Corrélats neuronaux du circuit des récompenses chez les jeunes à risque parental de troubles de l'humeur

Cette thèse a pour objectif l’investigation du circuit des récompenses, sur les plans comportementaux et neuronaux, chez des adolescents à risque parental élevé de dépression majeure et de trouble bipolaire, en comparaison à des jeunes à risque parental peu élevé. Plus précisément, le but est d’identifier des marqueurs comportementaux et neuronaux du risque de développer une dépression majeure ou un trouble bipolaire, afin d’être en mesure de détecter et de prévenir ces troubles le plus tôt possible pour éviter, ou du moins retarder, leur émergence. Pour ce faire, nous avons réalisé deux études, présentées ici dans deux articles empiriques. Dans le premier article, le fonctionnement comportemental et neuronal du circuit des récompenses a été investigué au moyen d’une tâche d’anticipation et d’obtention de gains et de pertes monétaires, chez des adolescents à risque parental de dépression majeure (i.e., jeunes asymptomatiques dont un des parents souffre de dépression majeure), des adolescents à risque parental de trouble bipolaire (i.e., jeunes asymptomatiques dont un des parents souffre de trouble bipolaire) et des adolescents contrôles (i.e., jeunes asymptomatiques dont les deux parents sont en bonne santé mentale). Au niveau comportemental, les résultats ont révélé une meilleure performance chez les jeunes à risque de dépression majeure lorsqu’ils devaient éviter d’obtenir des pertes monétaires de magnitude variée (0,20$, 1$ ou 5$), ainsi qu’une meilleure performance chez les jeunes à risque de trouble bipolaire sur les essais impliquant d’éviter des pertes monétaires de magnitude nulle (0$). Au niveau neuronal, les jeunes à risque de dépression majeure démontraient une diminution de l’activation du cortex préfrontal dorsolatéral lors de l’anticipation de potentielles pertes monétaires de magnitude variée, tandis que les jeunes à risque de trouble bipolaire démontraient une diminution de l’activation du cortex préfrontal dorsolatéral lors de l’anticipation de potentielles pertes monétaires de magnitude nulle. De plus, les jeunes à risque de dépression majeure tendaient à démontrer une augmentation de l’activité du cortex orbitofrontal durant l’évitement réussi de pertes monétaires, tandis que les jeunes à risque de trouble bipolaire tendaient à démontrer une augmentation de l’activité du cortex orbitofrontal lors de l’obtention de pertes monétaires. Dans le deuxième article, l’intégrité structurelle des régions fronto-limbiques a été investiguée, au moyen de mesures du volume, de l’épaisseur corticale et de la superficie corticale. Les résultats ont mis en évidence, chez les jeunes à risque de trouble bipolaire, un volume plus élevé du cortex préfrontal dorsolatéral, par rapport aux jeunes à risque de dépression majeure et contrôles. De plus, les jeunes à risque de trouble bipolaire présentaient un volume plus élevé du cortex cingulaire postérieur, en comparaison aux jeunes à risque de dépression majeure. Enfin, une diminution de l’épaisseur corticale du cortex orbitofrontal et du gyrus frontal moyen a été observée chez les adolescents à risque de trouble bipolaire, en comparaison au groupe contrôle. L’ensemble de ces résultats démontre ainsi l’existence de particularités comportementales et d’altérations neuronales sur les plans fonctionnel et structurel, chez des jeunes à risque élevé de troubles de l’humeur, et ce, avant même l’émergence des premiers symptômes thymiques. Plus particulièrement, ces caractéristiques pourraient constituer des marqueurs du risque de développer un trouble de l’humeur. Par conséquent, ces marqueurs pourraient aider à mieux identifier les jeunes qui sont le plus à risque de développer un trouble de l’humeur, et ainsi permettre la mise en place précoce de stratégies préventives adaptées, afin d’éviter des trajectoires développementales psychopathologiques.

Synthèse systématique des écrits : les instruments d’évaluation de la comorbidité psychiatrique présentée par les adolescent(e)s.

