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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., (Copyright © 2023 Society of Biological Psychiatry. All rights reserved.)

Available treatment methods have shown little effect on the burden associated with mental health disorders. We review promising universal, selective, and indicated preventive mental health strategies that might reduce the incidence of mental health disorders, or shift expected trajectories to less debilitating outcomes. Some of these interventions also seem to be cost-effective. In the transition to mental illness, the cumulative lifetime effect of multiple small effect size risk factors progressively increases vulnerability to mental health disorders. This process might inform different levels and stages of tailored interventions to lessen risk, or increase protective factors and resilience, especially during sensitive developmental periods. Gaps between knowledge, policy, and practice need to be bridged. Future steps should emphasise mental health promotion, and improvement of early detection and interventions in clinical settings, schools, and the community, with essential support from society and policy makers., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Schizophrenia is a disorder of brain connectivity and altered neurodevelopmental processes. Cross-sectional case-control studies in different age groups have suggested that deficits in cortical thickness in childhood-onset schizophrenia may normalize over time, suggesting a disorder-related difference in cortical growth trajectories., Methods: We acquired magnetic resonance imaging scans repeated over several years for each subject, in a sample of 106 patients with childhood-onset schizophrenia and 102 age-matched healthy volunteers. Using semiparametric regression, we modeled the effect of schizophrenia on the growth curve of cortical thickness in ~80,000 locations across the cortex, in the age range 8 to 30 years. In addition, we derived normative developmental modules composed of cortical regions with similar maturational trajectories for cortical thickness in typical brain development., Results: We found abnormal nonlinear growth processes in prefrontal and temporal areas that have previously been implicated in schizophrenia, distinguishing for the first time between cortical areas with age-constant deficits in cortical thickness and areas whose maturational trajectories are altered in schizophrenia. In addition, we showed that when the brain is divided into five normative developmental modules, the areas with abnormal cortical growth overlap significantly only with the cingulo-fronto-temporal module., Conclusions: These findings suggest that abnormal cortical development in schizophrenia may be modularized or constrained by the normal community structure of developmental modules of the human brain connectome., (Copyright © 2014 Society of Biological Psychiatry. All rights reserved.)

Objective: The hippocampus has been implicated in the pathogenesis of schizophrenia, and hippocampal volume deficits have been a consistently reported abnormality, but the subregional specificity of the deficits remains unknown. The authors explored the nature and developmental trajectory of subregional shape abnormalities of the hippocampus in patients with childhood-onset schizophrenia (COS), their healthy siblings, and healthy volunteers., Method: Two hundred twenty-five anatomic brain magnetic resonance images were obtained from 103 patients with COS, 169 from their 79 healthy siblings, and 255 from 101 age- and sex-matched healthy volunteers (age range = 9-29 years). The hippocampus was segmented using FreeSurfer automated image analysis software, and hippocampal shape was evaluated by comparing subjects at more than 6,000 vertices on the left and right hippocampal surfaces. Longitudinal data were examined using mixed model regression analysis., Results: Patients with COS showed significant bilateral inward deformation in the anterior hippocampus. Healthy siblings also showed a trend for anterior inward deformation. However, the trajectory of shape change did not differ significantly between the groups. Inward deformations in the anterior hippocampus were positively related to positive symptom severity, whereas outward surface displacement was positively related to overall functioning., Conclusion: This is the first and largest longitudinal three-way analysis of subregional hippocampal shape abnormalities in patients with COS and their healthy siblings compared with healthy controls. The anterior hippocampal abnormalities in COS suggest the pathophysiologic importance of this subregion in schizophrenia. The trend level and overlapping shape abnormalities in the healthy siblings suggest a more subtle, subregionally specific neuroanatomic endophenotype., (Published by Elsevier Inc.)

Background: In recent years, transcranial direct current stimulation (tDCS) has been used to study and treat many neuropsychiatric conditions. However, information regarding its tolerability in the pediatric population is lacking., Objective: This study aims to investigate the tolerability aspects of tDCS in the childhood-onset schizophrenia (COS) population., Methods: Twelve participants with COS completed this inpatient study. Participants were assigned to one of two groups: bilateral anodal dorsolateral prefrontal cortex (DLPFC) stimulation (n = 8) or bilateral cathodal superior temporal gyrus (STG) stimulation (n = 5). Patients received either 2 mA of active treatment or sham treatment (with possibility of open active treatment) for 20 minutes, for a total of 10 sessions (2 weeks)., Results: tDCS was well tolerated in the COS population with no serious adverse events occurring during the study., Conclusions: This is the first study to demonstrate that a 20-minute duration of 2 mA of bilateral anodal and bilateral cathodal DC polarization to the DLPFC and STG was well tolerated in a pediatric population., (Published by Elsevier Inc.)

