Duration of Adjunctive Antidepressant Maintenance in Bipolar I Depression.

BACKGROUND: Antidepressants are used to treat acute depression in patients with bipolar I disorder, but their effect as maintenance treatment after the remission of depression has not been well studied. METHODS: We conducted a multisite, double-blind, randomized, placebo-controlled trial of maintenance of treatment with adjunctive escitalopram or bupropion XL as compared with discontinuation of antidepressant therapy in patients with bipolar I disorder who had recently had remission of a depressive episode. Patients were randomly assigned in a 1:1 ratio to continue treatment with antidepressants for 52 weeks after remission or to switch to placebo at 8 weeks. The primary outcome, assessed in a time-to-event analysis, was any mood episode, as defined by scores on scales measuring symptoms of hypomania or mania, depression, suicidality, and mood-episode severity; additional treatment or hospitalization for mood symptoms; or attempted or completed suicide. Key secondary outcomes included the time to an episode of mania or hypomania or depression. RESULTS: Of 209 patients with bipolar I disorder who participated in an open-label treatment phase, 150 who had remission of depression were enrolled in the double-blind phase in addition to 27 patients who were enrolled directly. A total of 90 patients were assigned to continue treatment with the prescribed antidepressant for 52 weeks (52-week group) and 87 were assigned to switch to placebo at 8 weeks (8-week group). The trial was stopped before full recruitment was reached owing to slow recruitment and funding limitations. At 52 weeks, 28 of the patients in the 52-week group (31%) and 40 in the 8-week group (46%) had a primary-outcome event. The hazard ratio for time to any mood episode in the 52-week group relative to the 8-week group was 0.68 (95% confidence interval [CI], 0.43 to 1.10; P = 0.12 by log-rank test). A total of 11 patients in the 52-week group (12%) as compared with 5 patients in the 8-week group (6%) had mania or hypomania (hazard ratio, 2.28; 95% CI, 0.86 to 6.08), and 15 patients (17%) as compared with 35 patients (40%) had recurrence of depression (hazard ratio, 0.43; 95% CI, 0.25 to 0.75). The incidence of adverse events was similar in the two groups. CONCLUSIONS: In a trial involving patients with bipolar I disorder and a recently remitted depressive episode, adjunctive treatment with escitalopram or bupropion XL that continued for 52 weeks did not show a significant benefit as compared with treatment for 8 weeks in preventing relapse of any mood episode. The trial was stopped early owing to slow recruitment and funding limitations. (Funded by the Canadian Institutes of Health Research; ClinicalTrials.gov number, NCT00958633.).

Efficacy and safety of established and off-label ADHD drug therapies for cognitive impairment or attention-deficit hyperactivity disorder symptoms in bipolar disorder: A systematic review by the ISBD Targeting Cognition Task Force.

BACKGROUND: Abnormalities in dopamine and norepinephrine signaling are implicated in cognitive impairments in bipolar disorder (BD) and attention-deficit hyperactivity disorder (ADHD). This systematic review by the ISBD Targeting Cognition Task Force therefore aimed to investigate the possible benefits on cognition and/or ADHD symptoms and safety of established and off-label ADHD therapies in BD. METHODS: We included studies of ADHD medications in BD patients, which involved cognitive and/or safety measures. We followed the procedures of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 statement. Searches were conducted on PubMed, Embase and PsycINFO from inception until June 2023. Two authors reviewed the studies independently using the Revised Cochrane Collaboration's Risk of Bias tool for Randomized trials. RESULTS: Seventeen studies were identified (N = 2136), investigating armodafinil (k = 4, N = 1581), methylphenidate (k = 4, N = 84), bupropion (k = 4, n = 249), clonidine (k = 1, n = 70), lisdexamphetamine (k = 1, n = 25), mixed amphetamine salts (k = 1, n = 30), or modafinil (k = 2, n = 97). Three studies investigated cognition, four ADHD symptoms, and 10 the safety. Three studies found treatment-related ADHD symptom reduction: two involved methylphenidate and one amphetamine salts. One study found a trend towards pro-cognitive effects of modafinil on some cognitive domains. No increased risk of (hypo)mania was observed. Five studies had low risk of bias, eleven a moderate risk, and one a serious risk of bias. CONCLUSIONS: Methylphenidate or mixed amphetamine salts may improve ADHD symptoms in BD. However, there is limited evidence regarding the effectiveness on cognition. The medications produced no increased mania risk when used alongside mood stabilizers. Further robust studies are needed to assess cognition in BD patients receiving psychostimulant treatment alongside mood stabilizers.