Ce mémoire présente les résultats d’une synthèse systématique (SS) des écrits traitant des instruments d’évaluation multidimensionnelle des troubles concomitants qui peuvent être présentés par les adolescent(e)s. La SS a permis d’identifier 11 instruments en mesure d’évaluer les troubles comorbides de l’Axe I du DSM-IV, incluant chaque fois les troubles liés à l’utilisation de substances psychoactives (TUS). Une fois les instruments répertoriés, une seconde recherche fut effectuée afin identifier les études les ayant mis à l’épreuve du point de vue de leur validité et de leur fidélité diagnostique : 57 études furent identifiées. La robustesse méthodologique de ces études fut analysée à l’aide de la grille du QUADAS-2 et 47 études furent retenues pour l’échantillon final. Les résultats sont présentés par diagnostics (troubles liés à l’utilisation des substances (TUS) (obligatoire), trouble d’anxiété généralisée (TAG), épisode dépressif majeur (ÉDM), troubles des conduites (TC), trouble du déficit de l’attention /hyperactivité (TDA/H), état de stress post-traumatique (ÉSPT) et par instrument retenu. Suite à l’analyse des données recueillies, il s’avère difficile de comparer les instruments les uns aux autres, étant donnée la très grande diversité des échelles qu’ils contiennent, ainsi que les devis fort différents des études qui les ont mis à l’épreuve. Par contre, deux instruments se distinguent par la robustesse méthodologique des études à leur sujet, ainsi que leur excellente performance globale. Il s’agit du ChIPS et du K-SADS.

Adolescent suicide attempts and adult adjustment

Background: Adolescent suicide attempts are disproportionally prevalent and frequently of low severity, raising questions regarding their long-term prognostic implications. In this study, we examined whether adolescent attempts were asso- ciated with impairments related to suicidality, psychopathology, and psychosocial functioning in adulthood (objective 1) and whether these impairments were better accounted for by concurrent adolescent confounders (objective 2). Method: Eight hundred and sixteen adolescents were assessed using interviews and question- naires at four time points from adolescence to adulthood. We examined whether lifetime suicide attempts in adolescence (by T2, mean age 17) predicted adult out- comes (by T4, mean age 30) using linear and logistic regressions in unadjusted models (objective 1) and adjusting for sociodemographic background, adolescent psychopathology, and family risk factors (objective 2). Results: In unadjusted analyses, adolescent suicide attempts predicted poorer adjustment on all outcomes, except those related to social role status. After adjustment, adolescent attempts remained predictive of axis I and II psychopathology (anxiety disorder, antisocial and borderline personality disorder symptoms), global and social adjustment, risky sex, and psychiatric treatment utilization. However, adolescent attempts no longer predicted most adult outcomes, notably suicide attempts and major depressive disorder. Secondary analyses indicated that associations did not differ by sex and attempt characteristics (intent, lethality, recurrence). Conclusions: Adolescent suicide attempters are at high risk of protracted and wide-ranging im- pairments, regardless of the characteristics of their attempt. Although attempts specifically predict (and possibly influence) several outcomes, results suggest that most impairments reflect the confounding contributions of other individual and family problems or vulnerabilites in adolescent attempters.

WHOQOL-BREF as a measure of quality of life in older patients with depression

Objective: To assess the reliability and validity of a brief measure of quality of life recently developed by the World Health Organization, the WHOQOL-BREF, and to examine its association with a variety of clinical and sociodemographic factors in older depressed patients. Design: Cross-sectional study. Methods: Older depressed patients (N=41) underwent diagnostic assessment using the Composite International Diagnostic Interview (CIDI) and were independently assessed on a variety of measures including the WHOQOL-BREF (a 26-item self-report questionnaire generating four domain scores), Hamilton Depression Rating Scale (HAM-D); Geriatric Depression Scale (GDS); Mini-mental State Examination (MMSE); Modified Barthel Index (MBI); Instrumental activities of daily living (IADL), and measures of physical health status and social relationships. Estimates of inter-rater and test-retest reliability, and concurrent validity were made. Results: 39 subjects completed the study. The majority of subjects (94.9%) received a diagnosis of DSM-IV Major Depressive Disorder. Levels of comorbidity were high. Three of the four domains of the WHOQOL-BREF (Physical, Psychological and Environment domains) demonstrated satisfactory reliability and validity. However, the Social Relationships domain exhibited poor validity. Quality of life scores were strongly correlated with severity of depression, number of self-reported physical symptoms and self-assessed general health status. There was no relationship between diagnostic comorbidity and quality of life scores. Conclusions: The WHOQOL-BREF was successfully administered to older depressed patients although the concurrent validity of one of its four domains was poor. Quality of life scores were strongly correlated with severity of depression, raising the issue of measurement redundancy.

