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Biomedical subjects

Judith L Rapoport

Publications and source records attributed to Judith L Rapoport.

At least 19 recordsLinked to original sources
PubMed2004

Comparison of progressive cortical gray matter loss in childhood-onset schizophrenia with that in childhood-onset atypical psychoses.

BACKGROUND: Recent anatomical brain magnetic resonance imaging (MRI) studies show a striking postpsychotic progressive loss of cortical gray matter (GM) in patients with childhood-onset schizophrenia (COS), which appears greater than that seen for adult patients. However, the diagnostic specificity and the relationship of these changes to drug treatment and cognitive functioning remain unclear. We performed a comparative prospective brain MRI study in patients with COS and pediatric patients with transient psychosis with behavior problems (psychosis not otherwise specified) provisionally considered multidimensionally impaired (MDI). We hypothesized that cortical GM loss would occur in patients with COS but not in adolescents with atypical psychoses. METHODS: Anatomical brain MRI was performed at baseline and follow-up in 19 patients in the MDI group (mean [SD] age of 13.3 [3.1] years); in 23 patients with COS matched for age, sex, IQ score, and drug treatment (mean [SD] age of 13.9 [2.5] years); and 38 healthy control subjects matched for age and sex (mean [SD] age of 13.3 [3.1] years). The mean (SD) follow-up was 2.5 (0.8) years. Volumes of the cerebrum and total and regional GM were obtained by using automated analysis, and percent change in volume across time was calculated. One-way analyses of variance with post hoc Tukey Honestly Significantly Different comparisons were performed to examine group differences in the percent change in GM across follow-up. RESULTS: The COS group had significantly greater total, frontal, temporal, and parietal GM loss than did the MDI or healthy control groups; analysis of variance post hoc P values ranged from.03 to.001. The MDI and control groups did not differ significantly from each other. CONCLUSIONS: The cortical GM volume loss in COS appears diagnostically specific; it was not seen in children and adolescents with atypical psychosis. Because both patient groups had similar early developmental patterns, cognitive functioning, medications, and hospitalizations, this progressive loss appears to be intrinsic to COS. An ongoing neurodevelopmental process and/or brain response specific to the illness could account for these changes.

Adolescent↗
PubMed2003

Corpus callosum development in childhood-onset schizophrenia.

OBJECTIVE: Corpus callosum (CC) size and interhemispheric communication differences have been reported between patients with schizophrenia and normal controls. Childhood-onset schizophrenia (COS) is a severe form of the disorder that is continuous with later-onset disorder. Corpus callosal area was examined for COS at initial scan and prospectively through adolescence, and related to other developmental abnormalities for this group. METHOD: A total of 113 anatomic brain MRI scans were obtained from 55 COS (22 female) and 110 scans from 56 age- and gender-matched healthy volunteers (22 female), across ages 8-24. Baseline and prospective rescans were obtained at approximately 2-year intervals. The midsagittal areas for total corpus callosum and seven subregions were calculated using an automated system. Cross-sectional and longitudinal data were combined using mixed model regression analysis to compare developmental changes for the two groups. RESULTS: No diagnostic differences were seen at time of initial scan. Longitudinally, and in contrast to healthy volunteers, patients with schizophrenia showed a significant difference in developmental trajectory for the area of the splenium, both before (p=0.012) and after (p=0.05) adjustment for total cerebral volume. The area of the splenium becomes significantly smaller in COS, starting at about age 22. CONCLUSION: Patients with schizophrenia showed a significant difference in developmental trajectory for the splenial area, which seems to decline for COS. If replicated, this may reflect anticipated late occipital and extrastriate changes in brain regions.

Adolescent↗
PubMed2003

Deformation-based surface morphometry applied to gray matter deformation.

We present a unified statistical approach to deformation-based morphometry applied to the cortical surface. The cerebral cortex has the topology of a 2D highly convoluted sheet. As the brain develops over time, the cortical surface area, thickness, curvature, and total gray matter volume change. It is highly likely that such age-related surface changes are not uniform. By measuring how such surface metrics change over time, the regions of the most rapid structural changes can be localized. We avoided using surface flattening, which distorts the inherent geometry of the cortex in our analysis and it is only used in visualization. To increase the signal to noise ratio, diffusion smoothing, which generalizes Gaussian kernel smoothing to an arbitrary curved cortical surface, has been developed and applied to surface data. Afterward, statistical inference on the cortical surface will be performed via random fields theory. As an illustration, we demonstrate how this new surface-based morphometry can be applied in localizing the cortical regions of the gray matter tissue growth and loss in the brain images longitudinally collected in the group of children and adolescents.

