Julia W Tossell

National Institute of Mental Health (NIMH), Bethesda, MD, United States

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Publications (22)131.85 Total impact

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    ABSTRACT: Abstract Objective: The purpose of this study was to retrospectively analyze rates of neutropenia and risk factors for neutropenia in hospitalized children and adolescents treated with clozapine. Methods: A retrospective chart review was conducted for all patients who received clozapine at any time during a hospitalization at the National Institute of Mental Health (NIMH) between 1990 and 2011. All patients satisfied screening criteria for the NIMH childhood-onset schizophrenia study, including onset of psychosis before the age of 13 years. Absolute neutrophil count (ANC) values recorded during inpatient hospitalization were extracted for 87 eligible patients with a mean age of 13.35±2.46 years at hospitalization and a mean length of stay of 117±43 days. Results: Mild neutropenia only (lowest ANC<2000/mm(3) but>1500/mm(3)) was observed in 27 (31%) patients and moderate neutropenia (any ANC<1500/mm(3)) was observed in 17 (20%) patients. There were no cases of agranulocytosis or severe infection. Significant risk factors for mild neutropenia compared with no hematologic adverse effects (HAEs) were male gender (p=0.012) and younger age (p<0.001). Male gender was also a significant risk factor for moderate neutropenia compared with no HAEs (p=0.003). If a child of African American ethnicity developed neutropenia during hospitalization at all that child was significantly more likely to develop moderate neutropenia than mild neutropenia only (p=0.017). African American boys had the highest rate of moderate neutropenia at 47%. Sixteen of the 17 patients exhibiting moderate neutropenia were successfully treated with clozapine by the time of discharge; 8 of these 16 required adjunctive lithium carbonate administration to maintain ANC>2000/mm(3). Conclusions: Our study shows that the rates of neutropenia in clozapine-treated children and adolescents are considerably higher than in the adult population. Younger age, African American ethnicity, and male gender were significant risk factors. These are also risk factors for benign neutropenia in healthy children and adolescents. Despite these high rates of neutropenia, all but one of the patients with neutropenia during hospitalization were successfully discharged on clozapine.
    Journal of child and adolescent psychopharmacology 03/2013; 23(2):110-6. · 2.59 Impact Factor
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    ABSTRACT: 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. This study aims to investigate the tolerability aspects of tDCS in the childhood-onset schizophrenia (COS) population. 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). tDCS was well tolerated in the COS population with no serious adverse events occurring during the study. 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.
    Brain Stimulation 10/2011; 4(4):275-80. · 4.54 Impact Factor
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    ABSTRACT: Cortical gray matter (GM) abnormalities in patients with childhood-onset schizophrenia (COS) progress during adolescence ultimately localizing to prefrontal and temporal cortices by early adult age. A previous study of 52 nonpsychotic siblings of COS probands had significant prefrontal and temporal GM deficits that appeared to "normalize" by age 17 years. Here we present a replication with nonoverlapping groups of healthy full siblings and healthy controls. Using an automated measure and prospectively acquired anatomical brain magnetic resonance images, we mapped cortical GM thickness in nonpsychotic full siblings (n = 43, 68 scans; ages 5 through 26 years) of patients with COS, contrasting them with age-, gender-, and scan interval-matched healthy controls (n = 86, 136 scans). The false-discovery rate procedure was used to control for type I errors due to multiple comparisons. As in our previous study, young nonpsychotic siblings (<17 years) showed significant GM deficits in bilateral prefrontal and left temporal cortices and, in addition, smaller deficits in the parietal and right inferior temporal cortices. These deficits in nonpsychotic siblings normalized with age with minimal abnormalities remaining by age 17. Our results support previous findings showing nonpsychotic siblings of COS probands to have early GM deficits that ameliorate with time. At early ages, prefrontal and/or temporal loss may serve as a familial/trait marker for COS. Late adolescence appears to be a critical period for greatest localization of deficits in probands or normalization in nonpsychotic siblings.