Changes in Media Reporting Quality and Suicides Following National Media Engagement on Responsible Reporting of Suicide in Canada: Changements de la Qualité des reportages dans les médias sur les suicides suite à l'engagement des médias nationaux à la déclaration responsable du suicide au Canada.

OBJECTIVE: Responsible media reporting is an accepted strategy for preventing suicide. In 2015, suicide prevention experts launched a media engagement initiative aimed at improving suicide-related reporting in Canada; its impact on media reporting quality and suicide deaths is unknown. METHOD: This pre-post observational study examined changes in reporting characteristics in a random sample of suicide-related articles from major publications in the Greater Toronto Area (GTA) media market. Articles (n = 900) included 450 from the 6-year periods prior to and after the initiative began. We also examined changes in suicide counts in the GTA between these epochs. We used chi-square tests to analyse changes in reporting characteristics and time-series analyses to identify changes in suicide counts. Secondary outcomes focused on guidelines developed by media professionals in Canada and how they may have influenced media reporting quality as well as on the overarching narrative of media articles during the most recent years of available data. RESULTS: Across-the-board improvement was observed in suicide-related reporting with substantial reductions in many elements of putatively harmful content and substantial increases in all aspects of putatively protective content. However, overarching article narratives remained potentially harmful with 55.2% of articles telling the story of someone's death and 20.8% presenting an other negative message. Only 3.6% of articles told a story of survival. After controlling for potential confounders, a nonsignificant numeric decrease in suicide counts was identified after initiative implementation (ω = -5.41, SE = 3.43, t = 1.58, p = 0.12). CONCLUSIONS: We found evidence that a strategy to engage media in Canada changed the content of reporting, but there was only a nonsignificant trend towards fewer suicides. A more fundamental change in media narratives to focus on survival rather than death appears warranted.

Canadian Network for Mood and Anxiety Treatments (CANMAT) 2023 Update on Clinical Guidelines for Management of Major Depressive Disorder in Adults: Réseau canadien pour les traitements de l'humeur et de l'anxiété (CANMAT) 2023 : Mise à jour des lignes directrices cliniques pour la prise en charge du trouble dépressif majeur chez les adultes.

BACKGROUND: The Canadian Network for Mood and Anxiety Treatments (CANMAT) last published clinical guidelines for the management of major depressive disorder (MDD) in 2016. Owing to advances in the field, an update was needed to incorporate new evidence and provide new and revised recommendations for the assessment and management of MDD in adults. METHODS: CANMAT convened a guidelines editorial group comprised of academic clinicians and patient partners. A systematic literature review was conducted, focusing on systematic reviews and meta-analyses published since the 2016 guidelines. Recommendations were organized by lines of treatment, which were informed by CANMAT-defined levels of evidence and supplemented by clinical support (consisting of expert consensus on safety, tolerability, and feasibility). Drafts were revised based on review by patient partners, expert peer review, and a defined expert consensus process. RESULTS: The updated guidelines comprise eight primary topics, in a question-and-answer format, that map a patient care journey from assessment to selection of evidence-based treatments, prevention of recurrence, and strategies for inadequate response. The guidelines adopt a personalized care approach that emphasizes shared decision-making that reflects the values, preferences, and treatment history of the patient with MDD. Tables provide new and updated recommendations for psychological, pharmacological, lifestyle, complementary and alternative medicine, digital health, and neuromodulation treatments. Caveats and limitations of the evidence are highlighted. CONCLUSIONS: The CANMAT 2023 updated guidelines provide evidence-informed recommendations for the management of MDD, in a clinician-friendly format. These updated guidelines emphasize a collaborative, personalized, and systematic management approach that will help optimize outcomes for adults with MDD.

