Nonanxious Depression Research Articles

Temporoparietal structural-functional coupling abnormalities in drug-naïve first-episode major depressive disorder

IntroductionMajor depressive disorder (MDD) is a debilitating and heterogeneous disease. Many MDD patients experience concurrent anxiety symptoms, often referred to as anxious depression (MDD-ANX). The relationships between network alterations in structural connectivity (SC) and functional connectivity (FC) in MDD and its anxiety-related subtype remain areas that require further investigation. MethodsWe investigated SC-FC coupling at the system and regional levels in 80 never-treated first-episode MDD patients and 80 healthy control (HC) subjects. For brain systems and regions showing significant between-group coupling differences, we further conducted subgroup comparisons between MDD-ANX, non-anxious depression (MDD-NANX) and HC. We also investigated topological features at the corresponding levels, and assessed the correlation patterns between significant coupling alterations and the topological and clinical characteristics. ResultsRelative to HC, MDD patients showed increased SC-FC coupling in the temporal system (right hippocampus and left superior temporal gyrus [STG]) but decreased coupling in the parietal system (right postcentral gyrus and left angular gyrus). These systems and regions were further characterized by disturbed inter-module connections and impaired structural network efficiency in MDD. Notably, SC-FC coupling of the right hippocampus was significantly increased in MDD-ANX compared to MDD-NANX, which further showed distinct correlation patterns with structural network efficiency. ConclusionsAlterations in both SC-FC coupling and topological properties in the temporal and parietal regions provide insights into the interplay between the structural and functional network abnormalities in MDD. SC-FC coupling alterations in the right hippocampus, associated with structural nodal efficiency, may be implicated in the neuropathology of anxious depression.

The Effects of Variation in the GABAA Receptor Gene on Anxious Depression are Mediated by the Functional Connectivity Between the Amygdala and Middle Frontal Gyrus.

γ-aminobutyric acid (GABA) and its main receptor, the GABAA receptor, are implicated in major depressive disorder (MDD). Anxious depression (AD) is deemed to be a primary subtype of MDD. The amygdala and the dorsolateral prefrontal cortex (DLPFC) are key brain regions involved in emotional regulation. These regions contain the most GABAA receptors. Although the GABAergic deficit hypothesis of MDD is generally accepted, few studies have demonstrated how GABAA receptor gene polymorphisms affect the functions of specific brain regions, in particular, the amygdala and the DLPFC. The sample comprised 83 patients with AD, 70 patients with non-anxious depression (NAD), and 62healthy controls (HC).All participants underwent genotyping for polymorphisms of GABAA receptor subunit genes, followed by a resting-state fMRI scan. The HAMD-17 was used to evaluate the severity of MDD. ANOVA was performed to obtain the difference in the imaging data, GABAA receptor multi-locus genetic profile scores (MGPS), and HAMD-17 scores among three groups, then the significant differences between AD and NAD groups were identified. Mediating effect analysis was used to explore the role of functional connectivity (FC) between the amygdala and DLPFC in the association between the GABAA receptor gene MGPS and AD clinical features. Compared with the NAD group, the AD group had a higher GABAA receptor MGPS. AD patients exhibited a negative correlation between the MGPS and FC of the right centromedial (CM) subregion, and the right middle frontal gyrus (MFG). A negative correlation was also observed between the MGPS and anxiety/somatic symptoms. More importantly, the right CM and right MFG connectivity mediated the association between the GABAA receptor MGPS and anxiety/somatic symptoms in patients with AD. The decreased FC between the right MFG and right CM subregion mediates the association between GABAA receptor MGPS and AD.

Brain structural and functional abnormalities in affective network are associated with anxious depression

BackgroundAnxious 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.MethodsOne 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.ResultsDecreased 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.ConclusionBy 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.

The Clinical Characteristics and Manifestation of Anxious Depression Among Patients With Major Depressive Disorders-Results From a Taiwan Multicenter Study.

