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Jean A Frazier,
Anthony J Giuliano,
Jacqueline L Johnson,
Lauren Yakutis,
Eric A Youngstrom,
David Breiger,
Linmarie Sikich,
Robert L Findling, Jon McClellan,
Robert M Hamer,
Benedetto Vitiello,
Jeffrey A Lieberman,
Stephen R Hooper
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ABSTRACT: To assess neurocognitive outcomes following antipsychotic intervention in youth enrolled in the National Institute of Mental Health (NIMH)-funded Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS).
Neurocognitive functioning of youth (ages 8 to 19 years) with schizophrenia or schizoaffective disorder was evaluated in a four-site, randomized, double-blind clinical trial comparing molindone, olanzapine, and risperidone. The primary outcomes were overall group change from baseline in neurocognitive composite and six domain scores after 8 weeks and continued treatment up to 52 weeks. Age and sex were included as covariates in all analyses.
Of 116 TEOSS participants, 77 (66%) had post-baseline neurocognitive data. No significant differences emerged in the neurocognitive outcomes of the three medication groups. Therefore, the three treatment groups were combined into one group to assess overall neurocognitive outcomes. Significant modest improvements were observed in the composite score and in three of six domain scores in the acute phase, and in four of six domain scores in the combined acute and maintenance phases. Partial correlation analyses revealed very few relationships among Positive and Negative Syndrome Scale (PANSS) baseline or change scores and neurocognition change scores.
Antipsychotic intervention in youth with early-onset schizophrenia spectrum disorders (EOSS) led to modest improvement in measures of neurocognitive function. The changes in cognition were largely unrelated to baseline symptoms or symptom change. Small treatment effect sizes, easily accounted for by practice effects, highlight the critical need for the development of more efficacious interventions for the enduring neurocognitive deficits seen in EOSS. Clinical trial registry information-Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS); http://www.clinicaltrials.gov; NCT00053703.
Journal of the American Academy of Child and Adolescent Psychiatry 05/2012; 51(5):496-505. · 4.98 Impact Factor
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Jon McClellan
Journal of the American Academy of Child and Adolescent Psychiatry 07/2011; 50(7):642-4. · 4.98 Impact Factor
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Robert L Findling,
Vivian Kafantaris,
Mani Pavuluri,
Nora K McNamara, Jon McClellan,
Jean A Frazier,
Linmarie Sikich,
Robert Kowatch,
Jacqui Lingler,
Jon Faber,
Brieana M Rowles,
Traci E Clemons,
Perdita Taylor-Zapata
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ABSTRACT: The primary goal of this exploratory study was to obtain data that could lead to evidence-based dosing strategies for lithium in children and adolescents suffering from bipolar I disorder.
Outpatients aged 7-17 years meeting Diagnostic and Statistical Manual of Mental Disorders, 4th edition, diagnostic criteria for bipolar I disorder (manic or mixed) were eligible for 8 weeks of open label treatment with lithium in one of three dosing arms. In Arm I, participants began treatment at a dose of 300 mg of lithium twice daily. The starting dose of lithium in Arms II and III was 300 mg thrice daily. Patients in Arms I and II could have their dose increased by 300 mg/day, depending on clinical response, at weekly visits. Patients in Arm III also had mid-week telephone interviews after which they could also have their dose of lithium increased by 300 mg per day. Youths weighing <30 kg were automatically assigned to Arm I, whereas youths weighing ≥30 kg were randomly assigned to Arm I, II, or III. Randomization was balanced by age (7-11 years, 12-17 years) and sex in approximately equal numbers. A priori response criteria were defined as a Clinical Global Impressions-Improvement scale score of ≤ 2 and a 50% decrease from baseline on the Young Mania Rating Scale.
Of the 61 youths [32 males (52.5%)] who received open-label lithium, 60 youths completed at least 1 week of treatment and returned for a postbaseline assessment. Most patients had a ≥ 50% improvement in Young Mania Rating Scale score, and more than half of the patients (58%) achieved response. Overall, lithium was well tolerated. All three treatment arms had similar effectiveness, side effect profiles, and tolerability of lithium.
On the basis of these results, a dosing strategy in which pediatric patients begin lithium at a dose of 300 mg thrice daily (with an additional 300 mg increase during the first week), followed by 300 mg weekly increases until a priori stopping criteria are met, will be used in an upcoming randomized, placebo-controlled trial.