Proof-of-concept randomized controlled trial of single-session nitrous oxide treatment for refractory bipolar depression: Focus on cerebrovascular target engagement.

BACKGROUND: There remain few efficacious treatments for bipolar depression, which dominates the course of bipolar disorder (BD). Despite multiple studies reporting associations between depression and cerebral blood flow (CBF), little is known regarding CBF as a treatment target, or predictor and/or indicator of treatment response, in BD. Nitrous oxide, an anesthetic gas with vasoactive and putative antidepressant properties, has a long history as a neuroimaging probe. We undertook an experimental medicine paradigm, coupling in-scanner single-session nitrous oxide treatment of bipolar depression with repeated measures of CBF. METHODS: In this double-blind randomized controlled trial, 25 adults with BD I/II and current treatment-refractory depression received either: (1) nitrous oxide (20 min at 25% concentration) plus intravenous saline (n = 12), or (2) medical air plus intravenous midazolam (2 mg total; n = 13). Study outcomes included changes in depression severity (Montgomery-Asberg Depression Rating Scale scores, primary) and changes in CBF (via arterial spin labeling magnetic resonance imaging). RESULTS: There were no significant between-group differences in 24-h post-treatment MADRS change or treatment response. However, the nitrous oxide group had significantly greater same-day reductions in depression severity. Lower baseline regional CBF predicted greater 24-h post-treatment MADRS reductions with nitrous oxide but not midazolam. In region-of-interest and voxel-wise analyses, there was a pattern of regional CBF reductions following treatment with midazolam versus nitrous oxide. CONCLUSIONS: Present findings, while tentative and based on secondary endpoints, suggest differential associations of nitrous oxide versus midazolam with bipolar depression severity and cerebral hemodynamics. Larger studies integrating neuroimaging targets and repeated nitrous oxide treatment sessions are warranted.

Caring Contacts to Reduce Psychiatric Morbidity Following Hospitalization During the COVID-19 Pandemic: A Pilot Randomized Controlled Trial.

OBJECTIVES: Caring Contacts are an emerging intervention that aims to reduce distress and suicide risk after acute psychiatric care. This trial aimed to determine whether, during a pandemic, there was any evidence that the mental health benefits and reduction in suicidal ideation (SI) associated with delivering Caring Contacts to recently discharged psychiatric patients were greater than a control communication. The secondary objective was to identify whether the predicted benefits were greater among people living alone or those diagnosed with depression. METHOD: A single-site pilot randomized clinical trial (n = 100), with patients recruited from the adult Inpatient Psychiatry Unit at Sunnybrook Health Sciences Centre, Toronto, Canada between August 2020 and May 2021. Participants were randomized (1:1) to the Caring Contact or control group. Participants received three Caring Contact or control communications via email or mail (on days 4, 21, and 56 post-discharge). Mental health symptoms were assessed using the self-report Hopkins Symptom Checklist-25 (HSCL-25) scores at discharge (baseline) and when participants received each communication. Analysis of variance was used for the primary comparisons and exploratory analyses for subgroups. RESULTS: Both groups experienced a significant worsening of mental health symptoms at all time points post-discharge relative to baseline. There were no significant differences between groups at any time point, however, on day 4 there was a 24.2% and 72.6% attenuated worsening in the Caring Contact group compared to the control group for total symptom severity and SI, respectively. There was no significant interaction effect for the depression subgroup or those living alone. CONCLUSIONS: While this pilot study was not powered to identify significant differences between groups, results are indicative of feasibility and acceptability of the intervention and provide some indication that Caring Contacts may have benefited patients in the days following discharge, supporting the need for larger-scale trials. The study was registered with clinicaltrials.gov (study ID NCT04456062).

The Canadian Network for Mood and Anxiety Treatments (CANMAT) Task Force Report: Serotonergic Psychedelic Treatments for Major Depressive Disorder.

