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Objectives The 2018 Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) guidelines provided clinicians with pragmatic treatment recommendations for bipolar disorder (BD). While these guidelines included commentary on how mixed features may direct treatment selection, specific recommendations were not provided- a critical gap which the current update aims to address. Method Overview of research regarding mixed presentations in BD, with treatment recommendations developed using a modified CANMAT/ISBD rating methodology. Limitations are discussed, including the dearth of high-quality data and reliance on expert opinion. Results No agents met threshold for first line treatment of DSM-5 manic or depressive episodes with mixed features. For mania + mixed features second line treatment options include asenapine, cariprazine, divalproex, and aripiprazole. In depression + mixed features, cariprazine and lurasidone are recommended as second line options. For DSM-IV defined mixed episodes, with a longer history of research, asenapine and aripiprazole are first line, and olanzapine (monotherapy or combination), carbamazepine, and divalproex are second line. Research on maintenance treatments following a DSM-5 mixed presentation is extremely limited, with third-line recommendations based on expert opinion. For maintenance treatment following a DSM-IV mixed episode, quetiapine (monotherapy or combination) is first line, and lithium and olanzapine identified as second line options. Conclusion The CANMAT and ISBD groups hope these guidelines provide valuable support for clinicians providing care to patients experiencing mixed presentations, as well as further influence investment in research to improve diagnosis and treatment of this common and complex clinical state.

Objectives The COVID-19 pandemic has disrupted the provision of essential and potentially life-saving procedural treatments such as electroconvulsive therapy (ECT). We surveyed ECT providers across Canada to understand how the first wave of the pandemic affected ECT delivery between mid-March 2020 and mid-May 2020. Methods The survey was administered to ECT team members and decision makers at 107 Canadian health care centers with a focus on 5 domains: operations, decision-making, hospital resources, ECT procedure, and patient impact. Responses were obtained from 72 institutions, and collected answers were used to derive representative responses reflecting the situation at each ECT center. For specific domains, responses were split into 2 databases representing the perspective of psychiatrists (n = 67 centers) and anesthesiologists (n = 24 centers). Results Provision of ECT decreased in 64% centers and was completely suspended in 27% of centers after the onset of the pandemic. Outpatient and maintenance ECT were more affected than inpatient and acute ECT. Programs reported a high level of collaboration between psychiatry and hospital leadership (59%) but a limited input from clinical ethicists (18%). Decisions were mostly made ad hoc leading to variability across institutions in adopted resource allocation, physical location of ECT delivery, and triaging frameworks. The majority of centers considered ECT to be aerosol-generating and incorporated changes to airway management. Conclusions Electroconvulsive therapy services in Canada were markedly disrupted by the COVID-19 pandemic. The variability in decision-making across centers warrants the development of a rational approach toward offering ECT in pandemic contexts.

Identifying biomarkers of antidepressant response may advance personalized treatment of major depressive disorder (MDD). We aimed to identify longitudinal changes in gene expression associated with response to antidepressants in a sample of MDD patients treated with escitalopram. Patients (N = 153) from the CAN-BIND-1 cohort were treated for 8 weeks, and depressive symptoms were assessed using the Montgomery-Åsberg Depression Rating Scale at 0, 2, 4, 6, and 8 weeks. We identified three groups of patients according to response status: early responders (22.9%), later responders (32.0%), and nonresponders (45.1%). RNA sequencing was performed in blood obtained at weeks 0, 2, and 8. RNA expression was modeled using growth models, and differences in the longitudinal changes in expression according to response were investigated using multiple regression models. The expression of RNAs related to response was investigated in the brains of depressed individuals, as well as in neuronal cells in vitro. We identified four RNAs (CERCAM, DARS-AS1, FAM228B, HBEGF) whose change over time was independently associated with a response status. For all except HBEGF, responders showed higher expression over time, compared to nonresponders. While the change in all RNAs differentiated early responders from nonresponders, changes in DARS-AS1 and HBEGF also differentiated later responders from nonresponders. Additionally, HBEGF was downregulated in the brains of depressed individuals, and increased in response to escitalopram treatment in vitro. In conclusion, using longitudinal assessments of gene expression, we provide insights into biological processes involved in the intermediate stages of escitalopram response, highlighting several genes with potential utility as biomarkers of antidepressant response.

Non-response to first-line treatment for major depressive disorder (MDD) is common; for such individuals, quality of life (QoL) impairments can be severe. Identifying predictors of QoL changes may support the management of cases with persistent depressive symptoms despite adequate initial pharmacological/psychological treatment. The present study aimed to explore predictors of domain-specific QoL improvement following adjunctive aripiprazole treatment for inadequate response to initial antidepressant therapy. We evaluated secondary QoL outcomes from a CAN-BIND (Canadian Biomarker Integration Network in Depression) study in patients with MDD who did not respond to an initial 8 weeks of escitalopram and received a further 8 weeks of adjunctive aripiprazole (n = 96). Physical, psychological, social, and environmental QoL domains were assessed using the World Health Organization QoL Scale Brief Version (WHOQOL-BREF). Clinician-rated depressive symptoms were assessed using the Montgomery–Asberg Depression Rating Scale (MADRS). Functioning was measured with the Sheehan Disability Scale (SDS). Satisfaction with medication was assessed with a single item from the Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF). Exploratory t-tests were used to describe domain score changes. A hierarchical linear regression was used to explore demographic, clinical, and treatment-related predictors of improvement. Across domains, QoL improved with adjunctive aripiprazole treatment. Satisfaction with medication and MADRS and SDS scores similarly improved. Symptom reduction was a predictor for positive change to physical and psychological QoL; functioning improvements were predictive of increases to all QoL domains. Satisfaction with medication predicted improvements to physical and psychological domains, whereas number of medication trials was a predictor of worsening QoL in the physical domain. The final model explained the most variance in psychological (68%) and physical (67%) QoL. Less variance was explained for environmental (43%) and social QoL (33%), highlighting a need for further exploration of predictors in these domains. Strategies such as functional remediation may have potential to support QoL for individuals with persistent depressive symptoms. ClinicalTrials.gov identifier: NCT016557.

Introduction Many individuals with major depressive disorder (MDD) do not respond to initial antidepressant monotherapy. Adjunctive aripiprazole is recommended for treatment non-response; however, the impacts on quality of life (QoL) for individuals who receive this second-line treatment strategy have not been described. Methods We evaluated secondary QoL outcomes in patients with MDD (n=179). After 8 weeks of escitalopram, non-responders ( Results Escitalopram responders experienced the most QoL improvements in the first treatment phase. For non-responders, QoL improved with a large effect during adjunctive aripiprazole treatment. At the endpoint, 47% of patients achieving symptomatic remission still had impaired QoL. Discussion Individuals who were treated with adjunctive aripiprazole after non-response to escitalopram experienced improved QoL, but a substantial degree of QoL impairment persisted. Since QoL deficits may predict MDD recurrence, attention to ways to support this outcome is required.

