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Symptoms of irritability, anxiety, panic, and insomnia are common in patients with depression, and their worsening after antidepressant treatment initiation is associated with poorer long-term outcomes. The Concise Associated Symptom Tracking (CAST) scale was developed to measure these symptoms in adults with major depressive disorder (MDD). Here, we evaluate the psychometric properties of CAST in an ongoing community-based observational study involving children, adolescents, and young adults. Individuals from the ongoing Texas Youth Depression and Suicide Research Network (TX-YDSRN; N = 952) with CAST data available were included. Fit statistics [Goodness of Fit Index (GFI), Comparative Fit Index (CFI), and Root Mean Square Error of Approximation (RMSEA)] from confirmatory factor analyses were used to evaluate the five- and four-domain structure of CAST. Item response theory (IRT) analyses were also used. Individuals were grouped based on age (in years) as youths (8-17) and young adults (18-20). Correlations with other clinical measures were used to inform construct validity. Four-domain (irritability, anxiety, panic, and insomnia) 12-item structure of CAST (CAST-12) was optimal for youths (N = 709, GFI = 0.906, CFI = 0.919, RMSEA = 0.095) and young adults (N = 243, GFI = 0.921, CFI = 0.938, RMSEA = 0.0797) with Cronbach's alpha of 0.87 and 0.88, respectively. Slope of each item exceeded 1.0 on IRT analyses suggesting adequate discrimination for each item. Scores on irritability, anxiety, panic, and insomnia were significantly correlated with similar items on other scales. Together these findings suggest that CAST-12 is a valid self-report measure of irritability, anxiety, insomnia, and panic in youths and young adults., Competing Interests: Declaration of competing interest Dr. Jha has received contract research grants from Acadia Pharmaceuticals, Neurocrine Bioscience, Navitor/Supernus and Janssen Research & Development, educational grant to serve as Section Editor of the Psychiatry & Behavioral Health Learning Network, consultant fees from Eleusis Therapeutics US, Inc, Janssen Global Services, Janssen Scientific Affairs, Worldwide Clinical Trials/Eliem and Inversargo, and Guidepoint Global, and honoraria from North American Center for Continuing Medical Education, Medscape/WebMD, Clinical Care Options, and Global Medical Education. Dr. Blader reports having received consultant and speakers' honoraria from Supernus Pharmaceuticals. Dr. Brown has received consulting fees from Sage and Biogen Pharmaceuticals. Dr. Kennard receives royalties from Guilford, Press, Inc; and serves on the board of trustees for the Jerry M. Lewis, III, MD Research Foundation. Dr. Soutullo reports for the period 2018–2022 non-personal research funds from Lundbeck and Janssen; is a consultant/advisory board member of Editorial Médica Panamericana, EUNETHYDIS (European Network on Hyperkinetic Disorder), NeuroTech Solutions Ltd (Israel), Limbix Health DSMB (United States), MEDEA (Spain), Tech Innosphere Engineering LTD (Germany), and Shire/now part of Takeda (Spain); received speaker's bureau fees from Bial (Portugal), Cuquerella Medical Consulting (Spain), Medice (Germany), Rubio (Spain), Tecnofarma (Peru), and Shire/now part of Takeda (Spain), and royalties from Editorial Médica Panamericana (Spain). Dr. Storch reports receiving research funding to his institution from the Ream Foundation, International OCD Foundation, and NIH. He is a consultant for Brainsway and Biohaven Pharmaceuticals. He owns stock less than $5000 in NView. He receives book royalties from Elsevier, Wiley, Oxford, American Psychological Association, Guildford, Springer, and Jessica Kingsley. Dr. Trivedi has provided consulting services to Alkermes Inc, Axsome Therapeutics, Biogen MA Inc., Cerebral Inc., Circular Genomics Inc, Compass Pathfinder Limited, GH Research Limited, Heading Health Inc, Janssen, Legion Health Inc, Merck Sharp & Dohme Corp., Mind Medicine (MindMed) Inc, Merck Sharp & Dhome LLC, Naki Health, Ltd., Neurocrine Biosciences Inc, Noema Pharma AG, Orexo US Inc, Otsuka American Pharmaceutical Inc, Otsuka Canada Pharmaceutical Inc, Otsuka Pharmaceutical Development & Commercialization Inc, Praxis Precision Medicines Inc, SAGE Therapeutics, Sparian Biosciences Inc, Takeda Pharmaceutical Company Ltd, WebMD. He sits on the Scientific Advisory Board of Alto Neuroscience Inc, Cerebral Inc., Compass Pathfinder Limited, Heading Health, GreenLight VitalSign6 Inc, Legion Health Inc, Merck Sharp & Dohme Corp, Orexo US Inc, Signant Health. He holds stock in Alto Neuroscience Inc, Cerebral Inc, Circular Genomics Inc, GreenLight VitalSign6 Inc, Legion Health Inc. Additionally, he has received editorial compensation from American Psychiatric Association, and Oxford University Press. Drs. Minhajuddin, Slater, Garza, Shotwell, Wakefield, and Mrs. Mayes have no declarations to report., (Copyright © 2023. Published by Elsevier Ltd.)

