Prediction of anxious depression using multimodal neuroimaging and machine learning.

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.

Sex differences and risk factors of self-reported suicide attempts in middle-aged Chinese Han patients with first-episode drug-naïve anxious depression: a large-scale cross-sectional study.

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.

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

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. CONCLUSION: 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.

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

BACKGROUND: Anxious 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. METHOD: Resting-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. RESULTS: Compared 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). CONCLUSION: The 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.

Effects of Anxious Depression on Antidepressant Treatment Response.

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.

Longitudinal changes in term and preterm infant night wakings: The role of caregiver anxious-depression.

Changes in infant night waking during the first year of life are associated with individual (e.g., prematurity) and family (e.g., caregiver psychopathology) factors. This study examined the association between infant night waking and caregiver anxious-depressive symptoms during the first year of life in preterm and term infants. We considered between-person differences and within-person changes in caregiver anxious-depressive symptoms in relation to changes in infant night waking from 2- to 9-months. Racially (30.0% Black, 60.4% White, 9.5% multiracial/other) and socioeconomically (40.0% below median household income) diverse caregivers (N = 445) of full term (n = 258) and preterm (n = 187) infants were recruited from hospitals and clinics in two midwestern states. Caregivers completed measures of anxious-depression and their infant's night waking at four sampling periods (2-, 4-, 6-, and 9-months). Infant night wakings declined from 2- to 9-months. Between-person differences were observed, such that caregivers with higher average anxious-depressive symptoms or infants born full term reported more night wakings. Within-person effects of caregiver anxious-depressive symptoms were not significant. Caregiver anxious-depression is closely associated with infant night wakings. By considering a caregiver's average severity of anxious-depression, healthcare providers can more effectively plan infant sleep interventions. If caregiver anxious-depressive symptoms are ameliorated, night wakings may also decrease.

Los cambios en el despertar nocturno del infante durante el primer año de vida se asocian con factores individuales (v.g. nacimiento prematuro) y familiares (v.g. sicopatología de quien presta el cuidado). Este estudio examinó la asociación entre el despertar nocturno del infante y los síntomas de depresión por ansiedad de quien presta el cuidado durante el primer año de vida de infantes nacidos prematuramente y de ciclo completo. Tomamos en cuenta las diferencias entre las personas y los cambios dentro de las personas en los síntomas de depresión por ansiedad de quien presta el cuidado con relación a los cambios en el despertar nocturno del infante de los 2 a los 9 meses. Se reclutaron en hospitales y clínicas de dos estados del medio oeste cuidadores (N = 445) racial (30.0% de raza negra, 60.4% blancos, 9.5% multirraciales o de otra raza) y socioeconómicamente (40.0% por debajo del promedio de ingresos caseros) diversos, de infantes de ciclo completo (n = 258) y prematuros (n = 187). Los cuidadores completaron medidas de depresión por ansiedad y el despertar nocturno de sus infantes en cuatro períodos muestra (a los 2, 4, 6 y 9 meses). El despertar nocturno del infante declinó de los 2 a los 9 meses. Se observaron las diferencias entre personas, de tal manera que los cuidadores con un promedio mayor de síntomas de depresión por ansiedad o infantes nacidos en el ciclo completo reportaron más despertar nocturno. Los efectos de dentro de las personas de los síntomas de depresión por ansiedad del cuidador no fueron significativos. La depresión por ansiedad del cuidador se asocia cercanamente con el despertar nocturno del infante. Por medio de considerar el promedio de la severidad de la depresión por ansiedad del cuidador, quienes ofrecen el cuidado de salud pueden planear más eficazmente las intervenciones en cuanto al sueño del infante. Si se mejoran los síntomas de depresión por ansiedad de quien presta el cuidado, el despertar nocturno también podría disminuir.