Anxious depression is a prevalent characteristic observed in Asian psychiatric patients diagnosed with major depressive disorder (MDD). This study aims to investigate the prevalence and clinical presentation of anxious depression in Taiwanese individuals diagnosed with MDD. We recruited psychiatric outpatients aged over 18 who had been diagnosed with MDD through clinical interviews. This recruitment took place at five hospitals located in northern Taiwan. We gathered baseline clinical and demographic information from the participants. Anxious depression was identified using a threshold of an anxiety/somatization factor score ≥7 on the 21-item Hamilton Rating Scale for Depression (HAM-D). In our study of 399 patients (84.21% female), 64.16% met the criteria for anxious depression. They tended to be older, married, less educated, with more children, and an older age of onset. Anxious depression patients had higher HAM-D and Clinical Global Impression-Severity scale score, more panic disorder (without agoraphobia), and exhibited symptoms like agitation, irritability, concentration difficulties, psychological and somatic anxiety, somatic complaints, hypochondriasis, weight loss, and increased insight. Surprisingly, their suicide rates did not significantly differ from non-anxious depression patients. This highlights the importance of recognizing and addressing these unique characteristics. Our study findings unveiled that the prevalence of anxious depression among Taiwanese outpatients diagnosed with MDD was lower compared to inpatients but substantially higher than the reported rates in European countries and the United States. Furthermore, patients with anxious depression exhibited a greater occurrence of somatic symptoms.

Differences in prefrontal cortex activation in Chinese college students with different severities of depressive symptoms: A large sample of functional near-infrared spectroscopy (fNIRS) findings

BackgroundPrevious studies proposed that functional near-infrared spectroscopy (fNIRS) can be used to distinguish between not only different severities of depressive symptoms but also different subgroups of depression, such as anxious and non-anxious depression, bipolar and unipolar depression, and melancholia and non-melancholia depression. However, the differences in brain haemodynamic activation between depression subgroups (such as confirmed depression [CD] and suspected depression [SD]) with different symptom severities and the possible correlation between symptom severity and haemodynamic activation in specific brain regions using fNIRS have yet to be clarified. MethodsThe severity of depression symptoms was classified using the Hospital Anxiety and Depression scale (HADS) and the Mini International Neuropsychiatric Interview by psychiatrists. We recruited 654 patients with depression who had varying severities of depressive symptoms, including 276 with SD and 378 with CD, and 317 with HCs from among Chinese college students. The 53-channel fNIRS was used to detect the cerebral hemodynamic difference of the three groups during the VFT (verbal fluency task). ResultsCompared with the HC, region-specific fNIRS leads indicate CD patients had significant lower haemodynamic activation in three particular prefrontal regions: 1) right dorsolateral prefrontal cortex (DLPFC), 2) bilateral frontopolar cortex (FPC), and 3) right Broca's area (BA). SD vs. HC comparisons revealed only significant lower haemodynamic activation in the right FPC area. Compared to SD patients, CD patients exhibited decreased hemodynamic activation changes in the right DLPFC and the right BA. Correlation analysis established a significant negative correlation between the hemodynamic changes in the bilateral FPC and the severity of depressive symptoms. ConclusionsThe right DLPFC and right BA are expected to be physiological mechanisms to distinguish depression subgroups (CD, SD) with different symptom severities. The haemodynamic changes in the bilateral FPC was nagatively associated with the symptom severity of depression.

Altered fractional amplitude of low-frequency fluctuations in the superior temporal gyrus: a resting-state fMRI study in anxious depression

BackgroundAnxious depression, which is a common subtype of major depressive disorder, has distinct clinical features from nonanxious depression. However, little is known about the neurobiological characteristics of anxious depression. In this study, we explored resting-state regional brain activity changes between anxious depression and nonanxious depression.MethodResting-state functional magnetic resonance (rs-fMRI) imaging data were collected from 60 patients with anxious depression, 38 patients with nonanxious depression, and 60 matched healthy controls (HCs). One-way analysis of variance was performed to compare the whole-brain fractional amplitude of low-frequency fluctuation (fALFF) in the three groups. The correlation between the fALFF values and the clinical measures was examined.ResultsCompared with those of HCs, the fALFF values in the left superior temporal gyrus (STG) in patients with anxious depression were significantly increased, while the fALFF values in the left middle temporal gyrus (MTG), left STG, and right STG in patients with nonanxious depression were significantly increased. Patients with anxious depression showed reduced fALFF values in the right STG compared with patients with nonanxious depression (p < 0.001, corrected). Within the anxious depression group, fALFF value in the right STG was positively correlated with the cognitive disturbance score (r = 0.36, p = 0.005 corrected).ConclusionThe bilateral STG and left MTG, which are related to the default mode network, appear to be key brain regions in nonanxious depression, while the right STG plays an essential role in the neuropathological mechanism of anxious depression.

