Reciprocal and Indirect Effects Among Intervention, Perceived Social Support, and Anxiety Sensitivity Within a Randomized Controlled Trial for Anxiety Disorders.

Social support may facilitate adaptive reappraisal of stressors, including somatic symptoms. Anxiety sensitivity refers to negative beliefs about somatic symptoms of anxiety, which may influence one's perception of social support. Evidence-based treatment may impact these associations. The current longitudinal study evaluated reciprocal relationships between perceived social support and anxiety sensitivity, and explored indirect intervention effects, in a randomized controlled trial for anxiety disorders that compared cognitive behavioral therapy with or without medications (CALM) to usual care. Data collected over 18 months from 940 primary care patients were examined in random intercept cross-lagged panel models. There were significant reciprocal associations between perceived social support increases and anxiety sensitivity decreases over time. There were significant indirect effects from intervention to perceived social support increases through anxiety sensitivity decreases and from intervention to anxiety sensitivity decreases through perceived social support increases. These data suggest that, relative to usual care, CALM predicted changes in one construct, which predicted subsequent changes in the other. Secondary analyses revealed an influence of anxiety and depressive symptoms on reciprocal associations and indirect effects. Findings suggest that future treatments could specifically address perceived social support to enhance reappraisal of somatic symptoms, and vice versa.

Mediators of Ethnic Differences in Dropout Rates From a Randomized Controlled Treatment Trial Among Latinx and Non-Latinx White Primary Care Patients With Anxiety Disorders.

ABSTRACT: Disparities in treatment engagement and adherence based on ethnicity have been widely recognized but are inadequately understood. Few studies have examined treatment dropout among Latinx and non-Latinx White (NLW) individuals. Using Andersen's Behavioral Model of Health Service Use (A behavioral model of families' use of health services. 1968; J Health Soc Behav. 1995; 36:1-10) as a framework, we examine whether pretreatment variables (categorized as predisposing, enabling, and need factors) mediate the relationship between ethnicity and premature dropout in a sample of Latinx and NLW primary care patients with anxiety disorders who participated in a randomized controlled trial (RCT) of cognitive behavioral therapy. Data from a total of 353 primary care patients were examined; 96 Latinx and 257 NLW patients participated. Results indicated that Latinx patients dropped out of treatment more often than NLW patients, resulting in roughly 58% of Latinx patients failing to complete treatment compared with 42% of NLW, and approximately 29% of Latinx patients dropping out before engaging in modules related to cognitive restructuring or exposure, relative to 11% of NLW patients. Mediation analyses suggest that social support and somatization partially explained the relationship between ethnicity and treatment dropout, highlighting the importance of these variables in understanding treatment disparities.

Prospective relations between anxiety sensitivity and transdiagnostic anxiety following cognitive-behavioral therapy: Evidence from the Coordinated Anxiety Learning management trial.

Previous research has implicated reductions in anxiety sensitivity (AS) - the dispositional tendency to fear anxiety-related sensations - as critical to change during cognitive behavioral therapy (CBT) for anxiety. However, the relationship of AS to anxiety symptom remittance following CBT remains largely unknown. To address this gap, the current study evaluated prospective associations between AS and symptoms of various anxiety disorders following completion of the Coordinated Anxiety Learning and Management (CALM) study- a large clinical trial evaluating the efficacy of a brief, computer-facilitated CBT intervention for transdiagnostic anxiety within primary care. Participants were randomized to CALM (n = 460) or a control treatment (n = 501) and completed self-report measures of general and disorder-specific anxiety symptoms at pretreatment and at 6-month, 12-month, and 18-month follow-up. Longitudinal relations between AS and each anxiety measure across timepoints and within each treatment group were assessed using cross-lagged panel models. Results indicated that higher AS following CALM predicted greater anxiety symptoms at the subsequent timepoint for all anxiety symptoms except social anxiety symptoms. Higher anxiety following treatment also predicted later AS. These findings implicate AS as an indicator of transdiagnostic anxiety remittance and suggest that targeting AS could be useful for reducing clinical anxiety relapse following CBT.

Examining Individual and Synergistic Contributions of PTSD and Genetics to Blood Pressure: A Trans-Ethnic Meta-Analysis.