Background: It was recently found that the development of typical patterns of prefrontal, but not posterior, cortical asymmetry is disrupted in right-handed youth with attention-deficit/hyperactivity disorder (ADHD). Using longitudinal data, we tested the hypothesis that there would be a congruent disruption in the growth of the anterior corpus callosum, which contains white matter tracts connecting prefrontal cortical regions., Methods: Areas of five subregions of the corpus callosum were quantified using a semiautomated method from 828 neuroanatomic magnetic resonance scans acquired from 236 children and adolescents with ADHD (429 scans) and 230 typically developing youth (399 scans), most of whom had repeated neuroimaging. Growth rates of each diagnostic group were defined using mixed-model linear regression., Results: Right-handed participants with ADHD showed a significantly higher rate of growth in the anterior-most region of the corpus callosum (estimated annual increase in area of .97%, SEM .12%) than their typically developing peers (annual increase in area of .32% SEM .13%; t = 3.64, p = .0003). No significant diagnostic differences in growth rates were found in any other regions in right-handed participants, and no significant diagnostic differences were found in non-right-handed participants., Conclusions: As hypothesized, we found anomalous growth trajectories in the anterior corpus callosum in ADHD. This disrupted anterior callosal growth may reflect, or even drive, the previously reported disruption in the development of prefrontal cortex asymmetry. The finding documents the dynamic, age-dependent nature of callosal and congruent prefrontal cortical abnormalities characterizing ADHD., (Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: To highlight emerging evidence for clinical and biological links between autism/pervasive developmental disorder (PDD) and schizophrenia, with particular attention to childhood-onset schizophrenia (COS)., Method: Clinical, demographic, and brain developmental data from the National Institute of Mental Health (and other) COS studies and selected family, imaging, and genetic data from studies of autism, PDD, and schizophrenia were reviewed., Results: In the two large studies that have examined this systematically, COS is preceded by and comorbid with PDD in 30% to 50% of cases. Epidemiological and family studies find association between the disorders. Both disorders have evidence of accelerated trajectories of anatomic brain development at ages near disorder onset. A growing number of risk genes and/or rare small chromosomal variants (microdeletions or duplications) are shared by schizophrenia and autism., Conclusions: Biological risk does not closely follow DSM phenotypes, and core neurobiological processes are likely common for subsets of these two heterogeneous clinical groups. Long-term prospective follow-up of autistic populations and greater diagnostic distinction between schizophrenia spectrum and autism spectrum disorders in adult relatives are needed.

Objective: The authors systematically examined a sample of patients who were referred to an ongoing National Institute of Mental Health (NIMH) study of childhood-onset schizophrenia (COS), but who received diagnoses of mood disorders at the NIMH, to analyze the reliability of these research-setting diagnoses and to characterize the patients clinically. Pilot data regarding the clinical course of these patients over a 2- to 7-year follow-up period were also obtained., Method: Thirty-three cases were selected from the 215 pediatric patients who had been screened in person from 1991 to 1999 for admission to the COS study. These 33 patients had been excluded from the COS study on the basis of a day-long evaluation, including a structured diagnostic interview, which yielded a diagnosis of a mood disorder rather than schizophrenia. This subgroup, together with six COS subjects (for a total N= 39), were included in a diagnostic reliability study in which they were reevaluated by three psychiatrists who were blind to the initial research diagnosis. In addition, pilot follow-up data regarding current function and treatment status were obtained for 25 of the 33 patients with mood disorders., Results: Overall, the interrater reliability of the three raters was excellent (kappa = 0.90). Global reliability between these raters and the NIMH research diagnoses was good (average kappa across diagnoses = 0.61), and agreement for those patients who had mood disorders was good (86% agreement; kappa = 0.60). Pilot follow-up data indicate that none of the subjects with a diagnosed mood disorder developed a clinical course resembling schizophrenia., Conclusions: Many of the patients referred to the NIMH COS study with clinical diagnoses of schizophrenia had psychotic mood disorders diagnosed on the basis of a comprehensive research evaluation including structured diagnostic interviews, and these research diagnoses were reliable. The diagnosis of COS is difficult and requires a time-consuming evaluation process.

Abstract-Because as many as 50% of obsessive-compulsive disorder (OCD) cases have had onset by age 15, interest in its detection in childhood is strong. Clinical experience indicates that children often try to keep their OCD secret and that parental report may give marked underestimates. The authors examined the prevalence of childhood OCD in the NIMH Methods for the Epidemiology of Child and Adolescent Mental Disorders (MECA) Study, a four-site community survey which allowed comparison of both parent and child report of the child's OCD and related symptoms and disorders. OCD cases, based on structured interviews (DISC-2.3 with DSM-III-R criteria) with 1,285 caretaker-child pairs, were identified separately for parent and child (aged 9 through 17) informants from the MECA database. Cases were then examined for demographic characteristics, for obsessive-compulsive symptoms and other diagnoses reported in cases "missed" by one reporter, and for comorbid disorders. Of a total of 35 (2.7%) identified cases, four (0.3%) were identified by the parent and 32 (2.5%) were identified by the child, with only one overlapping case. In general, when OCD cases were "missed" by one reporter, that reporter did not substitute another disorder. These findings support clinical data that children with OCD often hide their illness and underscore the importance of child interviews for its detection.

Patients with childhood-onset obsessive-compulsive disorder (OCD) with symptom exacerbations following streptococcal infections benefit from treatment with plasma exchange. In this study, 5 patients with treatment-refractory OCD without a history of streptococcus-related exacerbations underwent an open 2-week course of therapeutic plasma exchange. Behavioral ratings, completed at baseline and 4 weeks after the initial treatment, included the Clinical Global Impressions Scale and the Yale-Brown Obsessive Compulsive Scale. All 5 patients completed the trial with few side effects, but none showed significant improvement. Plasma exchange does not benefit children and adolescents with OCD who do not have streptococcus-related exacerbations.