Journal of child and adolescent psychopharmacology 06/2011; 21(3):195-205. · 2.59 Impact Factor
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ABSTRACT: The past 5 five years have seen major advances in the diagnosis and treatment of schizophrenia in children and adolescents. This article, reviews the clinical and diagnostic characteristics of schizophrenia in youth with an eye toward recent findings. This article also provides a more extensive review and update of the psychopharmacology of early-onset schizophrenia.
Pediatric Clinics of North America 02/2011; 58(1):205-18, xii. · 2.24 Impact Factor
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Vladimir Vacic,
Shane McCarthy,
Dheeraj Malhotra,
Fiona Murray,
Hsun-Hua Chou,
Aine Peoples,
Vladimir Makarov,
Seungtai Yoon,
Abhishek Bhandari,
Roser Corominas, [......],
Derek W Morris,
Michael Gill,
Aiden Corvin,
Paul A Insel, Jon McClellan,
Mary-Claire King,
Maria Karayiorgou,
Deborah L Levy,
Lynn E DeLisi,
Jonathan Sebat
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ABSTRACT: Rare copy number variants (CNVs) have a prominent role in the aetiology of schizophrenia and other neuropsychiatric disorders. Substantial risk for schizophrenia is conferred by large (>500-kilobase) CNVs at several loci, including microdeletions at 1q21.1 (ref. 2), 3q29 (ref. 3), 15q13.3 (ref. 2) and 22q11.2 (ref. 4) and microduplication at 16p11.2 (ref. 5). However, these CNVs collectively account for a small fraction (2-4%) of cases, and the relevant genes and neurobiological mechanisms are not well understood. Here we performed a large two-stage genome-wide scan of rare CNVs and report the significant association of copy number gains at chromosome 7q36.3 with schizophrenia. Microduplications with variable breakpoints occurred within a 362-kilobase region and were detected in 29 of 8,290 (0.35%) patients versus 2 of 7,431 (0.03%) controls in the combined sample. All duplications overlapped or were located within 89 kilobases upstream of the vasoactive intestinal peptide receptor gene VIPR2. VIPR2 transcription and cyclic-AMP signalling were significantly increased in cultured lymphocytes from patients with microduplications of 7q36.3. These findings implicate altered vasoactive intestinal peptide signalling in the pathogenesis of schizophrenia and indicate the VPAC2 receptor as a potential target for the development of new antipsychotic drugs.
Nature 02/2011; 471(7339):499-503. · 36.28 Impact Factor
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Robert L Findling,
Cornelia B Landersdorfer,
Vivian Kafantaris,
Mani Pavuluri,
Nora K McNamara, Jon McClellan,
Jean A Frazier,
Linmarie Sikich,
Robert Kowatch,
Jacqui Lingler,
Jon Faber,
Perdita Taylor-Zapata,
William J Jusko
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ABSTRACT: This study examines the pharmacokinetics of oral doses of lithium carbonate immediate-release capsules after administration of 600 or 900 mg in children and adolescents with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, bipolar I disorder. Lithium plasma concentrations were followed over 48 to 72 hours in 39 subjects (20 male and 19 female subjects; ages, 7-17 years) with mixed or manic episodes enrolled at 7 clinical sites participating in the Collaborative Lithium Trials. Population pharmacokinetic modeling was performed using NONMEM, and influences of patient covariates on pharmacokinetics parameters were examined. The pharmacokinetics of lithium was best described using a 2-compartment model with a lag time and first-order absorption. There was considerable variability in lithium exposures. Lithium clearance related best to fat-free mass. Inclusion of fat-free mass as a covariate reduced the between-subject variability from 52% to 42%. Lithium clearances did not vary systematically with age group, dose, sex, or creatinine clearances. Allometrically scaled clearance and volume of distribution from the population analysis were within the range reported in adults. Single-dose profiles of lithium in young patients with BP-1 show marked variability. Therefore, ongoing serum monitoring is needed during continued therapy. The developed population pharmacokinetic model may be used to predict other dosage regimens, support scaling from adult to pediatric pharmacokinetics, and support the design of future clinical trials.