Growing research suggests that posttraumatic stress disorder (PTSD) may be a risk factor for poor cardiovascular health, and yet our understanding of who might be at greatest risk of adverse cardiovascular outcomes after trauma is limited. In this study, we conducted the first examination of the individual and synergistic contributions of PTSD symptoms and blood pressure genetics to continuous blood pressure levels. We harnessed the power of the Psychiatric Genomics Consortium-PTSD Physical Health Working Group and investigated these associations across 11 studies of 72,224 trauma-exposed individuals of European (n = 70,870) and African (n = 1,354) ancestry. Genetic contributions to blood pressure were modeled via polygenic scores (PGS) for systolic blood pressure (SBP) and diastolic blood pressure (DBP) that were derived from a prior trans-ethnic blood pressure genome-wide association study (GWAS). Results of trans-ethnic meta-analyses revealed significant main effects of the PGS on blood pressure levels [SBP: ß = 2.83, standard error (SE) = 0.06, p < 1E-20; DBP: ß = 1.32, SE = 0.04, p < 1E-20]. Significant main effects of PTSD symptoms were also detected for SBP and DBP in trans-ethnic meta-analyses, though there was significant heterogeneity in these results. When including data from the largest contributing study - United Kingdom Biobank - PTSD symptoms were negatively associated with SBP levels (ß = -1.46, SE = 0.44, p = 9.8E-4) and positively associated with DBP levels (ß = 0.70, SE = 0.26, p = 8.1E-3). However, when excluding the United Kingdom Biobank cohort in trans-ethnic meta-analyses, there was a nominally significant positive association between PTSD symptoms and SBP levels (ß = 2.81, SE = 1.13, p = 0.01); no significant association was observed for DBP (ß = 0.43, SE = 0.78, p = 0.58). Blood pressure PGS did not significantly moderate the associations between PTSD symptoms and blood pressure levels in meta-analyses. Additional research is needed to better understand the extent to which PTSD is associated with high blood pressure and how genetic as well as contextual factors may play a role in influencing cardiovascular risk.

Genomic influences on self-reported childhood maltreatment.

Childhood maltreatment is highly prevalent and serves as a risk factor for mental and physical disorders. Self-reported childhood maltreatment appears heritable, but the specific genetic influences on this phenotype are largely unknown. The aims of this study were to (1) identify genetic variation associated with self-reported childhood maltreatment, (2) estimate SNP-based heritability (h2snp), (3) assess predictive value of polygenic risk scores (PRS) for childhood maltreatment, and (4) quantify genetic overlap of childhood maltreatment with mental and physical health-related phenotypes, and condition the top hits from our analyses when such overlap is present. Genome-wide association analysis for childhood maltreatment was undertaken, using a discovery sample from the UK Biobank (UKBB) (n = 124,000) and a replication sample from the Psychiatric Genomics Consortium-posttraumatic stress disorder group (PGC-PTSD) (n = 26,290). h2snp for childhood maltreatment and genetic correlations with mental/physical health traits were calculated using linkage disequilibrium score regression. PRS was calculated using PRSice and mtCOJO was used to perform conditional analysis. Two genome-wide significant loci associated with childhood maltreatment (rs142346759, p = 4.35 × 10-8, FOXP1; rs10262462, p = 3.24 × 10-8, FOXP2) were identified in the discovery dataset but were not replicated in PGC-PTSD. h2snp for childhood maltreatment was ~6% and the PRS derived from the UKBB was significantly predictive of childhood maltreatment in PGC-PTSD (r2 = 0.0025; p = 1.8 × 10-15). The most significant genetic correlation of childhood maltreatment was with depressive symptoms (rg = 0.70, p = 4.65 × 10-40), although we show evidence that our top hits may be specific to childhood maltreatment. This is the first large-scale genetic study to identify specific variants associated with self-reported childhood maltreatment. Speculatively, FOXP genes might influence externalizing traits and so be relevant to childhood maltreatment. Alternatively, these variants may be associated with a greater likelihood of reporting maltreatment. A clearer understanding of the genetic relationships of childhood maltreatment, including particular abuse subtypes, with a range of phenotypes, may ultimately be useful in in developing targeted treatment and prevention strategies.

Genome-wide profiling of DNA methylome and transcriptome in peripheral blood monocytes for major depression: A Monozygotic Discordant Twin Study.