Objectives: Deletion of chromosome 22q11 (velocardiofacial syndrome) is associated with early neurodevelopmental abnormalities and with schizophrenia in adults. The rate of 22q11 deletions was examined in a series of patients with childhood-onset schizophrenia (COS), in whom early premorbid developmental and cognitive impairments are more pronounced than in adult-onset cases., Method: Through extensive recruiting and screening, a cohort of 47 patients was enrolled in a comprehensive study of very-early-onset schizophrenia. All were tested with fluorescence in situ hybridization for deletions on chromosome 22q11., Results: Three (6.4%) of 47 patients were found to have a 22q11 deletion. All 3 COS patients with 22q11 deletions had premorbid impairments of language, motor, and social development, although their physical characteristics varied. Brain magnetic resonance imaging revealed increased midbody corpus callosum area and ventricular volume in relation both to healthy controls and to other COS patients., Conclusions: The rate of 22q11 deletions in COS is higher than in the general population (0.025%, p < .001) and may be higher than reported for adult-onset schizophrenia (2.0%, p = .09). These results suggest that 22q11 deletions may be associated with an earlier age of onset of schizophrenia, possibly mediated by a more salient neurodevelopmental disruption.

Childhood-onset schizophrenia (defined by an onset of psychosis by age 12) is a rare and severe form of the disorder that is clinically and neurobiologically continuous with the adult-onset disorder. There is growing evidence for more salient risk or etiologic factors, particularly familial, in this possibly more homogeneous patient population. For the 49 patients with very early onset schizophrenia studied to date at the National Institute of Mental Health, there were more severe premorbid neuro-developmental abnormalities, a higher rate of cytogenetic anomalies, and a seemingly higher rate of familial schizophrenia and spectrum disorders than later onset cases. There was no evidence for increased obstetric complications or environmental stress. These data, while preliminary, suggest that a very early age of onset of schizophrenia may be secondary to greater familial vulnerability. Consequently, genetic studies of these patients may be particularly informative and may provide important etiologic information.

Background: Previous NIMH childhood onset schizophrenia (COS) anatomic brain MRI studies found progression of ventricular volume and other structural brain anomalies at 2-year follow up across mean ages 14 to 16 years. However, studies in adult patients generally do not show progression of ventricular volume or correlation of ventricular volume with duration of illness. To address issues of progression of brain anomalies in schizophrenia, this report extends previous studies to include a third longitudinal scan, uses a larger sample size, and includes measures of the amygdala and hippocampus., Methods: Volumes of the total cerebrum, lateral ventricles, hippocampus, and amygdala were quantified on 208 brain magnetic resonance imaging scans from 42 adolescents with COS (23 with one or more repeat scan) and 74 age- and gender-matched controls (36 with one or more repeat scan). A statistical technique permitting combined use of cross-sectional and longitudinal data was used to assess age-related changes, linearity, and diagnostic group differences., Results: Differential nonlinear progression of brain anomalies was seen during adolescence with the total cerebrum and hippocampus decreasing and lateral ventricles increasing in the COS group. The developmental curves for these structures reached an asymptote by early adulthood for the COS group and did not significantly change with age in the control group., Conclusions: These findings reconcile less striking progression of anatomic brain images usually seen for adult schizophrenia and complement other data consistent with time-limited, diagnostic-specific decreases in brain tissue. Adolescence appears to be a unique period of differential brain development in schizophrenia.

Objectives: To present a critical overview of the available evidence for the efficacy and safety of antipsychotic agents in children and adolescents and to identify knowledge gaps and needs for further research. Data from adults that are relevant to children are discussed., Method: Mainly reports of double-blind, placebo-controlled studies were reviewed., Results: In children and adolescents, antipsychotics are used to treat psychotic and a variety of nonpsychotic conditions. The amount of data based on well-designed, double-blind, placebo-controlled studies with satisfactory sample sizes in diagnostically homogeneous subjects is modest., Conclusions: Currently available standard antipsychotics have a definite role in the treatment of children and adolescents. The use of these agents is limited mainly by tardive and withdrawal dyskinesias and, in some patients, by excessive sedation. The atypical antipsychotics should be critically assessed and compared with psychosocial interventions; if effective, the combination of both types of treatments should be evaluated.

Objective: Olanzapine, a potent 5-HT2a/2c, dopamine D1D2D4 antagonist with anticholinergic activity, has a profile of known receptor affinity similar to that of clozapine. This pilot study examined the efficacy of olanzapine for treatment-refractory childhood-onset schizophrenia in eight patients who had received 8-week open-label trials. For comparison, data are included from 15 patients who had received 6-week open-label clozapine trials using identical rating instruments (largely by the same raters) in the same treatment setting., Method: Twenty-three children and adolescents with an onset of DSM-III-R schizophrenia by age 12 for whom at least two different typical neuroleptics had been ineffective participated in the two separate studies. Some of the patients were intolerant of clozapine, although it had been effective (n = 4). Patients receiving olanzapine were evaluated over 8 weeks with the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Positive Symptoms, the Scale for the Assessment of Negative Symptoms, and the Clinical Global Impressions Scale for Improvement., Results: For the eight patients who received olanzapine trials, at week 8 there was a 17% improvement in the BPRS total score, a 27% improvement in the Scale for the Assessment of Negative Symptoms, and a 1% improvement in the Scale for the Assessment of Positive Symptoms, relative to "ideal" admission status on typical neuroleptics. In contrast, the magnitude of the effect sizes for each of the clinical ratings was larger at week 6 of the previous clozapine trial than for an 8-week olanzapine trial, relative to admission status on typical neuroleptics. For the four children who had received both clozapine and olanzapine, BPRS total scores were significantly lower at week 6 of clozapine treatment compared with week 6 of olanzapine treatment (p = .03)., Conclusion: These data provide preliminary evidence for the efficacy of olanzapine for some children and adolescents with treatment-refractory schizophrenia, but they also suggest the need for a more rigorous double-blind comparison of these two atypical antipsychotics.

