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Articles by M Uhr
Total Records ( 2 ) for M Uhr
  M Ising , S Lucae , E. B Binder , T Bettecken , M Uhr , S Ripke , M. A Kohli , J. M Hennings , S Horstmann , S Kloiber , A Menke , B Bondy , R Rupprecht , K Domschke , B. T Baune , V Arolt , A. J Rush , F Holsboer and B. Muller Myhsok
 

Context  The efficacy of antidepressant drug treatment in depression is unsatisfactory; 1 in 3 patients does not fully recover even after several treatment trials. Genetic factors and clinical characteristics contribute to the failure of a favorable treatment outcome.

Objective  To identify genetic and clinical determinants of antidepressant drug treatment outcome in depression.

Design  Genomewide pharmacogenetic association study with 2 independent replication samples.

Setting  We performed a genomewide association study in patients from the Munich Antidepressant Response Signature (MARS) project and in pooled DNA from an independent German replication sample. A set of 328 single-nucleotide polymorphisms highly related to outcome in both genomewide association studies was genotyped in a sample of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study.

Participants  A total of 339 inpatients with a depressive episode (MARS sample), a further 361 inpatients with depression (German replication sample), and 832 outpatients with major depression (STAR*D sample).

Main Outcome Measures  We generated a multilocus genetic variable that described the individual number of alleles of the selected single nucleotide polymorphisms associated with beneficial treatment outcome in the MARS sample ("response" alleles) to evaluate additive genetic effects on antidepressant drug treatment outcome.

Results  Multilocus analysis revealed a significant contribution of a binary variable that categorized patients as carriers of a high vs low number of response alleles in the prediction of antidepressant drug treatment outcome in both samples (MARS and STAR*D). In addition, we observed that patients with a comorbid anxiety disorder combined with a low number of response alleles showed the least favorable outcome.

Conclusion  These results demonstrate the importance of multiple genetic factors combined with clinical features in the prediction of antidepressant drug treatment outcome, which underscores the multifactorial nature of this trait.

  M. A Kohli , D Salyakina , A Pfennig , S Lucae , S Horstmann , A Menke , S Kloiber , J Hennings , B. B Bradley , K. J Ressler , M Uhr , B Muller Myhsok , F Holsboer and E. B. Binder
 

Context  A consistent body of evidence supports a role of reduced neurotrophic signaling in the pathophysiology of major depressive disorder (MDD) and suicidal behavior. Especially in suicide victims, lower postmortem brain messenger RNA and protein levels of neurotrophins and their receptors have been reported.

Objective  To determine whether the brain-derived neurotrophic factor (BDNF) gene or its high-affinity receptor gene, receptor tyrosine kinase 2 (NTRK2), confer risk for suicide attempt (SA) and MDD by investigating common genetic variants in these loci.

Design  Eighty-three tagging single-nucleotide polymorphisms (SNPs) covering the genetic variability of these loci in European populations were assessed in a case-control association design.

Setting  Inpatients and screened control subjects.

Participants  The discovery sample consisted of 394 depressed patients, of whom 113 had SA, and 366 matched healthy control subjects. The replication studies comprised 744 German patients with MDD and 921 African American nonpsychiatric clinic patients, of whom 152 and 119 were positive for SA, respectively.

Interventions  Blood or saliva samples were collected from each participant for DNA extraction and genotyping.

Main Outcome Measures  Associations of SNPs in BDNF and NTRK2 with SA and MDD.

Results  Independent SNPs within NTRK2 were associated with SA among depressed patients of the discovery sample that could be confirmed in both the German and African American replication samples. Multilocus interaction analysis revealed that single SNP associations within this locus contribute to the risk of SA in a multiplicative and interactive fashion (P = 4.7 x 10–7 for a 3-SNP model in the combined German sample). The effect size was 4.5 (95% confidence interval, 2.1-9.8) when patients carrying risk genotypes in all 3 markers were compared with those without any of the 3 risk genotypes.

Conclusions  Our results suggest that a combination of several independent risk alleles within the NTRK2 locus is associated with SA in depressed patients, further supporting a role of neurotrophins in the pathophysiology of suicide.

Published online February 1, 2010 (doi:10.1001/archgenpsychiatry.2009.201).

 
 
 
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