Cognitive change process during group cognitive behaviour therapy for depression

Background: This study extended that of Kwon and Oei [Kwon, S.M., Oei, T.P.S., 2003. Cognitive change processes in a group cognitive behavior therapy of depression. J. Behav. Ther. Exp. Psychiatry, 3, 73-85], which outlined a number of testable models based on Beck's cognitive theory of depression. Specifically, the current study tested the following four competing models: the causal, consequential, fully and partially interactive cognitive models in patients with major depressive disorder. Methods: A total of 168 clinically depressed outpatients were recruited into a 12-week group cognitive behaviour therapy program. Data was collected at three time points: baseline, mid- and at termination of therapy using the ATQ DAS and BD1. The data were analysed with Amos 4.01 (Arbuckle, J.L., 1999. Amos 4.1. Smallwaters, Chicago.) structural equation modelling. Results: Results indicated that dysfunctional attitudes, negative automatic thoughts and symptoms of depression reduced significantly during treatment. Both the causal and consequential models equally provided an adequate fit to the data. The fully interactive model provided the best fit. However, after removing non-significant pathways, it was found that reduced depressive symptom contributed to reduced depressogenic automatic thoughts and dysfunctional attitudes, not the reverse. Conclusion: These findings did not fully support Beck's cognitive theory of depression that cognitions are primary in the reduction of depressed mood. (c) 2006 Elsevier B.V. All rights reserved.

Neuropsychological assessment of an eighty-nine year old man

A case of first onset of the symptoms of mania in an eighty-nine year old man is reported. Organic contributions appear to be particularly important in cases of mania in older adults. In cases of first onset of mania in older adults the major differential diagnosis is between primary mania and a wide range of possible secondary etiological factors. This man had no known history of affective disorder and at the time of initial examination no organic explanation for his symptoms could be identified. While lateonset bipolar disorder has been reported in the literature, such cases are rare and are usually proceeded by a history of major depressive disorder or dysthymia. A range of neuropsychological assessment instruments were administered as part of a comprehensive inpatient examination of this man, commenting on his cognitive functioning and competence to manage his affairs. This assessment indicated that while his functioning was intact in some areas, there were areas of significant difficulty. The case illustrates the difficulties in interpreting neuropsychological assessment results obtained during a manic phase, and highlights some of the difficulties of conducting research with older adults.

Elevated amygdala activity to sad facial expressions:a state marker of bipolar but not unipolar depression

Background - Difficulties in emotion processing and poor social function are common to bipolar disorder (BD) and major depressive disorder (MDD) depression, resulting in many BD depressed individuals being misdiagnosed with MDD. The amygdala is a key region implicated in processing emotionally salient stimuli, including emotional facial expressions. It is unclear, however, whether abnormal amygdala activity during positive and negative emotion processing represents a persistent marker of BD regardless of illness phase or a state marker of depression common or specific to BD and MDD depression. Methods - Sixty adults were recruited: 15 depressed with BD type 1 (BDd), 15 depressed with recurrent MDD, 15 with BD in remission (BDr), diagnosed with DSM-IV and Structured Clinical Interview for DSM-IV Research Version criteria; and 15 healthy control subjects (HC). Groups were age- and gender ratio-matched; patient groups were matched for age of illness onset and illness duration; depressed groups were matched for depression severity. The BDd were taking more psychotropic medication than other patient groups. All individuals participated in three separate 3T neuroimaging event-related experiments, where they viewed mild and intense emotional and neutral faces of fear, happiness, or sadness from a standardized series. Results - The BDd—relative to HC, BDr, and MDD—showed elevated left amygdala activity to mild and neutral facial expressions in the sad (p < .009) but not other emotion experiments that was not associated with medication. There were no other significant between-group differences in amygdala activity. Conclusions - Abnormally elevated left amygdala activity to mild sad and neutral faces might be a depression-specific marker in BD but not MDD, suggesting different pathophysiologic processes for BD versus MDD depression.