Objective: An apparent excess of sex chromosome aneuploidies (XXY, XXX, and possibly XYY) has been reported in patients with adult-onset schizophrenia and with unspecified psychoses. This study describes the results of cytogenetic screening carried out for pediatric patients meeting DMS-III-R criteria for childhood-onset schizophrenia (COS) and a subgroup of patients with childhood-onset psychotic disorder not otherwise specified, provisionally labeled by the authors as multidimensionally impaired (MDI)., Method: From August 1990 to July 1997, karyotypes were determined for 66 neuroleptic-nonresponsive pediatric patients (28 MDI, 38 COS), referred to the National Institute of Mental Health for an inpatient treatment trial of clozapine., Results: Four (6.1%) of 66 patients (3 MDI, 1 COS) were found to have sex chromosome anomalies (mosaic 47,XXY; 47,XXY; 47,XYY; mosaic 45,XO, respectively), which is higher than the expected rate of 1 per 426 children or 2.34 per 1,000 in the general population (4/66 versus 1/426, chi 2 = 19.2, df = 1, p = .00001). All cases had been previously undiagnosed., Conclusions: These findings lend support to a hypothesis that a loss of balance of gene products on the sex chromosomes may predispose affected individuals to susceptibility to additional genetic and environmental insults that result in childhood-onset psychotic disorders. Karyotyping of children with psychotic disorders should be routine.

Objective: Neuroleptic-treated pediatric patients with childhood-onset schizophrenia (COS) are at risk for developing extrapyramidal side effects and involuntary movement disorders. A preliminary examination of the incidence of withdrawal dyskinesias (WD), tardive dyskinesia (TD), and extrapyramidal side effects in these patients is presented., Method: Thirty-four COS patients (mean age +/- SD, 14.2 +/- 2.1 years) were examined for TD using the Abnormal Involuntary Movements Scale and for extrapyramidal side effects using the Simpson-Angus Neurologic Rating Scale, after a 14- to 28-day drug-free period (n = 33), at week 6 of treatment and 2 to 4 years after completion of the study (n = 14). The mean (+/-SD) number of months of prior neuroleptic exposure for the group was 22.4 (15.0) months., Results: Seventeen (50%) of 34 patients were noted to have either WD or TD at some point during their participation in the studies. The majority of patients experienced WD that were mainly in the orofacial region, transient in nature, and diminished with haloperidol and clozapine. Patients with TD/WD had greater levels of premorbid impairment (p = .02), increased severity of positive symptoms of schizophrenia (p < .01), and a trend toward more months of neuroleptic exposure (p = .10, one-tailed)., Conclusions: A high proportion of COS patients were found to have TD/WD. The majority of these abnormal movements were not severe and generally improved over time. TD/WD in COS appears to be associated with greater premorbid impairment, severity of illness, and duration of neuroleptic exposure. J. Am. Acad.

Objective: To examine the validity of diagnostic criteria for a subgroup of children with atypical psychosis (n = 19), designated here as "multidimensionally impaired." These children are characterized by poor attention and impulse control, psychotic symptoms, and poor affective control., Method: Children and adolescents (n = 19) meeting our criteria for multidimensionally impaired syndrome with onset of psychotic symptoms at or before age 12 years were identified from a total of 150 in-person screenings for very early-onset schizophrenia between 1990 and 1996. We compared the premorbid adjustment, family history, follow-up status, and laboratory measures for a subgroup of these children with those of (1) a rigorously defined group of 29 children with DSM-III-R schizophrenia and (2) 19 children with attention-deficit hyperactivity disorder., Results: Patients with multidimensionally impaired syndrome and patients with very early-onset schizophrenia shared a similar pattern of early transient autistic features, postpsychotic cognitive decline, and an elevated risk of schizophrenic-spectrum disorders among their first-degree relatives. This pattern was not seen in the attention-deficit hyperactivity disorder group. In contrast to very early-onset schizophrenia, the multidimensionally impaired group had significantly poorer scores on the Freedom From Distractibility factor on the WISC-R, a less deviant pattern of autonomic reactivity, and no progression to schizophrenia., Conclusions: The findings support the distinction of the multidimensionally impaired cases as separate from those with other psychiatric disorders, and there is somewhat greater evidence to suggest that this disorder belongs in the schizophrenia spectrum.

Objective: To determine the effects of methylphenidate (MPH) and dextroamphetamine (DEX) on tic severity in boys with attention-deficit/hyperactivity disorder (ADHD) comorbid with Tourette's syndrome., Method: A 9-week, placebo-controlled, double-blind crossover using a wide range of doses was completed by 20 subjects in three cohorts., Results: Relatively high doses of MPH and DEX in the first cohort produced significant increases in tic severity which were sustained on higher doses of DEX but which attenuated on MPH. Overall, 14 of 20 subjects continued stimulant treatment for 1 to 3 years, generally in combination with other psychotropics. Stimulant-associated adverse effects, including tic exacerbations, were reversible in all cases., Conclusion: A substantial minority of comorbid subjects had consistent worsening of tics on stimulants, although the majority experienced improvement in ADHD symptoms with acceptable effects on tics. MPH was better tolerated than DEX.

