Depression and Anxiety

Background Perinatal anxiety affects 20% of women, and untreated maternal mental illness can cause deleterious effects for women and their children. Benzodiazepines are commonly used to treat anxiety disorders. The reported risk of congenital malformations after in utero benzodiazepine exposure has been inconsistent. Methods The Massachusetts General Hospital National Pregnancy Registry for Psychiatric Medications prospectively enrolls pregnant women with psychiatric illness who take one or more psychiatric medications. Participants are interviewed twice during pregnancy and at 12 weeks postpartum. Women taking any benzodiazepine during the first trimester of pregnancy were compared with a group of women taking psychiatric medication(s) other than benzodiazepines during pregnancy. Results A total of 1053 women were eligible for this analysis; N = 151 women who had taken a benzodiazepine during the first trimester, and the comparison group was N = 902 women. There were 5 (3.21%) major malformations in the exposure group and 32 (3.46%) in the comparison group (odds ratio 0.92; 95% confidence interval 0.35−2.41). Conclusion This ongoing pregnancy registry offers reassurance that benzodiazepines do not appear to have major teratogenic effects. The precision of relative risk estimate will improve as the number of participants increases. This and other pregnancy registries will better inform the reproductive safety of benzodiazepines.

Background Internalizing psychopathologies (IPs) are highly comorbid and exhibit substantial overlap, such as aberrant affective reactivity. Neural reactivity to emotional images, measured via the late positive potential (LPP) event‐related potential (ERP) component, has been utilized to index affective reactivity in IPs. The LPP is often examined in isolation with a specific disorder, ignoring overlap between IPs. The current study examined how transdiagnostic IP symptom dimensions relate to neural affective reactivity in a highly comorbid patient sample. Methods Participants (N = 99) completed a battery of IP symptom assessments as well as a target categorization task while viewing pleasant, unpleasant, and neutral images during electroencephalography recording. ERPs to each image valence were averaged from 400 to 1000 ms following picture onset at pooled centroparietal and occipital electrodes to calculate the LPP. A principal components analysis performed on the IP symptom measures resulted in two factors: affective distress/misery and fear‐based anxiety. Results Fear‐based anxiety was associated with enhanced LPP reactivity to unpleasant, but not pleasant, images. Distress/misery was related to attenuated average LPP reactivity across images. Conclusions Results revealed a dissociable effect of IP symptom factors in a transdiagnostic sample such that enhanced reactivity to negative images was specific to enhanced fear‐based anxiety symptoms while distress/misery symptoms predicted blunted affective reactivity. Neural affective reactivity may serve as an objective biological marker to elucidate the nature of psychological concerns in individuals with comorbid IPs.

Background Recent studies in both human and experimental animals have identified fragmented and unpredictable parental and environmental signals as a novel source of early‐life adversity. Early‐life unpredictability may be a fundamental developmental factor that impacts brain development, including reward and emotional memory circuits, affecting the risk for psychopathology later in life. Here, we tested the hypothesis that self‐reported early‐life unpredictability is associated with psychiatric symptoms in adult clinical populations. Methods Using the newly validated Questionnaire of Unpredictability in Childhood, we assessed early‐life unpredictability in 156 trauma‐exposed adults, of which 65% sought treatment for mood, anxiety, and/or posttraumatic stress disorder (PTSD) symptoms. All participants completed symptom measures of PTSD, depression and anhedonia, anxiety, alcohol use, and chronic pain. Relative contributions of early‐life unpredictability versus childhood trauma and associations with longitudinal outcomes over a 6‐month period were determined. Results Early‐life unpredictability, independent of childhood trauma, was significantly associated with higher depression, anxiety symptoms, and anhedonia, and was related to higher overall symptom ratings across time. Early‐life unpredictability was also associated with suicidal ideation, but not alcohol use or pain symptoms. Conclusions Early‐life unpredictability is an independent and consistent predictor of specific adult psychiatric symptoms, providing impetus for studying mechanisms of its effects on the developing brain that promote risk for psychopathology.

Background Comorbid anxiety disorders and anxious distress are highly prevalent in major depressive disorder (MDD). The presence of the DSM‐5 anxious distress specifier (ADS) has been associated with worse treatment outcomes and chronic disease course. However, little is known about the neurobiological correlates of anxious distress in MDD. Methods We probed the relation between the DSM‐5 ADS and task‐related reactivity to emotional faces, as well as resting‐state functional connectivity patterns of intrinsic salience and basal ganglia networks in unmedicated MDD patients with (MDD/ADS+, N = 24) and without ADS (MDD/ADS−, N = 48) and healthy controls (HC, N = 59). Both categorical and dimensional measures of ADS were investigated. Results MDD/ADS+ patients had higher left amygdala responses to emotional faces compared to MDD/ADS− patients (p = .015)—part of a larger striato‐limbic cluster. MDD/ADS+ did not differ from MDD/ADS− or controls in resting‐state functional connectivity of the salience or basal ganglia networks. Conclusions Current findings suggest that amygdala and striato‐limbic hyperactivity to emotional faces may be a neurobiological hallmark specific to MDD with anxious distress, relative to MDD without anxious distress. This may provide preliminary indications of the underlying mechanisms of anxious distress in depression, and underline the importance to account for heterogeneity in depression research.

Background Prevalence estimates of COVID‐19‐related posttraumatic stress disorder (PTSD) have ranged from 1% to over 60% in the general population. Individuals with lived experience of a psychiatric disorder may be particularly vulnerable to COVID‐19‐related PTSD but this has received inadequate attention. Methods Participants were 1571 adults with lived experience of psychiatric disorder who took part in a longitudinal study of mental health during the COVID‐19 pandemic. PTSD was assessed by the International Trauma Questionnaire (ITQ) anchored to the participant's most troubling COVID‐19‐related experiencevent. Factors hypothesised to be associated with traumatic stress symptoms were investigated by linear regression. Results 40.10% of participants perceived some aspect of the pandemic as traumatic. 5.28% reported an ICD‐11 PTSD qualifying COVID‐19 related traumatic exposure and 0.83% met criteria for probable ICD‐11 COVID‐19‐related PTSD. Traumatic stress symptoms were associated with younger age, lower income, lower social support, and financial worries, and lived experience of PTSD/complex PTSD. Depression and anxiety measured in June 2020 predicted traumatic stress symptoms at follow‐up approximately 20 weeks later in November 2020. Conclusions We did not find evidence of widespread COVID‐19‐related PTSD among individuals with lived experience of a psychiatric disorder. There is a need for future research to derive valid prevalence estimates of COVID‐19‐related PTSD.

Background Cognitive remediation (CR) is a promising technique in the treatment of the cognitive dimension of depression. The present study evaluated the potential of CR in treating depressive symptoms and provides practical information about its usefulness in clinical settings. Methods We performed two meta‐analyses of published randomized (and nonrandomized) clinical trials, comparing CR to control conditions in subjects with current depressive symptomatology. The superiority meta‐analysis aimed to determine the superiority of CR when compared with placebo/waiting list interventions and its efficacy when used as an augmentation therapy. The noninferiority meta‐analysis determined whether CR had noninferior efficacy compared with standard antidepressant interventions. Results CR was found to significantly improve depressive symptomatology in the superiority meta‐analysis (CR: n = 466, control n = 478). Moreover, CR seemed to be noninferior to standard antidepressant interventions (CR: n = 230, control n = 235). CR was more effective when addressing hot (vs. cold) cognition, when involving younger patients (i.e., <30 years), and in the case of mild‐moderate (vs. severe) depression. Conclusions CR should be considered an augmentation treatment to improve treatment outcomes in depressed subjects, especially among young individuals. Interventions addressing hot cognition seem to be the most promising.

