studies with neurotransmitter system selective agents, which showed only weak effects, and suggest that multiple neurotransmitter alterations may be required for stimulant drug effects in ADD. The immediate response to MAOIs indicates a different mechanism from that mediating antidepressant effect. The MAOIs may be useful alternate treatments in selected cases of ADD.

Clomipramine treatment of childhood obsessive-compulsive disorder. A double-blind controlled study.

Nineteen children (mean [+/- SD] age, 14.5 +/- 2.3 years) with severe, primary obsessive-compulsive disorder completed a ten-week, double-blind, controlled trial of clomipramine hydrochloride (mean dosage, 141 mg/day) or placebo, each of which was administered for five weeks. Half of the subjects had not responded to previous treatment with other tricyclic antidepressants. There was a significant improvement in observed and self-reported obsessions and compulsions that was independent of the presence of depressive symptoms at baseline. Improvement in obsessive-compulsive symptoms did not correlate significantly with plasma concentrations of the drug or its metabolites. Clomipramine appears to be effective in the treatment of children with obsessive-compulsive disorder and the treatment seems to be independent of an antidepressant effect.

A double-blind comparison of clomipramine, desipramine, and placebo in the treatment of autistic disorder.

OBJECTIVE: To determine whether clomipramine hydrochloride, a serotonin reuptake blocker with unique anti-obsessional properties, is differentially effective for obsessive-compulsive and stereotyped motor behaviors in autistic disorder compared with placebo and with the noradrenergic tricyclic antidepressant agent, desipramine hydrochloride. DESIGN: Following a 2-week, single-blind placebo washout phase, 12 autistic subjects completed a 10-week, double-blind, crossover comparison of clomipramine and placebo, and 12 different subjects completed a similar comparison of clomipramine and desipramine. SETTING: Outpatient clinic. PATIENTS: A referral sample of 30 male and female autistic patients were enrolled, and 24 completed the study. MEASURES: Key outcome measures were the Autism Relevant Subscale of the Children's Psychiatric Rating Scale, the Modified Comprehensive Psychopathological Rating Scale-Obsessive-Compulsive Disorder Subscale, and the Clinical Global Impressions Scale. RESULTS: Clomipramine was superior to both placebo and desipramine on ratings of autistic symptoms (including stereotypies), anger, and compulsive, ritualized behaviors (P < .05), with no differences between desipramine and placebo. Clomipramine was equal to desipramine and both tricyclic agents were superior to placebo for amelioration of hyperactivity. CONCLUSION: Biological links between compulsions and stereotyped, repetitive behaviors in autistic disorder should be explored.

A naturalistic assessment of the motor activity of hyperactive boys. I. Comparison with normal controls.

The motor activity of hyperactive and normal boys was studied in 12 age- and classroom-matched pairs. Activity was measured continuously for a one-week period with a portable solid-state monitor. Hyperactives exhibited generally higher levels of motor activity than normal controls regardless of the time of day, including during sleep and on weekends. In a situation-by-situation analysis, hyperactives were most consistently and significantly more active than the controls during structured school activities. Little evidence was found, however, to support the hypothesis that hyperactivity is simply an artifact of the structure and attentional demands of a given setting. Pervasive increases in simple motor behavior are a clear attribute of hyperactive behavior and distinguished hyperactives from controls as well as did a standardized measure of attention.