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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.

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.

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.

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.

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.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).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.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 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.A single-site pilot randomized clinical trial (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.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).Les contacts attentionnés sont une nouvelle intervention qui vise à réduire le risque de détresse et de suicide après des soins intensifs psychiatriques. Le présent essai visait à déterminer si, durant une pandémie, des données probantes indiquaient que les avantages pour la santé mentale et la réduction de l'idéation suicidaire (IS) associés à la prestation de soins attentionnés à des patients psychiatriques récemment mis en congé étaient plus puissants que le contrôle des communications. L'objectif secondaire était d'identifier si les avantages escomptés étaient plus grands chez les personnes vivant seules ou chez celles où la dépression était diagnostiquée.Un essai clinique randomisé (n = 100) d'un seul site, dont les patients étaient recrutés à l'Unité de psychiatrie pour patients hospitalisés adultes du Centre des sciences de la santé Sunnybrook de Toronto, Canada, entre août 2020 et mai 2021. Les participants ont été randomisés (1:1) aux Contacts attentionnés ou au groupe témoin. Les participants ont reçu trois communications des Contacts attentionnés ou des témoins par courriel ou courrier (aux jours 4, 21, 56 après-congé). Les symptômes de santé mentale ont été évalués à l'aide des scores auto-déclarés à la liste de contrôle des symptômes de Hopkins-25 (HSCL-25) au congé (à la base) et quand les participants ont reçu chaque communication. ANOVA a été utilisée pour les comparaisons primaires, et les analyses exploratoires pour les sous-groupes.Les deux groupes ont connu une aggravation significative des symptômes de santé mentale à différents moments après le congé relativement à la base. Il n'y avait pas de différences significatives entre les groupes à tout moment, cependant au jour 4 il y avait une aggravation atténuée de 24,2% et de 72,6% dans le groupe des Contacts attentionnés comparé au groupe témoin pour la gravité totale des symptômes et les IS respectivement. Il n'y avait pas d'effet d'interaction significatif pour le sous-groupe de la dépression ou de ceux vivant seuls.Bien que cette étude pilote n'ait pas été mandatée pour identifier les différences significatives entre les groupes, les résultats indiquent la faisabilité et l'acceptabilité de l'intervention et offrent certaines indications à l'effet que Contacts attentionnés puissent avoir été bénéfiques pour les patients dans les jours suivant le congé, appuyant ainsi le besoin d'essais à plus grande échelle. L'étude a été enregistrée à clinicaltrials.gov (ID de l'étude NCT04456062).

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.

ObjectivesIn the process of scientific progress, prior evidence is both relied on and supplanted by new discoveries. We use the term ‘knowledge half-life’ to refer to the phenomenon in which older knowledge is discounted in favour of newer research. By quantifying the knowledge half-life, we sought to determine whether research published in more recent years is preferentially cited over older research in medical and scientific articles.DesignAn observational study employing a directed, systematic search of current literature.Data sourcesBMJ,PNAS,JAMA,NEJM,The Annals of Internal Medicine,The Lancet,ScienceandNaturewere searched.Eligibility criteria for selecting studiesEight high-impact medical and scientific journals were sampled examining original research articles from the first issue of every year over a 25-year span (1996–2020). The outcome of interest was the difference between the publication year of the article and references cited, termed ‘citation lag’.Data extraction and synthesisAnalysis of variance was used to identify significant differences in citation lag.ResultsA total of 726 articles and 17 895 references were included with a mean citation lag of 7.5±8.4 years. Across all journals, >70% of references had been published within 10 years of the citing article. Approximately 15%–20% of referenced articles were 10–19 years old, and articles more than 20 years old were cited infrequently. Medical journals articles had references with significantly shorter citation lags compared with general science journals (p≤0.01). Articles published before 2009 had references with significantly shorter citation lags compared with those published in 2010–2020 (pConclusionsThis study found evidence of a small increase in the citation of older research in medical and scientific literature over the past decade. This phenomenon deserves further characterisation and scrutiny to ensure that ‘old knowledge’ is not being lost.

