Parental Schizophrenia Spectrum Disorders in Childhood-Onset and Adult-Onset Schizophrenia

Nicolson, Rob; Brookner, Frances; Lenane, Marge; Gochman, Peter; Ingraham, Loring J.; Egan, Michael; Kendler, Kenneth S.; Pickar, David; Weinberger, Daniel R.; Rapoport, Judith L.

doi:10.1176/appi.ajp.160.3.490

Cited by 97 publications

(67 citation statements)

References 26 publications

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“…5,6 Since 1989, these patients have been sought nationally at the National Institute of Mental Health (NIMH). Studies of first-degree relatives of these patients indicate higher familial rates of schizophrenia spectrum disorders, 7 and smooth pursuit eye movement abnormalities compared to families of later onset patients. 8 In addition, COS patients are characterized by more pronounced early delays in social, motor and language function.…”

Section: Introductionmentioning

confidence: 86%

Neuregulin 1 (8p12) and childhood-onset schizophrenia: susceptibility haplotypes for diagnosis and brain developmental trajectories

Addington¹,

Gornick²,

Shaw³

et al. 2006

Mol Psychiatry

110

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Childhood-onset schizophrenia (COS), defined as onset of psychosis by the age of 12, is a rare and malignant form of the illness, which may have more salient genetic influence. Since the initial report of association between neuregulin 1 (NRG1) and schizophrenia in 2002, numerous independent replications have been reported. In the current study, we genotyped 56 markers (54 single-nucleotide polymorphisms (SNPs) and two microsatellites) spanning the NRG1 locus on 78 COS patients and their parents. We used family-based association analysis for both diagnostic (extended transmission disequilibrium test) and quantitative phenotypes (quantitative transmission disequilibrium test) and mixed-model regression. Most subjects had prospective anatomic brain magnetic resonance imaging (MRI) scans at 2-year intervals. Further, we genotyped a sample of 165 healthy controls in the MRI study to examine genetic risk effects on normal brain development. Individual markers showed overtransmission of alleles to affecteds (P = 0.009-0.05). Further, several novel four-marker haplotypes demonstrated significant transmission distortion. There was no evidence of epistasis with SNPs in erbB4. The risk allele (0) at 420M9-1395 was associated with poorer premorbid social functioning. Further, possession of the risk allele was associated with different trajectories of change in lobar volumes. In the COS group, risk allele carriers had greater total gray and white matter volume in childhood and a steeper rate of subsequent decline in volume into adolescence. By contrast, in healthy children, possession of the risk allele was associated with different trajectories in gray matter only and was confined to frontotemporal regions, reflecting epistatic or other illness-specific effects mediating NRG1 influence on brain development in COS. This replication further documents the role of NRG1 in the abnormal brain development in schizophrenia. This is the first demonstration of a disease-specific pattern of gene action in schizophrenia.

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Section: Introductionmentioning

confidence: 86%

Neuregulin 1 (8p12) and childhood-onset schizophrenia: susceptibility haplotypes for diagnosis and brain developmental trajectories

Addington¹,

Gornick²,

Shaw³

et al. 2006

Mol Psychiatry

110

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“…Although neurobiologically continuous with the adult onset form of schizophrenia (Nicolson & Rapoport 1999, Rapoport et al 2005, COS subjects have more pronounced delays in social, motor and language function (AlaghbandRad et al 1995, Hollis 1995, a 10% rate of chromosomal abnormalities (Sporn et al 2004), higher familial rates of schizophrenia spectrum disorders (Nicolson et al 2003), and smooth pursuit eye movement abnormalities (Sporn et al 2005). These features suggest that genetic influences may be more salient in COS (Rapoport et al 2005).…”

Section: Trajectories Of Brain Development In Childhood-onset Schizopmentioning

confidence: 99%

Trajectories of Anatomic Brain Development as a Phenotype

Giedd

Lenroot²,

Shaw³

et al. 2008

Novartis Foundation Symposia

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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.

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“…The Child Psychiatry Branch of the NIMH has assembled a unique cohort of COS patients (n = 131, to date) which had a pattern of chronic, treatment-resistant illness, with insidious onset, resembling that of poor outcome adult-onset schizophrenia (AOS) (Nicolson et al 2003;Rapoport et al 2012). Converging evidence shows clinical and biological continuity of COS with AOS McKenna et al 1994;Frazier et al 1996;Jacobsen et al 1996a,b;Zahn et al 1997;Kumra et al 2000;Asarnow et al 2001;Levitt et al 2001;Nicolson et al 2003;Sporn et al 2005;Kranzler et al 2006;Gogtay 2008;Addington and Rapoport 2009;Rapoport et al 2012;Ahn et al 2014).…”

Section: Introductionmentioning

confidence: 99%

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

Kasoff

Ahn

Gochman

et al. 2016

Journal of Child and Adolescent Psychopharmacology

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

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Parental Schizophrenia Spectrum Disorders in Childhood-Onset and Adult-Onset Schizophrenia

Cited by 97 publications

References 26 publications

Neuregulin 1 (8p12) and childhood-onset schizophrenia: susceptibility haplotypes for diagnosis and brain developmental trajectories

Neuregulin 1 (8p12) and childhood-onset schizophrenia: susceptibility haplotypes for diagnosis and brain developmental trajectories

Trajectories of Anatomic Brain Development as a Phenotype

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

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