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Articles by M Rietschel
Total Records ( 8 ) for M Rietschel
  R Uher , N Perroud , M. Y. M Ng , J Hauser , N Henigsberg , W Maier , O Mors , A Placentino , M Rietschel , D Souery , T Zagar , P. M Czerski , B Jerman , E. R Larsen , T. G Schulze , A Zobel , S Cohen Woods , K Pirlo , A. W Butler , P Muglia , M. R Barnes , M Lathrop< , A Farmer , G Breen , K. J Aitchison , I Craig , C. M Lewis and P. McGuffin
  Objective

The purpose of this study was to identify genetic variants underlying the considerable individual differences in response to antidepressant treatment. The authors performed a genome-wide association analysis of improvement of depression severity with two antidepressant drugs.

Method

High-quality Illumina Human610-quad chip genotyping data were available for 706 unrelated participants of European ancestry treated for major depression with escitalopram (N=394) or nortriptyline (N=312) over a 12-week period in the Genome-Based Therapeutic Drugs for Depression (GENDEP) project, a partially randomized open-label pharmacogenetic trial.

Results

Single nucleotide polymorphisms in two intergenic regions containing copy number variants on chromosomes 1 and 10 were associated with the outcome of treatment with escitalopram or nortriptyline at suggestive levels of significance and with a high posterior likelihood of true association. Drug-specific analyses revealed a genome-wide significant association between marker rs2500535 in the uronyl 2-sulphotransferase gene and response to nortriptyline. Response to escitalopram was best predicted by a marker in the interleukin-11 (IL11) gene. A set of 72 a priori-selected candidate genes did not show pharmacogenetic associations above a chance level, but an association with response to escitalopram was detected in the interleukin-6 gene, which is a close homologue of IL11.

Conclusions

While limited statistical power means that a number of true associations may have been missed, these results suggest that efficacy of antidepressants may be predicted by genetic markers other than traditional candidates. Genome-wide studies, if properly replicated, may thus be important steps in the elucidation of the genetic basis of pharmacological response.

  R. H Perlis , J. W Smoller , J Mysore , M Sun , T Gillis , S Purcell , M Rietschel , M. M Nothen , S Witt , W Maier , D. V Iosifescu , P Sullivan , A. J Rush , M Fava , H Breiter , M Macdonald and J. Gusella
  Objective

Presymptomatic individuals with the Huntingtin (HTT) CAG expansion mutation that causes Huntington's disease may have higher levels of depressive symptoms than healthy comparison populations. However, the prevalence of HTT CAG repeat expansions among individuals diagnosed with major depressive disorder has not been established.

Method

This was a case-control genetic association study of HTT CAG allele size in two discovery cohorts of individuals with major depressive disorder and comparison subjects without major depression as well as a replication cohort of individuals with major depression and comparison subjects without major depression.

Results

CAG repeat lengths of 36 or greater were observed in six of 3,054 chromosomes from individuals with major depression, compared with none of 4,155 chromosomes from comparison subjects. In a third cohort, one expanded allele was observed among 1,202 chromosomes in the major depression group, compared with none of 2,678 chromosomes in comparison subjects. No clear pattern of clinical features was shared among individuals with the expanded repeats.

Conclusions

In clinical populations of individuals diagnosed with major depression, approximately 3 in 1,000 carried expanded HTT CAG alleles.

  R. H Perlis , J Huang , S Purcell , M Fava , A. J Rush , P. F Sullivan , S. P Hamilton , F. J McMahon , T Schulze , J. B Potash , P. P Zandi , V. L Willour , B. W Penninx , D. I Boomsma , N Vogelzangs , C. M Middeldorp , M Rietschel , M Nothen , S Cichon , H Gurling , N Bass , A McQuillin , M Hamshere , Craddock Wellcome Trust Case Control Consortium Bipolar Disorder Group , P Sklar and J. W. Smoller
  Objective:

Family and twin studies suggest that liability for suicide attempts is heritable and distinct from mood disorder susceptibility. The authors therefore examined the association between common genomewide variation and lifetime suicide attempts.

Method:

The authors analyzed data on lifetime suicide attempts from genomewide association studies of bipolar I and II disorder as well as major depressive disorder. Bipolar disorder subjects were drawn from the Systematic Treatment Enhancement Program for Bipolar Disorder cohort, the Wellcome Trust Case Control Consortium bipolar cohort, and the University College London cohort. Replication was pursued in the NIMH Genetic Association Information Network bipolar disorder project and a German clinical cohort. Depression subjects were drawn from the Sequential Treatment Alternatives to Relieve Depression cohort, with replication in the Netherlands Study of Depression and Anxiety/Netherlands Twin Register depression cohort.

