Prototyping the implementation of a suicide prevention protocol in primary care settings using PDSA cycles: a mixed method study.

Introduction: In Canada, approximately 4,500 individuals die by suicide annually. Approximately 45% of suicide decedents had contact with their primary care provider within the month prior to their death. Current versus never smokers have an 81% increased risk of death by suicide. Those who smoke have additional risks for suicide such as depression, chronic pain, alcohol, and other substance use. They are more likely to experience adverse social determinants of health. Taken together, this suggests that smoking cessation programs in primary care could be facilitators of suicide prevention, but this has not been studied. Study objectives: The objectives of the study are to understand barriers/facilitators to implementing a suicide prevention protocol within a smoking cessation program (STOP program), which is deployed by an academic mental health and addiction treatment hospital in primary care clinics and to develop and test implementation strategies to facilitate the uptake of suicide screening and assessment in primary care clinics across Ontario. Methods: The study employed a three-phase sequential mixed-method design. Phase 1: Conducted interviews guided by the Consolidated Framework for Implementation Research exploring barriers to implementing a suicide prevention protocol. Phase 2: Performed consensus discussions to map barriers to implementation strategies using the Expert Recommendations for Implementing Change tool and rank barriers by relevance. Phase 3: Evaluated the feasibility and acceptability of implementation strategies using Plan Do Study Act cycles. Results: Eleven healthcare providers and four research assistants identified lack of training and the need of better educational materials as implementation barriers. Participants endorsed and tested the top three ranked implementation strategies, namely, a webinar, adding a preamble before depression survey questions, and an infographic. After participating in the webinar and reviewing the educational materials, all participants endorsed the three strategies as acceptable/very acceptable and feasible/very feasible. Conclusion: Although there are barriers to implementing a suicide prevention protocol within primary care, it is possible to overcome them with strategies deemed both acceptable and feasible. These results offer promising practice solutions to implement a suicide prevention protocol in smoking cessation programs delivered in primary care settings. Future efforts should track implementation of these strategies and measure outcomes, including provider confidence, self-efficacy, and knowledge, and patient outcomes.

Treatment-resistant depression: definition, prevalence, detection, management, and investigational interventions.

Treatment-resistant depression (TRD) is common and associated with multiple serious public health implications. A consensus definition of TRD with demonstrated predictive utility in terms of clinical decision-making and health outcomes does not currently exist. Instead, a plethora of definitions have been proposed, which vary significantly in their conceptual framework. The absence of a consensus definition hampers precise estimates of the prevalence of TRD, and also belies efforts to identify risk factors, prevention opportunities, and effective interventions. In addition, it results in heterogeneity in clinical practice decision-making, adversely affecting quality of care. The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have adopted the most used definition of TRD (i.e., inadequate response to a minimum of two antidepressants despite adequacy of the treatment trial and adherence to treatment). It is currently estimated that at least 30% of persons with depression meet this definition. A significant percentage of persons with TRD are actually pseudo-resistant (e.g., due to inadequacy of treatment trials or non-adherence to treatment). Although multiple sociodemographic, clinical, treatment and contextual factors are known to negatively moderate response in persons with depression, very few factors are regarded as predictive of non-response across multiple modalities of treatment. Intravenous ketamine and intranasal esketamine (co-administered with an antidepressant) are established as efficacious in the management of TRD. Some second-generation antipsychotics (e.g., aripiprazole, brexpiprazole, cariprazine, quetiapine XR) are proven effective as adjunctive treatments to antidepressants in partial responders, but only the olanzapine-fluoxetine combination has been studied in FDA-defined TRD. Repetitive transcranial magnetic stimulation (TMS) is established as effective and FDA-approved for individuals with TRD, with accelerated theta-burst TMS also recently showing efficacy. Electroconvulsive therapy is regarded as an effective acute and maintenance intervention in TRD, with preliminary evidence suggesting non-inferiority to acute intravenous ketamine. Evidence for extending antidepressant trial, medication switching and combining antidepressants is mixed. Manual-based psychotherapies are not established as efficacious on their own in TRD, but offer significant symptomatic relief when added to conventional antidepressants. Digital therapeutics are under study and represent a potential future clinical vista in this population.