    Journal of the American Academy of Child and Adolescent Psychiatry 07/2011; 50(7):697-704. · 6.97 Impact Factor
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    ABSTRACT: To document high rates and clinical correlates of nonauditory hallucinations in childhood onset schizophrenia (COS). Within a sample of 117 pediatric patients (mean age 13.6 years), diagnosed with COS, the presence of auditory, visual, somatic/tactile, and olfactory hallucinations was examined using the Scale for the Assessment of Positive Symptoms (SAPS). We also compared hallucination modality membership (presence/absence) groups on gender, socioeconomic status, ethnicity, age of onset (of psychosis), Full Scale IQ, Verbal IQ, and clinical severity (Children's Global Assessment Scale [CGAS) and Scale for the Assessment of Negative Symptoms [SANS]). A total of 111 COS patients (94.9%) had auditory and 94 patients (80.3%) had visual hallucinations. Somatic/tactile (60.7%) and olfactory (29.9%) hallucinations occurred almost exclusively in patients who also had visual hallucinations. Children who had visual hallucinations had lower IQ, earlier age of onset, and more severe illness relative to children who did not have visual hallucinations. In this study, we observed that patients with COS have high rates of hallucinations across all modalities. An increased rate of visual hallucinations is associated with greater clinical impairment and greater compromise in overall brain functioning. Somatic and olfactory hallucinations reflect an additive rather than alternative symptom pattern.
    Journal of the American Academy of Child and Adolescent Psychiatry 07/2011; 50(7):681-686.e3. · 6.97 Impact Factor
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    ABSTRACT: Background: Progressive cortical gray matter (GM) abnormalities are an established feature of schizophrenia and are more pronounced in rare, severe, and treatment refractory childhood-onset schizophrenia (COS) cases. The effect of sex on brain development in schizophrenia is poorly understood and studies to date have produced inconsistent results. Methods: Using the largest to date longitudinal sample of COS cases (n = 104, scans = 249, Male/Female [M/F] = 57/47), we compared COS sex differences with sex differences in a sample of matched typically developing children (n = 104, scans = 244, M/F = 57/47), to determine whether or not sex had differential effects on cortical and subcortical brain development in COS. RESULTS:  Our results showed no significant differential sex effects in COS for either GM cortical thickness or subcortical volume development (sex × diagnosis × age interaction; false discovery rate q = 0.05). Conclusion: Sex appears to play a similar role in cortical and subcortical GM development in COS as it does in normally developing children.
    Schizophrenia Bulletin 06/2011; · 8.80 Impact Factor
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    Molecular psychiatry 09/2010; · 15.05 Impact Factor
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    ABSTRACT: Childhood-onset schizophrenia (COS) is a rare, severe form of the adult-onset illness, with more salient neurobiological causes. Previous cross-sectional structural neuroimaging research has suggested that normal cortical asymmetry patterns [(R-L)/(R+L)] may be altered in adult schizophrenia, although these findings were not well replicated. Recent studies show dynamic changes in brain asymmetry during childhood and adolescence. We hypothesized that COS patients would show a lack of normal development of asymmetry and decreased overall asymmetry. Prospective structural magnetic resonance scans were obtained at baseline and at two-year follow-up visits in 49 right-handed COS patients (mean baseline age: 14.72+/-2.63, 117 scans) and 50 age and sex-matched, right-handed healthy controls (mean baseline age: 15.15+/-3.37, 125 scans). Cortical thickness was calculated at 40,962 homologous points across each cerebral hemisphere using a fully automated, validated method. Differences in developmental asymmetry patterns across the cortical surface were analyzed using a linear mixed effects regression model. No significant asymmetry differences were found either for cross-sectional comparisons of COS and healthy controls across the lateral and medial cortical surfaces or with respect to timing of developmental changes in asymmetry. The present findings do not support asymmetry differences for this severe, early form of schizophrenia.