Dissociable patterns of neural activity during response inhibition in depressed adolescents with and without suicidal behavior

Objectives - Impaired attentional control and behavioral control are implicated in adult suicidal behavior. Little is known about the functional integrity of neural circuitry supporting these processes in suicidal behavior in adolescence. Method - Functional magnetic resonance imaging was used in 15 adolescent suicide attempters with a history of major depressive disorder (ATTs), 15 adolescents with a history of depressive disorder but no suicide attempt (NATs), and 14 healthy controls (HCs) during the performance of a well-validated go-no-go response inhibition and motor control task that measures attentional and behavioral control and has been shown to activate prefrontal, anterior cingulate, and parietal cortical circuitries. Questionnaires assessed symptoms and standardized interviews characterized suicide attempts. Results - A 3 group by 2 condition (go-no-go response inhibition versus go motor control blocks) block-design whole-brain analysis (p < .05, corrected) showed that NATs showed greater activity than ATTs in the right anterior cingulate gyrus (p = .008), and that NATs, but not ATTs, showed significantly greater activity than HCs in the left insula (p = .004) to go-no-go response inhibition blocks. Conclusions - Although ATTs did not show differential patterns of neural activity from HCs during the go-no-go response inhibition blocks, ATTs and NATs showed differential activation of the right anterior cingulate gyrus during response inhibition. These findings indicate that suicide attempts during adolescence are not associated with abnormal activity in response inhibition neural circuitry. The differential patterns of activity in response inhibition neural circuitry in ATTs and NATs, however, suggest different neural mechanisms for suicide attempt versus major depressive disorder in general in adolescence that should be a focus of further study.

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.

Comparison of medical and forensic profiling potential of volatile biomarkers from different biological specimens from individuals and across populations

There is limited scientific knowledge on the composition of human odor from different biological specimens and the effect that physiological and psychological health conditions could have on them. There is currently no direct comparison of the volatile organic compounds (VOCs) emanating from different biological specimens collected from healthy individuals as well as individuals with certain diagnosed medical conditions. Therefore the question of matching VOCs present in human odor across various biological samples and across health statuses remains unanswered. The main purpose of this study was to use analytical instrumental methods to compare the VOCs from different biological specimens from the same individual and to compare the populations evaluated in this project. The goals of this study were to utilize headspace solid-phase microextraction gas chromatography mass spectrometry (HS-SPME-GC/MS) to evaluate its potential for profiling VOCs from specimens collected using standard forensic and medical methods over three different populations: healthy group with no diagnosed medical or psychological condition, one group with diagnosed type 2 diabetes, and one group with diagnosed major depressive disorder. The pre-treatment methods of collection materials developed for the study allowed for the removal of targeted VOCs from the sampling kits prior to sampling, extraction and analysis. Optimized SPME-GC/MS conditions has been demonstrated to be capable of sampling, identifying and differentiating the VOCs present in the five biological specimens collected from different subjects and yielded excellent detection limits for the VOCs from buccal swab, breath, blood, and urine with average limits of detection of 8.3 ng. Visual, Spearman rank correlation, and PCA comparisons of the most abundant and frequent VOCs from each specimen demonstrated that each specimen has characteristic VOCs that allow them to be differentiated for both healthy and diseased individuals. Preliminary comparisons of VOC profiles of healthy individuals, patients with type 2 diabetes, and patients with major depressive disorder revealed compounds that could be used as potential biomarkers to differentiate between healthy and diseased individuals. Finally, a human biological specimen compound database has been created compiling the volatile compounds present in the emanations of human hand odor, oral fluids, breath, blood, and urine.

Influence of gender and life stressors on longitudinal depression treatment outcomes among older primary care patients

Purpose: Depression in older females is a significant and growing problem. Females who experience life stressors across the life span are at higher risk for developing problems with depression than their male counterparts. The primary aim of this study was (a) to examine gender-specific differences in the correlates of depression in older primary care patients based on baseline and longitudinal analyses; and (b) to examine the longitudinal effect of biopsychosocial risk factors on depression treatment outcomes in different models of behavioral healthcare (i.e., integrated care and enhanced referral). Method: This study used a quantitative secondary data analysis with longitudinal data from the Primary Care Research in Substance Abuse and Mental Health for Elderly (PRISM-E) study. A linear mixed model approach to hierarchical linear modeling was used for analysis using baseline assessment, and follow-up from three-month and six-month. Results: For participants diagnosed with major depressive disorder female gender was associated with increased depression severity at six-month compared to males at six-month. Further, the interaction between gender and life stressors found that females who reported loss of family and friends, family issues, money issues, medical illness was related to higher depression severity compared to males whereas lack of activities was related to lower depression severity among females compared to males. Conclusion: These findings suggest that gender moderated the relationship between specific life stressors and depression severity similar to how a protective factor can impact a person's response to a problem and reduce the negative impact of a risk factor on a problem outcome. Therefore, life stressors may be a reliable predictor of depression for both females and males in either behavioral health treatment model. This study concluded that life stressors influence males basic comfort, stability, and survival whereas life stressors influence females' development, personal growth, and happiness; therefore, life stressors may be a useful component to include in gender-based screening and assessment tools for depression. ^

