BACKGROUND: Anxious depression (AD) is a common subtype of major depressive disorder (MDD). Neuroimaging studies of AD have revealed inconsistent and heterogeneous brain alterations with the use of single-model methods. Therefore, it is necessary to explore the pathogenesis of AD using multi-model imaging analyses to obtain more homogeneous and robust results.
METHODS: One hundred and eighty-two patients with MDD and 64 matched healthy controls (HCs) were recruited. Voxel-based morphometry (VBM) was used to estimate the gray matter volume (GMV) of all subjects. The GMV differences between the AD and non-anxious depression (NAD) participants were used as regions of interest (ROIs) for subsequent resting state functional connectivity (rs-FC) analyses. Correlation analysis was used to evaluate the associations between clinical symptoms and abnormal function in specific brain areas.
RESULTS: Decreased GMV in the medial frontal gyrus (MFG) and the superior frontal gyrus (SFG) was observed in the AD group compared to the NAD group. Taking the MFG and SFG as ROIs, the rs-FC analysis revealed decreased FC between the left SFG and left temporal pole and between the left SFG and right MFG in the AD group compared to the NAD group. Finally, the FC between the left SFG and left temporal pole was negatively correlated with HAMD-17 scores in the AD group.
CONCLUSIONS: By combining the GMV and rs-FC models, this study revealed that structural and functional disruption of the affective network may be an important pathophysiology underlying AD. The structural impairment may serve as the foundation of the functional impairment.

OBJECTIVE: Using functional near-infrared spectroscopy (fNIRS) previous studies have found that activation differences in the dorsolateral prefrontal cortex (DLPFC) during an autobiographical memory task (AMT) under the condition of different emotional valences may be neurophysiological markers of depression and different depression subtypes. Additionally, compared with non-anxious depression, anxious depression presents abnormal hemodynamic activation in the DLPFC. This study aimed to use fNIRS to investigate hemodynamic activation in the DLPFC of depression patients with and without anxiety during AMT triggered by different emotional valence stimuli.
METHODS: We recruited 194 patients with depression (91 with non-anxious depression, 103 with anxious depression) and 110 healthy controls from Chinese college students. A 53-channel fNIRS was used to detect cerebral hemodynamic differences in the three groups during AMT.
RESULTS: The results showed that: (1) the activation of oxy-Hb in the left DLPFC was significantly higher under positive emotional valence than under negative emotional valence for healthy controls and patients with non-anxious depression, while there was no significant difference between positive and negative emotional valence observed in response to anxious depression; and (2) Oxy-Hb activation under negative emotional valence was significantly higher in the anxious depression group than in the non-anxious depression group.
CONCLUSIONS: This study revealed that the hemodynamic hyperactivation of negative emotional valence in the left DLPFC may be due to the neurophysiological differences between anxious and non-anxious patients with depression.

BACKGROUND: Anxious depression is a prevalent subtype of depression associated with adverse outcomes such as higher depression severity and higher rates of suicidality. This study leveraged a state-wide research registry of depressed and/or suicidal youth to compare the prevalence, clinical correlates, and symptom patterns of those with versus without anxious depression.
METHODS: We included baseline data from 797 participants (ages 8-20) with a diagnosis of a depressive disorder. A score on the Generalized Anxiety Disorder Scale (GAD-7) ≥ 10 was used to define individuals with and without anxious depression. A structured battery was used to capture psychiatric diagnostic status, depression/anxiety severity, suicide risk, history of trauma, functioning, and resilience.
RESULTS: The prevalence of anxious depression among youth with depressive disorders was 59.5 % (n = 474). Youth with anxious depression had greater depression severity and anxiety symptoms, higher suicidality, and a higher prevalence of comorbid anxiety disorders than those without. Youth with anxious depression had greater impairment in functioning defined as worse pain interference, pain severity, fatigue, and social relationships compared to those without anxious depression. Youth with anxious depression also reported higher rates of depressive symptoms such as irritable mood, feelings of guilt, and psychomotor agitation compared to those without anxious depression.
CONCLUSIONS: Anxious depression is associated with worse depression severity, higher suicidality, and lower functioning. Longitudinal work is needed to examine long-term courses of anxious depression to explore its stability as a diagnostic subcategory.