Adolescent↗
PubMed2003

Clozapine-induced neutropenia in children: management with lithium carbonate.

Clozapine, an atypical antipsychotic, is the most effective medication for treatment-resistant schizophrenia, but its use is limited by the high risk of neutropenia and agranulocytosis. In children, the rate of clozapine-induced neutropenia is even higher than in adults. We report two cases of children 7- and 12-years old diagnosed with very early onset schizophrenia, who developed neutropenia when treated with clozapine. In both cases addition of lithium carbonate elevated the white blood count (WBC) allowing clozapine rechallenge. WBC and total neutrophil count remained stable long-term with coadministration of clozapine (400-425 mg per day) and lithium with the blood level of 0.8-1.1 microg/mL. This report supports the use of adjunct lithium for clozapine-induced neutropenia as a safe and successful strategy in children.

Antipsychotic Agents↗
PubMed2003

Monozygotic twins discordant for attention-deficit/hyperactivity disorder: ascertainment and clinical characteristics.

OBJECTIVE: Nongenetic factors and phenomenology of attention-deficit/hyperactivity disorder (ADHD) were examined in monozygotic (MZ) twin pairs discordant for ADHD. METHOD: Recruitment included telephone screening (n = 297 pairs), behavioral ratings obtained from parents and teachers (n = 59 pairs), and, finally, in-person assessment (n = 25 pairs; structured classroom observation, diagnostic interview, psychoeducational evaluation, birth record review, establishment of monozygosity, and anatomic brain imaging). Affected twins were further contrasted with previously studied affected singletons. RESULTS: Of the 25 MZ twin pairs qualifying for in-person evaluation, only 10 proved discordant for ADHD. Affected twins were mostly comparable with affected singletons on clinical measures, although fathers' self-ratings of childhood ADHD status were significantly lower in twins than in singletons. CONCLUSIONS: Discordance for ADHD in MZ twins appears to be ascribable to greater environmental discordance and decreased familiality. Despite these differences, affected twins were phenotypically comparable with affected singletons. Thus MZ twins discordant for ADHD, while rare, can inform research on the etiology and pathophysiology of this disorder.

Adolescent↗
PubMed2003

Clozapine pharmacokinetics in children and adolescents with childhood-onset schizophrenia.

Clozapine (CLZ) dose-related adverse effects may be more common in children than adults, perhaps reflecting developmental pharmacokinetic (PK) differences. However, no pediatric CLZ PK data are available. Accordingly, we studied CLZ and its metabolites, norclozapine (NOR), and clozapine-N-oxide (NOX) in six youth, ages 9-16 years, with childhood onset schizophrenia (COS). At the time of the PK study, mean CLZ dose was 200 mg (3.4 mg/kg). Serum was collected during week 6 on CLZ before and 0.5-8 h after a morning dose. Serum concentrations were assayed by liquid chromatography/UV-detection. Mean concentration, area-under-the-curve (AUC), and clearance were calculated. CLZ clearance averaged 1.7 L/kg-h. NOR concentrations (410) exceeded CLZ (289) and NOX (63 ng/ml) and AUC(0-8h) of NOR (3,356) > CLZ (2,359) > NOX (559 ng/ml-h) [53, 38, and 9% of total analytes, respectively]. In adults, NOR serum concentrations on average are 10-25% < CLZ, differing significantly from our sample. Dose normalized concentrations of CLZ (mg/kg-d) did not vary with age and were similar to reported adult values. Clinical improvement seen in 5/6 patients correlated with serum CLZ concentrations. In addition, clinical response and total number of side effects correlated with NOR concentrations. NOR (a neuropharmacologically active metabolite) and free CLZ may contribute to the effectiveness and adverse effects in youth.

Adolescent↗
PubMed2003

An immunological marker (D8/17) associated with rheumatic fever as a predictor of childhood psychiatric disorders in a community sample.