Características psicológicas do paciente obeso grave e suas implicações pós-operatórias na cirurgia bariátrica

Obesity is a chronic disease that has multi-factorial aetiology, characterized by high degree of body fat; the degree of obesity will vary according to the Body Mass Index (BMI=m2 /kg). The severe degree of obesity is characterized by BMI>40 and it is regularly associated to endocrine-metabolic or mechanic clinical alterations, and to psychological disorders. Binge Eating (BE) results were overly high for this population. The Bariatric Surgery has been the treatment chosen by those diagnosed with severe obesity as this intervention provides prompt outcomes for loss of weight and clinical improvement conditions. However, recent research has acquiesced that after two years between 20% and 30% of people subject to this intervention gained weight. The main objective of this research is to assess the psychological and behavioral characteristics of those diagnosed with severe obesity that have been subject to Gastric Bypass Surgery in the past 24 months. Specific aspects were investigated: (1) characteristics of different personalities and diagnose of clinic and personality disorders; (2) BE and its relation with loss of weight; (2) the difference between the groups regarding post-surgery care, e.g. physical activity, psychological and dietician input. Method: 40 adults (women and men) aged 23 and 60 year-old who went through a bariatric surgery in the past 24 months, in the city of Natal-RN (Brazil); they were assembled in two groups n=20, Gain group displaying loss of < 50% of their initial surplus of weight, and the Loss group displaying loss of >50%. The research protocol is made of a socio-demographic questionnaire and 3 psychometric instruments: Rorschach – Comprehensive System; Millon Personality Inventory (MCMI-III); and the Binge Eating Scale (Escala de Compulsão Alimentar Periódica (ECAP). Through Rorschach significant differences between these groups were verified according to the kind of personality (EB) - more EB Extratensivo in Gain group and Intratensivo in Loss group – and the lack of control to express affect, increasing the answer for Color Pure at Group I. Concerning the people standardization, the sample as a whole tends to show psychic pain, denigrated selfperception, high levels of self-criticism, distorted perceptions, vulnerability to develop mood disorders and high scores regarding Suicide. MCMI-III results showed more clinic and personality disorders in Group I: Depressive Disorder and Schizotypal, Anxiety, Dysthymia, Major Depressive Disorder; Thought Disorder, Bipolar- Manic and Posttraumatic Stress Disorder. In relation to ECAP, the results indicated significant differences, showing increased BE results in Gain group. There were found significant differences between BE severity and the presence of clinic and personality disorders. Concerning the post-surgery care, the observed differences are statistically significant regarding physical activities with median-increased differences in Loss group. There is a difference between the initial weight and the time post-surgery, indicating that the higher the initial weight and the time after the surgery the higher the re-gain of weight post-surgery. Finally, the results show that the participants with more than 3 years of surgery will have Clinic and Major Depressive Disorders; Somatoform Disorder; Dysthymia. These results confirm prior studies related to BE post-surgery and re-gain of weight as well as the proneness of clinic disorders in severe obesity people. That means the results reinforce that the surgery process is a facet of the severe obesity treatment. The post-surgery process needs to be the main focus of attention and have a long-term input to sustain the care of the surgery results and the quality of life of the patients.

Bridging the link between trauma, brain development and depression: epigenetic mechanisms

