Factors Associated with Transition to Serious Mental Illness.

OBJECTIVE: There is increasing interest in early intervention and detection strategies for youth at-risk of developing a serious mental illness (SMI). Little is known about early factors that may be related to the later development of a SMI; thus, the aim of this study was to determine what clinical factors might relate to the development of in this study psychosis, bipolar disorder and severe or recurrent major depression in at-risk youth. METHOD: The sample consisted of 162 youth aged 12-26 years at different stages of risk. Thirty-one participants developed a SMI during the study. Those who made a transition were compared on a range of baseline clinical and functional measures with those who did not make the transition. A Cox regression model was used to assess the association between measures and later development of a SMI. RESULTS: Female sex, attenuated psychotic symptoms as assessed with the Scale of Psychosis-Risk Symptoms (SOPS) and ratings on the K-10 Distress Scale, were found to be significantly associated with the later transition to mental illness. Females were 2.77 times more likely to transition compared to males. For the SOPS and K-10 scales, there is a 14% increase in the transition rate relative to a one-scale increase in SOPS and a 7% increase in the transition rate relative to a one-point increase in the K-10. CONCLUSIONS: Results from these longitudinal data provide further insight into the specific clinical measures that may be pertinent in early detection of mental illnesses.

Cerebello-cerebral Functional Connectivity Networks in Major Depressive Disorder: a CAN-BIND-1 Study Report.

Neuroimaging studies have demonstrated aberrant structure and function of the "cognitive-affective cerebellum" in major depressive disorder (MDD), although the specific role of the cerebello-cerebral circuitry in this population remains largely uninvestigated. The objective of this study was to delineate the role of cerebellar functional networks in depression. A total of 308 unmedicated participants completed resting-state functional magnetic resonance imaging scans, of which 247 (148 MDD; 99 healthy controls, HC) were suitable for this study. Seed-based resting-state functional connectivity (RsFc) analysis was performed using three cerebellar regions of interest (ROIs): ROI1 corresponded to default mode network (DMN)/inattentive processing; ROI2 corresponded to attentional networks, including frontoparietal, dorsal attention, and ventral attention; ROI3 corresponded to motor processing. These ROIs were delineated based on prior functional gradient analyses of the cerebellum. A general linear model was used to perform within-group and between-group comparisons. In comparison to HC, participants with MDD displayed increased RsFc within the cerebello-cerebral DMN (ROI1) and significantly elevated RsFc between the cerebellar ROI1 and bilateral angular gyrus at a voxel threshold (p < 0.001, two-tailed) and at a cluster level (p < 0.05, FDR-corrected). Group differences were non-significant for ROI2 and ROI3. These results contribute to the development of a systems neuroscience approach to the diagnosis and treatment of MDD. Specifically, our findings confirm previously reported associations between MDD, DMN, and cerebellum, and highlight the promising role of these functional and anatomical locations for the development of novel imaging-based biomarkers and targets for neuromodulation therapies. ClinicalTrials.gov TRN: NCT01655706; Date of Registration: August 2nd, 2012.

Pro-inflammatory markers are associated with response to sequential pharmacotherapy in major depressive disorder: a CAN-BIND-1 report.

OBJECTIVE: There is limited literature on associations between inflammatory tone and response to sequential pharmacotherapies in major depressive disorder (MDD). METHODS: In a 16-week open-label clinical trial, 211 participants with MDD were treated with escitalopram 10-20 mg daily for 8 weeks. Responders continued escitalopram while non-responders received adjunctive aripiprazole 2-10 mg daily for 8 weeks. Plasma levels of pro-inflammatory markers-C-reactive protein, interleukin (IL)-1ß, IL-6, IL-17, interferon-gamma (IFN)-Γ, tumor necrosis factor (TNF)-α, and Chemokine C-C motif ligand-2 (CCL-2)-measured at baseline, and after 2, 8 and 16 weeks were included in logistic regression analyzes to assess associations between inflammatory markers and treatment response. RESULTS: Pre-treatment IFN-Γ and CCL-2 levels were significantly associated with a lower of odds of response to escitalopram at 8 weeks. Increases in CCL-2 levels from weeks 8 to 16 in escitalopram non-responders were significantly associated with higher odds of non-response to adjunctive aripiprazole at week 16. CONCLUSION: Higher pre-treatment levels of IFN-Γ and CCL-2 were associated with non-response to escitalopram. Increasing levels of these pro-inflammatory markers may be associated with non-response to adjunctive aripiprazole. These findings require validation in independent clinical populations.

