The antidepressant mechanism of electroconvulsive therapy (ECT) remains not clearly understood. This study aimed to detect the changes in gray matter volume (GMV) in patients with major depressive disorder (MDD) caused by ECT and exploratorily analyzed the potential functional mechanisms.

A total of 24 patients with MDD who underwent eight ECT sessions were included in the study. Clinical symptom assessments and MRI scans were conducted and compared. Using whole-brain micro-array measurements provided by the Allen Human Brain Atlas (AHBA), regional gene expression profiles were calculated. The differential gene PLS1 was obtained through Partial Least Squares (PLS) regression analysis, and PLS1 was divided into positive contribution (PLS1+) and negative contribution (PLS1−) genes. Through gene function enrichment analysis, the functional pathways and cell types of PLS1 enrichment were identified.

Gray matter volume (GMV) in the somatosensory and motor cortices, occipital cortex, prefrontal cortex, and insula showed an increasing trend after ECT, while GMV in the temporal cortex, posterior cingulate cortex, and orbitofrontal cortex decreased. PLS1 genes were enriched in synapse- and cell-related biological processes and cellular components (such as ‘pre- and post-synapse’, ‘synapse organization’ etc.). A large number of genes in the PLS1+ list were involved in neurons (inhibitory and excitatory), whereas PLS1− genes were significantly involved in Astrocytes (Astro) and Microglia (Micro).

This study established a link between treatment-induced GMV changes and specific functional pathways and cell types, which suggests that ECT may exert its effects through synapse-associated functional and affect neurons and glial cells.

Major depressive disorder (MDD) is marked by significant changes to the local synchrony of spontaneous neural activity across various brain regions. However, many methods for assessing this local connectivity use fixed or arbitrary neighborhood sizes, resulting in a decreased capacity to capture smooth changes to the spatial gradient of local correlations. A newly developed method sensitive to classical anatomo-functional boundaries, Iso-Distant Average Correlation (IDAC), was therefore used to examine depression associated alterations to the local functional connectivity of the brain.

One-hundred and forty-seven adolescents and young adults with MDD and 94 healthy controls underwent a resting-state functional magnetic resonance imaging (fMRI) scan. Whole-brain functional connectivity maps of intracortical neural activity within iso-distant local areas (5–10, 15–20, and 25–30 mm) were generated to characterize local fMRI signal similarities.

Across all spatial distances, MDD participants demonstrated greater local functional connectivity of the bilateral posterior hippocampus, retrosplenial cortex, dorsal insula, fusiform gyrus, and supplementary motor area. Local connectivity alterations in short and medium distances (5–10 and 15–20 mm) in the mid insula cortex were additionally associated with expressive suppression use, independent of depressive symptom severity.

Our study identified increased synchrony of the neural activity in several regions commonly implicated in the neurobiology of depression. These effects were relatively consistent across the three distances examined. Longitudinal investigation of this altered local connectivity will clarify whether these differences are also found in other age groups and if this relationship is modified by increased disease chronicity.

A substantial subset of patients with major depressive disorder (MDD) experience treatment-resistant depression (TRD), typically defined as failure to respond to at least two sequential antidepressant trials at adequate dose and length.

To examine clinical and service-level associations of TRD, and the experiences of people with TRD and clinicians involved in their care within a large, diverse National Health Service trust in the UK.

This mixed-methods study integrated quantitative analysis of electronic health records with thematic analysis of semi-structured interviews. Chi-squared tests and one-way analysis of variance were used to assess associations between lines of antidepressant treatments and sociodemographic and clinical variables, and binary logistic regression was used to identify associations of TRD status.

Nearly half (48%) of MDD patients met TRD criteria, with 36.9% having trialled ≥4 antidepressant treatments. People with TRD had higher rates of recurrent depression (odds ratio = 1.24, 95% CI: 1.05–1.45, P = 0.008), comorbid anxiety disorders (odds ratio = 1.21, 95% CI: 1.03–1.41, P = 0.019), personality disorders (odds ratio=1.35, 95% CI: 1.10–1.65, P = 0.003), self-harm (odds ratio = 1.76, 95% CI: 1.06–2.93, P = 0.029) and cardiovascular diseases (odds ratio = 1.46, 95% CI: 1.02–2.07, P = 0.0374). Greater treatment resistance was linked to increased economic inactivity and functional loss. Qualitative findings revealed severe emotional distress and frustration with existing treatments, as well as organisational and illness-related barriers to effective care.

