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.

Music as an Intervention to Improve the Hemodynamic Response of Ketamine in Depression: A Randomized Clinical Trial.

This randomized clinical trial explores whether music improves the hemodynamic response of ketamine among patients with treatment-resistant depression in Canada.

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.).

Emotion regulation in bipolar disorder type-I: multivariate analysis of fMRI data.

BACKGROUND: Bipolar disorder type-I (BD-I) patients are known to show emotion regulation abnormalities. In a previous fMRI study using an explicit emotion regulation paradigm, we compared responses from 19 BD-I patients and 17 matched healthy controls (HC). A standard general linear model-based univariate analysis revealed that BD patients showed increased activations in inferior frontal gyrus when instructed to decrease their emotional response as elicited by neutral images. We implemented multivariate pattern recognition analyses on the same data to examine if we could classify conditions within-group as well as HC versus BD. METHODS: We reanalyzed explicit emotion regulation data using a multivariate pattern recognition approach, as implemented in PRONTO software. The original experimental paradigm consisted of a full 2 × 2 factorial design, with valence (Negative/Neutral) and instruction (Look/Decrease) as within subject factors. RESULTS: The multivariate models were able to accurately classify different task conditions when HC and BD were analyzed separately (63.24%-75.00%, p = 0.001-0.012). In addition, the models were able to correctly classify HC versus BD with significant accuracy in conditions where subjects were instructed to downregulate their felt emotion (59.60%-60.84%, p = 0.014-0.018). The results for HC versus BD classification demonstrated contributions from the salience network, several occipital and frontal regions, inferior parietal lobes, as well as other cortical regions, to achieve above-chance classifications. CONCLUSIONS: Our multivariate analysis successfully reproduced some of the main results obtained in the previous univariate analysis, confirming that these findings are not dependent on the analysis approach. In particular, both types of analyses suggest that there is a significant difference of neural patterns between conditions within each subject group. The multivariate approach also revealed that reappraisal conditions provide the most informative activity for differentiating HC versus BD, irrespective of emotional valence (negative or neutral). The current results illustrate the importance of investigating the cognitive control of emotion in BD. We also propose a set of candidate regions for further study of emotional control in BD.

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.

Atorvastatin lowers serum calcium levels in lithium-users: results from a randomized controlled trial.

BACKGROUND: Although lithium is considered the gold-standard treatment for bipolar disorder (BD), it is associated with a variety of major endocrine and metabolic side effects, including parathyroid hormone (PTH) dependent hypercalcemia. Aside from surgery and medication discontinuation, there are limited treatments for hypercalcemia. This paper will assess data from a randomized controlled trial (RCT). METHODS: This is a secondary analysis of an RCT that explored the effects of atorvastatin (n = 27) versus placebo (n = 33) on lithium-induced nephrogenic diabetes insipidus (NDI) in patients with BD and major depressive disorder (MDD) using lithium (n = 60), over a 12-week period. This secondary analysis will explore serum calcium levels and thyroid stimulating hormone (TSH) measured at baseline, week 4, and week 12. RESULTS: At 12-weeks follow-up while adjusting results for baseline, linear regression analyses found that corrected serum calcium levels were significantly lower in the treatment group (mean (M) = 2.30 mmol/L, standard deviation (SD) = 0.07) compared to the placebo group (M = 2.33 mmol/L, SD = 0.07) (ß = - 0.03 (95% C.I.; - 0.0662, - 0.0035), p = 0.03) for lithium users. There were no significant changes in TSH. CONCLUSION: In lithium users with relatively normal calcium levels, receiving atorvastatin was associated with a decrease in serum calcium levels. Although exciting, this is a preliminary finding that needs further investigation with hypercalcemic patients. Future RCTs could examine whether atorvastatin can treat PTH dependent hypercalcemia due to lithium and other causes.

Melatonergic agents influence the sleep-wake and circadian rhythms in healthy and psychiatric participants: a systematic review and meta-analysis of randomized controlled trials.