Background: To address the clinical heterogeneity of Major Depressive Disorder (MDD), this investigation determined whether resting state functional magnetic resonance imaging (fMRI) could be deployed to identify circuit based homogeneous subgroups, and whether subgroups identified show differential treatment outcomes., Methods: Pretreatment resting state fMRIs obtained from 278 outpatients with nonpsychotic MDD from Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care for Depression Study were used to create data-driven subgroups using CLICK clustering. These subgroups were then compared using baseline clinical data, as well as baseline-to-week 8 changes in depression severity measured using the 17-item Hamilton Rating Scale for Depression (HAMD 17 ) and response/remission rates by treatment group., Results: Three subgroups were identified. Cluster-1 was characterized by overallhyperconnectivity coupled with profound hypoconnectivity between the supramarginal gyrus (executive control network; ECN) and the superior frontal cortex (dorsal attention network; DAN). Cluster-2 was characterized by overall hypoconnectivity coupled with hyperconnectivity between supramarginal gyrus (ECN) and superior frontal cortex (DAN). Cluster-3 showed hypoconnectivity, especially profound between the angular cortex (default mode network; DMN) and middle frontal cortex (ECN). While baseline clinical measures did not differentiate the three clusters, Cluster-3 had the remission rate (51.6%) compared to Cluster-1 and Cluster-2 (32.7% and 31.9%) when treated with sertraline., Limitations: Due to the exploratory nature of these analyses, there were no adjustments for multiple comparisons., Conclusions: Baseline functional connectivity can be used to subgroup patients with MDD that differ in acute phase treatment outcomes. Measures of connectivity may address the heterogeneity of MDD., (Copyright © 2022. Published by Elsevier Ltd.)

Background: The brain circuitry of depression and anxiety/fear is well-established, involving regions such as the limbic system and prefrontal cortex. We expand prior literature by examining the extent to which four discrete factors of anxiety (immediate state anxiety, physiological/panic, neuroticism/worry, and agitation/restlessness) among depressed outpatients are associated with differential responses during reactivity to and regulation of emotional conflict., Methods: A total of 172 subjects diagnosed with major depressive disorder underwent functional magnetic resonance imaging while performing an Emotional Stroop Task. Two main contrasts were examined using whole brain voxel wise analyses: emotional reactivity and emotion regulation. We also evaluated the association of these contrasts with the four aforementioned anxiety factors., Results: During emotional reactivity, participants with higher immediate state anxiety showed potentiated activation in the rolandic operculum and insula, while individuals with higher levels of physiological/panic demonstrated decreased activation in the posterior cingulate. No significant results emerged for any of the four factors on emotion regulation. When re-analyzing these statistically-significant brain regions through analyses of a subsample with (n = 92) and without (n = 80) a current anxiety disorder, no significant associations occurred among those without an anxiety disorder. Among those with an anxiety disorder, results were similar to the full sample, except the posterior cingulate was associated with the neuroticism/worry factor., Conclusions: Divergent patterns of task-related brain activation across four discrete anxiety factors could be used to inform treatment decisions and target specific aspects of anxiety that involve intrinsic processing to attenuate overactive responses to emotional stimuli., (Copyright © 2022. Published by Elsevier Ltd.)

