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Evidence from preclinical animal models suggests that the stress-buffering function of the endocannabinoid (eCB) system may help protect against stress-related reductions in hippocampal volume, as is documented in major depressive disorder (MDD). However, stress exposure may also lead to dysregulation of this system. Thus, pathways from marked stress histories, such as childhood maltreatment (CM), to smaller hippocampal volumes and MDD in humans may depend on dysregulated versus intact eCB functioning. We examined whether the relation between MDD and peripheral eCB concentrations would vary as a function of CM history. Further, we examined whether eCBs moderate the relation of CM/MDD and hippocampal volume. Ninety-one adults with MDD and 62 healthy comparison participants (HCs) were recruited for a study from the Canadian Biomarker Integration Network in Depression program (CAN-BIND-04). The eCBs, anandamide (AEA) and 2-arachidonylglycerol (2-AG), were assessed from blood plasma. Severe CM history was assessed retrospectively via contextual interview. MDD was associated with eCBs, though not all associations were moderated by CM or in the direction expected. Specifically, MDD was associated with higher AEA compared to HCs regardless of CM history, a difference that could be attributed to psychotropic medications. MDD was also associated with higher 2-AG, but only for participants with CM. Consistent with hypotheses, we found lower left hippocampal volume in participants with versus without CM, but only for those with lower AEA, and not moderate or high AEA. Our study presents the first evidence in humans implicating eCBs in stress-related mechanisms involving reduced hippocampal volume in MDD., (© 2024. The Author(s).)

Background: A critical challenge in the study and management of major depressive disorder (MDD) is predicting relapse. We examined the temporal correlation/coupling between depression and anxiety (called Depression-Anxiety Coupling Strength, DACS) as a predictor of relapse in patients with MDD., Methods: We followed 97 patients with remitted MDD for an average of 394 days. Patients completed weekly self-ratings of depression and anxiety symptoms using the Quick Inventory of Depressive Symptoms (QIDS-SR) and the Generalized Anxiety Disorder 7-item scale (GAD-7). Using these longitudinal ratings we computed DACS as random slopes in a linear mixed effects model reflecting individual-specific degree of correlation between depression and anxiety across time points. We then tested DACS as an independent variable in a Cox proportional hazards model to predict relapse., Results: A total of 28 patients (29 %) relapsed during the follow-up period. DACS significantly predicted confirmed relapse (hazard ratio [HR] 1.5, 95 % CI [1.01, 2.22], p = 0.043; Concordance 0.79 [SE 0.04]). This effect was independent of baseline depressive or anxiety symptoms or their average levels over the follow-up period, and was identifiable more than one month before relapse onset., Limitations: Small sample size, in a single study. Narrow phenotype and comorbidity profiles., Conclusions: DACS may offer opportunities for developing novel strategies for personalized monitoring, early detection, and intervention. Future studies should replicate our findings in larger, diverse patient populations, develop individual patient prediction models, and explore the underlying mechanisms that govern the relationship of DACS and relapse., Competing Interests: Declaration of competing interest RM has received consulting and speaking honoraria from AbbVie, Eisai, Janssen, Lallemand, Lundbeck, Neonmind, and Otsuka, and research grants from CAN-BIND, CIHR, Janssen, Nubiyota, OBI and OMHF. RWL has received honoraria for ad hoc speaking or advising/consulting, or received research funds, from: Abbvie, Asia-Pacific Economic Cooperation, Bausch, BC Leading Edge Foundation, Brain Canada, Canadian Institutes of Health Research, Canadian Network for Mood and Anxiety Treatments, CAN-BIND Solutions, Carnot, Grand Challenges Canada, Healthy Minds Canada, Janssen, Lundbeck, Lundbeck Institute, Medscape, Michael Smith Foundation for Health Research, MITACS, Neurotorium, Ontario Brain Institute, Otsuka, Pfizer/Viatris, Shanghai Mental Health Center, Sunnybrook Health Sciences Center, Unity Health, Vancouver Coastal Health Research Institute, and VGH-UBCH Foundation. JAF has served on the Scientific Advisory Board for MRM Health NL and has received consulting/speaker fees from Klaire Labs, WebMD, Takeda Canada and Rothman, Benson, Hedges Inc. QSL is an employee of Janssen Research & Development, LLC and is a shareholder in Johnson & Johnson, which is the parent company of the Janssen companies. QSL declares that, except for income received from her primary employer, no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional service, and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest. JJN is partially supported by a Marshall Fellowship Award from the UBC Institute of Mental Health. RU is supported by the Canada Research Chairs program. CS has received research funds from Clairvoyant Therapeutics, Otsuka, Eisai Inc. and served as an Advisory Board Member for Bayer, Pfizer, Eisai, Boheringer-Ingelheim. SHK has received engagements from Boehringer-Ingelheim, Janssen, Lundbeck, Merck, Neurotorium, Otsuka. CAN-BIND is an Integrated Discovery Program carried out in partnership with, and financial support from, the Ontario Brain Institute, an independent non-profit corporation, funded partially by the Ontario government. The opinions, results and conclusions are those of the authors and no endorsement by the Ontario Brain Institute is intended or should be inferred. Additional funding is provided by the Canadian Institutes of Health Research (CIHR), Lundbeck, Servier. Funding and/or in kind support is also provided by the investigators' universities and academic institutions. All study medications for the CAN-BIND-1 Trial were independently purchased at wholesale market values. The Wellness Monitoring Study was partially funded by Janssen Research & Development, LLC with research funding from Janssen to University Health Network., (Copyright © 2024. Published by Elsevier B.V.)

Background: Patients with major depressive disorder (MDD) can present with altered brain structure and deficits in cognitive function similar to those seen in aging. However, the interaction between age-related brain changes and brain development in MDD remains understudied. In a cohort of adolescents and adults with and without MDD, we assessed brain aging differences and associations through a newly developed tool that quantifies normative neurodevelopmental trajectories., Methods: A total of 304 participants with MDD and 236 control participants without depression were recruited and scanned from 3 studies under the Canadian Biomarker Integration Network for Depression. Volumetric data were used to generate brain centile scores, which were examined for 1) differences between participants with MDD and control participants; 2) differences between individuals with versus without severe childhood maltreatment; and 3) correlations with depressive symptom severity, neurocognitive assessment domains, and escitalopram treatment response., Results: Brain centiles were significantly lower in the MDD group than in the control group. Brain centile was also significantly correlated with working memory in the control group but not the MDD group. No significant associations were observed between depression severity or antidepressant treatment response and brain centiles. Likewise, childhood maltreatment history did not significantly affect brain centiles., Conclusions: Consistent with previous work on machine learning models that predict brain age, brain centile scores differed in people diagnosed with MDD, and MDD was associated with differential relationships between centile scores and working memory. The results support the notion of atypical development and aging in MDD, with implications for neurocognitive deficits associated with aging-related cognitive function., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

A common conjecture is that social success relies on "theory of mind"-the everyday skill of imputing mental states to others. We test the hypothesis that individuals with stronger theory of mind skills and motivation garner more positive first impressions because of how they interact with others. Participants included 334 young adults who were paired with a peer for a first-time meeting. Dyads completed a cooperative Lego-building task, which was videotaped and later coded for behavioral manifestations of theory of mind by independent raters. Theory of mind accuracy and motivation were assessed with validated laboratory tasks and a self-report questionnaire, respectively. First impressions were assessed based on partner's ratings of participant likeability, enjoyment of the interaction, and changes in positive affect. Results of actor-partner interdependence mediation models revealed that the associations between theory of mind and first impressions are indirect and mediated through behaviors. Specifically, participants with stronger theory of mind demonstrated greater cognitive sensitivity and pragmatic conversational skills. However, only cognitive sensitivity subsequently predicted more favorable first impressions. This research shows that social-cognitive skills can affect others' social impressions through their behavioral manifestations. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