Efficacy of repeated intravenous esketamine in adolescents with anxious versus non-anxious depression

BackgroundPatients with anxious major depressive disorder (MDD) are more likely to have poorer outcomes than those with non-anxious MDD. However, the effect of esketamine on adolescents with anxious versus non-anxious...

Evidence-Based Pharmacotherapy of Anxiety Symptoms in Patients with Major Depressive Disorder: Focus on Agomelatine.

Patients with depression require thorough clinical assessment, which should include symptom profile, severity and staging, personality factors, antecedent and concurrent psychiatric comorbidity, physical comorbidity, neurocognitive function, exposure to stressors in early life (e.g. trauma) or recently (e.g. bereavement), and protective factors. The presence of anxiety symptoms in a depressed patient is associated with more severe depression, increased suicidality and worse outcomes compared with non-anxious depression. A network meta-analysis of antidepressant treatments found that agomelatine, citalopram, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine and vortioxetine were all significantly more effective than other antidepressants for the treatment of depression, and that agomelatine, citalopram, escitalopram, fluoxetine, sertraline and vortioxetine were better tolerated than other antidepressants. Agomelatine has been shown to have two major effects-relieving depressive symptoms, and supporting symptomatic and functional recovery-and these benefits have been demonstrated in patients with depression as well as in patients with generalised anxiety disorder, including those with more severe symptoms. Agomelatine has also been shown to be efficacious and well tolerated in patients with depression plus concomitant anxiety symptoms. A pooled analysis of data from six agomelatine studies of depression (three placebo-controlled and three with active comparators-fluoxetine, sertraline and venlafaxine) found that agomelatine was significantly more effective than placebo at relieving the anxiety subscore on the Hamilton Depression Rating Scale, and that the difference between agomelatine and placebo was even more marked in the subgroup of patients with severe anxiety symptoms at baseline. Irrespective of the pharmacotherapy used in patients with depression, the likelihoods of response and remission are increased when pharmacotherapy is combined with psychotherapy, with this approach being more effective than either pharmacotherapy or psychotherapy alone. Persistence with treatment is important, and clinicians should therefore encourage patients to keep trying to obtain relief.

Directed brain network analysis in anxious and non-anxious depression based on EEG source reconstruction and graph theory

Patients with anxious depression have more severe symptoms, more side effects, and higher resistance to treatment than patients with non-anxious depression; therefore, it is crucial to clarify the differences between these two types of patients. In this study, a 5-minute resting EEG was recorded in 15 patients with anxious depression and 9 patients with non-anxious depression under eyes open and closed conditions. Sixty-eight subcortical regions were extracted using exact low resolution brain electromagnetic tomography (eLORETA). The directed transfer function was then used to construct brain networks. Specific features based on graph theory including the strength of connectivity and betweenness centrality (BC) were calculated from the networks. Finally, significant features were selected using the Mann-Whitney U test, and patients were classified into anxious and non-anxious depressive groups using the Support Vector Machine (SVM). Results showed that features of outward connectivity strength led to the highest accuracy, F-score, and specificity with 91.66%, 87. 5%, and 100% in the eyes-closed state, respectively. Moreover, we found that the strength of connectivity in both directions increased for the anxious depressive group during the eyes-open state. In particular, higher outward connectivity was observed in the right hemisphere for the anxious depressive group. Further findings also revealed that features with the most significant difference were mainly associated with the beta band. In addition, significant increased inward and outward connectivity and decreased nodal centrality were observed in the posterior regions of the default mode network. These preliminary findings might provide new insights into the recognition of anxious depressed patients.

The Anxiolytic and Antidepressant Effects of Transcranial Magnetic Stimulation in Patients With Anxious Depression.