Deaths due to suicide are one of the leading causes of mortality among youths and young adults. Active suicidal ideation (SI) is considered one of the strongest risk factors for suicide. Here, we evaluated the neurocircuitry of SI in a sample of youths and young adults (aged 10-26 years) with current or past diagnosis of either major depression or bipolar disorder who were enrolled in Texas Resilience Against Depression Study (T-RAD), and had neuroimaging and SI (assessed with the 3-item Suicidal Thoughts factor of Concise Health Risk Tracking self-report scale) data available (n = 72, 53 females). Resting-state functional connectivity (FC) was computed amongst 121 cortical and subcortical regions of interest resulting in 7260 FC pairs. Mean (SD) age and SI levels of participants were 19.6 years (4.01) and 1.48 (2.36) respectively. In univariate analyses, 34 out of the 7260 FC pairs were correlated with SI (p < .005). Stronger connectivity of default mode network (DMN) with striatum was associated with higher SI. Conversely, higher SI was associated with weaker connectivity of limbic network with hippocampus, DMN, dorsal attention network, and executive control network. In multivariate analyses, these 34 FC pairs together had an average correlation of 0.54 after five-fold cross-validation. In conclusion, SI was associated with distinct patterns of resting-state functional connectivity among youths and young adults with regions in DMN and the ventral striatum as key nodes., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Several self-report rating scales have been developed to assess suicidal ideation, yet most have limited utility in predicting future suicide attempts. This is particularly critical in adolescence, where suicide is the second leading cause of death. This study evaluated the Concise Health Risk Tracking Self-Report (CHRT-SR) as a prospective predictor of suicide attempts and events in high-risk adolescents enrolled in a suicide-prevention intensive outpatient program (IOP)., Methods: Data were collected by retrospective chart review of adolescents treated in IOP for youth with severe suicidality. At baseline, youth completed the 14-item CHRT-SR (CHRT-SR 14 ), which assesses suicide risk based on 3 subscales: Propensity, Impulsivity, and Suicidal Thoughts. Two outcomes were assessed: actual suicide attempts and suicidal events (suicide attempt, inpatient hospitalization, or emergency department visit) during the IOP., Results: Of the 251 adolescents who completed the baseline CHRT-SR 14 , 26 had a suicidal event during IOP (mean time in IOP: 5.4 ± 2.3 weeks), of whom 14 had an actual suicide attempt. Youth with any suicidal event had higher scores than those without an event on the CHRT-SR 14 Total (p = .005), Propensity (p = .008), and Suicidal Thoughts (p = .001) scales at baseline. Youth who made a suicide attempt had significantly higher scores than those without an event for the Total Score, Propensity, and Suicidal Thoughts subscales. CHRT-SR 14 Total Score of 28 had a sensitivity of 85.7% and specificity of 56.5% in predicting suicide attempts. A score of 22 predicted suicidal events, with a sensitivity of 80.8% and specificity of 40.9%. CHRT-SR 7 Total Score of 12 predicted suicide attempts, with a sensitivity of 85.7% and specificity of 53.4%., Conclusions: The CHRT-SR 14 self-report predicts suicide attempts and events with at least 80% sensitivity and acceptable specificity in adolescents at high-risk for suicide., Competing Interests: Declaration of competing interest Dr. Rush has received consulting fees from Akili, Brain Resource Inc., Compass Inc., Curbstone Consultant LLC, Emmes Corp., Johnson and Johnson (Janssen), Liva-Nova, Mind Linc, Otsuka-US, Sunovion; speaking fees from Liva-Nova; and royalties from Guilford Press and the University of Texas Southwestern Medical Center, Dallas, TX (for the Inventory of Depressive Symptoms and its derivatives). He is also named co-inventor on two patents: U.S. Patent No. 7,795,033: Methods to Predict the Outcome of Treatment with Antidepressant Medication, Inventors: McMahon FJ, Laje G, Manji H, Rush AJ, Paddock S, Wilson AS; and U.S. Patent No. 7,906,283: Methods to Identify Patients at Risk of Developing Adverse Events During Treatment with Antidepressant Medication, Inventors: McMahon FJ, Laje G, Manji H, Rush AJ, Paddock S. Dr. Emslie has received research/grant from Duke University, Forest Research Institute, and Janssen Research & Development. Dr. Emslie is a consultant for Assurex Health Inc., Lundbeck, Neuronetics Inc., Otsuka, and Pfizer Inc. Dr. Kennard is currently serving on the Board of Trustees for the Jerry M. Lewis, M.D. Mental Health Research Foundation. Dr. Kennard receives royalties from Guilford Press, Inc. Dr. Jha has received research funding from Acadia Pharmaceuticals and Janssen Research & Development, and honoraria for CME presentations from North American Center