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Brain regulation of emotional conflict predicts antidepressant treatment response for depression.

ABSTRACT: The efficacy of antidepressant treatment for depression is controversial due to the only modest superiority demonstrated over placebo. However, neurobiological heterogeneity within depression may limit overall antidepressant efficacy. We sought to identify a neurobiological phenotype responsive to antidepressant treatment by testing pretreatment brain activation during response to, and regulation of, emotional conflict as a moderator of the clinical benefit of the antidepressant sertraline versus placebo. Using neuroimaging data from a large randomized controlled trial, we found widespread moderation of clinical benefits by brain activity during regulation of emotional conflict, in which greater downregulation of conflict-responsive regions predicted better sertraline outcomes. Treatment-predictive machine learning using brain metrics outperformed a model trained on clinical and demographic variables. Our findings demonstrate that antidepressant response is predicted by brain activity underlying a key self-regulatory emotional capacity. Leveraging brain-based measures in psychiatry will forge a path toward better treatment personalization, refined mechanistic insights and improved outcomes.

SUBMITTER: Fonzo GA

PROVIDER: S-EPMC6908746 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Brain regulation of emotional conflict predicts antidepressant treatment response for depression.

Fonzo Gregory A GA Etkin Amit A Zhang Yu Y Wu Wei W Cooper Crystal C Chin-Fatt Cherise C Jha Manish K MK Trombello Joseph J Deckersbach Thilo T Adams Phil P McInnis Melvin M McGrath Patrick J PJ Weissman Myrna M MM Fava Maurizio M Trivedi Madhukar H MH

Nature human behaviour 20190923 12

The efficacy of antidepressant treatment for depression is controversial due to the only modest superiority demonstrated over placebo. However, neurobiological heterogeneity within depression may limit overall antidepressant efficacy. We sought to identify a neurobiological phenotype responsive to antidepressant treatment by testing pretreatment brain activation during response to, and regulation of, emotional conflict as a moderator of the clinical benefit of the antidepressant sertraline versu ...[more]

PMID: 31548678

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Project description:Adverse experiences and chronic stress are well-known risk factors for the development of major depression, and an impaired stress response regulation is frequently observed in acute depression. Impaired glucocorticoid receptor (GR) signalling plays an important role in these alterations, and a restoration of GR signalling appears to be a prerequisite of successful antidepressant treatment. Variants in genes of the stress response regulation contribute to the vulnerability to depression in traumatized subjects. Consistent findings point to an important role of FKBP5, the gene expressing FK506-binding protein 51 (FKBP51), which is a strong inhibitor of the GR, and thus, an important regulator of the stress response. We investigated the role of FKBP5 and FKB51 expression with respect to stress response regulation and antidepressant treatment outcome in depressed patients. This study included 297 inpatients, who participated in the Munich Antidepressant Response Signature (MARS) project and were treated for acute depression. In this open-label study, patients received antidepressant treatment according to the attending doctor's choice. In addition to the FKBP5 genotype, changes in blood FKBP51 expression during antidepressant treatment were analyzed using RT-PCR and ZeptoMARKTM reverse phase protein microarray (RPPM). Stress response regulation was evaluated in a subgroup of patients using the combined dexamethasone (dex)/corticotropin releasing hormone (CRH) test. As expected, increased FKBP51 expression was associated with an impaired stress response regulation at baseline and after six weeks was accompanied by an elevated cortisol response to the combined dex/CRH test. Further, we demonstrated an active involvement of FKBP51 in antidepressant treatment outcome. While patients responding to antidepressant treatment had a pronounced reduction of FKBP5 gene and FKBP51 protein expression, increasing expression levels were observed in nonresponders. This effect was moderated by the genotype of the FKBP5 single nucleotide polymorphism (SNP) rs1360780, with carriers of the minor allele showing the most pronounced association. Our findings demonstrate that FKBP5 and, specifically, its expression product FKBP51 are important modulators of antidepressant treatment outcome, pointing to a new, promising target for future antidepressant drug development.

Project description:Introduction: The prediction of antidepressant treatment response may improve outcome. Functional magnetic resonance imaging (fMRI) of emotion processing in major depressive disorder (MDD) may reveal regional brain function serving as predictors of response to treatment with selective serotonin reuptake inhibitor (SSRI). Methods: We examined the association between pre-treatment neural activity by means of fMRI during the perception of emotional stimuli in 22 patients with MDD and the treatment outcome after 6 weeks' medication with an SSRI. A whole brain correlation analysis with Beck Depression Inventory (BDI) change between pre- to post-treatment was conducted to identify neural regions associated with treatment response. Results: During the perception of positive stimuli, responders were characterized by more activation in posterior cingulate cortex (PCC), medial prefrontal cortex, and thalamus as well as middle temporal gyrus. During perception of negative stimuli, PCC, and pregenual anterior cingulate cortex showed the highest correlation with treatment response. Furthermore, responders exhibited higher activation to emotional stimuli than to neutral stimuli in all the above-mentioned regions, while non-responders demonstrated an attenuated neural response to emotional compared to neutral stimuli. Conclusion: Our data suggest that the activity of distinct brain regions is correlated with SSRI treatment outcome and may serve as treatment response predictor. While some regions, in which activity was correlated with treatment response, can be assigned to networks that have been implied in the pathophysiology of depression, most of our regions of interest could also be matched to the default mode network (DMN). Higher DMN activity has been associated with increased rumination as well as negative self-referential processing in previous studies. This may suggest our responders to SSRI to be characterized by such dysregulations and that SSRIs might modify the function associated with this network.

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Brain regulation of emotional conflict predicts antidepressant treatment response for depression.

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Brain regulation of emotional conflict predicts antidepressant treatment response for depression.

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