We examine structural brain characteristics across three diagnostic categories: at risk for serious mental illness; first-presenting episode and recurrent major depressive disorder (MDD). We investigate whether the three diagnostic groups display a stepwise pattern of brain changes in the cortico-limbic regions. Integrated clinical and neuroimaging data from three large Canadian studies were pooled (total n = 622 participants, aged 12-66 years). Four clinical profiles were used in the classification of a clinical staging model: healthy comparison individuals with no history of depression (HC, n = 240), individuals at high risk for serious mental illness due to the presence of subclinical symptoms (SC, n = 80), first-episode depression (FD, n = 82), and participants with recurrent MDD in a current major depressive episode (RD, n = 220). Whole-brain volumetric measurements were extracted with FreeSurfer 7.1 and examined using three different types of analyses. Hippocampal volume decrease and cortico-limbic thinning were the most informative features for the RD vs HC comparisons. FD vs HC revealed that FD participants were characterized by a focal decrease in cortical thickness and global enlargement in amygdala volumes. Greater total amygdala volumes were significantly associated with earlier onset of illness in the FD but not the RD group. We did not confirm the construct validity of a tested clinical staging model, as a differential pattern of brain alterations was identified across the three diagnostic groups that did not parallel a stepwise clinical staging approach. The pathological processes during early stages of the illness may fundamentally differ from those that occur at later stages with clinical progression., Competing Interests: Declaration of competing interest Dr. Sidney Kennedy has received funding for Consulting or Speaking engagements from Abbvie, Boehringer-Ingelheim, Janssen, Lundbeck, Lundbeck Institute, Merck, Otsuka Pfizer, Sunovion and Servier. Dr. Kennedy has received Research Support from Abbott, Brain Canada, CIHR (Canadian Institutes of Health Research), Janssen, Lundbeck, Ontario Brain Institute, Otsuka, Pfizer, SPOR (Canada's Strategy for Patient-Oriented Research); and has stock/stock options in Field Trip Health. No other disclosures or conflict of interests stated by authors of this work. SJR has received consulting or research funding from Allergan, Janssen, Neurocrine, and Pfizer Canada., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: Swann's self-verification theory proposes that negative feedback seeking (NFS)-the solicitation of negative feedback from others that confirms one's self-views-works in a negative cycle to maintain and exacerbate depression in the face of interpersonal stress. We propose a cognitive-interpersonal integration account of NFS such that this maladaptive behavior prospectively predicts depression only among those with a trait tendency to ruminate on the causes and consequences of depressed mood and stress., Method: Participants included 91 young adults who were over-sampled for a lifetime history of a unipolar depressive disorder (age 17-33; 69% women; 67% lifetime depressive disorder). At baseline, participants completed a structured diagnostic interview and self-report measures of NFS, rumination, and depression symptoms. In addition, participants engaged in an interpersonal rejection task (the Yale Interpersonal Stressor) followed by a behavioral measure of NFS. At a 3-month follow-up, depression symptoms were again assessed by self-report and exposure to stressful interpersonal life events in the intervening period were assessed with a rigorous contextual interview and independent rating system., Results: Controlling for baseline depression severity, greater self-reported, and behaviorally assessed NFS predicted greater follow-up depression severity, but only among those with higher trait tendency to ruminate. For self-reported NFS, this association was further moderated by level of interpersonal, but not noninterpersonal, life events experienced over follow-up., Conclusion: These findings suggest that rumination may represent a modifiable intervention target that could break the vicious interpersonal cycle of depression and, thus, mitigate the depressogenic effects of NFS., (© 2023 The Authors. Journal of Clinical Psychology published by Wiley Periodicals LLC.)

Preclinical research implicates stress-induced upregulation of the enzyme, serum- and glucocorticoid-regulated kinase 1 (SGK1), in reduced hippocampal volume. In the current study, we tested the hypothesis that greater SGK1 mRNA expression in humans would be associated with lower hippocampal volume, but only among those with a history of prolonged stress exposure, operationalized as childhood maltreatment (physical, sexual, and/or emotional abuse). Further, we examined whether baseline levels of SGK1 and hippocampal volume, or changes in these markers over the course of antidepressant treatment, would predict treatment outcomes in adults with major depression [MDD]. We assessed SGK1 mRNA expression from peripheral blood, and left and right hippocampal volume at baseline, as well as change in these markers over the first 8 weeks of a 16-week open-label trial of escitalopram as part of the Canadian Biomarker Integration Network in Depression program (MDD [n = 161] and healthy comparison participants [n = 91]). Childhood maltreatment was assessed via contextual interview with standardized ratings. In the full sample at baseline, greater SGK1 expression was associated with lower hippocampal volume, but only among those with more severe childhood maltreatment. In individuals with MDD, decreases in SGK1 expression predicted lower remission rates at week 16, again only among those with more severe maltreatment. Decreases in hippocampal volume predicted lower week 16 remission for those with low childhood maltreatment. These results suggest that both glucocorticoid-related neurobiological mechanisms of the stress response and history of childhood stress exposure may be critical to understanding differential treatment outcomes in MDD. ClinicalTrials.gov: NCT01655706 Canadian Biomarker Integration Network for Depression Study., Competing Interests: Declaration of Competing Interest RM, SC, SH, LF, NN, BNF, KH reported no relevant conflict of interests. RVM has received consulting and speaking honoraria from AbbVie, Allergan, Eisai, Janssen, KYE, Lallemand, Lundbeck, Otsuka, and Sunovion, and research grants from CAN-BIND, Canadian Institutes for Health Research, Janssen, Lallemand, Lundbeck, Nubiyota, Ontario Brain Institute and Ontario Mental Health Foundation. RWL has received honoraria for ad hoc speaking or advising/consulting, or received research funds, from Asia-Pacific Economic Cooperation, BC Leading Edge Foundation, Canadian Institutes for Health Research, Canadian Network for Mood and Anxiety Treatments, Healthy Minds Canada, Janssen, Lundbeck, Lundbeck Institute, Michael Smith Foundation for Health Research, MITACS, Myriad Neuroscience, Ontario Brain Institute, Otsuka, Pfizer, Sanofi, Unity Health, and VGH-UBCH Foundation. SCS received funding from the Ontario Brain Institute and Canadian Institutes for Health Research (MOP137097) for neuroimaging analysis in CAN-BIND, and SCS is a Senior Scientific Advisor and co-owner of ADMdx, Inc., a neuroimaging consulting company. SRA has carried out consultancy work for Indoc Research. SR holds a patent "Teneurin C-Terminal Associated Peptides (TCAP) and methods and uses thereof. Inventors: David Lovejoy, R.B. Chewpoy, Dalia Barsyte, Susan Rotzinger." SHK has received research funding or honoraria from the following sources: Abbott, Alkermes, Abbvie, Brain Canada, Canadian Institutes for Health Research, Janssen, Lundbeck, Lundbeck Institute, Ontario Brain Institute, Ontario Research Fund, Otsuka, Pfizer, Servier, Sunovion and Xian-Janssen and holds stock in Field Trip Health., (Copyright © 2023 Elsevier B.V. and ECNP. All rights reserved.)