BACKGROUND: Previous studies have documented that various behavioral disturbances accompany Sydenham's chorea, a neurologic variant of rheumatic fever. Further, an immunological marker associated with rheumatic fever (monoclonal antibody D8/17) has been reported to be elevated in several neuropsychiatric disorders, most frequently tics and obsessive-compulsive disorder. We examined this association in a community sample of children previously identified as being D8/17 positive or negative. It was hypothesized that D8/17 positivity would predict increased rates of tics and obsessive-compulsive disorder, even in the absence of Sydenham's chorea. Possible associations with other disorders accompanying Sydenham's chorea--hyperactivity, anxiety, and depression, also were explored. METHOD: From 1991 to 1995, 2631 children (mean age = 9.6 +/- 1.6 years) from a low socioeconomic area of Mexico City were screened for the D8/17 marker. In a 2- to 5-year follow-up of 240 of these children (108 positive and 132 negative), structured psychiatric interviews and rating scales were administered to the child and main caretaker. Assessments were conducted and scored blind to the child's D8/17 status. RESULTS: No association was seen between D8/17 positivity and tics or OCD. CONCLUSION: This study failed to provide support for the generalized use of D8/17 as a marker of susceptibility to tics and OCD in a community sample.

Antibodies, Monoclonal↗
PubMed2003

Progressive loss of cerebellar volume in childhood-onset schizophrenia.

OBJECTIVE: Childhood-onset schizophrenia is a severe and unremitting form of the disorder. Prospective brain magnetic resonance imaging (MRI) studies have found progressive loss of total cerebral volume during adolescence, primarily attributable to accelerated loss of cortical gray matter. Because there is evidence of cerebellar involvement in schizophrenia, the authors examined cerebellar volume and its relation to cortical gray matter development during adolescence in patients with childhood-onset schizophrenia and healthy comparison subjects. METHOD: Total cerebellar volume was algorithmically calculated for 108 anatomical brain MRI scans from 50 patients (20 of whom were female) and 101 scans from 50 age- and gender-matched healthy volunteers (20 of whom were female). The age range of the patients and comparison subjects was 8 to 24. Midsagittal vermal area and posterior-inferior vermal lobe volume were measured by hand. Prospective rescans were obtained at approximately 2-year intervals. Cross-sectional and longitudinal data were combined in mixed model regressions to compare developmental changes for the groups. RESULTS: In contrast to healthy volunteers, patients with schizophrenia showed a progressive loss of cerebellar volume during adolescence. Cerebellar and cerebral volume decreases were significantly correlated in childhood-onset schizophrenia. CONCLUSIONS: Childhood-onset schizophrenia is associated with significant progressive loss of cerebellar volume during adolescence, consistent with previously reported decreases in total cerebral and cortical gray matter. At least in these patients with severe early-onset schizophrenia, the loss appears secondary to a generalized process.

Adolescent↗
PubMed2003

Progressive brain volume loss during adolescence in childhood-onset schizophrenia.

OBJECTIVE: Previous reports have documented a striking progressive reduction in cortical gray matter volume during adolescence in patients with childhood-onset schizophrenia. This study examined the rate of loss in cortical gray matter volume in relation to age and clinical status in adolescent patients over a follow-up period of 2-6 years. METHOD: A total of 131 brain magnetic resonance imaging scans were acquired for 60 subjects with childhood-onset schizophrenia (mean age=14.5 years, SD=2.5), and 140 scans were acquired for 64 matched healthy comparison subjects. One or more follow-up scans were acquired at approximately 2-year intervals for 39 subjects with childhood-onset schizophrenia and 43 healthy subjects. Developmental trajectories for total and regional brain volumes were examined in relation to age by using polynomial growth models and data from all available scans. The rate of gray matter reduction in patients with childhood-onset schizophrenia was examined in relation to developmental and clinical measures by using stepwise regression. RESULTS: Rates of brain volume reduction were significantly higher for patients with childhood-onset schizophrenia than for healthy comparison subjects. In childhood-onset schizophrenia, the rate of gray matter reduction was related to premorbid impairment and baseline severity of clinical symptoms but not to gender, ethnicity, or age at onset of the disorder. Unexpectedly, greater clinical improvement was significantly related to a higher rate of gray matter reduction. Longitudinal trajectories suggested that the rate of cortical loss plateaus during adolescence. CONCLUSIONS: Striking loss of cerebral gray matter is seen through adolescence in patients with childhood-onset schizophrenia. The rate of reduction was related to premorbid impairment and baseline symptom severity, but it may also be in part a plastic response to illness.

Adolescent↗
PubMed2003

Parental schizophrenia spectrum disorders in childhood-onset and adult-onset schizophrenia.

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

Adult↗
PubMed2003

Structural brain MRI abnormalities in healthy siblings of patients with childhood-onset schizophrenia.