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

Abstract: Background: The content of suicide-specific social media posts may impact suicide rates, and putatively harmful and/or protective content may vary by the author’s influence. Aims: This study sought to characterize how suicide-related Twitter content differs according to user influence. Method: Suicide-related tweets from July 1, 2015, to June 1, 2016, geolocated to Toronto, Canada, were collected and randomly selected for coding (n = 2,250) across low, medium, or high user influence levels (based on the number of followers, tweets, retweets, and posting frequency). Logistic regression was used to identify differences by user influence for various content variables. Results: Low- and medium-influence users typically tweeted about personal experiences with suicide and associations with mental health and shared morbid humor/flippant tweets. High-influence users tended to tweet about suicide clusters, suicide in youth, older adults, indigenous people, suicide attempts, and specific methods. Tweets across influence levels predominantly focused on suicide deaths, and few described suicidal ideation or included helpful content. Limitations: Social media data were from a single location and epoch. Conclusion: This study demonstrated more problematic content vis-à-vis safe suicide messaging in tweets by high-influence users and a paucity of protective content across all users. These results highlight the need for further research and potential intervention.

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.

Individuals with pre-existing psychiatric diagnoses appear to be vulnerable to worsening mental health symptoms during the coronavirus disease 2019 (COVID-19) pandemic. Furthermore, psychiatric hospitalizations during the pandemic may be complicated by increased risk of SARS-Cov-2 infection and limited social engagement due to changes in hospital policies. The objective of our exploratory study was to determine whether social, economic, and health-related variables were associated with thoughts of suicide and/or self-harm since March 2020 in individuals admitted to a psychiatric inpatient unit during the COVID-19 pandemic. Chi-square tests revealed four variables were significantly associated with thoughts of suicide and/or self-harm: 1) difficulty with cancellation of important events, 2) some form of loneliness, 3) decreased time spent in green spaces, and 4) increased time spent using devices with screens. The logistic regression model showed a significant association between suicidal and/or self-harm thoughts and cancellation of important events. Further investigation of the loneliness variable components revealed a significant association between suicidal and/or self-harm thoughts and feeling a lack of companionship, feeling isolated, and feeling alone. These results suggest that social challenges experienced during the pandemic were associated with negative mental health symptoms of individuals admitted to a psychiatric inpatient unit.

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.

Antidepressant efficacy is influenced by patient expectations and, in randomized controlled trials (RCTs), the probability of receiving a placebo. It is unclear whether tolerability demonstrates a similar pattern. This study aimed to determine whether study design influences adverse event (AE) rates in antidepressant trials for subjects receiving active treatment or placebo.RCTs comparing one antidepressant to another antidepressant, placebo, or both in major depressive disorder (MDD) (1996-2018) were retrieved from Medline and PsycINFO. Clinicaltrials.gov was searched for unpublished trials. Of 1,997 studies screened, 77 trials were included. Studies were classified as drug-drug, drug-drug-placebo, or drug-placebo based on design and overall number of subjects experiencing any AE was recorded. Subgroup meta-analysis of proportions and meta-regression techniques were used to compare AE rates across study designs in patients receiving active antidepressant treatment and placebo.Among the actively treated, AE rates were lower in drug-drug trials (58.5%) compared to drug-drug-placebo (75.7%) and drug-placebo (76.4%) (the model reported coefficients for percent differences between AE rates of different study designs were B=17.0, p0.001 and B=17.8, p0.001, respectively). AE rates in patients receiving placebo were not different between study designs.The present study is limited by the diverse range of study populations, variability in reporting of AEs, and specific antidepressants employed in the included trials.The inclusion of a placebo arm in the study design was unexpectedly associated with higher rates of AEs among patients receiving active medication in antidepressant trials. This observation has important implications for interpretation of trial tolerability findings.

