Browsing by Subject "Anxiety disorders"
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Item A randomized proof-of-mechanism trial applying the 'fast-fail' approach to evaluating κ-opioid antagonism as a treatment for anhedonia(Springer Nature, 2020) Krystal, Andrew D.; Pizzagalli, Diego A.; Smoski, Moria; Mathew, Sanjay J.; Nurnberger, John, Jr.; Lisanby, Sarah H.; Iosifescu, Dan; Murrough, James W.; Yang, Hongqiu; Weiner, Richard D.; Calabrese, Joseph R.; Sanacora, Gerard; Hermes, Gretchen; Keefe, Richard S. E.; Song, Allen; Goodman, Wayne; Szabo, Steven T.; Whitton, Alexis E.; Gao, Keming; Potter, William Z.; Psychiatry, School of MedicineThe National Institute of Mental Health (NIMH) 'fast-fail' approach seeks to improve too-often-misleading early-phase drug development methods by incorporating biomarker-based proof-of-mechanism (POM) testing in phase 2a. This first comprehensive application of the fast-fail approach evaluated the potential of κ-opioid receptor (KOR) antagonism for treating anhedonia with a POM study determining whether robust target engagement favorably impacts the brain circuitry hypothesized to mediate clinical effects. Here we report the results from a multicenter, 8-week, double-blind, placebo-controlled, randomized trial in patients with anhedonia and a mood or anxiety disorder (selective KOR antagonist (JNJ-67953964, 10 mg; n = 45) and placebo (n = 44)). JNJ-67953964 significantly increased functional magnetic resonance imaging (fMRI) ventral striatum activation during reward anticipation (primary outcome) as compared to placebo (baseline-adjusted mean: JNJ-67953964, 0.72 (s.d. = 0.67); placebo, 0.33 (s.d. = 0.68); F(1,86) = 5.58, P < 0.01; effect size = 0.58 (95% confidence interval, 0.13-0.99)). JNJ-67953964, generally well tolerated, was not associated with any serious adverse events. This study supports proceeding with assessment of the clinical impact of target engagement and serves as a model for implementing the 'fast-fail' approach.Item Attachment Avoidance and Depressive Symptoms: A Test of Moderation by Cognitive Abilities(2014-09-04) Shea, Amanda Marie; Rand, Kevin L.; Stewart, Jesse C.; Cyders, Melissa A.; Ashburn-Nardo, Leslie; Grahame, Nicholas J.The substantial interpersonal and economic costs of depression make it imperative to better understand the predictors and moderators of depressive symptoms. The ability to use social support protects people from depressive symptoms, but individuals high in attachment avoidance tend not to use others as sources of support. Research has found that attachment avoidance is related to depressive symptoms in some samples but not in others (Mikulincer & Shaver, 2007; Shea, 2011). Thus, there appear to be factors that moderate the relationship between attachment avoidance and depressive symptoms. The present study examined if cognitive abilities that facilitate effective emotion regulation strategies moderate the relationship between attachment avoidance and depressive symptoms. Using a sample of college students, attachment avoidance, cognitive abilities, depressive symptoms, and other indices of psychological distress and well-being were measured and examined for evidence of moderation via hierarchical linear regression. The hypothesis that cognitive abilities moderate the relationship between attachment avoidance and depressive symptoms was not supported (ΔR2 = 0.02, p = .68). Factors contributing to the null findings are discussed and conceptual and methodological suggestions are offered for future research.Item Correction to: Selective kappa-opioid antagonism ameliorates anhedonic behavior: evidence from the Fast-fail Trial in Mood and Anxiety Spectrum Disorders (FAST-MAS)(Springer Nature, 2021) Pizzagalli, Diego A.; Smoski, Moria; Ang, Yuen-Siang; Whitton, Alexis E.; Sanacora, Gerard; Mathew, Sanjay J.; Nurnberger, John, Jr.; Lisanby, Sarah H.; Iosifescu, Dan V.; Murrough, James W.; Yang, Hongqiu; Weiner, Richard D.; Calabrese, Joseph R.; Goodman, Wayne; Potter, William Z.; Krystal, Andrew D.; Psychiatry, School of MedicineCorrection to: Neuropsychopharmacology 10.1038/s41386-020-0738-4, published online 16 June 2020 In this article a conflict of interest was missing. The co-author Sanjay J. Mathew served as a consultant to Alkermes. The original article has been corrected. The original article can be found online at 10.1038/s41386-020-0738-4.Item Investigating feelings of imposterism in first‐year medical student narratives(Wiley, 2025) Kruskie, Megan E.; Frankel, Richard M.; Isaacson, J. Harry; Mehta, Neil; Byram, Jessica N.; Anatomy, Cell Biology and Physiology, School of MedicineIntroduction: Imposter phenomenon (IP), feeling as if a person does not belong, has been reported in medical students at various rates. In medical literature, this