OBJECTIVE: Childhood-onset schizophrenia shows progressive brain magnetic resonance imaging (MRI) changes during adolescence, which follow a back-to-front "wave." The authors' goal was to examine whether healthy siblings of patients with childhood-onset schizophrenia show structural brain abnormalities and the age-related pattern of abnormalities seen in patients with childhood-onset schizophrenia. METHOD: Anatomic brain MRI scans were obtained from 15 psychiatrically healthy full siblings of 15 patients with childhood-onset schizophrenia and from 32 matched community volunteers. Automated measures were used to compare total and regional brain volumes of the siblings and volunteers. RESULTS: Siblings of patients with childhood-onset schizophrenia had smaller total cerebral volume and total, frontal, and parietal gray matter volumes than volunteers. When divided into younger and older groups, younger siblings had smaller parietal gray matter volumes and older siblings showed trends for smaller total and frontal gray matter volumes. CONCLUSIONS: Healthy siblings of patients with childhood-onset schizophrenia share brain MRI abnormalities with the patients that may follow a similar pattern of progression. Developmental brain abnormalities in childhood-onset schizophrenia may thus be genetic trait markers.

Adolescent↗
PubMed2003

Anatomic brain abnormalities in monozygotic twins discordant for attention deficit hyperactivity disorder.

OBJECTIVE: To examine brain-behavior relationships in attention deficit hyperactivity disorder (ADHD), the authors obtained magnetic resonance imaging (MRI) scans of monozygotic twins discordant for ADHD. METHOD: National recruitment was followed by in-person assessment. MRI scans were measured algorithmically for nine pairs of monozygotic twins discordant for ADHD. RESULTS: The affected twins had significantly smaller caudate volumes (mean difference=-0.56 ml, CI=-0.92 to -0.21) than their unaffected co-twins. CONCLUSIONS: These results provide further support for striatal models of ADHD pathophysiology.

Adolescent↗
PubMed2002

Genetic variation in the 22q11 locus and susceptibility to schizophrenia.

An increased prevalence of microdeletions at the 22q11 locus has been reported in samples of patients with schizophrenia. 22q11 microdeletions represent the highest known genetic risk factor for the development of schizophrenia, second only to that of the monozygotic cotwin of an affected individual or the offspring of two schizophrenic parents. It is therefore clear that a schizophrenia susceptibility locus maps to chromosome 22q11. In light of evidence for suggestive linkage for schizophrenia in this region, we hypothesized that, whereas deletions of chromosome 22q11 may account for only a small proportion of schizophrenia cases in the general population (up to approximately 2%), nondeletion variants of individual genes within the 22q11 region may make a larger contribution to susceptibility to schizophrenia in the wider population. By studying a dense collection of markers (average one single nucleotide polymorphism20 kb over 1.5 Mb) in the vicinity of the 22q11 locus, in both family- and population-based samples, we present here results consistent with this assumption. Moreover, our results are consistent with contribution from more than one gene to the strikingly increased disease risk associated with this locus. Finer-scale haplotype mapping has identified two subregions within the 1.5-Mb locus that are likely to harbor candidate schizophrenia susceptibility genes.

Amino Acid Sequence↗
PubMed2002

Developmental trajectories of brain volume abnormalities in children and adolescents with attention-deficit/hyperactivity disorder.