Objective: To determine the extent that treatment with transcranial magnetic stimulation (TMS) in diverse clinical settings has anxiolytic and antidepressant effects in patients with major depressive disorder (MDD) and moderate-to-severe anxiety symptoms and to contrast anxious and nonanxious depression subgroups in antidepressant effects.Methods: Within the NeuroStar Advanced Therapy System Clinical Outcomes Registry, 1,820 patients were identified with a diagnosis of MDD (using ICD-9, ICD-10, or DSM-IV) who completed the Patient Health Questionnaire-9 (PHQ-9) and Global Anxiety Disoder-7 scale (GAD-7) at baseline and following at least 1 TMS treatment between May 2016 and January 2021. Anxious depression was defined as a baseline GAD-7 score of 10 or greater (n = 1,514) and nonanxious depression by GAD-7 scores below this threshold (n = 306). Intent-to-treat and Completer samples were defined for patients treated with any TMS protocol and for the subgroup treated only with high-frequency left dorsolateral prefrontal cortex stimulation.Results: Patients with anxious depression showed clinically meaningful anxiolytic and antidepressant effects, averaging approximately 50% or greater reductions in both GAD-7 and PHQ-9 scores following TMS in all samples. The anxious and nonanxious depression groups had equivalent absolute improvement in PHQ-9 scores (P values ≥ .29). However, the anxious group had higher scores both at baseline and following TMS resulting in significantly lower categorical rates of response (P values < .02) and remission (P values < .001) in depressive symptoms. Among those with anxious depression, the change in anxiety and depression symptoms strongly covaried (r1512 = 0.75, P < .001).Conclusions: Routine TMS delivered in diverse clinical settings results in marked anxiolytic and antidepressant effects in patients with anxious depression. The extent of improvement in anxiety and depression symptoms strongly covaries.

Functional connectivity differences in the amygdala are related to the antidepressant efficacy of ketamine in patients with anxious depression

BackgroundThe antidepressant effects of ketamine in patients with anxious depression (AD) remain unclear. Functional connectivity (FC) differences in the amygdala have been linked to depression improvement after ketamine treatment in depressed patients, but their role in AD patients is uncertain. We investigated the correlation between depression improvement after ketamine treatment and amygdala FC in AD patients. MethodsThirty-one AD patients and 18 non-anxious depression (NAD) patients received six intravenous ketamine infusions (0.5 mg/kg) over two weeks. AD patients were further divided into responders (defined as a ≥50% MADRS total score reduction on day 13) and non-responders. The FC of the amygdala subregions, including the laterobasal amygdala (LBA), centromedial amygdala (CMA), and superficial amygdala, were compared between the groups. Receiver operating characteristic curves were used to predict treatment response after ketamine infusions. ResultsThe baseline FC difference in the left LBA and the left precuneus between responders and non-responders among AD patients was found to be associated with depression improvement and was a significant predictor of treatment response to ketamine. A marked reduction in baseline LBA-precuneus FC after ketamine infusion was observed in responders. Unlike in patients with NAD, a lower right CMA-right middle temporal gyrus FC was found in AD patients. LimitationsThe sample size is rather small. ConclusionsOur findings may suggest that amygdala FC is a significant predictor of treatment response to ketamine infusions in patients with AD. Further studies exploring the potential antidepressant mechanisms of ketamine may aid in the treatment of AD patients.

The right prefrontal cortex (PFC) can distinguish anxious depression from non-anxious depression: A promising functional near infrared spectroscopy study (fNIRS)

BackgroundAnxious depression is a serious mental disorder characterized by comorbidity of anxiety and depression, and its symptoms are similar to those of non-anxious depression. This study aimed to use functional near-infrared spectroscopy (fNIRS) as a tool to distinguish between patients with anxious and non-anxious depression based on differences in hemodynamic changes in the right prefrontal cortex during the verbal fluency task. It is helpful to improve the diagnostic accuracy of the two disorders to further promote their therapeutic effect and prognosis. MethodsA total of 105 subjects, comprising 39 patients with anxious depression, 32 patients with non-anxious depression, and 32 healthy controls, were evaluated using 53-channel fNIRS and the Depression and Anxiety Clinical Scale. ResultsHemodynamic activation was significantly enhanced in the right dorsolateral prefrontal cortex (DLPFC) and right frontopole cortex (FPC) in the anxious depressed group compared with the non-anxious depressed and healthy groups. LimitationsFirst, Hospital Anxiety and Depression Scale (HADS) was used to evaluate the scores of anxiety and depression among the three groups in our study. Different scales may result in different research results. Therefore, other scales (HAM, the Montgomery Asberg Depression Rating Scale, or the Beck Depression Inventory) should be used for further verification. Second, although all the samples we have chosen were patients with the diagnosis of anxious depression or no-anxious depression, we did not distinguish between different severity of anxious depression or no-anxious depression. Third, pure anxiety was not included as the control condition in our study. ConclusionsThere are significant differences in activation patterns of the right DLPFC and right FPC areas between patients with and without anxious depression. Moreover, the right FPC area is promising as a brain region to assess the severity of anxious depression. fNIRS may be a potential tool to improve diagnostic accuracy for both disorders.