Identifying clinically relevant predictors of depressive recurrence following treatment for Major Depressive Disorder (MDD) is critical for relapse prevention. Implicit self-depressed associations (SDAs), defined as implicit cognitive associations between elements of depression (e.g., sad, miserable) and oneself, often persist following depressive episodes and may represent a cognitive biomarker for future recurrences. Thus, we examined whether SDAs, and changes in SDAs over time, prospectively predict depressive recurrence among treatment responders in the CAN-BIND Wellness Monitoring for MDD Study, a prospective cohort study conducted across 5 clinical centres. A total of 96 patients with MDD responding to various treatments were followed an average of 1.01 years. Participants completed the Depression Implicit Association Test (DIAT) - a computer-based measure of SDAs - every 8 weeks on a tablet device. Survival analyses indicated that greater SDAs at baseline and increases in SDAs over time predicted shorter time to MDD recurrence, even after accounting for depressive symptom severity. The findings show that SDAs are a robust prognostic indicator of risk for MDD recurrence, and that the DIAT may be a feasible and low-cost clinical screening tool. SDAs also represent a potential mechanism underlying the course of recurrent depression and are a promising target for relapse prevention interventions., Competing Interests: Declaration of Competing Interest KR, JM, IJT, TC, JF, BNF, KLH, KH, LCQ, and RU disclose no relevant conflict of interests. QSL is an employee of Janssen Research and Development, LLC. RM has received consulting and speaking honoraria from AbbVie, Eisai, Janssen, Lallemand, Lundbeck, Neonmind, and Otsuka, and research grants from CAN-BIND, CIHR, Janssen, Nubiyota, OBI and OMHF. SR has grant funding from Ontario Brain Institute and holds a patent “Teneurin C-Terminal Associated Peptides (TCAP) and methods and uses thereof.” CNS has received consulting honoraria from Eisai, Lundbeck, Otsuka, Diamond Therapeutics and Bayer and research grants from Ontario Brain Institute, SEAMO Innovation Funds and Clairvoyant. SHK has received research funding or honoraria from Abbvie, Abbott, Brain Canada, Boehringer-Ingelheim, Canadian Institutes of Health Research, Janssen, Lundbeck, Lundbeck Institute, Merck, Neurocrine, Ontario Brain Institute, Otsuka, Pfizer, SPOR (Canada's Strategy for Patient-Oriented Research), Sunovion and Servier; and holds stock/stock options in Field Trip Health. RWL has received honoraria for ad hoc speaking or advising/consulting, or received research funds, from Abbvie, Asia-Pacific Economic Cooperation, Bausch, BC Leading Edge Foundation, Brain Canada, Canadian Institutes of Health Research, Canadian Network for Mood and Anxiety Treatments, Healthy Minds Canada, CAN-BIND Solutions, Janssen, Lundbeck, Medscape, Michael Smith Foundation for Health Research, MITACS, Neurotorium, Ontario Brain Institute, Otsuka, Pfizer/Viatris, Unity Health, and VGH-UBCH Foundation., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Individual differences in cortisol output may influence adolescents' adjustment to the COVID-19 pandemic; however, boys and girls may differ in terms of associations between cortisol output and internalizing symptoms in the context of COVID-19-related stress. We examined whether pre-pandemic cortisol output during an acute stressor, assessed approximately three years prior to the pandemic, predicted change in adolescents' internalizing symptoms early during the COVID-19 pandemic. Consistent with previous work on other life stressors, girls' cortisol output was positively associated with anxious and somatic symptoms early in the pandemic. Conversely, cortisol output and depressive symptoms were negatively associated for boys; boys with higher cortisol had depressive symptoms which significantly decreased over time. Findings suggest that hypothalamic-pituitary-adrenal axis stress functioning plays a role in shaping differences between adolescent boys' and girls' adjustment during the experience of a ubiquitous chronic stressor., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Childhood maltreatment (CM) is a strong transdiagnostic risk factor for future psychopathology. This risk is theorized to emerge partly because of glucocorticoid-mediated atrophy in the hippocampus, which leaves this area sensitive to further volume loss even through adulthood in the face of future stress and the emergence of psychopathology. This proof-of-principle study examines which specific dimensions of internalizing psychopathology in the context of a CM history are associated with decreases in hippocampal volume over a 6-month period. This study included 80 community-recruited adults (ages 18-66 years, 61.3% women) oversampled for a lifetime history of internalizing psychopathology. At baseline and a naturalistic 6-month follow-up, the symptom dimensions of the tripartite model (anxious arousal, anhedonic depression, and general distress) were assessed by self-report. Hippocampal volume was derived through T1-weighted magnetic resonance imaging scanning segmented via the volBrain HIPS pipeline. CM severity was determined via a semistructured, contextual interview with independent ratings. We found that higher levels of anxious arousal predicted decreases in hippocampal volume over time in those with greater severity of CM but were associated at a trend with increases in hippocampal volume over time in those with lower severity of maltreatment. Findings were specific to anxious arousal and the CA1 subregion of the hippocampus. These novel results suggest that for individuals with a history of CM, transdiagnostic interventions that target and reduce psychological and physiological arousal may result in the preservation of hippocampal structure and, thus, improvements in cognitive and emotional regulation in the face of stress. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Objective: Childhood maltreatment is a potent enviromarker of risk for poor response to antidepressant medication (ADM). However, childhood maltreatment is a heterogeneous construct that includes distinct exposures that have distinct neurobiological and psychological correlates. The purpose of the current study is to examine the differential associations of emotional, physical, and sexual maltreatment to ADM outcome and to examine the unique role of anhedonia in driving poor response in patients with specific maltreatment histories., Methods: In a multicentre clinical trial of major depression, 164 individuals were assessed for childhood emotional, physical, and sexual maltreatment with a contextual interview with independent, standardized ratings. All individuals received 8 weeks of escitalopram, with nonresponders subsequently also receiving augmentation with aripiprazole, with outcomes measured with depression rating scales and an anhedonia scale., Results: Greater severity of emotional maltreatment perpetrated by the mother was a significant and direct predictor of lower odds of week 16 remission (odds ratio [OR] = 1.68, P  = 0.02). In contrast, the relations of paternal-perpetrated emotional maltreatment and physical maltreatment to week 16 remission were indirect, mediated through greater severity of anhedonia at week 8., Conclusions: We identify emotional maltreatment as a specific early exposure that places patients at the greatest risk for nonremission following pharmacological treatment. Further, we suggest that anhedonia is a key symptom domain driving nonremission in patients with particular maltreatment histories.

Abstract: Cognitive impairment is experienced by many individuals with major depressive disorder (MDD) and is significantly related to sustained disability. Recent work has begun to explore the relationship between childhood adversity (CA) and cognitive impairment in MDD, but this work is limited by unreliable measures of CA. Furthermore, no previous research has examined whether CA relates to cognitive remediation response. The current study clarifies how CA and clinical characteristics of illness explain cognitive variance. In addition, we investigate whether CA is associated with response to cognitive remediation. Thirty-nine individuals who completed cognitive remediation were rerecruited to complete a retrospective interview on CA. Results showed that CA, repeated depressive episodes, and earlier age at diagnosis were associated with poorer cognition. We did not observe a difference in treatment response based on CA. Findings suggest that CA is an important variable to consider when examining the expression of depressive illness and areas for intervention., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Childhood maltreatment increases risk for sexual and physical revictimization in adulthood. The goal of the current study was to examine whether this risk is associated with specific maltreatment types (i.e., sexual vs. physical vs. emotional maltreatment vs. neglect) and perpetrators (i.e., mother vs. father). Participants included 720 adult women from North America and the United Kingdom, recruited through the online platform Prolific Academic. The severity of childhood maltreatment and adult physical and sexual victimization were assessed in two separate sessions through self-report questionnaires. All maltreatment types were modeled together to account for their co-occurrence. Greater severity of sexual maltreatment was significantly and independently associated with greater risk for sexual, physical, and sexual + physical revictimization. Further, in the full sample, risk of revictimization was predicted by greater severity of father-perpetrated emotional and physical maltreatment. In contrast, in subgroup analyses focusing on plurisexual (i.e., bi/pansexual) women, risk of revictimization was predicted by greater severity of mother-perpetrated emotional and physical maltreatment. These results suggest that girls with sexual and emotional maltreatment histories are at highest risk for revictimization. Future research identifying the biological, psychological, and social sequelae of these specific exposures may enable the development of specific intervention programs that have the potential for maximum efficacy in preventing further violence against women most at risk.

Background: In treatment studies of major depressive disorder (MDD), exposure to major life events predicts less symptom improvement and greater likelihood of relapse. In contrast, the impact of minor life events has received less attention. We hypothesized that the impact of minor events on symptom improvement and risk of relapse would be heightened in the presence of concurrent chronic stress. We also hypothesized that major events would predict less symptom improvement and greater risk of relapse independently of chronic stress., Methods: Adult patients experiencing an episode of MDD were enrolled into a 16-week trial with antidepressant treatments (n = 156). Forty-three fully remitted patients agreed to participate in a naturalistic 18-month follow-up, and 30 had full data for analyses. Life events and chronic stressors were assessed using a contextual life stress interview., Results: Greater exposure to minor events predicted greater improvement in symptoms during acute treatment, but this relation was specific to those who reported greater severity of chronic stress. During follow-up, however, major life events predicted increased risk of relapse, and this effect was not moderated by chronic stress., Limitation: High attrition rates led to a small sample size for the follow-up analyses., Conclusions: Exposure to minor events may provide an opportunity to practice problem-solving skills, thereby facilitating symptom improvement. Nevertheless, acute treatment did not protect patients from relapse when they subsequently faced major events during follow-up. Therefore, adjunctive strategies may be needed to enhance outcomes during pharmacotherapy, consolidating benefits from acute treatment and providing skills to prevent relapse., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Major depression is one of the most prevalent and debilitating personal and public health conditions worldwide. Less appreciated is that depression's tremendous burdens are not shared equally among all who become depressed. Some will suffer recurrences over the rest of their lives, whereas half or more will never have a recurrence. Based on these two distinctive life course prototypes, we propose a subtype distinction for research on the origins and lifetime course of major depression. A pressing goal is to determine at the time of depression's first onset who will follow which clinical trajectory. The lack of recognition of this distinction has resulted in many obstacles, including conceptual biases, methodological oversights, and definitional dead ends. Current theories are reviewed and compared. The implications for contemporary diagnostic controversies, reevaluating research on treatment and prevention, and enhancing the predictive strength of traditionally weak indicators of recurrences and recurrent depression are discussed.