Objective:Patients with major depressive disorder often have limited response to first-line and second-line medications; hence, novel pharmacological treatments are needed for treatment-resistant depression (TRD). Ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, has demonstrated rapid antidepressant effects in patients with TRD. The Canadian Network for Mood and Anxiety Treatments (CANMAT) convened a task force to review the evidence for efficacy and safety of racemic ketamine and to provide recommendations for its use in clinical practice.Methods:A systematic review was conducted with computerized search of electronic databases up to January 31, 2020 using combinations of search terms, inspection of bibliographies, and review of other ketamine guidelines and consensus statements. The level of evidence and lines of treatment were assigned according to CANMAT criteria. Recommendations were given in question–answer format.Results:Intravenous (IV) racemic ketamine given as a single infusion has Level 1 evidence for efficacy in adults with TRD. The evidence for multiple infusions, given as an acute series or as ongoing maintenance treatment, is limited to Level 3. Adverse events associated with ketamine infusions include behavioral (e.g., dissociative symptoms) and physiological (e.g., hypertension) events. There is only Level 3 or 4 evidence for non-IV formulations of racemic ketamine. Consensus recommendations are given for clinical administration of IV ketamine including patient selection, facility and personnel issues, monitoring, and maintaining response.Conclusions:Single-dose IV racemic ketamine is a third-line recommendation for adults with TRD. The need for repeated and maintenance ketamine infusions should be carefully assessed on a case-by-case basis with consideration of potential risks and benefits. Because of limited evidence for efficacy and risk for misuse and diversion, the use of oral and other formulations of racemic ketamine should be limited to specialists with ketamine-prescribing expertise and affiliations with tertiary or specialized centers.

Objective Evaluate the clinical utility of combinatorial pharmacogenomic testing for informing medication selection among older adults who have experienced antidepressant medication failure for major depressive disorder (MDD). Design Post hoc analysis of data from a blinded, randomized controlled trial comparing two active treatment arms. Setting Psychiatry specialty and primary care clinics across 60 U.S. community and academic sites. Participants Adults age 65 years or older at baseline (n = 206), diagnosed with MDD and inadequate response to at least one medication on the combinatorial pharmacogenomic test report during the current depressive episode. Intervention Combinatorial pharmacogenomic testing to inform medication selection (guided-care), compared with treatment as usual (TAU). Outcomes Mean percent symptom improvement, response rate, and remission rateat week 8, measured using the 17-item Hamilton Depression Rating Scale; medication switching; and comorbidity moderator analysis. Results At week 8, symptom improvement was not significantly different for guided-care than for TAU (∆ = 8.1%, t = 1.64, df = 187; p = 0.102); however, guided-care showed significantly improved response (∆ = 13.6%, t = 2.16, df = 187; p = 0.032) and remission (∆ = 12.7%, t = 2.49, df = 189; p = 0.014) relative to TAU. By week 8, more than twice as many patients in guided-care than in TAU were on medications predicted to have no gene-drug interactions (χ2 = 19.3, df = 2; p Conclusions Combinatorial pharmacogenomic test-informed medication selection improved outcomes over TAU among older adults with depression.

Objective This work was undertaken to define and characterize the role of currently available somatic treatments in psychiatry in either increasing or reducing the risk for suicide. Methods Members of the Suicide Prevention Task Group of the National Network of Depression Centers performed a literature review of somatic treatments known to increase or reduce the risk for suicide. The reviews ventured to include all relevant information about the risk for both suicide ideation and completed suicides. Results Lithium and clozapine are the only two somatic treatments that have high‐quality data documenting their antisuicide effects in mood disorders and schizophrenia, respectively. Lithium discontinuation is also associated with increased suicide risk. Ketamine and esketamine may have a small, but immediate, antisuicide effect. Despite the recent Food and Drug Administration approval of esketamine use in depressed suicidal patients, the small disproportional overrepresentation of suicide in subjects who had received esketamine versus placebo (3 vs. 0 among > 3500 subjects) requires ongoing evaluation. The purported antisuicide effect of electroconvulsive therapy is based on low‐quality data. The effect of antidepressants is not at all clear. There appears to be direct evidence for antidepressants increasing suicidal ideation and the risk for suicide over the short‐term in young people, but indirect (low quality) evidence that antidepressants reduce suicide risk over the long term. Conclusions Clinicians have an expanding pharmacopeia to address suicide potential in their patients. Some of the agents with documented antisuicide effects may also increase suicidality under specific circumstances., Systemic review of controlled trials of effect of medications on suicide revealed that lithium and clozapine have a documented antisuicide effect in bipolar illness and schizophrenia, respectively. Antidepressants appear to be associated with an increase of suicide ideation for young people acutely, but there is weak evidence that they may reduce suicide ideation or completed suicide over the long term. Ketamine, and possibly esketamine, appear to have a transient antisuicide effect.

Background Approximately two-thirds of patients with major depressive disorder do not achieve remission during their first treatment. There has been increasing interest in the use of digital, artificial intelligence–powered clinical decision support systems (CDSSs) to assist physicians in their treatment selection and management, improving the personalization and use of best practices such as measurement-based care. Previous literature shows that for digital mental health tools to be successful, the tool must be easy for patients and physicians to use and feasible within existing clinical workflows. Objective This study aims to examine the feasibility of an artificial intelligence–powered CDSS, which combines the operationalized 2016 Canadian Network for Mood and Anxiety Treatments guidelines with a neural network–based individualized treatment remission prediction. Methods Owing to the COVID-19 pandemic, the study was adapted to be completed entirely remotely. A total of 7 physicians recruited outpatients diagnosed with major depressive disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria. Patients completed a minimum of one visit without the CDSS (baseline) and 2 subsequent visits where the CDSS was used by the physician (visits 1 and 2). The primary outcome of interest was change in appointment length after the introduction of the CDSS as a proxy for feasibility. Feasibility and acceptability data were collected through self-report questionnaires and semistructured interviews. Results Data were collected between January and November 2020. A total of 17 patients were enrolled in the study; of the 17 patients, 14 (82%) completed the study. There was no significant difference in appointment length between visits (introduction of the tool did not increase appointment length; F2,24=0.805; mean squared error 58.08; P=.46). In total, 92% (12/13) of patients and 71% (5/7) of physicians felt that the tool was easy to use; 62% (8/13) of patients and 71% (5/7) of physicians rated that they trusted the CDSS. Of the 13 patients, 6 (46%) felt that the patient-clinician relationship significantly or somewhat improved, whereas 7 (54%) felt that it did not change. Conclusions Our findings confirm that the integration of the tool does not significantly increase appointment length and suggest that the CDSS is easy to use and may have positive effects on the patient-physician relationship for some patients. The CDSS is feasible and ready for effectiveness studies. Trial Registration ClinicalTrials.gov NCT04061642; http://clinicaltrials.gov/ct2/show/NCT04061642

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

Objective Although bariatric surgery is a durable treatment for patients with severe obesity, it does not directly address behavioural and psychological factors that potentially contribute to weight regain post-surgery. Psychological interventions, such as cognitive behavioural therapy (CBT), can be challenging to access due to physical limitations and practical barriers. Telephone-based CBT (Tele-CBT) can improve eating psychopathology and psychological distress before and after surgery. Given the frequent occurrence/recurrence of problematic eating-related and psychological issues many patients face 1-year post-surgery, this open-trial pilot study aimed to evaluate the effectiveness of Tele-CBT delivered 1-year post-surgery as an adjunctive treatment to the usual standard of bariatric care. Methods Patients (n = 43) received six 1-h Tele-CBT sessions delivered weekly beginning at 1-year post-surgery. Patients completed questionnaire packages before and after the intervention to assess changes in binge eating (BES), emotional eating (EES), depression (PHQ-9), and anxiety (GAD-7). Results Thirty-two patients completed Tele-CBT yielding a 74.4% completion rate. Participants reported significant improvements on the Binge Eating Scale (t(31) = 3.794, p = 0.001), Emotional Eating Scale (t(31) = 3.508, p = 0.001), Patient Health Questionnaire-9 Item Scale (z = −2.371, p = 0.018), and Generalised Anxiety Disorder-7 Item Scale (z = −3.546, p Discussion The results demonstrate that Tele-CBT delivered 1-year post-surgery may improve binge eating, emotional eating, depression, and anxiety. Additional research is warranted to examine whether these changes translate into long-term improvements in bariatric surgery outcomes.

