Jennifer Holcomb

Genome Scan Meta-Analysis of Schizophrenia and Bipolar Disorder, Part II: Schizophrenia

Schizophrenia is a common disorder with high heritability and a 10-fold increase in risk to siblings of probands. Replication has been inconsistent for reports of significant genetic linkage. To assess evidence for linkage across studies, rank-based genome scan meta-analysis (GSMA) was applied to data from 20 schizophrenia genome scans. Each marker for each scan was assigned to 1 of 120 30-cM bins, with the bins ranked by linkage scores (1 = most significant) and the ranks averaged across studies (R(avg)) and then weighted for sample size (N(sqrt)[affected casess]). A permutation test was used to compute the probability of observing, by chance, each bins average rank (P(AvgRnk)) or of observing it for a bin with the same place (first, second, etc.) in the order of average ranks in each permutation (P(ord)). The GSMA produced significant genomewide evidence for linkage on chromosome 2q (PAvgRnk<.000417). Two aggregate criteria for linkage were also met (clusters of nominally significant P values that did not occur in 1,000 replicates of the entire data set with no linkage present): 12 consecutive bins with both P(AvgRnk) and P(ord)<.05, including regions of chromosomes 5q, 3p, 11q, 6p, 1q, 22q, 8p, 20q, and 14p, and 19 consecutive bins with P(ord)<.05, additionally including regions of chromosomes 16q, 18q, 10p, 15q, 6q, and 17q. There is greater consistency of linkage results across studies than has been previously recognized. The results suggest that some or all of these regions contain loci that increase susceptibility to schizophrenia in diverse populations.

Elevated interleukin-6 in the cerebrospinal fluid of a previously delineated schizophrenia subtype.

Evidence of immune activation has occasionally, but not consistently, been reported in schizophrenia. Investigations of cytokine abnormalities in serum, and occasionally in CSF, have yielded inconsistent results, which have been difficult to resolve. In such studies, schizophrenia has been assumed to consist of a single process rather than a group of disorders. This study assesses differences in the pro-inflammatory cytokine, interleukin-6 (IL-6) in the cerebrospinal fluid (CSF) in two previously delineated subtypes of schizophrenics (‘delayed-responders’ (DR) (n=23) and ‘poor-responders’ (PR) (n=8)) during periods of neuroleptic-free psychotic exacerbation, and in a comparison group of normal controls (n=14). The two response subtypes were separated by subsequent treatment response (greater/less than 60% reduction of SAPS scores from baseline during 6 months of systematic treatment). The IL-6 assay, a sandwich enzyme-linked immunosorbent assay, was sensitive and reliable to detect IL-6 levels in the CSF of all subjects. CSF IL-6 was found to be significantly higher in the DR than the PR (P=0.017) and the controls (P=0.013). In addition to supporting the concept of heterogeneity in schizophrenia, this study also provides evidence that a central immune process may be occurring centrally in one subtype of schizophrenia.

Cerebral Cortical Gray Expansion Associated with Two Second-Generation Antipsychotics

BACKGROUND Second-generation antipsychotics (SGAs) differ from first-generation antipsychotics (FGAs) with respect to induction of less extrapyramidal morbidity, partially reducing negative symptoms, and causing modest improvement in neurocognitive functioning in patients with schizophrenia. SGAs demonstrate 5-HT2a antagonism. Differential effects of SGAs and FGAs on cortical gray volumes are explored herein. METHODS Cerebral cortical gray was examined volumetrically in 19 patients with schizophrenia before and following 28 days of treatment with two SGAs (risperidone and ziprasidone; n = 13) or a FGA (haloperidol; n = 6). Seven (untreated) control subjects were also assessed at a similar interval. RESULTS During treatment with the SGAs risperidone and ziprasidone, cerebral cortical gray of 13 patients with schizophrenia expanded 20.6 +/- 11.4 cc (p < .0005). Six patients receiving the FGA haloperidol, as well as 7 control subjects, showed no change in cortical gray volumes (p = .983 and p = .932, respectively) at the time of reassessment. CONCLUSIONS Volumetric increase of cerebral cortical gray occurred early in the course of treatment with the SGAs ziprasidone and risperidone, but not with the FGA haloperidol. Such cortical gray expansion may be relevant to the reported enhanced neurocognition and quality of life associated with SGA treatment.

