Patterns of pharmacotherapy for bipolar disorder: A GBC survey.

OBJECTIVES: To understand treatment practices for bipolar disorders (BD), this study leveraged the Global Bipolar Cohort collaborative network to investigate pharmacotherapeutic treatment patterns in multiple cohorts of well-characterized individuals with BD in North America, Europe, and Australia. METHODS: Data on pharmacotherapy, demographics, diagnostic subtypes, and comorbidities were provided from each participating cohort. Individual site and regional pooled proportional meta-analyses with generalized linear mixed methods were conducted to identify prescription patterns. RESULTS: This study included 10,351 individuals from North America (n = 3985), Europe (n = 3822), and Australia (n = 2544). Overall, participants were predominantly female (60%) with BD-I (60%; vs. BD-II = 33%). Cross-sectionally, mood-stabilizing anticonvulsants (44%), second-generation antipsychotics (42%), and antidepressants (38%) were the most prescribed medications. Lithium was prescribed in 29% of patients, primarily in the Australian (31%) and European (36%) cohorts. First-generation antipsychotics were prescribed in 24% of the European versus 1% in the North American cohort. Antidepressant prescription rates were higher in BD-II (47%) compared to BD-I (35%). Major limitations were significant differences among cohorts based on inclusion/exclusion criteria, data source, and time/year of enrollment into cohort. CONCLUSIONS: Mood-stabilizing anticonvulsants, second-generation antipsychotics, and antidepressants were the most prescribed medications suggesting prescription patterns that are not necessarily guideline concordant. Significant differences exist in the prescription practices across different geographic regions, especially the underutilization of lithium in the North American cohorts and the higher utilization of first-generation antipsychotics in the European cohorts. There is a need to conduct future longitudinal studies to further explore these differences and their impact on outcomes, and to inform and implement evidence-based guidelines to help improve treatment practices in BD.

A Randomized Evaluation of MoodFX, a Patient-Centred e-Health Tool to Support Outcome Measurement for Depression: Une évaluation randomisée de MoodFX, un outil de santé en ligne centré sur le patient pour soutenir la mesure du résultat dans la dépression.

BACKGROUND: e-Health tools using validated questionnaires to assess outcomes may facilitate measurement-based care for psychiatric disorders. MoodFX was created as a free online symptom tracker to support patients for outcome measurement in their depression treatment. We conducted a pilot randomized evaluation to examine its usability, and clinical utility. METHODS: Patients presenting with a major depressive episode (within a major depressive or bipolar disorder) were randomly assigned to receive either MoodFX or a health information website as the intervention and control condition, respectively, with follow-up assessment surveys conducted online at baseline, 8 weeks and 6 months. The primary usability outcomes included the percentage of patients with self-reported use of MoodFX 3 or more times during follow up (indicating minimally adequate usage) and usability measures based on the System Usability Scale (SUS). Secondary clinical outcomes included the Quick Inventory of Depressive Symptomatology, Self-Rated (QIDS-SR) and Patient Health Questionnaire (PHQ-9). RESULTS: Forty-nine participants were randomized (24 to MoodFX and 25 to the control condition). Of the 23 participants randomized to MoodFX who completed the user survey, 18 (78%) used MoodFX 3 or more times over the 6 months of the study. The mean SUS score of 72.7 (65th-69th percentile) represents good usability. Compared to the control group, the MoodFX group had significantly better improvement on QIDS-SR and PHQ-9 scores, with large effect sizes and higher response rates at 6 months. There were no differences between conditions on other secondary outcomes such as functioning and quality of life. CONCLUSION: MoodFX demonstrated good usability and was associated with reduction in depressive symptoms. This pilot study supports the use of digital tools in depression treatment.

E-health tools may be useful for measuring and tracking symptoms and other outcomes during treatment for depression. This study is a randomized evaluation of MoodFX, a free web-based app that helps patients track their symptoms using validated questionnaires, and also offers depression information and self-management tips. A total of 49 participants with clinical depression were randomized to using MoodFX or a health information website, for 6 months. In a survey, the participants that used MoodFX found it easy and useful to use. In addition, the participants that used MoodFX had greater improvement in depressive symptoms after 6 months, compared to those who used the health information website. These results suggest that MoodFX may be a useful tool to monitor outcomes and support depression treatment.

Neuroanatomical predictors of problematic alcohol consumption in adolescents: a systematic review of longitudinal studies.