OBJECTIVE: Serotonergic psychedelics are re-emerging as potential novel treatments for several psychiatric disorders including major depressive disorder. The Canadian Network for Mood and Anxiety Treatments (CANMAT) convened a task force to review the evidence and provide a consensus recommendation for the clinical use of psychedelic treatments for major depressive disorder. METHODS: A systematic review was conducted to identify contemporary clinical trials of serotonergic psychedelics for the treatment of major depressive disorder and cancer-related depression. Studies published between January 1990 and July 2021 were identified using combinations of search terms, inspection of bibliographies and review of other psychedelic reviews and consensus statements. The levels of evidence for efficacy were graded according to the Canadian Network for Mood and Anxiety Treatments criteria. RESULTS: Only psilocybin and ayahuasca have contemporary clinical trials evaluating antidepressant effects. Two pilot studies showed preliminary positive effects of single-dose ayahuasca for treatment-resistant depression (Level 3 evidence). Small randomized controlled trials of psilocybin combined with psychotherapy showed superiority to waitlist controls and comparable efficacy and safety to an active comparator (escitalopram with supportive psychotherapy) in major depressive disorder, with additional randomized controlled trials showing efficacy specifically in cancer-related depression (Level 3 evidence). There was only one open-label trial of psilocybin in treatment-resistant unipolar depression (Level 4 evidence). Small sample sizes and functional unblinding were major limitations in all studies. Adverse events associated with psychedelics, including psychological (e.g., psychotomimetic effects) and physical (e.g., nausea, emesis and headaches) effects, were generally transient. CONCLUSIONS: There is currently only low-level evidence to support the efficacy and safety of psychedelics for major depressive disorder. In Canada, as of 2022, psilocybin remains an experimental option that is only available through clinical trials or the special access program. As such, Canadian Network for Mood and Anxiety Treatments considers psilocybin an experimental treatment and recommends its use primarily within clinical trials, or, less commonly, through the special access program in rare, special circumstances.

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

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

Is the narrative the message? The relationship between suicide-related narratives in media reports and subsequent suicides.

OBJECTIVES: When journalists report on the details of a suicide, the way that they contextualize the meaning of the event (i.e. the 'narrative') can have significant consequences for readers. The 'Werther' and 'Papageno' narrative effects refer to increases and decreases in suicides across populations following media reports on suicidal acts or mastery of crises, respectively. The goal of this study was to investigate the impact of these different narrative constructs on subsequent suicides. METHODS: This study examined the change in suicide counts over time in Toronto, Canada. It used latent difference score analysis, examining suicide-related print media reports in the Toronto media market (2011-2014). Articles (N = 6367) were coded as having a potentially harmful narrative if they described suicide in a celebrity or described a suicide death in a non-celebrity and included the suicide method. Articles were coded as having potentially protective narratives if they included at least one element of protective content (e.g. alternatives to suicide) without including any information about suicidal behaviour (i.e. suicide attempts or death). RESULTS: Latent difference score longitudinal multigroup analyses identified a dose-response relationship in which the trajectory of suicides following harmful 'Werther' narrative reports increased over time, while protective 'Papageno' narrative reports declined. The latent difference score model demonstrated significant goodness of fit and parameter estimates, with each group demonstrating different trajectories of change in reported suicides over time: (χ2[6], N = 6367) = 13.16; χ2/df = 2.19; Akaike information criterion = 97.16, comparative fit index = 0.96, root mean square error of approximation = 0.03. CONCLUSION: Our findings support the notion that the 'narrative' matters when reporting on suicide. Specifically, 'Werther' narratives of suicides in celebrities and suicides in non-celebrities where the methods were described were associated with more subsequent suicides while 'Papageno' narratives of survival and crisis mastery without depictions of suicidal behaviours were associated with fewer subsequent suicides. These results may inform efforts to prevent imitation suicides.

Clinical correlates of suicidality and self-injurious behaviour among Canadian adolescents with bipolar disorder.