Les changements dans le réveil nocturne du bébé pendant la première année sont liés à des facteurs individuels (par exemple la prématurité) et familiaux (par exemple la psychopathologie de la personne prenant soin de l'enfant). Cette étude a examiné le lien entre le réveil nocturne du bébé et les symptômes anxieux-dépressifs de la personne prenant soin de l'enfant durant la première année de vie de bébés prématurés et à terme. Nous avons considéré les différences entre les personnes et les changements au sein de la personne dans les symptômes anxieux-dépressifs de la personne prenant soin de l'enfant, en lien aux changements dans le réveil nocturne du bébé de 2 à 9 mois. Des personnes (N = 445) prenant soin d'un bébé à plein terme (n = 258) et prématuré (n = 187), divers du point de vue de leur race (30,0% noirs, 60,4% blancs, 9,5% multiracial/autre) et de leur statut socioéconomique (40,0% en dessous du revenu moyen d'une famille) ont été recrutés dans des hôpitaux et des cliniques des états au centre nord des Etats-Unis. Les personnes prenant soin du bébé ont rempli des mesures de dépression anxiété et de la nuit de leur bébé à quatre périodes de prélèvement des renseignements (2-, 4-, 6-, et 9- mois). Les réveils nocturnes du bébé ont décliné de 2- à 9- mois. Des différences entre les personnes ont été observées, au point que les personnes prenant soin du bébé avec la moyenne de symptômes anxieux-dépressifs la plus élevée ou des bébé nés à terme ont fait état de plus de réveils nocturnes. Les effets au sein de la personne des personnes prenant soin du bébé avec des symptômes anxieux-dépressifs n'étaient pas importants. La personne prenant du bébé avec une dépression anxieuse est fortement liée aux réveils nocturnes du bébé. En considérant la sévérité moyenne de la dépression anxieuse de la personne prenant soin du bébé, les prestataires de santé peuvent planifier les interventions concernant le sommeil du bébé de manière plus efficace. Si les symptômes anxieux-dépressifs de la personne prenant soin du bébé sont améliorer, alors les réveils nocturnes pourraient aussi diminuer.

The effect of esketamine in patients with treatment-resistant depression with and without comorbid anxiety symptoms or disorder.

BACKGROUND: Comorbid anxiety is generally associated with poorer response to antidepressant treatment. This post hoc analysis explored the efficacy of esketamine plus an antidepressant in patients with treatment-resistant depression (TRD) with or without comorbid anxiety. METHODS: TRANSFORM-2, a double-blind, flexible-dose, 4-week study (NCT02418585), randomized adults with TRD to placebo or esketamine nasal spray, each with a newly-initiated oral antidepressant. Comorbid anxiety was defined as clinically noteworthy anxiety symptoms (7-item Generalized Anxiety Disorder scale [GAD-7] score ≥10) at screening and baseline or comorbid anxiety disorder diagnosis at screening. Treatment effect based on change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score, and response and remission were examined by presence/absence of comorbid anxiety using analysis of covariance and logistic regression models. RESULTS: Approximately 72% (162/223) of patients had baseline comorbid anxiety. Esketamine-treated patients with and without anxiety demonstrated significant reductions in MADRS (mean [SD] change from baseline at day 28: -21.0 [12.51] and -22.7 [11.98], respectively). Higher rates of response and remission, and a significantly greater decrease in MADRS score at day 28 were observed compared to antidepressant/placebo, regardless of comorbid anxiety (with anxiety: difference in LS means [95% CI] -4.2 [-8.1, -0.3]; without anxiety: -7.5 [-13.7, -1.3]). There was no significant interaction of treatment and comorbid anxiety (p = .371). Notably, in the antidepressant/placebo group improvement was similar in those with and without comorbid anxiety. CONCLUSION: Post hoc data support efficacy of esketamine plus an oral antidepressant in patients with TRD, regardless of comorbid anxiety.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

[Effect of Baihe Dihuang Decoction on synaptic plasticity of hippocampus in rats with anxious depression].

To explore the effect of Baihe Dihuang Decoction on the synaptic plasticity of hippocampal neurons in rats with anxious depression. Fifty SD rats were randomly divided into normal group, model group, venlafaxine group(6.75 mg·kg~(-1)), high-dose Baihe Dihuang Decoction group(8.64 g·kg~(-1)) and low-dose Baihe Dihuang Decoction group(4.32 g·kg~(-1)). Chronic restraint stress(6 h) combined with corticosterone(ih, 30 mg·kg~(-1)) was used to establish an anxious depression model, and 7 days after modeling, the administration started and continued for 21 days. The anxiety and depression-like behaviors of the rats were evaluated. Golgi-Cox staining and electron microscopy were used to observe the morphology and ultrastructural changes of synaptic dendrites. Immunofluorescence was used to detect the expression of hippocampal synaptic plasticity protein synapsin-1 and postsynaptic density protein 95(PSD-95). Western blot method was used to detect the expression of functional protein synaptophysin(SYP) and synaptic Ras GTPase activating protein(SynGap). The results showed that the rats in the model group had obvious anxiety and depression-like behaviors, the hip-pocampal dendritic spine density and branch length were reduced, the number of synapses was cut, and the internal structure was da-maged. The average fluorescence intensity of synapsin-1 and PSD-95 was significantly reduced and the expression of SYP and SynGap also decreased. High-dose Baihe Dihuang Decoction could significantly improve the anxiety and depression-like behaviors of model rats, relieve synaptic damage, and increase the expression of synapsin-1, PSD-95, SYP, and SynGap proteins. Therefore, we believe that Baihe Dihuang Decoction can improve anxiety and depression behaviors by regulating the synaptic plasticity of hippocampal neurons.