TRD is characterised by increasing mental and physical morbidity and functional decline, with individuals experiencing barriers to effective care. Improved pathways, service structures and more effective biological and psychological interventions are needed.

We utilize a novel contrastive genetic-epidemiological method, the Maternal Half-Sibling Families with Discordant Fathers (MHSFDF) design, to examine cross-generational genetic transmission of posttraumatic stress disorder (PTSD) and related internalizing major depression (MD), and externalizing disorders: alcohol use disorder (AUD) and drug use disorder (DUD).

Using Swedish national registries, we identified 72,467 maternal half-sibling pairs reared together whose biological fathers were discordant for the diagnoses of PTSD, MD, AUD, and DUD. Offspring selected had to have less than 1 year of contact with their affected fathers. We examined the differences in outcome for within- and cross-disorder risk of diagnosis in the half-siblings with an affected versus unaffected father.

Paternal PTSD increased the risk of PTSD (HR: 1.43, 95% CI: 1.05–1.96) and MD (HR: 1.55, CI: 1.28–1.88) in offspring. It did not, however, elevate the risk of externalizing disorders (AUD or DUD). Offspring of fathers with AUD, DUD, or MD had increased risk of PTSD, suggesting sharing of vertically transmitted genetic risk between these disorders. No sex effects were found for any studied diagnosis.

This study is the first to show cross-generation genetic transmission for PTSD using the MHSFDF design. The pattern of cross-disorder genetic risk broadly supported an internalizing versus externalizing disorder split.

Numerous studies have explored the relationship between brain aging and major depressive disorder (MDD) and attempted to explain the phenomenon of faster brain aging in patients with MDD from multiple perspectives. However, a major challenge in this field is elucidating the ontological basis of these changes. Here, we aimed to explore the relationship between brain structural changes in MDD-related brain aging and neurotransmitter expression levels and transcriptomics.

Imaging data from 670 Japanese participants (MDD: health controls = 233:437) and the support vector regression model were utilized to predict and compare brain age between MDD patients and healthy controls. A map of differences in cortical thickness was generated, furthermore, spatial correlation analysis with neurotransmitters and correlation analysis with gene expression were performed.

The degree of brain aging was found to be significantly higher in patients with MDD. Moreover, significant cortical thinning was observed in the left ventral area, and premotor eye field in patients with MDD. A significant correlation was observed between MDD-related cortical thinning and neurotransmitter receptors/transporters, including dopaminergic, serotonergic, and glutamatergic systems. Enriched Gene Ontology terms, including protein binding, plasma membrane, and protein processing, contribute to MDD-related cortical thinning.

The findings of this study provide further evidence that patients with MDD experience more severe brain aging, deepening our understanding of the underlying neural mechanisms and genetic basis of the brain changes involved. Additionally, these findings hold promise for the development of interventions aimed at preventing further deterioration in MDD-related brain aging, thus offering potential therapeutic avenues.

Panic disorder (PD) may increase the likelihood of suicidal ideation and behaviors because of psychiatric comorbidities such as major depressive disorder (MDD). However, research has yet to demonstrate a direct relationship between PD and suicide mortality.

Using data from Taiwan’s National Health Insurance Research Database, we identified 171,737 individuals with PD and 686,948 age- and sex-matched individuals without PD during 2003–2017. We assessed the risk of suicide within the same period. Psychiatric comorbidities such as schizophrenia, bipolar disorder, MDD, obsessive-compulsive disorder (OCD), autism, alcohol use disorder (AUD), and substance use disorder (SUD) were also evaluated. Time-dependent Cox regression models were used to compare the risk of suicide in different groups after adjustment for demographic data and psychiatric comorbidities.

Our Cox regression model revealed that PD was an independent risk factor for suicide (hazard ratio [HR] = 1.85, 95% confidence interval [CI] = 1.59–2.14), regardless of psychiatric comorbidities. Among all comorbidities, MDD with PD was associated with the highest risk of suicide (HR = 6.08, 95% CI = 5.48–6.74), followed by autism (HR = 4.52, 95% CI = 1.66–12.29), schizophrenia (HR = 3.34, 95% CI = 2.7–4.13), bipolar disorder (HR = 3.20, 95% CI = 2.71–3.79), AUD (HR = 2.99, 95% CI = 2.41–3.72), SUD (HR = 2.82, 95% CI = 2.28–3.47), and OCD (HR = 2.10, 95% CI = 1.64–2.67).

PD is an independent risk factor for suicide. Psychiatric comorbidities (i.e. schizophrenia, bipolar disorder, MDD, OCD, AUD, SUD, and autism) with PD increase the risk of suicide.

