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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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

Background: Antidepressant medications, Cognitive-Behavioral Therapy (CBT) and Interpersonal Psychotherapy (IPT) are equally efficacious in the acute treatment of Major Depressive Disorder (MDD). Nevertheless, remission rates remain unacceptably low. Examining the differential time course of remission of specific symptom clusters across treatments may provide a basis for assigning patients to treatments that have the highest chance of being effective., Methods: This study re-analyzed data from the NIMH Treatment of Depression Collaborative Research Project (TDCRP), which included 250 adult outpatients with MDD randomized to 16 weeks of CBT, IPT, imipramine+clinical management (IMI-CM), or pill placebo (PLA-CM). We derived four symptom factors from the 23-item Hamilton Depression Rating Scale, and three symptom factors from the Beck Depression Inventory. Within-subject hierarchical regression models were specified to examine the linear and quadratic patterns of symptom remission over five assessment points., Results: IMI-CM produced a more rapid rate of remission than CBT or IPT for both the somatic/vegetative and cognitive-affective symptoms of MDD. There were no statistically significant differences in the rates of improvement of any of the symptom factors between the IMI-CM and PLA-CM groups., Limitations: Some core symptoms of depression were excluded due to low factor loadings. Past research has argued that the CBT arm in the TDCRP may have been weak., Conclusions: We failed to find evidence that treatments act preferentially on specific symptom clusters. Therefore, the symptoms of MDD may be inter-dependent when it comes to their courses of remission in treatment., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: The present study examines the moderating role of global depression severity on the relation of melancholic versus non-melancholic depression to severe and non-severe levels of stress., Method: A community sample of 50 women with unipolar major depressive disorder, of which 54% met Research Diagnostic Criteria for melancholic depression, were interviewed regarding stressful life events experienced prior to onset. Events were coded as severe or non-severe based on the rigorous Bedford College contextual rating system., Results: Greater severity of depression was related to a higher likelihood of a severely stressful event prior to onset only for women with non-melancholic major depression. By contrast, greater severity of depression was related to a higher likelihood of a non-severe, more minor, stressful event prior to onset only for women with melancholic major depression., Limitations: The present study was limited by its use of a female volunteer sample, which might not be entirely representative of the population of individuals with major depression. In addition, the study employed a cross-sectional design, which limits conclusions relating to the causal relation of stress to melancholic versus non-melancholic depression., Conclusions: Far from being autonomous of stress, individuals with severe melancholic depression may be especially sensitive to stress, such that their episodes are influenced by more minor stressors than those of individuals with non-melancholic depression.

Background: Depression is associated with profound impairments in social functioning. Past research and theory suggests that these impairments may be related to a difficulty in the ability of depressed individuals to identify and decode others' social cues. However, the nature of this difficulty is equivocal. This investigation is the first to adopt a theory-of-mind framework to examine unipolar depressed individuals' ability to identify complex mental states from eye expressions., Methods: Women with unipolar clinical depression (N=52) and nondepressed controls (N=30) completed the "Reading the Mind in the Eyes Task" (). All participants also completed self-report measures assessing depressive and anxious symptoms., Results: Depressed women were significantly impaired in their ability to identify mental states in the Eyes task compared to nondepressed participants. This difference remained after controlling for anxiety and was stronger for the affective than the somatic symptoms of depression., Limitations: The present study was limited by its sample size, resulting in low power for some comparisons. In addition, the study is limited by its use of a heterogeneous depressed sample, including outpatients and volunteers from the community, as well as its use of only female participants., Conclusions: Our results demonstrate that severely depressed individuals are significantly impaired in their ability to decode others' mental states. We suggest that strategies based on improving basic theory-of-mind reasoning could be incorporated into current therapeutic interventions for depressed individuals to ameliorate their understanding and interpretation of social information.