Subcortical nuclei – including the thalamus, basal ganglia, and hippocampus-amygdala complex – are key regions in schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD). While cortical–subcortical connectivity is well studied, fine intra- and inter-subcortical patterns are less known. This study aimed to identify shared and distinct functional connectivity alterations across SZ, BD, and MDD using a high-resolution subcortical atlas.

Resting-state functional magnetic resonance imaging data from 800 participants (200 per group: SZ, BD, MDD, and healthy controls) in a single-site cohort were analyzed. Subcortical structures were parcellated into 27 regions per hemisphere – thalamus (8 regions), hippocampus (5 regions), amygdala (2 regions), and striatum (12 regions) – based on the a priori atlas. Pairwise functional connectivity among the 54 regions was computed for each participant, and group differences were assessed using general linear models.

Patients with SZ exhibited significantly reduced intra-thalamic connectivity and increased intra-striatal connectivity, as well as enhanced connectivity between the thalamus, striatum, and limbic regions. Patients with BD showed reduced intra-thalamic and intra-striatal connectivity, along with decreased thalamus–amygdala and thalamus–striatum connectivity. In MDD, the predominant finding was reduced intra-limbic connectivity, accompanied by mild reductions in intra-thalamic and striatum–limbic connectivity.

The results suggest that intra-thalamic hypoconnectivity appears common to SZ, BD, and MDD, with graded degrees of severity. In contrast, distinct alterations in intra-striatal and striatum–limbic connectivity may differentiate mood disorders from SZ. These shared and disorder-specific subcortical connectivity patterns enhance the understanding of psychiatric neurobiology and may guide the development of targeted, disorder-tailored interventions.

Patients with major depressive disorder (MDD) are known to be at a heightened risk of suicide. Research indicates that comorbid anxiety may further elevate this risk. However, studies specifically examining the prevalence of anxiety and its associated factors among patients with MDD and history of a recent suicide attempt (RSA) remain limited.

To investigate the prevalence of anxiety and the factors associated with its severity in patients with MDD.

A total of 1718 patients with MDD were included. Hypothesis testing and binary logistic regression were employed to examine differences in anxiety severity and clinical factors between patients with and without an RSA, as well as the association between anxiety severity and RSA. Subsequently, patients with MDD were categorised into three subgroups based on anxiety severity. One-way analysis of variance and multivariate logistic regression were then conducted to identify factors associated with anxiety symptoms.

Anxiety severity was identified as an independent correlate of RSA. Compared with patients with anxiety, patients with MDD and significant or severe anxiety had a 2.9-fold and 11.8-fold increased risk of RSA, respectively. Furthermore, Hamilton Rating Scale for Depression score, Positive and Negative Syndrome Scale positive subscale score, and thyroid function indices (free triiodothyronine and thyroid-stimulating hormone levels) were also determined to be independent correlates of anxiety severity.

Anxiety is associated with risk of RSA in patients with MDD, and depressive symptoms, positive psychotic symptoms and thyroid function may be related factors for severity of anxiety.

Subthreshold depression (StD) is considered a prodromal stage of major depressive disorder (MDD). This study aims to investigate the neurobiological mechanisms of StD by analyzing functional connectivity (FC) and cognitive function in comparison to MDD.

A total of 153 StD individuals, 188 MDD patients, and 110 healthy controls (HCs) were studied using resting-state functional magnetic resonance imaging (fMRI). Whole-brain FC was calculated using seeds from the default mode network (DMN), salience network (SN), executive control network, and affective network (AN). Cognitive function was assessed across seven domains.

StD showed only a deficit in social cognition, while MDD exhibited multidomain cognitive impairments compared to HCs. Both MDD and StD exhibited reduced FC between the right anterior insula (AI) and the left inferior frontal gyrus (IFG), and increased FC between the right subcallosal cingulate cortex and the left posterior cingulate cortex (PCC), key areas of the SN and AN, compared to HCs. MDD particularly showed decreased connectivity between the left PCC and the left middle temporal gyrus, and within the left PCC, while no abnormal FC of the DMN was found in StD. Altered AI-IFG FC was positively correlated with social cognition in StD.