The current study provided a novel investigation of relations among particular types of childhood maltreatment (emotional vs. physical vs. sexual maltreatment), specific cognitive schema themes and the generation of dependent versus independent life events. Participants included 227 adolescents and emerging adults (74% female; aged 12-29) in a current episode of a unipolar depressive disorder drawn from three archival cross-sectional studies. Childhood maltreatment and life events from the past 6 months were assessed using detailed contextual interviews with independent, standardized ratings. Emotional maltreatment was uniquely associated with schema themes of emotional deprivation and subjugation, and sexual maltreatment was uniquely associated with schema themes of abandonment, vulnerability and dependence/incompetence. Further, subjugation and abandonment cross-sectionally mediated the relations of emotional and sexual maltreatment, respectively, to greater dependent, but not independent, life events. Physical maltreatment was not associated with cognitive schemas or recent life events after accounting for its overlap with emotional and sexual maltreatment. Results suggest targets for cognitive intervention that may improve outcomes for youth with specific histories of emotional and sexual maltreatment., (© 2021 John Wiley & Sons, Ltd.)

Theory of mind (ToM) - the understanding that others' behaviors are connected with internal mental states - is an important part of everyday social cognition. There is increasing behavioral evidence that ToM reasoning can be affected by mood. To gain insight into the ways sad mood may affect the underlying mechanisms of ToM reasoning, we recorded event-related brain potentials (ERPs) as dysphoric ( N = 16) and non-dysphoric ( N = 24) participants reasoned about a protagonist's true or false beliefs about an object's location. Results showed significant group effects on early components of the ERP - individuals in the dysphoric group showed greater amplitudes for the anterior N1 and N2/P2 components relative to those in the non-dysphoric group. Later in the ERP, non-dysphoric individuals showed evidence of neurocognitive dissociations between true and false belief. Dysphoric individuals, however, did not show evidence for these later dissociations. This evidence suggests that dysphoria may be associated with effortful reasoning about other's mental states, even when that effort is not necessary (i.e., when reasoning about true beliefs). We discuss the implications of these findings for understanding how mood affects ToM reasoning and for how especially deliberative ToM processing in dysphoria may lead to social difficulties.

The COVID-19 pandemic has led to radical disruptions to the routines of individuals and families, but there are few psychometrically assessed measures for indexing behavioural responses associated with a modern pandemic. Given the likelihood of future pandemics, valid tools for assessing pandemic-related behavioral responses relevant to mental health are needed. This need may be especially salient for studies involving families, as they may experience higher levels of stress and maladjustment related to school and business closures. We therefore created the Pandemic Avoidance and Concern Scales (PACS) to assess caregivers' and youths' adjustment to COVID-19 and future pandemics. Concern and Avoidance factors derived from exploratory factor analyses were associated with measures of internalizing symptoms, as well as other indices of pandemic-related disruption. Findings suggest that the PACS is a valid tool for assessing pandemic-related beliefs and behaviors in adults and adolescents. Preliminary findings related to differential adjustment between caregivers and youths are discussed., Competing Interests: Conflict of InterestThe authors have no relevant financial or non-financial interests to declare., (© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Anhedonia is a core feature of psychopathological conditions that have recent exposure to stress and trauma as central to their etiology. Indeed, evolutionary accounts of depression suggest that decreased motivation to pursue reward may be an adaptive strategy in the face of social stress, in particular, as it may serve to defuse interpersonal conflict. Through a review of rodent models and research with humans, we show that exposure to stress, particularly when it is chronic, repeated, and/or involves themes of social rejection or defeat, is consistently associated with reduced hedonic capacity ("liking"), motivation to pursue reward ("wanting"), and ability to learn from reward ("reward learning"). Further, across rodent and human research, there is evidence that females show greater stress-induced blunting of reward processing than males. In humans, this sex difference emerges most strongly when examining individual differences in the stress response rather than group differences in stress exposure. We discuss the implications of these findings for understanding the etiology of, and sex differences in, stress-related psychopathology, including depression and addiction., (© 2022. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Exposure to stressful life events and individual differences in the personality trait neuroticism are important risk factors that interact to predict major depressive disorder (MDD). Less is known about their effect on treatment response in depression. Here, we examine whether stressful life events experienced prior to and during treatment interact with neuroticism to predict response to 16-week pharmacotherapy for MDD. Participants included 159 outpatients with MDD who were initially treated with 8 weeks of escitalopram. Those who responded to the initial treatment continued on escitalopram monotherapy, whereas non-responders received 8 weeks of adjunctive aripiprazole. Personality was assessed using the NEO-Five Factor Inventory, and stressful life events were assessed using the Life Events and Difficulties Schedule, a rigorous contextual interview that includes independent ratings of threatening life events. High baseline neuroticism was associated with a lower likelihood of response when patients experienced one or more negative life events before treatment. Secondary analyses indicated that this effect was specific to neuroticism, and not better accounted for by its self-criticism or negative affect facets. Our results suggest that assessing personality and stressful life events at baseline can help clinicians assess which patients will respond to antidepressant therapy and which may need treatment augmentation., (© 2021 John Wiley & Sons, Ltd.)

Depression is associated with blunted reactivity to acute stress, as well as blunted responsivity to rewards. However, the extent to which responses to stress are associated with responses to reward in individuals meeting criteria for a depressive disorder is unknown. The goal of this study was to examine the relation of responses to stress and reward, and to determine if this relation is moderated by depression diagnosis, anhedonia, and sex. Participants included 114 adults (68 depressed, 46 non-depressed; 75% women) recruited from the community. Stress reactivity was operationalized as the total salivary cortisol output to the Trier Social Stress Test (TSST; Kirschbaum et al., 1993). Response bias to monetary reward was assessed following the TSST recovery period with a probabilistic reward task (PRT; Pizzagalli et al., 2005). In men only, total cortisol output during the TSST was more strongly positively associated with response bias to reward across the three blocks of the PRT. In addition, among depressed participants with high levels of anhedonia, higher cortisol output during the TSST was significantly associated with higher overall response bias to reward. We suggest that in men, the stress and reward systems may both respond quickly, and resolve rapidly, in the face of acute stress. Further, in depression, our findings suggest that anhedonia may represent a specific phenotype in which the stress and reward systems are particularly tuned together., (Copyright © 2021. Published by Elsevier B.V.)

Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis is considered one of the mechanisms underlying the development of major depressive disorder (MDD), but the exact nature of this dysfunction is unknown. We investigated the relationship between hypothalamus volume (HV) and blood-derived DNA methylation in MDD. We obtained brain MRI, clinical and molecular data from 181 unmedicated MDD and 90 healthy control (HC) participants. MDD participants received a 16-week standardized antidepressant treatment protocol, as part of the first Canadian Biomarker Integration Network in Depression (CAN-BIND) study. We collected bilateral HV measures via manual segmentation by two independent raters. DNA methylation and RNA sequencing were performed for three key HPA axis-regulating genes coding for the corticotropin-binding protein (CRHBP), glucocorticoid receptor (NR3C1) and FK506 binding protein 5 (FKBP5). We used elastic net regression to perform variable selection and assess predictive ability of methylation variables on HV. Left HV was negatively associated with duration of current episode (ρ = -0.17, p = 0.035). We did not observe significant differences in HV between MDD and HC or any associations between HV and treatment response at weeks 8 or 16, overall depression severity, illness duration or childhood maltreatment. We also did not observe any differentially methylated CpG sites between MDD and HC groups. After assessing functionality by correlating methylation levels with RNA expression of the respective genes, we observed that the number of functionally relevant CpG sites differed between MDD and HC groups in FKBP5 (χ 2 = 77.25, p < 0.0001) and NR3C1 (χ 2 = 7.29, p = 0.007). Cross-referencing functionally relevant CpG sites to those that were highly ranked in predicting HV in elastic net modeling identified one site from FKBP5 (cg03591753) and one from NR3C1 (cg20728768) within the MDD group. Stronger associations between DNA methylation, gene expression and HV in MDD suggest a novel putative molecular pathway of stress-related sensitivity in depression. Future studies should consider utilizing the epigenome and ultra-high field MR data which would allow the investigation of HV sub-fields., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

There has been extensive discussion about gender gaps in representation and career advancement in the sciences. However, psychological science itself has yet to be the focus of discussion or systematic review, despite our field's investment in questions of equity, status, well-being, gender bias, and gender disparities. In the present article, we consider 10 topics relevant for women's career advancement in psychological science. We focus on issues that have been the subject of empirical study, discuss relevant evidence within and outside of psychological science, and draw on established psychological theory and social-science research to begin to chart a path forward. We hope that better understanding of these issues within the field will shed light on areas of existing gender gaps in the discipline and areas where positive change has happened, and spark conversation within our field about how to create lasting change to mitigate remaining gender differences in psychological science.