Baseline Functional Connectivity in Resting State Networks Associated with Depression and Remission Status after 16 Weeks of Pharmacotherapy: A CAN-BIND Report.

Understanding the neural underpinnings of major depressive disorder (MDD) and its treatment could improve treatment outcomes. So far, findings are variable and large sample replications scarce. We aimed to replicate and extend altered functional connectivity associated with MDD and pharmacotherapy outcomes in a large, multisite sample. Resting-state fMRI data were collected from 129 patients and 99 controls through the Canadian Biomarker Integration Network in Depression. Symptoms were assessed with the Montgomery-Åsberg Depression Rating Scale (MADRS). Connectivity was measured as correlations between four seeds (anterior and posterior cingulate cortex, insula and dorsolateral prefrontal cortex) and all other brain voxels. Partial least squares was used to compare connectivity prior to treatment between patients and controls, and between patients reaching remission (MADRS ≤ 10) early (within 8 weeks), late (within 16 weeks), or not at all. We replicated previous findings of altered connectivity in patients. In addition, baseline connectivity of the anterior/posterior cingulate and insula seeds differentiated patients with different treatment outcomes. The stability of these differences was established in the largest single-site subsample. Our replication and extension of altered connectivity highlighted previously reported and new differences between patients and controls, and revealed features that might predict remission prior to pharmacotherapy. Trial registration:ClinicalTrials.gov: NCT01655706.

Canadian Network for Mood and Anxiety Treatments (CANMAT) Task Force Report: A Systematic Review and Recommendations of Cannabis use in Bipolar Disorder and Major Depressive Disorder.

BACKGROUND: Given the increasing acceptability and legalization of cannabis in some jurisdictions, clinicians need to improve their understanding of the effect of cannabis use on mood disorders. OBJECTIVE: The purpose of this task force report is to examine the association between cannabis use and incidence, presentation, course and treatment of bipolar disorder and major depressive disorder, and the treatment of comorbid cannabis use disorder. METHODS: We conducted a systematic literature review using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, searching PubMed, Embase, PsycINFO, CINAHL and Cochrane Central Register of Controlled Trials from inception to October 2020 focusing on cannabis use and bipolar disorder or major depressive disorder, and treatment of comorbid cannabis use disorder. The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach was used to evaluate the quality of evidence and clinical considerations were integrated to generate Canadian Network for Mood and Anxiety Treatments recommendations. RESULTS: Of 12,691 publications, 56 met the criteria: 23 on bipolar disorder, 21 on major depressive disorder, 11 on both diagnoses and 1 on treatment of comorbid cannabis use disorder and major depressive disorder. Of 2,479,640 participants, 12,502 were comparison participants, 73,891 had bipolar disorder and 408,223 major depressive disorder without cannabis use. Of those with cannabis use, 2,761 had bipolar disorder and 5,044 major depressive disorder. The lifetime prevalence of cannabis use was 52%-71% and 6%-50% in bipolar disorder and major depressive disorder, respectively. Cannabis use was associated with worsening course and symptoms of both mood disorders, with more consistent associations in bipolar disorder than major depressive disorder: increased severity of depressive, manic and psychotic symptoms in bipolar disorder and depressive symptoms in major depressive disorder. Cannabis use was associated with increased suicidality and decreased functioning in both bipolar disorder and major depressive disorder. Treatment of comorbid cannabis use disorder and major depressive disorder did not show significant results. CONCLUSION: The data indicate that cannabis use is associated with worsened course and functioning of bipolar disorder and major depressive disorder. Future studies should include more accurate determinations of type, amount and frequency of cannabis use and select comparison groups which allow to control for underlying common factors.

