Findings show that the directionality of neurovegetative symptoms indexes genetic heterogeneity within MDD, with metabolic biology as a central axis of differentiation.
Abstract
Major depressive disorder (MDD) is a complex psychiatric disorder, characterized by a range of mood, cognitive, and neurovegetative symptoms. Current diagnostic criteria treat opposite symptom directions as equivalent; weight gain or loss, and increased or decreased sleep, each count toward a single diagnosis. We defined three subgroups of individuals meeting criteria for MDD: AERS+ (hypersomnia with increased appetite/weight gain), AERS- (insomnia with appetite/weight loss), and an Uncategorized group, and conducted genome-wide association meta-analyses for each (N_eff = 47,858, 156,624, and 215,828, respectively). We identified 27 genome-wide significant loci across subtypes, 4 for AERS+, 10 for AERS- and 13 for Uncategorized. AERS+ showed higher SNP-based heritability (10.9%) and lower polygenicity (1.7% of SNPs) than AERS- (7.9%; 2.9%) or Uncategorized (8.6%; 5.3%), with larger effect sizes at its associated loci. The AERS+ and AERS- subtypes were moderately genetically correlated (r_g= 0.64, se = 0.04). Metabolic traits emerged as a primary differentiator: AERS+ correlated positively with BMI, metabolic syndrome, and related traits, whereas AERS- correlated weakly in the opposite direction. These findings show that the directionality of neurovegetative symptoms indexes genetic heterogeneity within MDD, with metabolic biology as a central axis of differentiation.
Social anxiety disorder (SAD) is a common anxiety disorder (ANX) with moderate heritability that often co-occurs with other mental disorders. Until now, sample sizes in genetic analyses of SAD have been limited, so that the genetic basis of SAD and its subphenotypes is still largely unknown. In a large cohort comprising n = 1,194 SAD patients derived from five German cohorts and n = 3,409 controls from the Heinz Nixdorf Recall Study, we computed polygenic risk scores (PRS) at six p-thresholds using PRSice-2 based on large-scale genome-wide association studies for depression, major depressive disorder (MDD), ANX, schizophrenia (SCZ), bipolar disorder (BD), attention-deficit/hyperactivity disorder (ADHD), anorexia nervosa (AN), autism spectrum disorder (ASD), and alcohol dependence (AD). We used general linear models to examine the association between the PRS and SAD status. In SAD subsamples, we investigated whether the PRS are associated with SAD subphenotypes (i.e., SAD severity, current depressive symptoms, comorbid MDD) using correlation analyses and a general linear model. Results were corrected for multiple testing. The SAD status was significantly associated with PRS for depression, MDD, ANX, SCZ, BD, AN, and ASD (pBH-adjusted<0.05), but not with PRS for ADHD and AD. In SAD subsamples, the subphenotype analyses revealed no significant associations after correction for multiple testing (pBH-adjusted>0.05). Our results support that SAD seems to be genetically highly overlapping with other mental disorders, which might underline a common psychopathological factor. No significant association was found with SAD severity, current depressive symptoms or comorbid MDD. A better understanding of the genetic architecture of SAD may help to develop new diagnostic and treatment approaches.
L. Sindermann, Angelina Röhrig, F. David et al.· Translational Psychiatry· 0 citations
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.
Yuhua Yang, Ningning Li, Li Zhou et al.· Molecular Psychiatry· 0 citations
Introduction: Cognitive impairment and disturbed rest-activity patterns often persist between episodes of major depressive disorder (MDD) and bipolar disorder (BD). Whether these deficits are disorder-specific or transdiagnostic remains unclear, as does the existence of a link between rest-activity phenotypes and cognitive performance. Methods: Using the All of Us Research Program, we derived normative deviation scores across four cognitive domains (sustained attention, inhibitory control, reward-based impulsivity, social cognition) from non-clinical controls (NCC), then compared deviations in MDD and BD. MDD was adequately powered to regress deviation scores on four 90-day Fitbit-derived phenotypes (step count, sleep duration, wakefulness after sleep onset, sleep timing variability); the same analysis was run on NCC as a sensitivity check. Results: Samples were substantially larger than prior works (MDD 5,087-6,536; BD 545-739; NCC 40,589-51,491). Relative to NCC, MDD and BD exhibited worse sustained attention (Delta Glass = -0.081 vs. -0.187) and higher impulsivity (Delta Glass = 0.092 vs. 0.240), with deficits more pronounced in BD. No wearable phenotype was significantly associated with cognitive performance in MDD (R2< 0.01); NCC associations, though significant, were of negligible magnitude (R2 <= 1.2%). Discussion: Inter-episode cognitive impairment was domain-selective rather than global, with a gradient BD > MDD. Despite adequate power, wearable rest-activity phenotypes were not associated with cognition in MDD. Whether this extends to BD, where deficits were largest, could not be tested due to limited power. Community-dwelling samples likely underestimate impairment relative to clinical cohorts.
F. Corponi, M. Kalfas, M. Reami et al.· medRxiv· 0 citations
Results indicate that multi-omics integration, in addition to explaining the molecular architecture of MDD, also characterizes patient subgroups with pathophysiological mechanisms, dimensions of symptoms, and disease treatment, which demonstrates that there is a shift in psychiatry toward a more mechanistic approach.
E. Amjad, B. Sokouti· OBM Neurobiology· 0 citations
Major Depressive Disorder (MDD) is a prevalent and disabling psychiatric disorder. Its clinical heterogeneity undermines diagnostic precision and treatment effectiveness. While DSM-5 defines melancholic and anxious subtypes based on symptoms, their neurophysiological bases remain unclear. Resting-state electroencephalography (EEG) provides a non-invasive approach for investigating neurophysiological heterogeneity in depression. Beta-band oscillations are associated with reward processing, motivation, and cortical arousal, which may differ across subtypes.
We analyzed 325 patients with MDD, classified into melancholic (
n
= 108), anxious (
n
= 102), and non-melancholic and non-anxious (
n
= 115) groups. Relative spectral power and phase-locking value (PLV) in beta1 (12–20 Hz) and beta2 (20–30 Hz) bands were compared. Logistic regression and subtype-specific correlation analyses assessed classification and clinical associations.
Melancholic depression was associated with widespread reductions in beta2 power and higher suicide risk, whereas anxious depression showed altered beta-band functional connectivity, particularly involving left temporal-region connections. Both subtypes shared reduced prefrontal–temporal connectivity. Exploratory classification analyses showed modest discriminative performance after leakage-controlled cross-validation. Associations between beta1 activity and symptom severity were observed only in the anxious subtype.
Melancholic and anxious depression showed partially distinct beta-band EEG patterns. These findings provide preliminary evidence that beta-band EEG features may capture subtype-related neurophysiological heterogeneity in MDD, with subtype-specific associations between neural activity and symptom severity. Further validation is required before these features can be considered clinically applicable.
The trial was registered at the Chinese Clinical Trial Registry on 04/23/2022 ( www.chictr.org.cn ChiCTRID ChiCTR2200059053).
Mengyuan Cheng, Ziyao Su, Haoran Zhang et al.· BMC Psychiatry· 0 citations
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.
Sidney Zisook, Lori L Davis, Trisha Suppes et al.· Journal of Psychopharmacolog...· 0 citations
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