phenomenon has often been defined as a 'syndrome', but other studies have described it as a dynamic experience that can have various impacts on different people at different time points. Although studies have linked IP with other phenomena such as burnout in residents and physicians, no studies have examined its aetiology nor how these feelings are experienced by medical students. Methods: With the use of social identity theory as a framework, the authors analysed 233 reflective essays for elements of IP across eight cohorts of medical students from two institutions. Students responded to a prompt that asked: 'What was one part of your identity that you thought you would have to change in order to become a physician?' Included reflections were analysed using the framework method. Results: Elements of IP were identified in 121 reflections (52%) and were categorised into three major themes: (1) Comparing oneself to an idealised image of a medical student, (2) Comparing oneself to an idealised image of a physician and (3) Concerns about presentation of self to others. Each theme contained two or more sub-themes. Commonly, students discussed how their own personality traits, experiences, backgrounds and identities cast doubt on their sense of belonging in medicine. Discussion: The results of this study were consistent across both institutions, suggesting that imposter feelings are common among all first-year medical students. However, the extent of the impact of these feelings on their identity formation depends on the individual lived experiences of students and the context in which these feelings arise. Encouraging reflective journaling and sharing of stories from all stages of education can normalise imposter feelings during the development of the professional identity as a physician.Item Olfactory Reference Syndrome: A Case Report and Screening Tool(Springer, 2020-04) Chernyak, Yelena; Chapleau, Kristine M.; Tanious, Shariff F.; Dattilo, Natalie C.; Diaz, David R.; Landsberger, Sarah A.Olfactory reference syndrome (ORS) is a lesser known disorder that is related to obsessive–compulsive disorder. ORS is the obsessional and inaccurate belief that one is emitting a foul odor leading to embarrassment or concern about offending others, excessive hygiene behaviors, and social avoidance that significantly interferes with daily functioning. Although ORS is rare, it is challenging to diagnose. ORS-sufferers first seek treatment from non- psychiatric providers (e.g., dermatologists, dentists.) to alleviate the perceived odor, which frequently leads to misdiagnosis and unnecessary treatments. Additionally, because ORS-sufferers can have limited insight and ideas of reference, they can be misdiagnosed as having a psychotic or delusional disorder. We present a case report of a 42-year-old woman with ORS, and how the correct diagnosis of ORS provided with psychiatric treatment led to significant improvement in her daily functioning. We provide a literature review on the disorder as well as a short screener to assess ORS.Item Patient Health Questionnaire Anxiety and Depression Scale: Initial Validation in Three Clinical Trials(Wolters Kluwer, 2016-07) Kroenke, Kurt; Wu, Jingwei; Yu, Zhangsheng; Bair, Matthew J.; Kean, Jacob; Stump, Timothy; Monahan, Patrick O.; Medicine, School of MedicineOBJECTIVE: We examine the reliability and validity of the Patient Health Questionnaire Anxiety and Depression Scale (PHQ-ADS)-which combines the nine-item Patient Health Questionnaire depression scale and seven-item Generalized Anxiety Disorder scale-as a composite measure of depression and anxiety. METHODS: Baseline data from 896 patients enrolled in two primary-care based trials of chronic pain and one oncology-practice-based trial of depression and pain were analyzed. The internal reliability, standard error of measurement, and convergent, construct, and factor structure validity, as well as sensitivity to change of the PHQ-ADS were examined. RESULTS: The PHQ-ADS demonstrated high internal reliability (Cronbach α values of .8 to .9) in all three trials. PHQ-ADS scores can range from 0 to 48 (with higher scores indicating more severe depression/anxiety), and the estimated standard error of measurement was approximately 3 to 4 points. The PHQ-ADS showed strong convergent (most correlations, 0.7-0.8 range) and construct (most correlations, 0.4-0.6 range) validity when examining its association with other mental health, quality of life, and disability measures. PHQ-ADS cutpoints of 10, 20, and 30 indicated mild, moderate, and severe levels of depression/anxiety, respectively. Bifactor analysis showed sufficient unidimensionality of the PHQ-ADS score. PHQ-ADS change scores at 3 months differentiated (p < .0001) between individuals classified as worse, stable, or improved