Common Data Elements to Facilitate Sharing and Re-use of Participant-Level Data: Assessment of Psychiatric Comorbidity Across Brain Disorders.

The Ontario Brain Institute's "Brain-CODE" is a large-scale informatics platform designed to support the collection, storage and integration of diverse types of data across several brain disorders as a means to understand underlying causes of brain dysfunction and developing novel approaches to treatment. By providing access to aggregated datasets on participants with and without different brain disorders, Brain-CODE will facilitate analyses both within and across diseases and cover multiple brain disorders and a wide array of data, including clinical, neuroimaging, and molecular. To help achieve these goals, consensus methodology was used to identify a set of core demographic and clinical variables that should be routinely collected across all participating programs. Establishment of Common Data Elements within Brain-CODE is critical to enable a high degree of consistency in data collection across studies and thus optimize the ability of investigators to analyze pooled participant-level data within and across brain disorders. Results are also presented using selected common data elements pooled across three studies to better understand psychiatric comorbidity in neurological disease (Alzheimer's disease/amnesic mild cognitive impairment, amyotrophic lateral sclerosis, cerebrovascular disease, frontotemporal dementia, and Parkinson's disease).

Treatment-resistant major depressive disorder: Canadian expert consensus on definition and assessment.

BACKGROUND: Treatment-resistant depression (TRD) is a debilitating chronic mental illness that confers increased morbidity and mortality, decreases the quality of life, impairs occupational, social, and offspring development, and translates into increased costs on the healthcare system. The goal of this study is to reach an agreement on the concept, definition, staging model, and assessment of TRD. METHODS: This study involved a review of the literature and a modified Delphi process for consensus agreement. The Appraisal of Guidelines for Research & Evaluation II guidelines were followed for the literature appraisal. Literature was assessed for quality and strength of evidence using the grading, assessment, development, and evaluations system. Canadian national experts in depression were invited for the modified Delphi process based on their prior clinical and research expertize. Survey items were considered to have reached a consensus if 80% or more of the experts supported the statement. RESULTS: Fourteen Canadian experts were recruited for three rounds of surveys to reach a consensus on a total of 27 items. Experts agreed that a dimensional definition for treatment resistance was a useful concept to describe the heterogeneity of this illness. The use of staging models and clinical scales was recommended in evaluating depression. Risk factors and comorbidities were identified as potential predictors for treatment resistance. CONCLUSIONS: TRD is a meaningful concept both for clinical practice and research. An operational definition for TRD will allow for opportunities to improve the validity of predictors and therapeutic options for these patients.

THE DEPRESSION INVENTORY DEVELOPMENT SCALE: Assessment of Psychometric Properties Using Classical and Modern Measurement Theory in a CAN-BIND Trial.

