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.
Highlights
Affective disorders are a leading cause of morbidity and mortality worldwide.[1,2] currently available antidepressant drugs are safe and effective, the vast majority of patients do not respond until 3–5 weeks after the initiation of treatment, with only o50% of them achieving remission with the first compound prescribed.[3]despite the overt need for improved treatment modalities, including compounds with a more rapid onset of action,[4] efforts to develop conceptually novel antidepressants have been relatively unsuccessful so far.[5]
Translating our preclinical findings to the human situation, we are able to provide evidence that the activin system has a role in response to antidepressant drug treatment in depressed patients: in a genetic association study, we identify specific polymorphisms in the betaglycan gene, a co-receptor binding inhibin and mediating functional antagonism of activin signalling,[14] to significantly predict antidepressant drug treatment outcome in depression
To identify strong candidates in this translational approach, we compared genes that were shown to be significantly regulated by chronic paroxetine treatment in the mouse hippocampus, with the 43 genes showing nominally significant association with antidepressant treatment response in both the Munich Antidepressant Response Signature (MARS) projects as well as STAR*D the activin pathway was the only pathway that showed this pattern of dual association and was chosen for further analysis
Summary
Affective disorders are a leading cause of morbidity and mortality worldwide.[1,2] currently available antidepressant drugs are safe and effective, the vast majority of patients do not respond until 3–5 weeks after the initiation of treatment, with only o50% of them achieving remission with the first compound prescribed.[3]despite the overt need for improved treatment modalities, including compounds with a more rapid onset of action,[4] efforts to develop conceptually novel antidepressants have been relatively unsuccessful so far.[5]. Affective disorders are a leading cause of morbidity and mortality worldwide.[1,2] currently available antidepressant drugs are safe and effective, the vast majority of patients do not respond until 3–5 weeks after the initiation of treatment, with only o50% of them achieving remission with the first compound prescribed.[3]. Distinct single-nucleotide polymorphisms (SNPs) have been shown to predict specific aspects of antidepressant treatment response in affective disorder.[6,7,8,9] despite tremendous efforts in identifying novel, yet unexplored predictive genes in large genome-wide association studies, the results are fairly modest. None of the SNPs identified in those studies achieved genome-wide significance or was consistently replicated across studies, suggesting that alternative pharmacogenetic strategies need to be established.[10,11]
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