Journal of clinical psychopharmacology 08/2010; 30(4):404-10. · 5.09 Impact Factor
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Cell 08/2010; 142(3):353-5. · 32.40 Impact Factor
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ABSTRACT: The earth is shifting beneath psychiatric genetics. Schizophrenia and other complex neuropsychiatric disorders are characterized by genetic heterogeneity to an extent far greater than previously recognized. Individually rare mutations, many de novo and others a few generations old, may be collectively responsible for a substantial portion of mental illness. The degree of heterogeneity is so great that most unrelated patients may have a different genetic cause. This phenomenon has fundamental implications for translational and interventional research.
JAMA The Journal of the American Medical Association 06/2010; 303(24):2523-4. · 30.03 Impact Factor
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Robert L Findling,
Jacqueline L Johnson, Jon McClellan,
Jean A Frazier,
Benedetto Vitiello,
Robert M Hamer,
Jeffrey A Lieberman,
Louise Ritz,
Nora K McNamara,
Jacqui Lingler,
Stefanie Hlastala,
Leslie Pierson,
Madeline Puglia,
Ann E Maloney,
Emily Michael Kaufman,
Nancy Noyes,
Linmarie Sikich
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ABSTRACT: To examine the long-term safety and efficacy of three antipsychotics in early-onset schizophrenia spectrum disorders.
Patients (8 to 19 years old) who had improved during an 8-week, randomized, double-blind acute trial of olanzapine, risperidone, or molindone (plus benztropine) were eligible to continue on the same medication for up to 44 additional weeks under double-blind conditions. Adjunctive medications were allowed according to defined algorithms. Standardized symptom, safety, and functional assessments were conducted every 4 weeks.
Of the 116 youths randomized in the acute trial, 54 entered maintenance treatment (molindone, n = 20; olanzapine, n = 13; risperidone, n = 21). Fourteen (26%) completed 44 weeks of treatment. Adverse effects (n = 15), inadequate efficacy (n = 14), or study nonadherence (n = 8) were the most common reasons for discontinuation. The three treatment arms did not significantly differ in symptom decrease or time to discontinuation. Akathisia was more common with molindone and elevated prolactin concentrations more common with risperidone. Although weight gain and metabolic adverse events had occurred more often with olanzapine and risperidone during the acute trial, no significant between-drug differences emerged in most of these parameters during maintenance treatment.
Only 12% of youths with early-onset schizophrenia spectrum disorders continued on their originally randomized treatment at 52 weeks. No agent demonstrated superior efficacy, and all were associated with side effects, including weight gain. Improved treatments are needed for early-onset schizophrenia spectrum disorders. Clinical trial registry information-Treatment of Schizophrenia and Related Disorders in Children and Adolescents; URL: http://www.clinicaltrials.gov, unique identifier: NCT00053703.
Journal of the American Academy of Child and Adolescent Psychiatry 06/2010; 49(6):583-94; quiz 632. · 4.98 Impact Factor
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ABSTRACT: Strong evidence suggests that rare mutations of severe effect are responsible for a substantial portion of complex human disease. Evolutionary forces generate vast genetic heterogeneity in human illness by introducing many new variants in each generation. Current sequencing technologies offer the possibility of finding rare disease-causing mutations and the genes that harbor them.
Cell 04/2010; 141(2):210-7. · 32.40 Impact Factor
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Stephen R Hooper,
Anthony J Giuliano,
Eric A Youngstrom,
David Breiger,
Linmarie Sikich,
Jean A Frazier,
Robert L Findling, Jon McClellan,
Robert M Hamer,
Benedetto Vitiello,
Jeffrey A Lieberman
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ABSTRACT: We examined the neuropsychological functioning of youth enrolled in the NIMH funded trial, Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS). We compared the baseline neuropsychological functioning of youth with schizophrenia (SZ, n = 79) to those with schizoaffective disorder (SA, n = 40), and examined the relationship of different variables of illness severity and adaptive behavior to neuropsychological functioning.
Participants ranged in age from 8 to 19 years. Diagnostic status was confirmed via structured interview over multiple time points. Domains of neuropsychological functioning included fine-motor, attention, working memory, problem-solving efficiency, inhibitory control, and social cognition. Other variables included intelligence (IQ), academic achievement skills, adaptive behavior, and different measures of illness severity.
The two groups did not differ on IQ or on any of the neuropsychological domains. The SZ group performed significantly lower in spelling. A high proportion of individuals in both groups reflected significant intellectual and academic achievement skill deficits. Significant correlations were found between the neurocognitive domains and both illness severity and adaptive behavior variables.