Background: The current study presents a randomized controlled 8-week trial of Bikram yoga, aerobic exercise, and waitlist for depression. Bikram yoga was chosen specifically for its standardized nature. Further, we examined changes in three stress-related constructs-perceived stress, rumination, and mindfulness-as mediators of antidepressant effects., Method: Fifty-three women (age 18-65; 74% White) with a unipolar depressive disorder were randomly assigned to one of the three conditions. Response was defined as >50% reduction on the Hamilton Rating Scale for Depression (HAM-D). Remission was defined as no longer meeting criteria for depression and a HAM-D ≤ 7. Self-reported perceived stress, rumination, and mindfulness were assessed weekly., Results: In the intention-to-treat sample (n = 53), response rates were significantly higher in the Bikram yoga (61.1%; χ 2  = 10.48, p = .001) and aerobic exercise (60.0%; χ 2  = 10.44, p = .001) conditions relative to waitlist (6.7%). In the completer sample (n = 42), 73.3% (χ 2  = 11.41, p = .001) of women in yoga and 80.0% (χ 2  = 13.72, p < .001) in exercise achieved response compared to 8.3% in waitlist. Reductions in rumination significantly mediated HAM-D change for both active treatments, and mindful acceptance was a partial mediator in the exercise condition., Limitations: The sample was small in size, consisted of women only, and was ethnically homogenous. Inter-rater reliability was not assessed, aerobic exercise was not standardized, and mediators were assessed by self-report., Conclusions: Bikram yoga showed descriptively similar efficacy to aerobic exercise and both may work, in part, by helping individuals interrupt negative thinking., (Copyright © 2020. Published by Elsevier B.V.)

Background: Patients with major depressive disorder (MDD) display cognitive deficits in acutely depressed and remitted states. Childhood maltreatment is associated with cognitive dysfunction in adults, but its impact on cognition and treatment related cognitive outcomes in adult MDD has received little consideration. We investigate whether, compared to patients without maltreatment and healthy participants, adult MDD patients with childhood maltreatment display greater cognitive deficits in acute depression, lower treatment-associated cognitive improvements, and lower cognitive performance in remission., Methods: Healthy and acutely depressed MDD participants were enrolled in a multi-center MDD predictive marker discovery trial. MDD participants received 16 weeks of standardized antidepressant treatment. Maltreatment and cognition were assessed with the Childhood Experience of Care and Abuse interview and the CNS Vital Signs battery, respectively. Cognitive scores and change from baseline to week 16 were compared amongst MDD participants with (DM+, n = 93) and without maltreatment (DM-, n = 90), and healthy participants with (HM+, n = 22) and without maltreatment (HM-, n = 80). Separate analyses in MDD participants who remitted were conducted., Results: DM+ had lower baseline global cognition, processing speed, and memory v. HM-, with no significant baseline differences amongst DM-, HM+, and HM- groups. There were no significant between-group differences in cognitive change over 16 weeks. Post-treatment remitted DM+, but not remitted DM-, scored significantly lower than HM- in working memory and processing speed., Conclusions: Childhood maltreatment was associated with cognitive deficits in depressed and remitted adults with MDD. Maltreatment may be a risk factor for more severe and persistent cognitive deficits in adult MDD.

Childhood maltreatment is widely implicated as the strongest developmental risk factor for depression onset. The current research is novel in examining the fine-grained associations of childhood emotional versus physical versus sexual maltreatment to indices of the severity, course, and presence of anxiety and trauma-related psychopathology in depression. An amalgamation across 6 previous investigations resulted in a sample of 575 adolescents and adults (76% female; age range 12-70, M = 27.88, SD = 13.58). All participants were in a current episode of a unipolar depressive disorder. Retrospective reports of childhood maltreatment were assessed using a rigorous contextual interview with independent, standardized ratings. Higher levels of emotional maltreatment and/or sexual maltreatment emerged as significantly associated with greater depression severity, number of previous episodes, and risk for posttraumatic stress disorder (PTSD), and were significantly more strongly associated with these characteristics than was physical maltreatment. Further, emotional maltreatment perpetrated by mothers was significantly associated with depression severity and history, whereas emotional maltreatment perpetrated by fathers was significantly associated with a greater risk of PTSD. These latter results suggest that prevention and intervention efforts may need to focus on the unique roles of mothers versus fathers on the development of depressive- versus threat-related psychopathology, respectively. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

The Reading the Mind in the Eyes task (RMET; Baron-Cohen, Wheelwright, Hill, Raste, & Plumb, 2001) is commonly used to assess theory of mind abilities in adults. In the task, participants pair one of four mental state descriptors with a picture of the eye region of a face. The items have varying emotional valence, and nearly 100 studies have examined whether performance on this task varies with item valence. However, efforts to address this question have been hampered by cross-study inconsistencies in how item valence is assessed. Thus, the goal of this study was to establish reference ratings for the valence of RMET items. In Study 1, we recorded valence ratings for each RMET item with a large sample of raters ( n = 164). We illustrated how valence categories are essentially arbitrary and largely influenced by sample size. In addition, valence ratings were continuously distributed, further questioning the validity of imposing categorical distinctions. In Study 2, we used an archival dataset to demonstrate how the different categorization schemes resulted in conflicting conclusions about the association between item valence and RMET performance. However, when we examined the association between item valence and performance in a continuous manner, a clear U-shaped pattern emerged: Items that had more extreme valence ratings (negative or positive) were associated with better performance than items with more neutral ratings. We conclude that using the item valence ratings we report, and treating item valence as a continuous rather than categorical predictor, will help bring consistency to the study of the association between item valence and performance in the RMET. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Finding a clinically useful neuroimaging biomarker that can predict treatment response in patients with major depressive disorder (MDD) is challenging, in part because of poor reproducibility and generalizability of findings across studies. Previous work has suggested that posterior hippocampal volumes in depressed patients may be associated with antidepressant treatment outcomes. The primary purpose of this investigation was to examine further whether posterior hippocampal volumes predict remission following antidepressant treatment. Magnetic resonance imaging (MRI) scans from 196 patients with MDD and 110 healthy participants were obtained as part of the first study in the Canadian Biomarker Integration Network in Depression program (CAN-BIND 1) in which patients were treated for 16 weeks with open-label medication. Hippocampal volumes were measured using both a manual segmentation protocol and FreeSurfer 6.0. Baseline hippocampal tail (Ht) volumes were significantly smaller in patients with depression compared to healthy participants. Larger baseline Ht volumes were positively associated with remission status at weeks 8 and 16. Participants who achieved early sustained remission had significantly greater Ht volumes compared to those who did not achieve remission by week 16. Ht volume is a prognostic biomarker for antidepressant treatment outcomes in patients with MDD.