Abstract. Background: Many studies have demonstrated suicide contagion through mainstream journalism; however, few have explored suicide-related social media events and their potential relationship to suicide deaths. Aims: To determine whether Twitter events were associated with changes in subsequent suicides. Methods: Suicide-related Twitter events that garnered at least 100 tweets originating in Ontario, Canada (July 1, 2015 to June 30, 2016) were identified and characterized as putatively "harmful" or "innocuous" based on recommendations for responsible media reporting. The number of suicides in Ontario during the peak of each Twitter event and the subsequent 6 days ("exposure window") was compared with suicides occurring during a pre-event period of the same length ("control window"). Results: There were 17 suicide-related Twitter events during the period of study (12 putatively harmful and five putatively innocuous). The number of tweets per event ranged from 121 for "physician-assisted suicide law in Quebec" to 6,202 for the "Attawapiskat suicide crisis." No significant relationship was detected between Twitter events and actual suicides. Notably, a comprehensive examination of the details of Twitter events showed that even the putatively harmful events lacked many of the characteristics commonly associated with contagion. Limitations: This was an uncontrolled experiment in only one epoch and a single Canadian province. Discussion: This study found no evidence of suicide contagion associated with Twitter events. This finding must be interpreted with caution given the relatively innocuous content of suicide-related Tweets in Ontario during 2015–2016.

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.

BackgroundDeveloping 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.MethodsWe 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.ResultsWe 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.ConclusionsModulation 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.

Background Adverse events (AEs) are known to occur while patients are treated with placebos, part of the so-called nocebo effect. Yet evidence is limited regarding the likelihood that specific AEs occurring with antidepressant treatment are or are not due to nocebo effects. Methods This study identified 56 placebo-controlled, randomized controlled trials (RCTs) of antidepressant monotherapy for adults with major depressive disorder that reported AE rates in sufficient detail for comparison. Poisson regression analyses compared rates of AEs according to antidepressant class weighted by study population to determine which separated from placebo. A “nocebo index” was also calculated (with 0 defined as the lowest rate and 1 or higher indicating the same or greater rate of an AE in the placebo group). Results Numerous AEs did not differ statistically between antidepressant classes and placebo including worsening psychiatric symptoms, all forms of pain, weight gain and respiratory symptoms. Nevertheless, a number of AEs were significantly more common in antidepressants than placebos across multiple antidepressant classes. These were predominantly neurological, sexual and anticholinergic effects. Several AEs that separated statistically between antidepressants and placebos nevertheless had moderate nocebo indices (≥0.5). For example, dizziness in SSRIs separated significantly from placebo (OR 1.50, 95%CI 1.13–1.99) but had a nocebo index of 0.67. Limitations This study relied on multiple RCTs with subtle design differences. Conclusions This study identified several AEs that are likely the physiological result of antidepressants and many that likely represent nocebo effects. These results should inform clinical decision making and discussions with patients.

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.

IntroductionEsketamine is the S-enantiomer of racemic ketamine and has been approved by the Food and Drug Administration for the management of treatment resistant depression, demonstrating effective and long-lasting benefits. The objective of this observational study is to elucidate the association of intranasal (IN) esketamine with beneficial and negative outcomes in the management of treatment resistant major depressive disorder.Methods and analysisThis is a multicentre prospective cohort observational study of naturalistic clinical practice. We expect to recruit 10 patients per research centre (6 centres, total 60 subjects). After approval to receive IN esketamine as part of their standard of care management of moderate to severe treatment resistant depression, patients will be invited to participate in this study. Association of esketamine treatment with outcomes in the management of depression will be assessed by measuring the severity of depression symptoms using the Montgomery-Åsberg Depression Rating Scale (MADRS), and tolerability by systematically tracking common side effects of ketamine treatment, dissociation using the simplified 6-Item Clinician Administered Dissociative Symptom Scale and potential for abuse using the Likeability and Craving Questionnaire (LCQ). Change in depressive symptoms (MADRS total scores) over time will be evaluated by within-subject repeated measures analysis of variance. We will calculate the relative risk associated with the beneficial (reduction in total scores for depression) outcomes, and the side effect and dropout rates (tolerability) of adding IN esketamine to patients’ current pharmacological treatments. Covariate analysis will assess the impact of site and demographic variables on treatment outcomes.Ethics and disseminationApproval to perform this study was obtained through the Health Sciences Research Ethics Board at Queen’s University. Findings will be shared among collaborators, through departmental meetings, presented on different academic venues and publishing our manuscript.