    Schizophrenia Research 10/2009; 115(1):12-6. · 4.59 Impact Factor
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    ABSTRACT: Clozapine, a dibenzodiazepine antipsychotic, is the most effective medication for treatment-resistant schizophrenia. However, its use has been limited by the high risk of neutropenia. In children, the rate of neutropenia is higher when compared to adults. We decided to explore the use of lithium to manage neutropenia in childhood-onset schizophrenia (COS) through a systematic audit of COS cases. Medical records were reviewed for patients with COS who had been treated with the combination of clozapine and lithium carbonate. Seven patients were found to have been treated with both clozapine and lithium. After initiation of lithium, ANC increased significantly in six out of seven subjects by 29 to 106% with a mean of 66%. In addition, six out of seven subjects continued using both clozapine and lithium for over 2 years (range: 2.0-7.2 years) and do not have immediate plans for discontinuation of either medications. Our study bolsters support for the use of lithium in the management of neutropenia in children treated with clozapine. Although the coadministration of lithium and clozapine appears effective in the management of neutropenia, it is not without its risks and clinicians must be diligent in their joint use of these medications.
    Human Psychopharmacology Clinical and Experimental 09/2009; 24(7):584-9. · 2.10 Impact Factor
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    ABSTRACT: Many cognitive, emotional and behavioural traits, as well as psychiatric disorders are highly heritable. However, identifying the specific genes and mechanisms by which this heritability manifests has been elusive. One approach to make this problem more tractable has been to attempt to identify and quantify biological markers that are intermediate steps along the gene-to-behaviour path. The field of neuroimaging offers several anatomic and physiologic possibilities to quantify. Stability over time has been proposed as a desired feature for these intermediate phenotypes. However, in this paper we discuss the value of looking at trajectories of anatomic brain development (i.e. morphometric changes over time), as opposed to static measures, as a phenotype. Examples drawn from longitudinal anatomic magnetic resonance imaging studies of typical development, attention deficit/hyperactivity disorder, and childhood-onset schizophrenia are used to demonstrate the utility of trajectories of brain development as a phenotypic bridge between genes and behaviour in health and in illness.
    Novartis Foundation symposium 02/2008; 289:101-12; discussion 112-8, 193-5.
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    ABSTRACT: 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. 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. 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. The NDMC/clozapine ratio may be a valuable predictor of response to clozapine and may suggest new approaches to clozapine treatment.
    Journal of the American Academy of Child & Adolescent Psychiatry 10/2007; 46(10):1349-56. · 6.97 Impact Factor
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    ABSTRACT: An extra X chromosome in males (XXY), known as Klinefelter syndrome, is associated with characteristic physical, cognitive, and behavioral features of variable severity. The objective of this study was to examine possible neuroanatomical substrates of these cognitive and behavioral features during childhood and adolescence. MRI brain scans were acquired for 42 XXY and 87 healthy XY age-matched control males. We compared these 2 groups on regional brain volumes and cortical thickness. Total cerebral volume and all lobar volumes except parietal white matter were significantly smaller in the XXY group, whereas lateral-ventricle volume was larger. Consistent with the cognitive profile, the cortex was significantly thinner in the XXY group in left inferior frontal, temporal, and superior motor regions. The brain-imaging findings of preferentially affected frontal, temporal, and motor regions and relative sparing of parietal regions are consistent with observed cognitive and behavioral strengths and weaknesses in XXY subjects.
    PEDIATRICS 02/2007; 119(1):e232-40. · 4.47 Impact Factor
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    ABSTRACT: 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.
    Schizophrenia Research 09/2006; 86(1-3):123-9. · 4.59 Impact Factor
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    ABSTRACT: 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. To compare the efficacy and safety of olanzapine and clozapine, hypothesizing that clozapine would be more efficacious. Double-blind randomized 8-week controlled trial, with a 2-year open-label follow-up. National Institute of Mental Health study, January 1998 to June 2005. Patients underwent reassessment 2 years after discharge. 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. 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). The Clinical Global Impression Severity of Symptoms Scale and Schedule for the Assessment of Negative/Positive Symptoms. 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). 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.
    Archives of General Psychiatry 08/2006; 63(7):721-30. · 13.77 Impact Factor
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    ABSTRACT: Puberty is a time of striking changes in cognition and behavior. To indirectly assess the effects of puberty-related influences on the underlying neuroanatomy of these behavioral changes we will review and synthesize neuroimaging data from typically developing children and adolescents and from those with anomalous hormone or sex chromosome profiles. The trajectories (size by age) of brain morphometry differ between boys and girls, with girls generally reaching peak gray matter thickness 1-2 years earlier than boys. Both boys and girls with congenital adrenal hyperplasia (characterized by high levels of intrauterine testosterone), have smaller amygdala volume but the brain morphometry of girls with CAH did not otherwise significantly differ from controls. Subjects with XXY have gray matter reductions in the insula, temporal gyri, amygdala, hippocampus, and cingulate-areas consistent with the language-based learning difficulties common in this group.
