Sleep neurophysiology in childhood onset schizophrenia.

Altered sleep neurophysiology has consistently been reported in adult patients with schizophrenia. Converging evidence suggests that childhood onset schizophrenia (COS), a rare but severe form of schizophrenia, is continuous with adult onset schizophrenia. The aim of the current study was to characterize sleep neurophysiology in COS. An overnight sleep electroencephalogram (EEG) was recorded in 17 children and adolescents with COS (16 years ± 6.6) and 17 age and gender-matched controls. Non-rapid eye movement (NREM) and rapid eye movement (REM) sleep EEG power and coherence for the frequency bands delta (1.6-4.8 Hz), theta (5-8.4 Hz), alpha (8.6-11 Hz), beta 1 (16.4-20.2 Hz) and beta 2 (20.4-24.2 Hz) were compared between COS patients and controls. COS patients exhibited significant and widespread deficits in beta power during NREM and REM sleep. With regard to coherence, we found increases in COS patients across brain regions, frequency bands and sleep states. This study demonstrates the utility of the sleep EEG for studying vulnerable populations and its potential to aid diagnosis.

15q13.3 duplication in two patients with childhood-onset schizophrenia.

We report two cases of paternally inherited 15q13.3 duplications in carriers diagnosed with childhood-onset schizophrenia (COS), a rare neurodevelopmental disorder of proposed polygenic origin with onset in children before age 13. This study documents that the 15q13.3 deletion and duplication exhibit pathogenicity for COS, with both copy number variants (CNVs) sharing a disrupted CHRNA7 gene. CHRNA7 encodes the neuronal alpha7 nicotinic acetylcholine receptor (α7nAChR) and is a candidate gene that has been suggested as a pathophysiological process mediating adult-onset schizophrenia (AOS) and other neurodevelopmental disorders. These results support the incomplete penetrance and variable expressivity of this CNV and represent the first report of 15q13.3 duplication carriers exhibiting COS. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals, Inc.

Activity-Dependent Transcriptional Program in NGN2+ Neurons Enriched for Genetic Risk for Brain-Related Disorders.

BACKGROUND: Converging evidence from large-scale genetic and postmortem studies highlights the role of aberrant neurotransmission and genetic regulation in brain-related disorders. However, identifying neuronal activity-regulated transcriptional programs in the human brain and understanding how changes contribute to disease remain challenging. METHODS: To better understand how the activity-dependent regulome contributes to risk for brain-related disorders, we profiled the transcriptomic and epigenomic changes following neuronal depolarization in human induced pluripotent stem cell-derived glutamatergic neurons (NGN2) from 6 patients with schizophrenia and 5 control participants. RESULTS: Multiomic data integration associated global patterns of chromatin accessibility with gene expression and identified enhancer-promoter interactions in glutamatergic neurons. Within 1 hour of potassium chloride-induced depolarization, independent of diagnosis, glutamatergic neurons displayed substantial activity-dependent changes in the expression of genes regulating synaptic function. Depolarization-induced changes in the regulome revealed significant heritability enrichment for schizophrenia and Parkinson's disease, adding to mounting evidence that sequence variation within activation-dependent regulatory elements contributes to the genetic risk for brain-related disorders. Gene coexpression network analysis elucidated interactions among activity-dependent and disease-associated genes and pointed to a key driver (NAV3) that interacted with multiple genes involved in axon guidance. CONCLUSIONS: Overall, we demonstrated that deciphering the activity-dependent regulome in glutamatergic neurons reveals novel targets for advanced diagnosis and therapy.

Childhood-onset schizophrenia: the challenge of diagnosis.

During the past two decades, the Child Psychiatry Branch at the National Institute of Mental Health has conducted a longitudinal study (including long-term prospective follow-up) of childhood-onset schizophrenia, a rare form of the disorder. Critical to this research has been accurate diagnosis. Outpatient screening has accurately diagnosed 55% of the 121 childhood-onset schizophrenia patients in the study to date. However, inpatient observation including drug-free observation has proven crucial to ruling out 96 children with alternative diagnoses who had been provisionally admitted for inpatient study. Standardized clinical ratings from outpatient screening only predicted 62% of these nonschizophrenia patients. Historically, medication-free observation was standard clinical care for difficult and unusual patients; this should be employed when possible in similar situations.