Childhood trauma and amygdala nuclei volumes in youth at risk for mental illness.

BACKGROUND: Adults with significant childhood trauma and/or serious mental illness may exhibit persistent structural brain changes within limbic structures, including the amygdala. Little is known about the structure of the amygdala prior to the onset of SMI, despite the relatively high prevalence of trauma in at-risk youth. METHODS: Data were gathered from the Canadian Psychiatric Risk and Outcome study. A total of 182 youth with a mean age of 18.3 years completed T1-weighted MRI scans along with clinical assessments that included questionnaires on symptoms of depression and anxiety. Participants also completed the Childhood Trauma and Abuse Scale. We used a novel subfield-specific amygdala segmentation workflow as a part of FreeSurfer 6.0 to examine amygdala structure. RESULTS: Participants with higher trauma scores were more likely to have smaller amygdala volumes, particularly within the basal regions. Among various types of childhood trauma, sexual and physical abuse had the largest effects on amygdala subregions. Abuse-related differences in the right basal region mediated the severity of depression and anxiety symptoms, even though no participants met criteria for clinical diagnosis at the time of assessment. CONCLUSION: The experience of physical or sexual abuse may leave detectable structural alterations in key regions of the amygdala, potentially mediating the risk of psychopathology in trauma-exposed youth.

Brain aging in major depressive disorder: results from the ENIGMA major depressive disorder working group.

Major depressive disorder (MDD) is associated with an increased risk of brain atrophy, aging-related diseases, and mortality. We examined potential advanced brain aging in adult MDD patients, and whether this process is associated with clinical characteristics in a large multicenter international dataset. We performed a mega-analysis by pooling brain measures derived from T1-weighted MRI scans from 19 samples worldwide. Healthy brain aging was estimated by predicting chronological age (18-75 years) from 7 subcortical volumes, 34 cortical thickness and 34 surface area, lateral ventricles and total intracranial volume measures separately in 952 male and 1236 female controls from the ENIGMA MDD working group. The learned model coefficients were applied to 927 male controls and 986 depressed males, and 1199 female controls and 1689 depressed females to obtain independent unbiased brain-based age predictions. The difference between predicted "brain age" and chronological age was calculated to indicate brain-predicted age difference (brain-PAD). On average, MDD patients showed a higher brain-PAD of +1.08 (SE 0.22) years (Cohen's d = 0.14, 95% CI: 0.08-0.20) compared with controls. However, this difference did not seem to be driven by specific clinical characteristics (recurrent status, remission status, antidepressant medication use, age of onset, or symptom severity). This highly powered collaborative effort showed subtle patterns of age-related structural brain abnormalities in MDD. Substantial within-group variance and overlap between groups were observed. Longitudinal studies of MDD and somatic health outcomes are needed to further assess the clinical value of these brain-PAD estimates.

Brain connectomes in youth at risk for serious mental illness: an exploratory analysis.

BACKGROUND: Identifying early biomarkers of serious mental illness (SMI)-such as changes in brain structure and function-can aid in early diagnosis and treatment. Whole brain structural and functional connectomes were investigated in youth at risk for SMI. METHODS: Participants were classified as healthy controls (HC; n = 33), familial risk for serious mental illness (stage 0; n = 31), mild symptoms (stage 1a; n = 37), attenuated syndromes (stage 1b; n = 61), or discrete disorder (transition; n = 9) based on clinical assessments. Imaging data was collected from two sites. Graph-theory based analysis was performed on the connectivity matrix constructed from whole-brain white matter fibers derived from constrained spherical deconvolution of the diffusion tensor imaging (DTI) scans, and from the correlations between brain regions measured with resting state functional magnetic resonance imaging (fMRI) data. RESULTS: Linear mixed effects analysis and analysis of covariance revealed no significant differences between groups in global or nodal metrics after correction for multiple comparisons. A follow up machine learning analysis broadly supported the findings. Several non-overlapping frontal and temporal network differences were identified in the structural and functional connectomes before corrections. CONCLUSIONS: Results suggest significant brain connectome changes in youth at transdiagnostic risk may not be evident before illness onset.