Exogenous melatonergic agents are widely used to treat insomnia and sleep disturbance. Several studies have shown that they might also modulate circadian rhythms. The purpose of this systematic review and meta-analysis was to summarize current knowledge about the effects of melatonin supplements and melatonin agonists on the sleep-wake cycle as well as on the circadian rhythm of melatonin in healthy participants and in patients with psychiatric disorders. The following electronic databases were searched: EMBASE, PubMed, Web of Science, CINAHL, and Cochrane Library. Of the 12,719 articles, we finally selected 30 studies including 1294 healthy participants and 8 studies including 687 patients with psychiatric disorders. Cochrane risk of bias tool was used to assess the risk of bias. Using meta-ANOVA, studies on healthy participants showed advancing effects of melatonergic supplements and agonists on sleep-wake cycle according to dosing time and dosage, despite the fact that the original individual melatonin rhythm was within a normal range (fixed effect model standardized mean difference [95% Confidence Interval] = -0.639[-0.968 to -0.310]). In a limited number of randomized controlled trials with psychiatric patients, the findings seemed similar to those with healthy participants, despite the psychiatric disorders and treatment related factors affecting circadian rhythms. Given the unmet clinical need for evidence-based treatments to correct circadian rhythms in psychiatric disorders, efficacy of melatonergic agents seen in healthy participants, and similarity of findings among psychiatric patients, large scale, well-designed randomized controlled trials are needed to test efficacy on circadian parameters in psychiatric disorders.

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.

Clinical and demographic factors associated with delayed diagnosis of bipolar disorder: Data from Health Outcomes and Patient Evaluations in Bipolar Disorder (HOPE-BD) study.

BACKGROUND: The diagnosis of Bipolar Disorder (BD) is frequently delayed. In this study, we aimed to examine the clinical and demographic factors associated with delayed diagnosis of BD, defined as the difference between the age at first mood episode (depressive, manic, or hypomanic) and the age at the correct diagnosis of BD, using data from a Canadian multicentre naturalistic study. METHODS: The sample included 192 patients with Bipolar I Disorder (BD-I) and 127 with Bipolar II Disorder (BP-II) who participated in the Health Outcomes and Patient Evaluations in Bipolar Disorder (HOPE-BD) study. Sociodemographic characteristics and clinical features that had been previously associated with delayed diagnosis of BD were included in the analysis. RESULTS: The median delay in diagnosis was 5.0 years in BD-I and 11.0 years in BD-II. Clinical factors such as earlier age of onset, lifetime suicide attempts and comorbid anxiety disorders were associated with a longer delay, whereas the presence of lifetime psychotic symptoms and psychiatric hospitalizations were associated with a shorter delay. Quantile regression analysis showed older age at which professional help was first sought and younger age of onset as predictors of increased delay in diagnosis of BD-I and BD-II. Depression as first episode predicted longer delay in diagnosis of BD-I but not BD-II. CONCLUSION: Our findings identified the ongoing lag in identification of a BD diagnosis and the clinical markers most associated with this delay, highlighting the need for implementation of strategies for early identification and interventions in BD.

Obesity and metabolic comorbidity in bipolar disorder: do patients on lithium comprise a subgroup? A naturalistic study.

BACKGROUND: Bipolar disorders (BD) are associated with increased prevalence of obesity and metabolic syndrome (MetS). Nevertheless, there is a wide range in prevalence estimates, with little known about the contributions of pharmacotherapy. It has been suggested that lithium might have a more favorable metabolic profile. We hypothesized that lithium use is associated with less increased body mass index (BMI), MetS, and type II diabetes, when compared with non-lithium users (those on anticonvulsants, second-generation antipsychotics). METHODS: Cross-sectional study of 129 patients aged 18-85 with bipolar disorder, followed at tertiary care clinics in Montreal. Patients using lithium were compared with those not on lithium, for body mass index and metabolic syndrome. RESULTS: The prevalence of obesity and metabolic syndrome in the sample of lithium-using patients with BD was 42.4 and 35.7% respectively, with an average BMI of 29.10 (+/- 6.70). Lithium and non-lithium groups did not differ in BMI or prevalence of MetS. However, compared to the non-lithium group, lithium users had lower hemoglobin A1C (5.24 +/- 0.53 versus 6.01 +/- 1.83, U = 753.5, p = 0.006) and lower triglycerides (1.46 +/- 0.88 versus 2.01 +/- 1.25, U = 947, p = 0.020). CONCLUSIONS: There is a high prevalence of obesity and metabolic syndrome among patients with bipolar disorder. However, this did not appear to be associated with lithium use, when compared to those not on lithium. The lithium subgroup was also associated with lower prevalence of type II diabetes. Future prospective and intervention studies with larger sample sizes are necessary to further explore the association between lithium and insulin resistance, as well as its underlying mechanisms.

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.

Irregular eating patterns associate with hypomanic symptoms in bipolar disorders.