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

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.

Neuronal impact of patient-specific aberrant NRXN1α splicing.

NRXN1 undergoes extensive alternative splicing, and non-recurrent heterozygous deletions in NRXN1 are strongly associated with neuropsychiatric disorders. We establish that human induced pluripotent stem cell (hiPSC)-derived neurons well represent the diversity of NRXN1α alternative splicing observed in the human brain, cataloguing 123 high-confidence in-frame human NRXN1α isoforms. Patient-derived NRXN1+/- hiPSC-neurons show a greater than twofold reduction in half of the wild-type NRXN1α isoforms and express dozens of novel isoforms from the mutant allele. Reduced neuronal activity in patient-derived NRXN1+/- hiPSC-neurons is ameliorated by overexpression of individual control isoforms in a genotype-dependent manner, whereas individual mutant isoforms decrease neuronal activity levels in control hiPSC-neurons. In a genotype-dependent manner, the phenotypic impact of patient-specific NRXN1+/- mutations can occur through a reduction in wild-type NRXN1α isoform levels as well as the presence of mutant NRXN1α isoforms.

Symptom dimensions and subgroups in childhood-onset schizophrenia.

OBJECTIVE: This study investigated symptom dimensions and subgroups in the National Institute of Mental Health (NIMH) childhood-onset schizophrenia (COS) cohort and their similarities to adult-onset schizophrenia (AOS) literature. METHOD: Scores from the Scales for the Assessment of Positive and Negative Symptoms (SAPS & SANS) from 125 COS patients were assessed for fit with previously established symptom dimensions from AOS literature using confirmatory factor analysis (CFA). K-means cluster analysis of each individual's scores on the best fitting set of dimensions was used to form patient clusters, which were then compared using demographic and clinical data. RESULTS: CFA showed the SAPS & SANS data was well suited to a 2-dimension solution, including positive and negative dimensions, out of five well established models. Cluster analysis identified three patient groups characterized by different dimension scores: (1) low scores on both dimensions, (2) high negative, low positive scores, and (3) high scores on both dimensions. These groups had different Full scale IQ, Children's Global Assessment Scale (CGAS) scores, ages of onset, and prevalence of some co-morbid behavior disorders (all p<3.57E-03). CONCLUSION: Our analysis found distinct symptom-based subgroups within the NIMH COS cohort using an established AOS symptom structure. These findings confirm the heterogeneity of COS and were generally consistent with AOS literature.

Reduced Functional Brain Activation and Connectivity During a Working Memory Task in Childhood-Onset Schizophrenia.

OBJECTIVE: Working memory (WM) deficits are consistently reported in schizophrenia and are related to poor functional outcomes. Functional magnetic resonance imaging studies of adult-onset schizophrenia have reported decreased functional activations and connectivity in the WM network, but no prior functional magnetic resonance imaging study has examined WM in childhood-onset schizophrenia (COS). The aim of this study was to examine the neural correlates of WM in COS. METHOD: Adult patients with COS (n = 32, 21.3 ± 1.1 years), nonpsychotic siblings of patients with COS (n = 30, 19.4 ± 0.8 years), and healthy controls (n = 39, 20.0 ± 0.7 years) completed 1- and 2-back WM tasks during 3-T functional magnetic resonance imaging. Functional activation and connectivity analyses were conducted. A separate group of 23 younger patients with COS (17.9 ± 7.4 years) could not perform the tasks after twice completing a standard training and are not included in this report. RESULTS: Patients with COS who were included scored significantly lower than controls on all tasks (p < .001). Patients with COS showed significantly lower activations in the dorsolateral prefrontal cortices, posterior parietal cortices, cerebellum, and caudate and decreased frontoparietal and corticostriatal functional connectivity compared with controls (p < .05, corrected). Siblings had functional activations and connectivity intermediate between those of patients and controls in a similar set of regions (p < .05, corrected). In patients, functional connectivity strength in the left frontoparietal network correlated positively with accuracy scores during the 1-back task (p = .0023, corrected). CONCLUSION: Decreased functional activation and connectivity in the WM network in COS supports pathophysiologic continuity with adult-onset schizophrenia. The low participation rate and accuracy of the patients highlights the disease severity of COS. Hypo-activations and hypo-connectivity were shared by siblings of patients with COS, suggesting COS as a potential endophenotype. CLINICAL TRIAL REGISTRATION INFORMATION: Evaluating Genetic Risk Factors for Childhood-Onset Schizophrenia; http://ClinicalTrials.gov;NCT00001198.

