Alexandra Sporn

GAD1 (2q31.1), which encodes glutamic acid decarboxylase (GAD 67 ), is associated with childhood-onset schizophrenia and cortical gray matter volume loss

Postmortem brain studies have shown deficits in the cortical γ-aminobutyric acid (GABA) system in schizophrenic individuals. Expression studies have shown a decrease in the major GABA-synthesizing enzyme (glutamic acid decarboxylase (GAD67) mRNA levels in neurons in dorsolateral prefrontal cortex in schizophrenics relative to controls. In the present study, SNPs in and around the GAD1 gene, which encodes the protein GAD67, were tested on a rare, severely ill group of children and adolescents with childhood-onset schizophrenia (COS) (n=72), in a family-based association analysis. Compared to adult-onset samples, the COS sample has evidence for more salient familial, and perhaps genetic, risk factors for schizophrenia, as well as evidence for frontal cortical hypofunction, and greater decline in cortical gray matter volume on anatomic brain MRI scans during adolescence. We performed family-based TDT and haplotype association analyses of the clinical phenotype, as well as association analyses with endophenotypes using the QTDT program. Three adjacent SNPs in the 5′ upstream region of GAD1 showed a positive pairwise association with illness in these families (P=0.022–0.057). Significant transmission distortion of 4-SNP haplotypes was also observed (P=0.003–0.008). Quantitative trait TDT analyses showed an intriguing association between several SNPs and increased rate of frontal gray matter loss. These observations, when taken together with the positive results reported recently in two independent adult-onset schizophrenia pedigree samples, suggest that the gene encoding GAD67 may be a common risk factor for schizophrenia.

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 Aspergers 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.

22q11 deletion syndrome in childhood onset schizophrenia: an update.

SIR – The 22q11 deletion syndrome (22q11DS) is a relatively common (population rate 0.01%) genetic anomaly associated with congenital physical defects and psychosis. To date, 22q11DS rates in adult onset schizophrenia (AOS) are reported as: two out of 100, one out of 300, one out of 329 cases of adult onset, and none among 141 cases of ‘juvenile onset’ (o18 years old, mean age1⁄4 15.6) (Table 1). Thus, combined rate of 22q11DS in AOS samples is 4/870 (0.46%). Childhood onset schizophrenia (COS) is a rare but severe form of the illness hypothesized to have high genetic loading. In COS, a high rate of several cytogenetic abnormalities including 22q11DS has been reported previously. Here, we provide an update on the rate and neurobiological characteristics of 22q11DS in COS and compare the rate with that in AOS. The NIMH COS sample consists of 75 nationally recruited children and adolescents, meeting the DSMIIIR/IV criteria for schizophrenia with the onset of psychosis before the 13th birthday (mean age of onset 10.4 years). The diagnosis of COS was carried out by structured interviews and medication-free inpatient observation. Significant medical or neurological illnesses or premorbid IQ below 70 were exclusionary. Clinical and neurobiological measures including anatomical MRI scans were obtained at admission and 2-year follow-up visits. The rate of total gray matter reduction was calculated for patients with two or more scans (defined as follow-up scan value minus first scan value divided by time elapsed between scans). Cytogenetic testing for the 22q11 deletion was carried out using fluorescence in situ hybridization (FISH) with the cosmid probe D22S75. In addition, all cases were tested with multiplex ligation-dependent probe amplification (MLPA) using MLPA test kit for DiGeorge/VCFS syndrome to confirm 22q11 deletion. The probe mixture contained 11 probes for the 22q11 region as well as probes for 4q, 8p23, 10p12–23, and 10q. Parental origins of the deletions were established by genotyping probands and parents for four polymorphic dinucleotide repeat markers (D22S941, D22S944, D22S264, and D 22S311) using techniques described elsewhere. All cases of 22q11DS were checked for paternity. The rate of VCFS in the NIMH COS sample was compared with reported rates across three independent AOS samples (total number 870) using Fisher’s exact test. Phenotypic and biological measures were compared for COS subjects with and without 22q11DS and to 22q11DS cases without schizophrenia reported elsewhere. Out of 75 COS patients, four (5.3%) were found to have a spontaneous 3 Mb deletion at 22q11, which is significantly higher than the 0.46% found for AOS cases (P1⁄4 0.002). All cases identified by FISH were confirmed by MLPA and no new deletions were identified in 22q11or any of the other regions covered by MLPA probes. All four cases had subtle craniofacial and body dysmorphic characteristics that had not been noticed previously. Three of the four 22q11 deletions were from maternal chromosomes. The 22q11DS cases did not differ from the other COS patients in the age of onset, IQ, premorbid functioning, or severity of psychosis, but had fewer negative symptoms as measured by Scale for the Assessment of Negative Symptoms (30.5726.3 vs 70.1726.9; P1⁄40.006). All four had good clinical response to atypical neuroleptics (clozapine, olanzapine, or quetiapine); however, three developed epileptiform EEG changes/seizures. There were no significant differences in total cerebral, total gray mater, lateral ventricle volumes, or progressive reduction of gray matter (all P-values 40.25). The rate of progressive gray matter reduction in 22q11DS cases ( 18.7712.3 ml/year) was similar to that reported in a cross-sectional study of nine VCFS cases (age1⁄4 12.172.9) without psychosis with maternal origin of 22q11 deletion ( 12.5 ml/year) (A Reiss, personal communication). This report confirms that the rate of 22q11DS in COS is significantly higher than that in the commu-

Correlation of Antipsychotic and Prolactin Concentrations in Children and Adolescents Acutely Treated with Haloperidol, Clozapine, or Olanzapine