Background The 2019 coronavirus disease (COVID‐19) pandemic has had a profound impact on the mental health of people worldwide. This study examined dysfunctional coronavirus anxiety in nonpsychotic psychiatric outpatients during the pandemic using the coronavirus anxiety scale (CAS) and examined the relationship between coronavirus anxiety and clinical symptoms using network analysis. Methods In this cross‐sectional study, 192 patients who first visited the psychiatric outpatient clinic of Severance Hospital during the COVID‐19 pandemic with chief complaints of depressed mood, anxiety, somatic symptoms, or insomnia were included. We compared the clinical characteristics of patients with and without dysfunctional coronavirus anxiety. Network analysis was conducted to estimate the network of coronavirus anxiety and depressive, anxious, and hypochondriacal psychopathology. Results The results showed that 7.8% of patients exhibited dysfunctional coronavirus anxiety (CAS ≥ 5). Patients with dysfunctional coronavirus anxiety showed higher levels of health worry, somatic preoccupation, and subjective anxiety compared to patients without dysfunctional coronavirus anxiety. In the network analysis, the health worry node (Item 6 of the WI) showed the greatest number of connections with coronavirus anxiety nodes. Conclusions These findings suggest that health worry may be an important bridge symptom that connects coronavirus anxiety and other clinical psychopathology. Patients with elevated health worries should be carefully monitored during the COVID‐19 pandemic for exacerbation of previous symptoms and COVID‐19‐related psychopathology. Understanding the psychological factors in the face of the pandemic and their relationships with clinical psychiatric symptoms would help people prevent and overcome mental health problems during the pandemic.

Introduction Prior studies have shown inconsistent findings of an association between depression and epigenetic aging. DNA methylation (DNAm) age acceleration can measure biological aging. We adopted a robust co‐twin control study design to examine whether depression is associated with DNAm age acceleration after accounting for the potential confounding influences of genetics and family environment. Methods We analyzed data on a sub‐cohort of the Vietnam Era Twin Registry. A total of 291 twins participated at baseline and 177 at follow‐up visit after a mean of 11.7 years, with 111 participants having DNA samples for both time points. Depression was measured using the Beck Depression Inventory II (BDI‐II). Six measures of DNAm age acceleration were computed at each time point, including Horvath's DNAm age acceleration (HorvathAA), intrinsic epigenetic age acceleration (IEAA), Hannum's DNAm age acceleration (HannumAA), extrinsic epigenetic age acceleration (EEAA), GrimAge acceleration (GrimAA), and PhenoAge acceleration (PhenoAA). Mixed‐effects modeling was used to assess the within‐pair association between depression and DNAm age acceleration. Results At baseline, a 10‐unit higher BDI‐II total score was associated with HannumAA (0.73 years, 95% confidence interval [CI] 0.13–1.33, p = .019) and EEAA (0.94 years, 95% CI 0.22–1.66, p = .012). At follow‐up, 10‐unit higher BDI‐II score was associated with PhenoAA (1.32 years, 95% CI 0.18–2.47, p = .027). Conclusion We identified that depression is associated with higher levels of DNAm age acceleration. Further investigation is warranted to better understand the underlying mechanisms for the potential causal relationship between depression and accelerated aging.

Posttraumatic stress disorder (PTSD) has long been associated with a heightened risk of cardiovascular disease (CVD). A number of mechanisms have been implicated to underlie this brain–heart axis relationship, such as altered functioning of the autonomic nervous system and increased systemic inflammation. While neural alterations have repeatedly been observed in PTSD, they are rarely considered in the PTSD–CVD link. The brain–heart axis is a pathway connecting frontal and limbic brain regions to the brainstem and periphery via the autonomic nervous system and it may be a promising model for understanding CVD risk in PTSD given its overlap with PTSD neural deficits. We first provide a summary of the primary mechanisms implicated in the association between PTSD and CVD. We then review the brain–heart axis and its relevance to PTSD, as well as findings from PTSD trials demonstrating that a number of PTSD treatments have effects on areas of the brain–heart axis. Finally, we discuss sex considerations in the PTSD–CVD link. A critical next step in this study is to determine if PTSD treatments that affect the brain–heart axis (e.g., brain stimulation that improves autonomic function) also reduce the risk of CVD.

Background Studies have searched for neurobiological markers of trauma exposure, posttraumatic stress disorder (PTSD) diagnosis, and resilience to trauma to identify therapeutic targets for PTSD. Despite some promising results, findings are inconsistent. Aims The present study adopted a data‐driven approach to systematically explore whether structural brain markers of trauma, PTSD, or resilience emerge when all are explored. Materials & Methods Differences between clusters in the proportion of PTSD, healthy controls (HC), and trauma‐exposed healthy controls (TEHC) served to indicate the presence of PTSD, trauma, and resilience markers, respectively. A total of 129 individuals, including 46 with PTSD, 49 TEHCs, and 34 HCs not exposed to trauma were scanned. Volumes, cortical thickness, and surface areas of interest were obtained from T1 structural MRI and used to identify data‐driven clusters. Results Two clusters were identified, differing in the proportion of TEHCs but not of PTSDs or HCs. The cluster with the higher proportion of TEHCs, referred to as the resilience cluster, was characterized by higher volume in brain regions implicated in trauma exposure, especially the thalamus and rostral middle frontal gyrus. Cross‐validation established the robustness and consistency of the identified clusters. Discussion & Conclusion Findings support the existence of structural brain markers of resilience.

Objective Underdeveloped cognitive control (CC)—the capacity to flexibly adjust to changing environments—may predispose some children to early onset anxiety disorders and represents a promising intervention target. The current study established and pilot‐tested “Camp Kidpower”—a novel group‐based, interactive CC training intervention—and assessed its impacts on behavioral and neurophysiological indices of CC among preschool children with elevated anxiety symptoms. Methods Forty‐four anxious children (4–6 years) were enrolled in Camp Kidpower, delivered in four sessions over 10 days. Before and after camp, children's capacity for CC was measured using well‐validated, non‐trained behavioral tasks and error‐related negativity (ERN). Child anxiety symptoms were measured by parent report on the Spence Preschool Anxiety Scale. Results Thirty‐two children completed the study, as defined by completion of pre‐ and follow‐up assessments and at least three camp sessions. From baseline to after camp, performance on behavioral tests of CC improved, ERN amplitude increased, and anxiety symptoms decreased. Conclusion Results provide initial evidence that play‐based cognitive training targeted to behavioral and brain markers of CC reduces anxiety in preschoolers.

Background Although much has been learned about the physical and psychological impacts of deployment and combat injury on military service members, less is known about the effects of these experiences on military spouses. Methods The present study examined self‐reported mental health symptoms (using the Brief Symptom Inventory [BSI]‐18 and the posttraumatic stress disorder [PTSD] Checklist [PCL‐C]) in wives of service members who were combat‐injured (CI; n = 60); noninjured with cumulative deployment longer than 11 months (NI‐High; n = 51); and noninjured with cumulativel deployment less than 11 months (NI‐Low; n = 53). Results 36.7% and 11.7% of CI wives endorsed above threshold symptoms on the PCL‐C and overall BSI‐18, respectively. Multivariate linear regressions revealed that being a CI wife was associated with higher PCL‐C, overall BSI‐18, and BSI‐18 anxiety subscale scores compared to NI‐Low wives in models adjusted for individual and family characteristics, as well as prior trauma and childhood adversities. Compared with the NI‐High group, the CI group was associated with higher overall BSI‐18 scores. Conclusions While CI wives evidenced fewer mental symptoms than expected, these findings suggest a negative impact of service member's combat injury on wives’ mental health above that attributable to deployment, highlighting the need for trauma‐informed interventions designed to support the needs of military wives affected by combat injury.

Background Amotivation is a typical feature in major depressive disorders and refers to individuals exhibiting reduced willingness to exert effort for rewards. However, the motivation pattern when deciding whether to exert effort for self versus others in people with depression remains unclear. Methods We conducted a functional magnetic resonance imaging study and employed an adapted Effort‐Expenditure for Rewards Task in subthreshold depressive (SD) participants (n = 33) and healthy controls (HC) (n = 32). This required participants to choose between a fixed low‐effort/low‐reward and a variable high‐effort/high‐reward option, and then immediately exert effort to obtain corresponding rewards for themselves or for unfamiliar people. Results Compared with the HC group, the SD group showed blunted activity in the left dorsal anterior cingulate cortex/dorsomedial prefrontal cortex, bilateral anterior insula (AI), and right putamen‐left dorsolateral prefrontal cortex functional connectivity when choosing to exert effort for themselves. Additionally, the SD group exhibited increased willingness and greater activation in the bilateral AI when choosing to exert effort for others. Furthermore, these brain activations and functional connectivity were positively related to self‐reported motivation. Conclusions These findings show altered motivation during effort‐based decision‐making in individuals with the mild depressive state, particularly with higher motivation for others. Thus, this suggests that motivational behaviors and prefrontal–striatal circuitry are altered in individuals with SD, which can be utilized to discover treatment targets and develop strategies to address mental illness caused by motivation disorders.