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.

Current prescribing practices for major depressive disorder (MDD) produce limited treatment success. Although pharmacogenomics may improve outcomes by identifying genetically inappropriate medications, studies to date were limited in scope. Outpatients (N = 1167) diagnosed with MDD and with a patient- or clinician-reported inadequate response to at least one antidepressant were enrolled in the Genomics Used to Improve DEpression Decisions (GUIDED) trial – a rater- and patient-blind randomized controlled trial. Patients were randomized to treatment as usual (TAU) or a pharmacogenomics-guided intervention arm in which clinicians had access to a pharmacogenomic test report to inform medication selections (guided-care). Medications were considered congruent (‘use as directed’ or ‘use with caution’ test categories) or incongruent (‘use with increased caution and with more frequent monitoring’ test category) with test results. Unblinding occurred after week 8. Primary outcome was symptom improvement [change in 17-item Hamilton Depression Rating Scale (HAM-D17)] at week 8; secondary outcomes were response (≥50% decrease in HAM-D17) and remission (HAM-D17 ≤ 7) at week 8. At week 8, symptom improvement for guided-care was not significantly different than TAU (27.2% versus 24.4%, p = 0.107); however, improvements in response (26.0% versus 19.9%, p = 0.013) and remission (15.3% versus 10.1%, p = 0.007) were statistically significant. Patients taking incongruent medications prior to baseline who switched to congruent medications by week 8 experienced greater symptom improvement (33.5% versus 21.1%, p = 0.002), response (28.5% versus 16.7%, p = 0.036), and remission (21.5% versus 8.5%, p = 0.007) compared to those remaining incongruent. Pharmacogenomic testing did not significantly improve mean symptoms but did significantly improve response and remission rates for difficult-to-treat depression patients over standard of care (ClinicalTrials.gov NCT02109939).

The increased recognition of patients' mental health needs after bariatric surgery has resulted in the emergence of accessible psychosocial interventions; however, there is a dearth of literature on patient experience and satisfaction with these interventions. We explored patients' perceptions and experiences of telephone-based cognitive behavioural therapy (Tele-CBT) in this qualitative study. Ten participants from the Toronto Western Hospital Bariatric Surgery Program in Toronto, Canada who completed the Tele-CBT (ClinicalTrials.gov Identifier: NCT02920112) were individually interviewed from November 2014 to June 2016 until thematic saturation occurred (ie, no more new coding groups emerged). Interviews were transcribed, independently coded, checked for discrepancies, and analysed using grounded theory. Four themes emerged: (1) participants were generally satisfied with Tele-CBT (eg, therapeutic alliance, resources provided, relevance of therapy to their own bariatric journey), (2) participants noticed emotional, cognitive, and behavioural changes following therapy, (3) the optimal time to deliver the Tele-CBT was when weight loss plateaued, generally at one-year post-surgery, and (4) participants found the telephone modality convenient. CBT was generally found to be helpful and the telephone format increased convenience and accessibility. Patients reported learning skills and receiving resources that could help them improve their well-being following bariatric surgery.

We evaluated the clinical validity of a combinatorial pharmacogenomic test and single-gene Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines against patient outcomes and medication blood levels to assess their ability to inform prescribing in major depressive disorder (MDD). This is a secondary analysis of the Genomics Used to Improve DEpression Decisions (GUIDED) randomized-controlled trial, which included patients with a diagnosis of MDD, and ≥1 prior medication failure. The ability to predict increased/decreased medication metabolism was validated against blood levels at screening (adjusted for age, sex, smoking status). The ability of predicted gene-drug interactions (pharmacogenomic test) or therapeutic recommendations (single-gene guidelines) to predict patient outcomes was validated against week 8 outcomes (17-item Hamilton Depression Rating Scale; symptom improvement, response, remission). Analyses were performed for patients taking any eligible medication (outcomes N=1,022, blood levels N=1,034) and the subset taking medications with single-gene guidelines (outcomes N=584, blood levels N=372). The combinatorial pharmacogenomic test was the only significant predictor of patient outcomes. Both the combinatorial pharmacogenomic test and single-gene guidelines were significant predictors of blood levels for all medications when evaluated separately; however, only the combinatorial pharmacogenomic test remained significant when both were included in the multivariate model. There were no substantial differences when all medications were evaluated or for the subset with single-gene guidelines. Overall, this evaluation of clinical validity demonstrates that the combinatorial pharmacogenomic test was a superior predictor of patient outcomes and medication blood levels when compared with guidelines based on individual genes.

Objective Differential predictors of response to alternative treatment options are needed to improve the outcomes in major depressive disorder. The symptom dimension comprising loss of interest and reduced activity has been reported as a predictor of poor outcome of treatment with antidepressants. We hypothesized that augmentation with partial dopamine agonist aripiprazole will be effective for individuals with pronounced interest-activity symptoms. Methods We tested the hypothesis in the 2-phase Canadian Biomarker Integration Network in Depression trial 1 (CAN-BIND-1). All participants had a primary diagnosis of major depressive disorder confirmed with the Mini-International Neuropsychiatric Interview. In phase 1, 188 individuals received escitalopram monotherapy 10-20 mg daily for 8 weeks. In phase 2, nonresponders received augmentation with aripiprazole 2-10 mg daily while responders continued escitalopram monotherapy for another 8 weeks. Outcomes were measured with the Montgomery-Asberg Depression Rating Scale (MADRS) every 2 weeks. Effects of baseline interest-activity symptoms on outcomes were tested in repeated-measures mixed-effects models. Results Higher baseline interest-activity score (indicative of more severe loss of interest and reduction in activity) predicted worse outcome of escitalopram monotherapy in phase 1 (b = 1.75; 95% CI, 0.45 to 3.05; P = .009), but the association disappeared with the augmentation option in phase 2 (b = -0.19; 95% CI, -1.30 to 0.92; P = .739). A significant interaction between the baseline interest-activity score and aripiprazole reflected the opposite direction of the relationship between baseline interest-activity score and degree of improvement with escitalopram monotherapy versus aripiprazole augmentation (b = -1.60; 95% CI, -2.35 to -0.84; P Conclusions Individuals with prominent loss of interest and reduction in activity benefit less from escitalopram monotherapy and more from aripiprazole augmentation. Future trials may test the benefits of early prodopaminergic augmentation guided by interest-activity symptoms. Trial registration ClinicalTrials.gov identifier: NCT01655706.