Abnormal connectivity patterns of the SN and AN may contribute to the development of depressive symptoms in StD and MDD, while altered FC of the DMN may be involved in the onset of the disease. A social cognition deficit appeared first in StD, relating to the abnormal connectivity of the SN.

Acupuncture is a clinically recognized treatment for major depressive disorder (MDD), but the associations of efficacy with dosage, treatment course, frequency, acupuncture modality, needle retention time, and manipulation remain unclear. This study evaluated the efficacy and safety of acupuncture for MDD and explored potential moderating factors.

Randomized controlled trials of acupuncture for MDD were searched in CNKI, VIP Database, Wanfang Data, SinoMed, PubMed, Embase, Web of Science, and the Cochrane Library from inception to May 2025. Risk of bias was assessed using RoB 2, and certainty of evidence using GRADE. Data were analyzed in Stata 18.0.

36 trials involving 3843 participants were included. Compared with sham/placebo acupuncture, acupuncture showed greater antidepressant effects (SMD −1.12, 95% CI −1.57 to −0.67, P < 0.01). Very low-quality evidence suggested similar efficacy between acupuncture and antidepressants. Electroacupuncture was superior to manual acupuncture (SMD −0.24, 95% CI −0.42 to −0.07, P < 0.01). High- and moderate-dose acupuncture were more effective than low-dose regimens, and meta-regression suggested a linear dose-response relationship, with 30 sessions as the optimal dosage. Better outcomes were associated with treatment course >6 wk, 3 times weekly, needle retention time of 20–30 minutes, and electroacupuncture. No significant difference was found between needle manipulation and non-manipulation.

Acupuncture significantly alleviates depressive symptoms in MDD. Efficacy appears to be influenced by dosage, acupuncture modality, treatment course, frequency, and needle retention time, with 30 sessions, treatment course > 6 wk, 3 sessions weekly, 20–30 minutes retention, and electroacupuncture showing the most favorable outcomes.

Functional magnetic resonance imaging (fMRI) has revealed inconsistent neural activity patterns in major depressive disorder (MDD) across cognitive and affective domains, and this study used an activation likelihood estimation (ALE) meta-analysis to examine brain function abnormalities in working memory, reward processing, and emotion processing.

A systematic search was conducted in PubMed, Embase, Web of Science, ScienceDirect, and CNKI for fMRI studies comparing MDD patients with healthy controls (HCs), including data up to 3 December 2024. ALE meta-analysis was performed to examine activation patterns. Jackknife sensitivity analysis, risk of bias, and Newcastle–Ottawa scale were used to assess robustness and publication bias. Meta-regression analyses were conducted to explore the impact of covariates on the results.

Sixty-nine studies (2,073 MDD individuals and 2,009 HCs) were included. MDD individuals showed hyperactivation in the bilateral parahippocampal gyrus, subcallosal gyrus, lentiform nucleus, left claustrum, insula, and anterior cingulate cortex, alongside hypoactivation in the right lentiform nucleus, parahippocampal gyrus, fusiform gyrus, and other regions. Domain-specific analyses revealed working memory-related hyperactivation in the right middle and superior frontal gyrus, reward-related hyperactivation in the bilateral lentiform nucleus, right claustrum, and left caudate, and emotion-related hyperactivation in the bilateral parahippocampal gyrus, bilateral lentiform nucleus, right subcallosal gyrus, right anterior cingulate cortex, and left claustrum. Jackknife sensitivity analysis confirmed robustness, with no significant publication bias or covariate impact.

Aberrant activation in the lentiform and caudate nuclei across reward and emotion tasks suggests striatal dysfunction plays a key role in emotion-motivation interplay, highlighting the striatum as a potential target for future therapies.

Low heart rate variability (HRV) levels may be a susceptibility factor for major depressive disorder (MDD). Sleep-state HRV may be more likely to reveal the pathological features of MDD compared with resting state HRV (RS-HRV). This study aimed to elucidate HRV alterations in the sleep states of patients with MDD.