There is high risk of suicidality in bipolar disorder (BD), particularly in early onset cases. The literature regarding correlates and putative predictors of suicide attempts (SA), non-suicidal self-injury (NSSI) and suicidal ideation (SI) among youth with BD remains sparse. Participants included 197 adolescents with BD, divided into 4 groups: SA (with or without NSSI), NSSI (with or without SI), SI only, and comparison group (CG; no SA/NSSI/SI). Diagnoses, treatment, and suicidality measures were determined via semi-structured interviews, conducted between 2009 and 2017. Univariate analyses were followed by multinomial regression. Overall, 73.6% of participants had history of SA, NSSI, and/or SI. In comparison to CG, SA and NSSI were each associated with BD-II/-NOS (odds ratio [OR] = 15.99, p = 0.002; OR = 16.76, p = 0.003), female sex (OR = 6.89, p = 0.006; OR = 3.76, p = 0.02), and emotion dysregulation (OR = 1.10, p < 0.001; OR = 1.07, p = 0.004). NSSI and SI were each associated with most severe lifetime depression (OR = 1.10, p = 0.01; OR = 1.10, p = 0.01). SA and SI were associated with psychiatric hospitalization (OR = 19.45, p = 0.001; OR = 6.09, p = 0.03). SA was associated with poorer global functioning at most severe episode (OR = 0.88, p = 0.008). NSSI was associated with not living with both natural parents (OR = 0.22, p = 0.009). Study limitations include cross-sectional and retrospective design, stringent cut-offs for SA and NSSI, and recruitment from a tertiary clinical setting. Three quarters of adolescents with BD have had suicidality and/or self-injury. SA and NSSI were most similar to one another, and most different from CG, supporting the broader construct of self-harm. Future research should address the gap in knowledge regarding how sex differences and neurobiology are associated with the observed clinical differences.

Inflammatory markers, brain-derived neurotrophic factor, and the symptomatic course of adolescent bipolar disorder: A prospective repeated-measures study.

BACKGROUND: Numerous studies have found elevated pro-inflammatory markers and reduced brain-derived neurotrophic factor (BDNF) during symptomatic episodes of bipolar disorder (BD) in adults. There is a paucity of research examining these markers in youth with BD, or longitudinally in any BD age group. METHODS: 79 adolescents, ages 13-19 years, were enrolled, including 43 symptomatic adolescents with BD and 36 age-matched healthy controls (HC). Blood samples were collected from all participants at intake, and repeatedly from BD participants at pre-specified intervals over the course of two years. Serum was assayed for levels of pro-inflammatory markers (c-reactive protein [CRP], interleukin [IL]-6, tumor necrosis factor alpha [TNF-α]), BDNF and the anti-inflammatory marker, IL-10. Week-by-week severity of mood symptoms was assessed using semi-structured interviews. RESULTS: Adolescents with BD provided an average of 4.6 blood samples, on average every 5.0 months. During the most severe symptomatic interval (i.e., highest sum of mood symptom scores) among BD adolescents, levels of CRP (p = 0.01) and pro- to anti-inflammatory ratios (CRP/IL-10; p < 0.001 and IL-6/IL-10; p = 0.046) were significantly greater, and IL-10 levels (p = 0.004) were significantly lower, vs. HC. There were no differences between BD and HC in IL-6, TNF-α or BDNF. Within BD participants, higher BDNF (p = 0.01) and IL-10 levels (p = 0.001) significantly predicted greater burden of mood symptoms over the subsequent epoch. Moreover, higher CRP levels (p = 0.009) at intake predicted greater time to recovery from the index symptomatic episode. CONCLUSIONS: In the first repeated-measures study on this topic in adolescents with BD, we found evidence that CRP, an inexpensive and ubiquitous blood test, may be useful in predicting the prospective course of BD symptoms. Future larger studies are warranted.

Use of a point-of-care web-based application to enhance adherence to the CANMAT and ISBD 2018 guidelines for the management of bipolar disorder.