AIMS: This study aimed to systematically review the literature on neuroanatomical predictors of future problematic drinking in adolescents. METHODS: Using PRISMA guidelines, a systematic review was conducted to evaluate neuroanatomical predictors of problematic alcohol consumption in adolescents. EMBASE, MEDLINE, and PsycINFO databases were searched from inception to 6 January 2023. Studies were included if they were original, had a prospective design, had a sample size of at least 12, had a follow-up period of at least 1 year, had at least one structural neuroimaging scan before 18 with no prior alcohol use, and had alcohol use as the primary outcome. Studies were excluded if they had animals only and were not in English. Risk of bias was conducted using the CASP tool. RESULTS: Out of 1412 studies identified, 19 studies met the criteria, consisting of 11 gray matter (n = 4040), 5 white matter (n = 319), and 3 assessing both (n = 3608). Neuroanatomical predictors of future problematic drinking in adolescents were reported to be distributed across various brain regions such as the orbitofrontal cortex and paralimbic regions. However, the findings were largely heterogeneous. CONCLUSIONS: This is the first systematic review to map out the existing literature on neuroanatomical predictors of problematic drinking in adolescents. Future research should focus on the aforementioned regions to determine their role in predicting future problematic drinking with more certainty.

Grey matter abnormalities in first-episode mania: A systematic review and meta-analysis of voxel-based morphometry studies.

OBJECTIVES: It has been proposed that different stages of bipolar disorder may be underpinned by distinct neurobiological substrates. However, structural neuroimaging studies in early stages of the illness are limited by small sample sizes yielding inconsistent findings. The purpose of this systematic review and meta-analysis, therefore, was to identify regional grey matter volume (GMV) changes that are consistently associated with first episode of mania (FEM). METHODS: Following PRISMA guidelines, we conducted a systematic search of the literature to identify Voxel-Based Morphometry (VBM) studies in FEM patients compared with healthy individuals. We then conducted a voxel-wise meta-analysis using Seed-based d-Mapping technique. Finally, we performed univariate meta-regression analyses to explore the potential effects of moderator variables including age, gender, and percentage of lithium users on GMV alterations. RESULTS: We identified 15 VBM studies and included 12 studies in the meta-analysis. Four studies found no regional differences in GM volumes while other 11 studies reported volume changes in frontal and temporal regions as well as anterior cingulate cortex (ACC), cerebellum and basal ganglia. The meta-analysis revealed a single cluster of GMV reduction in bilateral pregenual ACC in patients with FEM compared to healthy individuals (P < .001). The Egger's test showed no evidence of publication bias at peak voxel level (P = .447). Meta-regression analyses revealed no significant effects of moderators evaluated. CONCLUSIONS: Structural brain changes are evident in the early stages of bipolar disorder. GMV reduction in bilateral pregenual ACC is the most consistent finding in VBM studies of FEM.

Cognitive subgroups in first episode bipolar I disorder: Relation to clinical and brain volumetric variables.

OBJECTIVE: Distinct cognitive subgroups are seen in patients with long duration bipolar I disorder (BDI), possibly reflective of underlying pathophysiological differences. It is unknown whether such cognitive heterogeneity is present at illness onset. We applied latent class analysis (LCA) to cognitive test scores in first episode BDI patients. Exploratory analysis elucidated whether impaired subgroups were characterized by 'early neurodevelopmental' (low premorbid IQ and intracranial volume) versus 'later neurodevelopmental' (decline from premorbid to current IQ, changes in relative grey (GM)/white (WM) matter volumes) pathology. METHODS: Recently recovered first manic episode BDI patients (n = 91) and healthy controls (HC, n = 63) comprised the study sample. LCA identified subgroups based on processing speed, verbal memory, non-verbal memory, executive functioning, attention and working memory scores. Subgroups were compared amongst each other and HC on premorbid/current IQ, intracranial (ICV), total brain and regional volumes. RESULTS: Three cognitive subgroups emerged: (i) globally impaired (GI, n = 31), scoring 0.5-1 SD below demographically corrected norms across domains, (ii) selectively impaired (SI, n = 47), with predominant processing speed deficits and (iii) high performing (HP, n = 13), with above-average cognitive performance. GI patients showed a 'later neurodevelopmental' pattern, with normal ICV, significant decline from premorbid to current IQ, higher total GM and lower total WM (with respect to total brain volume) versus SI and HC (p = 0.003). GI patients had higher left frontal pole GM versus HC (p < 0.05, FWE corrected). CONCLUSIONS: A globally impaired patient subgroup is identifiable in first episode BDI, possibly characterized by unique neurodevelopmental pathologic processes proximal to illness onset.

New Developments in the Use of Atypical Antipsychotics in the Treatment of Bipolar Disorder: a Systematic Review of Recent Randomized Controlled Trials.