for Continuing Medical Education and Global Medical Education. Dr. Hughes receives royalties from Guilford Press. Dr. Trivedi has received research funding from NIMH, NIDA, and Patient-Centered Outcomes Research Institute (PCORI), Cancer Prevention Research Institute of Texas (CPRIT); has served as a consultant for Allergan, Alto Neuroscience Inc, Applied Clinical Intelligence LLC, Axsome Therapeutics, Boegringer Ingelheim, Engage Health Media, GreenLight VitalSign6 Inc, Janssen, Lundbeck Research USA, Merck Sharp & Dohme Corp., Navitor Pharmaceutical Inc, Otsuka, Perception Neuroscience, Pharmerit International, SAGE Therapeutics, Signant Health; and has received editorial compensation from American Psychiatric Association (Deputy Editor for American Journal of Psychiatry), Oxford University Press; Dr. Carmody owns stock in Vertex Pharmaceuticals and CRISPR Therapeutics; Ms. Mayes and Drs. Killian, and King, have no financial relationships with commercial interests., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Depression has a chronic and recurrent course often with early onset and is the leading cause of disability worldwide. In contrast to diagnoses for other conditions which rely on precise medical tests, the diagnosis of depression still focuses exclusively on symptom reports. As a result, heterogeneous patient groups are included under broad categories. Furthermore, in the absence of companion diagnostic tests, choosing specific treatments for patients remains imprecise with only one-third of patients entering remission with initial treatment, with others requiring multiple intervention steps to achieve remission. In addition to improving treatment outcomes, disease prevention is essential to reduce overall disease burden. Adolescence is a critical window where complex emotional, social, familial, and biological shifts may predispose to lifelong depression. Thus, personalized medicine, integrating individual variability in genes, brain function, and clinical phenotypes, can offer a comprehensive approach to provide precise diagnosis, novel drug development, optimal treatment assignment, and prevention of illness and its associated burden. Texas Resilience Against Depression study (T-RAD) encompasses two natural history, longitudinal (10 + years), prospective studies (D2K and RAD), each enrolling 2500 participants. The D2K study follows participants (ages 10 years and older) who have a current or past diagnosis of depression or bipolar disorder. The RAD study follows participants aged 10-24 years who are at risk for depression but not yet suffering from the disease. The T-RAD study will help to uncover the socio-demographic, lifestyle, clinical, psychological, and neurobiological factors that contribute to mood disorder onset, recurrence, progression, and differential treatment response., Competing Interests: Declaration of competing interest Dr. Trivedi has received funding from Agency for Healthcare Research and Quality (AHRQ), Cyberonics Inc., National Alliance for Research in Schizophrenia and Depression, National Institute of Mental Health (NIMH), National Institute on Drug Abuse (NIDA), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and Johnson & Johnson. He has also served as an advisor or consultant for Abbott Laboratories Inc., Akzo (Organon Pharmaceuticals Inc.), Allergan Sales LLC, Alkermes, Arcadia Pharmaceuticals Inc., AstraZeneca, Axon Advisors, Brintellix, Bristol-Myers Squibb Company, Cephalon Inc., Cerecor, Eli Lilly & Company, Evotec, Fabre Kramer Pharmaceuticals Inc., Forest Pharmaceuticals, GlaxoSmithKline, Global Medical Education Inc., Health Research Associates, Johnson & Johnson, Lundbeck, MedAvante, Medscape, Medtronic, Merck, Mitsubishi Tanabe Pharma Development America Inc., MSI Methylation Sciences Inc., Nestle Health Science-PamLab Inc., Naurex, Neuronetics, One Carbon Therapeutics Ltd., Otsuka Pharmaceuticals, Pamlab, Parke-Davis Pharmaceuticals Inc., Pfizer Inc., PgxHealth, Phoenix Marketing Solutions, Rexahn Pharmaceuticals, Ridge Diagnostics, Roche Products Ltd., Sepracor, SHIRE Development, Sierra, SK Life and Science, Sunovion, Takeda, Tal Medical/Puretech Venture, Targacept, Transcept, VantagePoint, Vivus, and Wyeth-Ayerst Laboratories. Dr. Jha has received contract research funding from Acadia Pharmaceutical and Janssen Research. Dr. Trombello currently owns stock in Merck and Gilead Sciences. Dr. Hughes has served as Youth Aware of Mental Health (YAM) trainer, consulting for Mental Health in Mind International. Dr. Hughes also receives royalties from Guilford Press. Dr. Greer has received contract research support from Janssen Research and Development, grant funding from NARSAD, and consultant/honoraria for Lundbeck and Takeda. Drs. Chin Fatt, Cooper, Mason, Toll, Gadad, Czysz, Minhajuddin, Fuller, Carmody, Ms. Sethuram, Mrs. Mayes have no disclosures to report., (Copyright © 2019. Published by Elsevier Ltd.)