Patients with a Diagnostic and Statistical Manual of Mental Disorders (third edition, revised) diagnosis of schizophrenia or psychotic disorder not otherwise specified with onset of psychosis before the age of 13 participated in 6- to 8-week open or double-blind trials of haloperidol (n = 15, mean dose 15.4 +/- 8.1 mg/day [0.27 +/- 0.15 mg/kg/day]), clozapine (n = 30, mean dose 269.9 +/- 173.3 mg/day [4.4 +/- 2.6 mg/kg/day]), or olanzapine (n = 12, mean dose 17.5 +/- 2.8 mg/day [0.30 +/- 0.13 mg/kg/day]). Blood samples were obtained at 6 weeks for evaluation of haloperidol, reduced haloperidol, clozapine, desmethylclozapine, and olanzapine plasma concentrations and serum prolactin concentrations. No gender differences were noted for antipsychotic dose or concentration within each treatment group. Correlations between antipsychotic plasma concentration and serum prolactin concentration were significant only for the olanzapine treatment group (r = 0.80, p = 0.002). Separate correlations for gender were significant only for females receiving olanzapine (r = 0.91, p = 0.03); the patient with the highest serum prolactin experienced galactorrhea. Further studies evaluating the prolactin-elevating properties of antipsychotics are warranted in this population.

IQ stabilization in childhood-onset schizophrenia

OBJECTIVE To examine the long term IQ trajectory for childhood-onset schizophrenia (COS) in an expanded, prospective longitudinal study. METHODS Seventy children meeting DSM criteria for schizophrenia were tested at 2 year intervals with age appropriate Wechsler intelligence tests and repeated administration of information and comprehension WISC subtests even after age 18. For a subgroup with 31 patients, pre-NIH IQ test administrations were available including 18 pre-psychotic and 13 post-psychotic subjects. The pattern of IQ performance over time was determined using mixed model regression analysis. RESULTS No progressive cognitive decline was seen up to 13+ years post psychosis onset. For the subgroup of subjects with pre-illness scores, there had been an initial steep decline in IQ, from about 2 years prior to 1.7 years after onset of psychotic symptoms, as reported for adult patients. CONCLUSIONS The level long-term trajectory of IQ measures in COS appears stable, similar to that reported for adult onset patients. For COS, level cognitive functioning extends up to 13+ years post psychosis onset, in spite of chronic illness and concomitant, progressive loss of cortical gray matter.

Clozapine-Induced Neutropenia in Children: Management with Lithium Carbonate

Clozapine, an atypical antipsychotic, is the most effective medication for treatment-resistant schizophrenia, but its use is limited by the high risk of neutropenia and agranulocytosis. In children, the rate of clozapine-induced neutropenia is even higher than in adults. We report two cases of children 7- and 12-years old diagnosed with very early onset schizophrenia, who developed neutropenia when treated with clozapine. In both cases addition of lithium carbonate elevated the white blood count (WBC) allowing clozapine rechallenge. WBC and total neutrophil count remained stable long-term with coadministration of clozapine (400-425 mg per day) and lithium with the blood level of 0.8-1.1 microg/mL. This report supports the use of adjunct lithium for clozapine-induced neutropenia as a safe and successful strategy in children.

Childhood onset schizophrenia: familial neurocognitive measures

OBJECTIVE Early onset disorders may have more salient familial/genetic etiology. Neurocognitive deficits which are seen in families of adult onset schizophrenic patients were examined in healthy family members of patients with childhood-onset schizophrenia (COS). METHODS Trail Making Tests (TMT) A and B, Wechsler Intelligence Scale-Revised Digit Span and Vocabulary subtests were administered to 67 parents and 24 siblings of patients with childhood-onset schizophrenia and 114 healthy community controls (CC) comparable in sex, age, and educational level. RESULTS COS siblings performed significantly more poorly than did controls on Trails Making Test B with a trend for poorer performance evident on Trails Making Test A. COS parents performed more poorly than controls only on Trails Making Test A. CONCLUSIONS Healthy first-degree relatives of COS probands have subtle deficits in tests involving oculomotor/psychomotor speed, working memory and executive function. This provides further support for continuity between COS and later onset schizophrenia and for a familial/genetic factor associated with the illness.

Childhood-onset schizophrenia: smooth pursuit eye-tracking dysfunction in family members.

BACKGROUND Childhood-onset schizophrenia (COS), a severe form of the disorder, is of interest for etiologic studies. Smooth pursuit eye-tracking dysfunction (ETD) is a biological marker for schizophrenia. AIMS To compare familial eye-tracking abnormalities for COS and adult-onset schizophrenia (AOS). METHOD Eye-tracking performance for 70 COS parents, 64 AOS parents and 20 COS siblings was compared to their respective age-matched control groups. RESULTS COS and AOS parents had higher rate of dichotomously rated eye-tracking dysfunction than their respective controls (16% vs. 1% and 22% vs. 4%, respectively). COS parents and siblings also differed from controls on several continuous measures. However, scores for COS, AOS and control groups overlapped extensively. CONCLUSIONS Genetic factors underlying eye-tracking dysfunction appear more salient for COS. However, eye-tracking measures have to be used with caution for endophenotypic definition due to low predictive power. DECLARATION OF INTEREST The study was done at the National Institutes of Health.

Clozapine-induced akathisia in children with schizophrenia.

Akathisia is a relatively rare side effect with the newer atypical antipsychotic agents, particularly clozapine, and is easily misdiagnosed in children. As children are often unable to describe their symptoms verbally, their akathisia can be misdiagnosed as worsening of their psychosis, prompting an unnecessary increase in their neuroleptic dose. Two cases of childhood-onset schizophrenia associated with clozapine-induced akathisia responsive to beta-blocker treatment are described. Akathisia should be considered in all cases of apparent nonresponse to atypical antipsychotics.