This prognostic study of patients with major depressive disorder estimates how accurately an outcome of escitalopram treatment can be predicted from electroencephalographic data., Key Points Question Is it possible to predict whether the condition of a patient with depression will improve after escitalopram treatment by analyzing their resting-state electroencephalographic signals? Findings In this prognostic study of data from 122 patients diagnosed with major depressive disorder, support vector machine classifiers demonstrated an accuracy of 82.4% for predicting escitalopram treatment outcome. Meaning When complemented by appropriate analysis methods, resting-state electroencephalographic recordings may be instrumental in improving treatment of patients with depression., Importance Social and economic costs of depression are exacerbated by prolonged periods spent identifying treatments that would be effective for a particular patient. Thus, a tool that reliably predicts an individual patient’s response to treatment could significantly reduce the burden of depression. Objective To estimate how accurately an outcome of escitalopram treatment can be predicted from electroencephalographic (EEG) data on patients with depression. Design, Setting, and Participants This prognostic study used a support vector machine classifier to predict treatment outcome using data from the first Canadian Biomarker Integration Network in Depression (CAN-BIND-1) study. The CAN-BIND-1 study comprised 180 patients (aged 18-60 years) diagnosed with major depressive disorder who had completed 8 weeks of treatment. Of this group, 122 patients had EEG data recorded before the treatment; 115 also had EEG data recorded after the first 2 weeks of treatment. Interventions All participants completed 8 weeks of open-label escitalopram (10-20 mg) treatment. Main Outcomes and Measures The ability of EEG data to predict treatment outcome, measured as accuracy, specificity, and sensitivity of the classifier at baseline and after the first 2 weeks of treatment. The treatment outcome was defined in terms of change in symptom severity, measured by the Montgomery-Åsberg Depression Rating Scale, before and after 8 weeks of treatment. A patient was designated as a responder if the Montgomery-Åsberg Depression Rating Scale score decreased by at least 50% during the 8 weeks and as a nonresponder if the score decrease was less than 50%. Results Of the 122 participants who completed a baseline EEG recording (mean [SD] age, 36.3 [12.7] years; 76 [62.3%] female), the classifier was able to identify responders with an estimated accuracy of 79.2% (sensitivity, 67.3%; specificity, 91.0%) when using only the baseline EEG data. For a subset of 115 participants who had additional EEG data recorded after the first 2 weeks of treatment, use of these data increased the accuracy to 82.4% (sensitivity, 79.2%; specificity, 85.5%). Conclusions and Relevance These findings demonstrate the potential utility of EEG as a treatment planning tool for escitalopram therapy. Further development of the classification tools presented in this study holds the promise of expediting the search for optimal treatment for each patient.

Background Previous research suggests that the 17-item Hamilton Depression Rating Scale (HAM-D17) is less sensitive in detecting differences between active treatment and placebo for major depressive disorder (MDD) than is the HAM-D6 scale, which focuses on six core depression symptoms. Whether HAM-D6 shows greater sensitivity when comparing two active MDD treatment arms is unknown. Methods This post hoc analysis used data from the intent-to-treat (ITT) cohort (N = 1541) of the Genomics Used to Improve DEpression Decisions (GUIDED) trial, a rater- and patient-blinded randomized controlled trial. GUIDED compared combinatorial pharmacogenomics-guided care with treatment as usual (TAU) in patients with MDD. Percent of symptom improvement, response rate and remission rate from baseline to week 8 were evaluated using both scales. Analyses were performed for the full cohort and for the subset of patients who at baseline were taking medications predicted by the test to have moderate or significant gene-drug interactions. A Mokken scale analysis was conducted to compare the homogeneity of HAM-D17 with that of HAM-D6. Results At week 8, the guided-care arm demonstrated statistically significant benefit over TAU when the HAM-D6 (∆ = 4.4%, p = 0.023) was used as the continuous measure of symptom improvement, but not when using the HAM-D17 (∆ = 3.2%, p = 0.069). Response rates increased significantly for guided-care compared with TAU when evaluated using both HAM-D6 (∆ = 7.0%, p = 0.004) and HAM-D17 (∆ = 6.3%, p = 0.007). Remission rates also were significantly greater for guided-care versus TAU using both measures (HAM-D6 ∆ = 4.6%, p = 0.031; HAM-D17 ∆ = 5.5%, p = 0.005). Patients in the guided-care arm who at baseline were taking medications predicted to have gene-drug interactions showed further increased benefit over TAU at week 8 for symptom improvement (∆ = 7.3%, p = 0.004) response (∆ = 10.0%, p = 0.001) and remission (∆ = 7.9%, p = 0.005) using HAM-D6. All outcomes showed continued improvement through week 24. Mokken scale analysis demonstrated the homogeneity and unidimensionality of HAM-D6, but not of HAM-D17, across treatment arms. Conclusions The HAM-D6 scale identified a statistically significant difference in symptom improvement between combinatorial pharmacogenomics-guided care and TAU, whereas the HAM-D17 did not. The demonstrated utility of pharmacogenomics-guided treatment over TAU as detected by the HAM-D6 highlights its value for future biomarker-guided trials comparing active treatment arms. Trial registration Clinicaltrials.gov: NCT02109939. Registered 10 April 2014.

Background The HOPE-BD was a naturalistic study established to follow individuals in Canada seeking treatment for bipolar disorder (BD). The study aimed to examine the course of BD and describe how clinical and sociodemographic factors are associated with outcomes. Methods Individuals with BD had their clinical data recorded at enrolment and were naturalistically treated. Participant were followed for up to four years, and visits occurred at least once every three months. We investigated the longitudinal outcomes with logistic, Cox, and quantile regressions. Results Among the 354 participants, 57.3% had BD type I. Depression as first episode, younger ages at onset and older ages of the first professional help predicted longer delays in correct diagnosis. Among the symptomatic patients at baseline, the median time to remission was 10.9 months. Comorbid alcohol use disorder and the severity of baseline depressive symptoms predicted longer times to remission. Among the euthymic participants, the median time to recurrence was 14.5 months. History of anxiety disorder and younger ages at onset predicted shorter times to recurrence. Baseline depression scores predicted recurrence in euthymic patients. Limitations We did not investigate the predictors of each polarity. Our findings may not apply to individuals followed in non-specialised outpatient services. Conclusion Our study reinforces the necessity of early diagnosis and interventions, as well as the importance of treating depressive symptoms and comorbidities.

The Canadian Network for Mood and Anxiety Treatments (CANMAT) previously published treatment guidelines for bipolar disorder in 2005, along with international commentaries and subsequent updates in 2007, 2009, and 2013. The last two updates were published in collaboration with the International Society for Bipolar Disorders (ISBD). These 2018 CANMAT and ISBD Bipolar Treatment Guidelines represent the significant advances in the field since the last full edition was published in 2005, including updates to diagnosis and management as well as new research into pharmacological and psychological treatments. These advances have been translated into clear and easy to use recommendations for first, second, and third- line treatments, with consideration given to levels of evidence for efficacy, clinical support based on experience, and consensus ratings of safety, tolerability, and treatment-emergent switch risk. New to these guidelines, hierarchical rankings were created for first and second- line treatments recommended for acute mania, acute depression, and maintenance treatment in bipolar I disorder. Created by considering the impact of each treatment across all phases of illness, this hierarchy will further assist clinicians in making evidence-based treatment decisions. Lithium, quetiapine, divalproex, asenapine, aripiprazole, paliperidone, risperidone, and cariprazine alone or in combination are recommended as first-line treatments for acute mania. First-line options for bipolar I depression include quetiapine, lurasidone plus lithium or divalproex, lithium, lamotrigine, lurasidone, or adjunctive lamotrigine. While medications that have been shown to be effective for the acute phase should generally be continued for the maintenance phase in bipolar I disorder, there are some exceptions (such as with antidepressants); and available data suggest that lithium, quetiapine, divalproex, lamotrigine, asenapine, and aripiprazole monotherapy or combination treatments should be considered first-line for those initiating or switching treatment during the maintenance phase. In addition to addressing issues in bipolar I disorder, these guidelines also provide an overview of, and recommendations for, clinical management of bipolar II disorder, as well as advice on specific populations, such as women at various stages of the reproductive cycle, children and adolescents, and older adults. There are also discussions on the impact of specific psychiatric and medical comorbidities such as substance use, anxiety, and metabolic disorders. Finally, an overview of issues related to safety and monitoring is provided. The CANMAT and ISBD groups hope that these guidelines become a valuable tool for practitioners across the globe.