UNASSIGNED: Anxious depression (AD) is a common, distinct depression subtype. This exploratory subgroup analysis aimed to explore the effects of acupuncture as an add-on therapy of selective serotonin reuptake inhibitors (SSRIs) for patients with AD or non-anxious depression (NAD).
UNASSIGNED: Four hundred and sixty-five patients with moderate-to-severe depression from the AcuSDep pragmatic trial were included in analysis. Patients were randomly assigned to receive MA+SSRIs, EA+SSRIs, or SSRIs alone (1:1:1) for six weeks. AD was defined by using dimensional criteria. The measurement instruments included 17-items Hamilton Depression Scale (HAMD-17), Self-Rating Depression Scale (SDS), Clinical Global Impression (CGI), Rating Scale for Side Effects (SERS), and WHO Quality of Life-BREF (WHOQOL-BREF). Comparison between AD and NAD subgroups and comparisons between groups within either AD or NAD subgroups were conducted.
UNASSIGNED: Eighty percent of the patients met the criteria for AD. The AD subgroup had poorer clinical manifestations and treatment outcomes compared to those of the NAD subgroup. For AD patients, the HAMD response rate, remission rate, early onset rate, and the score changes on each scale at most measurement points on the two acupuncture groups were significantly better than the SSRIs group. For NAD patients, the HAMD early onset rates of the two acupuncture groups were significantly better than the SSRIs group.
UNASSIGNED: For AD subtype patients, either MA or EA add-on SSRIs showed comprehensive improvements, with small-to-medium effect sizes. For NAD subtype patients, both the add-on acupuncture could accelerate the response to SSRIs treatment. The study contributed to the existing literature by providing insights into the potential benefits of acupuncture in combination with SSRIs, especially for patients with AD subtypes. Due to its limited nature as a post hoc subgroup analysis, prospectively designed, high-quality trials are warranted.
UNASSIGNED: ChiCTR-TRC-08000297.

This study aims to investigate sex differences and risk factors for self-reported suicide attempts among Chinese Han middle-aged patients with first-episode drug-naïve (FEDN) anxious depression (AD). A total of 1796 patients with FEDN major depressive disorder were enrolled in this study, including 341 middle-aged patients with AD. We compared the prevalence, demographics, and clinical characteristics of suicide attempts between male and female patients with FEDN middle-aged AD. We also explored the risk factors for self-reported suicide attempts in this population using binary logistic regression analysis. The male/female ratio was 91/250 and the age of onset was 51.50 ± 4.13. Our results showed that there were no significant sex differences in the prevalence of self-reported suicide attempts in middle-aged patients with FEDN AD. However, we did find significant differences in several demographic and clinical characteristics between self-reported suicide attempters and non-suicide attempters. Moreover, severe anxiety, measured by the Hamilton Anxiety Rating Scale score, was identified as a risk factor for self-reported suicide attempts in female middle-aged AD patients. Additionally, elevated thyroid peroxidase antibody (TPOAb) levels were linked to self-reported suicide attempts in male AD patients. Our findings suggest that there are no significant sex differences in the prevalence of self-reported suicide attempts in this population, but there may be sex-specific risk factors for self-reported suicide attempts in middle-aged AD. Clinical psychiatrists need to pay attention to thyroid hormone levels in middle-aged anxious depression.

BACKGROUND: Major depressive disorder (MDD) is a heterogeneous mental disorder, and accompanying anxiety symptoms, known as anxious depression (AD), are the most common subtype. However, the pathophysiology of AD may be distinct in depressed patients without anxiety (NAD) and remains unknown. This study aimed to investigate the relationship between functional connectivity and peripheral transcriptional profiles in patients with AD and NAD.
METHODS: Functional imaging data were collected to identify differences in functional networks among patients with AD (n = 66), patients with NAD (n = 115), and healthy controls (HC, n = 200). The peripheral transcriptional data were clustered as co-expression modules, and their associations with AD, AND, and HC were analyzed. The gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses of the genes in the significant module were performed. Correlation analysis was performed to identify functional network-associated gene co-expression modules.
RESULTS: A network was identified which consisted of 23 nodes and 28 edges that were significantly different among three sample groups. The regions of the network were located in temporal and occipital lobe. Two gene co-expression modules were shown to be associated with NAD, and one of which was correlated with the disrupted network in the AD group. The biological function of this module was enriched in immune regulation pathways.
CONCLUSIONS: The results suggested that immune-related mechanisms were associated with functional networks in AD.

BACKGROUND: Psychotic symptoms (PS) frequently occur in young adults with anxious depression (AD), yet the mediators of the associations between depression and PS remain unclear. This study aimed to investigate the prevalence and risk factors of PS in first-episode and drug-naïve (FEDN) young adults with AD and attempted to elucidate the relationship between thyroid-stimulating hormone (TSH) levels, anxiety, depression, and PS, as well as to identify potential mediating roles.
METHODS: 369 FEDN young adults with AD were recruited. Clinical symptoms were assessed using the Positive and Negative Syndrome Scale\'s positive subscale, the Hamilton Depression Rating Scale (HAMD), and the Hamilton Anxiety Rating Scale (HAMA). Fasting glucose, lipids, and thyroid function were also collected.
RESULTS: The prevalence of PS in young adults with AD (21.68 %) was 12.24 times higher than in non-AD patients. The HAMD scores (P = 0.005, OR = 1.23), HAMA scores (P < 0.001, OR = 1.62), and TSH levels (P = 0.025, OR = 1.20) were significant predictors of PS. The combined area under the curve value for distinguishing young adults with AD with and without PS was 0.86. We also identified serial multiple mediating effects of TSH levels and anxiety on the association of depression with PS.
CONCLUSIONS: These findings emphasize the role of anxiety and TSH levels as serial mediators of the association between depression and PS. Therefore, when treating PS in young adults with AD, it is important to focus not only on depression, but also on TSH levels and anxiety to maximize benefit.