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.

Therapeutic High-Frequency Repetitive Transcranial Magnetic Stimulation Concurrently Improves Mood and Anxiety in Patients Using Benzodiazepines.

OBJECTIVES/HYPOTHESIS: In this study, we tested the use of repetitive transcranial magnetic stimulation (rTMS) to reduce depression and anxiety in patients using or not using benzodiazepines. We hypothesized that rTMS would concurrently reduce symptoms in both depression and anxiety and that these reductions would correlate with patients using benzodiazepines. MATERIALS AND METHODS: This retrospective study screened for patients treated in a TMS clinic within a five-year period. Each patient had received high-frequency (10 or 20 Hz) rTMS over the left dorsolateral prefrontal cortex and completed pre- and posttreatment Beck Depression Inventory and Visual Analog Scale-Anxiety ratings. Fifty-eight patients (37 women) met these criteria and 37 (63.8%) took benzodiazepines. We used two mixed analysis of variance analyses to separately evaluate the effects of rTMS on depression and anxiety. We additionally directly evaluated the relationship between reductions in depression and anxiety by computing three linear correlations (all patients, benzodiazepine users, nonbenzodiazepine users). RESULTS: rTMS was an effective treatment of depression for all patients (p < 0.001). rTMS also reduced anxiety scores from pre- to posttreatment (p = 0.002). Furthermore, reductions in depression and anxiety were correlated (p = 0.002). These changes in depression and anxiety only correlated with benzodiazepine users (p < 0.001) and not nonbenzodiazepine users (p = 0.608). CONCLUSIONS: rTMS concurrently improved both depression and anxiety, and changes in these measures correlated with patients using benzodiazepines. With further investigation, rTMS may be a helpful treatment for both anxiety and depression simultaneously.

Anxious depression as a clinically relevant subtype of pediatric major depressive disorder.

In adults, anxious depression has been identified as a more severe form of major depressive disorder (MDD), associated with higher depression severity, more suicidal ideation and worse treatment outcome. Research in pediatric depression, however, has been sparse. 126 children and adolescents aged 8-18 years with a primary diagnosis of MDD were categorized into a MDD-only group and an anxious depression group based on clinically elevated scores on the Beck Anxiety Inventory. One-third of the sample was classified as having anxious depression with females being overrepresented in the anxious depressed compared to the MDD-only group. 42.2% of the anxious depressed youth met diagnostic criteria for a comorbid anxiety disorder. Anxious depressed youth were more likely to suffer recurrent depressive episodes, showed higher depression severity and a unique pattern of depressive symptoms characterized by more severe sleep problems, more somatic complaints, more severely depressed mood and more frequent suicidal ideations. Scores on a suicidal ideation scale were increased even when controlling for overall depression severity. However, when comparing depressed patients with and without comorbid anxiety disorders, no differences in depression severity, symptom patterns or suicidal ideations were observed. The results indicate that high anxiety levels in depressed youth are clinically relevant, and given the increase in suicidal ideation, anxiety symptoms during depressive episodes should routinely be screened in clinical practice even in the absence of a fully formed comorbid anxiety disorder.

Heart rate variability as a biomarker of anxious depression response to antidepressant medication.