Attenuated resting-state functional connectivity in patients with childhood- and adult-onset schizophrenia.

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<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 default-mode network regions, but including higher-order cognitive areas only in COS. Decreased connectivity between these two networks was notable (P<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 state-related.

Clozapine treatment of childhood-onset schizophrenia: evaluation of effectiveness, adverse effects, and long-term outcome.

OBJECTIVE: Clozapine is a unique atypical antipsychotic with superior efficacy in treatment-resistant schizophrenia. Plasma concentration of clozapine and its major metabolite N-desmethylclozapine (NDMC) as well as the ratio of NDMC to clozapine have been reported to be predictors of clozapine response. Here we evaluate these as well as other measures in an effort to find predictors of response to clozapine in our early-onset treatment-refractory population. METHOD: Fifty-four children and adolescents participated in double-blind (n = 22) or open-label (n = 32) clozapine trials. Clinical evaluations took place at baseline, week 6 on clozapine, and at 2- to 6-year follow-up. The data were analyzed in relation to demographics, age at onset, IQ, clozapine dose, and plasma concentrations of prolactin, clozapine, NDMC, and NDMC/clozapine ratio. Stepwise regression and correlation analyses were performed to find predictors of treatment response. RESULTS: Clinical improvement after 6 weeks of clozapine treatment, as measured by the percentage of improvement on the Brief Psychiatric Rating Scale and the Scale for the Assessment of Positive Symptoms, was strongly associated with the NDMC/clozapine ratio at the 6-week time point (Pearson correlation coefficient: r = 0.41; p < .01 for Brief Psychiatric Rating Scale and r = 0.43; p < .01 for Scale for the Assessment of Positive Symptoms). Although the rate of side effects was higher than that typically found in the adult population, it did not appear to be related to clozapine dose, clozapine or NDMC plasma concentrations, or NDMC/clozapine ratio. Outcome at long-term follow-up, as measured by Children's Global Assessment Scale, was associated with lesser illness severity at baseline and with greater improvement during the initial 6 weeks of clozapine treatment. CONCLUSIONS: The NDMC/clozapine ratio may be a valuable predictor of response to clozapine and may suggest new approaches to clozapine treatment.

Childhood-onset schizophrenia: A double-blind, randomized clozapine-olanzapine comparison.

BACKGROUND: Childhood-onset schizophrenia is a rare but severe form of the disorder that is frequently treatment resistant. The psychiatrist has a limited evidence base to guide treatment, particularly as there are no trials in children comparing atypical antipsychotics, the mainstay of current treatment. OBJECTIVE: To compare the efficacy and safety of olanzapine and clozapine, hypothesizing that clozapine would be more efficacious. DESIGN: Double-blind randomized 8-week controlled trial, with a 2-year open-label follow-up. SETTING: National Institute of Mental Health study, January 1998 to June 2005. Patients underwent reassessment 2 years after discharge. PATIENTS: Children and adolescents recruited nationally, aged 7 to 16 years, meeting unmodified DSM-IV criteria for schizophrenia, and resistant to treatment with at least 2 antipsychotics. INTERVENTIONS: After drug washout and a 1- to 3-week antipsychotic-free period, patients were randomized to treatment with clozapine (n = 12) or olanzapine (n = 13). MAIN OUTCOME MEASURES: The Clinical Global Impression Severity of Symptoms Scale and Schedule for the Assessment of Negative/Positive Symptoms. RESULTS: Clozapine was associated with a significant reduction in all outcome measures, whereas olanzapine showed a less consistent profile of clinical improvement. While there were moderate to large differential treatment effects in favor of clozapine, these reached significance only in the alleviation of negative symptoms from an antipsychotic-free baseline (P = .04; effect size, 0.89). Clozapine was associated with more overall adverse events. At 2-year follow-up, 15 patients were receiving clozapine with evidence of sustained clinical improvement, but additional adverse events emerged, including lipid anomalies (n = 6) and seizures (n = 1). CONCLUSIONS: While not demonstrating definitively the superiority of clozapine compared with olanzapine in treatment-refractory childhood-onset schizophrenia, the study suggests that clozapine has a more favorable profile of clinical response, which is balanced against more associated adverse events.