Objective: To examine the relation between specific frontostriatal structures (prefrontal cortex and basal ganglia) and response inhibition deficits observed in attention-deficit/hyperactivity disorder (ADHD)., Method: Children with ADHD and age-matched normal controls were scanned using magnetic resonance imaging (MRI) and tested on three response inhibition tasks. Behavioral performance was correlated with MRI-based anatomical measures of frontostriatal circuitry (prefrontal cortex and basal ganglia) implicated in ADHD., Results: First, significant differences in performance by children with ADHD and normal volunteers were observed on all three response inhibition tasks. Second, performance on these tasks correlated only with those anatomical measures of frontostriatal circuitry observed to be abnormal in children with ADHD (e.g., the region of the prefrontal cortex, caudate, and globus pallidus, but not the putamen) in the authors' previous study. Third, significant correlations between task performance and anatomical measures of the prefrontal cortex and caudate nuclei were predominantly in the right hemisphere, supporting a role of right frontostriatal circuitry in response inhibition and ADHD., Conclusion: The data suggest a role of the right prefrontal cortex in suppressing responses to salient, but otherwise irrelevant events while the basal ganglia appear to be involved in executing these behavioral responses.

Several lines of evidence have implicated central dopaminergic pathways in the modulation of blink rate. In the present study, blink rate during smooth pursuit was examined in 17 children with childhood-onset schizophrenia, on and off of clozapine, and compared to that of age-matched normal children and unmedicated children with attention-deficit hyperactivity disorder (ADHD). As has been observed in adolescent and adult schizophrenics, blink rate was significantly higher in schizophrenic children relative to normal and ADHD controls. Within the schizophrenic group, blink rate did not significantly change with the introduction of clozapine and was not related to clinical variables. Blink rate was positively correlated with deterioration in smooth pursuit in normal subjects.

Abnormalities of the smooth pursuit eye movements of adults with schizophrenia have been well described. We examined smooth pursuit eye movements in schizophrenic children, contrasting them with normal and attention-deficit hyperactivity disorder (ADHD) subjects, to determine whether there is continuity of eye movement dysfunction between childhood- and adult-onset forms of schizophrenia. Seventeen schizophrenic children with onset of illness by age 12, 18 ADHD children, and 22 normal children were studied while engaged in a smooth pursuit eye tracking task. Eye tracking variables were compared across the three groups. Schizophrenic children exhibited significantly greater smooth pursuit impairments than either normal or ADHD subjects. Within the schizophrenic group, there were no significant relationships between eye tracking variables and clinical variables, or ventricular/brain ratio. Childhood-onset schizophrenia is associated with a similar pattern of smooth pursuit abnormalities to that seen in later-onset schizophrenia.

A technique for quantifying the midsagittal size and shape of the corpus callosum (CC) from magnetic resonance brain scans is presented. The technique utilizes the distances to the ventral and dorsal boundaries of small sectors of the CC from a reference point to compute the size and shape parameters of the CC and its subdivisions. Intrarater and interrater interclass correlation coefficients for the area measurements ranged from 0.88 to 0.99. Correlations between these automated measures and those obtained by pixel counting were equally high. The corpus callosa of 104 (57 male and 47 female) right-handed healthy children and adolescents, ages 4-18, were examined in relation to age and sex. Corpus callosum growth was most striking for the splenium and isthmus with some changes in the midbody regions. The area and perimeter of these regions increased, shapes became more compact, and the boundaries became more regular with age. The length and curvature at the anterior and posterior regions of the CC increased more rapidly in males than in females. These significant and consistent results indicate that the method is reliable and sensitive to developmental changes of the CC.

Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAs) may arise when antibodies directed against invading bacteria cross-react with basal ganglia structures, resulting in exacerbations of obsessive-compulsive disorder (OCD) or tic disorders. This is a report of severe worsening of obsessive-compulsive symptoms in an adolescent boy following infection with group A beta-hemolytic streptococci for whom serial magnetic resonance imaging scans of the brain were acquired to assess the relationship between basal ganglia size, symptom severity, and treatment with plasmapheresis. These data provide further support for basal ganglia-mediated dysfunction in OCD and the potential for immunological treatments in PANDAs patients.

Deficits in sensorimotor gating, defined by prepulse inhibition (PPI), have been associated with subcortical dopaminergic overactivity in animal and clinical studies. Utilizing supraorbital nerve electrical stimulation, we produced adequate blink responses and measured decreases in amplitude resulting from electric prestimuli just above sensory threshold. Seven boys comorbid for attention-deficit hyperactivity disorder (ADHD) and a tic disorder had significantly reduced PPI, compared to 14 screened controls and seven boys with ADHD alone. If independently replicated, these results may reflect greater neurologic immaturity in these comorbid subjects. Alternatively, these findings, together with other converging lines of evidence, suggest that deficient pallidal inhibition may be etiologically related to tic and movement disorders.

A segmentation method is presented for gray matter, white matter, and cerebrospinal fluid (CSF) in thin-sliced single-channel brain magnetic resonance (MR) scans. The method is based on probabilistic modeling of intensity distributions and on a region growing technique. Interrater and intrarater reliabilities for the method were high, and comparison with phantom studies and hand-traced results from an experienced rater indicated good validity. The method was designed to account for spatially dependent image intensity inhomogeneities. Segmentation of MR brain scans of 105 (56 male and 49 female) healthy children and adolescents showed that although the total brain volume was stable over age 4-18, white matter increased and gray matter decreased significantly. There were no sex differences in total gray and white matter growth after correction for total brain volume. White matter volume increased the most in superior and posterior regions and laterality effects were seen in hemisphere tissue volumes. These findings are consistent with other reports, and further validate the segmentation technique.