Approximately half of the people who suffer a major depressive episode for the first time experience recurrences, while the other half do not. Among the initially depressed, however, who will have recurrences remains a mystery, and cannot be forecasted with any statistical or clinical confidence. It is well documented, though, that highly stressful life events commonly precede first episodes of major depression, and that these experiences become progressively less common prior to recurrences. Determining the basis for this consistent empirical observation holds promise for discovering among the initially depressed who will become recurrent, helping to solve the current-day conundrum of recurrences. The present article has 2 overarching objectives. First, we evaluate stress sensitization, the prevailing theory for explaining the decreasing association of major life events with successive recurrences. Conceptual gaps, discrepancies, and misunderstandings are found for understanding the decreasing association, as well as for understanding recurrences. Research practices and logical errors also are exposed that compromise the integrity of the existing empirical record. Second, alternative theoretical accounts are proposed to explain the decreasing association of major life stress with recurrences. Two "dual pathway models" provide viable alternative explanations, fill in existing theoretical gaps, and supply additional advantages for understanding life stress, depression, and recurrences. Recommendations are made for evaluating the 3 respective models. In closing, limitations and remaining questions are discussed for discovering who, early in the lifetime course of major depression, is likely to have a lifetime of repeated recurrences. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Subtle changes in hippocampal volumes may occur during both physiological and pathophysiological processes in the human brain. Assessing hippocampal volumes manually is a time-consuming procedure, however, creating a need for automated segmentation methods that are both fast and reliable over time. Segmentation algorithms that employ deep convolutional neural networks (CNN) have emerged as a promising solution for large longitudinal neuroimaging studies. However, for these novel algorithms to be useful in clinical studies, the accuracy and reproducibility should be established on independent datasets. Here, we evaluate the performance of a CNN-based hippocampal segmentation algorithm that was developed by Thyreau and colleagues - Hippodeep. We compared its segmentation outputs to manual segmentation and FreeSurfer 6.0 in a sample of 200 healthy participants scanned repeatedly at seven sites across Canada, as part of the Canadian Biomarker Integration Network in Depression consortium. The algorithm demonstrated high levels of stability and reproducibility of volumetric measures across all time points compared to the other two techniques. Although more rigorous testing in clinical populations is necessary, this approach holds promise as a viable option for tracking volumetric changes in longitudinal neuroimaging studies., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Studies of clinical populations that combine MRI data generated at multiple sites are increasingly common. The Canadian Biomarker Integration Network in Depression (CAN-BIND; www.canbind.ca) is a national depression research program that includes multimodal neuroimaging collected at several sites across Canada. The purpose of the current paper is to provide detailed information on the imaging protocols used in a number of CAN-BIND studies. The CAN-BIND program implemented a series of platform-specific MRI protocols, including a suite of prescribed structural and functional MRI sequences supported by real-time monitoring for adherence and quality control. The imaging data are retained in an established informatics and databasing platform. Approximately 1300 participants are being recruited, including almost 1000 with depression. These include participants treated with antidepressant medications, transcranial magnetic stimulation, cognitive behavioural therapy and cognitive remediation therapy. Our ability to analyze the large number of imaging variables available may be limited by the sample size of the substudies. The CAN-BIND program includes a multimodal imaging database supported by extensive clinical, demographic, neuropsychological and biological data from people with major depression. It is a resource for Canadian investigators who are interested in understanding whether aspects of neuroimaging — alone or in combination with other variables — can predict the outcomes of various treatment modalities., Competing Interests: G. MacQueen reports consultancy/speaker fees from Lundbeck, Pfizer, Johnson & Johnson and Janssen, outside the submitted work. B. Frey reports grants and personal fees from Pfizer and personal fees from Sunovion, outside the submitted work. R. Milev reports grants, nonfinancial support and honoraria from Lundbeck, Janssen and Pfizer; personal fees and honoraria from Sunovion, Shire, Allergan and Otsuka; grants from Boehringer Ingelheim; and grants from the Ontario Brain Institute, the Canadian Institutes for Health Research and CAN-BIND, outside the submitted work. F. Vila-Rodriguez reports nonfinancial support from Magventure during the conduct of the study; grants from the Canadian Institutes for Health Research, Brain Canada, the Michael Smith Foundation for Health Research, and the Vancouver Coastal Health Research Institute; and personal fees from Janssen, outside the submitted work. S. Rizvi reports grants from Pfizer Canada, outside the submitted work. S. Strother reports grants from Canadian Biomarker Integration Network in Depression during the conduct of the study and grants from Ontario Brain Institute, outside the submitted work. He is also the chief scientific officer of the neuroimaging data analysis company ADMdx, Inc (www. admdx.com), which specializes in brain image analysis to enable diagnosis, prognosis and drug effect detection for Alzheimer disease and various other forms of dementia. R. Lam reports grants from Canadian Institutes of Health Research during the conduct of the study; grants from Asia-Pacific Economic Cooperation, VGH-UBCH Foundation, BC LEading Edge Endowment Fund, Janssen, Lundbeck, Pfizer and St. Jude Medical, outside the submitted work; personal fees from Allergan, Akili, CME Institute, Canadian Network for Mood and Anxiety Treatments, Janssen, Lundbeck, Lundbeck Institute, Pfizer, Otsuka, Medscape and Hansoh, outside the submitted work; travel expenses from Asia-Pacific Economic Cooperation outside the submitted work; and stock options from Mind Mental Health Technologies., (© 2019 Joule Inc. or its licensors)

Depression is the most common mental disorder in pregnancy. An important risk factor in the development of prenatal depression is lifetime history of abuse. The current review quantitatively synthesized research on the association between history of abuse and prenatal depressive symptoms using a meta-analytic technique. A total of 3322 articles were identified through electronic searches of the following databases: PsycINFO, PubMed, CINAHL, and EMBASE Cochrane Collaboration databases between the years of 1980 and 2016. All were independently screened against the following inclusion criteria: articles reporting on original data that included measures of prenatal depression and abuse. Data were extracted by the first and second authors. Descriptive analyses were conducted using Excel version 15.32, and all analyses involving effect sizes were conducted using comprehensive meta-analysis (CMA) version 3.0. Seventy articles met the inclusion criteria and were included in the meta-analyses. Meta-bias detected no publication bias. Abuse had a significant positive relation with prenatal depressive symptoms, with effect sizes in the moderate range for any abuse ([Formula: see text] = 0.287), physical abuse ([Formula: see text] = 0.271), sexual abuse ([Formula: see text] = 0.259), and emotional abuse ([Formula: see text] = 0.340; Cohen 1969. Statistical power analysis for the behavioral sciences. Academic Press, New York). The meta-analyses found a robust relation between abuse and prenatal depressive symptoms holding across a variety of demographic and study design characteristics. These results reinforce the established association between trauma victimization and subsequent psychopathology, extending current knowledge to specifically address the under-studied area of prenatal depression. These findings highlight the need for women who have survived child or adulthood abuse to receive appropriate referral and psychological treatment to mitigate their risk for prenatal depression.

Background: Childhood maltreatment is one of the strongest predictors of sexual and peer bullying re-victimization. However, it is not clear which types of maltreatment are associated with the greatest risk., Objective: The current study examined the differential relations of maternal- versus paternal-perpetrated emotional maltreatment, neglect, and physical maltreatment, as well as sexual maltreatment, to sexual victimization and peer bullying victimization outside the home. It was hypothesized that paternal-perpetrated emotional maltreatment would be the strongest predictor of later sexual and peer bullying victimization, and that sexual maltreatment would predict sexual re-victimization., Participants and Setting: Participants included data from 263 adolescent and young adult women who had previously taken part in one of three larger studies conducted in an academic research setting investigating the relation between stress and depression. All participants had been recruited from the wider community or clinician referral and met criteria for a unipolar depressive disorder., Methods: Psychiatric diagnoses were assessed with a structured diagnostic interview. Childhood maltreatment and victimization were assessed retrospectively with a semi-structured contextual interview that includes standardized ratings., Results: Paternal-perpetrated emotional abuse was the only maltreatment type that was independently associated with sexual (OR = 3.09, p =  .004) and peer bullying (OR = 1.41, p =  .05) re-victimization over other forms of maltreatment and indicators of depression severity., Conclusions: These findings provide an important foundation for future research examining the mechanisms driving the relation between father's hostility, criticism, and rejection and daughters' revictimization that can ultimately provide targets for prevention in girls at highest risk., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: To report the symptomatic and functional outcomes in patients with major depressive disorder (MDD) during a 2-phase treatment trial and to estimate the value of early improvement after 2 weeks in predicting clinical response to escitalopram and subsequently to adjunctive treatment with aripiprazole., Methods: Participants with MDD (N = 211) identified with the Montgomery-Asberg Depression Rating Scale (MADRS) and confirmed with the Mini-International Neuropsychiatric Interview were recruited from 6 outpatient centers across Canada (August 2013 through December 2016) and treated with open-label escitalopram (10-20 mg) for 8 weeks (Phase 1). Clinical and functional outcomes were evaluated using the MADRS, Quick Inventory of Depressive Symptomatology-Self-Rated (QIDS-SR), Sheehan Disability Scale (SDS), and Lam Employment Absence and Productivity Scale (LEAPS). Participants were evaluated at 8 and 16 weeks for clinical and functional response and remission. Phase 1 responders continued escitalopram while nonresponders received adjunctive aripiprazole (2-10 mg) for a further 8 weeks (Phase 2)., Results: After Phase 1, MADRS response (≥ 50% decrease from baseline) and remission (score ≤ 10) were, respectively, 47% and 31%, and SDS response (score ≤ 12) and remission (score ≤ 6) were, respectively, 53% and 24%. Response to escitalopram was maintained in 91% of participants at week 16, while 61% of the adjunctive aripiprazole group achieved MADRS response during Phase 2. Response and remission rates with the QIDS-SR were lower than with the MADRS. The LEAPS demonstrated significant occupational improvement (P < .05). Early symptomatic improvement predicted outcomes with modest accuracy., Conclusions: This study demonstrates comparable symptomatic and functional outcomes to those of other large practical-design studies. There was a high response rate with the adjunctive use of aripiprazole in escitalopram nonresponders. Given the limited value of early clinical improvement to predict outcome, integration of clinical and biological markers deserves further exploration., Trial Registration: ClinicalTrials.gov identifier: NCT01655706., (© Copyright 2019 Physicians Postgraduate Press, Inc.)