Purpose The severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) pandemic is associated with worsening mental health among young adults, but further research is necessary to quantify the associations with depression and anxiety. Methods Using Monitoring the Future data (N = 1244 young adults, modal age: 19, Fall 2020 supplement), we examined internalizing symptoms (Patient Health Questionnaire‐8 and Generalized Anxiety Disorder Scale‐7 separately), dividing the sample into those without clinically significant scores, significant scores but minimal pandemic‐attributed symptoms, and significant scores with substantial pandemic‐attributed symptoms. Logistic regression analyses linked demographic factors, pandemic‐related experiences, and coping methods to symptom groups. Results Internalizing symptoms were highly prevalent, with many occurring among a majority at least several days over the past 2 weeks. Major changes in education, employment, and resource availability predicted elevated symptom risk (e.g., lacking a place to sleep or money for rent, gas, or food led to 4.43 [95% confidence interval: 2.59–7.55] times the risk of high depressive symptoms significantly attributed to the pandemic). High internalizing symptoms were linked to underutilization of healthy coping behaviors, substance use overutilization, and dietary changes. High depressive and anxious symptoms attributed to the pandemic were marked by high levels of taking breaks from the news/social media and contacting healthcare providers. Conclusions The pandemic's associations with young adults' depressive and anxious symptoms warrants urgent attention through improved mental health treatment infrastructure and stronger structural support.

Background Stressful events, such as those imposed by the COVID‐19 pandemic, are associated with depression risk, raising questions about processes that make some people more susceptible to the effects of stress on mental health than others. Emotion regulation may be a key process, but methods for objectively measuring emotion regulation abilities in youth are limited. We leveraged event‐related potential (ERP) measures and a longitudinal study of adolescents oversampled for depression and depression risk to examine emotion regulation difficulties as prospective predictors of depressive symptoms in response to pandemic‐related stress. Methods Before the pandemic, adolescents with (n = 28) and without (n = 34) clinical depression (N = 62 total) completed an explicit emotion regulation task while ERP data were recorded and measures of depressive symptoms. Adolescents were re‐contacted during the pandemic to report on COVID‐19 related stressful events and depressive symptoms (n = 48). Results Adolescents who had never experienced a depressive episode showed an increase in depressive symptoms during the pandemic, but adolescents who were clinically depressed before the pandemic did not exhibit significant changes in symptoms. Neural markers of emotion regulation abilities interacted with pandemic‐related stressful events to predict depressive symptoms during the pandemic, such that stressors predicted increases in depressive symptoms only for adolescents with greater difficulty modulating responses to negative images before the pandemic. Conclusions Results provide insight into adolescent mental health during the COVID‐19 pandemic and highlight the role of emotion regulatory brain function in risk and resilience for depression.

Background The association between adversity and psychopathology in adolescents and adults is characterized by equifinality. These associations, however, have not been assessed during early childhood when psychopathology first emerges. Defining adversity using both dimensional and cumulative risk approaches, we examined whether specific types of adversity are differentially associated with psychopathology in preschool‐aged children. Methods Measures of threat, deprivation, and total adversities (i.e., cumulative risk) were calculated based on parent‐reported information for 755 2‐ to 5‐year old children recruited from pediatric primary care clinics. Logistic regression was used to estimate cross‐sectional associations between type of adversity and anxiety, depression, ADHD, and behavioral disorder diagnoses. Results Threat and cumulative risk exhibited independent associations with psychopathology. Threat was strongly related to behavioral disorders. Cumulative risk was consistently related to all psychopathologies. Conclusions Using mutually adjusted models, we identified differential associations between threat and psychopathology outcomes in preschool‐aged children. This selectivity may reflect different pathways through which adversity increases the risk for psychopathology during this developmentally important period. As has been observed at other ages, a cumulative risk approach also effectively identified the cumulative impact of all forms of adversity on most forms of psychopathology during early childhood.

Background: Obsessive-compulsive disorder (OCD) implicates alterations in cortico-striato-thalamo-cortical and fronto-limbic circuits. Building on prior structural findings, this is the largest study to date examining subcortical surface morphometry in OCD. Methods: Structural magnetic resonance imaging data were collected from 200 participants across development (5-55 years): 28 youth and 75 adults with OCD and 27 psychiatrically healthy youth and 70 adults. General linear models were used to assess group differences and group-by-age interactions on subcortical shape (FSL FIRST). Results: Compared to healthy participants, those with OCD exhibited surface expansions on the right nucleus accumbens and inward left amygdala deformations, which were associated with greater OCD symptom severity ([Children's] Yale-Brown Obsessive-Compulsive Scale). Group-by-age interactions indicated that accumbens group differences were driven by younger participants and that right pallidum shape was associated inversely with age in healthy participants, but not in participants with OCD. No differences in the shape of other subcortical regions or in volumes (FreeSurfer) were detected in supplementary analyses. Conclusions: This study is the largest to date examining subcortical shape in OCD and the first to do so across the developmental spectrum. NAcc and amygdala shape deformation builds on extant neuroimaging findings and suggests subtle, subregional alterations beyond volumetric findings. Results shed light on morphometric alterations in OCD, informing current pathophysiological models.

Background Youth suicide has been increasing at an alarming rate. Identifying how youth at risk for suicide cope with daily distress and suicidal thoughts could inform prevention and intervention efforts. We investigated the relationship between previous‐day coping and next‐day suicidal urge intensity in a high‐risk adolescent sample for a 4‐week period. We also investigated the influence of adolescents' average coping levels, over 4 weeks, on daily severity of suicidal urges. Methods A total of 78 adolescents completed daily diaries after psychiatric hospitalization (n = 1621 observations). Each day, adolescents reported their use of specific coping strategies, overall coping helpfulness, and intensity of suicidal urges. Results Greater professional support seeking from providers/crisis lines and perceptions of coping helpfulness on the previous day were associated with lower next‐day suicidal urges. Adolescents who reported greater average use of cognitive strategies, personal support seeking from family/friends, and higher average perceptions of coping helpfulness, relative to others, had lower daily suicidal urges. Noncognitive strategy use was not related to daily suicidal urge intensity. Conclusion Findings point to the benefit of intervention efforts focusing on strengthening personal and professional supportive relationships, assisting youth with developing a broader coping repertoire, and working with adolescents to identify strategies they perceive to be helpful.

Background Genetic factors contribute to the development of anxiety disorders, yet few risk genes have been previously identified. One genomic approach that has achieved success in identifying risk genes in related childhood neuropsychiatric conditions is investigations of de novo variants, which has yet to be leveraged in childhood anxiety disorders. Methods We performed whole‐exome DNA sequencing in 76 parent‐child trios (68 trios after quality control) recruited from a childhood anxiety disorder clinic and compared rates of rare and ultra‐rare de novo variants with 790 previously sequenced control trios (783 trios after quality control). We then explored overlap with risk genes for other neuropsychiatric conditions and enrichment in biologic pathways. Results Rare and ultra‐rare de novo likely gene disrupting and predicted damaging missense genetic variants are enriched in anxiety disorder probands compared with controls (rare variant rate ratio 1.97, 95% confidence interval [CI]: 1.11–3.34, p = .03; ultra‐rare variant rate ratio 2.59, 95% CI: 1.35–4.70, p = .008). These de novo damaging variants occur in individuals with a variety of childhood anxiety disorders and impact genes that have been associated with other neuropsychiatric conditions. Exploratory network analyses reveal enrichment of deleterious variants in canonical biological pathways. Conclusions These findings provide a path for identifying risk genes and promising biologic pathways in childhood anxiety disorders by de novo genetic variant detection. Our results suggest the discovery potential of applying this approach in larger anxiety disorder cohorts to advance our understanding of the underlying biology of these common and debilitating conditions.