Antianhedonic effects of serial intravenous subanaesthetic ketamine in anxious versus nonanxious depression

ObjectivesPatents with anxious depression have poor treatment outcomes compared to their nonanxious counterparts. Ketamine has a rapid and robust antianhedonic effect, independent of depressive symptoms. The difference in the antianhedonic effect of ketamine between patients with anxious versus nonanxious depression remains unknown. MethodsOne hundred thirty-five Chinese individuals with anxious depression (n = 92) and nonanxious depression (n = 43) received six intravenous infusions of ketamine (0.5 mg/kg). Post hoc analyses compared changes in anhedonic symptoms, as measured by the Montgomery–Åsberg Depression Rating Scale (MADRS), between patients with anxious depression (defined by a Hamilton Depression Rating Scale Anxiety-Somatization score ≥7) and nonanxious depression. ResultsIn this study, 68.1 % of patients were found to have anxious depression. Anxious depressed patients were associated with a relatively lower antianhedonic response (47.8 % versus 51.2 %, p > 0.05) and remission (17.4 % versus 27.9 %, p > 0.05) than their nonanxious counterparts. When compared to baseline, a significant reduction in anhedonic symptoms was observed from the first infusion to the last infusion and 2-week follow-up in both groups (all p < 0.05). A linear mixed model did not find a significant group main effect on the MADRS anhedonia subscale scores (F = 0.5, p = 0.46). ConclusionThis preliminary study shows that repeated intravenous infusions of ketamine rapidly ameliorate anhedonic symptoms in individuals experiencing anxious depression, but these individuals displayed a weaker antianhedonic response to ketamine than nonanxious depressed patients.

Therapeutic Potential of Vortioxetine for Anxious Depression: A Post Hoc Analysis of Data from a Clinical Trial Conducted in Japan.

AimAntidepressants, including selective serotonin reuptake inhibitors, often elicit a poor response in patients with major depressive disorder (MDD) with significant anxiety symptoms. This study investigated the effects of the multimodal antidepressant vortioxetine in patients with MDD and associated anxiety.MethodsThis was a post hoc analysis of data from an 8-week, randomized, double-blind, placebo-controlled, Phase 3 study of vortioxetine (10 mg or 20 mg) in Japanese patients aged 20–75 years with recurrent MDD and a Montgomery–Åsberg Depression Rating Scale (MADRS) score of at least 26. Changes from baseline to week 8 in MADRS total score and Hamilton Depression Rating Scale (HAM-D) anxiety/somatization factor score were assessed in patients with anxious depression (HAM-D anxiety/somatization factor score ≥7) and without anxious depression.ResultsData were available for 489 patients. In patients with anxious depression, the least-squares (LS) mean difference (95% confidence interval [CI]) versus placebo in change in MADRS total score was −3.44 (−6.10, −0.77) for vortioxetine 10 mg and −4.51 (−7.15, −1.87) for vortioxetine 20 mg. In patients with non-anxious depression, the LS mean difference (95% CI) versus placebo was −1.81 (−4.71, 1.09) and −1.05 (−4.00, 1.90) for vortioxetine 10 mg and 20 mg, respectively. Changes from baseline in HAM-D anxiety/somatization factor score were greater in patients treated with vortioxetine 10 mg or 20 mg than in those treated with placebo.ConclusionVortioxetine may be effective for patients with anxiety symptoms in MDD. Further research is warranted to investigate these effects in a real-world clinical setting.Clinical Trials RegistrationClinicalTrials.gov identifier for primary study: NCT02389816.