Objective: The goal of the Depression Inventory Development (DID) project is to develop a comprehensive and psychometrically sound rating scale for major depressive disorder (MDD) that reflects current diagnostic criteria and conceptualizations of depression. We report here the evaluation of the current DID item bank using Classical Test Theory (CTT), Item Response Theory (IRT) and Rasch Measurement Theory (RMT). Methods: The present study was part of a larger multisite, open-label study conducted by the Canadian Biomarker Integration Network in Depression (ClinicalTrials.gov: NCT01655706). Trained raters administered the 32 DID items at each of two visits (MDD: baseline, n=211 and Week 8, n=177; healthy participants: baseline, n=112 and Week 8, n=104). The DID's "grid" structure operationalizes intensity and frequency of each item, with clear symptom definitions and a structured interview guide, with the current iteration assessing symptoms related to anhedonia, cognition, fatigue, general malaise, motivation, anxiety, negative thinking, pain, and appetite. Participants were also administered the Montgomery- Åsberg Depression Rating Scale (MADRS) and Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR) that allowed DID items to be evaluated against existing "benchmark" items. CTT was used to assess data quality/reliability (i.e., missing data, skewness, scoring frequency, internal consistency), IRT to assess individual item performance by modelling an item's ability to discriminate levels of depressive severity (as assessed by the MADRS), and RMT to assess how the items perform together as a scale to capture a range of depressive severity (item targeting). These analyses together provided empirical evidence to base decisions on which DID items to remove, modify, or advance. Results: Of the 32 DID items evaluated, eight items were identified by CTT as problematic, displaying low variability in the range of responses, floor effects, and/or skewness; and four items were identified by IRT to show poor discriminative properties that would limit their clinical utility. Five additional items were deemed to be redundant. The remaining 15 DID items all fit the Rasch model, with person and item difficulty estimates indicating satisfactory item targeting, with lower precision in participants with mild levels of depression. These 15 DID items also showed good internal consistency (alpha=0.95 and inter-item correlations ranging from r=0.49 to r=0.84) and all items were sensitive to change following antidepressant treatment (baseline vs. Week 8). RMT revealed problematic item targeting for the MADRS and QIDSSR, including an absence of MADRS items targeting participants with mild/moderate depression and an absence of QIDS-SR items targeting participants with mild or severe depression. Conclusion: The present study applied CTT, IRT, and RMT to assess the measurement properties of the DID items and identify those that should be advanced, modified, or removed. Of the 32 items evaluated, 15 items showed good measurement properties. These items (along with previously evaluated items) will provide the basis for validation of a penultimate DID scale assessing anhedonia, cognitive slowing, concentration, executive function, recent memory, drive, emotional fatigue, guilt, self-esteem, hopelessness, tension, rumination, irritability, reduced appetite, insomnia, sadness, worry, suicidality, and depressed mood. The strategies adopted by the DID process provide a framework for rating scale development and validation.

Fatigue in Patients with Major Depressive Disorder: Prevalence, Burden and Pharmacological Approaches to Management.

Fatigue is a frequently reported symptom in major depressive disorder, occurring in over 90% of patients. Clinical presentations of fatigue within major depressive disorder encompass overlapping physical, cognitive and emotional aspects. While this review addresses the epidemiology, burden, functional impact and management of fatigue in major depressive disorder, the main focus is on available pharmacotherapy options and their comparative efficacies. Our review of the effects of pharmacological treatments on fatigue in major depressive disorder found that medications with dopaminergic and/or noradrenergic action such as modafinil, flupenthixol and atomoxetine were most effective in improving symptoms of fatigue and low energy. However, significant variation across studies in assessment tools and study inclusion/exclusion criteria may have contributed to inconsistent findings. The efficacy of non-pharmacological interventions is also discussed, including light therapy and exercise.

Performance of the biological rhythms interview for assessment in neuropsychiatry: An item response theory and actigraphy analysis.

BACKGROUND: Biological rhythm disturbances are widely associated with the pathophysiology of mood disorders. The Biological Rhythms Interview for Assessment in Neuropsychiatry (BRIAN) is a self-report that indexes rhythm disturbance in sleep, activity, social and eating patterns. The aim of this study was to perform an Item Response Theory (IRT) analysis of the BRIAN and investigate its associations with objective sleep and rhythm disturbance measures. METHODS: 103 subjects (31 bipolar, 32 major depression and 40 healthy volunteers) wore an actiwatch for fifteen days, and completed a first morning urine sample and the BRIAN on day 15. IRT analysis assessed individual BRIAN items and their relationship to total score. Individual actiwatch records were processed to produce a sequence of transitions between rest/activity, and a likelihood of transitioning between states was calculated to investigate sleep-wake dynamics. Cosinor analysis produced daily activity rhythms (DARs). Spearman correlations were used to assess the association between sleep/DAR variables and the BRIAN. RESULTS: IRT analyses showed that 11 of 18 BRIAN items displayed a high level of discrimination between item options across a range of BRIAN total scores. Total BRIAN score correlated with wake after sleep onset, total activity count during sleep, and urinary 6-sulphatoxymelatonin. BRIAN Activity domain correlated with the daytime transition probability from rest to activity. LIMITATIONS: The sample size may have been underpowered for the graded-response model employed in IRT. The study lacked an objective comparison for BRIAN eating and social domain. CONCLUSION: The present study reveals the BRIAN displays promising external validity compared to objective parameters of circadian rhythmicity.