    Molecular and Cellular Endocrinology 08/2006; 254-255:154-62. · 4.04 Impact Factor
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    ABSTRACT: Weight gain is a serious side effect of atypical antipsychotics, especially in childhood. In this study, the authors examined six weight gain-related hormones in patients with childhood-onset schizophrenia (COS) after 6 weeks of clozapine treatment. Fasting serum samples for 24 patients with COS and 21 matched healthy controls (HC) were obtained. Levels of leptin, insulin, adiponectin, amylin, ghrelin, and tumor necrosis factor alpha were measured and compared between the groups. For 23 patients with COS, hormonal levels were measured at background and week 6 of clozapine treatment. Change in body mass index was correlated with levels of clozapine and changes in hormonal levels and clinical ratings. At baseline, COS did not differ significantly from HC on any hormonal measure. Clozapine treatment was associated with significant (7.9% +/- 8.5%) increase in mean body mass index. Only leptin levels increased significantly from baseline to week 6 on clozapine (p = .003). Body mass index increase was significantly correlated with decrease in ghrelin and adiponectin and was positively correlated with clinical improvement. This is the first study of weight gain-related hormones in children on clozapine. Hormonal changes are correlated with weight gain. How effectiveness of clozapine is linked to weight gain remains uncertain.
    Journal of the American Academy of Child & Adolescent Psychiatry 10/2005; 44(9):925-33. · 6.97 Impact Factor
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    ABSTRACT: Long-term outcomes in children with atypical psychosis have been poorly studied. Four to 6 weeks of inpatient observation and up to 11 years (mean, 4.0 +/- 1.3 years) of follow- up have afforded us some experience with this probably heterogeneous group of transiently psychotic patients commonly mislabeled as schizophrenic. Despite severe preadmission morbidity, some patients have successfully remained neuroleptic-free since discharge. Predictors of good versus poor outcome were sought. Of roughly 150 patients admitted with the presumptive diagnosis of schizophrenia, 32 patients were discharged meeting criteria for psychosis not otherwise specified (NOS), otherwise labeled by the NIMH team as "multidimensionally impaired" (MDI). Admission and biannual follow-up data included a semistructured clinical interview with the Schedule for Affective Disorders and Schizophrenia for School Age Children (K-SADS), IQ testing, clinical rating scales (e.g., Clinical Global Impression Scale (CGI), Children's Global Assessment Scale (C-GAS), Brief Psychiatric Rating Scale (BPRS), Scales for the Assessment Negative and Positive Symptoms (SANS and SAPS), and Bunney-Hamburg (B-H)). At follow-up (as of February 2005) 38% of patients (12 of 32) met criteria for bipolar 1 disorder, 12% (4 of 23) for major depressive disorder (MDD), and 3% (1 of 32) for schizoaffective disorder. The remaining 47% of patients (15 of 32) were divided into two groups on the basis of whether they were in remission and neuroleptic-free ("good outcome," n = 5) or still severely impaired and/or psychotic regardless of pharmacotherapy ("poor outcome," n = 10) at follow-up. Good-outcome patients had a significantly higher baseline level of functioning (on admission and on medications). This was demonstrated by better scores on CGI (3.5 +/- 0.6 versus 4.8 +/- 0.8; p = 0.03) and C-GAS (66.3 +/- 6.3 versus 38.6 +/- 11.5; p = 0.01). Groups were otherwise comparable in demographic data (gender, race, socioeconomic status, age at onset), months of neuroleptic exposure, severity of psychotic symptoms, and level of premorbid functioning. C-GAS (which correctly classified 85.7% of good-outcome subjects) and CGI at baseline appear to predict outcome. On other variables, MDI subgroups were remarkably similar.