Suicidal ideation (SI) is very common in patients with major depressive disorder (MDD). However, its neural mechanisms remain unclear. The anterior cingulate cortex (ACC) region may be associated with SI in MDD patients. This study aimed to elucidate the neural mechanisms of SI in MDD patients by analyzing changes in gray matter volume (GMV) in brain structures in the ACC region, which has not been adequately studied to date.

According to the REST-meta-MDD project, this study subjects consisted of 235 healthy controls and 246 MDD patients, including 123 MDD patients with and 123 without SI, and their structural magnetic resonance imaging data were analyzed. The 17-item Hamilton Depression Rating Scale (HAMD) was used to assess depressive symptoms. Correlation analysis and logistic regression analysis were used to determine whether there was a correlation between GMV of ACC and SI in MDD patients.

MDD patients with SI had higher HAMD scores and greater GMV in bilateral ACC compared to MDD patients without SI (all p < 0.001). GMV of bilateral ACC was positively correlated with SI in MDD patients and entered the regression equation in the subsequent logistic regression analysis.

Our findings suggest that GMV of ACC may be associated with SI in patients with MDD and is a sensitive biomarker of SI.

Recent neuroimaging studies have demonstrated that the heterogeneous antidepressant responsiveness in patients with major depressive disorder (MDD) is associated with diverse resting-state functional brain network (rsFBN) topology; however, only limited studies have explored the rsFBN using electroencephalography (EEG). In this study, we aimed to identify EEG-derived rsFBN-based biomarkers to predict pharmacotherapeutic responsiveness.

The resting-state EEG signals were acquired for demography-matched three groups: 98 patients with treatment-refractory MDD (trMDD), 269 those with good-responding MDD (grMDD), and 131 healthy controls (HCs). The source-level rsFBN was constructed using 31 sources as nodes and beta-band power envelope correlation (PEC) as edges. The degree centrality (DC) and clustering coefficients (CCs) were calculated for various sparsity levels. Network-based statistic and one-way analysis of variance models were employed for comparing PECs and network indices, respectively. The multiple comparisons were controlled by the false discovery rate.

Patients with trMDD were characterized by the altered dorsal attention network and salience network. Specifically, they exhibited hypoconnection between eye fields and right parietal regions (p = 0.0088), decreased DC in the right supramarginal gyrus (q = 0.0057), and decreased CC in the reward circuit (qs < 0.05). On the other hand, both MDD groups shared increased DC but decreased CC in the posterior cingulate cortex.

We confirmed that network topology was more severely deteriorated in patients with trMDD, particularly for the attention-regulatory networks. Our findings suggested that the altered rsFBN topologies could serve as potential pathologically interpretable biomarkers for predicting antidepressant responsiveness.

The emotion regulation network (ERN) in the brain provides a framework for understanding the neuropathology of affective disorders. Although previous neuroimaging studies have investigated the neurobiological correlates of the ERN in major depressive disorder (MDD), whether patients with MDD exhibit abnormal functional connectivity (FC) patterns in the ERN and whether the abnormal FC in the ERN can serve as a therapeutic response signature remain unclear.

A large functional magnetic resonance imaging dataset comprising 709 patients with MDD and 725 healthy controls (HCs) recruited across five sites was analyzed. Using a seed-based FC approach, we first investigated the group differences in whole-brain resting-state FC of the 14 ERN seeds between participants with and without MDD. Furthermore, an independent sample (45 MDD patients) was used to evaluate the relationship between the aforementioned abnormal FC in the ERN and symptom improvement after 8 weeks of antidepressant monotherapy.

Compared to the HCs, patients with MDD exhibited aberrant FC between 7 ERN seeds and several cortical and subcortical areas, including the bilateral middle temporal gyrus, bilateral occipital gyrus, right thalamus, calcarine cortex, middle frontal gyrus, and the bilateral superior temporal gyrus. In an independent sample, these aberrant FCs in the ERN were negatively correlated with the reduction rate of the HAMD17 score among MDD patients.

These results might extend our understanding of the neurobiological underpinnings underlying unadaptable or inflexible emotional processing in MDD patients and help to elucidate the mechanisms of therapeutic response.

Living with major depressive disorder (MDD) reduces life expectancy, with respiratory disease being a significant threat. However, evidence on respiratory disease in this population has not yet been meta-analyzed.