Background: The Canadian Network for Mood and Anxiety Treatments (CANMAT) conducted a revision of the 2009 guidelines by updating the evidence and recommendations. The scope of the 2016 guidelines remains the management of major depressive disorder (MDD) in adults, with a target audience of psychiatrists and other mental health professionals. Methods: Using the question-answer format, we conducted a systematic literature search focusing on systematic reviews and meta-analyses. Evidence was graded using CANMAT-defined criteria for level of evidence. Recommendations for lines of treatment were based on the quality of evidence and clinical expert consensus. “Complementary and Alternative Medicine Treatments” is the fifth of six sections of the 2016 guidelines. Results: Evidence-informed responses were developed for 12 questions for 2 broad categories of complementary and alternative medicine (CAM) interventions: 1) physical and meditative treatments (light therapy, sleep deprivation, exercise, yoga, and acupuncture) and 2) natural health products (St. John’s wort, omega-3 fatty acids; S-adenosyl-L-methionine [SAM-e], dehydroepiandrosterone, folate, Crocus sativus, and others). Recommendations were based on available data on efficacy, tolerability, and safety. Conclusions: For MDD of mild to moderate severity, exercise, light therapy, St. John’s wort, omega-3 fatty acids, SAM-e, and yoga are recommended as first- or second-line treatments. Adjunctive exercise and adjunctive St. John’s wort are second-line recommendations for moderate to severe MDD. Other physical treatments and natural health products have less evidence but may be considered as third-line treatments. CAM treatments are generally well tolerated. Caveats include methodological limitations of studies and paucity of data on long-term outcomes and drug interactions.

BackgroundPharmacogenomic testing has emerged to aid medication selection for patients with major depressive disorder (MDD) by identifying potential gene-drug interactions (GDI). Many pharmacogenomic tests are available with varying levels of supporting evidence, including direct-to-consumer and physician-ordered tests. We retrospectively evaluated the safety of using a physician-ordered combinatorial pharmacogenomic test (GeneSight) to guide medication selection for patients with MDD in a large, randomized, controlled trial (GUIDED).Materials and MethodsPatients diagnosed with MDD who had an inadequate response to ≥1 psychotropic medication were randomized to treatment as usual (TAU) or combinatorial pharmacogenomic test-guided care (guided-care). All received combinatorial pharmacogenomic testing and medications were categorized by predicted GDI (no, moderate, or significant GDI). Patients and raters were blinded to study arm, and physicians were blinded to test results for patients in TAU, through week 8. Measures included adverse events (AEs, present/absent), worsening suicidal ideation (increase of ≥1 on the corresponding HAM-D17 question), or symptom worsening (HAM-D17 increase of ≥1). These measures were evaluated based on medication changes [add only, drop only, switch (add and drop), any, and none] and study arm, as well as baseline medication GDI.ResultsMost patients had a medication change between baseline and week 8 (938/1,166; 80.5%), including 269 (23.1%) who added only, 80 (6.9%) who dropped only, and 589 (50.5%) who switched medications. In the full cohort, changing medications resulted in an increased relative risk (RR) of experiencing AEs at both week 4 and 8 [RR 2.00 (95% CI 1.41–2.83) and RR 2.25 (95% CI 1.39–3.65), respectively]. This was true regardless of arm, with no significant difference observed between guided-care and TAU, though the RRs for guided-care were lower than for TAU. Medication change was not associated with increased suicidal ideation or symptom worsening, regardless of study arm or type of medication change. Special attention was focused on patients who entered the study taking medications identified by pharmacogenomic testing as likely having significant GDI; those who were only taking medications subject to no or moderate GDI at week 8 were significantly less likely to experience AEs than those who were still taking at least one medication subject to significant GDI (RR 0.39, 95% CI 0.15–0.99, p=0.048). No other significant differences in risk were observed at week 8.ConclusionThese data indicate that patient safety in the combinatorial pharmacogenomic test-guided care arm was no worse than TAU in the GUIDED trial. Moreover, combinatorial pharmacogenomic-guided medication selection may reduce some safety concerns. Collectively, these data demonstrate that combinatorial pharmacogenomic testing can be adopted safely into clinical practice without risking symptom degradation among patients.FundingMyriad Neuroscience/Assurex Health

Introduction Six million people in the U.S. experience depression after age 65. Major depressive disorder (MDD) in later life is associated with longer length of illness, increased number of MDD episodes, and a greater risk of comorbidities. Challenges facing clinicians when making prescription decisions for older adults include increased drug-drug interactions, lower adherence, and higher rates of adverse events. Medication trials for MDD can be difficult to navigate in older patients due to increased polypharmacy for multiple conditions. As the aging population grows, the demand for data-driven tools to optimize medication prescribing for older patients with MDD is gaining momentum. Combinatorial pharmacogenomic (PGx) testing may improve and personalize medication prescribing for older patients by identifying medications that have patient-specific adverse gene-drug interactions. Methods The GUIDED study was a blinded, randomized controlled trial which sought to evaluate the use of a combinatorial PGx test in improving outcomes for patients with MDD by guiding medication treatment decisions. Patients were randomized to either the guided-care arm where the combinatorial PGx test result was available to providers to guide treatment decisions or to the treatment as usual (TAU) arm where the test result was not available to providers until after the primary endpoint. Both patients and raters were blinded to the arm until after the completion of the primary endpoint week 8 assessment. The primary endpoint was symptom improvement on the 17-Item Hamilton Depression Rating Scale (HAM-D17). Secondary endpoints included response (50% reduction in HAM-D17 from baseline) and remission (score ≤7 on HAM-D17). In this subanalysis, we evaluated whether patients aged 65 and older had differences in outcomes based on treatment guidance from combinatorial PGx testing. Results In the GUIDED study, 206 patients were 65+ years of age at baseline with a median age of 69; 108 patients in the treatment as usual (TAU) and 98 patients in the guided-care arm (combinatorial PGx test). The mean HAM-D17 score at baseline overall was 19.8 for all patients, 20.2 in the TAU arm and 19.4 in the guided-care arm. The average number of failed medication trials was 3.5 (3.7 in TAU and 3.3 in guided-care). At week 8, there was a 26.7% decrease in HAM-D17 scores in the guided-care arm (n=86) compared to an 18.7% decrease in TAU (n=98). The difference in symptom improvement between arms did not reach statistical significance (p=0.102). Response rate was significantly higher in the guided-care arm at week 8, with 29.6% of patients experiencing response, compared to 16.1% in TAU (p=0.032). The remission rate was also significantly higher in the guided-care arm at week 8 (20.1%), compared to TAU (7.4%, p=0.014). Conclusions Patients who were 65?years or older in the GUIDED trial whose medication treatment was guided by combinatorial PGx testing achieved significantly better response and remission rates compared to TAU. The difference in symptom improvement in this population did not reach statistical significance. Overall, the data presented here support the utility of using combinatorial PGx testing to help guide antidepressant medication selection with a goal to improve outcomes of depression. This research was funded by: Myriad Genetics, Inc.

