title: Resistance to antidepressant treatment is associated with polymorphisms in the leptin gene, decreased leptin mRNA expression, and decreased leptin serum levels.
abstract: Leptin, a peptide hormone from adipose tissue and key player in weight regulation, has been suggested to be involved in sleep and cognition and to exert antidepressant-like effects, presumably via its action on the HPA-axis and hippocampal function. This led us to investigate whether genetic variants in the leptin gene, the level of leptin mRNA-expression and leptin serum concentrations are associated with response to antidepressant treatment. Our sample consisted of inpatients from the Munich Antidepressant Response Signature (MARS) project with weekly Hamilton Depression ratings, divided into two subsamples. In the exploratory sample (n=251) 17 single nucleotide polymorphisms (SNPs) covering the leptin gene region were genotyped. We found significant associations of several SNPs with impaired antidepressant treatment outcome and impaired cognitive performance after correction for multiple testing. The SNP (rs10487506) showing the highest association with treatment response (p=3.9×10(-5)) was analyzed in the replication sample (n=358) and the association could be verified (p=0.021) with response to tricyclic antidepressants. In an additional meta-analysis combining results from the MARS study with data from the Genome-based Therapeutic Drugs for Depression (GENDEP) and the Sequenced Treatment Alternatives to Relieve Depression (STAR(⁎)D) studies, nominal associations of several polymorphisms in the upstream vicinity of rs10487506 with treatment outcome were detected (p=0.001). In addition, we determined leptin mRNA expression in lymphocytes and leptin serum levels in subsamples of the MARS study. Unfavorable treatment outcome was accompanied with decreased leptin mRNA and leptin serum levels. Our results suggest an involvement of leptin in antidepressant action and cognitive function in depression with genetic polymorphisms in the leptin gene, decreased leptin gene expression and leptin deficiency in serum being risk factors for resistance to antidepressant therapy in depressed patients.
authors.affiliation: Max-Planck-Institute of Psychiatry, Kraepelinstrasse 2-10, 80804 Munich, Germany. stkloiber@mpipsykl.mpg.de
authors.forename: Stefan
authors.initials: S
authors.lastname: Kloiber
authors.forename: Stephan
authors.initials: S
authors.lastname: Ripke
authors.forename: Martin A
authors.initials: MA
authors.lastname: Kohli
authors.forename: Simone
authors.initials: S
authors.lastname: Reppermund
authors.forename: Daria
authors.initials: D
authors.lastname: Salyakina
authors.forename: Rudolf
authors.initials: R
authors.lastname: Uher
authors.forename: Peter
authors.initials: P
authors.lastname: McGuffin
authors.forename: Roy H
authors.initials: RH
authors.lastname: Perlis
authors.forename: Steven P
authors.initials: SP
authors.lastname: Hamilton
authors.forename: Benno
authors.initials: B
authors.lastname: Pütz
authors.forename: Johannes
authors.initials: J
authors.lastname: Hennings
authors.forename: Tanja
authors.initials: T
authors.lastname: Brückl
authors.forename: Torsten
authors.initials: T
authors.lastname: Klengel
authors.forename: Thomas
authors.initials: T
authors.lastname: Bettecken
authors.forename: Marcus
authors.initials: M
authors.lastname: Ising
authors.forename: Manfred
authors.initials: M
authors.lastname: Uhr
authors.forename: Tatjana
authors.initials: T
authors.lastname: Dose
authors.forename: Paul G
authors.initials: PG
authors.lastname: Unschuld
authors.forename: Josef
authors.initials: J
authors.lastname: Zihl
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Binder
authors.forename: Bertram
authors.initials: B
authors.lastname: Müller-Myhsok
authors.forename: Florian
authors.initials: F
authors.lastname: Holsboer
authors.forename: Susanne
authors.initials: S
authors.lastname: Lucae
mesh_terms: D000928:Antidepressive Agents / Q000627:therapeutic use*; D003071:Cognition / Q000187:drug effects; D030541:Databases, Genetic; D003863:Depression / Q000097:blood / Q000188:drug therapy* / Q000235:genetics* / Q000523:psychology; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D020738:Leptin / Q000096:biosynthesis / Q000097:blood* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D000928:Antidepressive Agents; D020738:Leptin; D012333:RNA, Messenger