Dynamically spreading frontal and cingulate deficits mapped in adolescents with schizophrenia.

CONTEXT: We previously detected a dynamic wave of gray matter loss in childhood-onset schizophrenia that started in parietal association cortices and proceeded frontally to envelop dorsolateral prefrontal and temporal cortices, including superior temporal gyri. OBJECTIVE: To map gray matter loss rates across the medial hemispheric surface, including the cingulate and medial frontal cortex, in the same cohort studied previously. DESIGN: Five-year longitudinal study. SETTING: National Institute of Mental Health, Bethesda, Md. Subjects Twelve subjects with childhood-onset schizophrenia, 12 healthy controls, and 9 medication- and IQ-matched subjects with psychosis not otherwise specified. INTERVENTIONS: Three-dimensional magnetic resonance imaging at baseline and follow-up. MAIN OUTCOME MEASURES: Gyral pattern and shape variations encoded by means of high-dimensional elastic deformation mappings driving each subject's cortical anatomy onto a group average; changes in cortical gray matter mapped by computing warping fields that matched sulcal patterns across hemispheres, subjects, and time. RESULTS: Selective, severe frontal gray matter loss occurred bilaterally in a dorsal-to-ventral pattern across the medial hemispheric surfaces in the schizophrenic subjects. A sharp boundary in the pattern of gray matter loss separated frontal regions and cingulate-limbic areas. CONCLUSION: Frontal and limbic regions may not be equally vulnerable to gray matter attrition, which is consistent with the cognitive, metabolic, and functional vulnerability of the frontal cortices in schizophrenia.

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

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.

Sleep disturbances in childhood-onset schizophrenia.

Sleep disturbances in psychiatric disease have long been reported. However, research on sleep disturbances in child and adolescent psychiatric disorders is limited. We examined the relationship of sleep disturbance to clinical severity and co-morbid diagnoses (e.g. anxiety), for a population with childhood-onset schizophrenia (COS). Sixty-one COS patients underwent a medication-free inpatient observation period as part of an NIMH study of COS. Sleep quantity during the last 5-7 days of a patient's medication-free period was measured using safety records and daily nursing notes. Subjects were divided into two groups: "good sleepers" (>6 h) and "poor sleepers" (<6 h) based on the average of total hours slept per night. Comparisons between groups were made with respect to clinical ratings at both admission and during washout period, co-morbid diagnosis of generalized anxiety disorder (GAD) and a susceptibility gene (G72) for COS. The median average sleep score for the entire group was 6.1 (S.D.=2.01) h. The good and poor sleep groups differed significantly in terms of severity of positive symptoms (SAPS) and negative symptoms at admission (SANS) both on admission and during the medication-free period. There was no significant relationship between G72 genotypes and a past and/or present diagnosis of GAD. COS patients suffer from significant sleep disturbances and the sleep disturbance is highly related to the symptom severity. As there are numerous health implications of poor sleep, clinicians should have a low threshold for treating sleep disturbances in this population.

Strong Treatment Response and High Maintenance Rates of Clozapine in Childhood-Onset Schizophrenia.