Physiological signal data from the resting state before sleep, first non-rapid eye movement (NREM) and rapid eye movement (REM) stages, and last NREM and REM stages were acquired using polysomnography.

The RS-HRV indices (the standard deviation [SD] of all normal-to-normal [NN] intervals [SDNN], the square root of the mean of the sum of the squares of the differences between adjacent NN intervals [RMSSD], the percentage difference between adjacent NN intervals >50 ms [pNN50], high-frequency [HF], low-frequency [LF], very low frequency [VLF], SD1, and sample entropy [SampEn]) were lower in patients with MDD than in healthy controls (HCs). Patients with MDD had lower SDNN, RMSSD, pNN50, HF, LF, VLF, SD1, SD2, and SampEn and higher SD2/SD1, α1, and α2 than HCs in the NREM stage. They also had lower SDNN, RMSSD, pNN50, HF, LF, VLF, SD1, SD2, and SampEn and higher LF/HF than HCs in the REM stage. Fewer indices changed significantly during different sleep stages in patients with MDD than in HCs.

Patients with MDD had a generalised reduction in HRV in both RS and sleep state and decreased dynamic changes during sleep. Altered autonomic nervous system activity has been implicated in MDD pathology.

Major depressive disorder (MDD) is the leading cause of disability worldwide, affecting roughly 322 million people. Recently, doses of psilocybin have shown promise in treating mood disorders, sparking interest in other dosing practices. According to anecdotal reports and observational studies, microdosing psilocybin yields benefits to mental health; however, rigorously controlled trials have failed to produce compelling evidence for this.

To conduct a phase II, double-blind, placebo-controlled, randomised partial crossover trial to compare microdosing psilocybin to placebo for MDD, evaluating its safety, tolerability and preliminary antidepressant effects.

Forty adults with MDD will be randomised to four doses of psilocybin (2 mg) or placebo (maltodextrin) once weekly over 4 weeks, then four doses of psilocybin (2 mg) once weekly for an additional 4 weeks. The primary efficacy end-point will be change in depression symptoms, as measured at baseline (0 weeks), after the experimental phase (4 weeks), and after the open-label phase (8 weeks). A battery of mood, well-being, attention, creativity, mindfulness and pro-sociality measures will be administered at each time point. Follow-ups will occur every 6 months for up to 2 years after the trial start date, as part of a long-term extension study.

The results of the primary outcome of this trial will be published as a manuscript in a peer-reviewed science or medical journal regardless of the magnitude or direction of effect.

Findings will inform future research on microdosing psilocybin for MDD, regarding dose regimens, effect sizes and expectancy bias. Findings will also facilitate discussions on the comparable benefits of sub- versus threshold doses of psilocybin and the therapeutic value of radically altered perception.

ClinicalTrials.gov identifier: NCT05259943.

Trazodone is commonly used in the treatment of major depressive disorder (MDD) in adults. This study aimed to establish consensus on the clinical scenarios and patient profiles for which trazodone treatment is considered suitable.

A two-round Delphi process was conducted across eight European countries. Statements regarding trazodone were rated by a panel of 32 experts for agreement or disagreement using a 9-point Likert scale; those with <70% agreement among panelists were revised and reassessed by the panel.

There was strong consensus agreement on 68 out of 91 statements (75%) related to trazodone. According to the panel, trazodone is well tolerated, with low anticholinergic activity, minimal impact on sexual function, weight neutrality, and low potential for clinically relevant drug–drug interactions. Consensus agreement supported trazodone use across a broad spectrum of patients with MDD, including those with insomnia, anxiety, psychomotor agitation, substance use, physical comorbidities, neurological conditions, and treatment-resistant depression; consensus agreement was also achieved for trazodone use in elderly patients, and those experiencing adverse effects with other antidepressants.

This study suggests that trazodone is useful in the treatment of MDD across multiple patient profiles. These findings offer practical guidance to support individualized and evidence-based decision-making in clinical practice.

