Brain Regulation Of Emotional Conflict Predicts Antidepressant Treatment Response For Depression

The efficacy of antidepressant treatment for depression is controversial due to the only modest superiority demonstrated over placebo. However, neurobiological heterogeneity within depression may limit overall antidepressant efficacy. We sought to identify a neurobiological phenotype responsive to antidepressant treatment by testing pretreatment brain activation during response to, and regulation of, emotional conflict as a moderator of the clinical benefit of the antidepressant sertraline versus placebo. Using neuroimaging data from a large randomized controlled trial, we found widespread moderation of clinical benefits by brain activity during regulation of emotional conflict, in which greater downregulation of conflict-responsive regions predicted better sertraline outcomes. Treatment-predictive machine learning using brain metrics outperformed a model trained on clinical and demographic variables. Our findings demonstrate that antidepressant response is predicted by brain activity underlying a key self-regulatory emotional capacity. Leveraging brain-based measures in psychiatry will forge a path toward better treatment personalization, refined mechanistic insights and improved outcomes

The Concise Health Risk Tracking-self Report: Psychometrics Within A Placebo-controlled Antidepressant Trial Among Depressed Outpatients

Background/aims: While substantial prior research has evaluated the psychometric properties of the 12-item Concise Health Risk Tracking-Self Report (CHRT-SR12), a measure of suicide propensity and suicidal thoughts, no prior research has investigated its factor structure, sensitivity to change over time, and other psychometric properties in a placebo-controlled trial of antidepressant medication, nor determined whether symptoms change throughout treatment. Methods: Participants in the multi-site Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study (n=278) provided data to evaluate the factor structure and sensitivity to change over time of the CHRT-SR12 through eight weeks of a clinical trial in which participants received either placebo or antidepressant medication (sertraline). Results/Outcomes: Factor analysis confirmed two factors: propensity (comprised of first-order factors including pessimism, helplessness, social support, and despair) and suicidal thoughts. Internal consistency (α’s ranged from 0.69–0.92) and external validity were both acceptable, with the total score and propensity factor scores significantly correlated with total scores and single-item suicidal-thoughts scores on the self-report Quick Inventory of Depressive Symptoms and the clinician-rated 17-item Hamilton Rating Scale for Depression. Through analyzing CHRT-SR12 changes over eight treatment weeks, the total score and both the factors decreased regardless of baseline suicidal thoughts. Change in clinician-rated suicidal thoughts was reflected by change in both the total score and propensity factor score. Conclusions/interpretation: These results confirm the reliability, validity, and applicability of the CHRT-SR12 to a placebo-controlled clinical trial of depressed outpatients receiving antidepressant medication

Pretreatment Rostral Anterior Cingulate Cortex Theta Activity In Relation To Symptom Improvement In Depression: A Randomized Clinical Trial

OBJECTIVE To determine whether increased pretreatment rACC theta activity would predict symptom improvement regardless of randomization arm. DESIGN, SETTING, AND PARTICIPANTS A multicenter randomized clinical trial enrolled outpatients without psychosis and with chronic or recurrent MDD between July 29, 2011, and December 15, 2015 (Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care [EMBARC]). Patients were consecutively recruited from 4 university hospitals: 634 patients were screened, 296 were randomized to receive sertraline hydrochloride or placebo, 266 had electroencephalographic (EEG) recordings, and 248 had usable EEG data. Resting EEG data were recorded at baseline and 1 week after trial onset, and rACC theta activity was extracted using source localization. Intent-to-treat analysis was conducted. Data analysis was performed from October 7, 2016, to January 19, 2018. INTERVENTIONS An 8-week course of sertraline or placebo. MAIN OUTCOMES AND MEASURES The 17-item Hamilton Rating Scale for Depression score (assessed at baseline and weeks 1, 2, 3, 4, 6, and 8). RESULTS The 248 participants (160 [64.5%] women, 88 [35.5%] men) with usable EEG data had a mean (SD) age of 36.75 (13.15) years. Higher rACC theta activity at both baseline (b=−1.05; 95% CI, −1.77 to −0.34; P = .004) and week 1 (b=−0.83; 95% CI, −1.60 to −0.06; P < .04) predicted greater depressive symptom improvement, even when controlling for clinical and demographic variables previously linked with treatment outcome. These effects were not moderated by treatment arm. The rACC theta marker, in combination with clinical and demographic variables, accounted for an estimated 39.6% of the variance in symptom change (with 8.5% of the variance uniquely attributable to the rACC theta marker). CONCLUSIONS AND RELEVANCE Increased pretreatment rACC theta activity represents a nonspecific prognostic marker of treatment outcome. This is the first study to date to demonstrate that rACC theta activity has incremental predictive validity