Compromised myelin integrity during psychosis with repair during remission in drug-responding schizophrenia

Functional connection among the information-processing (grey-matter) centres within the CNS are necessary for the coordinated processing of perception, affect, thought and behaviour. Myelinated neuronal bundles provide the links among such processing centres. Magnetic resonance diffusion tensor imaging (DTI) can assess the physical integrity of myelin. Using DTI, the authors assessed diffusivity (Dm) within whole brain in 14 controls and within 13 acutely psychotic, drug-free schizophrenics both before and after 28 d of antipsychotic drug treatment. Drug-responder schizophrenicss (D-RS) (n=8) were differentiated from poor responders (PR) (n=5) according to previously defined criteria. Differences of Dm at both baseline and following treatment were assessed using Dm distributional analyses and Statistical Parametric Software (SPM2). Impaired physical integrity of myelin, demonstrated by an increase (overall p<0.05) of Dm, was found in the D-RS patients, with multiple regions demonstrating p<0.0005 patient-control differences. The pathological increase in Dm was reduced (p<0.03) following treatment-associated reduction of psychotic symptoms by 84%. Dm of PR patients did not differ from controls at baseline or following subacute treatment. While the pathophysiology(ies) underlying psychosis in poorly responsive (PR) schizophrenics does not appear to be related to a disordered myelin, the findings are consistent with a partially reversible disorder of myelin integrity, and may underlie a dys-synchrony of information processing in a major subgroup of drug-responsive patients with schizophrenia. An antipsychotic drug-induced cascade may partially restore myelin integrity and functional connectivity concomitant with antipsychotic effects in such D-RS patients.

Schizophrenia spectrum disorders: an autosomal-wide scan in multiplex pedigrees.

Genome-wide linkage studies, examining the relationship between the schizophrenia syndrome(s) and possible susceptibility regions within the human genome have identified multiple regions within which linkage to the syndrome may be explored. No regions have been found to provide supportive evidence for linkage in all cohorts. These findings are consistent with the schizophrenia syndrome being genetically heterogeneous, with genetic susceptibility arising from multiple sites which are differentially distributed in from pedigree to pedigree. The authors present data from an autosomal-wide scan of 30 multiplex pedigrees, each with a mean of 4.1 members affected with a schizophrenia spectrum disorder with respect to regions of interest for linkage with the schizophrenia spectrum disease(s). Partial, though not significant replications of susceptibility sites at D1S518 (P=0.029) described by Shaw et al. (1998: Shaw, S.H., Kelly, M., Smith, A.B., Shields, G., Hopkins, P.J., Loftus, J., Laval, S.H., Vita, A., DeHert, M., Cardon, L.R., Crow, T.J., Sherrington, R., DeLisi, L.E., 1998. A Genome-wide search for schizophrenia susceptibility genes. Am. J. Med. Genet. (Neuropsychiatric Genet.) 81, 364-376.), and at D5S426 (P=0.015) described by : Silverman, J.M., Greenberg, D.A., Altstiel, L.D., Siever, L.J., Mohs, R.C., Smith, C.J., Zhou, G., Hollander, T.Y., Yang, X.-P., Kedache, M., Li, G., Zaccario, M.L., Davis, K.L., 1996. Evidence of a locus for schizophrenia and related disorders on the short arm of chromosome 5 in a large pedigree. Am. J. Med. Genet. 67, 162-171.) were documented using multipoint non-parametric (NPL) statistics. Two additional novel regions worthy of further investigation were identified at D1S1150 (P=0.004) and at D20S171 (P=0.009). Previously reported genomic regions of interest for the schizophrenias are reviewed in the context of the same/flanking markers utilized with the present cohort of pedigrees. The data further suggests that only a fraction of pedigrees multiplex for schizophrenia link at any single susceptibility region.