by a reference measure, providing preliminary evidence for sensitivity to change. CONCLUSIONS: The PHQ-ADS may be a reliable and valid composite measure of depression and anxiety which, if validated in other populations, could be useful as a single measure for jointly assessing two of the most common psychological conditions in clinical practice and research.Item Pilot Study of Self-Distancing Augmentation to Exposure Therapy for Youth Anxiety(Springer Nature, 2023-05-26) Bilek, Emily L.; Meyer, Allison E.; Tomlinson, Rachel; Chen, Carol; Psychiatry, School of MedicineThis pilot examines a self-distancing augmentation to exposure. Nine youth with anxiety (ages 11-17; 67% female) completed treatment. The study employed a brief (eight session) crossover ABA/BAB design. Exposure difficulty, engagement with exposure, and treatment acceptability were examined as primary outcome variables. Visual inspection of plots indicated that youth completed more difficult exposures during augmented exposure sessions [EXSD] than classic exposure sessions [EX] by therapist- and youth-report and that therapists reported higher youth engagement during EXSD than EX sessions. There were no significant differences between EXSD and EX on exposure difficulty or engagement by therapist- or youth-report. Treatment acceptability was high, although some youth reported that self-distancing was "awkward". Self-distancing may be associated with increased exposure engagement and willingness to complete more difficult exposures, which has been linked to treatment outcomes. Future research is needed to further demonstrate this link, and link self-distancing to outcomes directly.Item Polygenic Scores and Mood Disorder Onsets in the Context of Family History and Early Psychopathology(American Medical Association, 2025-04-01) Freeman, Kathryn; Zwicker, Alyson; Fullerton, Janice M.; Hafeman, Danella M.; van Haren, Neeltje E. M.; Merranko, John; Goldstein, Benjamin I.; Stapp, Emma K.; de la Serna, Elena; Moreno, Dolores; Sugranyes, Gisela; Mas, Sergi; Roberts, Gloria; Toma, Claudio; Schofield, Peter R.; Edenberg, Howard J.; Wilcox, Holly C.; McInnis, Melvin G.; Propper, Lukas; Pavlova, Barbara; Stewart, Samuel A.; Denovan-Wright, Eileen M.; Rouleau, Guy A.; Castro-Fornieles, Josefina; Hillegers, Manon H. J.; Birmaher, Boris; Mitchell, Philip B.; Alda, Martin; Nurnberger, John I.; Uher, Rudolf; Biochemistry and Molecular Biology, School of MedicineImportance: Bipolar disorder (BD) and major depressive disorder (MDD) aggregate within families, with risk often first manifesting as early psychopathology, including attention-deficit/hyperactivity disorder (ADHD) and anxiety disorders. Objective: To determine whether polygenic scores (PGS) are associated with mood disorder onset independent of familial high risk for BD (FHR-BD) and early psychopathology. Design, setting, and participants: This cohort study used data from 7 prospective cohorts enriched in FHR-BD from Australia, Canada, the Netherlands, Spain, and the US. Participants with FHR-BD, defined as having at least 1 first-degree relative with BD, were compared with participants without FHR for any mood disorder. Participants were repeatedly assessed with variable follow-up intervals from July 1992 to July 2023. Data were analyzed from August 2023 to August 2024. Exposures: PGS indexed genetic liability for MDD, BD, anxiety, neuroticism, subjective well-being, ADHD, self-regulation, and addiction risk factor. Semistructured diagnostic interviews with relatives established FHR-BD. ADHD or anxiety disorder diagnoses before mood disorder onset constituted early psychopathology. Main outcomes and measures: The outcome of interest, mood disorder onset, was defined as a consensus-confirmed new diagnosis of MDD or BD. Cox regression examined associations of PGS, FHR-BD, ADHD, and anxiety with mood disorder onset. Kaplan-Meier curves and log-rank tests evaluated the probability of onset by PGS quartile and familial risk status. Results: A total of 1064 participants (546 [51.3%] female; mean [SD] age at last assessment, 21.7 [5.1] years), including 660 with FHR-BD and 404 without FHR for any mood disorder, were repeatedly assessed for mental disorders. A total of 399 mood disorder onsets occurred over a variable mean (SD) follow-up interval of 6.3 (5.7) years. Multiple PGS were associated with onset after correcting for FHR-BD and early psychopathology, including PGS for ADHD (hazard ratio [HR], 1.19; 95% CI, 1.06-1.34), self-regulation (HR, 1.19; 95% CI, 1.06-1.34), neuroticism (HR, 1.18; 95% CI, 1.06-1.32), MDD (HR, 1.17; 95% CI, 1.04-1.31), addiction risk factor (HR, 1.16; 95% CI, 1.04-1.30), anxiety (HR, 1.15; 95% CI, 1.02-1.28), BD (HR, 1.14; 95% CI, 1.02-1.28), and subjective well-being (HR, 0.89; 95% CI, 0.79-0.99). High PGS