Results:

Strongest evidence of association for suicide attempt in bipolar disorder was observed in a region without identified genes (rs1466846); five loci also showed suggestive evidence of association. In major depression, strongest evidence of association was observed for a single nucleotide polymorphism in ABI3BP, with six loci also showing suggestive association. Replication cohorts did not provide further support for these loci. However, meta-analysis incorporating approximately 8,700 mood disorder subjects identified four additional regions that met the threshold for suggestive association, including the locus containing the gene coding for protein kinase C-epsilon, previously implicated in models of mood and anxiety.

Conclusions:

The results suggest that inherited risk for suicide among mood disorder patients is unlikely to be the result of individual common variants of large effect. They nonetheless provide suggestive evidence for multiple loci, which merit further investigation.

  M Feyder , R. M Karlsson , P Mathur , M Lyman , R Bock , R Momenan , J Munasinghe , M. L Scattoni , J Ihne , M Camp , C Graybeal , D Strathdee , A Begg , V. A Alvarez , P Kirsch , M Rietschel , S Cichon , H Walter , A Meyer Lindenberg , S. G. N Grant and A. Holmes
  Objective:

Research is increasingly linking autism spectrum disorders and other neurodevelopmental disorders to synaptic abnormalities ("synaptopathies"). PSD-95 (postsynaptic density-95, DLG4) orchestrates protein-protein interactions at excitatory synapses and is a major functional bridge interconnecting a neurexinneuroligin-SHANK pathway implicated in autism spectrum disorders.

Method:

The authors characterized behavioral, dendritic, and molecular phenotypic abnormalities relevant to autism spectrum disorders in mice with PSD-95 deletion (Dlg4–/–). The data from mice led to the identification of single-nucleotide polymorphisms (SNPs) in human DLG4 and the examination of associations between these variants and neural signatures of Williams' syndrome in a normal population, using functional and structural neuroimaging.

Results:

Dlg4–/– showed increased repetitive behaviors, abnormal communication and social behaviors, impaired motor coordination, and increased stress reactivity and anxiety-related responses. Dlg4–/– had subtle dysmorphology of amygdala dendritic spines and altered forebrain expression of various synaptic genes, including Cyln2, which regulates cytoskeletal dynamics and is a candidate gene for Williams' syndrome. A signifi-cant association was observed between variations in two human DLG4 SNPs and reduced intraparietal sulcus volume and abnormal cortico-amygdala coupling, both of which characterize Williams' syndrome.

Conclusions:

These findings demonstrate that DLG4 gene disruption in mice produces a complex range of behavioral and molecular abnormalities relevant to autism spectrum disorders and Williams' syndrome. The study provides an initial link between human DLG4 gene variation and key neural endophenotypes of Williams' syndrome and perhaps corticoamygdala regulation of emotional and social processes more generally.

  J Schumacher , G Laje , R. A Jamra , T Becker , T. W Muhleisen , C Vasilescu , M Mattheisen , S Herms , P Hoffmann , A. M Hillmer , A Georgi , C Herold , T. G Schulze , P Propping , M Rietschel , F. J McMahon , M. M Nothen and S. Cichon
 

Association studies, as well as the initial translocation family study, identified the gene Disrupted-In-Schizophrenia-1 (DISC1) as a risk factor for schizophrenia. DISC1 encodes a multifunctional scaffold protein involved in neurodevelopmental processes implicated in the etiology of schizophrenia. The present study explores the contribution of the DISC locus to schizophrenia using three different approaches: (i) systematic association mapping aimed at detecting DISC risk variants in a schizophrenia sample from a central European population (556 SNPs, n = 1621 individuals). In this homogenous sample, a circumscribed DISC1 interval in intron 9 was significantly associated with schizophrenia in females (P = 4 x 10–5) and contributed most strongly to early-onset cases (P = 9 x 10–5). The odds ratios (ORs) were in the range of 1.46–1.88. (ii) The same sample was used to test for the locus-specific SNP–SNP interaction most recently associated with schizophrenia. Our results confirm the SNP interplay effect between rs1538979 and rs821633 that significantly conferred disease risk in male patients with schizophrenia (P = 0.016, OR 1.57). (iii) In order to detect additional schizophrenia variants, a meta-analysis was performed using nine schizophrenia samples from different European populations (50 SNPs, n = 10 064 individuals maximum, n = 3694 minimum). We found evidence for a common schizophrenia risk interval within DISC1 intron 4–6 (P = 0.002, OR 1.27). The findings point to a complex association between schizophrenia and DISC, including the presence of different risk loci and SNP interplay effects. Furthermore, our phenotype–genotype results—including the consideration of sex-specific effects—highlight the value of homogenous samples in mapping risk genes for schizophrenia in general, and at the DISC locus in particular.