Background:The Genomics Used to Improve DEpresssion Decisions (GUIDED) trial assessed outcomes associated with combinatorial pharmacogenomic (PGx) testing in patients with major depressive disorder (MDD). Analyses used the 17-item Hamilton Depression (HAM-D17) rating scale; however, studies demonstrate that the abbreviated, core depression symptom-focused, HAM-D6 rating scale may have greater sensitivity toward detecting differences between treatment and placebo. However, the sensitivity of HAM-D6 has not been tested for two active treatment arms. Here, we evaluated the sensitivity of the HAM-D6 scale, relative to the HAM-D17 scale, when assessing outcomes for actively treated patients in the GUIDED trial.Methods:Outpatients (N=1,298) diagnosed with MDD and an inadequate treatment response to >1 psychotropic medication were randomized into treatment as usual (TAU) or combinatorial PGx-guided (guided-care) arms. Combinatorial PGx testing was performed on all patients, though test reports were only available to the guided-care arm. All patients and raters were blinded to study arm until after week 8. Medications on the combinatorial PGx test report were categorized based on the level of predicted gene-drug interactions: ‘use as directed’, ‘moderate gene-drug interactions’, or ‘significant gene-drug interactions.’ Patient outcomes were assessed by arm at week 8 using HAM-D6 and HAM-D17 rating scales, including symptom improvement (percent change in scale), response (≥50% decrease in scale), and remission (HAM-D6 ≤4 and HAM-D17 ≤7).Results:At week 8, the guided-care arm demonstrated statistically significant symptom improvement over TAU using HAM-D6 scale (Δ=4.4%, p=0.023), but not using the HAM-D17 scale (Δ=3.2%, p=0.069). The response rate increased significantly for guided-care compared with TAU using both HAM-D6 (Δ=7.0%, p=0.004) and HAM-D17 (Δ=6.3%, p=0.007). Remission rates were also significantly greater for guided-care versus TAU using both scales (HAM-D6 Δ=4.6%, p=0.031; HAM-D17 Δ=5.5%, p=0.005). Patients taking medication(s) predicted to have gene-drug interactions at baseline showed further increased benefit over TAU at week 8 using HAM-D6 for symptom improvement (Δ=7.3%, p=0.004) response (Δ=10.0%, p=0.001) and remission (Δ=7.9%, p=0.005). Comparatively, the magnitude of the differences in outcomes between arms at week 8 was lower using HAM-D17 (symptom improvement Δ=5.0%, p=0.029; response Δ=8.0%, p=0.008; remission Δ=7.5%, p=0.003).Conclusions:Combinatorial PGx-guided care achieved significantly better patient outcomes compared with TAU when assessed using the HAM-D6 scale. These findings suggest that the HAM-D6 scale is better suited than is the HAM-D17 for evaluating change in randomized, controlled trials comparing active treatment arms.Funding Acknowledgements:Assurex Health, Inc.

Major depressive disorder (MDD) is primarily treated with antidepressants, yet many patients fail to respond adequately, and identifying antidepressant response biomarkers is thus of clinical significance. Some hypothesis-driven investigations of epigenetic markers for treatment response have been previously made, but genome-wide approaches remain unexplored. Healthy participants (n = 112) and MDD patients (n = 211) between 18–60 years old were recruited for an 8-week trial of escitalopram treatment. Responders and non-responders were identified using differential Montgomery-Åsberg Depression Rating Scale scores before and after treatment. Genome-wide DNA methylation and gene expression analyses were assessed using the Infinium MethylationEPIC Beadchip and HumanHT-12 v4 Expression Beadchip, respectively, on pre-treatment peripheral blood DNA and RNA samples. Differentially methylated positions (DMPs) located in regions of differentially expressed genes between responders (n = 82) and non-responders (n = 95) were identified, and technically validated using a targeted sequencing approach. Three DMPs located in the genes CHN2 (cg23687322, p = 0.00043 and cg06926818, p = 0.0014) and JAK2 (cg08339825, p = 0.00021) were the most significantly associated with mRNA expression changes and subsequently validated. Replication was then conducted with non-responders (n = 76) and responders (n = 71) in an external cohort that underwent a similar antidepressant trial. One CHN2 site (cg06926818; p = 0.03) was successfully replicated. Our findings indicate that differential methylation at CpG sites upstream of the CHN2 and JAK2 TSS regions are possible peripheral predictors of antidepressant treatment response. Future studies can provide further insight on robustness of our candidate biomarkers, and greater characterization of functional components.

OBJECTIVE The objective of the Genomics Used to Improve DEpression Decisions (GUIDED) trial was to evaluate the utility of pharmacogenomic testing to improve outcomes among patients with major depressive disorder (MDD) who had not responded to at least 1 prior medication trial. The objective of the present analysis was to assess outcomes for the subset of patients expected to benefit from combinatorial pharmacogenomic testing because they were taking medications with predicted gene-drug interactions. METHODS Participants (enrolled from April 14, 2014, to February 10, 2017) had an inadequate response to at least 1 psychotropic medication in the current episode of MDD. Patients were randomized to treatment as usual (TAU) or the guided-care arm, in which clinicians had access to a combinatorial pharmacogenomic test report to inform medication selection. Patients and raters were blinded to study arm through week 8. The following outcomes were assessed using the 17-item Hamilton Depre​ssion Rating Scale (HDRS-17): symptom improvement (percent change in HDRS-17 score), response (≥ 50% decrease in HDRS-17 score), and remission (HDRS-17 score ≤ 7). In the GUIDED trial, the primary endpoint of symptom improvement did not reach significance in the intent-to-treat cohort (P = .069). Here, a post hoc analysis of patients who were taking medications subject to gene-drug interactions at baseline as predicted by combinatorial pharmacogenomic testing (N = 912) is presented. RESULTS Among participants taking medications subject to gene-drug interactions at baseline, outcomes at week 8 were significantly improved for those in the guided-care arm compared to TAU (symptom improvement: 27.1% versus 22.1%, P = .029; response: 27.0% versus 19.0%, P = .008; remission: 18.2% versus 10.7%, P = .003). When patients who switched medications were assessed, all outcomes were significantly improved in the guided-care arm compared to TAU (P = .011 for symptom improvement, P = .011 for response, P = .008 for remission). CONCLUSIONS By identifying and focusing on the patients with predicted gene-drug interactions, use of a combinatorial pharmacogenomic test significantly improved outcomes among patients with MDD who had at least 1 prior medication failure. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02109939​.

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

Given the high prevalence of mental health problems among working adults, efforts to increase mental health promotion, prevention, and intervention are being increasingly directed toward the workplace. Research clearly shows that the earlier mental health issues are identified and treated, the sooner improvements in work functioning tend to occur. While employee assistance programs (EAPs) have proliferated over the last few decades and effective evidence-based treatments for most mental health conditions are known and often available, EAPs do not typically provide mental illness prevention or assistance for employees who are already struggling with a mental illness. This means many employees do not receive the treatment they need. This may result in social, personal, and economic problems for these employees, their employers, and society in general. First, this chapter addresses the various burdens of mental illness in the workplace, with a special focus on mood and anxiety disorders. Next, the authors discuss assessment and screening strategies and existing interventions and treatment methods. Finally, this chapter describes different aspects of workplace accommodations that are designed to help individuals with a mental health problem return to the workforce, as well as potential gaps in the knowledge base for addressing mood and anxiety disorders in the workplace.