BACKGROUND: There is a need to identify biomarkers of treatment outcomes for major depressive disorder (MDD) that can be disseminated. We investigated the predictive utility of pretreatment heart rate variability (HRV) for outcomes of antidepressant medication in MDD, with pretreatment anxious depression as a hypothesized moderator of HRV effects. METHODS: A large, randomized, multicenter practical trial (International Study to Predict Optimized Treatment in Depression) in patients with current nonpsychotic MDD (N = 1,008; 722 completers) had three arms: escitalopram, sertraline, and venlafaxine-extended release. At pretreatment, patients were defined as having anxious (N = 309) versus nonanxious (N = 413) depression and their resting high-frequency HRV (root mean square of successive differences) was assessed. Patients' usual treating clinicians managed medication. At 8 weeks, primary outcomes were clinician-rated depressive symptom response and remission; secondary outcomes were self-reported response and remission. RESULTS: Pretreatment HRV predicted antidepressant outcomes as a function of anxious versus nonanxious depression. In anxious depression, patients with higher HRV had better outcomes, whereas patients with lower HRV had poorer outcomes. In nonanxious depression, patients with lower HRV had better outcomes, whereas patients with higher HRV had poorer outcomes. Some simple effects were not significant. Results did not differ by treatment arm and remained significant when controlling for important covariates. CONCLUSIONS: These findings inform a precision medicine approach in which clinical and biological assessments may be integrated to facilitate treatment outcome prediction. Knowing about HRV may help determine which patients with anxious depression could benefit from antidepressants and which patients may require a different treatment approach.

Efficacy of intravenous ketamine treatment in anxious versus nonanxious unipolar treatment-resistant depression.

OBJECTIVE: To examine the effect of high baseline anxiety on response to ketamine versus midazolam (active placebo) in treatment-resistant depression (TRD). METHODS: In a multisite, double-blind, placebo-controlled trial, 99 subjects with TRD were randomized to one of five arms: a single dose of intravenous ketamine 0.1, 0.2, 0.5, 1.0 mg/kg, or midazolam 0.045 mg/kg. The primary outcome measure was change in the six-item Hamilton Rating Scale for Depression (HAMD6). A linear mixed effects model was used to examine the effect of anxious depression baseline status (defined by a Hamilton Depression Rating Scale Anxiety-Somatization score ≥7) on response to ketamine versus midazolam at 1 and 3 days postinfusion. RESULTS: N = 45 subjects had anxious TRD, compared to N = 54 subjects without high anxiety at baseline. No statistically significant interaction effect was found between treatment group assignment (combined ketamine treatment groups versus midazolam) and anxious/nonanxious status on HAMD6 score at either days 1 or 3 postinfusion (Day 1: F(1, 84) = 0.02, P = 0.88; Day 3: F(1, 82) = 0.12, P = 0.73). CONCLUSION: In contrast with what is observed with traditional antidepressants, response to ketamine may be similar in both anxious and nonanxious TRD subjects. These pilot results suggest the potential utility of ketamine in the treatment of anxious TRD.

Characterising anxiety in major depressive disorder and its use in predicting antidepressant treatment outcome: An iSPOT-D report.

OBJECTIVE: Major depressive disorder commonly co-occurs with one or more anxiety disorders or with clinically significant levels of anxiety symptoms. Although evidence suggests that anxious forms of depression are prognostic of poorer antidepressant outcomes, there is no clear definition of anxious depression, and inferences about clinical outcomes are thus limited. Our objective was to compare and evaluate definitions of anxious depression and anxiety-related scales according to clinical and antidepressant outcome criteria. METHOD: A total of 1008 adults with a current diagnosis of single-episode or recurrent, nonpsychotic, major depressive disorder were assessed at baseline on clinical features. Participants were then randomised to one of three antidepressants and reassessed at 8 weeks regarding remission and response of the 17-item Hamilton Rating Scale Depression (HRSD17) and the 16-item Quick Inventory of Depressive Symptomatology (QIDS-SR16). Anxious depression was defined as major depressive disorder with one or more anxiety disorders or major depressive disorder with a HRSD17 anxiety/somatisation factor score ⩾7. Anxiety-related scales included the HRSD17 anxiety/somatisation factor and the 42-item Depression Anxiety Stress Scales (DASS42) anxiety and stress subscales. RESULTS: Anxious depression definitions showed poor agreement (κ = 0.15) and the HRSD17 anxiety/somatisation factor was weakly correlated with both DASS42 anxiety (r = 0.24) and stress subscales (r = 0.20). Anxious depression definitions were also associated with few impairments on clinical features and did not predict poorer antidepressant treatment outcome. However, higher DASS42 anxiety predicted poorer HRSD17 and QIDS-SR16 remission, and item-level analysis found higher scores on items 9 (situational anxiety) and 23 (somatic anxiety) of the DASS42 predicted poorer treatment outcome, even after adjusting for covariates and multiple comparisons. CONCLUSION: Common definitions of anxious depression show poor agreement and do not predict poorer treatment outcome. Anxiety symptoms may be better characterised dimensionally using DASS42 when predicting treatment outcome.

