Prefrontal networks dynamically related to recovery from major depressive disorder: a longitudinal pharmacological fMRI study

Abstract

Due to lacking predictors of depression recovery, successful treatment of major depressive disorder (MDD) is frequently only achieved after therapeutic optimization leading to a prolonged suffering of patients. This study aimed to determine neural prognostic predictors identifying non-remitters prior or early after treatment initiation. Moreover, it intended to detect time-sensitive neural mediators indicating depression recovery. This longitudinal, interventional, single-arm, open-label, phase IV, pharmacological functional magnetic resonance imaging (fMRI) study comprised four scans at important stages prior (day 0) and after escitalopram treatment initiation (day 1, 28, and 56). Totally, 22 treatment-free MDD patients (age mean ± SD: 31.5 ± 7.7; females: 50%) suffering from a concurrent major depressive episode without any comorbid DSM-IV axis I diagnosis completed the study protocol. Primary outcome were neural prognostic predictors of depression recovery. Enhanced de-activation of anterior medial prefrontal cortex (amPFC, single neural mediator) indicated depression recovery correlating with MADRS score and working memory improvements. Strong dorsolateral PFC (dlPFC) activation and weak dlPFC-amPFC, dlPFC-posterior cingulate cortex (PCC), dlPFC-parietal lobe (PL) coupling (three prognostic predictors) hinted at depression recovery at day 0 and 1. Preresponse prediction of continuous (dlPFC-PL: R2day1 = 55.9%, 95% CI: 22.6–79%, P < 0.005) and dichotomous (specificity/sensitivity: SP/SNday1 = 0.91/0.82) recovery definitions remained significant after leave-one-out cross-validation. Identified prefrontal neural predictors might propel the future development of fMRI markers for clinical decision making, which could lead to increased response rates and adherence during acute phase treatment periods. Moreover, this study underscores the importance of the amPFC in depression recovery.

Major Depressive Disorder: Advances in Neuroscience Research and Translational Applications

“…fMRI, including resting-state and task-based fMRI, can divide the brain into self-related regions, such as the anterior cingulate cortex, posterior cingulate cortex, medial prefrontal cortex, precuneus, and dorsomedial thalamus. Many previous studies have shown the disturbance of several brain areas and intrinsic neural networks in patients with depression which could be rescued by antidepressants [113][114][115][116]. Further, some evidence also showed an association between brain network dysfunction and the clinical correlates of patients with depression, including clinical symptoms [117] and the response to antidepressants [118,119], ECT [120,121], and repetitive transcranial magnetic stimulation [122].…”

Neurobiological predictors for clinical trajectories in fully remitted depressed patients

“…In addition to the reward circuitry (Cho et al, 2013), we also decided to test the central‐executive network (CEN; Seeley et al, 2007) due to its importance in emotion regulation (Etkin et al, 2015). Hence, ROIs selected from the CONN toolbox's atlas (Cho et al, 2013; Supporting Information, Section 5, Table S2) covered key regions consistently related to a suboptimal course in previous prediction studies (Meyer et al, 2019; Phillips et al, 2015). ROI‐to‐ROI group analysis was based on correlation matrices between the averaged BOLD time courses of ROI pairs (Nieto‐Castanon, 2020).…”

“…The rate of MDD patients who achieve full remission but continue to have residual symptoms is up to 80% (Nierenberg et al, 1999) often requiring long‐term maintenance treatment to forestall recurrent episodes (National Collaborating Centre for Mental Health (UK), 2010). While the majority of predictive imaging studies have explored determinants of remission from MDEs (Meyer et al, 2019; Phillips et al, 2015), stratification informed by the neurobiology of chronicity, specifically in terms of recurrent MDE and impairing residual symptoms, remains elusive.…”

“…Prospective, predictive neuroimaging designs for fully remitted MDD (rMDD) are missing, despite their major advantage over group‐comparisons: rMDD's phenotypic heterogeneity (Insel et al, 2010) can be harnessed for stratification and differential prediction of illness trajectories. Previous structural and functional magnetic resonance imaging (sMRI/fMRI) studies suggest that treatment failures are related to a dysfunction of the posterior (PCC) and anterior (ACC) cingulate cortex within the default network (DN; Meyer et al, 2019; Pizzagalli, 2011). Clinically, these findings were related to dysfunctional self‐referential cognition and rumination, so‐called sticky thoughts (Andrews‐Hanna et al, 2014), that persist independent of symptom improvement (Shilyansky et al, 2016) even after full remission (Bartova et al, 2015; Pizzagalli, 2011).…”

Structural Plasticity Induced by Ketamine in Human Dopaminergic Neurons as Mechanism Relevant for Treatment-Resistant Depression

“…12,14 In human, neuroimaging evidence supports a normalization of the prefrontal cortex dysfunction in those MDD/TRD subject that responds to any antidepressant treatment. 15,16 Renormalization of hippocampal structural deficit was observed in TRD patients following augmentation therapies such as vagus nerve stimulation 17 or ECT. 18 Reduced DA neurotransmission in ventral striatum, amygdala, and hippocampus associated to anhedonia was observed in MDD/TRD patients and rodents exposed to chronic stress.…”