Jon McClellan

Rare Structural Variants Disrupt Multiple Genes in Neurodevelopmental Pathways in Schizophrenia

Schizophrenia is a devastating neurodevelopmental disorder whose genetic influences remain elusive. We hypothesize that individually rare structural variants contribute to the illness. Microdeletions and microduplications >100 kilobases were identified by microarray comparative genomic hybridization of genomic DNA from 150 individuals with schizophrenia and 268 ancestry-matched controls. All variants were validated by high-resolution platforms. Novel deletions and duplications of genes were present in 5% of controls versus 15% of cases and 20% of young-onset cases, both highly significant differences. The association was independently replicated in patients with childhood-onset schizophrenia as compared with their parents. Mutations in cases disrupted genes disproportionately from signaling networks controlling neurodevelopment, including neuregulin and glutamate pathways. These results suggest that multiple, individually rare mutations altering genes in neurodevelopmental pathways contribute to schizophrenia.

Genetic Heterogeneity in Human Disease

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.

Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes

BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

Microduplications of 16p11.2 are associated with schizophrenia.

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 × 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 × 10−7), bipolar disorder (P = 0.017) and autism (P = 1.9 × 10−7). In contrast, the reciprocal microdeletion was associated only with autism and developmental disorders (P = 2.3 × 10−13). Head circumference was larger in patients with the microdeletion than in patients with the microduplication (P = 0.0007).

Double-blind comparison of first- and second-generation antipsychotics in early-onset schizophrenia and schizo-affective disorder: findings from the treatment of early-onset schizophrenia spectrum disorders (TEOSS) study

OBJECTIVE 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. METHOD 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. RESULTS 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. CONCLUSIONS 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.

Childhood and Adolescent Schizophrenic, Bipolar, and Schizoaffective Disorders: A Clinical and Outcome Study

Fifty-nine child and adolescent psychotic patients (mean onset age 13.9, range 7-17, 83% 13 + years) had history and outcome studied using diagnoses confirmed at follow-up after 1 to 16 years (mean, 5 years). There were no differences in sex ratio, socioeconomic status, age of onset, and symptoms, but bipolar patients (N = 23) were often misdiagnosed as schizophrenic, had a better outcome, and a 50% homotypic family history. Schizophrenic subjects (N = 30) were more abnormal premorbidly, and only 17% were well at follow-up. Schizoaffective disorder was unreliable, infrequent, and more severe. Premorbid adjustment and IQ were the best predictors of outcome. Differences from the adult disorders were only quantitative. Careful follow-up of psychotic patients is needed to detect diagnostic errors.

Duplications of the neuropeptide receptor gene VIPR2 confer significant risk for schizophrenia

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.

Preschool Boys With Oppositional Defiant Disorder: Clinical Presentation and Diagnostic Change

OBJECTIVE Little is known about the clinical presentation and course of oppositional defiant disorder (ODD) when first diagnosed in the preschool years. Patterns of ODD symptomatology, comorbidity, persistence of disorder, and predictors of diagnostic outcome were examined in clinic-referred preschool boys. METHOD Boys (aged 4-5.5 years) with a DSM-III-R diagnosis of ODD were prospectively followed over a 2-year period. Multiple assessment procedures were used, including a modified version of the Diagnostic Interview Schedule for Children and parent and teacher ratings. RESULTS Ninety-two boys (mean age 56.9 months) with ODD were followed; 42 had comorbid attention-deficit hyperactivity disorder (ADHD). Among 79 boys assessed 2 years later, 76% had ODD, ADHD, or both. Of those, 25% had other diagnoses as well, primarily anxiety and/or mood disorders. Conduct disorder was rare. Subjects with comorbid ODD/ADHD at intake were significantly more likely to have a psychiatric disorder at follow-up, especially ADHD alone. CONCLUSIONS The findings suggest that ODD in the preschool period is a clear indicator of high risk, especially when co-occurring with ADHD. Further investigation of individual patterns of ODD symptom expression is recommended.

Efficacy and Tolerability of Second-Generation Antipsychotics in Children and Adolescents With Schizophrenia

Early-onset schizophrenia-spectrum (EOSS) disorders (onset of psychotic symptoms before 18 years of age) represent a severe variant associated with significant chronic functional impairment and poor response to antipsychotic treatment. All drugs with proven antipsychotic effects block dopamine D2 receptors to some degree. The ongoing development of the dopamine and other neurotransmitter receptor systems during childhood and adolescence may affect clinical response and susceptibility to side effects in youth. A literature search was conducted of clinical trials of antipsychotics in children and adolescents with EOSS disorders between 1980 and 2007 from the Medline database, reference lists, and conference proceedings. Trials were limited to double-blind studies of duration of 4 or more weeks that included 15 or more patients. Ten clinical trials were identified. Antipsychotic medications were consistently found to reduce the severity of psychotic symptoms in children and adolescents when compared with placebo. The superiority of clozapine has been now demonstrated relative to haloperidol, standard-dose olanzapine, and “high-dose” olanzapine for EOSS disorders. However, limited comparative data are available regarding whether there are differences among the remaining second-generation antipsychotics (SGAs) in clinical effectiveness. The available data from short-term studies suggest that youth might be more sensitive than adults to developing antipsychotic-related adverse side effects (eg, extrapyramidal side effects, sedation, prolactin elevation, weight gain). In addition, preliminary data suggest that SGA use can lead to the development of diabetes in some youth, a disease which itself carries with it significant morbidity and mortality. Such a substantial risk points to the urgent need to develop therapeutic strategies to prevent and/or mitigate weight gain and diabetes early in the course of treatment in this population.

A follow-up study of early onset psychosis : Comparison between outcome diagnoses of schizophrenia, mood disorders and personality disorders

This study examined the outcome of youth previously diagnosed with psychotic disorders at a public-sector tertiary care hospital. Of 95 children and adolescents retrospectively identified, follow-up information (mean interval 3.9 years) was obtained on 24 subjects with an outcome diagnosis of schizophrenia, 9 with psychotic mood disorders, 5 with personality disorders (antisocial or borderline), and 1 with schizo-affective disorder. The schizophrenic group was more often odd premorbidly and functioned worse at outcome, while the mood-disordered group had a shorter follow-up period and was more often anxious or dysthymic premorbidly. The personality-disordered group resembled the schizophrenics in their degree of impairment and chronicity. All three groups had high rates of family disruption, low SES, substance abuse, and chronicity, and were similar in their degree of premorbid impairment, length of prodrome, age of onset, initial diagnosis, and family psychiatric history. Misdiagnosis at onset was quite common and highlights the need for systematic longitudinal assessment of early onset psychotic disorders.