OBJECTIVES: While clinical guidelines exist for the management of bipolar disorder (BD), there are significant challenges to their widespread dissemination and implementation in clinical practice. The Canadian Network of Mood and Anxiety Treatment Improving Patient Care and Outcomes in the Treatment of Bipolar Disorder (C-IMPACT BD) web-based application was developed for use at the point-of-care to improve adherence to guidelines for evidence-based pharmacological management of BD. METHODS: C-IMPACT BD uses a point-of-care practice assessment which, via adaptive questioning of patient-specific information, text/video descriptions of the guidelines, and pop-up prompts delivers personalized, evidence-based treatment recommendations for patients with BD. In order to inform quality improvement of the newly developed tool, a sample of Canadian physicians were invited to use the application and record its influence on their prescribing behavior. RESULTS: Of 375 patients with bipolar I (BD-I) or bipolar II (BD-II) disorder for whom a point-of-care practice assessment was completed, a change in therapy was considered for 225 (60.0%). Prior to completing the assessment, 59.6% of these patients were receiving first-line therapy recommended for their phase of illness. Following the assessment, the overall number of patients for whom a first-line recommended therapy was being considered increased significantly to 76.9% (p = 0.0001). CONCLUSIONS: Outcomes suggest that the C-IMPACT BD web-based application has the potential to improve physician adherence to clinical treatment guidelines. Formal research investigations are warranted to explore the impact of this tool on physician prescribing behavior and patient outcomes.

Randomised controlled cognition trials in remitted patients with mood disorders published between 2015 and 2021: A systematic review by the International Society for Bipolar Disorders Targeting Cognition Task Force.

BACKGROUND: Cognitive impairments are an emerging treatment target in mood disorders, but currently there are no evidence-based pro-cognitive treatments indicated for patients in remission. With this systematic review of randomised controlled trials (RCTs), the International Society for Bipolar Disorders (ISBD) Targeting Cognition Task force provides an update of the most promising treatments and methodological recommendations. METHODS: The review included RCTs of candidate pro-cognitive interventions in fully or partially remitted patients with major depressive disorder or bipolar disorder. We followed the procedures of the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) 2020 statement. Searches were conducted on PubMed/MEDLINE, PsycInfo, EMBASE and Cochrane Library from January 2015, when two prior systematic reviews were conducted, until February 2021. Two independent authors reviewed the studies with the Revised Cochrane Collaboration's Risk of Bias tool for Randomised trials. RESULTS: We identified 16 RCTs (N = 859) investigating cognitive remediation (CR; k = 6; N = 311), direct current or repetitive magnetic stimulation (k = 3; N = 127), or pharmacological interventions (k = 7; N = 421). CR showed most consistent cognitive benefits, with two trials showing improvements on primary outcomes. Neuromodulatory interventions revealed no clear efficacy. Among pharmacological interventions, modafinil and lurasidone showed early positive results. Sources of bias included small samples, lack of pre-screening for objective cognitive impairment, no primary outcome and no information on allocation sequence masking. CONCLUSIONS: Evidence for pro-cognitive treatments in mood disorders is emerging. Recommendations are to increase sample sizes, pre-screen for impairment in targeted domain(s), select one primary outcome, aid transfer to real-world functioning, investigate multimodal interventions and include neuroimaging.

Can magnetic resonance imaging enhance the assessment of potential new treatments for cognitive impairment in mood disorders? A systematic review and position paper by the International Society for Bipolar Disorders Targeting Cognition Task Force.

BACKGROUND: Developing treatments for cognitive impairment is key to improving the functioning of people with mood disorders. Neuroimaging may assist in identifying brain-based efficacy markers. This systematic review and position paper by the International Society for Bipolar Disorders Targeting Cognition Task Force examines the evidence from neuroimaging studies of pro-cognitive interventions. METHODS: We included magnetic resonance imaging (MRI) studies of candidate interventions in people with mood disorders or healthy individuals, following the procedures of the Preferred Reporting Items for Systematic reviews and Meta-Analysis 2020 statement. Searches were conducted on PubMed/MEDLINE, PsycInfo, EMBASE, Cochrane Library, and Clinicaltrials.gov from inception to 30th April 2021. Two independent authors reviewed the studies using the National Heart, Lung, Blood Institutes of Health Quality Assessment Tool for Controlled Intervention Studies and the quality of neuroimaging methodology assessment checklist. RESULTS: We identified 26 studies (N = 702). Six investigated cognitive remediation or pharmacological treatments in mood disorders (N = 190). In healthy individuals, 14 studies investigated pharmacological interventions (N = 319), 2 cognitive training (N = 73) and 4 neuromodulatory treatments (N = 120). Methodologies were mostly rated as 'fair'. 77% of studies investigated effects with task-based fMRI. Findings varied but most consistently involved treatment-associated cognitive control network (CCN) activity increases with cognitive improvements, or CCN activity decreases with no cognitive change, and increased functional connectivity. In mood disorders, treatment-related default mode network suppression occurred. CONCLUSIONS: Modulation of CCN and DMN activity is a putative efficacy biomarker. Methodological recommendations are to pre-declare intended analyses and use task-based fMRI, paradigms probing the CCN, longitudinal assessments, mock scanning, and out-of-scanner tests.

