title: Convergent animal and human evidence suggests the activin/inhibin pathway to be involved in antidepressant response.
abstract: Despite the overt need for improved treatment modalities in depression, efforts to develop conceptually novel antidepressants have been relatively unsuccessful so far. Here we present a translational approach combining results from hypothesis-free animal experiments with data from a genetic association study in depression. Comparing genes regulated by chronic paroxetine treatment in the mouse hippocampus with genes showing nominally significant association with antidepressant treatment response in two pharmacogenetic studies, the activin pathway was the only one to show this dual pattern of association and therefore selected as a candidate. We examined the regulation of activin A and activin receptor type IA mRNA following antidepressant treatment. We investigated the effects of stereotaxic infusion of activin into the hippocampus and the amygdala in a behavioural model of depression. To analyse whether variants in genes in the activin signalling pathway predict antidepressant treatment response, we performed a human genetic association study. Significant changes in the expression of genes in the activin signalling pathway were observed following 1 and 4 weeks of treatment. Injection of activin A into the hippocampus exerts acute antidepressant-like effects. Polymorphisms in the betaglycan gene, a co-receptor mediating functional antagonism of activin signalling, significantly predict treatment outcome in our system-wide pharmacogenetics study in depression. We provide convergent evidence from mouse and human data that genes in the activin signalling pathway are promising novel candidates involved in the neurobiogical mechanisms underlying antidepressant mechanisms of action. Further, our data suggest this pathway to be a target for more rapid-acting antidepressants in the future.
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Ganea
authors.forename: A
authors.initials: A
authors.lastname: Menke
authors.forename: M V
authors.initials: MV
authors.lastname: Schmidt
authors.forename: S
authors.initials: S
authors.lastname: Lucae
authors.forename: G
authors.initials: G
authors.lastname: Rammes
authors.forename: C
authors.initials: C
authors.lastname: Liebl
authors.forename: D
authors.initials: D
authors.lastname: Harbich
authors.forename: V
authors.initials: V
authors.lastname: Sterlemann
authors.forename: C
authors.initials: C
authors.lastname: Storch
authors.forename: M
authors.initials: M
authors.lastname: Uhr
authors.forename: F
authors.initials: F
authors.lastname: Holsboer
authors.forename: E B
authors.initials: EB
authors.lastname: Binder
authors.forename: I
authors.initials: I
authors.lastname: Sillaber
authors.forename: M B
authors.initials: MB
authors.lastname: Müller
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics / Q000378:metabolism; D028341:Activins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D000328:Adult; D000368:Aged; D000679:Amygdala / Q000187:drug effects; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D018891:Dentate Gyrus / Q000187:drug effects; D003866:Depressive Disorder / Q000188:drug therapy / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D017374:Paroxetine / Q000494:pharmacology*; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D011509:Proteoglycans / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis*; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D015398:Signal Transduction
chemical_list: D000928:Antidepressive Agents; D011509:Proteoglycans; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; C422405:activin A; D028341:Activins; C071736:betaglycan; D017374:Paroxetine; D030201:Activin Receptors, Type I