Impaired fear learning and extinction, but not generalization, in anxious and non-anxious depression

Fear conditioning and generalization are well-known mechanisms in the pathogenesis of anxiety disorders. Extinction of conditioned fear responses is crucial for the psychotherapeutic treatment of these diseases. Anxious depression as a subtype of major depression shares characteristics with anxiety disorders. We therefore aimed to compare fear learning mechanisms in patients with anxious versus non-anxious depression. Fear learning mechanisms in patients with major depression (n = 79; for subgroup analyses n = 41 patients with anxious depression and n = 38 patients with non-anxious depression) were compared to 48 healthy participants. We used a well-established differential fear conditioning paradigm investigating acquisition, generalization, and extinction. Ratings of valence, arousal and probability of expected threat were assessed as well as skin conductance response as an objective psychophysiological measure. Patients with major depression showed impaired acquisition of conditioned fear. In addition, depressed patients showed impaired extinction of conditioned fear responses after successful fear conditioning. Generalization was not affected. However, there was no difference between patients with anxious and non-anxious depression. Results differed between objective and subjective measures. Our findings show altered fear acquisition and extinction in major depression as compared to healthy controls, but they do not favor differential fear learning and extinction mechanisms in the pathogenesis of anxious versus non-anxious depression. The results of impaired extinction warrant future studies addressing extinction learning elements in the treatment of depression.

Research on Cognitive Function in Anxious Depression Patients in China

Background: This study aimed to evaluate cognitive function in patients with anxious depression.Methods: This was a part of the “Objective Diagnostic Indicators and Individualized Drug Intervention of Major Depressive Disorder (MDD)” study. All participants, including patients with MDD and healthy controls (HCs), completed the 17-item Hamilton Depression Scale (HAMD17) and the Hamilton Anxiety Scale (HAMA). Anxious depression was defined as a HAMD17 anxiety/somatization factor score ≥7. Cognitive function was assessed at baseline and at the end of week 8. HC cognitive function was assessed at baseline.Results: A total of 1048 people were included in the analysis, including 328 patients in the anxious depression group (G1=328), 221 patients in the MDD without anxious depression group (G2=221), and 499 in the HC group (G3=499). There were significant differences in the HAMA at baseline (t=13.050, p<0.001), HAMD17 at baseline (t=16.722, p<0.001), and HAMA at weekend 8 (z=-3.477, p=0.001) between G1 and G2. Cognitive functioning on the Hopkins Verbal Learning Test-Revised (HVLT-R) (t=2.948, p=0.003) and the Brief Visual Memory Test-Revised (BVMT-R) (t=2.843, p=0.005) was better in G1 than in G2 at baseline. Cognitive functioning on the HVLT-R (OR=1.081, p=0.006) was better in G1 than in G2 at weekend 8. The Stroop-color-word test (SCWT) (OR=0.976, p=0.004) and the Continuous Performance Test (CPT) (OR=0.698, p=0.007) showed significant differences at baseline; however, after the acute treatment phase, there were no significant differences in executive function (assessed by SCWT) (p=0.148) or attention/vigilance (assessed by CPT) (p=0.416) between G1 and G3.Conclusions: Patients with anxious depression have more severe depressive symptoms but better cognitive function, especially for verbal learning, compared with nonanxious depression patients. After the acute treatment phase, executive function and attention/vigilance in anxious depression patients may be remitted.

Brain functional abnormalities in the amygdala subregions is associated with anxious depression

BackgroundFunctional neuroimaging studies have provided strong support for the critical role the amygdala plays in emotional processing. The amygdala is composed of three primary distinct nuclei that have different functions in emotional regulation. Anxious depression (AD) was considered as a common dimensional symptom of Major Depressive Disorder (MDD). However, the neuroimaging basis of this special MDD subtype remains largely unknown. Therefore, it is necessary to study the functional connectivity of the amygdala's subregions in AD patients. MethodsEighty-three patients with AD, 70 non-anxious depression (NAD) patients, and 62 healthy controls were collected. Age and gender were well-matched. The functional connectivity of three amygdala subregions, including centromedial (CM), laterobasal (LB), and superficial (SF), were compared among the AD, NAD, and HC groups. The correlation between functional connectivity in the amygdala subregions and the HAMD factor scores were further analyzed. ResultsPatients with AD showed decreased functional connectivity between the right CM/LB and the right middle frontal gyrus relative to the NAD group. The NAD patients showed decreased functional connectivity between the right precentral gyrus and the right CM/SF compared to the HC group. The functional connectivity between the right CM and the right middle frontal gyrus was negatively correlated with the anxiety/somatization factor. ConclusionThe functional connectivity between the right CM/LB and the right middle frontal gyrus might be the neurobiological mechanism of anxious depression. The FC between the right CM and the right middle frontal gyrus may help to explain the special clinical feature of the AD patients.