DNA methylation plays an important role in major depressive disorder (MDD), but the specific genes and genomic regions associated with MDD remain largely unknown. Here we conducted genome-wide profiling of DNA methylation (Infinium MethylationEPIC BeadChip) and gene expression (RNA-seq) in peripheral blood monocytes from 79 monozygotic twin pairs (mean age 38.2 ± 15.6 years) discordant on lifetime history of MDD to identify differentially methylated regions (DMRs) and differentially expressed genes (DEGs) associated with MDD, followed by replication in brain tissue samples. Integrative DNA methylome and transcriptome analysis and network analysis was performed to identify potential functional epigenetic determinants for MDD. We identified 39 DMRs and 30 DEGs associated with lifetime history of MDD. Some genes were replicated in postmortem brain tissue. Integrative DNA methylome and transcriptome analysis revealed both negative and positive correlations between DNA methylation and gene expression, but the correlation pattern varies greatly by genomic locations. Network analysis revealed distinct gene modules enriched in signaling pathways related to stress responses, neuron apoptosis, insulin receptor signaling, mTOR signaling, and nerve growth factor receptor signaling, suggesting potential functional relevance to MDD. These results demonstrated that altered DNA methylation and gene expression in peripheral blood monocytes are associated with MDD. Our results highlight the utility of using peripheral blood epigenetic markers and demonstrate that a monozygotic discordant co-twin control design can aid in the discovery of novel genes associated with MDD. If validated, the newly identified genes may serve as novel biomarkers or druggable targets for MDD and related disorders.

Doubly Randomized Preference Trial of Prolonged Exposure Versus Sertraline for Treatment of PTSD.

OBJECTIVE: The authors examined the effect of patient treatment preference on the differential effectiveness of prolonged exposure and sertraline for the treatment of posttraumatic stress disorder (PTSD). METHOD: In a doubly randomized preference trial, 200 patients with PTSD viewed standardized treatment rationales prior to randomization. Patients were first randomized to choice of treatment or no choice. Those assigned to no choice were then randomized to prolonged exposure or sertraline. Acute treatment was 10 weeks, with 24-month follow-up. Interviewer-rated PTSD symptom severity was the main outcome measure, and depression, anxiety, and functioning were assessed as additional outcomes. RESULTS: Patients preferred prolonged exposure over sertraline (number needed to benefit [NNTB]=4.5). Using intent-to-treat analyses (N=200), both prolonged exposure and sertraline showed large gains that were maintained over 24 months. Although no differential effect was observed on interviewer-rated PTSD severity, there was a significant benefit of prolonged exposure over sertraline on interview-rated loss of PTSD diagnosis (NNTB=7.0), responder status (NNTB=5.7), and self-reported PTSD, depression, and anxiety symptoms and functioning (effect sizes, 0.35-0.44). Patients who received their preferred treatment were more likely to be adherent, lose their PTSD diagnosis (NNTB=3.4), achieve responder status (NNTB=3.4), and have lower self-reported PTSD, depression, and anxiety symptoms (effect sizes, 0.40-0.72). CONCLUSIONS: Prolonged exposure and sertraline confer significant benefits for PTSD, with some evidence of an advantage for prolonged exposure. Giving patients with PTSD their preferred treatment also confers important benefits, including enhancing adherence.

Study Design and Rationale for the Mood and Methylation Study: A Platform for Multi-Omics Investigation of Depression in Twins.

Major depression is a complex disorder with no single, direct causal mechanism. Morbidity has been linked to genetic processes, developmental history, and unique environmental exposures. Epigenetic mechanisms, especially DNA methylation, are also likely important factors in the pathogenesis of major depressive disorder (MDD). A community-based twin sample has many advantages for epigenetic studies, given the shared genetic and developmental histories of same-sex twin pairs. This article describes the rationale and study design for the Mood and Methylation Study in which 133 twin pairs (101 monozygotic and 32 dizygotic), both discordant and concordant for lifetime history of MDD, were evaluated on a large number of variables related to MDD. The twins also provided blood samples for an epigenome-wide association study of differentially methylated regions (DMR) relevant to MDD. Although MDD is typically considered a disorder of the central nervous system, it is unfeasible to obtain a large sample of brain tissues. However, epigenetic variation is not limited to the affected tissue but can also be detected in peripheral blood leukocytes. Thus, this study focused on monocytes for the major analyses. Additional plans for the study include gene expression analysis from the same set of twins using RNA-seq and validation of significant DMRs in postmortem brain tissues from a separate sample. Moreover, sufficient samples have been collected to perform future 'multi-omic' analyses, including metabolome, microbiome, and transcriptome. Our long-term goal is to understand how epigenomic and other 'omic' factors can be manipulated for diagnostic, preventive, and therapeutic purposes for MDD and its related conditions.