Peripheral inflammation is associated with poor response to antidepressant treatments. However, whether sex differentially affects this association remains unknown. Participants of Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC) with baseline plasma samples were included in this study (n = 220; male n = 75, female n = 145). Depression severity [Hamilton Rating Scale for Depression 17-item (HAMD-17)] was measured at baseline and weeks- 1, 2, 3, 4, 6, and 8. Plasma c-reactive protein (CRP) was measured with commercially-available ELISA kits at baseline, week-1, and week-8. Sex difference in prediction of baseline-to-week-8 HAMD-17 change by baseline CRP was tested with sex-by-baseline-CRP-by-time interaction in mixed model analysis. Additionally, changes in CRP from baseline-to-week-8 CRP and its association with HAMD-17 changes over that period were also evaluated. Covariates included body mass index, site, smoking status, and age. There was a significant sex difference in association of baseline-to-week-8 HAMD-17 reduction with baseline CRP (p = 0.033). Higher baseline CRP was associated with lower baseline-to-week-8 HAMD-17 reduction in females (p < 0.0001) but not in males (p = 0.632). Additionally, CRP was significantly reduced (p = 0.041, effect size = 0.254) from baseline-to-week-8, but there were no sex differences in this reduction (p = 0.249). Baseline-to-week-8 changes in HAMD-17 and CRP were not significantly associated either overall (p = 0.348) or based on sex (p = 0.370). In a large study of depressed outpatients, we replicated previous findings that elevated baseline CRP levels are associated with worse antidepressant treatment outcomes. However, this effect was limited only to females. These findings emphasize the importance of studying sex differences in biological mechanisms linking inflammation and depression., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Animal and human studies suggest an association between depression and aberrant immune response. Further, common inflammatory markers may change during the course of antidepressant treatment in patients. The objective of this study was to evaluate changes in inflammatory markers and clinical outcomes from subjects enrolled in the Combining Medications to Enhance Depression Outcome (CO-MED) trial. At baseline and week 12 (treatment completion), plasma samples of 102 participants were analyzed via a multiplex assay comprised of inflammatory markers using a 27-plex standard assay panel plus a 4-plex human acute phase xMAP technology based platform. We carried out analyses in two steps. First, t-tests were used to identify inflammatory marker levels that changed between baseline and week 12. For markers that were altered, logistic regression models were then conducted to look for associated changes in remission at week 12. Among the 31 inflammatory markers analyzed, several cytokines (IL-5, IFN-γ, IL-13), two chemokines (Eotaxin-1/CCL11, RANTES) and an acute-phase reactant (serum amyloid P component) showed change from baseline to week 12. However, only two indicated differential remission responses. Interestingly, increased levels of Eotaxin-1/CCL11 correlated with remission at week 12, whereas decreased levels of IFN-γ correlated with non-remission at week 12. Results suggest that these inflammatory proteins may serve as predictors of treatment response., (Copyright © 2017 Elsevier Ltd. All rights reserved.)