Objective: We present novel dimensional methods to describe the timing of eating in psychopathology. We focused on the relationship between current mood in bipolar disorder (BD) and the stability of the temporal pattern of daily eating events. Methods: Consenting BD patients (n = 69) from an outpatient, tertiary care clinic completed hourly charts of mood and eating for two weeks. Mood was also evaluated with Montgomery-Åsberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS). Results: Illustrative displays, or eatograms, enabling visualization of all recorded eating events were used to guide assessment of the temporal structure of eating across the two week assessment period. We computed indices to quantify irregularities in timing of eating, namely IFRQ, ITIM and IINT for the variability of frequency, timing, and interval of eating events, respectively. In this cohort, irregular temporal pattern of eating correlated with hypomanic symptoms (YMRS with IFRQ, Spearman rank order rh = 0.28, p = .019, with ITIM, rh = 0.44, p < .001, and with IINT rh = 0.38, p = .001), but not depressive symptoms or anthropometric measures. Conclusions: Our data suggest a link between the instability of the temporal order of daily eating and mood. The dimensional measures for eating pattern introduced here enable future investigations of correlations with psychopathology.

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.

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.

Properties of common anxiety scales among patients with bipolar disorder.

OBJECTIVES: Almost half of the patients with a bipolar disorder (BD) have anxiety disorder(s) (AD) during their lifetime, but feasible measures for all AD are few. Furthermore, cognitive impairments can compromise reliability of existing scales, since many are needed for full coverage. Thus, we investigated how reliably patients responded to anxiety scales and any symptom overlap to propose future improvements to anxiety assessments. METHODS: We collected 152 observations in patients with BD with the Clinically Useful Anxiety Outcome Scale, Social Phobia Inventory, Panic Disorder Severity Measurement, and Trauma Screening Questionnaire (in total, 57 items). The scales were analyzed as a set in a Rasch model. RESULTS: During our analyses, we found indication that BD outpatients had difficulty differentiating response options to 70% (40/57) of items which were rescored or deleted. Only one case was misfitting (-2.65±.41). In total, 22 items were locally dependent and one indicated misfit. The final model included 25-items and fit the Rasch model (χ2=35.92, DF=50, p=.93). The model was unidimensional, without losing appropriate associations with depression (r = 0.62), suicidality (r = 0.37), and hypomania (r= -0.01). LIMITATIONS: Bolstering the size of less frequent subgroups should be accomplished in future work. CONCLUSION: A unidimensional rather than categorical approach to severity of anxiety might be both useful and feasible in this population. Further development of screens is necessary to enable systematic screening and measurement of anxiety in BD.

Group Cognitive Behavioral Analysis System of Psychotherapy (CBASP): A Pilot Study for Bipolar Depression.

OBJECTIVES: Cognitive Behavioral Analysis System of Psychotherapy (CBASP) is an individually administered treatment model designed specifically for Persistent Depression however bipolar patients have traditionally been excluded from CBASP studies. There is a perception that bipolar depression will be harder to treat and requires a unique psychological approach. This pilot study reports on the feasibility of administering the same 20-week manualized group CBASP therapy with bipolar patients currently in a depressive episode. METHODS: This non-randomized, single-arm prospective pilot study, reports on an a posteriori exploration of benefits to bipolar depressed patients (n=26) of the same 20-week group CBASP intervention administered to unipolar depressed patients (n=81). The clinical trial for the initial phase examining benefits of the manualized 20-week group CBASP intervention with unipolar patients was registered with the ISRCTN registry, study ID: ISRCTN95149444. Results reported here include mixed ANOVA analyses, across group treatment models and diagnostic categories. Changes over time in self-reported depressive symptoms (Inventory of Depressive Symptoms -IDS-SR), self-reported social functioning, interpersonal problems and interpersonal dispositions are documented for all patients. An exploratory longitudinal latent class analysis was used to examine patients' trajectories of improvement in depressive symptoms. Finally, the best predictors of change in reported depressive symptoms were explored with a logistic regression for all patients. RESULTS: Improvements in depressive symptoms and in social functioning over time were significant for all patients with bipolar patients trending towards a greater improvement in depressive symptoms after controlling for baseline differences. An exploratory Latent Class Analysis identified two different treatment trajectories for the entire sample: 1) moderate to severely depressed patients who improved significantly (49%) and 2) severely depressed patients who did not improve (51%). The best predictors of non-response to group therapy include high baseline problems in social functioning and low rates of self-reported Perceived Improvements in overall health. CONCLUSION: Bipolar patients in a depressive episode appear to benefit from the same 20-week group CBASP model designed originally for the treatment of Persistent Depressive Disorder. Bipolar patients seem more easily mobilized both during and outside of group therapy sessions and report more interpersonal confidence and more agency than unipolar depressed patients.