Resting state fMRI scanner instabilities revealed by longitudinal phantom scans in a multi-center study.

Quality assurance (QA) is crucial in longitudinal and/or multi-site studies, which involve the collection of data from a group of subjects over time and/or at different locations. It is important to regularly monitor the performance of the scanners over time and at different locations to detect and control for intrinsic differences (e.g., due to manufacturers) and changes in scanner performance (e.g., due to gradual component aging, software and/or hardware upgrades, etc.). As part of the Ontario Neurodegenerative Disease Research Initiative (ONDRI) and the Canadian Biomarker Integration Network in Depression (CAN-BIND), QA phantom scans were conducted approximately monthly for three to four years at 13 sites across Canada with 3T research MRI scanners. QA parameters were calculated for each scan using the functional Biomarker Imaging Research Network's (fBIRN) QA phantom and pipeline to capture between- and within-scanner variability. We also describe a QA protocol to measure the full-width-at-half-maximum (FWHM) of slice-wise point spread functions (PSF), used in conjunction with the fBIRN QA parameters. Variations in image resolution measured by the FWHM are a primary source of variance over time for many sites, as well as between sites and between manufacturers. We also identify an unexpected range of instabilities affecting individual slices in a number of scanners, which may amount to a substantial contribution of unexplained signal variance to their data. Finally, we identify a preliminary preprocessing approach to reduce this variance and/or alleviate the slice anomalies, and in a small human data set show that this change in preprocessing can have a significant impact on seed-based connectivity measurements for some individual subjects. We expect that other fMRI centres will find this approach to identifying and controlling scanner instabilities useful in similar studies.

Exploring brain connectivity changes in major depressive disorder using functional-structural data fusion: A CAN-BIND-1 study.

There is a growing interest in examining the wealth of data generated by fusing functional and structural imaging information sources. These approaches may have clinical utility in identifying disruptions in the brain networks that underlie major depressive disorder (MDD). We combined an existing software toolbox with a mathematically dense statistical method to produce a novel processing pipeline for the fast and easy implementation of data fusion analysis (FATCAT-awFC). The novel FATCAT-awFC pipeline was then utilized to identify connectivity (conventional functional, conventional structural and anatomically weighted functional connectivy) changes in MDD patients compared to healthy comparison participants (HC). Data were acquired from the Canadian Biomarker Integration Network for Depression (CAN-BIND-1) study. Large-scale resting-state networks were assessed. We found statistically significant anatomically-weighted functional connectivity (awFC) group differences in the default mode network and the ventral attention network, with a modest effect size (d < 0.4). Functional and structural connectivity seemed to overlap in significance between one region-pair within the default mode network. By combining structural and functional data, awFC served to heighten or reduce the magnitude of connectivity differences in various regions distinguishing MDD from HC. This method can help us more fully understand the interconnected nature of structural and functional connectivity as it relates to depression.

Cognition and Its Association with Psychosocial and Occupational Functioning during Treatment with Escitalopram in Patients with Major Depressive Disorder: A CAN-BIND-1 Report: La Cognition Et Son Association Avec Le Fonctionnement Psychosocial Et Professionnel Durant Le Traitement Par Escitalopram Chez Des Patients Souffrant De Trouble Dépressif Majeur: Une Étude Can-Bind-1.