There were few differences between the SZ and SA groups on IQ, achievement, or neuropsychological functioning; however, both groups showed significantly high rates of deficits in IQ and basic academic skills. Correlations of the neurocognitive functions with illness severity and adaptive behavior were small to moderate in magnitude. These findings continue to implicate the importance of neurocognitive functioning as a key area of vulnerability in the study of youth with schizophrenia spectrum disorders.
Journal of the American Academy of Child and Adolescent Psychiatry 01/2010; 49(1):52-60. · 4.98 Impact Factor
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Shane E McCarthy,
Vladimir Makarov,
George Kirov,
Anjene M Addington, Jon McClellan,
Seungtai Yoon,
Diana O Perkins,
Diane E Dickel,
Mary Kusenda,
Olga Krastoshevsky, [......],
Michael C O'Donovan,
Tamim H Shaikh,
Ezra Susser,
Lynn E Delisi,
Patrick F Sullivan,
Curtis K Deutsch,
Judith Rapoport,
Deborah L Levy,
Mary-Claire King,
Jonathan Sebat
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ABSTRACT: Recurrent microdeletions and microduplications of a 600-kb genomic region of chromosome 16p11.2 have been implicated in childhood-onset developmental disorders. We report the association of 16p11.2 microduplications with schizophrenia in two large cohorts. The microduplication was detected in 12/1,906 (0.63%) cases and 1/3,971 (0.03%) controls (P = 1.2 x 10(-5), OR = 25.8) from the initial cohort, and in 9/2,645 (0.34%) cases and 1/2,420 (0.04%) controls (P = 0.022, OR = 8.3) of the replication cohort. The 16p11.2 microduplication was associated with a 14.5-fold increased risk of schizophrenia (95% CI (3.3, 62)) in the combined sample. A meta-analysis of datasets for multiple psychiatric disorders showed a significant association of the microduplication with schizophrenia (P = 4.8 x 10(-7)), bipolar disorder (P = 0.017) and autism (P = 1.9 x 10(-7)). In contrast, the reciprocal microdeletion was associated only with autism and developmental disorders (P = 2.3 x 10(-13)). Head circumference was larger in patients with the microdeletion than in patients with the microduplication (P = 0.0007).
Nature Genetics 11/2009; 41(11):1223-7. · 35.53 Impact Factor
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William Bernet,
Oscar Bukstein,
Heather Walter,
Valerie Arnold,
R. Scott Benson,
Joseph Beitchman,
Allan Chrisman,
Tiffany R. Farchione,
John Hamilton,
Helene Keable,
Joan Kinlan, Jon McClellan
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ABSTRACT: The purpose of this practice parameter is to promote the appropriate and safe use of psychotropic medications in children and adolescents with psychiatric disorders by emphasizing the best practice principles that underlie medication prescribing. The evidence base supporting the use of psychotropic medication for children and adolescents with psychiatric disorders has increased over the past 15-20 years as has their use. It is hoped that clinicians who implement the principles outlined in this parameter will be more likely to use medications with the potential for pharmacological benefit in children safely and to reduce the use of ineffective and inappropriate medications or medication combinations. The best practice principles covered in this parameter include (1) completing a psychiatric and medical evaluation, (2) developing a treatment and monitoring plan, (3) educating the patient and family regarding the child's disorder and the treatment and monitoring plan, (4) completing and documenting assent of the child and consent of the parent, (5) conducting an adequate medication treatment trial, (6) managing the patient who does not respond as expected, (7) establishing procedures to implement prior to using medication combinations, and (8) following principles for the discontinuation of medication.
Journal of The American Academy of Child and Adolescent Psychiatry - J AMER ACAD CHILD ADOLESC PSY. 01/2009; 48(9):961-973.
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Linmarie Sikich,
Jean A Frazier, Jon McClellan,
Robert L Findling,
Benedetto Vitiello,
Louise Ritz,
Denisse Ambler,
Madeline Puglia,
Ann E Maloney,
Emily Michael,
Sandra De Jong,
Karen Slifka,
Nancy Noyes,
Stefanie Hlastala,
Leslie Pierson,
Nora K McNamara,
Denise Delporto-Bedoya,
Robert Anderson,
Robert M Hamer,
Jeffrey A Lieberman
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ABSTRACT: Atypical (second-generation) antipsychotics are considered standard treatment for children and adolescents with early-onset schizophrenia and schizoaffective disorder. However, the superiority of second-generation antipsychotics over first-generation antipsychotics has not been demonstrated. This study compared the efficacy and safety of two second-generation antipsychotics (olanzapine and risperidone) with a first-generation antipsychotic (molindone) in the treatment of early-onset schizophrenia and schizoaffective disorder.