Anxious Depression and Neurocognition among Middle-Aged and Older Hispanic/Latino Adults: Hispanic Community Health Study/Study of Latinos (HCHS/SOL) Results.

OBJECTIVE: The purpose of this study is to examine the association between verbal learning, fluency, and processing speed with anxious depression symptomatology (ADS) among diverse Hispanics. We hypothesized an inverse association of anxious depression with neurocognition among Hispanics of different heritage. DESIGN: Data are from the Hispanic Community Health Study/Study of Latinos. The sample included 9,311participants aged 45-74 years (mean: 56.5 years). A latent class analysis of items from the Center for Epidemiological Studies for Depression scale and the Spielberger Trait Anxiety Inventory was used to derive an anxious depression construct. Neurocognitive measures included scores on the Brief Spanish English Verbal Learning Test (B-SEVLT, learning and recall trials), Word Fluency (WF), Digit Symbol Substitution (DSS) test, and a Global Cognitive Score (GCS). We fit survey linear regression models to test the associations between anxious depression symptomatology and cognitive function. We tested for effect modification by sex, Hispanic heritage, and age groups. RESULTS: Among men, 71.6% reported low, 23.3% moderate, and 5.1% high ADS. Among women, 55.1% reported low, 33.2% moderate, and 11.8% high ADS. After controlling for age, sex, sociodemographic characteristics, cardiovascular risk factors and disease, and antidepressant use, we found significant inverse associations between moderate and high anxious depression (ref:low) with B-SEVLT learning and recall, DSS and GCS. Moderate, but not high, anxious depression was inversely associated with WF. Associations were not modified by sex, Hispanic heritage, or age. CONCLUSIONS: Increased anxious depression symptomatology is associated with decreased neurocognitive function among Hispanics. Longitudinal studies are needed to establish temporality and infer if negative emotional symptoms precede cognitive deficits.

The importance of personality and life-events in anxious depression: from trait to state anxiety.

OBJECTIVES: Anxious depression is associated with severe impairment and bad prognoses. We hypothesize that recent life-events are associated with more anxiety in late-life depression and that this is conditional upon the level of certain personality traits. METHOD: Baseline data of the Netherlands Study of Depression in Older Persons (NESDO) were used. In 333 patients (≥60 years) suffering from a major depressive disorder, anxiety was assessed with the BAI, personality traits with the NEO-FFI and the Mastery Scale, and life-events with the Brugha questionnaire. Multiple linear regression analyses were applied with anxiety severity as dependent and life-events and personality traits as independent variables. RESULTS: 147 patients (44.1%) had recently experienced one or more life-events. The presence of a life-event is not associated with anxiety (p = .161) or depression severity (p = .440). However, certain personality traits interacted with life-events in explaining anxiety severity. Stratified analyses showed that life-events were associated with higher anxiety levels in case of high levels of neuroticism and openness and low levels of conscientiousness or mastery. CONCLUSIONS: In the face of a life-event, personality traits may play a central role in increased anxiety levels in late-life depression.

A single infusion of ketamine improves depression scores in patients with anxious bipolar depression.