OBJECTIVES: Major depressive disorder (MDD) is associated with impairments in both cognition and functioning. However, whether cognitive deficits significantly contribute to impaired psychosocial and occupational functioning, independent of other depressive symptoms, is not well established. We examined the relationship between cognitive performance and functioning in depressed patients before and after antidepressant treatment using secondary data from the first Canadian Biomarker Integration Network in Depression-1 study. METHODS: Cognition was assessed at baseline in unmedicated, depressed participants with MDD (n = 207) using the Central Nervous System Vital Signs computerized battery, psychosocial functioning with the Sheehan Disability Scale (SDS), and occupational functioning with the Lam Employment Absence and Productivity Scale (LEAPS). Cognition (n = 181), SDS (n = 175), and LEAPS (n = 118) were reassessed after participants received 8 weeks of open-label escitalopram monotherapy. A series of linear regressions were conducted to determine (1) whether cognitive functioning was associated with psychosocial and occupational functioning prior to treatment, after adjusting for overall depressive symptom severity and (2) whether changes in cognitive functioning after an 8-week treatment phase were associated with changes in psychosocial and occupational functioning, after adjusting for changes in overall symptom severity. RESULTS: Baseline global cognitive functioning, after adjusting for depression symptom severity and demographic variables, was associated with the SDS work/study subscale (ß = -0.17; P = 0.03) and LEAPS productivity subscale (ß = -0.17; P = 0.05), but not SDS total (ß = 0.19; P = 0.12) or LEAPS total (ß = 0.41; P = 0.17) scores. Although LEAPS and SDS scores showed significant improvements after 8 weeks of treatment (P < 0.001), there were no significant associations between changes in cognitive domain scores and functional improvements. CONCLUSION: Cognition was associated with occupational functioning at baseline, but changes in cognition were not associated with psychosocial or occupational functional improvements following escitalopram treatment. We recommend the use of more comprehensive functional assessments to determine the impact of cognitive change on functional outcomes in future research.

Reliability of a functional magnetic resonance imaging task of emotional conflict in healthy participants.

Task-based functional neuroimaging methods are increasingly being used to identify biomarkers of treatment response in psychiatric disorders. To facilitate meaningful interpretation of neural correlates of tasks and their potential changes with treatment over time, understanding the reliability of the blood-oxygen-level dependent (BOLD) signal of such tasks is essential. We assessed test-retest reliability of an emotional conflict task in healthy participants collected as part of the Canadian Biomarker Integration Network in Depression. Data for 36 participants, scanned at three time points (weeks 0, 2, and 8) were analyzed, and intra-class correlation coefficients (ICC) were used to quantify reliability. We observed moderate reliability (median ICC values between 0.5 and 0.6), within occipital, parietal, and temporal regions, specifically for conditions of lower cognitive complexity, that is, face, congruent or incongruent trials. For these conditions, activation was also observed within frontal and sub-cortical regions, however, their reliability was poor (median ICC < 0.2). Clinically relevant prognostic markers based on task-based fMRI require high predictive accuracy at an individual level. For this to be achieved, reliability of BOLD responses needs to be high. We have shown that reliability of the BOLD response to an emotional conflict task in healthy individuals is moderate. Implications of these findings to further inform studies of treatment effects and biomarker discovery are discussed.

Association Between Side Effects and Blood microRNA Expression Levels and Their Targeted Pathways in Patients With Major Depressive Disorder Treated by a Selective Serotonin Reuptake Inhibitor, Escitalopram: A CAN-BIND-1 Report.