Characterizing Anxiety Subtypes And The Relationship To Behavioral Phenotyping In Major Depression: Results From The Embarc Study

The current study aimed to characterize the multifaceted nature of anxiety in patients with major depression by evaluating distinct anxiety factors. We then related these derived anxiety factors to performance on a Flanker Task of cognitive control, in order to further validate these factors. Data were collected from 195 patients with nonpsychotic chronic or recurrent major depression or dysthymic disorder. At baseline, participants completed self-report measures of anxiety, depression, and other related symptoms (mania, suicidality) and clinicians administered a structured diagnostic interview and the Hamilton Rating Scale for Depression, including anxiety/ somatization items. Four discrete factors (State Anxiety, Panic, Neuroticism/Worry, and Restlessness/Agitation) emerged, with high degrees of internal consistency. Discriminant and convergent validity analyses also yielded findings in the expected direction. Furthermore, the neuroticism/worry factor was associated with Flanker Task interference, such that individuals higher on neuroticism/worry responded more incorrectly (yet faster) to incongruent vs. congruent trials whereas individuals higher on the fear/panic factor responded more slowly, with no accuracy effect, to the Flanker Task stimuli. These results parse anxiety into four distinct factors that encompass physiological, psychological, and cognitive components of anxiety. While state anxiety, panic and neuroticism/worry are related to existing measures of anxiety, the Restlessness/Agitation factor appears to be a unique measure of general anxious arousal. Furthermore, two factors were independently validated through the Flanker Task. These results suggest that these anxiety domains have distinct behavioral profiles and could have differential responses to distinct treatments

Depression and Relationship Dysfunction from Adolescence to Adulthood

This project employs a developmental framework guided by interpersonal theories of depression and the transmission of intimate relationship dysfunction to offspring. We use two datasets to consider the independent and interactive impact of depression history, parental divorce and conflict, and relationship quality with parents on subsequent intimate relationship functioning from adolescence throughout the first eight years of marriage. The first study, using a longitudinal sample of adolescents, determined that participant/maternal relationship quality and parental marital stability predicted relationship conflict and satisfaction approximately 13 years later. Furthermore, adolescent depression history amplified the effect of some family-of-origin variables on some relationship outcomes. Study 2, using a longitudinal sample of newlywed couples, found that neither depression history nor family-of-origin variables predicted or interacted to enhance risky partner selection (with partner's risk defined through a factor- analyzed construct of emotion dysregulation). Instead, one's own level of risk was a strong predictor of partner's risk, supportive assortative mating theories. Study 3, again using the longitudinal newlywed sample, examined which components of intimate relationship communication predicted depressive symptoms approximately eight years later. Results demonstrated that participant's post-interaction evaluations of a negative mood were more consistent predictors of future depression than externally-rated communication behaviors, affect or skills, for both men and women. In addition, among men, a history of clinical or subclinical depression amplified the association between participant's negative evaluations of marital interactions and subsequent depressive symptoms. Taken together, these results suggest that factors well before relationship entry (i.e., psychopathology, familial functioning, emotion dysregulation) impact the quality of later intimate relationships, as well as characteristics of selected relationship partners. Furthermore, we provide evidence supporting attending to participant's evaluations and interpretations of marital interactions as predictors of later depressive symptoms beyond the content of this interpersonal communication

Marital quality and health: A meta-analytic review.

This meta-analysis reviewed 126 published empirical articles over the past 50 years describing associations between marital relationship quality and physical health in over 72,000 individuals. Health outcomes included clinical endpoints (objective assessments of function, disease severity, and mortality; subjective health assessments) and surrogate endpoints (biological markers that substitute for clinical endpoints, such as blood pressure). Biological mediators included cardiovascular reactivity and hypothalamic-pituitary-adrenal axis activity. Greater marital quality was related to better health, with mean effect sizes from r = .07 to .21, including lower risk of mortality, r = .11, and lower cardiovascular reactivity during marital conflict, r = −.13, but not daily cortisol slopes or cortisol reactivity during conflict. The small effect sizes were similar in magnitude to previously found associations between health behaviors (e.g., diet) and health outcomes. Effect sizes for a small subset of clinical outcomes were susceptible to publication bias. In some studies, effect sizes remained significant after accounting for confounds such as age and socioeconomic status. Studies with a higher proportion of women in the sample demonstrated larger effect sizes, but we found little evidence for gender differences in studies that explicitly tested gender moderation, with the exception of surrogate endpoint studies. Our conclusions are limited by small numbers of studies for specific health outcomes, unexplained heterogeneity, and designs that limit causal inferences. These findings highlight the need to explicitly test affective, health behavior, and biological mechanisms in future research, and focus on moderating factors that may alter the relationship between marital quality and health

Marital quality and health: a meta-analytic review.