Background Widespread structural alterations have been shown to be implicated in individuals with generalized anxiety disorder (GAD). However, there have been inconsistent findings in cortical volume (CV) differences. Most structural neuroimaging studies looking at GAD used region-based approach with relatively small sample sizes, let alone be specific to adolescents with GAD. We believe this is the first study to look at CV measures using a network-based approach in a larger sample of adolescents with GAD. The goal of the current study was to focus on three different brain networks (i.e., Limbic, Frontoparietal, and Default Mode Network [DMN]) in adolescents with GAD. Method The study involved 81 adolescents with GAD and 112 typically developing (TD) comparison individuals matched on age (15.98 and 15.63 respective means), sex (42F/39M and 45F/67M), and IQ (101.90 and 103.94 respective means). Participants underwent structural MRI. Freesurfer was used to estimate CV (both network-specific and region-specific within networks) and region-specific sub-cortical volume measures. Multivariate analysis of covariance (MANCOVA; with sex, age, IQ, and intracranial volume [ICV] as potential covariates) was used to estimate group differences. Results We found significantly lower CV for the DMN in adolescents with GAD, compared with TD individuals. Adolescents with GAD also showed significantly lower hemispheric mean CV of the default-mode regions (particularly the prefrontal and temporal regions) and the hippocampus, compared with TD individuals. Conclusion The current findings suggest structural alterations in adolescents with GAD. These structural alterations will need to be addressed when implementing and developing treatments for patients with GAD.

Objective To examine the efficacy of weight‐adjusted D‐cycloserine (DCS) (35 or 70 mg) relative to placebo augmentation of intensive exposure therapy for youth with obsessive‐compulsive disorder (OCD) in a double‐blind, randomised controlled trial, and examine whether antidepressant medication or patient age moderated outcomes. Methods Youth (n = 100, 7–17 years) with OCD were randomised in a 1:1 ratio to either DCS + exposure (n = 49) or placebo + exposure (n = 51). Assessments occurred posttreatment, 1 month later, and at 3 and 6 months. Pills were ingested immediately before sessions. Results Significant improvements on all outcomes were observed at posttreatment, and to 6‐month follow‐up. Treatment arms did not differ across time, with no significant time‐by‐medication interactions on symptom severity (T1 to T2 estimate: 9.3, 95% confidence interval [CI]: −11.2 to −7.4, and estimate −10.7, 95% CI: −12.6 to −8.7), diagnostic severity (T1 to T2 estimate: −2.0, 95% CI: −2.4 to −1.5 and estimate −2.5, 95% CI: −3.0 to −2.0) or global functioning (T1 to T2 estimate: 13.8, 95% CI: 10.6 to 17.0, and estimate 16.6, 95% CI: 13.2 to 19.9). Neither antidepressants at baseline nor age moderated primary outcomes. There were significantly fewer responders/remitters at 1‐ and 6‐month follow‐up among youth in the DCS condition stabilised on SSRIs, relative to youth not taking SSRIs. Conclusions DCS augmented intensive exposure therapy did not result in overall additional benefits relative to placebo. Intensive exposure proved effective in reducing symptoms for the overall sample.

Trauma‐focused guided self‐help (TF‐GSH) is an important alternative to psychological therapy delivered by a therapist. This meta‐analysis evaluates the efficacy of TF‐GSH in reducing posttraumatic stress disorder (PTSD) symptoms and comorbid depressive and anxiety symptoms. A total of 17 trials were included that compared a TF‐GSH intervention (N = 610) to various control comparators (N = 570). Control conditions included treatment as usual (k = 2), waiting list (k = 11), phone monitoring (k = 1), nontrauma writing (k = 1), general support (k = 1), and supportive counseling (k = 1). A moderate‐ to large‐sized effect favouring TF‐GSH was observed for PTSD (k = 17, g = −0.81, 95% confidence interval [CI]: −1.24, −0.39) and a moderate‐sized effect was observed for depressive (k = 13, g = −0.73, 95% CI: −1.16, −0.31) and anxiety (k = 11, g = −0.72, 95% CI: −1.18, −0.27) symptoms, with considerable heterogeneity. Moderator analyses were all not statistically significant. Results indicate that TF‐GSH is a promising treatment for PTSD and comorbid depressive and anxiety symptoms. We discuss the nature, extent, and quality of the literature to provide a point of departure for future research. TF‐GSH (and unguided self‐help) may not be appropriate for certain individuals at certain times. Exploring a broad range of treatment delivery modalities will move the field closer towards a model of evidence‐based care in which the likely appropriate dose and type of intervention can be matched to individuals based on presenting problems and other variables.

Background The underlying mechanism between sensory impairments (SIs) and depressive symptoms among Chinese older adults is not well understood. This study aims to explore the mediating role of functional limitation on the longitudinal relationship between SIs and depressive symptoms among older adults in China. Methods A total of 4130 older adults who participated in the 3‐year follow‐up China Health and Retirement Longitudinal Study (CHARLS) were included in the analysis. The hierarchical multiple linear regression model and nonparametric bootstrapping method were employed to explore the relationship between SIs and depressive symptoms, and the mediating role of functional limitation in this link. Results The prevalence of self‐reported hearing impairment (HI) only, vision impairment (VI) only, and dual sensory impairment (DSI) at baseline were 5.7%, 22.2%, and 58.6%, respectively. After adjusting for controlling variables, older adults with DSI had significantly higher levels of depressive symptoms compared with those without SIs at baseline (β = .07, p = .005). The magnitude of mediation effect from DSI to depressive symptoms via functional limitation was a*b = 0.060 (BCa 95% confidence interval: 0.031–0.094). Conclusions Functional limitation partially mediated the relationship between DSI and depressive symptoms among Chinese older adults. Interventions of DSI and functional limitation should be included in depressive symptoms prevention among older adults in China.

Background Social support (SS) has been reported as a factor preventing suicide death, but whether this association is independent of mental status is unclear. The present study examined the effect modification of SS on the association between psychological distress status and risk of suicide death. Methods Follow‐up data for 43,015 subjects participating in a prospective cohort study were analyzed. At baseline, the subjects were asked about SS and mental status with the Kessler six‐item Distress (K6) Scale. A Cox model was used to estimate the multivariate‐adjusted hazard ratios (HRs) of suicide death according to two levels of psychological distress (K6 ≤ 4, K6 ≥ 5). The HRs in each SS subtype (emotional and instrumental) were also calculated. Results There was a significant association between SS and a lower risk of suicide death in the stratum of K6 ≥ 5, with an HR of 0.58 (95% confidence interval, 0.35–0.96). On the other hand, the association with the K6 ≤ 4 strata was not significant. Conclusion SS appears to be associated with a lower risk of suicide death only among participants with moderate or severe psychological distress. These results imply that early detection of psychological distress and provision of SS is important for preventing suicide death.

Importance Improving treatment outcomes for smokers with major depressive disorder (MDD) can have significant public health implications. Objective To evaluate the safety and efficacy of smoking cessation pharmacotherapy among smokers with MDD. Design Secondary analysis of a randomized, double‐blind, active‐ (nicotine patch) and placebo‐controlled trial of 12 weeks of either varenicline or bupropion with a 12–week follow‐up. Participants Community volunteers 18−75 years of age; smoke 10+ cigarettes/day; with clinically stable MDD (N = 2635) or no psychiatric disorder (N = 4028), from 140 sites in 16 countries. Intervention Twelve weeks of pharmacotherapy (placebo [PLA], nicotine replacement therapy [NRT], bupropion [BUP], varenicline [VAR]) plus brief cessation counseling. Measure(s) Primary safety outcome: the occurrence of ≥1 treatment‐emergent, moderate to severe neuropsychiatric adverse event (NPSAE). Primary efficacy outcome: biochemically confirmed continuous abstinence (CA) during the final 4 weeks of treatment (Weeks 9–12). Results A total of 6653 participants (56% female; 39% MDD) ~47 years old. Risk of NPSAEs did not differ by medication for MDD. MDD had higher risk (p < .0001) for NPSAEs than the NPC. Efficacy (6653; intent‐to‐treat): CA rates for MDD versus NPC respectively were 31.2% versus 38.0% VAR; 23.0% versus 26.1% BUP; 22.6% versus 26.4% NRT; and 13.4% versus 13.7% PLA but no differential treatment effect was noted within the cohorts. All active treatments differed from PLA but VAR showed the largest effect. Conclusions Results suggest that for MDD smokers, inclusive of those with recurrent episode, varenicline plus counseling may be the best pharmacological option for the treatment of smoking given its greater efficacy effect size and similar risk of NPSAEs. Trial registration ClinicalTrials.gov Identifier: NCT01456936. https://clinicaltrials.gov/ct2/show/NCT01456936.