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.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.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; p0.001 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.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.

Abstract. Background: US suicide rates correlate with firearm availability. Little is known about variability in rates across countries. Aims: To observe the relationship between firearm/overall suicide rates in Toronto, Canada, and the five most populous US metropolitan areas. Method: Centers for Disease Control suicide rates by age and sex for New York, Los Angeles, Chicago, Dallas-Fort Worth, and Houston metropolitan areas were compared with equivalent data for Toronto (1999–2015). Results: Suicide rates by firearm, per 100,000 population, ranged from 0.45 in Toronto to 6.03 in Houston while rates by other methods ranged from 4.34 in Dallas-Fort Worth to 7.11 in Toronto. Overall rates of suicide ranged from 6.14 in New York to 10.45 in Houston. The two cities with the highest firearm suicide rates, Dallas-Fort Worth and Houston, also had much higher overall rates. Firearm suicides were most common in men over the age of 65 in all cities. Limitations: This study could not account for cultural differences between cities/countries. Conclusion: Much higher overall rates of suicide observed for Dallas-Fort Worth and Houston appear to be associated with high rates of suicide by firearm. Advocacy for means safety should target cities with high rates of firearm suicide and, in particular, elderly men.

Objective: “13 Reasons Why,” a Netflix series, included a controversial depiction of suicide that has raised fears about possible contagion. Studies of youth suicide in the United States found an increase on the order of 10% following release of the show, but this has not been replicated in other countries. This study aims to begin to address that gap by examining the relationship between the show’s release and youth suicide in Canada’s most populous province. Methods: Suicides in young people (under the age of 30) in the province of Ontario following the show’s release on March 31, 2017, were the outcome of interest. Time-series analyses were performed using data from January 2013 to March 2017 to predict expected deaths from April to December 2017 with a simple seasonal model (stationary R 2 = 0.732, Ljung-Box Q = 15.1, df = 16, P = 0.52, Bayesian information criterion = 3.09) providing the best fit/used for the primary analysis. Results: Modeling predicted 224 suicides; however, 264 were observed corresponding to 40 more deaths or an 18% increase. In the primary analysis, monthly suicides exceeded the 95% confidence limit for 3 of the 9 months (May, July, and October). Conclusion: The statistical strength of the findings here is limited by small numbers; however, the results are in line with what has been observed in the United States and what would be expected if contagion were occurring. Further research in other locations is needed to increase confidence that the associations found here are causal.

Background Ketamine is known to rapidly reduce depressive symptoms and suicidal ideation (SI) in patients with major depressive disorder (MDD), but evidence is limited for its acceptability and effectiveness in “real-world” settings. This case series examines serial ketamine infusions in reducing SI and depression scores in adults with MDD admitted to a tertiary care hospital. Methods Five inpatients with MDD and SI admitted to hospital in Toronto, Canada received six infusions of 0.5 mg/kg intravenous (IV) ketamine (n = 5) over approximately 12 days, in addition to treatment-as-usual. Suicide and depression rating scores (Scale for Suicidal Ideation, SSI; Montgomery-Asberg Depression Rating Scale, MADRS) were obtained at baseline, on treatment days, on days 14 and 42 (primary endpoint). Results All patients experienced benefit with ketamine. SSI scores diminished by 84% from 14.0 ± 4.5 at baseline to 2.2 ± 2.5 at study endpoint. MADRS scores diminished by 47% from 42.2 ± 5.3 at baseline to 22.4 ± 8.0. Two patients withdrew from the study, one to initiate electroconvulsive therapy and one due to an adverse event (dissociative effects) during the ketamine infusion. Limitations The major limitation of this study is the small sample size. Discussion These preliminary pilot data are promising with a greater than two-fold reduction in SI following ketamine infusions. They demonstrate that six serial ketamine infusions may be safe and feasible. These findings support the need for large scale randomized controlled trials to confirm the efficacy of serial ketamine for treatment of SI in “real-world” settings.