This meta-analysis examines respiratory disease prevalence and odds ratio (OR) in patients with MDD and treatment resistant depression (TRD). A systematic literature search was conducted, with a snowball search of reference and citation lists. Inclusion criteria covered studies in MDD and TRD patients with confirmed diagnoses of respiratory diseases (asthma, chronic obstructive pulmonary disease [COPD], pneumonia, lung cancer, and tuberculosis), comparing with a control group when possible.

From 4,138 retrieved articles, 15 (including 476,927 individuals with MDD, 50,680 with TRD, and 1,108,979 control group) met the inclusion criteria. In MDD patients, COPD prevalence was 9.0% (95% CI: 3.8–19.6%), asthma 8.6% (95% CI: 5.7–12.8%), and pneumonia 2.5% (95% CI: 2.2–2.9%). In TRD patients, COPD prevalence was 9.9% (95% CI: 4.2–21.9%) and asthma 10.9% (95% CI: 10.7–11.2%), but meta-analysis limited to those diseases showed no significant relative risk differences. Compared to the general population, individuals with MDD had significantly higher rates of COPD (OR 1.79, 95% CI: 1.49–2.16), even higher in younger populations (1.85 [95% CI: 1.74–1.97]) and more prevalent in women.

This first meta-analysis on this topic shows that MDD is associated with an increased risk of respiratory illness compared to the general population. The prevalence of asthma doubles the mean described in the general population worldwide, and in COPD, women and younger people are at particular risk. Prevention policies are urgently needed.

Depressive disorders are the most common diagnosis among individuals who die by suicide, and intermittent theta-burst stimulation (iTBS) is a noninvasive treatment for those with difficult-to-treat depression who are at higher risk for suicide. Previous data suggests that pairing iTBS with D-cycloserine, a partial N-methyl-D-aspartate (NMDA) receptor agonist, improves antidepressant outcomes. However, its impact on suicide risk is not known.

We examine suicidal ideation and implicit suicide risk after iTBS+D-cycloserine in two clinical trials (open-label trial [n = 12] and randomized placebo-controlled trial [RCT, n = 50]) involving adults with major depressive disorder and the acute effects of D-cycloserine on implicit suicide risk in a crossover trial (n = 18). Implicit suicide risk was assessed using the computerized death/suicide implicit association test (IAT), and depressive symptoms and suicidal ideation were assessed using the clinician-rated Montgomery–Asberg Depression Rating Scale (MADRS).

Open-label iTBS+D-cycloserine was associated with a rapid reduction in suicidal ideation, and iTBS+D-cycloserine was superior to iTBS+placebo in reducing suicidal ideation. Similarly, open-label iTBS+D-cycloserine was associated with decreased implicit suicide risk as measured by the death/suicide IAT, and iTBS+D-cycloserine was associated with greater decreases in death/suicide IAT scores compared to iTBS+placebo. A single acute dose of D-cycloserine in the absence of iTBS had no effect on implicit suicide risk.

Adjunctive D-cycloserine with iTBS is a promising strategy to reduce suicidal ideation and implicit suicide risk in depression.

Esketamine nasal spray (ESK) is approved in combination with an oral antidepressant (OAD) for the treatment of adults with treatment-resistant depression (TRD); however, direct comparisons with atypical antipsychotics for TRD are limited. This secondary analysis of the ESCAPE-TRD study compared rates of remission and response, and improvements in depressive symptoms over time, between ESK and quetiapine extended-release (XR) in patients with TRD treated in accordance with US prescribing information (USPI).

ESCAPE-TRD (NCT04338321) was a randomized, open-label, rater-blinded phase 3b trial investigating ESK versus quetiapine XR for acute and maintenance treatment of patients with TRD. This secondary analysis included patients aged 18–64 years who were treated/dosed according to USPI. The primary endpoint was remission, defined as Montgomery–Åsberg Depression Rating Scale (MADRS) total score ≤ 10. Treatment-emergent adverse events (TEAEs) leading to discontinuation were summarized descriptively.

Among 636 patients in this secondary analysis (ESK, n = 316; quetiapine XR, n = 320), significantly more ESK-treated patients achieved remission starting at week 8 (28.3% versus 18.6%; P = 0.005) through week 32 (55.7% versus 36.3%; P < 0.001), compared with quetiapine XR–treated patients. There were clinically and statistically significant improvements in MADRS scores with ESK versus quetiapine XR at each visit from day 8 onwards. Fewer patients discontinued treatment because of TEAEs with ESK (4.5%) versus quetiapine XR (10.1%).

Consistent with the primary analysis, this secondary analysis demonstrated that ESK improves short- and long-term outcomes compared with quetiapine XR in patients with TRD treated according to USPI.