Objective: To derive new criteria sets for defining manic and hypomanic episodes (and thus for defining the bipolar I and II disorders), an international Task Force was assembled and termed AREDOC reflecting its role of Assessment, Revision and Evaluation of DSM and other Operational Criteria. This paper reports on the first phase of its deliberations and interim criteria recommendations. Method: The first stage of the process consisted of reviewing Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, and recent International Classification of Diseases criteria, identifying their limitations and generating modified criteria sets for further in-depth consideration. Task Force members responded to recommendations for modifying criteria and from these the most problematic issues were identified. Results: Principal issues focussed on by Task Force members were how best to differentiate mania and hypomania, how to judge ‘impairment’ (both in and of itself and allowing that functioning may sometimes improve during hypomanic episodes) and concern that rejecting some criteria (e.g. an imposed duration period) might risk false-positive diagnoses of the bipolar disorders. Conclusion: This first-stage report summarises the clinical opinions of international experts in the diagnosis and management of the bipolar disorders, allowing readers to contemplate diagnostic parameters that may influence their clinical decisions. The findings meaningfully inform subsequent Task Force stages (involving a further commentary stage followed by an empirical study) that are expected to generate improved symptom criteria for diagnosing the bipolar I and II disorders with greater precision and to clarify whether they differ dimensionally or categorically.

Background: The Canadian Network for Mood and Anxiety Treatments (CANMAT) conducted a revision of the 2009 guidelines by updating the evidence and recommendations. The scope of the 2016 guidelines remains the management of major depressive disorder (MDD) in adults, with a target audience of psychiatrists and other mental health professionals. Methods: Using the question-answer format, we conducted a systematic literature search focusing on systematic reviews and meta-analyses. Evidence was graded using CANMAT-defined criteria for level of evidence. Recommendations for lines of treatment were based on the quality of evidence and clinical expert consensus. This section is the first of six guidelines articles. Results: In Canada, the annual and lifetime prevalence of MDD was 4.7% and 11.3%, respectively. MDD represents the second leading cause of global disability, with high occupational and economic impact mainly attributable to indirect costs. DSM-5 criteria for depressive disorders remain relatively unchanged, but other clinical dimensions (sleep, cognition, physical symptoms) may have implications for depression management. e-Mental health is increasingly used to support clinical and self-management of MDD. In the 2-phase (acute and maintenance) treatment model, specific goals address symptom remission, functional recovery, improved quality of life, and prevention of recurrence. Conclusions: The burden attributed to MDD remains high, whether from individual distress, functional and relationship impairment, reduced quality of life, or societal economic cost. Applying core principles of care, including comprehensive assessment, therapeutic alliance, support of self-management, evidence-informed treatment, and measurement-based care, will optimize clinical, quality of life, and functional outcomes in MDD.

This study aimed to determine the feasibility and preliminary efficacy of a post-operative telephone-based cognitive behavioral therapy intervention (Tele-CBT) in improving eating pathology and psychosocial functioning. Six-month post-operative bariatric surgery patients (n = 19) received six sessions of Tele-CBT. Study outcome variables included binge eating (BES), emotional eating (EES), depressive symptoms (PHQ-9), and anxiety symptoms (GAD-7). Retention was 73.7 % post-intervention. Tele-CBT resulted in significant reductions in mean difference scores on BES, EES-Total, EES-Anxiety, EES-Anger, PHQ9, and GAD7. Tele-CBT patients experienced a mean weight loss of 8.62 ± 15.02 kg between 6-months post-surgery (pre-Tele-CBT) and 12-months post-surgery. These preliminary results suggest that post-surgery Tele-CBT is feasible and can improve post-surgery symptoms of psychopathology in this uncontrolled study, supporting the need for a randomized controlled trial.

OBJECTIVE To investigate how the combination of clinical and molecular biomarkers can predict worsening of suicidal ideation during antidepressant treatment. METHODS Samples were obtained from 237 patients with major depressive disorder (DSM-IV criteria) treated with either duloxetine or placebo in an 8-week randomized controlled trial. Data were collected between 2007 and 2011. The relationship between treatment-worsening suicidal ideation (TWSI) and a number of clinical variables, as well as peripheral expression of messenger RNA (mRNA) and microRNA (miRNA), was assessed at baseline. We generated 4 predictive models for TWSI: clinical, mRNA, miRNA, and a combined model comprising the best predictive variables from clinical, mRNA, and miRNA data. RESULTS Eleven patients (9.8%) presented with TWSI in the duloxetine group. Among the clinical variables, only baseline depressive severity was found to be mildly predictive of TWSI. Two mRNAs (stathmin 1 [STMN1] and protein phosphatase 1 regulatory subunit 9B [PPP1R9B]) and 2 miRNAs (miR-3688 and miR-5695) were identified that were significantly predictive of TWSI when mRNA and miRNA were assessed separately (P = .002, .044, .004, and .005, respectively). The best model included baseline depression severity and expression of STMN1 and miR-5695 and predicted TWSI with area under the curve = 0.94 (P < .001). Additionally, the combined model did not significantly predict TWSI in the placebo group. CONCLUSIONS This study generated a predictive tool for TWSI that combines both biological and clinical variables. These biological variables can be easily quantified in peripheral tissues, thus rendering them viable targets to be used in both clinical practice and future studies of suicidal behaviors. TRIAL REGISTRATION ClinicalTrials.gov identifiers: NCT00635219, NCT00599911, and NCT01140906.

Depression is the most burdensome noncommunicable condition among young persons aged 10–24 years, with rates of depression rising steeply during the postpubertal period corresponding to the intermediate and secondary school years. Although a high number of children and adolescents experience depressive symptoms or clinical depression, many will not or cannot access health services, and the number of potential cases cannot be dealt with entirely by the health-care system. As such, a public health perspective, which encourages the application of mental health promotion and primary and early secondary prevention, has gained increasing acceptance, as represented by the expansion of school-based depression and mental health interventions. The objective of this chapter is threefold. First, it provides an overview of the accomplishments in school-based depression intervention and mental health promotion and prevention research by presenting both universal and selective prevention approaches, which are delivered prior to the onset of symptoms or a diagnosis. Second, the chapter showcases two successful school-based intervention programs and presents guidance on how to implement each of these models. Third, the chapter discusses limitations in the field, highlights recommendations for implementation, and offers a roadmap for potential future avenues for research, including lessons for adaptation of programs to allow translation to other settings and nations.

The Peer-to-Peer Depression Awareness Program (P2P) is a school-based program that aims to decrease mental illness and promote well-being among students by empowering high school students as both learners and educators. Specific goals include improving the school climate around mental health, directing students to resources, and encouraging help-seeking behavior.In the 2015-2016 academic year, 121 students across 10 high schools organized into teams and were trained to develop and implement peer-to-peer depression awareness campaigns. Outcomes were assessed via pre- and posttest questionnaires.A total of 878 students completed questionnaires. Outcomes demonstrated improved knowledge and attitudes toward depression, increased confidence in identifying and referring peers with depression, improved help-seeking intentions, and reduced stigma.The P2P program increased depression literacy through the use of youth-designed and youth-implemented depression awareness and outreach activities, which may ultimately result in earlier detection of depression and in fewer depression sequelae.

