Association of schizophrenia onset age and white matter integrity with treatment effect of D-cycloserine : a randomized placebo-controlled double-blind crossover study

Background: It has been reported that drugs which promote the N-Methyl-D-aspartate-type glutamate receptor function by stimulating the glycine modulatory site in the receptor improve negative symptoms and cognitive dysfunction in schizophrenia patients being treated with antipsychotic drugs. Methods: We performed a placebo-controlled double-blind crossover study involving 41 schizophrenia patients in which D-cycloserine 50 mg/day was added-on, and the influence of the onset age and association with white matter integrity on MR diffusion tensor imaging were investigated for the first time. The patients were evaluated using the Positive and Negative Syndrome Scale (PANSS), Scale for the Assessment of Negative Symptoms (SANS), Brief Assessment of Cognition in Schizophrenia (BACS), and other scales. Results: D-cycloserine did not improve positive or negative symptoms or cognitive dysfunction in schizophrenia. The investigation in consideration of the onset age suggests that D-cycloserine may aggravate negative symptoms of early-onset schizophrenia. The better treatment effect of D-cycloserine on BACS was observed when the white matter integrity of the sagittal stratum/ cingulum/fornix stria terminalis/genu of corpus callosum/external capsule was higher, and the better treatment effect on PANSS general psychopathology (PANSS-G) was observed when the white matter integrity of the splenium of corpus callosum was higher. In contrast, the better treatment effect of D-cycloserine on PANSS-G and SANS-IV were observed when the white matter integrity of the posterior thalamic radiation (left) was lower. Conclusion: It was suggested that response to D-cycloserine is influenced by the onset age and white matter integrity

Association studies of WD repeat domain 3 and chitobiosyldiphosphodolichol beta-mannosyltransferase genes with schizophrenia in a Japanese population

<div><p>Schizophrenia and schizophrenia-like symptoms induced by the dopamine agonists and <i>N</i>-methyl-D aspartate type glutamate receptor antagonists occur only after the adolescent period. Similarly, animal models of schizophrenia by these drugs are also induced after the critical period around postnatal week three. Based upon the development-dependent onsets of these psychotomimetic effects, by using a DNA microarray technique, we identified the WD repeat domain 3 (<i>WDR3</i>) and chitobiosyldiphosphodolichol beta-mannosyltransferase (<i>ALG1</i>) genes as novel candidates for schizophrenia-related molecules, whose mRNAs were up-regulated in the adult (postnatal week seven), but not in the infant (postnatal week one) rats by an indirect dopamine agonist, and phencyclidine, an antagonist of the NMDA receptor. WDR3 and other related proteins are the nuclear proteins presumably involved in various cellular activities, such as cell cycle progression, signal transduction, apoptosis, and gene regulation. ALG1 is presumed to be involved in the regulation of the protein <i>N</i>-glycosylation. To further elucidate the molecular pathophysiology of schizophrenia, we have evaluated the genetic association of <i>WDR3</i> and <i>ALG1</i> in schizophrenia. We examined 21 single nucleotide polymorphisms [SNPs; W1 (rs1812607)-W16 (rs6656360), A1 (rs8053916)-A10 (rs9673733)] from these genes using the Japanese case-control sample (1,808 schizophrenics and 2,170 matched controls). No significant genetic associations of these SNPs were identified. However, we detected a significant association of W4 (rs319471) in the female schizophrenics (allelic <i>P</i> = 0.003, genotypic <i>P</i> = 0.008). Based on a haplotype analysis, the observed haplotypes consisting of W4 (rs319471)–W5 (rs379058) also displayed a significant association in the female schizophrenics (<i>P</i> = 0.016). Even after correction for multiple testing, these associations remained significant. Our findings suggest that the <i>WDR3</i> gene may likely be a sensitive factor in female patients with schizophrenia, and that modification of the WDR3 signaling pathway warrants further investigation as to the pathophysiology of schizophrenia.</p></div

LD block structure of <i>WDR3</i> and <i>ALG1</i> genes.

<p>(A) <i>WDR3</i> gene consists of three, and (B) <i>ALG1</i> gene consists of two haplotype blocks in schizophrenia. In the left panel, the number in the box represents D’ (×100), blank means D’ = 1. In the right panel, the number in the box represents r² (×100).</p

Association of schizophrenia onset age and white matter integrity with treatment effect of D-cycloserine: a randomized placebo-controlled double-blind crossover study

Abstract Background It has been reported that drugs which promote the N-Methyl-D-aspartate-type glutamate receptor function by stimulating the glycine modulatory site in the receptor improve negative symptoms and cognitive dysfunction in schizophrenia patients being treated with antipsychotic drugs. Methods We performed a placebo-controlled double-blind crossover study involving 41 schizophrenia patients in which D-cycloserine 50 mg/day was added-on, and the influence of the onset age and association with white matter integrity on MR diffusion tensor imaging were investigated for the first time. The patients were evaluated using the Positive and Negative Syndrome Scale (PANSS), Scale for the Assessment of Negative Symptoms (SANS), Brief Assessment of Cognition in Schizophrenia (BACS), and other scales. Results D-cycloserine did not improve positive or negative symptoms or cognitive dysfunction in schizophrenia. The investigation in consideration of the onset age suggests that D-cycloserine may aggravate negative symptoms of early-onset schizophrenia. The better treatment effect of D-cycloserine on BACS was observed when the white matter integrity of the sagittal stratum/ cingulum/fornix stria terminalis/genu of corpus callosum/external capsule was higher, and the better treatment effect on PANSS general psychopathology (PANSS-G) was observed when the white matter integrity of the splenium of corpus callosum was higher. In contrast, the better treatment effect of D-cycloserine on PANSS-G and SANS-IV were observed when the white matter integrity of the posterior thalamic radiation (left) was lower. Conclusion It was suggested that response to D-cycloserine is influenced by the onset age and white matter integrity. Trial registration UMIN Clinical Trials Registry (number UMIN000000468 ). Registered 18 August 200

Power estimation of case-control sample and classified groups.

<p>Power estimation of case-control sample and classified groups.</p

Genotyping and allele distribution of SNPs on <i>WDR3</i> and <i>ALG1</i> genes in schizophrenia and controls from the Japanese population.

<p>Genotyping and allele distribution of SNPs on <i>WDR3</i> and <i>ALG1</i> genes in schizophrenia and controls from the Japanese population.</p

Stratification analysis of sex on <i>WDR3</i> and <i>ALG1</i> gene in schizophrenia and controls from Japanese population.

<p>Stratification analysis of sex on <i>WDR3</i> and <i>ALG1</i> gene in schizophrenia and controls from Japanese population.</p