Objective: With the increased use of tricyclic antidepressants in children, and several reports of several sudden deaths associated with desipramine (DMI) treatment, systematic study of their cardiac effects is indicated. In the present study, DMI's and clomipramine's (CMI) short-term effects on the electrocardiogram (ECG) were compared, as well as the long-term effects of CMI., Method: The ECGs of 47 children and adolescents in treatment trials were examined at baseline, after 5 weeks of CMI and of DMI treatment, and during CMI maintenance (mean duration 24.6 months)., Results: At 5 weeks of CMI and of DMI treatment, the heart rate, PR, QRS, and QT-corrected (QTc) intervals on ECG were significantly increased from baseline (p < .05); DMI increased PR and QRS intervals more than CMI (p < .05), and CMI increased QTc more (p < .05). Tachycardia was the most common change (36%). More patients experienced an incomplete intraventricular conduction delay during DMI treatment (23%, 9/39) than during CMI (2%, 1/47) (p < .05). Four patients (9%) acutely developed a prolonged QTc during either DMI or CMI. Long-term maintenance ECGs during CMI treatment (n = 25) were not significantly different from that at week 5, although some individuals developed or resolved specific ECG changes., Conclusion: CMI and DMI both produced ECG changes typically reported for tricyclic antidepressants, and they differed on specific ECG changes. Changes in ECG measures for individuals from short to long term suggest that continued monitoring is required.

Objective: To review the premorbid histories of 23 children meeting DSM-III-R criteria for schizophrenia with onset before age 12 years and to compare these with childhood data of later-onset schizophrenics., Method: Premorbid features up to 1 year before onset of first psychotic symptoms were rated from hospital and clinic records, clinical interviews, rating scales, and tests., Results: In keeping with previous studies, specific developmental disabilities and transient early symptoms of autism, particularly motor stereotypies, were common. Comparison with the childhood of later-onset schizophrenics showed greater delay in language development, and more premorbid speech and language disorders, learning disorders, and disruptive behavior disorders. (Sixty percent had received or were estimated to meet criteria for one or more clinical diagnoses.), Conclusions: Childhood-onset schizophrenia may represent a more malignant form of the disorder, although selection and ascertainment bias cannot be ruled out. The presence of prepsychotic language difficulties focuses attention on the importance of early temporal and frontal lobe development; early transient motor stereotypies suggest developmental basal ganglia abnormalities and extend previous findings seen in the childhood of later-onset patients.

We studied the ability of human peritoneal mesothelial cells (HPMC) to produce the major pro-inflammatory cytokines interleukin-1 alpha (IL-1 alpha) and -beta when stimulated by lipopolysaccharide (LPS), tumor necrosis factor alpha (TNF alpha) or IL-1 alpha, or combinations of these three factors. Biological activity of IL-1 was measured by bioassay, and levels of IL-1 alpha and beta were determined using specific radioimmunoassays. We found that HPMC are capable of secreting IL-1 alpha and -beta in response to stimulation by these substances, but stimulation with a combination of LPS + TNF alpha, LPS + IL-1 alpha, or TNF alpha + IL-1 alpha, had a marked synergistic effect on cytokine production. A combination of all three substances together had a significantly enhanced synergistic effect. Using reverse transcription PCR, we found a peak in IL-1 alpha and beta mRNA levels three hours after stimulation. We found that LPS, TNF alpha and IL-1 alpha alone, or in combination, caused an increase in IL-1 alpha and -beta mRNA levels. Cycloheximide and actinomycin D blocked the production of IL-1 alpha and -beta protein, showing that de novo production of IL-1 or synthesis of mRNA stabilizing proteins are needed after stimulation. We thus conclude that HPMC play an important role in the amplification of the initial peritoneal inflammatory response which originates in the peritoneal macrophages, and these findings are of importance in understanding the peritoneal response to infection in continuous ambulatory peritoneal dialysis (CAPD) patients.

Objective: To review timely research on childhood-onset schizophrenia in view of advances in biological research on, and neurodevelopmental theories of, the later-onset disorder., Method: Research issues are outlined including further clarification of ICD- and DSM-defined childhood schizophrenia, and differentiation from autism "spectrum" and other subtle, chronic developmental disorders. Key neurobiological advances are reviewed for which child studies are relevant and feasible., Conclusion: It is anticipated that narrowly defined childhood-onset schizophrenics will constitute a predominantly male population. A high rate of family illness or chromosomal and/or brain developmental abnormalities, which will be instructive regarding the pathophysiology of later-onset schizophrenia, is expected.

Objective: To review the response of 11 adolescents with childhood-onset schizophrenia to a 6-week open clozapine trial., Method: Eleven children meeting DSM-III-R criteria for schizophrenia had a 6-week open trial of clozapine (mean sixth week daily dose 370 mg). Behavioral ratings included the Brief Psychiatric Rating Scale and Children's Global Assessment Scale., Results: More than half showed marked improvement in Brief Psychiatric Rating Scale ratings by 6 weeks of clozapine therapy compared to admission drug rating and compared to a systematic 6-week trial of haloperidol., Conclusions: This open trial indicates that clozapine may be a promising treatment for children and adolescents with schizophrenia who do not respond well to typical neuroleptics. A double-blind placebo-controlled study is ongoing.

