Negative feedback-seeking in depression: The moderating roles of rumination and interpersonal life stress.

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.

The Differential Relation of Emotional, Physical, and Sexual Abuse Histories to Antidepressant Treatment Remission and Persistence of Anhedonia in Major Depression: A CAN-BIND-1 Report.

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.

Childhood Adversity, Cognition, and Response to Cognitive Remediation in Major Depressive Disorder.

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.

Major Depression and Its Recurrences: Life Course Matters.

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.

Specific early maladaptive schemas differentially mediate the relations of emotional and sexual maltreatment to recent life events in youth with depression.

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.

Childhood maltreatment and cognitive functioning in patients with major depressive disorder: a CAN-BIND-1 report.

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.

Testing a deep convolutional neural network for automated hippocampus segmentation in a longitudinal sample of healthy participants.

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.

The Canadian Biomarker Integration Network in Depression (CAN-BIND): magnetic resonance imaging protocols

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.

Abuse as a risk factor for prenatal depressive symptoms: a meta-analysis.

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.

Testing a Revised Interpersonal Theory of Depression Using a Laboratory Measure of Excessive Reassurance Seeking.

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; Mage = 18.58, SDage = 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.

Childhood Abuse History in Depression Predicts Better Response to Antidepressants with Higher Serotonin Transporter Affinity: A Pilot Investigation.

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.

Discovering biomarkers for antidepressant response: protocol from the Canadian biomarker integration network in depression (CAN-BIND) and clinical characteristics of the first patient cohort.

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.

The Relation of Childhood Maltreatment to Psychotic Symptoms in Adolescents and Young Adults With 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.

Acute and chronic stress exposure predicts 1-year recurrence in adult outpatients with residual depression symptoms following response to treatment.

BACKGROUND: One of the strongest predictors of depression recurrence in those who respond to treatment is the presence of residual depressive symptoms. Our goal was to examine stressful life event exposure as a mechanism of recurrence in previously depressed patients with residual depression symptoms. That is, we predicted that higher levels of residual symptoms will significantly predict exposure to acute life events that will then heighten prospective recurrence risk. METHODS: Participants included 68 adult outpatients with major depression (42 women; age 18-60) who completed a 12-month naturalistic follow-up after achieving remission in a 20-week randomized, open label trial of interpersonal psychotherapy, cognitive-behavioral therapy, or antidepressant medication. Depression recurrence was defined as the reemergence of an episode of major depression as determined by structured interview. Acute life events and chronic stressors were assessed at the end of follow-up using a contextual interview. RESULTS: Posttreatment depression scores significantly prospectively predicted an increased risk for recurrence, and acute life events in the follow-up period. Cox regression survival analyses modeling life events as time-dependent covariates showed that life event exposure mediated the relation of residual symptoms to recurrence even controlling for chronic stress. CONCLUSIONS: Our findings implicate residual symptoms in heightening depression recurrence risk through exposure to stressful life events. Depression recurrence adds significantly to the burden of the disorder. Therefore, rigorous follow-up of patients targeting the stressful context has the potential to prevent a lifelong pattern of illness.

The differential relation of childhood maltreatment to stress sensitization in adolescent and young adult depression.

Childhood maltreatment has been shown to have a stronger etiological relation to depression onset in adolescence than in adulthood. We propose that a maltreatment history may more strongly sensitize individuals to the depressogenic effects of proximal stressful life events in adolescence compared to adulthood. In an amalgamated sample of 176 unipolar depressed adolescents (age 12-17) and emerging adults (age 18-29), we examined the moderating role of age group on the relation of childhood maltreatment to sensitization to stressors that occurred just prior to episode onset. Among adolescents, but not among adults, those with a maltreatment history reported a lower severity level of life events prior to episode onset than reported by those without such a history. Further, this relation was specific to emotional abuse, and not physical or sexual abuse. We suggest that the pathological mechanisms associated with translating childhood maltreatment to depression may differ across developmental periods.

How theory of mind leads to positive first impressions.

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).

Relation of hippocampal volume and SGK1 gene expression to treatment remission in major depression is moderated by childhood maltreatment: A CAN-BIND-1 report.

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.

Depression-Anxiety Coupling Strength as a predictor of relapse in major depressive disorder: A CAN-BIND wellness monitoring study report.

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.

Atypical Brain Aging and Its Association With Working Memory Performance in Major Depressive Disorder.

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.

An empirical analysis of structural neuroimaging profiles in a staging model of depression.

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.