Background: Major depressive disorder (MDD) is primarily treated with antidepressants, yet many patients fail to respond to adequate trials. Understanding who is likely to respond to antidepressant treatment and/or what mediates this response is of considerable clinical importance. As part of the Canadian Biomarker Integration Network in Depression (CAN-BIND-1) initiative, we aimed to identify differential DNA methylation marks as epigenetic predictors of antidepressant response (ADR) in MDD patients. Methods: Healthy participants (n=112) and depressed participants (n=211) between 18-60 years of age were recruited across six Canadian clinical centers. Eligible depressed patients with MDD by DSM-IV-TR criteria and a Montgomery-Asberg Depression Rating Scale (MADRS) score of ≥24 were enrolled. Genome-wide DNA methylation analysis was conducted using the Infinium MethylationEPIC Beadchipb with DNA extracted from baseline peripheral blood samples prior to beginning an eight-week trial of escitalopram. Genome-wide mRNA expression analysis was conducted on the HumanHT-12 v4 Expression Beadchip in RNA extracted from leukocytes at baseline. Depressed patients were classified as non-responders (NRES) and responders (RES) according to changes in MADRS scores following eight weeks of treatment. Differentially methylated positions (DMPs) were identified in regions of differentially expressed genes and validated using a targeted sequencing approach. Replication was conducted with patients participating in a similar trial, the Douglas Biomarker Study. CAN-BIND-1 clinical trial was registered with the ClinicalTrials.gov identification #: NCT101655706. Findings: After depressed participants concluded the 8-week trial, 82 RES and 95 NRES were included in this study. Genome-wide differential DNA methylation revealed 2,572 DMPs (p

Atypical antipsychotic adjunctive therapy to lithium or valproate is effective in treating acute mania. Although continuation of atypical antipsychotic adjunctive therapy after mania remission reduces relapse of mood episodes, the optimal duration is unknown. As many atypical antipsychotics cause weight gain and metabolic syndrome, they should not be continued unless the benefits outweigh the risks. This 52-week double-blind placebo-controlled trial recruited patients with bipolar I disorder (n=159) who recently remitted from a manic episode during treatment with risperidone or olanzapine adjunctive therapy to lithium or valproate. Patients were randomized to one of three conditions: discontinuation of risperidone or olanzapine and substitution with placebo at (i) entry (‘0-weeks' group) or (ii) at 24 weeks after entry (‘24-weeks' group) or (iii) continuation of risperidone or olanzapine for the full duration of the study (‘52-weeks' group). The primary outcome measure was time to relapse of any mood episode. Compared with the 0-weeks group, the time to any mood episode was significantly longer in the 24-weeks group (hazard ratio (HR) 0.53; 95% confidence interval (CI): 0.33, 0.86) and nearly so in the 52-weeks group (HR: 0.63; 95% CI: 0.39, 1.02). The relapse rate was similar in the 52-weeks group compared with the 24-weeks group (HR: 1.18; 95% CI: 0.71, 1.99); however, sub-group analysis showed discordant results between the two antipsychotics (HR: 0.48, 95% CI: 0.17; 1.32 olanzapine patients; HR: 1.85, 95% CI: 1.00, 3.41 risperidone patients). Average weight gain was 3.2 kg in the 52-weeks group compared with a weight loss of 0.2 kg in the 0-weeks and 0.1 kg in the 24-weeks groups. These findings suggest that risperidone or olanzapine adjunctive therapy for 24 weeks is beneficial but continuation of risperidone beyond this period does not reduce the risk of relapse. Whether continuation of olanzapine beyond this period reduces relapse risk remains unclear but the potential benefit needs to be weighed against an increased risk of weight gain.

Background This study aims to compare the effectiveness of EEG frequency band activity including interhemispheric asymmetry and prefrontal theta cordance in predicting response to escitalopram therapy at 8-weeks post-treatment, in a multi-site initiative. Methods Resting state 64-channel EEG data were recorded from 44 patients with a diagnosis of major depressive disorder (MDD) as part of a larger, multisite discovery study of biomarkers in antidepressant treatment response, conducted by the Canadian Biomarker Integration Network in Depression (CAN-BIND). Clinical response was measured at 8-weeks post-treatment as change from baseline Montgomery-Asberg Depression Rating Scale (MADRS) score of 50% or more. EEG measures were analyzed at (1) pre-treatment baseline (2) 2 weeks post-treatment and (3) as an ‘‘early change” variable defined as change in EEG from baseline to 2 weeks post-treatment. Results At baseline, treatment responders showed elevated absolute alpha power in the left hemisphere while non-responders showed the opposite. Responders further exhibited a cortical asymmetry in the parietal region. Groups also differed in pre-treatment relative delta power with responders showing greater power in the right hemisphere over the left while non-responders showed the opposite. At 2 weeks post-treatment, responders exhibited greater absolute beta power in the left hemisphere relative to the right and the opposite was noted for non-responders. A reverse pattern was noted for absolute and relative delta power at 2 weeks post-treatment. Responders exhibited early reductions in relative alpha power and early increments in relative theta power. Non-responders showed a significant early increase in prefrontal theta cordance. Conclusions Hemispheric asymmetries in the alpha and delta bands at baseline and at 2 weeks post-treatment have moderately strong predictive utility in predicting response to antidepressant treatment.

Bariatric surgery is the most effective treatment for extreme obesity; however, 20% to 50% of patients begin to regain their weight within the first 1.5 to 2 years following surgery. Despite some psychosocial factors predicting postoperative weight loss and weight regain, psychosocial interventions are not routinely offered in bariatric surgery programs. In this paper, we describe a 6-session cognitive behavioral therapy (CBT) intervention for preoperative and postoperative bariatric surgery patients with maladaptive eating behaviors or thought patterns, which can be delivered either in person or by telephone. In addition, we describe a small pilot study ( n = 8) designed to examine the feasibility and acceptability of the CBT intervention, as well as its effectiveness in improving eating pathology and psychosocial functioning. Most pilot study participants reported improvements in binge eating severity, emotional eating, and depression from pre- to posttreatment, and all participants provided positive qualitative feedback regarding the intervention.

BackgroundMajor depressive disorder is associated with significant impairment in occupational functioning and reduced productivity, which represents a large part of the overall burden of depression.AimsTo examine symptom-based and work functioning outcomes with combined pharmacotherapy and psychotherapy treatment of major depressive disorder.MethodEmployed patients with a DSM-IV diagnosis of major depressive disorder were treated with escitalopram 10–20mg/day and randomised to: (a) telephone-administered cognitive-behavioural therapy (telephone CBT) (n = 48); or (b) adherence-reminder telephone calls (n = 51). Outcomes included the Montgomery-åsberg Depression Rating Scale (MADRS), administered by masked evaluators via telephone, and self-rated work functioning scales completed online. (Registered at clinicaltrials.gov: NCT00702598.)ResultsAfter 12 weeks, there were no significant between-group differences in change in MADRS score or in response/remission rates. However, participants in the telephone-CBT group had significantly greater improvement on some measures of work functioning than the escitalopram-alone group.ConclusionsCombined treatment with escitalopram and telephone- administered CBT significantly improved some self-reported work functioning outcomes, but not symptom-based outcomes, compared with escitalopram alone.

Background Psychiatric stigma is pervasive injustice that complicates the course of illness and reduces quality of life for people with mental illnesses. This article reviews the research examining stigma towards bipolar disorder (BD) with a view to guiding the development of stigma reduction initiatives and ongoing research. Methods PsychInfo, Medline, and Embase databases were searched for peer-reviewed studies addressing stigma in BD. Results Stigma is a serious concern for individuals with BD and their families. Stigma occurs within affected individuals, families, social environments, work and school environments, and the healthcare industry. With stigma often come a loss of social support and occupational success, reduced functioning, higher symptom levels and lower quality of life. BD stigma is comparable to that of other severe mental illnesses, such as schizophrenia. Few interventions are available to specifically target stigma against BD. Limitations Most studies have used explicit, attitude-based measures of stigma without controlling for social desirability, which may not translate into real-world stigmatizing behaviors. Furthermore, many studies have not clearly delineated results in a manner consistent with the conceptual framework of stigmatization. Conclusions Stigma toward BD is ubiquitous and has insidious consequences for affected individuals and their families. Stigma reduction initiatives should target individuals living with BD, their families, workplaces, and the healthcare industry, taking into account the experiences and impacts of BD stigma to improve social support, course of illness, and quality of life.