The Depression Inventory Development Workgroup: A Collaborative, Empirically Driven Initiative to Develop a New Assessment Tool for Major Depressive Disorder.

The Depression Inventory Development project is an initiative of the International Society for CNS Drug Development whose goal is to develop a comprehensive and psychometrically sound measurement tool to be utilized as a primary endpoint in clinical trials for major depressive disorder. Using an iterative process between field testing and psychometric analysis and drawing upon expertise of international researchers in depression, the Depression Inventory Development team has established an empirically driven and collaborative protocol for the creation of items to assess symptoms in major depressive disorder. Depression-relevant symptom clusters were identified based on expert clinical and patient input. In addition, as an aid for symptom identification and item construction, the psychometric properties of existing clinical scales (assessing depression and related indications) were evaluated using blinded datasets from pharmaceutical antidepressant drug trials. A series of field tests in patients with major depressive disorder provided the team with data to inform the iterative process of scale development. We report here an overview of the Depression Inventory Development initiative, including results of the third iteration of items assessing symptoms related to anhedonia, cognition, fatigue, general malaise, motivation, anxiety, negative thinking, pain and appetite. The strategies adopted from the Depression Inventory Development program, as an empirically driven and collaborative process for scale development, have provided the foundation to develop and validate measurement tools in other therapeutic areas as well.

Depression and employment status in primary and tertiary care settings.

OBJECTIVE: Major depressive disorder (MDD) is a leading cause of disability. Impairment in work function considerably adds to symptom burden and increases the economic impact of this disorder. Our study aimed to investigate the factors associated with work status in MDD within primary and tertiary care. METHOD: We used data from 2 large databases for our analysis--Study 1: the InSight database, a chart review of MDD patients treated by primary care physicians across Canada (n=986); and Study 2: the International Mood Disorders Collaborative Project, a cross-sectional study of mood disorder patients (Canadian data only: n=274). RESULTS: Both studies demonstrated high rates of unemployment and disability (30.3% to 42.1%). Quebec showed the highest rate of unemployment (21%) and British Columbia had the greatest percentage of patients on disability (15%). Employed and unemployed groups were similar based on clinical characteristics; however, unemployed people may have higher age, prevalence of medical comorbidity, and greater likelihood of receiving a benzodiazepine. Increased disability rates were associated with history of childhood abuse, duration of current major depressive episode, comorbidity, benzodiazepine use, as well as greater depression and anxiety severity. The unemployed-disability groups had greater somatic symptoms and anhedonia. In keeping with this, anhedonia was the strongest predictor of disability. Absenteeism was also high across both studies. CONCLUSIONS: Unemployment and disability rates in MDD are high. The presence of anhedonia and medical comorbidity significantly influenced work status, emphasizing the need for treatment strategies to alleviate the additional symptom burden in this subpopulation.

A randomized controlled trial of psychoeducation or cognitive-behavioral therapy in bipolar disorder: a Canadian Network for Mood and Anxiety treatments (CANMAT) study [CME].