DNA hypomethylation of the Kr\xfcppel-like factor 11 (KLF11) gene promoter: a putative biomarker of depression comorbidity in panic disorder and of non-anxious depression?

Panic disorder (PD) is one of the most common anxiety disorders and often occurs comorbidly with major depressive disorder (MDD). Altered methylation of the monoamine oxidase A (MAOA) gene has been implicated in the etiology of both PD and MDD. The Krüppel-like factor 11 (KLF11; alias TIEG2), an activating transcription factor of the MAOA gene, has been found to be increased in MDD, but has not yet been investigated in PD. In an effort to further delineate the effects of the KLF11–MAOA pathway in anxiety and affective disorders, KLF11 promoter methylation was analyzed via pyrosequencing of sodium bisulfite-treated DNA isolated from human peripheral blood in two independent samples of PD patients with or without comorbid MDD in a case–control design (sample 1: N = 120) as well as MDD patients with and without anxious depression (sample 2: N = 170). Additionally, in sample 1, KLF11 methylation was correlated with Beck Depression Inventory (BDI-II) scores. No overall association of KLF11 promoter methylation with PD was detected. However, PD patients with comorbid MDD showed significant hypomethylation relative to both healthy controls (p = 0.010) and PD patients without comorbid MDD (p = 0.008). Furthermore, KLF11 methylation was negatively correlated with BDI-II scores in PD patients (p = 0.013). MDD patients without anxious features showed nominally decreased KLF11 methylation in comparison to MDD patients with anxious depression (p = 0.052). The present results suggest KLF11 promoter hypomethylation as a potential epigenetic marker of MDD comorbidity in PD or of non-anxious depression, respectively, possibly constituting a differential pathomechanism in anxiety and mood disorders.

Efficacy of low-dose ketamine infusion in anxious vs nonanxious depression: revisiting the Adjunctive Ketamine Study of Taiwanese Patients with Treatment-Resistant Depression.

The antidepressant effect of low-dose ketamine infusion on Taiwanese patients with anxious vs nonanxious treatment-resistant depression (ANX-TRD vs NANX-TRD) has remained unknown. In total, 71 patients with TRD were randomized to three groups. Each group had participants who received saline infusions mixed with 0 (a normal saline infusion), 0.2, and 0.5 mg/kg of ketamine. Participants were followed up for 2 weeks. Anxious depression was defined as major depressive disorder with a total score of 7 or more on the 17-item Hamilton Depression Rating Scale Anxiety-Somatization factor. Generalized estimating equation models were used to investigate the effects of treatment (ketamine vs placebo) and depression type (ANX-TRD vs NANX-TRD) in the reduction of depressive symptoms during the follow-up period. Patients with ANX-TRD were less likely to respond to a single low-dose ketamine infusion than those with NANX-TRD. Among patients with NANX-TRD, low-dose ketamine infusion was significantly superior to placebo for reducing depressive symptoms. However, among patients with ANX-TRD, ketamine was not superior to placebo; nonetheless, approximately 30% of the patients responded to ketamine infusion compared to 13% who responded to the placebo. Low-dose ketamine infusion was effective for Taiwanese patients with NANX-TRD but not so effective for those with ANX-TRD. A higher level of anxiety severity accompanying depression was related to greater depression severity. This may confound and reduce the antidepressant effect of ketamine infusion.

Comorbid Anxiety and Depression: Clinical and Conceptual Consideration and Transdiagnostic Treatment.

Although anxiety and depression have been considered as two distinct entities according to the diagnostic criteria, anxious depression (comorbid anxiety and depression) is relatively a common syndrome. According to the DSM-5 criteria, it uses "with anxious distress specifier" to define anxious depression in its MDD section. Anxious depression is known to have different neurobiological profiles compared to non-anxious depression. Several studies have revealed significant differences between anxious depression and non-anxious depression regarding the hypothalamic-pituitary-adrenal (HPA) axis function, structural and functional brain imaging findings, inflammation markers, etc. Patients with anxious depression were significantly more likely to be found in primary care setting and more likely to be associated with female gender, non-single, unemployed, less educated, and more severe depression. Previous reports also showed that patients with anxious depression had more frequent episodes of major depression and a higher risk of suicidal ideation and previous suicide attempts than those with non-anxious depression. Although anxious depression is known to be associated with poor treatment outcomes in several studies, recent researches have sought to find better treatment strategy to improve patients with anxious depression.