This meta-analysis reviewed 126 published empirical articles over the past 50 years describing associations between marital relationship quality and physical health in more than 72,000 individuals. Health outcomes included clinical endpoints (objective assessments of function, disease severity, and mortality; subjective health assessments) and surrogate endpoints (biological markers that substitute for clinical endpoints, such as blood pressure). Biological mediators included cardiovascular reactivity and hypothalamic-pituitary-adrenal axis activity. Greater marital quality was related to better health, with mean effect sizes from r = .07 to .21, including lower risk of mortality (r = .11) and lower cardiovascular reactivity during marital conflict (r = -.13), but not daily cortisol slopes or cortisol reactivity during conflict. The small effect sizes were similar in magnitude to previously found associations between health behaviors (e.g., diet) and health outcomes. Effect sizes for a small subset of clinical outcomes were susceptible to publication bias. In some studies, effect sizes remained significant after accounting for confounds such as age and socioeconomic status. Studies with a higher proportion of women in the sample demonstrated larger effect sizes, but we found little evidence for gender differences in studies that explicitly tested gender moderation, with the exception of surrogate endpoint studies. Our conclusions are limited by small numbers of studies for specific health outcomes, unexplained heterogeneity, and designs that limit causal inferences. These findings highlight the need to explicitly test affective, health behavior, and biological mechanisms in future research, and focus on moderating factors that may alter the relationship between marital quality and health

Marital quality and health: a meta-analytic review.

This meta-analysis reviewed 126 published empirical articles over the past 50 years describing associations between marital relationship quality and physical health in more than 72,000 individuals. Health outcomes included clinical endpoints (objective assessments of function, disease severity, and mortality; subjective health assessments) and surrogate endpoints (biological markers that substitute for clinical endpoints, such as blood pressure). Biological mediators included cardiovascular reactivity and hypothalamic-pituitary-adrenal axis activity. Greater marital quality was related to better health, with mean effect sizes from r = .07 to .21, including lower risk of mortality (r = .11) and lower cardiovascular reactivity during marital conflict (r = -.13), but not daily cortisol slopes or cortisol reactivity during conflict. The small effect sizes were similar in magnitude to previously found associations between health behaviors (e.g., diet) and health outcomes. Effect sizes for a small subset of clinical outcomes were susceptible to publication bias. In some studies, effect sizes remained significant after accounting for confounds such as age and socioeconomic status. Studies with a higher proportion of women in the sample demonstrated larger effect sizes, but we found little evidence for gender differences in studies that explicitly tested gender moderation, with the exception of surrogate endpoint studies. Our conclusions are limited by small numbers of studies for specific health outcomes, unexplained heterogeneity, and designs that limit causal inferences. These findings highlight the need to explicitly test affective, health behavior, and biological mechanisms in future research, and focus on moderating factors that may alter the relationship between marital quality and health

Adaption of tele-behavioral activation to increase physical activity in depression: Protocol for iterative development and evaluation

Background: Poor treatment outcomes, disease recurrence, and medical co-morbidities contribute to the significant burden caused by depressive disorders. Increasing physical activity in persons with depression has the potential to improve both depression treatment outcomes and physical health. However, evidence for physical activity interventions that can be delivered as part of depression treatment remains limited. This study will examine a Behavioral Activation teletherapy intervention adapted to include a specific focus on increasing physical activity. Methods: The two-phase study will include a preliminary pilot study (n = 15) to evaluate and refine the manualized intervention using a mixed-methods approach followed by a single-arm study to evaluate feasibility and preliminary efficacy of the adapted BA teletherapy. Participants will be adults, age 18–64, with moderate to severe depressive symptoms (defined as a PHQ-9 score ≥10) and who currently engage in 90 min or less of moderate-to-vigorous physical activity. Individuals will be excluded if they have a current or past manic or hypomanic episode, psychosis, schizophrenia or schizophreniform disorder, or active suicidal ideation, or if not medically-cleared to exercise. The BA intervention will consist of 8 weekly sessions, followed by 2 bi-weekly booster sessions. Feasibility outcomes will include metrics of screening, enrollment, intervention adherence and fidelity, and participant retention. Intervention preliminary efficacy will be evaluated through assessment of changes in depressive symptoms and moderate-to-vigorous physical activity. Conclusion: Data from this trial will be used to support the conduct of a randomized controlled trial to evaluate the efficacy of the adapted BA intervention