OBJECTIVE: Bipolar disorder is insufficiently controlled by medication, so several adjunctive psychosocial interventions have been tested. Few studies have compared these psychosocial treatments, all of which are lengthy, expensive, and difficult to disseminate. We compared the relative effectiveness of a brief psychoeducation group intervention to a more comprehensive and longer individual cognitive-behavioral therapy intervention, measuring longitudinal outcome in mood burden in bipolar disorder. METHOD: This single-blind randomized controlled trial was conducted between June 2002 and September 2006. A total of 204 participants (ages 18-64 years) with DSM-IV bipolar disorder type I or II participated from 4 Canadian academic centers. Subjects were recruited via advertisements or physician referral when well or minimally symptomatic, with few exclusionary criteria to enhance generalizability. Participants were assigned to receive either 20 individual sessions of cognitive-behavioral therapy or 6 sessions of group psychoeducation. The primary outcome of symptom course and morbidity was assessed prospectively over 72 weeks using the Longitudinal Interval Follow-up Evaluation, which yields depression and mania symptom burden scores for each week. RESULTS: Both treatments had similar outcomes with respect to reduction of symptom burden and the likelihood of relapse. Eight percent of subjects dropped out prior to receiving psychoeducation, while 64% were treatment completers; rates were similar for cognitive-behavioral therapy (6% and 66%, respectively). Psychoeducation cost $180 per subject compared to cognitive-behavioral therapy at $1,200 per subject. CONCLUSIONS: Despite longer treatment duration and individualized treatment, cognitive-behavioral therapy did not show a significantly greater clinical benefit compared to group psychoeducation. Psychoeducation is less expensive to provide and requires less clinician training to deliver, suggesting its comparative attractiveness. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00188838.

Neurostimulation therapies for treatment resistant depression: a focus on vagus nerve stimulation and deep brain stimulation.

Antidepressant treatments, including pharmacotherapy and psychotherapy, do not result in remission for the majority of patients with major depressive disorder. The high prevalence of treatment resistant depression (TRD) poses a significant issue for patients as well as both societal and economic costs. Due to the limited efficacy of existing therapies in this sub-population, alternative somatic treatments are being explored. Both vagus nerve stimulation (VNS) and deep brain stimulation (DBS) are neurostimulation treatments for TRD. While VNS has Food Drug Administration approval as an adjunctive therapy for MDD, DBS is still in the experimental stages. This article will review the evidence supporting the clinical utility of these therapies.

Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the management of major depressive disorder in adults. I. Classification, burden and principles of management.

BACKGROUND: Major depressive disorder (MDD) is one of the most burdensome illnesses in Canada. The purpose of this introductory section of the 2009 revised CANMAT guidelines is to provide definitions of the depressive disorders (with an emphasis on MDD), summarize Canadian data concerning their epidemiology and describe overarching principles of managing these conditions. This section on "Classification, Burden and Principles of Management" is one of 5 guideline articles in the 2009 CANMAT guidelines. METHODS: The CANMAT guidelines are based on a question-answer format to enhance accessibility to clinicians. An evidence-based format was used with updated systematic reviews of the literature and recommendations were graded according to the Level of Evidence using pre-defined criteria. Lines of Treatment were identified based on criteria that included evidence and expert clinical support. RESULTS: Epidemiologic data indicate that MDD afflicts 11% of Canadians at some time in their lives, and approximately 4% during any given year. MDD has a detrimental impact on overall health, role functioning and quality of life. Detection of MDD, accurate diagnosis and provision of evidence-based treatment are challenging tasks for both clinicians and for the health systems in which they work. LIMITATIONS: Epidemiologic and clinical data cannot be seamlessly linked due to heterogeneity of syndromes within the population. CONCLUSIONS: In the eight years since the last CANMAT Guidelines for Treatment of Depressive Disorders were published, progress has been made in understanding the epidemiology and treatment of these disorders. Evidence supporting specific therapeutic interventions is summarized and evaluated in subsequent sections.

Emerging drugs for major depressive disorder.