Substantial uncertainty exists about the prevalence of depressive disorders in individuals with autism spectrum disorder (ASD). This meta-analysis quantitatively summarized studies that assessed the lifetime and current prevalence of unipolar depressive disorders in children, adolescents, and adults with ASD. We also examined demographic, methodological, and study moderators. This meta-analysis adhered to PRISMA guidelines. A total of 7857 articles were identified through 5 databases (PubMed, Web of Science, PYSCInfo, CINAHL, ProQuest Dissertations and Theses), forward searches, and backward searches. Two reviewers independently screened articles and extracted data. Sixty-six articles met inclusion criteria. Results indicated that the pooled lifetime and current prevalence was 14.4% (95% CI 10.3-19.8) and 12.3% (95% CI 9.7-15.5), respectively. Rates of depressive disorders were highest among studies that used a standardized interview to assess depressive disorders (lifetime = 28.5%, 95% CI 20.1-38.8; current = 15.3%, 95% CI 11.0-20.9) and required participants to report on their own depressive symptoms (lifetime = 48.6%, 95% CI 33.3-64.2; current = 25.9%, 95% CI 17.0-37.3). Rates were also higher in studies that included participants with higher intelligence. Lifetime, but not current, prevalence was positively associated with age and the proportion of the sample that was White. In conclusion, we found that the rates of depressive disorders are high among individuals with ASD. Compared to typically developing individuals, individuals with ASD are 4-times more likely to experience depression in their lifetime. These results suggest that individuals with ASD should be regularly screened and offered treatment for depression.

Endothelial function, assessed by flow-mediated dilation (FMD), may be transiently attenuated in healthy adults following acute mental stress. However, the impact of acute mental stress on endothelial function in the context of clinical depression is unknown. This study examined the impact of acute mental stress on FMD in women with a diagnosis of a depressive disorder. Forty-three otherwise healthy women (33 ± 14 years) participated. Brachial artery diameter and blood velocity were assessed with ultrasound. FMD was assessed immediately prior to and 15 min following the Trier Social Stress Test (TSST). The FMD protocol included 5 min of forearm cuff occlusion (pressure = 250 mm Hg), followed by release. Shear stress was estimated by calculating shear rate (SR = brachial artery blood velocity/diameter). Stress reactivity was assessed via changes in mean arterial pressure (MAP), heart rate (HR) and salivary cortisol. Results are mean ± SD. A significant stress response was elicited by the TSST [MAP, HR and salivary cortisol increased (p < 0.05)]. Neither the SR stimulus nor FMD response differed pre-versus post-stress (p = 0.124 and p = 0.641, respectively). There was a modest negative correlation between cortisol reactivity and change in FMD from pre- to post-stress (R = -0.392, p = 0.011). To conclude, acute mental stress did not consistently impair endothelial function in women diagnosed with a depressive disorder; however, higher cortisol reactivity may increase the likelihood of post-stress endothelial dysfunction. Further research is required to better understand the factors influencing the relationship between acute mental stress, cortisol and endothelial function in women with depression., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The current study is the first to examine the relation of childhood abuse and neglect history to theory of mind decoding accuracy as moderated by depression. Fifty-five young adults with current or lifetime unipolar depression diagnosis and 70 never-depressed young adults completed the 'Reading the Mind in the Eyes task,' (RMET). Childhood emotional abuse, physical abuse, and neglect were assessed with a gold-standard contextual interview with standardized, independent ratings. Poorer RMET accuracy was associated with a history of emotional abuse in the depressed group and a history of physical abuse in the non-depressed group. In contrast, across both groups, those with a history of neglect showed significantly enhanced theory of mind decoding accuracy compared to those without. Further, differential accuracy across positive, negative, and neutral valenced stimuli in the RMET was observed in each model. These findings indicate that distinct theory of mind performance results from early experiences of threat versus deprivation, and suggest that early intervention may be most successful in preventing negative interpersonal outcomes of maltreatment by focusing on remediating theory of mind deficits resulting from abuse, and tempering heightened sensitivity in those exposed to neglect., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Youth with depression are theorized to generate stress in their lives because of a complex interaction between their personal characteristics and their chronic environmental context. Using a moderated regression approach, we provided a novel test of this hypothesis by examining whether adolescent 5-factor model personality traits moderate the associations between early emotional, physical, and sexual maltreatment and life events experienced in the past 6 months. Participants in this cross-sectional study were 110 adolescents (M = 16.24, SD = 1.53, age range = 13-17, 74.5% female) with major depressive disorder. The relation of physical maltreatment to dependent interpersonal life events was moderated by extraversion. Among physically maltreated youth, dependent interpersonal events were positively associated with extraversion. Further, the relation of sexual maltreatment to independent events were moderated by extraversion and agreeableness. Among sexually maltreated youth, independent events were negatively associated with extraversion and positively associated with agreeableness. The observed vulnerability-risk interactions are discussed in terms of their implications for understanding the role of stress generation mechanisms in an integrated model of depression. (PsycINFO Database Record, ((c) 2017 APA, all rights reserved).)

Objective: This study tested whether core beliefs with themes of abandonment and rejection moderated the link between trait and behavioral excessive reassurance seeking (ERS) and interpersonal rejection., Method: Participants were 118 women with high (n = 43; mean [M] age = 18.58, standard deviation [SD] age = 1.24) and low (n = 75; M age = 18.58, SD age = 1.24) levels of depression symptoms and their male romantic partners. Couples reported their depression, ERS, abandonment/rejection cognitions, and relationship quality. We also coded women's reassurance-seeking behavior during an audiotaped discussion task., Results: Among women with high levels of depression symptoms and low levels of abandonment/rejection core beliefs, behavioral ERS was associated with lower partner-reported relationship quality. Self-reported ERS was significantly associated with partner relationship quality, but the effect was not moderated by depression or core beliefs., Conclusions: ERS is a potent predictor of stress and subsequent depression. Our findings underscore the need to better understand factors (e.g., cognitions, partner characteristics) that may determine whether ERS behaviors beget interpersonal stress and rejection., (© 2016 Wiley Periodicals, Inc.)

The strongest proximal predictors of depression onset in adolescence are stressful life events (SLEs). Changes in the hypothalamic-pituitary-adrenal (HPA) axis response to stress are theorized to mediate the etiological effect of SLEs on depression onset. The goal of the current study was to examine differences in the cortisol response to a laboratory-induced stressor between youth with versus without at least one SLE in the etiologically-central 3-month period prior to depression onset. One hundred adolescents (24 first-onset depression, 18 recurrent depression, and 58 non-depressed controls) had five salivary cortisol samples collected over the course of the Trier Social Stress Test (TSST). SLEs were assessed using a rigorous contextual interview and rating system. Among those with an SLE, youth on their first onset of depression had a flatter cortisol reactivity slope relative to non-depressed adolescents, and youth on a recurrent episode of depression had a steeper recovery slope relative to first-onsets and non-depressed adolescents. In contrast, no between-group differences were found among those with no SLE prior to onset. These results suggest that differences in the HPA axis response pattern may represent a neurobiological mechanism that distinguishes depressed and non-depressed groups but only for adolescents whose depression is precipitated by SLEs. Further, this neurobiological mechanism may play a different role in the very first episode of depression than it does in recurrent episodes.

Life stress is a central factor in the onset and course of a wide range of medical and psychiatric conditions. Determining the precise etiological and pathological consequences of stress, though, has been hindered by weaknesses in prevailing definitional and measurement practices. The purpose of the current paper is to evaluate the primary strategies for defining and measuring major and minor acute life events, chronic stressors, and daily hassles as informed by 3 basic scientific premises. The first premise concerns the manner in which stress is conceptualized and operationally defined, and specifically we assert that stress measures must not conflate the stress exposure with the stress response. The second premise concerns how stress exposures are measured, and we provide guidelines for optimizing standardized and sensitive indicators of life stress. The third premise addresses the consequences of variations in the procedures for life event measurement with regard to the validity of the research designs employed. We show that life stress measures are susceptible to several sources of bias, and if these potential sources of bias are not controlled in the design of the research, spurious findings may result. Our goal is to provide a useful guide for researchers who consider life stress to be an important factor in their theoretical models of disease, wish to incorporate measures of life stress in their research, and seek to avoid the common pitfalls of past measurement practices. (PsycINFO Database Record, ((c) 2016 APA, all rights reserved).)