INTRODUCTION: Antidepressant drugs are effective therapies for major depressive disorder; however, they are frequently associated with side effects. Although there is some evidence for a relationship between genetic variation and side effects, little is known regarding the role of dynamic molecular factors as moderators of side effects. The aim of this study was to assess microRNA (miRNA) changes associated with side effects during escitalopram treatment and their downstream effects on target gene expression. METHODS: A total 160 patients with major depressive disorder from the CAN-BIND-1 cohort were included. Side effects were assessed with the Toronto Side Effect Scale after 2 weeks of treatment with escitalopram. We assessed the relationship between side effects and changes in peripheral expression of miRNAs between baseline and week 2. For miRNA whose expression changed, we used target prediction algorithms to identify putative messenger RNA (mRNA) targets and assessed their expression. RESULTS: Nausea was experienced by 42.5% of patients. We identified 45 miRNAs whose expression changed on initiation of escitalopram treatment, of which 10 displayed a negative association with intensity of nausea (miR15b-5p, miR17-5p, miR20a-5p, miR20b-5p, miR103a-3p, miR103b, miR106a-5p, miR182-5p, miR185-5p, and miR660-5p). Additionally, we found negative associations between 4 microRNAs (miR20a-5p, miR106a-5p, miR185-5p, miR660-5p) and mRNA targets. The expression of the miR185-5p target, CAMK2δ was significantly decreased [log 2 mean = -0.048 (0.233)] between weeks 0 and 2 (P = .01)]. CONCLUSIONS: We identified an overexpression of miR185-5p during escitalopram treatment of major depressive disorder, which was negatively associated with intensity of nausea, and identified a potential mRNA target that may mediate this effect.

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.

Yoga as a Therapy for Irritable Bowel Syndrome.

The aim of this state-of-the-art narrative review is to evaluate the current evidence about the effectiveness of yoga as therapy for IBS and explore its potential mechanisms of action. The current literature suggests yoga is effective and safe and may target multiple mechanisms involved in treatment of IBS. Evidence from randomized controlled trials identified yoga as more effective compared to pharmacological treatment and equally effective as dietary interventions or moderate-intensity walking. Improvements were seen in both physical health (IBS symptom severity, gastric motility, autonomic and somatic symptom scores, and physical functioning) and mental health outcomes (depression, anxiety, gastrointestinal-specific anxiety, and quality of life). Given favorable changes in IBS-related physical and mental health outcomes, preliminary data supports yoga as beneficial in this population. However, the relatively low-quality evidence resulting from heterogeneity of study designs, interventions, and outcome measures limit our ability to make specific recommendations about the use of yoga as therapy for patients with IBS.

Trauma in Youth At-Risk for Serious Mental Illness.

Childhood trauma has been shown to have detrimental consequences on mental health. It is unknown what impact childhood trauma may have on the early trajectory of serious mental illness (SMI). The purpose of this article is to estimate the baseline prevalence, perceived impact, and duration of trauma that occurred before the age of 18 years in youth at risk for SMI using a transdiagnostic approach. This study included 243 youths, ages 12 to 25 years (42 healthy controls, 43 non-help-seeking individuals [stage 0], 52 help-seeking youth experiencing distress and possibly mild symptoms of anxiety or depression [stage1a], and 108 youth demonstrating attenuated symptoms of an SMI such as bipolar disorder or psychosis [stage 1b]). Participants completed an adapted version of the Childhood Trauma and Abuse scale. There were high frequencies of reported trauma across all stages. Symptomatic individuals experienced more trauma and bullying. Stage 1b individuals reported more physical abuse. Stage 1b also indicated psychological bullying to have a longer duration and impact on their lives. Future work should aim to clarify the complex interrelations between trauma and risk of SMI.

The relationship between depression risk perception and self-help behaviours in high risk Canadians: a cross-sectional study.