for addiction risk factor, anxiety, BD, and MDD were associated with increased probability of onset in the control group. High PGS for ADHD and self-regulation increased rates of onset among participants with FHR-BD. PGS for self-regulation, ADHD, and addiction risk factors showed stronger associations with onsets of BD than MDD. Conclusions and relevance: In this cohort study, multiple PGS were associated with mood disorder onset independent of family history of BD and premorbid diagnoses of ADHD or anxiety. The association between PGS and mood disorder risk varied depending on family history status.Item Reduced top‐down attentional control in adolescents with generalized anxiety disorder(Wiley, 2021) Bashford-Largo, Johannah; Aloi, Joseph; Lukoff, Jennie; Johnson, Kimberly; White, Stuart F.; Dobbertin, Matthew; Blair, Robert James; Blair, Karina S.; Psychiatry, School of MedicineBackground: Generalized anxiety disorder (GAD) can significantly impair quality of life and is associated with a relatively poor long-term prognosis. Anxiety disorders are often associated with hyper-responsiveness to threat, perhaps coupled with impaired executive functioning. However, GAD, particularly adolescent GAD, has been the focus of little functional neuroimaging work compared to other anxiety disorders. Here, we examine the neural association of adolescent GAD with responsiveness to threat and response control. Methods: The study involved 35 adolescents with GAD and 34 healthy comparison individuals (N = 69) matched on age, gender, and IQ. Participants were scanned during an affective number Stroop task. Results: We found significant Group-by-Task Condition interactions in regions involved in response control/motor responding (bilateral precentral gyri and cerebellum) and/or cognitive control/attention (dorsomedial and lateral frontal cortex, posterior cingulate cortex, cuneus, and precuneus). In line with predictions, the youth with GAD showed significantly less recruitment during task trials than the healthy comparison individuals. However, no indications of specific heightened responses to threat were seen. Conclusions: GAD involves reduced capacity for engaging regions involved in response control/motor responding and/or cognitive control/attention. This might reflect either a secondary consequence of the patient's worry or an early risk factor for the development of worry.Item Towards precision medicine for anxiety disorders: objective assessment, risk prediction, pharmacogenomics, and repurposed drugs(Springer Nature, 2023) Roseberry, K.; Le-Niculescu, H.; Levey, D. F.; Bhagar, R.; Soe, K.; Rogers, J.; Palkowitz, S.; Pina, N.; Anastasiadis, W. A.; Gill, S. S.; Kurian, S. M.; Shekhar, A.; Niculescu, A. B.; Psychiatry, School of MedicineAnxiety disorders are increasingly prevalent, affect people's ability to do things, and decrease quality of life. Due to lack of objective tests, they are underdiagnosed and sub-optimally treated, resulting in adverse life events and/or addictions. We endeavored to discover blood biomarkers for anxiety, using a four-step approach. First, we used a longitudinal within-subject design in individuals with psychiatric disorders to discover blood gene expression changes between self-reported low anxiety and high anxiety states. Second, we prioritized the list of candidate biomarkers with a Convergent Functional Genomics approach using other evidence in the field. Third, we validated our top biomarkers from discovery and prioritization in an independent cohort of psychiatric subjects with clinically severe anxiety. Fourth, we tested these candidate biomarkers for clinical utility, i.e. ability to predict anxiety severity state, and future clinical worsening (hospitalizations with anxiety as a contributory cause), in another independent cohort of psychiatric subjects. We showed increased accuracy of individual biomarkers with a personalized approach, by gender and diagnosis, particularly in women. The biomarkers with the best overall evidence were GAD1, NTRK3, ADRA2A, FZD10, GRK4, and SLC6A4. Finally, we identified which of our biomarkers are targets of existing drugs (such as a valproate, omega-3 fatty acids, fluoxetine, lithium, sertraline, benzodiazepines, and ketamine), and thus can be used to match patients to medications and measure response to treatment. We also used our biomarker gene expression signature to identify drugs that could be repurposed for treating anxiety, such as estradiol, pirenperone, loperamide, and disopyramide. Given the detrimental impact of untreated anxiety, the current lack of objective measures to guide treatment, and the addiction potential of existing benzodiazepines-based anxiety medications, there is a urgent need for more precise and personalized approaches like the one we developed.