Despite its large impact on the individual and society, we currently have only a rudimentary understanding of the biological basis of Major Depressive Disorder, even less so in adolescent populations. This thesis focuses on two research questions. First, how do adolescents with depression differ from adolescents who have never been depressed on (1a) brain morphology and (1b) DNA methylation? We studied differences in the fronto-limbic system (a collection of areas responsible for emotion regulation) and methylation at the serotonin transporter (SLC6A4) and FK506 binding protein gene (FKBP5) genes (two genes strongly linked to stress regulation and depression). Second, how does childhood trauma, which is known to increase risk for depression, affect (2a) brain development and (2b) SLC6A4 and FKBP5 methylation? Further, (2c) how might DNA methylation explain how trauma affects brain development in depression? We studied these questions in 24 adolescent depressed patients and 21 controls. We found that (1a) depressed adolescents had decreased left precuneus volume and greater volume of the left precentral gyrus compared to controls; however, no differences in fronto-limbic morphology were identified. Moreover, (1b) individuals with depression had lower levels of FKBP5 methylation than controls. In line with our second hypothesis (2a) greater levels of trauma were associated with decreased volume of a number of fronto-limbic regions. Further, we found that (2b) greater trauma was associated with decreased SLC6A4, but not FKBP5, methylation. Finally, (2c) greater FKBP5, but not SLC6A4, methylation was associated with decreased volume of a number of fronto-limbic regions. The results of this study suggest an association among trauma, DNA methylation and brain development in youth, but the direction of these relationships appears to be inconsistent. Future studies using a longitudinal design will be necessary to clarify these results and help us understand how the brain and epigenome change over time in depressed youth.

ENVIRONMENTAL INFLUENCES AND EPIGENETIC MECHANISMS IN RISK FOR DEPRESSION

Genetic and environmental factors interact to influence vulnerability for internalizing psychopathology, including Major Depressive Disorder (MDD). The mechanisms that account for how environmental stress can alter biological systems are not yet well understood yet are critical to develop more accurate models of vulnerability and targeted interventions. Epigenetic influences, and more specifically, DNA methylation, may provide a mechanism by which stress could program gene expression, thereby altering key systems implicated in depression, such as frontal-limbic circuitry and its critical role in emotion regulation. This thesis investigated the role of environmental factors from infancy and throughout the lifespan affecting the serotonergic (5-HT) system in the vulnerability to and treatment of depression and anxiety and potential underlying DNA methylation processes. First, we investigated the contributions of additive genetic vs. environmental factors on an early trait phenotype for depression (negative emotionality) in infants and their stability over time in the first 2 years of life. We provided evidence of the substantial contributions of both genetic and shared environmental factors to this trait, as well as genetically- and environmentally- mediated stability and innovation. Second, we studied how childhood environmental stress is associated with peripheral DNA methylation of the serotonin transporter gene, SLC6A4, as well as long-term trajectories of internalizing behaviours. There was a relationship between childhood psychosocial adversity and SLC6A4 methylation in males, as well as between SLC6A4 methylation and internalizing trajectory in both sexes. Third, we investigated changes in emotion processing and epigenetic modification of the SLC6A4 gene in depressed adolescents before and after Mindfulness-Based Cognitive Therapy (MBCT). The alterations from pre- to post-treatment in connectivity between the ACC and other network regions and SLC6A4 methylation suggested that MBCT may work to optimize the connectivity of brain networks involved in cognitive control of emotion as well as also normalize the relationship between SLC6A4 methylation and activation patterns in frontal-limbic circuitry. Our results from these three studies strengthen the theory that environmental influences are critical in establishing early vulnerability factors for MDD, driving epigenetic processes, and altering brain processes as an individual undergoes treatment, or experiences relapse.

Diagnostic potential of structural neuroimaging for depression from a multi-ethnic community sample

Background At present, we do not have any biological tests which can contribute towards a diagnosis of depression. Neuroimaging measures have shown some potential as biomarkers for diagnosis. However, participants have generally been from the same ethnic background while the applicability of a biomarker would require replication in individuals of diverse ethnicities. Aims We sought to examine the diagnostic potential of the structural neuroanatomy of depression in a sample of a wide ethnic diversity. Method Structural magnetic resonance imaging (MRI) scans were obtained from 23 patients with major depressive disorder in an acute depressive episode (mean age: 39.8 years) and 20 matched healthy volunteers (mean age: 38.8 years). Participants were of Asian, African and Caucasian ethnicity recruited from the general community. Results Structural neuroanatomy combining white and grey matter distinguished patients from controls at the highest accuracy of 81% with the most stable pattern being at around 70%. A widespread network encompassing frontal, parietal, occipital and cerebellar regions contributed towards diagnostic classification. Conclusions These findings provide an important step in the development of potential neuroimaging-based tools for diagnosis as they demonstrate that the identification of depression is feasible within a multi-ethnic group from the community. Declaration of interests C.H.Y.F. has held recent research grants from Eli Lilly and Company and GlaxoSmithKline. L.M. is a former employee and stockholder of Eli Lilly and Company.