BACKGROUND: Self-help may reduce the risk of depression, and risk perception of depression may influence initiating self-help. It is unknown how risk perception is associated with self-help behaviours. The objectives of this study are to (1) describe the self-help strategies used by high-risk Canadians in relation to the accuracy of perceived depression risk, by sex, and (2) identify demographic and clinical factors associated with self-help behaviours. METHODS: Baseline data from a randomized controlled trial including 358 men and 356 women at high-risk of developing depression were used. Following methods used in cancer research, risk perception accuracy was determined by comparing the participant's self-perceived and objective risk of developing depression and classifying as accurate, over-estimation and under-estimation based on a ± 10% threshold. The participant's objective depression risk was assessed using sex-specific multivariable risk predictive algorithms. Frequency of using 14 self-help strategies was assessed. One-way ANOVA testing was used to detect if differences in risk perception accuracy groups existed, stratified by sex. Linear regression was used to investigate the clinical and demographic factors associated with self-help behaviours, also stratified. RESULTS: Compared to accurate-estimators, male over-estimators were less likely to "leave the house daily," and "participate in activities they enjoy." Male under-estimators were also less likely to "participate in activities they enjoy." Both male 'inaccurate' perception groups were more likely to 'create lists of strategies which have worked for feelings of depression in the past and use them'. There were no significant differences between self-help behaviours and risk perception accuracy in women. Regression modeling showed negative relationships between self-rated health and self-help scores, irrespective of sex. In women, self-help score was positively associated with age and educational attainment, and negatively associated with perceived risk. In men, a positive relationship with unemployment was also seen. CONCLUSIONS: Sex differences exist in the factors associated with self-help. Risk perception accuracy, work status, and self-rated health is associated with self-help behaviours in high-risk men. In women, factors related to self-help included age, education, self-rated health status, and perceived risk. More research is needed to replicate findings. TRIAL REGISTRATION: Prospectively registered at ClinicalTrials.gov (NCT02943876) as of 10/21/16.

Aberrant limbic brain structures in young individuals at risk for mental illness.

AIM: Alterations in limbic structures may be present before the onset of serious mental illness, but whether subfield-specific limbic brain changes parallel stages in clinical risk is unknown. To address this gap, we compared the hippocampus, amygdala, and thalamus subfield-specific volumes in adolescents at various stages of risk for mental illness. METHODS: MRI scans were obtained from 182 participants (aged 12-25 years) from the Canadian Psychiatric Risk and Outcome study. The sample comprised of four groups: asymptomatic youth at risk due to family history of mental illness (Stage 0, n = 32); youth with early symptoms of distress (Stage 1a, n = 41); youth with subthreshold psychotic symptoms (Stage 1b, n = 72); and healthy comparison participants with no family history of serious mental illness (n = 37). Analyses included between-group comparisons of brain measurements and correlational analyses that aimed to identify significant associations between neuroimaging and clinical measurements. A machine-learning technique examined the discriminative properties of the clinical staging model. RESULTS: Subfield-specific limbic volume deficits were detected at every stage of risk for mental illness. A machine-learning classifier identified volume deficits within the body of the hippocampus, left amygdala nuclei, and medial-lateral nuclei of the thalamus that were most informative in differentiating between risk stages. CONCLUSION: Aberrant subfield-specific changes within the limbic system may serve as biological evidence to support transdiagnostic clinical staging in mental illness. Differential patterns of volume deficits characterize those at risk for mental illness and may be indicative of a risk-stage progression.

A systematic review of interventions for treatment resistant major depressive disorder in adolescents.

To update a comparative effectiveness review (1980-2011) of treatments for adolescents whose depressive episode or disorder (MDE/MDD) did not respond to one or more trials of SSRI antidepressants. MEDLINE, Cochrane Central, PsychINFO, Cochrane Database of Systematic Reviews, EMBASE, CINAHL, and AMED were searched in addition to the grey literature. We spanned May 2011 to September 1, 2017 and included only articles in English. 11 new studies were reviewed based on the criteria of having tested a comparative treatment in adolescents with MDD or MDE who were confirmed to have failed one or more SSRI trials. Data were extracted using standardized forms and a reference guide in DistillerSR; a second reviewer verified the accuracy of the data fields and discrepancies were resolved by consensus. One trial (N = 29) found a small benefit of escalating doses of fluoxetine and the treatment of adolescent depression study (TORDIA, N = 334) found significant benefits of combined SSRI or venlafaxine treatment with CBT for most outcomes. No new studies were identified since the previous review (2012). One trial is currently registered that will be a cross over trial of rTMS; other registered trials are open label. Multiple secondary data analyses of TORDIA have identified important predictors of treatment response and relapse. No new comparative studies were identified since the original review. Trials are desperately needed to identify new treatments for youth with SSRI resistant MDD. These youth should not be deemed as treatment resistant until completing one or two failed trials of SSRI combined with evidence-based psychotherapy.

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.