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Background Although many studies have reported the biological basis of major depressive disorder (MDD), none have been put into practical use. Recently, we developed a generalizable brain network marker for MDD diagnoses (diagnostic marker) across multiple imaging sites using resting-state functional magnetic resonance imaging (rs-fMRI). We have planned this clinical trial to establish evidence for the practical applicability of this diagnostic marker as a medical device. In addition, we have developed generalizable brain network markers for MDD stratification (stratification markers), and the verification of these brain network markers is a secondary endpoint of this study. Methods This is a non-randomized, open-label study involving patients with MDD and healthy controls (HCs). We will prospectively acquire rs-fMRI data from 50 patients with MDD and 50 HCs and anterogradely verify whether our diagnostic marker can distinguish between patients with MDD and HCs. Furthermore, we will longitudinally obtain rs-fMRI and clinical data at baseline and 6 weeks later in 80 patients with MDD treated with escitalopram and verify whether it is possible to prospectively distinguish MDD subtypes that are expected to be effectively responsive to escitalopram using our stratification markers. Discussion In this study, we will confirm that sufficient accuracy of the diagnostic marker could be reproduced for data from a prospective clinical study. Using longitudinally obtained data, we will also examine whether the “brain network marker for MDD diagnosis” reflects treatment effects in patients with MDD and whether treatment effects can be predicted by “brain network markers for MDD stratification”. Data collected in this study will be extremely important for the clinical application of the brain network markers for MDD diagnosis and stratification. Trial registration Japan Registry of Clinical Trials (jRCTs062220063). Registered 12/10/2022.

Background: Patients with major depressive disorder (MDD) exhibit cognitive impairment, and evidence suggests that the semantic version of the verbal fluency task is a reliable cognitive marker of the disorder. Here, using functional magnetic resonance imaging (fMRI), we investigated the dysfunction of neural processing in acute depression and examined the effects of a 6-week pharmacological intervention. Methods: Sixteen patients with MDD participated in 2 fMRI sessions, and 16 healthy control (HC) subjects participated in 1 fMRI session. During each fMRI session, the participants performed a semantic verbal fluency task. Brain activity during the task was compared between groups (MDD 1st fMRI vs. HC) and times (MDD 1st fMRI vs. 2nd fMRI). Results: Significant brain hypoactivation was observed in MDD patients at the prefrontal, lateral parietal, and limbic regions compared to HC, and MDD patients exhibited hyperactivation at the left precuneus compared to HC. Hypoactivity of the left dorsolateral prefrontal cortex (DLPFC) and hyperactivity of the precuneus were normalized with treatment. Conclusions: Hypoactivation of the left DLPFC and hyperactivation of the precuneus should be considered as dysregulation of anticorrelated brain networks during a cognitive demanding task. This failure of network regulation may be an important factor in the pathophysiology of MDD.

Since a long-term administration of antidepressant drugs and mood stabilizers is required in the treatment of mood disorders, the regulation of gene expression by these drugs that is mediated by transcription factors, such as activator protein-1 (AP-1) complex, may play an important role in the therapeutic action. In this study, the authors investigated the influence of lithium, antidepressant drugs and stress on AP-1 binding activity in the rat brain. In addition, we examined pretreatment with these drugs on the expression of AP-1 binding activity in response to stress. A gel shift assay was used to measure the levels of AP-1 binding activity. Our results indicate that neither acute nor chronic treatment with antidepressant drugs affects in AP-1 binding activity in the rat frontal cortex or hippocampus. However, the authors found that acute restraint stress for 90 min upregulated the induction of AP-1 binding activity in the rat frontal cortex. In addition, chronic pretreatment with imipramine, but not lithium or paroxetine, downregulated the induction of AP-1 binding activity in response to acute restraint stress in the frontal cortex. The functional classification of antidepressant drugs based on the downregulation of restraint stress-induced AP-1 binding activity may contribute to the advances in our understanding of the pathogenesis of depression.