Objectives Despite the growing numbers and proportion of older adults with bipolar disorder (OABD), there are very limited guidelines for the use of lithium with its double-edged potential for effectiveness and toxicity in this population. The primary aims of this Delphi survey were: (a) To determine the place of lithium among the preferred choices for maintenance treatment of OABD. (b) To provide detailed clinical guidelines for the safe and effective use of lithium in OABD. Methods In the face of limited evidence, the Delphi survey method was used to achieve consensus by a group of 25 experts in OABD from nine countries. An oversight committee monitored and analyzed the results of each survey and formulated more focused questions with each subsequent iteration. Results A 100% response rate was achieved for all three iterations of the survey. Lithium was the preferred choice for maintenance monotherapy in OABD. Serum levels of 0.4-0.8 mmol/L were recommended for ages 60-79 and serum levels of 0.4-0.7 mmol/L were recommended for ages 80 and over. Specific recommendations achieved consensus for second line monotherapy as well as for other drugs to be used in combination with lithium if necessary. Guidelines for routine monitoring of lithium in OABD were provided for laboratory investigations and clinical assessments. Conclusions Lithium remains the preferred choice for maintenance monotherapy in OABD. Laboratories should report the therapeutic range for serum levels of lithium separately for older adults.

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.

Abstract. Background: Media guidelines can influence suicide-related reporting quality and may impact suicide rates. Aim: Our study aimed to investigate the quality of suicide-related reporting after the release of the 2009 Canadian Psychiatric Association (CPA) guidelines and their impact on suicides. Method: A random sample of suicide-related articles ( n = 988) were retrieved from 12 major Canadian print/online publications (2002–2015). Articles were coded for quality of content before and after guidelines release. Suicide mortality data were obtained from Ontario coroner records. Time series analyses were used to identify associations between guideline publication and subsequent suicides. Results: The CPA guidelines were associated with improvements in reporting quality with 10 putatively harmful elements being less frequent after their publication. These included less frequent front-page articles, monocausal (simplistic) explanations for suicide, and depictions of suicide methods. Two putatively protective factors, alternatives to suicide and messages of hope, were twice and four times as common, respectively, after the guidelines. The guidelines were not associated with a change in suicide counts. Limitations: This study could not prove exposure to suicide reporting. Conclusion: Publication of Canadian media guidelines was associated with significant, moderate-sized improvements in reporting quality but not with decreased suicides. The latter finding may reflect only modest dissemination and implementation of the guidelines.

