Vulnerability for new episodes in recurrent major depressive disorder: Protocol for the longitudinal DELTA-neuroimaging cohort study

The timeline of brain aging in major depression: A prospective study from before first-onset to established illness

Major depressive disorder (MDD) has been associated with accelerated structural brain aging, yet whether this reflects a pre-existing neurobiological vulnerability, a dynamic acute state effect, or an accumulating biological residual remains unresolved. Across two longitudinal cohorts (N=3220), including a unique sample of 78 initially healthy individuals who transitioned into their first depressive episode during the study course, we systematically tested all three hypotheses. Patients with diagnosed MDD showed elevated MRI-derived brain age relative to healthy controls (1.4 and 2.5 years across cohorts). For the vulnerability hypothesis, individuals scanned prior to their first episode showed no baseline elevation, despite already demonstrating subclinical elevations in self-reported symptom severity, indicating that advanced brain age does not precede illness onset. For the state hypothesis, we found no acceleration of brain aging following the first depressive episode, and longitudinal brain age trajectories were independent of acute clinical symptom severity. Finally, neither episode duration nor recurrence scaled with brain age. Accelerated brain aging in depression is therefore neither an antecedent vulnerability nor an acute state marker of the first episode, but rather a stable biological feature of a long term illness course.

Multilevel dynamic abnormalities of suicidal ideation in major depressive disorder from regional dynamics to network states.

BACKGROUND Suicidal ideation (SI) is a major clinical concern in major depressive disorder (MDD), yet its dynamic neural mechanisms remain poorly understood. METHODS A total of 237 MDD patients (109 MDD-SI and 128 MDD-NSI) were included in the baseline analyses, and 89 patients with baseline SI were included in the longitudinal analyses following 8 weeks of selective serotonin reuptake inhibitor (SSRI) treatment. Dynamic amplitude of low-frequency fluctuations (dALFF), dynamic functional connectivity (dFC), dynamic brain network state analyses, and exploratory spatial neurotransmitter mapping were performed. RESULTS Compared with MDD-NSI, MDD-SI exhibited increased dALFF in the right precentral gyrus, left calcarine cortex, left supplementary motor area, left putamen, and left pregenual anterior cingulate cortex, positively associated with trait SI severity. In exploratory analyses, stronger left calcarine-precuneus dFC was associated with greater recent SI severity. Furthermore, dynamic network analyses identified two recurrent states. Greater recent SI severity showed a potential association with increased persistence in a hyperconnected state, characterized by enhanced intra-network connectivity within the somatomotor, visual, and ventral attention systems. Longitudinally, greater SI reduction among SSRI responders showed a potential association with reduced transition toward the hyperconnected brain state. Exploratory analyses showed spatial associations between SI-related dALFF abnormalities and multiple neurotransmitter systems. CONCLUSIONS The somatomotor and visual systems are consistently implicated in MDD-SI. Moreover, regional and network-level dynamic abnormalities may differentially contribute to trait SI, recent SI, and treatment-related improvements. Together with exploratory neurotransmitter associations, these findings provide a multi-level perspective on the dynamic neural mechanisms of suicidality, which warrants further validation.

Gut Microbiome in Depression with and without REM Sleep Behavior Disorder.

Gut microbiome provides a candidate approach for potential risk stratification in psychiatric populations, and MDD + RBD may represent a biologically distinct depression subtype associated with potential neurodegenerative risk.

Advances in the Treatment of Cognitive Impairment in Major Depressive Disorder: Innovations and Research Challenges

Cognitive Reserve as a Stratification Factor for Cognitive Impairment and Disease Progression in Major Depressive Disorder.

What are the clinical implications of mixed features in major depressive disorder? A VAST-D report.

BACKGROUND Mixed manic/hypomanic symptoms commonly occur in major depressive disorder (MDD), yet their prognostic and therapeutic significance following inadequate response to monoaminergic treatment remains uncertain. This secondary analysis of the Veterans Affairs Augmentation and Switching Treatments for Improving Depression Outcomes (VAST-D) trial examined the prevalence, clinical correlates, and treatment implications of mixed features in 1522 nonbipolar outpatients with insufficient benefit from at least one prior monoaminergic agent. AIMS To explore the prevalence, clinical correlates, and potential treatment implications of mixed features among patients with antidepressant-nonresponsive MDD. METHODS Participants were randomized to switching to bupropion sustained release (S-BUP), combining their current monoaminergic agent with bupropion sustained release (C-BUP), or augmenting treatment with aripiprazole (A-ARI). Mixed features were categorized into five exploratory, non-Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) levels based on the number and intensity of manic/hypomanic symptoms. RESULTS Overall, 76.5% of participants endorsed at least one manic/hypomanic symptom occurring "a little" or "a lot," and 10.2% endorsed more than two symptoms occurring "a lot." Higher mixed-feature levels were associated with greater depressive severity, functional impairment, and recurrent depressive episodes. Mixed features were not associated with treatment retention, response, or suicidal ideation. However, remission rates declined progressively across mixed-feature levels in the S-BUP group, a pattern not observed in the C-BUP or A-ARI groups. CONCLUSIONS Mixed features were highly prevalent and associated with greater clinical burden. Assessment of mixed features may provide clinically relevant information when selecting next-step pharmacologic strategies, particularly when considering a switch to bupropion sustained release.