Introduction: The investigation of disease course-associated brain structural alterations in Major Depressive Disorder (MDD) have resulted in heterogeneous findings, possibly due to low reliability of single clinical variables used for defining disease course. The present study employed a principal component analysis (PCA) on multiple clinical variables to investigate effects of cumulative lifetime illness burden on brain structure in a large and heterogeneous sample of MDD patients. Methods: Gray matter volumes (GMV) was estimated in n = 681 MDD patients (mean age: 35.87 years; SD = 12.89; 66.6% female) using voxel-based-morphometry. Five clinical variables were included in a PCA to obtain components reflecting disease course to associate resulting components with GMVs. Results: The PCA yielded two main components: Hospitalization reflected by patients' frequency and duration of inpatient treatment and Duration of Illness reflected by the frequency and duration of depressive episodes. Hospitalization revealed negative associations with bilateral dorsolateral prefrontal cortex (DLPFC) and left insula volumes. Duration of Illness showed significant negative associations with left hippocampus and right DLPFC volumes. Results in the DLPFC and hippocampus remained significant after additional control for depressive symptom severity, psychopharmacotherapy, psychiatric comorbidities, and remission status. Conclusion: This study shows that a more severe and chronic lifetime disease course in MDD is associated with reduced volume in brain regions relevant for executive and cognitive functions and emotion regulation in a large sample of patients representing the broad heterogeneity of MDD disease course. These findings were only partly influenced by other clinical characteristics (e.g., remission status, psychopharmacological treatment).

Background Early‐onset (EO) major depressive disorder (MDD) patients experience more depressive episodes and an increased risk of relapse. Thus, on a neurobiological level, adult EO patients might display brain structure and function different from adult‐onset (AO) patients. Methods A total of 103 patients (66 females) underwent magnetic resonance imaging. Structural measures of gray matter volume (GMV) and functional connectivity networks during resting state were compared between EO (≤19 years) and AO groups. Four residual major depression symptoms, mood, anxiety, insomnia, and somatic symptoms, were correlated with GMV between groups. Results We found comparatively increased GMV in the EO group, namely the medial prefrontal and insular cortex, as well as the anterior hippocampus. Functional networks in EO patients showed a comparatively weaker synchronization of the left hippocampus with the adjacent amygdala, and a stronger integration with nodes in the contralateral prefrontal cortex and supramarginal gyrus. Volumetric analysis of depression symptoms associated the caudate nuclei with symptoms of insomnia, and persisting mood symptoms with the right amygdala, while finding no significant clusters for somatic and anxiety symptoms. Conclusions The study highlights the important role of the hippocampus and the prefrontal cortex in EO patients as part of emotion‐regulation networks. Results in EO patients demonstrated subcortical volume changes irrespective of sleep and mood symptom recovery, which substantiates adolescence as a pivotal developmental phase for MDD. Longitudinal studies are needed to differentiate neural recovery trajectories while accounting for age of onset.

Background Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for major depressive disorder (MDD). Psychostimulant medication use may be associated with improved rTMS outcomes, but a detailed understanding of these relationships is lacking. Methods We compared MDD subjects taking psychostimulants (n = 37) with those not taking one of these medications (n = 53) during a course of 30 rTMS treatments. Changes in the 30‐item Inventory of Depressive Symptomatology Self Report (IDS‐SR30) subscale scores were examined at treatment 30. We also subdivided subjects into three categories based on drug mechanism and looked at IDS‐SR30 total score after treatments 10, 20, and 30. Results Subjects taking psychostimulants had a significantly greater overall clinical improvement than those not taking these medications at treatment 30. The psychostimulant group also improved significantly more than the control group in “sleep” and “mood/cognition,” but not “anxiety/arousal” IDS‐SR30 subscales. No differences were detected among individual drug categories, which may reflect the limited sample size for individual medications. There was a negative dose–response relationship for the lisdexamfetamine/dextroamphetamine group, in which lower doses were associated with better clinical outcome. Conclusions Psychostimulant medications may enhance clinical efficacy of rTMS for MDD by preferentially impacting specific symptom domains. For some psychostimulants, these effects may be dose‐dependent. Prospective clinical trials are needed to guide psychostimulant augmentation of brain stimulation therapies.

Background Nonrestorative sleep (NRS), defined as insufficiently rested or refreshed sleep, is considered to play an important role in the development of depression. The aim of this study is to investigate the predictive ability of insomnia‐related symptoms, including NRS, for incident depressive symptoms (DEPs) in a longitudinal manner. Methods We used data of 1196 samples aged 18–64 years who participated in both the Hispanic Community Health Study/Study of Latinos conducted in 2008–2010 and the follow‐up study (Sueño Ancillary Study) conducted in 2010–2013. DEPs and insomnia‐related symptoms (difficulty initiating sleep [DIS], difficulty maintaining sleep [DMS], early morning awakening [EMA], difficulty returning to sleep [DRS], and NRS) were evaluated by the 10‐item Center for Epidemiologic Studies Depression Scale and the Women's Health Initiative Insomnia Rating Scale, respectively. A logistic regression analysis was used to evaluate the predictive ability of each insomnia‐related symptom at baseline for incident DEPs in couple‐years. Results In the univariate logistic regression analysis, all insomnia‐related symptoms had significant associations with incident DEPs (DIS, odds ratio [OR] = 1.6; DMS, OR = 1.6; EMA, OR = 1.5; DRS, OR = 1.9; NRS, OR = 2.5). After adjusting for sociodemographic factors and the confounding effects of other insomnia‐related symptoms, only NRS (OR = 2.2, 95% confidence interval = 1.4–3.5, p = .001) was significantly associated with incident DEPs. Conclusions NRS was a risk factor for incident DEPs, which includes a predictive ability for other insomnia‐related symptoms. Our results suggest that focusing on NRS is an effective strategy for preventing depression in public health promotions.

Background Major depressive disorder (MDD) is characterized by a high rate of treatment resistance. Omega (ω)−3 polyunsaturated fatty acids (PUFAs) were shown to correlate with depressive phenotype both in rodents and in humans. However, few studies to date have investigated the role of PUFAs in antidepressant response. The primary aim of this study was to assess the link between baseline PUFA composition and changes in depressive symptoms as well as antidepressant response in a multicenter study of depressed patients. Methods Sixty depressed adults who met criteria for MDD according to DSM‐IV‐TR were recruited. Neuropsychiatric evaluations occurred at baseline and after 4 and 8 weeks of treatment with standard antidepressants, including escitalopram (N = 45), sertraline (N = 13) and venlafaxine (N = 2). At study endpoint, patients were stratified into responders (R) or non‐responders (NR) based on their MADRS (Montgomery‐Åsberg Depression Rating Scale) score. Baseline PUFA levels were assessed and their association with clinical response was determined. Results Lower ω−3 PUFA levels were associated to worse baseline symptomatology. Baseline levels of PUFAs were significantly different between R and NR, with R exhibiting lower docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) and ω−3 index; and higher ω‐6/ω−3 ratio than NR before the start of antidepressant treatment. DHA levels as well as the ω−3 index and ω‐6/ω−3 ratio significantly predicted response to antidepressants at study endpoint. Conclusions These results show that baseline levels of PUFAs predict later response to standard antidepressants in depressed subjects. They suggest that PUFA intake and/or metabolism represent a novel modifiable tool for the management of unresponsive depressed patients.