OBJECTIVE: Childhood-onset schizophrenia (COS) is a rare but severe form of the disorder, which is often treatment refractory. Short-term studies have indicated a greater differential efficacy, evident through effect sizes, favoring clozapine over other agents in alleviating negative symptoms in COS patients compared with adult-onset patients (AOS). There have been no data for COS patients on long-term compliance with clozapine treatment. Therefore, we wanted to know, over a span of up to 24 years, how many of our COS cohort had remained on clozapine for at least 2 years. We review short-term treatment data and present updated long-term data on compliance and functioning for our patients. METHODS: We present the results for long-term medication maintenance over a 24 year observation period for our cohort of 131 patients. Of this cohort, 91.6% (120) were available for follow-up information from either in-person or telephone contact with the patient and/or family members. We defined clozapine compliance as ≥2 years receiving this medication and doing well. RESULTS: We were able to contact 120 of the 131 patients. In spite of the additional cost and inconvenience of regular blood monitoring, 87 patients (72.5%, 87/120) adhered to long-term clozapine maintenance therapy with dosages ranging from 50 to 900 mg, and a median dosage of 500 mg. This rate exceeds the long-term clozapine maintenance rates reported for AOS patients. CONCLUSIONS: Short-term data on differential efficacy and long-term maintenance data suggest a possibly greater efficacy of clozapine, relative to other antipsychotics, in COS than in AOS. Our overall findings indicate that very early-onset schizophrenic patients may be more responsive to clozapine. This extends other support for clozapine as an option in the treatment of early-onset schizophrenia.

Lack of Gender-Related Differences in Childhood-Onset Schizophrenia.

OBJECTIVE: Gender differences, including younger age of onset and greater premorbid deficits in men, have been reported in adult-onset schizophrenia. This study comprehensively evaluated gender differences in childhood-onset schizophrenia (COS), a rare variant of the disorder. METHOD: Demographic, premorbid, clinical, familial, and cognitive characteristics, presence of chromosomal abnormalities, and brain magnetic resonance imaging cortical volumes were evaluated in 133 patients with COS. Cortical analyses included age- and gender-matched healthy volunteers (n = 124). RESULTS: Males with COS (n = 72) had a slightly but significantly younger age of onset than females with COS (mean age 9.51 ± 2.28 versus 10.29 ± 1.63 years, t131 = 2.21, p = .03), higher verbal IQ scores (83.00 ± 15.97 versus 75.58 ± 15.10, t89 = 2.24, p = .03), and higher rates of comorbid pervasive developmental disorder (28.17% versus 6.90%, χ(2)1 = 9.54, p < .01) and attention-deficit/hyperactivity disorder (43.86% versus 21.43%, χ(2)1 = 5.40, p = .02). There were no significant gender differences across other demographic, IQ, or clinical measurements, frequency of chromosomal abnormalities, family clinical measurements, premorbid functioning, or in gender-by-disorder interactions for magnetic resonance imaging brain measurements. CONCLUSION: The present comprehensive examination found few remarkable gender differences in COS. Although less striking than that seen in adult-onset schizophrenia, males with COS had a younger age of onset. Attention-deficit/hyperactivity disorder and pervasive developmental disorder rates were high in COS overall, suggesting greater neurodevelopmental vulnerability in COS. However, the gender ratios of these comorbidities in COS mirror those of the general populations, indicating that these gender differences might be unrelated to COS.

Severity of Cortical Thinning Correlates With Schizophrenia Spectrum Symptoms.