High expectancy and early response produce optimal effects in sertraline treatment for post-traumatic stress disorder.

BACKGROUND: Better indicators of prognosis are needed to personalise post-traumatic stress disorder (PTSD) treatments.AimsWe aimed to evaluate early symptom reduction as a predictor of better outcome and examine predictors of early response. METHOD: Patients with PTSD (N = 134) received sertraline or prolonged exposure in a randomised trial. Early response was defined as 20% PTSD symptom reduction by session two and good end-state functioning defined as non-clinical levels of PTSD, depression and anxiety. RESULTS: Early response rates were similar in prolonged exposure and sertraline (40 and 42%), but in sertraline only, early responders were four times more likely to achieve good end-state functioning at post-treatment (Number Needed to Treat = 1.8, 95% CI 1.28-3.00) and final follow-up (Number Needed to Treat = 3.1, 95% CI 1.68-16.71). Better outcome expectations of sertraline also predicted higher likelihood of early response. CONCLUSIONS: Higher expectancy of sertraline coupled with early response may produce a cascade-like effect for optimal conditions for long-term symptom reduction. Therefore, assessing expectations and providing clear treatment rationales may optimise sertraline effects. DECLARATION OF INTEREST: None.

Change in anxiety sensitivity and substance use coping motives as putative mediators of treatment efficacy among substance users.

OBJECTIVE: Anxiety sensitivity and coping motives for substance use are processes implicated in anxiety and substance use disorder (SUD) comorbidity, and are malleable treatment targets. Little is known about whether changes in anxiety sensitivity or coping motives during cognitive behavioral therapy (CBT) for anxiety disorders (with or without CBT for SUD) mediate substance use outcomes among patients with comorbid anxiety disorders and SUD. We examined whether changes in anxiety sensitivity and coping motives during treatment for comorbid SUD and anxiety disorders (either CBT for SUD only or CBT for SUD and anxiety disorders) were associated with substance use outcomes. METHODS: Repeated measurements of anxiety sensitivity and coping motives throughout treatment were examined from a randomized clinical trial comparing usual, CBT-based treatment at a substance use disorder specialty clinic (UC) to that usual care plus a brief CBT for anxiety program for patients with comorbid anxiety and substance use disorders (CALM ARC). RESULTS: Anxiety sensitivity decline during treatment was significantly steeper among those who received CALM ARC than those in UC. Decreases in anxiety sensitivity mediated the effect of treatment group on alcohol use following treatment such that the greater reduction in anxiety sensitivity in CALM ARC explained the superior outcomes for alcohol use in CALM ARC compared to UC. Declines in substance use coping motives were not observed in either condition, and did not differ between CALM ARC and UC. Thus, declines in coping motives did not mediate substance use after treatment. CONCLUSIONS: These findings provide preliminary evidence suggesting alcohol use outcomes were related to decreasing anxiety sensitivity rather than decreasing coping motives. Implications and future directions are discussed.

Who needs more than standard care? Treatment moderators in a randomized clinical trial comparing addiction treatment alone to addiction treatment plus anxiety disorder treatment for comorbid anxiety and substance use disorders.