Objective Depression is a global key challenge in mental health care. The implementation of effective, low‐risk and cost‐effective interventions to reduce its disease burden is a necessity. The aim of this study was to investigate the efficacy of the new Meditation‐Based Lifestyle Modification (MBLM) program, a “second‐generation” mindfulness‐based intervention, in depressive outpatients. Methods Eighty‐one patients with mild to moderate depression were randomized into three groups: intervention group (MBLM), control group (CONTROL), and treatment as usual group (TAU). The primary outcome was the change of depressive symptoms as administered by the Beck Depression Inventory‐II (BDI‐II) after 4 and 8 weeks. Secondary outcome variables included the Brief Symptom Checklist‐18 and the Perceived Stress Scale‐10. A 6‐month follow‐up was conducted. Results A greater reduction of depressive symptoms was found in MBLM participants compared to CONTROL (p < .001, ηp² = 0.11, d = 0.70) and TAU (p < . 001 , η p 2 = 0 . 10 , d = 0 . 67 $p\lt .001,{\eta }_{{\rm{p}}}^{2}=0.10,d=0.67$) with a 13.15 points reduction of BDI‐II score versus 1.71 points (CONTROL) and 3.34 points (TAU) after 8 weeks. Between‐group post hoc tests for all secondary outcomes and at follow‐up also yielded significant between‐group differences with medium to large effect sizes in favor of MBLM. Conclusions Study results showed beneficial effects of MBLM in depressed outpatients. Further high‐quality controlled clinical studies including qualitative research are needed to investigate the specific and unspecific effects of the MBLM program in depression and other medical conditions.

Background There is a scarcity of literature on the association between physical multimorbidity (i.e., ≥2 chronic physical conditions) and depression among older adults, especially from low- and middle-income countries (LMICs). In addition, the mediators in this association are largely unknown. Therefore, we aimed to examine this association among adults aged ≥50 years from six LMICs (China, Ghana, India, Mexico, Russia, and South Africa), and to identify potential mediators. Methods Cross-sectional, nationally representative data from the Study on Global Ageing and Adult Health were analyzed. Depression was defined as past-12 months DSM-IV depression or receiving depression treatment in the last 12 months. Information on 11 chronic physical conditions were obtained. Multivariable logistic regression and mediation analyses were conducted. Results Data on 34,129 individuals aged ≥50 years were analyzed [mean (SD) age 62.4 (16.0) years; maximum 114 years; 52.1% females]. Compared to no chronic conditions, 2, 3, 4, and ≥5 chronic conditions were associated with 2.55 (95% CI = 1.90–3.42), 3.12 (95% CI = 2.25–4.34), 5.68 (95% CI = 4.02–8.03), and 8.39 (95% CI = 5.87–12.00) times higher odds for depression. Pain/discomfort (% mediated 39.0%), sleep/energy (33.2%), mobility (27.5%), cognition (13.8%), perceived stress (7.3%), disability (6.7%), loneliness (5.5%), and food insecurity (1.5%) were found to be significant mediators in the association between physical multimorbidity and depression. Conclusions Older adults with physical multimorbidity are at increased odds of depression in LMICs. Future studies should assess whether addressing the identified potential mediators in people with physical multimorbidity can lead to reduction in depression in this population.

Background Recently, an animal model for depression has shown that ketamine, an N-methyl- d-aspartate receptor (NMDAR) antagonist, elicits a rapid-acting antidepressant effect by blocking NMDAR-dependent bursting in the lateral habenula (Hb). However, evidence from human studies remains scarce. Methods This study explored the changes of resting-state functional connectivity (FC) of the Hb in responders and nonresponders who was diagnosed with unipolar or bipolar depression before and after ketamine treatment. The response was defined as a ≥50% reduction in the total MADRS score at Day 13 (24 h following the sixth infusion) in comparison with the baseline score. Correlation analyses were performed to identify an association between symptom improvement and the signals of the significantly different brain regions detected in the above imaging analysis. Results In the post-hoc region-of-interest analysis, an enhanced baseline FC between Hb and several hubs of the default mode network (including angulate cortex, precuneus, medial prefrontal cortex, and middle temporal cortex) was observed in responders (≥50% decrease in the Montgomery–Asberg Scale at 2 weeks) compared with nonresponders. Conclusions These pilot findings may suggest a potential neural mechanism by which ketamine exerts its robust antidepressant efficacy via downregulation of aberrant habenular FC with parts of the default mode network.

Background: The transition from military to civilian life is a dramatic change that is often stressful for veterans. However, little is known regarding how mental health symptoms fluctuate in the period leading up to and following separation from the military. Methods: The current study examined posttraumatic stress disorder and depression symptoms reported on surveys completed within 1 year of military separation from 23,887 active duty Millennium Cohort Study participants. A series of general linear models and graphs stratified by demographic and military characteristics examined the association between time until/since separation and mental health symptoms. Results: Character of discharge had the most striking relationship between time until/since separation and mental health. Personnel with Honorable discharges did not differ in their level of mental health symptoms across the study period. In contrast, personnel with Other than Honorable/General discharges reported normal levels of mental health symptoms 1 year-prior to separation but reported progressively greater symptoms leading to separation which persisted through the remainder of study period. Conclusions: This study suggests that additional outreach is needed for personnel with Other than Honorable/General discharges. However, for most other personnel, increased mental health symptomatology around military separation is not a normative phenomenon and any instance should be treated promptly.

Background PTSD and ADHD often occur comorbidly. Research indicates that the cognitive deficits in PTSD may be related to the same disturbance of fronto‐temporal systems as observed in ADHD, and ADHD has been shown to impact PTSD treatment outcomes. The presented study evaluated the safety and efficacy of atomoxetine in Veterans with comorbid ADHD/PTSD. Methods A double blind, randomized, placebo controlled, cross‐over pilot and feasibility study was conducted. Atomoxetine was examined as an adjunctive treatment over this 10 weeks, two phase, crossover study which compared treatment with atomoxetine 80 mg daily to placebo daily. The primary outcome was improvement in ADHD symptoms as measured by the Conners' Adult ADHD Rating Scales‐Self‐Report: Short Version (CAARS‐S:S), the Barkley Adult ADHD Rating Scale‐IV (BAARS‐IV), and the Adult ADHD Quality of Life‐29 (AAQoL‐29). Secondary outcomes included the Clinician Administered PTSD Scale (CAPS), Medical Outcomes Study 36‐Item Short‐Form Health Survey (SF‐36), and the response inhibition task Go/NoGo (GNG). Results Atomoxetine treated patients had greater reductions in ADHD symptoms as defined by total scores on the CAARS‐S:S (F(1, 29) = 6.37, p = .017); both the BAARS‐IV (F(1, 26) = 3.16, p = .087); and GNG overall errors test (F(1, 29) = 3.88, p = .06), reached a trend level of significance. No significant differences were noted in quality of life assessments, GNG latency periods, or CAPS scores. Atomoxetine was well‐tolerated with no serious adverse events observed. Conclusions In Veterans with ADHD comorbid with PTSD, atomoxetine demonstrated modest efficacy for ADHD symptoms; quality of life measures and PTSD symptoms were not affected.

Background Posttraumatic stress disorder (PTSD) is associated with inflammation and various forms of chronic disease. The Absent in Melanoma 2 (AIM2) gene has been implicated in mechanisms of inflammation and anxiety, and methylation at a particular locus in this gene (cg10636246) has previously been shown to influence the association between PTSD and elevated C‐reactive protein levels in blood. Method We tested if this association might extend to other indicators of inflammation and to plasma‐based measures of neuropathology in a cohort of post‐9/11 US military veterans. Using a Bayesian approach, mediation models were tested cross‐sectionally (n = 478) and longitudinally (n = 298). Peripheral markers of inflammation and neuropathology were measured with ultra‐sensitive Single Molecule Array (Simoa®) technology. Results Analyses revealed indirect effects of PTSD symptom severity on peripheral indices of both inflammation (interleukin [IL]6, IL‐10, tumor necrosis factor‐α; indirect standardized [std.] ß range = 0.018–0.023, all p‐values adjusted for multiple testing [padj] < 0.05) and neuropathology (neurofilament light [NFL]; indirect std. ß = −0.018, padj = 0.02) via AIM2 methylation. This indirect effect was also evident when predicting IL‐10 at a follow‐up assessment (indirect std. ß = −0.018, padj = 0.04) controlling for baseline IL‐10. Conclusions Given that AIM2 methylation mediated the association between PTSD symptoms and multiple inflammatory and neuropathology markers, our results suggest that AIM2 methylation may offer clinical utility for indexing risk for adverse health outcomes associated with these peripheral indices of inflammation and neuropathology. Results also suggest a possible shared etiology underlying the frequent co‐occurrence of inflammation and neuropathology.