OBJECTIVE: This study investigated the relationship between regional cortical gray matter thinning and symptoms of schizophrenia spectrum personality disorders (PDs) in siblings of patients with childhood-onset schizophrenia (COS). METHOD: A total of 66 siblings of patients with COS were assessed for symptoms of schizophrenia spectrum PDs (avoidant, paranoid, schizoid, schizotypal). Structural magnetic resonance images were obtained at approximately 2-year intervals from the siblings and from 62 healthy volunteers matched for age, sex, ethnicity, and handedness. Cortical thickness measures were extracted. Mixed effect regression models were used to test the relationship between symptoms and cortical gray matter thickness in siblings. Cortical thinning was also tested longitudinally in healthy volunteers and siblings. RESULTS: Cortical thinning was found to correlate with symptoms of schizotypal and, to a lesser extent, schizoid PDs. Thinning was most pronounced in the left temporal and parietal lobes and right frontal and parietal regions. Gray matter loss was found to be continuous with that measured in COS. Longitudinal thinning trajectories were found not to differ between siblings and healthy volunteers. CONCLUSION: The present investigation of cortical thinning in siblings of patients with COS indicates that symptoms of schizophrenia spectrum PDs correlate with regional gray matter loss. This finding supports the idea of cortical thinning as a schizophrenia endophenotype.

Dysregulation of miRNA-9 in a Subset of Schizophrenia Patient-Derived Neural Progenitor Cells.

Converging evidence indicates that microRNAs (miRNAs) may contribute to disease risk for schizophrenia (SZ). We show that microRNA-9 (miR-9) is abundantly expressed in control neural progenitor cells (NPCs) but also significantly downregulated in a subset of SZ NPCs. We observed a strong correlation between miR-9 expression and miR-9 regulatory activity in NPCs as well as between miR-9 levels/activity, neural migration, and diagnosis. Overexpression of miR-9 was sufficient to ameliorate a previously reported neural migration deficit in SZ NPCs, whereas knockdown partially phenocopied aberrant migration in control NPCs. Unexpectedly, proteomic- and RNA sequencing (RNA-seq)-based analysis revealed that these effects were mediated primarily by small changes in expression of indirect miR-9 targets rather than large changes in direct miR-9 targets; these indirect targets are enriched for migration-associated genes. Together, these data indicate that aberrant levels and activity of miR-9 may be one of the many factors that contribute to SZ risk, at least in a subset of patients.

IQ stabilization in childhood-onset schizophrenia.

OBJECTIVE: To examine the long term IQ trajectory for childhood-onset schizophrenia (COS) in an expanded, prospective longitudinal study. METHODS: Seventy children meeting DSM criteria for schizophrenia were tested at 2 year intervals with age appropriate Wechsler intelligence tests and repeated administration of information and comprehension WISC subtests even after age 18. For a subgroup with 31 patients, pre-NIH IQ test administrations were available including 18 pre-psychotic and 13 post-psychotic subjects. The pattern of IQ performance over time was determined using mixed model regression analysis. RESULTS: No progressive cognitive decline was seen up to 13+ years post psychosis onset. For the subgroup of subjects with pre-illness scores, there had been an initial steep decline in IQ, from about 2 years prior to 1.7 years after onset of psychotic symptoms, as reported for adult patients. CONCLUSIONS: The level long-term trajectory of IQ measures in COS appears stable, similar to that reported for adult onset patients. For COS, level cognitive functioning extends up to 13+ years post psychosis onset, in spite of chronic illness and concomitant, progressive loss of cortical gray matter.

Childhood-onset schizophrenia: smooth pursuit eye-tracking dysfunction in family members.

BACKGROUND: Childhood-onset schizophrenia (COS), a severe form of the disorder, is of interest for etiologic studies. Smooth pursuit eye-tracking dysfunction (ETD) is a biological marker for schizophrenia. AIMS: To compare familial eye-tracking abnormalities for COS and adult-onset schizophrenia (AOS). METHOD: Eye-tracking performance for 70 COS parents, 64 AOS parents and 20 COS siblings was compared to their respective age-matched control groups. RESULTS: COS and AOS parents had higher rate of dichotomously rated eye-tracking dysfunction than their respective controls (16% vs. 1% and 22% vs. 4%, respectively). COS parents and siblings also differed from controls on several continuous measures. However, scores for COS, AOS and control groups overlapped extensively. CONCLUSIONS: Genetic factors underlying eye-tracking dysfunction appear more salient for COS. However, eye-tracking measures have to be used with caution for endophenotypic definition due to low predictive power. DECLARATION OF INTEREST: The study was done at the National Institutes of Health.