Suicidal Ideation and Insomnia in Bipolar Disorders: Idéation suicidaire et insomnie dans les troubles bipolaires.

OBJECTIVE: Bipolar disorder (BD) confers elevated suicide risk and associates with misaligned circadian rhythm. Real-time monitoring of objectively measured sleep is a novel approach to detect and prevent suicidal behavior. We aimed at understanding associations between subjective insomnia and actigraphy data with severity of suicidal ideation in BDs. METHODS: This prospective cohort study comprised 76 outpatients with a BD aged 18 to 65 inclusively. Main measures included 10 consecutive days of wrist actigraphy; the Athens Insomnia Scale (AIS); the Montgomery-Åsberg Depression Rating Scale (MADRS); the Quick Inventory of Depressive Symptoms-16, self-rating (QIDS-SR-16); and the Columbia Suicide Severity Rating Scale. Diagnoses, medications, and suicide attempts were obtained from chart review. RESULTS: Suicidal ideation correlated moderately with subjective insomnia (AIS with QIDS-SR-16 item 12 ρ =0.26, P = 0.03; MADRS item 10 ρ = 0.33, P = 0.003). Graphical sleep patterns showed that suicidal patients were enriched among the most fragmented sleep patterns, and this was confirmed by correlations of suicidal ideation with actigraphy data at 2 visits. Patients with lifetime suicide attempts (n = 8) had more varied objective sleep (a higher standard deviation of center of daily inactivity [0.64 vs. 0.26, P = 0.01], consolidation of daily inactivity [0.18 vs. 0.10, P = <0.001], sleep offset [3.02 hours vs. 1.90 hours, P = <0.001], and total sleep [105 vs. 69 minutes, P = 0.02], and a lower consolidation of daily inactivity [0.65 vs. 0.79, P = 0.03]). CONCLUSIONS: Subjective insomnia, a nonstigmatized symptom, can complement suicidality screens. Longer follow-ups and larger samples are warranted to understand whether real-time sleep monitoring predicts suicidal ideation in patient subgroups or individually.

Inactograms and objective sleep measures as means to capture subjective sleep problems in patients with a bipolar disorder.

BACKGROUND: Sleep problems are common in bipolar disorders (BDs). To objectively characterize these problems in BDs, further methodological development is needed to capture subjective insomnia. AIM: To test psychometric properties of the Athens Insomnia Scale (AIS), and associations with actigraphy-derived measures, applying modifications in actigraphy data processing to capture features of perturbed sleep in patients with a BD. METHODS: Seventy-four patients completed the AIS and the Quick Inventory of Depressive Symptomatology, self-report (QIDS-SR-16). Locomotor activity was continuously recorded by wrist actigraphy for ≥10 consecutive days. We computed the sleep onset/offset, the center of daily inactivity (CenDI), as a proxy for chronotype, and the degree of consolidation of daily inactivity (ConDI), as a proxy for sleep-wake rhythm strength. RESULTS: AIS showed good psychometric properties (Cronbach's alpha = 0.84; test-retest correlation = 0.84, P<.001). Subjective sleep problems correlated moderately with a later sleep phase (CenDI with AIS rho = 0.34, P = .003), lower consolidation (ConDI with AIS rho = -0.22, P = .05; with QIDS-SR-16 rho = -0.27, P = .019), later timing of sleep offset (with AIS rho = 0.49, P = ≤.001, with QIDS-SR-16 rho = 0.36, P = .002), and longer total sleep (with AIS rho = 0.29, P = .012, with QIDS-SR-16 rho = 0.41, P = ≤.001). While AIS was psychometrically more solid, correlations with objective sleep were more consistent across time for QIDS-SR-16. CONCLUSIONS: AIS and QIDS-SR-16 are suitable for clinical screening of sleep problems among patients with a BD. Subjective insomnia associated with objective measures. For clinical and research purposes, actigraphy and data visualization on inactograms are useful for accurate longitudinal characterization of sleep patterns.

Remission and recurrence in bipolar disorder: The data from health outcomes and patient evaluations in bipolar disorder (HOPE-BD) study.

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