Objective: To review psychiatric referrals to a study of childhood-onset schizophrenia., Method: Children and adolescents (N = 71) and their parents selected from a total of 260 patients referred to the National Institute of Mental Health between 1990 and 1993, with onset of psychosis at or before age 12 years, were screened in person, using the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Epidemiologic Version, portions of the Diagnostic Interview for Children and Adolescents-Parent Version, and clinical interview. Best-estimate diagnoses using all sources of information were determined. Thought disorder was rated on a subset of subjects using standardized videotaped speech samples., Results: Interrater reliability (kappa) between two child psychiatrists for best-estimate primary diagnoses ranged from .65 to .81. Schizophrenia was diagnosed for 19 children who by history had had onset at or before age 12, but all were in puberty when interviewed. Affect disorders (N = 14) and Asperger's syndrome and pervasive developmental disorder not otherwise specified (N = 6) were also diagnosed. A large group of reliably identifiable children not completely described by any DSM-III-R category and provisionally called "multidimensionally impaired" (N = 21) with multiple language or learning disorders, mood lability, and transient psychotic symptoms was seen., Conclusions: Childhood-onset schizophrenia is often misdiagnosed, perhaps is often misdiagnosed, perhaps because of the rarity of the disorder and the ambiguity in applying primary criteria. An array of developmental disturbances are seen with less pervasive childhood-onset psychotic symptoms.

Objective: To examine thyroid indices in a community referred sample of boys with attention-deficit hyperactivity disorder (ADHD) for evidence of generalized resistance to thyroid hormone (GRTH)., Method: TSH, T3, and T4 values were gathered prospectively in 53 physician, school, and/or parent referred ADHD subjects, and in 41 age and gender-matched normal controls., Results: None were in the range suggestive of global or pituitary thyroid hormone resistance., Conclusions: GRTH is rare, and thyroid function should not be measured routinely in nonfamilial ADHD.

A multiple regression/discriminant analysis of positron emission tomographic cerebral metabolic (rCMRglc) data in 10 obsessive-compulsive disorder (OCD) patients before and during pharmacotherapy was carried out to see if rCMRglc interdependencies distinguished OCD patients from controls. Before therapy, a discriminant function reflecting parietal, sensorimotor, and midbrain rCMRglc interdependencies correctly classified eight (80%) of the 10 patients as OCD; after therapy, six (70%) were classified as controls, most of whom were responders. Before therapy, rCMRglc interdependencies involving basal ganglia, thalamus, limbic, and sensory and association cortical regions distinguished 67% of patients who clinically responded to drug (RESP, n = 6) and 75% of patients who did not (NRESP, n = 4) from controls. After therapy, all RESP were classified as controls; classification of NRESP remained unchanged. The results suggest the conjunctive utility of this method to assess individual differences in rCMRglc during pharmacotherapy, and to explore the neurobiology of OCD.

Individual symptoms of 79 children and adolescents with severe obsessive-compulsive disorder were obtained from chart review of at least two in-persons evaluations and recorded across an average of 7.9 years (range, 2 to 16). Symptoms were grouped according to the categories of the Yale-Brown Symptom Checklist. No significant age related trends were found with any one type of symptom, although patients with a very early onset of illness (less than 6 years old) were more likely to have compulsions than obsessions. Across the study period, patients reported symptoms from many different symptom categories, with 47% of the patients displaying both washing and checking compulsions at some time during their illness. No patient maintained the same constellation of symptoms from presentation to follow-up. These data support the concept of obsessive-compulsive disorder as an illness with varied clinical manifestations that individually change over time.

The active metabolite of vitamin D, 1,25-dihydroxycholecalciferol (1,25(OH)2D3), is produced mainly by the kidney, but there is evidence for extrarenal production in certain circumstances. We studied whether peritoneal macrophages (PM) from CAPD patients were capable of metabolizing 25-OH-D3 to 1,25(OH)2D3. We found that PM were able to metabolize 25-OH-D3 in vitro; the main product following 16 hours of incubation was 19-nor, 10-oxo, 25-OH-D3 with smaller amounts of 1,25(OH)2D3. However, after shorter incubations of three and five hours a larger portion of 1,25(OH)2D3 was produced. The metabolism of 25-OH-D3 was greatly enhanced in PM harvested during episodes of peritonitis. This property was specific for PM of CAPD patients, and was not found in PM from normal subjects. However, incubation of control PM with peritoneal effluent from CAPD patients resulted in induction of the ability of these cells to metabolize 25-OH-D3. This induction was enhanced by preincubation with peritoneal effluent from CAPD patients suffering from peritonitis. Prostaglandin E2 was found to be involved in this synthesis: addition of PGE2 to normal PM induced metabolism of 25-OH-D3, and incubation of PM from CAPD patients with indomethacin decreased the metabolism of 25-OH-D3. The vitamin D metabolites produced by PM from CAPD patients could have a role in immunological resistance to peritoneal infections.

One hundred and forty-five first-degree relatives (89 parents [96%] and 56 siblings [98%]) of 46 children and adolescents with severe primary obsessive compulsive disorder (OCD) were personally interviewed with clinical and structured psychiatric interviews. Parent interviews were scored by a rater blind to proband diagnosis. Thirty percent of probands had at least one first-degree relative with OCD: 25% of fathers and 9% of mothers received this diagnosis. Forty-five percent of fathers and 65% of mothers received one or more other psychiatric diagnoses. The increased familial rate of OCD over that expected from a general population, and over that found in parents of conduct disordered patients, is consistent with a genetic factor in OCD. Presenting obsessive compulsive symptoms of probands and their parents were usually dissimilar, arguing against any simple social or cultural transmission.