Introduction Trauma‐related guilt is common, associated with posttraumatic mental health problems, and can persist after posttraumatic stress disorder (PTSD) treatment. We compared the efficacy of two six‐session psychotherapies, Trauma‐Informed Guilt Reduction (TrIGR) and Supportive Care Therapy (SCT), for reducing trauma‐related guilt. TrIGR helps patients accurately appraise their role in the trauma and re‐engage in values. In SCT, patients guide session content. Methods A total of 184 veterans seeking VA mental health services were enrolled across two sites; 145 veterans (mean age: 39.2 [8.1]; 92.4% male; 84.8% with PTSD) who endorsed guilt related to a traumatic event that occurred during a post 9/11 Iraq or Afghanistan deployment were randomized and assessed at baseline, posttreatment, 3‐ and 6‐month follow‐up. Results Linear mixed models using intent‐to‐treat analyses showed guilt decreased in both conditions with a greater decrease for TrIGR (treatment × time, −0.22; F 1, 455.2 = 18.49, p = .001; d = 0.92) than supportive therapy. PTSD and depressive symptoms showed the same pattern. TrIGR had significantly higher likelihood of PTSD treatment response (67% vs. 40%), loss of PTSD diagnosis (50% vs. 14%), and meaningful change in depression (54% vs. 27%) than supportive therapy. Psychological distress and trait shame improved in both conditions. Quality of life did not change. Conclusions Targeting guilt appears to be an effective means for reducing posttraumatic symptoms and distress.

Background Emerging evidence has highlighted the moderating effect of childhood maltreatment (CM) in shaping neurobiological abnormalities in major depressive disorder (MDD). However, whether neural mechanisms underlying stress sensitivity in MDD are affected by the history of CM is unclear. Methods Two hundred and thirteen medication‐free female participants were recruited for a functional magnetic resonance imaging study assessing the effects of psychosocial stress on neural responses. The Montreal Imaging Stress Task was administrated to 44 female MDD patients with CM (MDD/CM), 32 female MDD patients without CM (MDD/noCM), 43 female healthy controls (HCs) with CM (HC/CM), and 94 female HCs without CM (HC/noCM). A CM (CM, noCM) × diagnosis (MDD, HC) whole‐brain voxel‐wise analysis was run to assess putative group differences in neural stress responses. Results A significant CM × Diagnosis interaction emerged in the medial prefrontal cortex (mPFC). Bonferroni‐corrected simple effects analysis clarified that (1) the MDD/CM group had less mPFC deactivation than the HC/CM group, (2) the MDD/noCM group exhibited greater mPFC deactivation than the HC/noCM group, and (3) the MDD/CM group exhibited less mPFC deactivation relative to the MDD/noCM group. In addition, the mPFC‐seed psychophysiological interaction analysis revealed that individuals in the CM groups had significantly greater stress‐related mPFC‐left superior frontal gyrus and mPFC‐right posterior cerebellum connectivity relative to the noCM groups. Conclusions Findings highlight distinct neural abnormalities in MDD depending on prior CM history, particularly potentiated stress‐related mPFC recruitment among MDD individuals reporting CM. Moreover, CM history was generally associated with the disruption in functional connectivity centered on the mPFC.

Background Intensive outpatient programs (IOPs) for trauma‐focused therapy, such as prolonged exposure (PE), have the potential to deliver highly effective treatment, quickly and with minimal dropout. Identifying factors that predict maintenance of gains after treatment can help triage individuals who may need additional services. Methods Growth mixture modeling (GMM) was used to identify classes of posttraumatic stress disorder (PTSD) and depression symptom trajectories across the year following a 2‐week IOP, delivering daily PE for PTSD for post‐9/11 Veterans. Predictors of trajectories were examined. Results Three classes of trajectories best‐fit the data for PTSD and depression symptoms. Two classes made up the majority of the sample (85%) and both maintained significantly reduced PTSD symptoms across the year following therapy. For a minority of the sample (14.6%), PTSD symptoms rebounded after treatment. These individuals were highly likely to be categorized in the persistent depression class. Conclusions IOP‐delivered PE is effective, and gains are largely maintained. The minority of patients who do not maintain their gains as robustly are likely to report persistent depressive symptoms in treatment and higher PTSD symptoms on a self‐report measure.

Background A common feature of complex posttraumatic stress disorder (CPTSD) is impulsivity. Despite the importance of this characteristic in functional difficulties in CPTSD, little is known about its mechanisms. The aim of this study was to identify the distinctive neural profile of CPTSD during attempted inhibition. Methods The present study examined functional alterations in neural networks involved in inhibitory control across functional magnetic resonance imaging (fMRI) and electroencephalogram (EEG) paradigms in CPTSD (n = 30), PTSD (n = 40), and healthy control (n = 40) participants who completed a Go/NoGo response inhibition task during separate fMRI and EEG sessions. Brain activations were calculated during the NoGo trials relative to the baseline to evaluate response inhibition functioning. Results There was reduced bilateral thalamic activation in participants with CPTSD relative to PTSD and controls during inhibition trials, but no activation differences between PTSD and controls for this brain region. There were no differences in functional connectivity between the thalamus and other regions involved in cognitive control between groups. No differences were observed between groups on EEG responses. Conclusions These findings provide initial evidence of aberrant functioning in the neurocircuitry of inhibitory control, involving the thalamus, in CPTSD. This evidence suggests that CPTSD is distinguished from PTSD by impaired neural processes implicated in response inhibition.

Background Problems with anger and aggression affect many veterans who have deployed to a warzone, resulting in serious impairment in multiple aspects of functioning. Controlled studies are needed to improve treatment options for these veterans. This randomized controlled trial compared an individually delivered cognitive behavioral therapy adapted from Novaco's Anger Control Therapy to a manualized supportive therapy to control for common therapeutic factors. Methods Ninety-two post-911 veterans deployed during Operation Enduring Freedom (OEF), Operation Iraqi Freedom (OIF), or Operation New Dawn (OND) with moderate to severe anger problems were randomized to receive the cognitive behavioral intervention (CBI) or the supportive intervention (SI). Anger, aggression, multiple areas of functioning and quality of life were assessed at multiple time points inclu\ding 3- and 6-month follow-up. Results Hierarchical linear modeling (HLM) analyses showed significant treatment effects favoring CBI for anger severity, social and interpersonal functioning, and quality of life. The presence of a PTSD diagnosis did not affect outcomes. Conclusions CBI is an effective treatment for OEF/OIF/OND veterans with anger problems following deployment, regardless of PTSD diagnosis.

Background Many psychological and obstetrical factors contribute to the development of postpartum depression. However, little is known about how postpartum hemorrhage (PPH) influences postpartum depressive symptoms. This study explored the relationship between PPH and postpartum depressive symptoms in the Chinese population. Methods A retrospective cohort study was conducted at the Baoan Maternal and Child Health Hospital in Shenzhen, China, from January 2016 to June 2020. The Edinburgh Postnatal Depression Scale was used to assess postpartum depressive symptoms. A multivariate logistic regression model was used to estimate the odds ratios (ORs) with 95% confidence intervals (95% CIs) between PPH and risk of postpartum depressive symptoms. Results Of the 7734 respondents, 293 (3.8%) and 7441 were in the PPH and control groups, respectively. Puerperal women with PPH were more likely to screen positive for postpartum depressive symptoms than those without PPH (16.4% vs. 11.7%, p = .016). Adjusting for other covariates, women with PPH still had higher risk of postpartum depressive symptoms (OR = 1.68, 95% CI: 1.16–2.42). Stratification analyses revealed no interaction between PPH and maternal age, prepregnancy body mass index, mode of delivery, and fetal sex in developing depressive symptoms (p for interaction > .05). Conclusions PPH may increase the risk of postpartum depressive symptoms. Therefore, women with PPH should be actively screened for depressive symptoms in the immediate postpartum period.

Background Depression and anxiety disorders confer a significant public health concern for youth and their co‐occurrence places youth at a higher risk for poorer psychosocial outcomes. In the present study, we use network analysis to investigate the role of and interactions among individual depression and anxiety symptoms in a treatment‐seeking clinical sample. Methods We estimate regularized partial correlation networks for youth‐ and parent reported symptoms in a transdiagnostic sample of youth (N = 417, ages 8–18). We examined features of the symptom‐level networks such as network stability, centrality, bridge symptoms, and communities in both youth‐ and parent‐reported networks. Results Results indicate stable networks with disorder‐specific clustering, such that symptoms were more interconnected within compared to between disorders. Symptoms related to self‐comparison to peers and negative views of the future were most central in both networks. Symptoms of depression and anxiety were connected by worries for the future and hopelessness in the youth‐reported network, whereas self‐comparison to peers and low self‐efficacy were bridge symptoms in the parent network. Distinct symptom clusters emerged in the parent‐ and youth‐reported networks. Conclusions Our findings indicate that negative self‐evaluation, negative views of the future, and repetitive negative thinking more generally are influential symptoms in the presentation and co‐occurrence of depression and anxiety and as such may be promising targets in the treatment and prevention of depression and anxiety in youth.