This double-blind multisite trial randomly assigned pediatric patients with early-onset schizophrenia and schizoaffective disorder to treatment with either olanzapine (2.5-20 mg/day), risperidone (0.5-6 mg/day), or molindone (10-140 mg/day, plus 1 mg/day of benztropine) for 8 weeks. The primary outcome was response to treatment, defined as a Clinical Global Impression (CGI) improvement score of 1 or 2 and >or=20% reduction in Positive and Negative Syndrome Scale (PANSS) total score after 8 weeks of treatment.
In total, 119 youth were randomly assigned to treatment. Of these subjects, 116 received at least one dose of treatment and thus were available for analysis. No significant differences were found among treatment groups in response rates (molindone: 50%; olanzapine: 34%; risperidone: 46%) or magnitude of symptom reduction. Olanzapine and risperidone were associated with significantly greater weight gain. Olanzapine showed the greatest risk of weight gain and significant increases in fasting cholesterol, low density lipoprotein, insulin, and liver transaminase levels. Molindone led to more self-reports of akathisia.
Risperidone and olanzapine did not demonstrate superior efficacy over molindone for treating early-onset schizophrenia and schizoaffective disorder. Adverse effects were frequent but differed among medications. The results question the nearly exclusive use of second-generation antipsychotics to treat early-onset schizophrenia and schizoaffective disorder. The safety findings related to weight gain and metabolic problems raise important public health concerns, given the widespread use of second-generation antipsychotics in youth for nonpsychotic disorders.
American Journal of Psychiatry 10/2008; 165(11):1420-31. · 12.54 Impact Factor
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Heather C Mefford,
Andrew J Sharp,
Carl Baker,
Andy Itsara,
Zhaoshi Jiang,
Karen Buysse,
Shuwen Huang,
Viv K Maloney,
John A Crolla,
Diana Baralle, [......],
Jonathan Sebat,
Corrado Romano,
Charles E Schwartz,
Joris A Veltman,
Bert B A de Vries,
Joris R Vermeesch,
John C K Barber,
Lionel Willatt,
May Tassabehji,
Evan E Eichler
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ABSTRACT: Duplications and deletions in the human genome can cause disease or predispose persons to disease. Advances in technologies to detect these changes allow for the routine identification of submicroscopic imbalances in large numbers of patients.
We tested for the presence of microdeletions and microduplications at a specific region of chromosome 1q21.1 in two groups of patients with unexplained mental retardation, autism, or congenital anomalies and in unaffected persons.
We identified 25 persons with a recurrent 1.35-Mb deletion within 1q21.1 from screening 5218 patients. The microdeletions had arisen de novo in eight patients, were inherited from a mildly affected parent in three patients, were inherited from an apparently unaffected parent in six patients, and were of unknown inheritance in eight patients. The deletion was absent in a series of 4737 control persons (P=1.1x10(-7)). We found considerable variability in the level of phenotypic expression of the microdeletion; phenotypes included mild-to-moderate mental retardation, microcephaly, cardiac abnormalities, and cataracts. The reciprocal duplication was enriched in nine children with mental retardation or autism spectrum disorder and other variable features (P=0.02). We identified three deletions and three duplications of the 1q21.1 region in an independent sample of 788 patients with mental retardation and congenital anomalies.
We have identified recurrent molecular lesions that elude syndromic classification and whose disease manifestations must be considered in a broader context of development as opposed to being assigned to a specific disease. Clinical diagnosis in patients with these lesions may be most readily achieved on the basis of genotype rather than phenotype.
New England Journal of Medicine 10/2008; 359(16):1685-99. · 53.30 Impact Factor
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Robert L Findling,
Jean A Frazier,
Vivian Kafantaris,
Robert Kowatch, Jon McClellan,
Mani Pavuluri,
Linmarie Sikich,
Stefanie Hlastala,
Stephen R Hooper,
Christine A Demeter,
Denise Bedoya,
Bernard Brownstein,
Perdita Taylor-Zapata
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ABSTRACT: Lithium is a benchmark treatment for bipolar illness in adults. However, there has been relatively little methodologically stringent research regarding the use of lithium in youth suffering from bipolarity.