Cognitive and behavioral symptoms of major depressive disorder (MDD) are linked to aberrant changes in the controllability of brain networks. However, previous studies examined network controllability using white matter tractography, neglecting the contributions of gray matter. We aimed to examine differences in the controllability of morphometric networks between patients with MDD and demographic-matched healthy controls and identify the associated neurobiological signatures.

Based on the structural and diffusion MRI data from two independent cohorts, we calculated the controllability of morphometric similarity networks for each participant. A generalized additive model was used to investigate the case–control differences in regional controllability and their cognitive and behavioral associations. We investigated the associations between imaging-derived controllability and neurotransmitters, brain metabolism, and gene transcription profiles using multivariate linear regression and partial least squares regression analyses.

In both cohorts, depression-related abnormalities of morphometric network controllability were primarily located in the prefrontal, cingulate, and visual cortices, contributing to memory, sensation, and perception processes. These abnormalities in network controllability were spatially aligned with the distributions of serotonergic transmission pathways as well as with altered oxygen and glucose metabolism. In addition, these abnormalities spatially overlapped with differentially expressed genes enriched in annotations related to protein catabolism and mitochondria in neuronal cells and were disproportionately located on chromosome 22.

Collectively, neuroimaging evidence revealed aberrant morphometric network controllability underlying MDD-related cognitive and behavioral deficits, and the associated genetic and molecular signatures may help identify the neurobiological mechanisms underlying MDD and provide feasible therapeutic targets.

Growing studies have reported an elevated risk of violence in patients with depression, yet the neurobiological underpinnings remain poorly understood. The present study explored the resting-state electroencephalogram (EEG) features in major depressive disorder (MDD) patients with violent offenses to identify potential neurological markers for violence prediction and intervention.

Twenty-nine MDD patients who committed violent offenses (violent depression [VD] group), 27 MDD patients without violent behaviors (nonviolent depression [NVD] group), and 25 healthy controls (HCs) were included. Resting-state EEGs were recorded for at least 5 min. EEG microstates, functional connectivity (FC), and graph theory metrics were analyzed and compared between groups.

First, the VD group had increased microstate A, more microstates A-B transition, but lower microstates B-D and C-D transition. Second, the VD group exhibited two enhanced functional brain networks compared to NVD and HCs, and three weakened functional brain networks compared to HCs, which were primarily distributed in the frontal and frontoparietal networks. Third, the VD group specifically exhibited reduced nodal efficiency (aNe) in the superior parietal lobe and increased aNe in the middle occipital gyrus.

MDD patients with violent offenses exhibited alterations in EEG microstates, FCs in the frontal lobe and frontoparietal network, and disrupted aNe in specific parietal and occipital lobes. These alternations are closely associated with deficits in emotional regulation, executive function, and inhibitory control, which may subserve as potential neurobiomarkers for violence risk assessment in patients with depression.

Anhedonia is a multidimensional concept, and it is not known which aspects of it are linked to the heterogeneity of treatment responses in major depressive disorder (MDD). We examine the role of anhedonia dimensions in predicting response to antidepressant medication and adjunctive pharmacotherapy.

In CAN-BIND-1, 187 adults with MDD completed the Dimensional Anhedonia Rating Scale (DARS) and the Snaith–Hamilton Pleasure Scale (SHAPS) before undergoing 8 weeks of treatment with escitalopram. At week 8, 90 nonresponders received adjunctive treatment with aripiprazole for an additional 8 weeks. Mixed-effects models tested the hobbies, food, social, and sensory subscales and items of DARS and SHAPS as predictors of change in the Montgomery-Åsberg Depression Rating Scale (MADRS).