The symptoms of obsessive compulsive disorder (OCD) have been viewed as extreme variants of normal developmental rituals and superstitiousness; however, difference in timing, content, and severity argue against this continuum. In a systematic comparison of 38 children with severe primary OCD and 22 matched normal controls, parents were interviewed about their child's early developmental rituals and current superstitions. Children were asked about superstitious beliefs. Children with OCD did not differ significantly from controls in number or type of superstitions. However, parents of the OCD children reported significantly more "marked" patterns of early ritualistic behavior than did parents of normal controls. When behaviors resembling primary OCD symptoms were excluded, other rituals did not differ leaving open the possibility that such behaviors were early manifestations of the disorder. Only a prospective study can determine whether these results reflect preclinical OCD or are an artifact of biased recall.

Whether the lumbar cerebrospinal fluid (CSF) concentration gradient of monoamine metabolites found in adults is influenced by age or pubertal status was studied in 26 children ranging from 6.5 to 17.3 years of age. Homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) were assayed by high-power liquid chromatography (HPLC) with electrochemical detection. Eight patients were prepubertal (Tanner stage I). The slopes in units of picomoles/milliliter/milliliter for regression lines for CSF monoamine metabolite concentrations versus milliliter of CSF collected were 5.07 +/- 0.65, 10.13 +/- 2.0, and 0.67 +/- 0.22 for 5-HIAA, HVA, and MHPG, respectively, for the group as a whole. Significant correlations with age, height, weight, or Tanner stage were not found for the HVA or MHPG concentration gradients. Tanner stage and 5-HIAA slope were significantly correlated. Three of eight prepubertal patients had nonsignificant 5-HIAA gradients. CSF studies in pediatric populations must control for aliquot collected, as the size of the gradient could produce differences sufficient to mimic a "positive" clinical study if the aliquots collected are not the same.

Calcium overload of tubular cells may occur in uremia, and may be the underlying functional abnormality in the continued deterioration of renal function in chronic renal failure. In order to study this question further, the effect of chronic uremia on the calcium transport properties and respiratory rates was examined in mitochondria (Mi) isolated from the cortex of the remnant kidneys of subtotally nephrectomized rats (SNX) and sham operated controls (C). Plasma calcium concentration was similar in both groups of rats, but a significant hyperphosphatemia was seen in SNX, 8.6 +/- 0.6 mg%, as compared to 7.2 +/- 0.2 mg% in C (P less than 0.001). Mi calcium and phosphate concentrations (nmol/mg protein) were significantly elevated in SNX, 49.9 +/- 7.9 and 35.1 +/- 4.2, respectively, in SNX compared to C, 21.2 +/- 4.2 and 21.4 +/- 2.7, respectively (P less than 0.01). Mi respiratory control ratio and ADP/O were similar in both experimental groups. Kinetic parameters for calcium uptake (Ca2+ concentrations in the medium of 1.25 to 16 microM) revealed initial velocities 1.5-fold higher in SNX Mi than in C. Mi retention of calcium in the presence of medium Ca2+ concentrations up to 500 microM was studied. Calcium retention was reduced in SNX: the Mi were unable to retain calcium at concentrations of 250 microM. The addition of ruthenium red to the medium substantially improved calcium retention by the uremic Mi. Chronic parathyroidectomy did not correct either the increased calcium uptake or the poor retention of uremic Mi.(ABSTRACT TRUNCATED AT 250 WORDS)

The aim of the present study was to examine calcium metabolism of the renal cortex in experimental chronic renal failure, together with morphologic criteria of nephrocalcinosis and to determine the effect of chronic verapamil administration on these parameters. In subtotally nephrectomized (SNX) rats 3 weeks after surgery, renal cortical calcium content increased more than two-fold. 45Ca incorporation into renal cortical slices in SNX revealed a 35% increase, associated with a 50% increase in a lanthanum-resistant fraction of 45Ca uptake. Radiocalcium wash-out curves in this group demonstrated abnormal retention of the isotope for up to 30 min of incubation. In contrast, radiocalcium incorporation and wash-out in SNX rats chronically treated with verapamil were similar to that obtained in the sham group. Verapamil administration significantly reduced, but did not normalize, renal cortical calcium content. Von Kossa staining demonstrated the deposition of calcium in the renal parenchyma of SNX rats. Ultrastructurally, it was accompanied by mitochondrial disorganization and calcification, as well as by the tubular basement membrane destruction and mineralization. These morphologic patterns of nephrocalcinosis were significantly ameliorated in SNX rats treated with verapamil. We conclude that chronic verapamil administration results in amelioration of uremic nephrocalcinosis.

The autoradiography of diffusible, hydrophilic solutes presents special problems in localization of the labeled solute under study. We present studies of the movement of 14C-labeled urea, and 14C- and 3H-labeled sucrose across the isolated urinary bladder of the toad, a vasopressin-sensitive epithelium, using a technique that avoids exposure to water throughout all processing steps and minimizes error caused by isotope scatter. We have shown a significant increase in 14C urea entry into epithelial cells following vasopressin, and a significant decrease following phloretin, an agent that selectively blocks vasopressin-stimulated urea transport. The autoradiographic technique confirms the luminal site of action of phloretin. Studies of 14C and 3H sucrose labeling show that this molecule is virtually excluded from the cell. The current method of grain counting is capable of yielding reliable information in studies of epithelial transport.