Bipolar disorder is associated with significant deficits in the decoding of others' mental states in comparison to healthy participants. However, differences in theory of mind decoding ability among patients in manic, depressed, and euthymic phases of bipolar disorder is currently unknown. Fifty-nine patients with bipolar I or II disorder (13 manic, 25 depressed, 20 euthymic) completed the "Reading the Mind in the Eyes" Task (Eyes task) and the Animals Task developed to control for non-mentalistic response demands of the Eyes Task. Patients also completed self-report and clinician-rated measures of depression, mania, and anxiety symptoms. Patients in the manic phase were significantly less accurate than those in the depressed and euthymic phases at decoding mental states in the Eyes task, and this effect was strongest for eyes of a positive or neutral valence. Further Eyes task performance was negatively correlated with the symptoms of language/thought disorder, pressured speech, and disorganized thoughts and appearance. These effects held when controlling for accuracy on the Animals task, response times, and relevant demographic and clinical covariates. Results suggest that the state of mania, and particularly psychotic symptoms that may overlap with the schizophrenia spectrum, are most strongly related to social cognitive deficits in bipolar disorder., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Major Depressive Disorder (MDD) is among the most prevalent and disabling medical conditions worldwide. Identification of clinical and biological markers ("biomarkers") of treatment response could personalize clinical decisions and lead to better outcomes. This paper describes the aims, design, and methods of a discovery study of biomarkers in antidepressant treatment response, conducted by the Canadian Biomarker Integration Network in Depression (CAN-BIND). The CAN-BIND research program investigates and identifies biomarkers that help to predict outcomes in patients with MDD treated with antidepressant medication. The primary objective of this initial study (known as CAN-BIND-1) is to identify individual and integrated neuroimaging, electrophysiological, molecular, and clinical predictors of response to sequential antidepressant monotherapy and adjunctive therapy in MDD., Methods: CAN-BIND-1 is a multisite initiative involving 6 academic health centres working collaboratively with other universities and research centres. In the 16-week protocol, patients with MDD are treated with a first-line antidepressant (escitalopram 10-20 mg/d) that, if clinically warranted after eight weeks, is augmented with an evidence-based, add-on medication (aripiprazole 2-10 mg/d). Comprehensive datasets are obtained using clinical rating scales; behavioural, dimensional, and functioning/quality of life measures; neurocognitive testing; genomic, genetic, and proteomic profiling from blood samples; combined structural and functional magnetic resonance imaging; and electroencephalography. De-identified data from all sites are aggregated within a secure neuroinformatics platform for data integration, management, storage, and analyses. Statistical analyses will include multivariate and machine-learning techniques to identify predictors, moderators, and mediators of treatment response., Discussion: From June 2013 to February 2015, a cohort of 134 participants (85 outpatients with MDD and 49 healthy participants) has been evaluated at baseline. The clinical characteristics of this cohort are similar to other studies of MDD. Recruitment at all sites is ongoing to a target sample of 290 participants. CAN-BIND will identify biomarkers of treatment response in MDD through extensive clinical, molecular, and imaging assessments, in order to improve treatment practice and clinical outcomes. It will also create an innovative, robust platform and database for future research., Trial Registration: ClinicalTrials.gov identifier NCT01655706 . Registered July 27, 2012.

Theory of mind-the ability to decode and reason about others' mental states-is a universal human skill and forms the basis of social cognition. Theory of mind accuracy is impaired in clinical conditions evidencing social impairment, including major depressive disorder. The current study is a preliminary investigation of the association of polymorphisms of the serotonin transporter (SLC6A4), dopamine transporter (DAT1), dopamine receptor D4 (DRD4), and catechol-O-methyl transferase (COMT) genes with theory of mind decoding in a sample of adults with major depression. Ninety-six young adults (38 depressed, 58 non-depressed) completed the 'Reading the Mind in the Eyes task' and a non-mentalistic control task. Genetic associations were only found for the depressed group. Specifically, superior accuracy in decoding mental states of a positive valence was seen in those homozygous for the long allele of the serotonin transporter gene, 9-allele carriers of DAT1, and long-allele carriers of DRD4. In contrast, superior accuracy in decoding mental states of a negative valence was seen in short-allele carriers of the serotonin transporter gene and 10/10 homozygotes of DAT1. Results are discussed in terms of their implications for integrating social cognitive and neurobiological models of etiology in major depression.

This study examined the relation between a history of maltreatment and the presence of psychotic symptoms in a community sample of adolescents and young adults with major depressive disorder. One hundred and twenty-nine depressed adolescents and young adults (M = 16.02 years, 77% female, 92% White) were recruited through community advertisement and clinician referral. Clinical diagnoses and psychotic symptoms (i.e., hallucinations and delusions) were assessed using a structured diagnostic interview. Childhood maltreatment was assessed using a contextual interview and standardized rating system. Logistic regression analyses examined the relation between childhood maltreatment and psychotic symptoms. As hypothesized, individuals with psychotic symptoms were significantly more likely to report a history of severe sexual maltreatment than those without psychotic symptoms (Wald = 5.44, odds ratio = 3.86, p = .020), 95% confidence interval [1.24, 12.01]. Further, those with psychotic symptoms were more likely to report being the victims of more than one type of maltreatment than those without, χ2(2) = 6.66, p = .036 (ϕ = .23; 40% vs. 16%). Results held upon adjusting for overall level of depression symptoms. A history of severe sexual maltreatment is related to a severe presentation of major depressive disorder even in the initial onset of the syndrome in adolescence and young adulthood. These findings underscore the importance of early assessment of both depression and maltreatment history to implement interventions that have the potential to prevent the emergence of psychotic psychopathology in young people at risk.

Social anxiety disorder is characterized by marked interpersonal impairment, particularly when presenting with comorbid major depression. However, the foundational social-cognitive skills that underlie interpersonal impairment in comorbid and non-comorbid manifestations of SAD has to date received very little empirical investigation. In a sample of 119 young adults, the current study examined differences in theory of mind (ToM), defined as the ability to decode and reason about others' mental states, across four groups: (a) non-comorbid SAD; (b) non-comorbid Lifetime MDD; (c) comorbid SAD and Lifetime MDD; and (d) healthy control. The non-comorbid SAD group was significantly less accurate at decoding mental states than the non-comorbid MDD and control groups. Further, both the comorbid and non-comorbid SAD groups made significantly more 'excessive' ToM reasoning errors than the non-comorbid MDD group, suggesting a pattern of over-mentalizing. Findings are discussed in terms of their implications for understanding the social cognitive foundations of social anxiety., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objectives: Childhood abuse is a powerful prognostic indicator in adults with major depressive disorder (MDD) and is associated with numerous biological risk factors for depression. The purpose of this investigation was to explore if antidepressant medication affinity for the serotonin transporter moderates the association between childhood abuse and treatment response., Methods: Our sample included 52 outpatients with MDD who had received up to 26 weeks of pharmacotherapy, stratifying antidepressant medications with a high versus a low affinity for the serotonin transporter. Patients completed the Hamilton Rating Scale for Depression, Beck Depression Inventory II, Home Environment Questionnaire, and Ontario Health Supplement: Child Abuse and Trauma Scale to assess depression and childhood abuse., Results: Medication class moderated the link between 3 indices of childhood abuse and treatment response such that higher levels of childhood abuse were associated with higher levels of depression severity after treatment only in those patients receiving antidepressant medications with a weak affinity for the serotonin transporter., Conclusions: This pilot study suggested that prolonged exposure to stress during childhood may result in biological vulnerabilities for depression, which may in turn be differentially targeted by pharmacological agents which target serotonin to a greater or lesser degree., (© 2017 S. Karger AG, Basel.)

This study represents the first replication of the BDNF Val66Met ⁎ 5-HTTLPR ⁎ childhood maltreatment effect on self-reported depression symptoms using a rigorous maltreatment interview. Participants included a community sample of 339 adolescents/young adults (age 12-33; 265 female). In the context of childhood neglect, among BDNF Met-carriers, s-allele carriers of 5-HTTLPR reported significantly higher depression than l/l homozygotes, whereas a differential relation of 5-HTTLPR genotype to depression was not seen among BDNF Val/Val homozygotes., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)