Of the four DARS subscales, sensory anhedonia predicted a worse treatment outcome with escitalopram (b = 1.14, 95%CI 0.08 to 2.20, p = 0.034) as did a three-item SHAPS sensory anhedonia subscale (b = 1.50, 95%CI 0.43 to 2.57, p = 0.006). A combined DARS–SHAPS sensory anhedonia subscale complemented the previously reported interest–activity symptom dimension to improve treatment outcome prediction. In contrast, food and social anhedonia dimensions predicted worse outcomes with adjunctive aripiprazole (b = 2.52, 95%CI 1.25 to 3.80, p < 0.001; b = 2.56, 95%CI 1.16 to 3.96, p < 0.001). Corresponding SHAPS items showed similar results.

The inability to enjoy sensory experiences and the lack of interest in food and social activities distinctly predict outcomes with serotonergic versus dopaminergic pharmacotherapy. These findings require replication and extension to other treatments.

Antidepressants are the primary treatment for major depressive disorder (MDD), yet their precise neurobiological mechanisms remain incompletely understood. This study aimed to elucidate neural differences between medicated and unmedicated MDD patients by analyzing resting-state functional magnetic resonance imaging data.

We conducted a coordinate-based meta-analysis, complemented by behavioral, genetic, and neurotransmitter-level evaluations to identify potential therapeutic targets and diagnostic biomarkers. Using seed-based d-mapping with permutation of subject images (SDM-PSI), we assessed brain activation changes associated with antidepressant treatment. The identified regions were further characterized using large-scale molecular and functional brain databases.

A total of 59 studies on unmedicated MDD (2,618 patients, 2,486 controls) and 15 studies on medicated MDD (541 patients, 483 controls) were included. The meta-analysis revealed significantly increased activation in the left striatum among medicated patients, a region linked to cognitive functions such as memory and perception. Gene expression analysis highlighted SLC5A7 and prolactin (PRL) as key genes in this region, while neurotransmitter mapping showed associations with serotonin (5-HT1a, 5-HT2a) and dopamine (D1, D2) receptors. Additionally, reduced activation in the left middle occipital gyrus (MOG) was observed across both medicated and unmedicated groups. This region, implicated in recognition and face processing, showed high expression of TFAP2B and PRL and was associated with serotonin and norepinephrine transporter distributions.

These findings suggest that the left striatum may represent a core neurofunctional target of antidepressant treatment, while the left MOG may serve as a stable neurobiological marker for MDD diagnosis, independent of pharmacological status.

Cognitive impairment in major depressive disorder (MDD) may be driven by neuro-inflammatory processes involving pro-inflammatory cytokines.

This study aimed to examine the relationship between serum tumour necrosis factor-alpha (TNF-α) levels and cognitive performance across different domains in individuals with MDD.

Sixty patients with MDD and 60 healthy controls were recruited. Cognitive function was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and serum TNF-α levels were measured via flow cytometry.

After adjusting for covariates, RBANS total and subscale scores were significantly lower in MDD patients compared with controls (P < 0.001), while log10-transformed TNF-α levels were significantly higher in the MDD group (P = 0.006). In MDD patients, log10TNF-α levels were inversely correlated with immediate memory scores after adjusting for confounding factors (r = −0.35, P = 0.009); however, this relationship was not observed in healthy controls (r = −0.02, P = 0.90). Stepwise multivariate regression analysis further confirmed the negative association of log10TNF-α with immediate memory scores in MDD patients (β = −14.58, t = −4.14, P < 0.001), but not in healthy controls (β = −0.02, t = −0.14, P = 0.89).

These findings suggest that elevated serum TNF-α may contribute to the pathophysiology of MDD and is specifically associated with deficits in immediate memory.

Mitochondrial dysfunction has been implicated in the pathogenesis of major depressive disorder (MDD); however, the causal contributions of specific mitochondrial genes across regulatory layers remain unclear.

We integrated genome-wide association study summary statistics from the Psychiatric Genomics Consortium and FinnGen with quantitative-trait-locus (QTL) datasets for DNA methylation, gene expression (eQTL), and protein abundance. Mitochondrial genes were annotated using the MitoCarta3.0 database. Summary-based Mendelian randomization and Bayesian colocalization were applied to assess causal relationships, with colocalization determined by the posterior probability of a shared causal variant (PPH4), and the false discovery rate used for multiple-testing correction. Brain-specific effects were evaluated using Genotype-Tissue Expression eQTL data. Prioritized genes were ranked based on cross-omics consistency and replication evidence.