Under the auspices of the Best Pharmaceuticals for Children Act (BPCA), a Written Request (WR) pertaining to the study of lithium in pediatric mania was issued by the United States Food and Drug Administration (FDA) to the National Institute of Child Health and Human Development (NICHD) in 2004. Accordingly, the NICHD issued a Request for Proposals (RFP) soliciting submissions to pursue this research. Subsequently, the NICHD awarded a contract to a group of investigators in order to conduct these studies.
The Collaborative Lithium Trials (CoLT) investigators, the BPCA-Coordinating Center, and the NICHD developed protocols to provide data that will: (1) establish evidence-based dosing strategies for lithium; (2) characterize the pharmacokinetics and biodisposition of lithium; (3) examine the acute efficacy of lithium in pediatric bipolarity; (4) investigate the long-term effectiveness of lithium treatment; and (5) characterize the short- and long-term safety of lithium. By undertaking two multi-phase trials rather than multiple single-phase studies (as was described in the WR), the feasibility of the research to be undertaken was enhanced while ensuring all the data outlined in the WR would be obtained. The first study consists of: (1) an 8-week open-label, randomized, escalating dose Pharmacokinetic Phase; (2) a 16-week Long-Term Effectiveness Phase; (3) a 28-week double-blind Discontinuation Phase; and (4) an 8-week open-label Restabilization Phase. The second study consists of: (1) an 8-week, double-blind, parallel-group, placebo-controlled Efficacy Phase; (2) an open-label Long-Term Effectiveness lasting either 16 or 24 weeks (depending upon blinded treatment assignment during the Efficacy Phase); (3) a 28-week double-blind Discontinuation Phase; and (4) an 8-week open-label Restabilization Phase. In December of 2006, enrollment into the first of these studies began across seven sites.
These innovative studies will not only provide data to inform the labeling of lithium in children and adolescents with bipolar disorder, but will also enhance clinical decision-making regarding the use of lithium treatment in pediatric bipolar illness.
NCT00442039.
Child and Adolescent Psychiatry and Mental Health 02/2008; 2(1):21.
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Jean A Frazier, Jon McClellan,
Robert L Findling,
Benedetto Vitiello,
Robert Anderson,
Benjamin Zablotsky,
Emily Williams,
Nora K McNamara,
Joseph A Jackson,
Louise Ritz, [......],
Leslie Pierson,
Jennifer A Varley,
Madeline Puglia,
Ann E Maloney,
Denisse Ambler,
Tyehimba Hunt-Harrison,
Robert M Hamer,
Nancy Noyes,
Jeffrey A Lieberman,
Linmarie Sikich
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ABSTRACT: We examined baseline demographic and clinical profiles of youths enrolled from 2001 to 2006 in the publicly funded multicenter, randomized controlled trial Treatment of Early-Onset Schizophrenia Spectrum Disorders.
Youths (8-19 years) with schizophrenia (SZ) and schizoaffective disorder were recruited at four academic sites. Diagnosis was made via structured and clinical interviews. Assessments of psychiatric symptoms and social and global functioning were included.
A total of 119 youths were enrolled. The mean age at illness onset was 11.1 +/- 3.5 years. Patients with SZ and schizoaffective disorder had similar ratings on the Positive and Negative Symptom Scale, Brief Psychiatric Rating Scale for Children, and Clinical Global Impression-Severity Scale. The overall level of functioning was similar in the two groups. A comparison to published reports of adults with SZ indicates that these youths may have more severe symptoms based on results of the Positive and Negative Symptom Scale.
This is one of the largest samples of youths with SZ spectrum disorders studied to date and the largest assessment of youths with schizoaffective disorder. High rates of symptoms and general psychopathology were noted. There was a substantial degree of social and functional impairment. The symptom profiles are consistent with, but more severe than, those reported in the adult literature.