BACKGROUND: There have been many studies on the benefits of repeated ketamine infusions on patients\' depression but few on the impact of ketamine on patients\' long-term quality of life (QoL). This study investigated long-term QoL in individuals with depression, both anxious and nonanxious.
METHODS: A total of 107 individuals with a diagnosis of depression were included in the study. The patients were evaluated on Days 0, 13 and 26 and Months 6 and 9, and they received six ketamine infusions over the course of two weeks. The World Health Organization Quality of Life-BREF (WHOQOL-BREF) Scale and the Patient Health Questionnaire-9 (PHQ-9) Scale were used to measure depressive symptoms and QoL. Linear mixed models were used to evaluate depressive symptoms and QoL during ketamine treatment.
RESULTS: A total of 67.2 % of patients were diagnosed with anxious depression. In the long term, there were no significant differences in the time-by-group interactions for general QoL (F = 0.510; P = 0.676), physical QoL (F = 2.092; P = 0.102), psychological QoL (F = 0.102; P = 0.959), social QoL (F = 2.180; P = 0.091), or environmental QoL (F = 1.849; P = 0.139) between the two groups.
CONCLUSIONS: The main limitation of this study is its open-label design.
CONCLUSIONS: The improvement in depression symptoms and QoL following ketamine treatment was not impacted by the presence or absence of anxiety in patients who were depressed prior to treatment. Only occasionally did depressed individuals with anxiety experience a worsening of their quality of life compared to those without anxiety.

Anxious depression represents a subtype of major depressive disorder and is associated with increased suicidality, severity, chronicity and lower treatment response. Only a few studies have investigated the differences between anxious depressed (aMDD) and non-anxious depressed (naMDD) patients regarding treatment dosage, serum-concentration and drug-specific treatment response. In our naturalistic and prospective study, we investigated whether the effectiveness of therapy including antidepressants (SSRI, SNRI, NaSSA, tricyclics and combinations) in aMDD patients differs significantly from that in naMDD patients. In a sample of 346 patients, we calculated the anxiety somatization factor (ASF) and defined treatment response as a reduction (≥50%) in the Hamilton Depression Rating Scale (HDRS)-21 score after 7 weeks of pharmacological treatment. We did not observe an association between therapy response and the baseline ASF-scores, or differences in therapy outcomes between aMDD and naMDD patients. However, non-responders had higher ASF-scores, and at week 7 aMDD patients displayed a worse therapy outcome than naMDD patients. In subgroup analyses for different antidepressant drugs, venlafaxine-treated aMDD patients showed a significantly worse outcome at week 7. Future prospective, randomized-controlled studies should address the question of a worse therapy outcome in aMDD patients for different psychopharmaceuticals individually.

Anxious depression is a common subtype of major depressive disorder (MDD) associated with adverse outcomes and severely impaired social function. It is important to clarify the underlying neurobiology of anxious depression to refine the diagnosis and stratify patients for therapy. Here we explored associations between anxiety and brain structure/function in MDD patients. A total of 260 MDD patients and 127 healthy controls underwent three-dimensional T1-weighted structural scanning and resting-state functional magnetic resonance imaging. Demographic data were collected from all participants. Differences in gray matter volume (GMV), (fractional) amplitude of low-frequency fluctuation ((f)ALFF), regional homogeneity (ReHo), and seed point-based functional connectivity were compared between anxious MDD patients, non-anxious MDD patients, and healthy controls. A random forest model was used to predict anxiety in MDD patients using neuroimaging features. Anxious MDD patients showed significant differences in GMV in the left middle temporal gyrus and ReHo in the right superior parietal gyrus and the left precuneus than HCs. Compared with non-anxious MDD patients, patients with anxious MDD showed significantly different GMV in the left inferior temporal gyrus, left superior temporal gyrus, left superior frontal gyrus (orbital part), and left dorsolateral superior frontal gyrus; fALFF in the left middle temporal gyrus; ReHo in the inferior temporal gyrus and the superior frontal gyrus (orbital part); and functional connectivity between the left superior temporal gyrus(temporal pole) and left medial superior frontal gyrus. A diagnostic predictive random forest model built using imaging features and validated by 10-fold cross-validation distinguished anxious from non-anxious MDD with an AUC of 0.802. Patients with anxious depression exhibit dysregulation of brain regions associated with emotion regulation, cognition, and decision-making, and our diagnostic model paves the way for more accurate, objective clinical diagnosis of anxious depression.