Five mitochondrial genes were prioritized. TDRKH showed consistent associations across methylation, transcription, and protein levels, with hypermethylation at cg24503712 linked to reduced expression and a lower risk of MDD (Tier 1). METAP1D (Tier 2) demonstrated protective effects at both the transcript and protein levels. LONP1, FIS1, and SCP2 (Tier 3) exhibited consistent but complex regulatory patterns. Several signals were replicated in brain tissues, including TDRKH in the caudate and METAP1D in the cortex.

This study provides multi-omics evidence for the causal involvement of mitochondrial genes in MDD. TDRKH and METAP1D emerged as key candidates, offering promising targets for future mechanistic research and therapeutic development.

Major depressive disorder (MDD) is a heterogeneous with underlying mechanisms that are insufficiently studied. We aimed to identify functional connectivity (FC)-based subtypes of MDD and investigate their biological mechanisms.

Consensus clustering of FC patterns was applied to a population of 829 MDD patients from the REST-Meta-MDD database, with validity assessed across multiple dimensions, including atlas replication, cross-validated classification, and drug-naïve subgroup analysis. Regression models were used to quantify FC alterations in each MDD subgroup compared with 770 healthy controls, and to analyze spatial associations between FC alterations and publicly available gene transcriptomic and neurotransmitter receptor/transporter density databases.

Two stable MDD subtypes emerged: hypoconnectivity (n = 527) and hyperconnectivity (n = 299), which had both shared and distinct regions with remarkable FC alterations (i.e. epicenters) in the default mode network.

There were several common enriched genes (e.g. axon/brain development, synaptic transmission/organization, etc.) related to FC alterations in both subtypes. However, glial cell and neuronal differentiation genes were specifically enriched in the hypoconnectivity and hyperconnectivity subtypes, respectively.

Both subtypes showed spatial associations between FC alterations and serotonin receptor/transporter density. In the hypoconnectivity subtype, FC alterations correlated with GABA and acetylcholine receptor densities, while norepinephrine transporter and glutamate receptor densities were linked to the hyperconnectivity subtype.

Our findings suggested the presence of two neuroimaging subtypes of MDD characterized by hypoconnectivity or hyperconnectivity, demonstrating robust reproducibility. The two subtypes had both shared and distinct genetic mechanisms and neurotransmitter receptor/transporter profiles, suggesting potential clinical implications for this heterogeneous disorder.

Major depressive disorder (MDD) patients exhibit a mood-congruent emotional processing bias within the amygdala toward negative facial stimuli at both unconscious and conscious levels. Therefore, our study aimed to investigate the temporal and spatial dynamics of amygdala along with its interactions with the whole brain during implicit and explicit conditions in MDD.

Thirty MDD patients and 26 healthy controls (HCs) underwent magnetoencephalography (MEG) recordings and performed implicit and explicit emotional face recognition tasks with happy, sad, and neutral facial expressions. Using the amygdala as a seed region, time frequency representations (TFR) and functional connectivity (FC) were calculated. Pearson correlation analyses measured the relationship between TFR and FC values with clinical symptoms.

During implicit processing, MDD patients exhibited left amygdala activation in the gamma power (60–70 Hz) before 250 ms in response to sad facial stimuli compared to HCs. In the implicit mode, there were increased FC between the right amygdala and several brain regions in the occipitoparietal lobes, as well as higher FC between the left amygdala and putamen in MDD patients. Additionally, the right amygdala was positively correlated with the severity of depression and anxiety during implicit processing.

MDD patients had lateralized amygdala activation in response to sad facial expressions during unconscious emotional recognition of facial stimuli. Our study provided valuable insights into the spatiotemporal dynamics of facial emotional recognition associated with depressive and anxiety-related cognitive bias during implicit and explicit processing.