Most current pharmacologic antidepressant treatments target either or both serotonin and norepinephrine systems in the brain to alleviate depressive symptoms. However, > or = 30% of patients with major depressive disorder fail to respond to these antidepressants, inciting a need for alternative treatment strategies. In the past decade, there has been extensive research into improving the mechanism of action for monoamine agents as well as identifying novel treatment targets for depression. For monoamines, drugs that increase serotonin, norepinephrine, melatonin or dopamine have been explored as putative antidepressants and in some cases approved (agomelatine and desvenlafaxine). Novel drugs that act on amino acid receptors, neurotrophic factors, cytokines, neuropeptides and acetylcholine are also in development. This review will discuss the scientific rationale for these targets, as well as highlight the current status of drugs in development.

Medical comorbidity in bipolar disorder: re-prioritizing unmet needs.

PURPOSE OF REVIEW: The aim of this review is to synthesize results from extant investigations which report on the co-occurrence of bipolar disorder and medical comorbidity. RECENT FINDINGS: We conducted a MEDLINE search of all English-language articles published between January 2004 and November 2006. Most studies report on medical comorbidity in bipolar samples; relatively fewer studies report the reciprocal association. Individuals with bipolar disorder are differentially affected by several 'stress-sensitive' medical disorders notably circulatory disorders, obesity and diabetes mellitus. Neurological disorders (e.g. migraine), respiratory disorders and infectious diseases are also prevalent. Although relatively few studies have scrutinized the co-occurrence of bipolar disorder in medical settings, individuals with epilepsy, multiple sclerosis, migraine and circulatory disorders may have a higher prevalence of bipolar disorder. A clustering of traditional and emerging (e.g. immuno-inflammatory activation) risk factors presage somatic health issues in the bipolar disorder population. Iatrogenic factors and insufficient access to primary, preventive and integrated healthcare systems are also contributory. SUMMARY: Somatic health issues in individuals with bipolar disorder are ubiquitous, under-recognized and suboptimally treated. Facile screening for risk factors and laboratory abnormalities along with behavioral modification for reducing medical comorbidity are warranted.

Bipolar disorder and diabetes mellitus: epidemiology, etiology, and treatment implications.

INTRODUCTION: Bipolar disorder (BD) is a highly prevalent and disabling condition with significant mortality risk from suicide and other unnatural causes. This ignominious description is alongside recent observations that the majority of excess deaths in BD are secondary to medical comorbidity. The medical burden in BD is associated with a clustering of risk factors (e.g., obesity, smoking, unhealthy dietary habits) and inadequate utilization of preventative and primary healthcare. Diabetes mellitus (DM) is also a prevalent multifactorial disease which imparts substantial illness burden. Preliminary investigations indicate that patients who suffer from BD with comorbid DM have a more severe course and outcome, lower quality of life, higher prevalence of medical comorbidity and higher cost of illness. METHODS: We conducted a MedLine search of all English-language articles 1966-2004 using the key words: bipolar disorder, major depressive disorder, diabetes mellitus, glucose metabolism, mortality, overweight, obesity, body mass index. The search was supplemented with manual review of relevant references. Priority was given to randomized controlled data, when unavailable; studies of sufficient sample size are presented. RESULTS: Subpopulations of BD patients should be considered at high risk for DM. The prevalence of DM in BD may be three times greater than in the general population. CONCLUSIONS: Bipolar disorder populations may be an at-risk group for glucose metabolic abnormalities. Opportunistic screening and vigilance for clinical presentations suggestive of DM is encouraged.

Antidepressants in clinical practice: limitations of assessment methods and drug response.

There is a recognized gap between knowledge derived from 'efficacy' data - based on usually brief randomized controlled trials and findings in natural practice 'effectiveness' studies. In considering the limitations of current antidepressants in clinical practice, we have selected three clinically important issues to examine in a natural practice data base that has been in existence for several years. These relate to: (1) Diagnostic heterogeneity and potential advances using functional brain imaging; (2) Variability of outcome measures during treatment and (3) Time to response and prediction of outcome. Copyright 2001 John Wiley & Sons, Ltd.