Journal of the American Academy of Child & Adolescent Psychiatry 09/2007; 46(8):979-88. · 6.44 Impact Factor
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Jon McClellan,
Linmarie Sikich,
Robert L Findling,
Jean A Frazier,
Benedetto Vitiello,
Stefanie A Hlastala,
Emily Williams,
Denisse Ambler,
Tyehimba Hunt-Harrison,
Ann E Maloney,
Louise Ritz,
Robert Anderson,
Robert M Hamer,
Jeffrey A Lieberman
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ABSTRACT: The Treatment of Early Onset Schizophrenia Spectrum Disorders Study is a publicly funded clinical trial designed to compare the therapeutic benefits, safety, and tolerability of risperidone, olanzapine, and molindone in youths with early-onset schizophrenia spectrum disorders. The rationale, design, and methods of the Treatment of Early Onset Schizophrenia Spectrum Disorders Study are described.
Using a randomized, double-blind, parallel-group design at four sites, youths with EOSS (ages 8-19 years) were assigned to an 8-week acute trial of risperidone (0.5-6.0 mg/day), olanzapine (2.5-20 mg/day), or molindone (10-140 mg/day). Responders continued double-blind treatment for 44 weeks. The primary outcome measure was responder status at 8 weeks, defined by a 20% reduction in baseline Positive and Negative Symptom Scale scores plus ratings of significant improvement on the Clinical Global Impressions. Secondary outcome measures included assessments of psychopathology, functional impairment, quality of life, and medication safety. An intent-to-treat analytic plan was used.
From February 2002 to May 2006, 476 youths were screened, 173 were further evaluated, and 119 were randomized. Several significant study modifications were required to address safety, the use of adjunctive medications, and the termination of the olanzapine treatment arm due to weight gain.
The Treatment of Early Onset Schizophrenia Spectrum Disorders Study will inform clinical practice regarding the use of antipsychotic medications for youths with early-onset schizophrenia spectrum disorders. Important safety concerns emerged during the study, including higher than anticipated rates of suicidality and problems tapering thymoleptic agents before randomization.
Journal of the American Academy of Child & Adolescent Psychiatry 09/2007; 46(8):969-78. · 6.44 Impact Factor
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ABSTRACT: This practice parameter reviews the literature on the assessment and treatment of children and adolescents with bipolar disorder. The parameter focuses primarily on bipolar 1 disorder because that is the type most often studied in juveniles. The presentation of bipolar disorder in youth, especially children, is often considered atypical compared with that of the classic adult disorder, which is characterized by distinct phases of mania and depression. Children who receive a diagnosis of bipolar disorder in community settings typically present with rapid fluctuations in mood and behavior, often associated with comorbid attention-deficit/hyperactivity disorder and disruptive behavior disorders. Thus, at this time it is not clear whether the atypical forms of juvenile mania and the classic adult form of the disorder represent the same illness. The question of diagnostic continuity has important treatment and prognostic implications. Although more controlled trials are needed, mood stabilizers and atypical antipsychotic agents are generally considered the first line of treatment. Although patients may respond to monotherapy, combination pharmacotherapy is necessary for some youth. Behavioral and psychosocial therapies are also generally indicated for juvenile mania to address disruptive behavior problems and the impact of the illness on family and community functioning.
Journal of the American Academy of Child & Adolescent Psychiatry 02/2007; 46(1):107-25. · 6.44 Impact Factor
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ABSTRACT: This study aimed to better characterize the phenomenology and diagnostic stability of youths that report atypical psychotic symptoms.
In a 2-year longitudinal follow-up study, youths reporting atypical psychotic symptoms (n = 20) were compared with youths with schizophrenia (n = 27) and youths with bipolar disorder with psychotic features (n = 22) on psychotic, dissociative, and general symptomatology, comorbid diagnoses, previous abuse, and overall functioning. Diagnoses were obtained using structured diagnostic interviews (i.e., the Structured Clinical Interview for DSM-IV and the Diagnostic Interview for Children and Adolescents).
None of the subjects reporting atypical psychotic symptoms went on to develop a classic psychotic illness by the year 2 follow-up. These subjects had significantly higher rates of abuse and dissociative symptoms, and were significantly more likely to receive a diagnosis of posttraumatic stress disorder (PTSD) or a depressive disorder than youths with schizophrenia or bipolar disorder.
Our findings suggest that youths with atypical, fleeting, or situationally specific hallucinations are more likely to have a mood or anxiety disorder (such as PTSD) than a current or prodromal psychotic illness.
Journal of Child and Adolescent Psychopharmacology 07/2005; 15(3):497-509. · 2.88 Impact Factor