Youth voices and experiences regarding a school-based cognitive behavioral therapy skills intervention: lessons for future engagement and adaptation.

BACKGROUND: The Cognitive Behavioral Therapy Skills Intervention (or CBTSI) aims to build mental health literacy and knowledge, allowing youth to build resilience and improve mental health broadly. In Ontario, Canada, youth voice is scant and European studies have largely reported on youth factors supporting stigma reduction, help-seeking intentions and overall satisfaction with a given intervention. Process evaluations and implementation that underpin what youth require to embrace mental health literacy interventions, particularly those that embed key learning principles in the everyday curriculum, have not been broached. The goal of this study is to understand both barriers and facilitators to engagement with the CBTSI (an intervention novel in itself because of the combined mental health plus cognitive behavior therapy (CBT) skills principles embedded in literacy) and the resources and structures that students report requiring, to fully engage with such an intervention. METHODS: Student focus groups were conducted utilizing qualitative interviews that were analyzed thematically. Analysis was informed using principles of pragmatism and analyzed inductively using thematic analysis (Braun and Clarke, Qual Res Psychol 3:77-101, 2006), first looking at the whole and then coding for themes, within an interpretivist framework. Youth were in middle school (grade 7 and 8) in Toronto, Canada who had received the CBTSI. Face to face interview guides with iterative questioning were conducted in February of 2020, and these interviews were audio-recorded and professionally transcribed. Teachers randomly chose a subset of youth whose parents consented to the research to ensure ethno-racial similarity to classroom demographics. RESULTS: There were eight groups with sixty students who participated. Students were 12 to 14 years of age. Major themes were identified: maximizing the opportunities for involvement and self-determination created an atmosphere where confidence and self-compassion could flourish, signalling to the students that they understood and were able to deploy the strategies they were taught; students expressed that the intervention needs to be adapted to enhance personal dignity, respecting both individual wishes and goals in light of the variability in student reported mental health. A model explains the structures and adaptations required to maximize learning based on youth feedback. INTERPRETATION: Mental health literacy incorporating CBT is a promising population-based health promotion intervention. Future adaptations and implementation decisions regarding the CBTSI need to address the wishes and experiences of these youth. Youth voice in this study explored factors that prevent and promote the uptake of the key lessons within the context of existing variability in student mental health that is often found within the context of a regular classroom. The results should be used to adapt the CBTSI as it is disseminated more broadly.

Emergency department visits for self-harm in adolescents after release of the Netflix series '13 Reasons Why'.

OBJECTIVE: To determine whether the release of the first season of the Netflix series '13 Reasons Why' was associated with changes in emergency department presentations for self-harm. METHODS: Healthcare utilization databases were used to identify emergency department and outpatient presentations according to age and sex for residents of Ontario, Canada. Data from 2007 to 2018 were used in autoregressive integrated moving average models for time series forecasting with a pre-specified hypothesis that rates of emergency department presentations for self-harm would increase in the 3-month period following the release of 13 Reasons Why (1 April 2017 to 30 June 2017). Chi-square and t tests were used to identify demographic and health service use differences between those presenting to emergency department with self-harm during this epoch compared to a control period (1 April 2016 to 30 June 2016). RESULTS: There was a significant estimated excess of 75 self-harm-related emergency department visits (+6.4%) in the 3 months after 13 Reasons Why above what was predicted by the autoregressive integrated moving average model (standard error = 32.4; p = 0.02); adolescents aged 10-19 years had 60 excess visits (standard error = 30.7; p = 0.048), whereas adults demonstrated no significant change. Sex-stratified analyses demonstrated that these findings were largely driven by significant increases in females. There were no differences in demographic or health service use characteristics between those who presented to emergency department with self-harm in April to June 2017 vs April to June 2016. CONCLUSIONS: This study demonstrated a significant increase in self-harm emergency department visits associated with the release of 13 Reasons Why. It adds to previously published mortality, survey and helpline data collectively demonstrating negative mental health outcomes associated with 13 Reasons Why.