OBJECTIVE: Patents with anxious bipolar disorder have worse clinical outcomes and are harder to treat with traditional medication regimens compared to those with non-anxious bipolar disorder. Ketamine has been shown to rapidly and robustly decrease symptoms of depression in depressed patients with bipolar disorder. We sought to determine whether baseline anxiety status reduced ketamine's ability to decrease symptoms of depression. METHODS: Thirty-six patients with anxious (n = 21) and non-anxious (n = 15) treatment-resistant bipolar depression (types I and II; concurrently treated with either lithium or valproate) received a single infusion of ketamine (0.5 mg/kg) over 40 min. Post-hoc analyses compared changes in the Montgomery-Åsberg Depression Rating Scale (MADRS) and Hamilton Depression Rating Scale (HDRS) in anxious versus non-anxious depressed patients with bipolar disorder through 14 days post-infusion. Anxious bipolar depression was defined as DSM-IV bipolar depression plus a HDRS Anxiety/Somatization Factor score of ≥ 7. RESULTS: A linear mixed model revealed a significant effect of anxiety group on the MADRS (p = 0.04) and HDRS (p = 0.04). Significant drug effects (all p < 0.001) suggested that both anxious and non-anxious groups had an antidepressant response to ketamine. The drug-by-anxiety interactions were not significant (all p > 0.28). CONCLUSIONS: Both anxious and non-anxious patients with bipolar depression had significant antidepressant responses to ketamine, although the anxious depressed group did not show a clear antidepressant response disadvantage over the non-anxious group. Given that anxiety has been shown to be a predictor of poor treatment response in bipolar depression when traditional treatments are used, our findings suggest a need for further investigations into ketamine's novel role in the treatment of anxious bipolar depression.

Comorbid anxiety disorders in late-life depression: results of a cohort study.

BACKGROUND: Comorbid anxiety disorders are common in late-life depression and negatively impact treatment outcome. This study aimed to examine personality characteristics as well as early and recent life-events as possible determinants of comorbid anxiety disorders in late-life depression, taking previously examined determinants into account. METHODS: Using the Composite International Diagnostic Interview (CIDI 2.0), we established comorbid anxiety disorders (social phobia (SP), panic disorder (PD), generalized anxiety disorder (GAD), and agoraphobia (AGO)) in 350 patients (aged ≥60 years) suffering from a major depressive disorder according to DSM-IV-TR criteria within the past six months. Adjusted for age, sex, and level of education, we first examined previously identified determinants of anxious depression: depression severity, suicidality, partner status, loneliness, chronic diseases, and gait speed in multiple logistic regression models. Subsequently, associations were explored with the big five personality characteristics as well as early and recent life-events. First, multiple logistic regression analyses were conducted with the presence of any anxiety disorder (yes/no) as dependent variable, where after analyses were repeated for each anxiety disorder, separately. RESULTS: In our sample, the prevalence rate of comorbid anxiety disorders in late-life depression was 38.6%. Determinants of comorbid anxiety disorders were a lower age, female sex, less education, higher depression severity, early traumatization, neuroticism, extraversion, and conscientiousness. Nonetheless, determinants differed across the specific anxiety disorders and lumping all anxiety disorder together masked some determinants (education, personality). CONCLUSIONS: Our findings stress the need to examine determinants of comorbid anxiety disorder for specific anxiety disorders separately, enabling the development of targeted interventions within subgroups of depressed patients.

Anxious-depression among Hispanic/Latinos from different backgrounds: results from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).

BACKGROUND: Anxious-depression is a constellation of symptoms, frequently encountered among patients in primary care centers. There is a need to study how anxious-depression presents among Hispanic/Latinos of different backgrounds. OBJECTIVE: To study the construct of anxious-depression among 16,064 Hispanic/Latinos of different backgrounds participating in the Hispanic Community Health Study/Study of Latinos. We hypothesized that Hispanic/Latinos will cluster in 3 classes: low anxiety/high depression, high anxiety/low depression and a combined anxious-depression construct. METHODS: Using latent profile analysis, symptoms of depression and anxiety measured by the 10-item Center for Epidemiologic Studies Depression Scale and 10-item State-Trait Anxiety Inventory were evaluated to determine if an anxious-depression typology would result. A multinomial logistic regression analysis explored the association of the 3-class solution with different Hispanic/Latino backgrounds controlling for age, gender, language, education and income. RESULTS: A 3-class mixed anxious-depression structure emerged with 10% of Hispanic/Latinos in the high, 30% in the moderate and 60% in the low anxious-depression category. After adjusting for age, gender, language preference, income and education, individuals of Puerto Rican background were more likely to experience high (OR = 1.79, p < 0.05) and moderate (OR = 1.36, p < 0.05) (vs. low) anxious-depression symptomatology compared to those of Mexican background. Individuals of Central American and South American background were less likely to experience high (OR = 0.68, p < 0.05) and moderate (OR = 0.8, p < 0.05) (vs. low) anxious-depression compared to those of Mexican background. CONCLUSION: Anxious-depression symptomatology varied among this sample of Hispanic/Latino groups. These classes should be investigated as to their relationship with different health outcomes relevant to the Hispanic/Latino of different backgrounds.