Background Patients who present to emergency departments after intentional self-harm are at an increased risk of dying by suicide. This applies particularly to men, who represent nearly two-thirds of those who die by suicide in Ontario. One way of potentially addressing this gap is to offer a course of blended problem-solving therapy, comprised of a brief course of evidence-based psychotherapy for individuals at risk for suicide, facilitated by the use of a patient-facing smartphone application and a clinician-facing “dashboard.” This approach has the potential to combine the benefits of face-to-face therapy and technology to create a novel intervention. Methods This is a cohort study nested within a larger pragmatic multicentre pre- and post-design cluster randomised trial. Suicidal ideation assessed by the Beck Scale for Suicide Ideation is the primary outcome variable. Secondary outcome measures include depression (Patient Health Questionnaire-9), anxiety (Generalized Anxiety Disorder 7-item scale), post-traumatic stress disorder (Primary Care PTSD Screen), health-related quality of life (EuroQol 5-dimension 5-level questionnaire), meaning in life (Experienced Meaning in Life Scale), perceived social supports (Multidimensional Scale of Perceived Social Support), alcohol use (Alcohol Use Disorders Identification Test), drug use (Drug Abuse Screening Test Short Form 10), problem-solving skills (Social Problem-Solving Inventory–Revised Short Form), and self-reported healthcare costs, as well as health service use measured using Ontario administrative health data. A process evaluation will also be conducted following study completion. Discussion The cohort study will test whether better adherence to the intervention results in better outcomes. The value of the cohort study design is that we can examine in more detail certain subgroups or other variables that are not available in the larger cluster randomised trial. This trial will aim to improve standards by informing best practice in management of men who self-harm and present to hospitals in Ontario. Trial registration ClinicalTrials.gov, NCT03473535. Registered on March 22, 2018.

Objective: A growing body of research has established that specific elements of suicide-related news reporting can be associated with increased or decreased subsequent suicide rates. This has not been systematically investigated for social media. The aim of this study was to identify associations between specific social media content and suicide deaths. Methods: Suicide-related tweets ( n = 787) geolocated to Toronto, Canada and originating from the highest level influencers over a 1-year period (July 2015 to June 2016) were coded for general, putatively harmful and putatively protective content. Multivariable logistic regression was used to examine whether tweet characteristics were associated with increases or decreases in suicide deaths in Toronto in the 7 days after posting, compared with a 7-day control window. Results: Elements independently associated with increased subsequent suicide counts were tweets about the suicide of a local newspaper reporter (OR = 5.27, 95% CI = [1.27, 21.99]), ‘other’ social causes of suicide (e.g. cultural, relational, legal problems; OR = 2.39, 95% CI = [1.17, 4.86]), advocacy efforts (OR = 2.34, 95% CI = [1.48, 3.70]) and suicide death (OR = 1.52, 95% CI = [1.07, 2.15]). Elements most strongly independently associated with decreased subsequent suicides were tweets about murder suicides (OR = 0.02, 95% CI = [0.002, 0.17]) and suicide in first responders (OR = 0.17, 95% CI = [0.05, 0.52]). Conclusions: These findings largely comport with the theory of suicide contagion and associations observed with traditional news media. They specifically suggest that tweets describing suicide deaths and/or sensationalized news stories may be harmful while those that present suicide as undesirable, tragic and/or preventable may be helpful. These results suggest that social media is both an important exposure and potential avenue for intervention.

OBJECTIVE: To evaluate the impact of a Harry Potter-based mental health literacy curriculum, imparting cognitive behavioral therapy (CBT) skills, on suicidality and well-being in middle-schoolers. METHODS: Students (aged 11-14; grades 7-8) who received a 3-month teacher-delivered intervention embedded in the language arts curriculum (N=200) were compared to a wait-list control group (N=230) in the largest urban school board in Canada. Suicidality defined as a composite measure of self-reported suicidal ideation and attempts [primary outcome], self-reported emotion dysregulation, interpersonal chaos, confusion about self, and impulsivity [Life Problems Inventory (LPI)] and self-reported depression and anxiety symptoms [Revised Child Anxiety and Depression Scale (RCADS)] were the outcomes of interest. Measurements occurred prior to and after curriculum delivery with independent t-tests used to compare mean change scores between groups clustered by class. RESULTS: Thirty-seven English teachers in 46 classes across 15 schools comprised the planned study cohort. Composite suicidality scores were significantly worse in the control than intervention group at endpoint (0.05±0.54 vs. 0.17±0.47, t= -2.60, df=428, p=0.01). There were also significant improvements in LPI and RCADS scores in the intervention group compared to controls (LPI:-3.74±7.98 vs. 1.16±10.77 t=5.28, df=428, p