Background Distinctions between major depressive disorder (MDD) and perinatal depression (PND) reflect varying views of PND, from a unique etiological subtype of MDD to an MDD episode that happens to coincide with childbirth. This case–control study investigated genetic differences between PND and MDD outside the perinatal period (non-perinatal depression or NPD). Methods We conducted a genome-wide association study using PND cases (Edinburgh Postnatal Depression Scale score ≥ 13) from the Australian Genetics of Depression Study 2018 data (n = 3804) and screened controls (n = 6134). Results of gene-set enrichment analysis were compared with those of women with non-PND. For six psychiatric disorders/traits, genetic correlations with PND were evaluated, and logistic regression analysis reported polygenic score (PGS) association with both PND and NPD. Results Genes differentially expressed in ovarian tissue were significantly enriched (stdBeta = 0.07, p = 3.3e−04), but were not found to be associated with NPD. The genetic correlation between PND and MDD was 0.93 (SE = 0.07; p = 3.5e−38). Compared with controls, PGS for MDD are higher for PND cases (odds ratio [OR] = 1.8, confidence interval [CI] = [1.7–1.8], p = 9.5e−140) than for NPD cases (OR = 1.6, CI = [1.5–1.7], p = 1.2e−49). Highest risk is for those reporting both antenatal and postnatal depression, irrespective of prior MDD history. Conclusions PND has a high genetic overlap with MDD, but points of distinction focus on differential expression in ovarian tissue and higher MDD PGS, particularly for women experiencing both antenatal and postpartum PND.

Background Despite evidence linking posttraumatic stress disorder (PTSD), depression, and head injury, separately, with worse cognitive performance, investigations of their combined effects on cognition are limited in civilian women. Methods The Cogstate Brief Battery assessment was administered in 10,681 women from the Nurses' Health Study II cohort, mean age 64.9 years (SD = 4.6). Psychological trauma, PTSD, depression, and head injury were assessed using online questionnaires. In this cross-sectional analysis, we used linear regression models to estimate mean differences in cognition by PTSD/depression status and stratified by history of head injury. Results History of head injury was prevalent (36%), and significantly more prevalent among women with PTSD and depression (57% of women with PTSD and depression, 21% of women with no psychological trauma or depression). Compared to having no psychological trauma or depression, having combined PTSD and depression was associated with worse performance on psychomotor speed/attention ( = −.15, p = .001) and learning/working memory ( = −.15, p < .001). The joint association of PTSD and depression on worse cognitive function was strongest among women with past head injury, particularly among those with multiple head injuries. Conclusions Head injury, like PTSD and depression, was highly prevalent in this sample of civilian women. In combination, these factors were associated with poorer performance on cognitive tasks, a possible marker of future cognitive health. Head injury should be further explored in future studies of PTSD, depression and cognition in women.

Objective To determine the prevalence of comorbid depression and anxiety symptoms in fathers and investigate the predictors for comorbidity during the first- and second-year following birth. Methods In a longitudinal Canadian study, couples were recruited within 3 weeks of childbirth. Fathers completed a survey after the birth of their child followed by questionnaires at 3, 6, 9, 12, 18, and 24 months postpartum on paternal depression and anxiety symptoms and potential risk factors. Sequential logistic regression was used for analysis. Results Of the 3217 enrolled fathers, 2544 (79.08%) provided data for at least one time point during the first year postpartum and 2442 (75.29%) in the second year. Overall, 569 fathers (22.4%) had comorbid depression and anxiety symptoms at some point during the first year postpartum (2.2% at baseline to 8.9% at 6 months), and 323 fathers (13.2%) had comorbidity at some point during their second year postpartum (8.1% at 18 months and 8.6% at 24 months). Strongest risk factors associated with paternal comorbidity were poor or fair perceived health at 4 weeks postpartum, depression before pregnancy, anxiety in the current pregnancy, significant adverse childhood experiences, positive ADHD screen, and victim of intimate partner violence. Conclusion High rates of comorbidity among fathers in the first 2 years postpartum demonstrate the importance of perinatal mental health management at a family level. The identification of important modifiable comorbidity risk factors highlights areas for further research and the development of interventions to support paternal mental health to optimize child and family outcomes.

Introduction Research suggests that certain parenting behaviors are best suited to promote optimal child development, depending on a child's distinctive temperamental presentation. This multimethod, longitudinal study examines the interactive effect of parenting and temperament in early childhood on the developmental trajectory of social anxiety in adolescence. Methods Longitudinal growth modeling was used to examine the developmental trajectory of child social anxiety from age 9–15 and the interactive effect of parenting and child temperament at 36 months on the developmental trajectory of child social anxiety from age 9–15. Results The slope of social anxiety from age 9–15 suggested a decrease in social anxiety throughout early adolescence. Furthermore, 36-month behavioral inhibition (BI) predicted the trajectory of child social anxiety from age 9–15 when parents displayed low and high levels of dismissive and supportive parenting (at 36 months). Conclusions Results support an interactive effect of infant temperament and parenting in early childhood (at 36 months) on the developmental trajectory of child social anxiety from age 9–15. Specifically, results suggest that engaging highly inhibited children with high supportive and low dismissive parenting may help reduce social anxiety over time in adolescence. Furthermore, parenting needs may differ for children high or low in BI to impact the developmental trajectory of social anxiety in adolescence, such that children who are high BI seem to benefit from low dismissive and high supportive parenting, and children who are low in BI seem to benefit more from high dismissive parenting.

Background The experience of sexual assault and harassment during military service (military sexual trauma [MST]) is associated with increased risk for perinatal and reproductive health problems among women veterans. The objective of this study was to examine the associations between mothers’ MST exposure and mother-infant bonding, as well as to examine whether there are any salient sociodemographic or military service characteristics among women veterans with greater impairment to mother-infant bonding, including stress during pregnancy and posttraumatic stress disorder (PTSD) diagnosis. Methods This study was a secondary analysis of data collected from prospective, longitudinal study of women veterans using VHA maternity care benefits at 15 VHA medical centers across the US between January 2016 and February 2020. Participants were 697 pregnant veterans using VHA maternity care benefits. Results MST was associated with higher maternal depression, and higher maternal depression was associated with poorer mother-infant bonding. The effect of MST on bonding was indirect through depression. PTSD diagnosis and life stressors during pregnancy also had significant indirect pathways with bonding through maternal depression. Conclusions Results underscore the need for access to high quality and trauma-informed perinatal mental health treatment for women veterans, for education on the unique risks conveyed by MST provided to civilian providers treating this population outside VA, and for further research to understand how to ameliorate the harmful effects of MST on perinatal women veterans and their children.

Background Previous research indicates that social support, loneliness, and major depressive disorder (MDD) are interrelated. Little is known about the potential pathways among these factors, in particular in the case of adults aged 50 years and older and suffering from MDD. The objective was to investigate whether loneliness mediates the association between low social support and recurrent episodes of MDD. Methods We used data from a cohort of the Spanish general population interviewed at three time‐points over a 7‐year period. We included 404 individuals aged 50+ suffering from MDD in the baseline assessment. A 12‐month major depressive episode was assessed with the Composite International Diagnostic Interview (CIDI) at each interview. The University of California, Los Angeles Loneliness Scale was used to measure loneliness, whereas social support was assessed through the Oslo Social Support Scale. We tested cross‐lagged and autoregressive longitudinal associations using structural equation modeling. Results We identified two significant longitudinal mediation patterns: lower social support predicted higher subsequent levels of loneliness (Coef. = −0.16; p < .05), which in turn predicted an increase in MDD recurrence (Coef. = 0.05; p < .05). Conclusions Interventions focused on promoting social support among older adults suffering from MDD may decrease feelings of loneliness and prevent recurrent episodes of MDD.