  P Huezo Diaz , R Uher , R Smith , M Rietschel , N Henigsberg , A Marusic , O Mors , W Maier , J Hauser , D Souery , A Placentino , A Zobel , E. R Larsen , P. M Czerski , B Gupta , F Hoda , N Perroud , A Farmer , I Craig , K. J Aitchison and P. McGuffin
 

Background

There have been conflicting reports on whether the length polymorphism in the promoter of the serotonin transporter gene (5-HTTLPR) moderates the antidepressant effects of selective serotonin reuptake inhibitors (SSRIs). We hypothesised that the pharmacogenetic effect of 5-HTTLPR is modulated by gender, age and other variants in the serotonin transporter gene.

Aims

To test the hypothesis that the 5-HTTLPR differently influences response to escitalopram (an SSRI) compared with nortriptyline (a noradrenaline reuptake inhibitor).

Method

The 5-HTTLPR and 13 additional markers across the serotonin transporter gene were genotyped in 795 adults with moderate-to-severe depression treated with escitalopram or nortriptyline in the Genome Based Therapeutic Drugs for Depression (GENDEP) project.

Results

The 5-HTTLPR moderated the response to escitalopram, with long-allele carriers improving more than short-allele homozygotes. A significant three-way interaction between 5-HTTLPR, drug and gender indicated that the effect was concentrated in males treated with escitalopram. The single-nucleotide polymorphism rs2020933 also influenced outcome.

Conclusions

The effect of 5-HTTLPR on antidepressant response is SSRI specific conditional on gender and modulated by another polymorphism at the 5' end of the serotonin transporter gene.

  Craddock Cross Disorder Phenotype Group of the Psychiatric GWAS Consortium , K Kendler , M Neale , J Nurnberger , S Purcell , M Rietschel , R Perlis , S. L Santangelo , T Schulze , J. W Smoller and A. Thapar
 

Over the past 2 years genome-wide association studies have made major contributions to understanding the genetic architecture of many common human diseases. This editorial outlines the development of such studies in psychiatry and highlights the opportunities for advancing understanding of the biological underpinnings and nosological structure of psychiatric disorders.

  R Uher , A Farmer , N Henigsberg , M Rietschel , O Mors , W Maier , D Kozel , J Hauser , D Souery , A Placentino , J Strohmaier , N Perroud , A Zobel , A Rajewska Rager , M. Z Dernovsek , E. R Larsen , P Kalember , C Giovannini , M Barreto , P McGuffin and K. J. Aitchison
 

Background

Adverse drug reactions are important determinants of non-adherence to antidepressant treatment, but their assessment is complicated by overlap with depressive symptoms and lack of reliable self-report measures.

Aims

To evaluate a simple self-report measure and describe adverse reactions to antidepressants in a large sample.

Method

The newly developed self-report Antidepressant Side-Effect Checklist and the psychiatrist-rated UKU Side Effect Rating Scale were repeatedly administered to 811 adult participants with depression in a part-randomised multicentre open-label study comparing escitalopram and nortriptyline.

Results

There was good agreement between self-report and psychiatrists’ ratings. Most complaints listed as adverse reactions in people with depression were more common when they were medication-free rather than during their treatment with antidepressants. Dry mouth (74%), constipation (33%) and weight gain (15%) were associated with nortriptyline treatment. Diarrhoea (9%), insomnia (36%) and yawning (16%) were more common during treatment with escitalopram. Problems with urination and drowsiness predicted discontinuation of nortriptyline. Diarrhoea and decreased appetite predicted discontinuation of escitalopram.

Conclusions

Adverse reactions to antidepressants can be reliably assessed by self-report. Attention to specific adverse reactions may improve adherence to antidepressant treatment.

 
 
 
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