INTRODUCTION: Understanding for whom treatments exert their greatest effects is crucial for prescriptive recommendations that can improve overall treatment efficacy. Anxiety and substance use disorder comorbidity is prevalent and a significant public health concern. Little is known about who should receive specialized, integrated treatments to address both problems. This study aimed to examine baseline patient characteristics that predict differential outcome between typical treatment for substance use disorders (UC) compared to that treatment combined with cognitive behavioral therapy for anxiety disorders (UC + CALM ARC). METHODS: We examined several putative treatment moderators in a dataset of community-based participants (N = 75) from a randomized clinical trial at an outpatient community substance use disorder (SUD) specialty clinic. Participants who met criteria for any anxiety disorder and any SUD were randomized to UC (the Intensive Outpatient Program at the clinic) or UC + CALM ARC. Outcome measures included anxiety symptoms, drug use, and alcohol use, and were assessed at pre-treatment, post-treatment, and a 6-month follow-up assessment. RESULTS: Older age and female gender were associated with greater improvement on anxiety outcomes in UC + CALM ARC compared to UC. The presence of an alcohol use disorder was associated with greater improvement in alcohol use in UC + CALM ARC compared to UC. Higher opiate-related withdrawal symptoms and the presence of more SUDs were associated with greater improvement in drug use outcomes in UC + CALM ARC compared to UC. CONCLUSIONS: Several pre-treatment characteristics are associated with a return of symptoms for those who receive only UC, whereas the addition of CALM ARC prevented the return of symptoms. Implications for future research and preliminary clinical recommendations are discussed.

Childhood Trauma, DNA Methylation of Stress-Related Genes, and Depression: Findings From Two Monozygotic Twin Studies.

OBJECTIVE: DNA methylation has been associated with both early life stress and depression. This study examined the combined association of DNA methylation at multiple CpG probes in five stress-related genes with depressive symptoms and tested whether these genes methylation mediated the association between childhood trauma and depression in two monozygotic (MZ) twin studies. METHODS: The current analysis comprised 119 MZ twin pairs (84 male pairs [mean = 55 years] and 35 female pairs [mean = 36 years]). Peripheral blood DNA methylation of five stress-related genes (BDNF, NR3C1, SLC6A4, MAOA, and MAOB) was quantified by bisulfite pyrosequencing or 450K BeadChip. We applied generalized Poisson linear-mixed models to examine the association between each single CpG methylation and depressive symptoms. The joint associations of multiple CpGs in a single gene or all five stress-related genes as a pathway were tested by weighted truncated product method. Mediation analysis was conducted to test the potential mediating effect of stress gene methylation on the relationship between childhood trauma and depressive symptoms. RESULTS: Multiple CpG probes showed nominal individual associations, but very few survived multiple testing. Gene-based or gene-set approach, however, revealed significant joint associations of DNA methylation in all five stress-related genes with depressive symptoms in both studies. Moreover, two CpG probes in the BDNF and NR3C1 mediated approximately 20% of the association between childhood trauma and depressive symptoms. CONCLUSIONS: DNA methylation at multiple CpG sites are jointly associated with depressive symptoms and partly mediates the association between childhood trauma and depression. Our results highlight the importance of testing the combined effects of multiple CpG loci on complex traits and may unravel a molecular mechanism through which adverse early life experiences are biologically embedded.

Cultural influences on mental health symptoms in a primary care sample of Latinx patients.

The present study examines how both between group (i.e., ethnic group membership) and within group cultural factors (i.e., nativity status, age of immigration, and perceived discrimination) may contribute to anxiety and related symptoms in Latinx with anxiety disorders. Baseline data were examined from patients who participated in one of the largest intervention studies for adults with anxiety disorders in primary care settings; 196 Latinx and 568 NLW (non-Latinx White) patients participated. Proportions of anxiety disorders were similar between Latinx and NLWs; however, Latinx, on average, had a greater number of anxiety disorders than NLWs. Levels of anxiety and depression symptom severity, anxiety sensitivity, and mental functional impairment were similar between the ethnic groups. Latinx expressed greater somatization and physical functional impairment than NLWs. Among Latinx, perceived discrimination, but not other cultural variables, was predictive of mental health symptoms while controlling for age, gender, education, and poverty. Overall, these findings suggest more similarities than differences in types and levels of anxiety and anxiety-related impairment, with some important exceptions, including greater levels of somatization and physical functional impairment among Latinx patients. Further, perceived discrimination may be an important factor to consider when examining risk for greater symptom burden among Latinx with anxiety.

Randomized clinical trial evaluating the preliminary effectiveness of an integrated anxiety disorder treatment in substance use disorder specialty clinics.

