Clozapine treatment of childhood-onset schizophrenia: evaluation of effectiveness, adverse effects, and long-term outcome.

OBJECTIVE: 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. METHOD: 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. RESULTS: 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. CONCLUSIONS: The NDMC/clozapine ratio may be a valuable predictor of response to clozapine and may suggest new approaches to clozapine treatment.

Hormonal correlates of clozapine-induced weight gain in psychotic children: an exploratory study.

OBJECTIVE: 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. METHOD: 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. RESULTS: 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. CONCLUSIONS: 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.

Polymorphisms in the 13q33.2 gene G72/G30 are associated with childhood-onset schizophrenia and psychosis not otherwise specified.

BACKGROUND: Childhood-onset schizophrenia (COS), defined as onset of psychotic symptoms by age 12 years, is a rare and severe form of the disorder that seems to be clinically and neurobiologically continuous with the adult disorder. METHODS: We studied a rare cohort consisting of 98 probands; 71 of these probands received a DSM-defined diagnosis of schizophrenia, and the remaining 27 were diagnosed as psychosis not otherwise specified (NOS) (upon 2-6 year follow-up, 13 have subsequently developed bipolar disorder). Two overlapping genes, G72 and G30 on 13q33.2, were identified through linkage-disequilibrium-based positional cloning. Single nucleotide polymorphisms (SNPs) at the G72/G30 locus were independently associated with both bipolar illness and schizophrenia. We analyzed SNPs at this locus with a family-based transmission disequilibrium test (TDT) and haplotype analyses for the discrete trait, as well as quantitative TDT for intermediate phenotypes, using the 88 probands (including COS and psychosis-NOS) with parental participation. RESULTS: We observed significant pairwise and haplotype associations between SNPs at the G72/G30 locus and psychotic illness. Furthermore, these markers showed associations with scores on a premorbid phenotype measured by the Autism Screening Questionnaire, and with age of onset. CONCLUSIONS: These findings, although limited by potential referral bias, confirm and strengthen previous reports that G72/G30 is a susceptibility locus both for schizophrenia and bipolar disorder.

Pervasive developmental disorder and childhood-onset schizophrenia: comorbid disorder or a phenotypic variant of a very early onset illness?

BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

Stimulant drug treatment in childhood-onset schizophrenia with comorbid ADHD: an open-label case series.

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.

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.