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Articles by K. J Ressler
Total Records ( 2 ) for K. J Ressler
  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).

  E. B Binder , M. J Owens , W Liu , T. C Deveau , A. J Rush , M. H Trivedi , M Fava , B Bradley , K. J Ressler and C. B. Nemeroff
 

Context  The corticotropin-releasing factor (CRF, or corticotropin-releasing hormone) and arginine vasopressin systems have been implicated in the pathophysiology of anxiety and depressive disorders and response to antidepressant treatment.

Objective  To study the association of genetic variants in 10 genes that regulate the CRF and arginine vasopressin systems with treatment response to citalopram in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) sample (N = 1768).

Design  Pharmacogenetic association study derived from the STAR*D study, a multicenter, prospective, open, 12-week effectiveness trial.

Setting  Outpatient primary care and psychiatric clinics.

Patients  Individuals with nonpsychotic major depressive disorder for whom DNA was available who were subsequently treated with citalopram hydrobromide for 4 to 12 weeks.

Intervention  Flexible doses of citalopram.

Main Outcome Measure  Association of genetic polymorphisms in genes encoding the CRF system with response and remission to citalopram treatment at exit visit.

Results  One single-nucleotide polymorphism (SNP) (rs10473984) within the CRHBP locus showed a significant association with both remission (P = 6.0 x 10–6; corrected, P = .0026) and reduction in depressive symptoms (P = 7.0 x 10–7; corrected, P = .00031) in response to citalopram. The T allele of this SNP was associated with poorer treatment outcome in 2 of the 3 ethnic subsamples (African American and Hispanic), despite large differences in minor allele frequency. This association was more pronounced in patients with features of anxious depression (P = .008). The nonresponse allele was shown to be associated with overall higher plasma corticotropin levels and more pronounced dexamethasone suppression of corticotropin.

Conclusions  These data indicate that a genetic variant within the CRHBP locus affects response to citalopram in African American and Hispanic patients, suggesting a role for this gene and for the CRF system in antidepressant treatment response.

 
 
 
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