    Journal of Child and Adolescent Psychopharmacology 07/2005; 15(3):510-9. · 2.77 Impact Factor
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    ABSTRACT: Extensive experience with the diagnosis of childhood-onset schizophrenia indicates a high rate of false positives. Most mislabeled patients have chronic disabling, affective, or behavioral disorders. The authors report the cases of three children who passed stringent initial childhood-onset schizophrenia "screens" but had no chronic psychotic disorder. For two, the European literature yielded more fitting diagnoses: psychosis not otherwise specified (e.g., reactive or psychogenic psychosis, paranoid schizophrenia), single episode in full remission (e.g., anxiety psychosis), and factitious disorder (DSM-IV 300.16). These cases illustrate that transient psychotic illnesses can be misdiagnosed as childhood-onset schizophrenia. Proper identification can prevent years of inappropriate therapies.
    Journal of the American Academy of Child & Adolescent Psychiatry 09/2004; 43(8):1026-9. · 6.97 Impact Factor
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    ABSTRACT: Childhood-onset schizophrenia (COS) is a severe form of the adult-onset disorder with a high rate of premorbid developmental abnormalities. Early symptoms of pervasive developmental disorder (PDD) have been reported in five independent studies of COS. In this study, we compared evidence for premorbid PDD as a nonspecific manifestation of impaired neurodevelopment seen in schizophrenia, or as an independent risk factor for COS. Diagnosis of past or current autism or PDD was made according to the DSM-IV criteria. COS patients with and without PDD were compared with respect to neuropsychological, clinical, and neurobiological measures. Several candidate genes for autism were examined in the entire COS sample and the subgroup with PDD using the Transmission Disequilibrium Test (TDT) and Quantitative TDT (QTDT). Nineteen (25%) of COS probands had a lifetime diagnosis of PDD: one met criteria for autism, two for Asperger's disorder, and 16 for PDD not otherwise specified. Premorbid social impairment was most common feature for COS-PDD subjects. The PDD group did not differ from the rest of the COS sample with respect to age of onset, IQ, response to medications, and rate of familial schizotypy. Unexpectedly, two siblings of COS-PDD probands met criteria for nuclear autism. There was no difference between PDD and non-PDD groups with respect to initial brain magnetic resonance imaging (MRI) measures. However, rate of gray matter loss was greater for PDD (n = 12) than for the non-PDD (n = 27) subgroup (-19.5 +/- 11.3 mL/year vs. -9.6 +/- 15.3 mL/year; p =.05). None of eight candidate genes for autism were associated with COS or COS-PDD. Premorbid PDD in COS is more likely to be a nonspecific marker of severe early abnormal neurodevelopment. However, the occurrence of two siblings of COS-PDD probands (17%) with nuclear autism remains to be understood.
    Biological Psychiatry 06/2004; 55(10):989-94. · 9.25 Impact Factor
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    Molecular Psychiatry 04/2004; 9(3):225-6. · 14.90 Impact Factor
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    ABSTRACT: The administration of psychostimulants to children with psychotic symptoms is controversial. This study reports the stimulant drug response of 5 children, aged 8-15 years, with childhood-onset schizophrenia (COS) and comorbid attention deficit hyperactivity disorder (ADHD). Four COS inpatients were given stimulants for comorbid ADHD after stabilization of psychosis on antipsychotic medication. A fifth COS inpatient received stimulants while still actively psychotic, despite concurrent neuroleptic treatment. Data from the 10-item Brief Conners Teachers Ratings Scale (BCTRS) were examined the week before, and the week after, stimulant addition. A paired t test, conducted using Conners Teachers data from these 4 subjects, indicated significant improvement in ADHD symptoms (p = 0.02). Data obtained from a retrospective chart review indicated no significant worsening of psychosis. The 2 subjects treated with mixed salts of dextroamphetamine sulfate and amphetamine sulfate remained on that medication at 6 months and at the 2-year follow-up. Our results suggest that ADHD comorbid with COS may be safely treated with a stimulant, once the psychosis is stabilized. A systematic investigation of this question may be warranted.
    Journal of Child and Adolescent Psychopharmacology 02/2004; 14(3):448-54. · 2.77 Impact Factor