A double-blind, randomized, placebo-controlled pilot trial of atorvastatin for nephrogenic diabetes insipidus in lithium users.

OBJECTIVE: Lithium remains an important treatment for mood disorders but is associated with kidney disease. Nephrogenic diabetes insipidus (NDI) is associated with up to 3-fold risk of incident chronic kidney disease among lithium users. There are limited randomized controlled trials (RCT) for treatments of lithium-induced NDI, and existing therapies can be poorly tolerated. Therefore, novel treatments are needed for lithium-induced NDI. METHOD: We conducted a 12-week double-blind pilot RCT to assess the feasibility and efficacy of 20 mg/d atorvastatin vs placebo in the treatment of NDI in chronic lithium users. Patients, recruited between September 2017 and October 2018, were aged 18 to 85, currently on a stable dose of lithium, and determined to have NDI. RESULTS: Urinary osmolality (UOsm) at 12 weeks adjusted for baseline was not statistically different between groups (+39.6 mOsm/kg [95% CI, -35.3, 114.5] in atorvastatin compared to placebo groups). Secondary outcomes of fluid intake and aquaporin-2 excretions at 12 weeks adjusted for baseline were -0.13 L [95% CI, -0.54, 0.28] and 98.68 [95% CI, -190.34, 387.70], respectively. A moderate effect size was observed for improvements in baseline UOsm by ≥100 mOsm/kg at 12 weeks in patients who received atorvastatin compared to placebo (38.45% (10/26) vs 22.58% (7/31); Cohen's d = 0.66). CONCLUSION: Among lithium users with NDI, atorvastatin 20 mg/d did not significantly improve urinary osmolality compared to placebo over a 12-week period. Larger confirmatory trials with longer follow-up periods may help to further assess the effects of statins on NDI, especially within patients with more severe NDI.

Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) recommendations for the management of patients with bipolar disorder with mixed presentations.

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.

Suicide-related Twitter Content in Response to a National Mental Health Awareness Campaign and the Association between the Campaign and Suicide Rates in Ontario.

OBJECTIVE: Mental health awareness (MHA) campaigns have been shown to be successful in improving mental health literacy, decreasing stigma, and generating public discussion. However, there is a dearth of evidence regarding the effects of these campaigns on behavioral outcomes such as suicides. Therefore, the objective of this article is to characterize the association between the event and suicide in Canada's most populous province and the content of suicide-related tweets referencing a Canadian MHA campaign (Bell Let's Talk Day [BLTD]). METHODS: Suicide counts during the week of BTLD were compared to a control window (2011 to 2016) to test for associations between the BLTD event and suicide. Suicide tweets geolocated to Ontario, posted in 2016 with the BLTD hashtag were coded for specific putatively harmful and protective content. RESULTS: There was no associated change in suicide counts. Tweets (n = 3,763) mainly included content related to general comments about suicide death (68%) and suicide being a problem (42.8%) with little putatively helpful content such as stories of resilience (0.6%) and messages of hope (2.2%). CONCLUSIONS: In Ontario, this national mental health media campaign was associated with a high volume of suicide-related tweets but not necessarily including content expected to diminish suicide rates. Campaigns like BLTD should strongly consider greater attention to suicide-related messaging that promotes help-seeking and resilience. This may help to further decrease stigmatization, and potentially, reduce suicide rates.

The Canadian Network for Mood and Anxiety Treatments (CANMAT) Task Force Recommendations for the Use of Racemic Ketamine in Adults with Major Depressive Disorder: Recommandations Du Groupe De Travail Du Réseau Canadien Pour Les Traitements De L'humeur Et De L'anxiété (Canmat) Concernant L'utilisation De La Kétamine Racémique Chez Les Adultes Souffrant De Trouble Dépressif Majeur.

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.