OBJECTIVE: Anxiety and substance use disorders are highly comorbid and mutually maintain each other. Treatments for anxiety disorders that are well integrated into substance use disorder treatment have the potential to improve both anxiety and substance use outcomes. METHOD: Ninety-seven individuals seeking treatment at a community-based, evidence-based intensive outpatient program for substance use disorders who also had anxiety disorders were randomized to either (a) usual care (UC) at the intensive outpatient program; or (b) UC + coordinated anxiety learning and management for addiction recovery centers (CALM ARC), a 7-session, group-based, computer-assisted but therapist-directed treatment for anxiety disorders adapted for individuals with anxiety disorder and substance use disorder comorbidity. RESULTS: CALM ARC + UC outperformed UC on measures of anxiety and substance use at posttreatment and at a 6-month follow-up. CONCLUSIONS: Adding CALM ARC to UC for patients with comorbid anxiety disorders and substance use disorders is superior to UC alone. Implications for future research and clinical practice are discussed. (PsycINFO Database Record

Age Differences in Death and Suicidal Ideation in Anxious Primary Care Patients.

OBJECTIVES: The objective of this study was to examine age differences in the likelihood of endorsing of death and suicidal ideation in primary care patients with anxiety disorders. METHOD: Participants were drawn from the Coordinated Anxiety Learning and Management (CALM) Study, an effectiveness trial for primary care patients with panic disorder (PD), generalized anxiety disorder (GAD), post-traumatic stress disorder (PTSD), and/or social anxiety disorder (SAD). RESULTS: Approximately one third of older adults with anxiety disorders reported feeling like they were better off dead. Older adults with PD and SAD were more likely to endorse suicidal ideation lasting at least more than half the prior week compared with younger adults with these disorders. Older adults with SAD endorsed higher rates of suicidal ideation compared with older adults with other anxiety disorders. Multivariate analyses revealed the importance of physical health, social support, and comorbid MDD in this association. CONCLUSIONS: Suicidal ideation is common in anxious, older, primary care patients and is particularly prevalent in socially anxious older adults. Findings speak to the importance of physical health, social functioning, and MDD in this association. CLINICAL IMPLICATIONS: When working with anxious older adults it is important to conduct a thorough suicide risk assessment and teach skills to cope with death and suicidal ideation-related thoughts.

Advancing Personalized Medicine: Application of a Novel Statistical Method to Identify Treatment Moderators in the Coordinated Anxiety Learning and Management Study.

There has been increasing recognition of the value of personalized medicine where the most effective treatment is selected based on individual characteristics. This study used a new method to identify a composite moderator of response to evidence-based anxiety treatment (CALM) compared to Usual Care. Eight hundred seventy-six patients diagnosed with one or multiple anxiety disorders were assigned to CALM or Usual Care. Using the method proposed by Kraemer (2013), 35 possible moderators were examined for individual effect sizes then entered into a forward-stepwise regression model predicting differential treatment response. K-fold cross validation was used to identify the number of variables to include in the final moderator. Ten variables were selected for a final composite moderator. The composite moderator effect size (r = .20) was twice as large as the strongest individual moderator effect size (r = .10). Although on average patients benefitted more from CALM, 19% of patients had equal or greater treatment response in Usual Care. The effect size for the CALM intervention increased from d = .34 to d = .54 when accounting for the moderator. Findings support the utility of composite moderators. Results were used to develop a program that allows mental health professionals to prescribe treatment for anxiety based on baseline characteristics (http://anxiety.psych.ucla.edu/treatmatch.html).

Changes in Physical Activity Barriers among American Indian Elders: A Pilot Study​.

The objective of the present study was to assess whether selfreported physical activity barriers could be reduced among American Indian elders who participated in a 6-week randomized physical activity trial that compared the use of a pedometer only to that of pedometers with step-count goal setting. Elders (N = 32) were compared on the Barriers to Being Physically Active Quiz after participating in a pilot physical activity trial. Elders were classified into high- and low-barrier groups at baseline and compared on self-reported physical activity, health-related quality of life, pedometer step counts, and 6-minute walk performance. At the conclusion of the 6-week trial, only the lack of willpower subscale significantly decreased. The low-barrier group reported significantly higher physical activity engagement and improved mental health quality of life than the high-barrier group. The groups did not differ on daily step counts or 6-minute walk performance. Additional research is needed with a larger sample to understand relevant activity barriers in this population and assess whether they can be modified through participation in structured physical activity and exercise programs.