CONTEXT: Various anatomic brain abnormalities have been reported for attention-deficit/hyperactivity disorder (ADHD), with varying methods, small samples, cross-sectional designs, and without accounting for stimulant drug exposure. OBJECTIVE: To compare regional brain volumes at initial scan and their change over time in medicated and previously unmedicated male and female patients with ADHD and healthy controls. DESIGN, SETTING, AND PARTICIPANTS: Case-control study conducted from 1991-2001 at the National Institute of Mental Health, Bethesda, Md, of 152 children and adolescents with ADHD (age range, 5-18 years) and 139 age- and sex-matched controls (age range, 4.5-19 years) recruited from the local community, who contributed 544 anatomic magnetic resonance images. MAIN OUTCOME MEASURES: Using completely automated methods, initial volumes and prospective age-related changes of total cerebrum, cerebellum, gray and white matter for the 4 major lobes, and caudate nucleus of the brain were compared in patients and controls. RESULTS: On initial scan, patients with ADHD had significantly smaller brain volumes in all regions, even after adjustment for significant covariates. This global difference was reflected in smaller total cerebral volumes (-3.2%, adjusted F(1,280) = 8.30, P =.004) and in significantly smaller cerebellar volumes (-3.5%, adjusted F(1,280) = 12.29, P =.001). Compared with controls, previously unmedicated children with ADHD demonstrated significantly smaller total cerebral volumes (overall F(2,288) = 6.65; all pairwise comparisons Bonferroni corrected, -5.8%; P =.002) and cerebellar volumes (-6.2%, F( 2,288) = 8.97, P<.001). Unmedicated children with ADHD also exhibited strikingly smaller total white matter volumes (F(2,288) = 11.65) compared with controls (-10.7%, P<.001) and with medicated children with ADHD (-8.9%, P<.001). Volumetric abnormalities persisted with age in total and regional cerebral measures (P =.002) and in the cerebellum (P =.003). Caudate nucleus volumes were initially abnormal for patients with ADHD (P =.05), but diagnostic differences disappeared as caudate volumes decreased for patients and controls during adolescence. Results were comparable for male and female patients on all measures. Frontal and temporal gray matter, caudate, and cerebellar volumes correlated significantly with parent- and clinician-rated severity measures within the ADHD sample (Pearson coefficients between -0.16 and -0.26; all P values were <.05). CONCLUSIONS: Developmental trajectories for all structures, except caudate, remain roughly parallel for patients and controls during childhood and adolescence, suggesting that genetic and/or early environmental influences on brain development in ADHD are fixed, nonprogressive, and unrelated to stimulant treatment.

Adolescent↗
PubMed2002

Genetic variation at the 22q11 PRODH2/DGCR6 locus presents an unusual pattern and increases susceptibility to schizophrenia.

The location of a schizophrenia susceptibility locus at chromosome 22q11 has been suggested by genome-wide linkage studies. Additional support was provided by the observation of a higher-than-expected frequency of 22q11 microdeletions in patients with schizophrenia and the demonstration that approximately 20-30% of individuals with 22q11 microdeletions develop schizophrenia or schizoaffective disorder in adolescence and adulthood. Analysis of the extent of these microdeletions by using polymorphic markers afforded further refinement of this locus to a region of approximately 1.5 Mb. Recently, a high rate of 22q11 microdeletions was also reported for a cohort of 47 patients with Childhood Onset Schizophrenia, a rare and severe form of schizophrenia with onset by age 13. It is therefore likely that this 1.5-Mb region contains one or more genes that predispose to schizophrenia. In three independent samples, we provide evidence for a contribution of the PRODH2/DGCR6 locus in 22q11-associated schizophrenia. We also uncover an unusual pattern of PRODH2 gene variation that mimics the sequence of a linked pseudogene. Several of the pseudogene-like variants we identified result in missense changes at conserved residues and may prevent synthesis of a fully functional enzyme. Our results have implications for understanding the genetic basis of the 22q11-associated psychiatric phenotypes and provide further insights into the genomic instability of this region.

Africa↗
PubMed2002

Correlation of antipsychotic and prolactin concentrations in children and adolescents acutely treated with haloperidol, clozapine, or olanzapine.

Patients with a Diagnostic and Statistical Manual of Mental Disorders (third edition, revised) diagnosis of schizophrenia or psychotic disorder not otherwise specified with onset of psychosis before the age of 13 participated in 6- to 8-week open or double-blind trials of haloperidol (n = 15, mean dose 15.4 +/- 8.1 mg/day [0.27 +/- 0.15 mg/kg/day]), clozapine (n = 30, mean dose 269.9 +/- 173.3 mg/day [4.4 +/- 2.6 mg/kg/day]), or olanzapine (n = 12, mean dose 17.5 +/- 2.8 mg/day [0.30 +/- 0.13 mg/kg/day]). Blood samples were obtained at 6 weeks for evaluation of haloperidol, reduced haloperidol, clozapine, desmethylclozapine, and olanzapine plasma concentrations and serum prolactin concentrations. No gender differences were noted for antipsychotic dose or concentration within each treatment group. Correlations between antipsychotic plasma concentration and serum prolactin concentration were significant only for the olanzapine treatment group (r = 0.80, p = 0.002). Separate correlations for gender were significant only for females receiving olanzapine (r = 0.91, p = 0.03); the patient with the highest serum prolactin experienced galactorrhea. Further studies evaluating the prolactin-elevating properties of antipsychotics are warranted in this population.

Adolescent↗