PURPOSE OF REVIEW: Atypical antipsychotics are increasingly used in the treatment of bipolar disorder (BD). This systematic review provides an overview of recently published randomized controlled trials (RCTs) on the efficacy and safety of atypical antipsychotics in BD. RECENT FINDINGS: Several studies supported efficacy of quetiapine monotherapy in acute bipolar I (BDI) and bipolar II (BDII) depression. Moreover, quetiapine adjunctive therapy showed superior efficacy to placebo in treatment-resistant bipolar depression. Cariprazine 1.5 mg was effective in treating bipolar I depression. Aripiprazole 400 mg IM once monthly was effective in preventing manic episodes with minimal metabolic effects. In youth with BD, lurasidone was effective and well-tolerated for acute depression while asenapine showed efficacy in treating acute manic and mixed episodes. Recently published RCTs generally support the efficacy of atypical antipsychotics in different phases of BD. Future studies should focus on understudied populations including pediatric BD and geriatric BD and BDII, as well as a focus on cognitive functioning and quality of life measures.

Preservation of Gray Matter Volume in Early Stage of Bipolar Disorder: A Case for Early Intervention: Préservation du volume de matière grise au stade précoce du trouble bipolaire: un cas pour intervention précoce.

OBJECTIVE: It has been proposed that different stages of the bipolar disorder might have distinct neurobiological changes. However, the evidence for this has not been consistent, as the studies in early stages of the illness are limited by small sample sizes. The purpose of this study was to investigate the gray matter volume changes in bipolar patients who recently recovered from their first episode of mania (FEM). METHODS: Using a whole-brain voxel-based analysis, we compared the regional gray matter volumes of 61 bipolar patients who have recovered from their FEM in the past 3 months with 43 age- and gender-matched healthy participants. We also performed a series of subgroup analyses to determine the effects of hospitalization during the FEM, history of depressive episodes, and exposure to lithium. RESULTS: No statistically significant difference was found between gray matter volumes of FEM patients and healthy participants, even at a more liberal threshold (P < 0.001, uncorrected for multiple comparisons). Voxel-based subgroup analyses did not reveal significant gray matter differences except for a trend toward decreased gray matter volume in left lateral occipital cortex (P < 0.001, uncorrected) in patients with a previous history of depression. CONCLUSION: This study represents the largest structural neuroimaging investigation of FEM published to date. Early stage of bipolar disorder was not found to be associated with significant gray matter volume changes. Our findings suggest that there might be a window of opportunity for early intervention strategies to prevent or delay neuroprogression in bipolar disorder.

Cariprazine in the treatment of Bipolar Disorder: A systematic review and meta-analysis.

OBJECTIVES: Cariprazine is a partial agonist at D2/D3 receptors that has been approved for the treatment of mania associated with bipolar disorder (BD). This meta-analysis aimed to assess the efficacy and tolerability of cariprazine in the treatment of BD. METHODS: Randomized controlled trials investigating the efficacy of cariprazine in BD were included. Of the 391 studies yielded by search, 7 were included. The PRISMA protocol was followed and a set of analyses involving random-effects model with restricted maximum-likelihood estimator were used to synthesize effect sizes. RESULTS: Cariprazine was associated with a moderate and significant reduction of manic symptoms based on YMRS change scores (SMD: -0.52; 95%CI: -0.82 to -0.21; P = .018). Cariprazine resulted in significantly higher remission (OR: 2.05; 95%CI: 1.61-2.61; P = .006) and response rates (OR: 2.31; 95%CI: 1.35-3.95; P = .021) for manic and mixed episodes compared with placebo. Both cariprazine 1.5 mg and 3 mg doses were associated with small but significant reduction in depressive symptoms assessed with MADRS scores (SMD: -0.26, 95%CI: -0.49 to -0.02; P = .040) (SMD: -0.21, 95%CI: -0.41 to -0.01; P = .045), respectively. Cariprazine was significantly associated with the development of adverse effects but not with dropouts due to these adverse effects, when compared to placebo. CONCLUSION: Cariprazine appears to be safe and efficacious in the treatment of acute mania and mixed episodes associated with BD. Cariprazine at doses of 1.5-3 mg/day is efficacious in acute bipolar depression but the effect sizes were smaller. Controlled studies evaluating its efficacy for prophylaxis are needed.

Treatment of Mixed Features in Bipolar Disorder: an Updated View.

PURPOSE OF REVIEW: Mixed presentations in bipolar disorder have long posed clinical and nosological challenges. The DSM-5 mixed features specifier was developed to provide a more flexible and clinically relevant definition of mixed presentations compared with narrowly defined DSM-IV mixed episodes. However, there is little guidance on treating such presentations. Here, we summarize the evidence for biological treatments of DSM-5 and similarly defined mixed features (MFs). RECENT FINDINGS: The literature on treating MFs is almost exclusively based on post hoc analyses. Within this limited evidence base is preliminary positive data for aripiprazole, asenapine, cariprazine, olanzapine, risperidone, and ziprasidone in treating acute mania with MFs, and cariprazine, lurasidone, olanzapine, and ziprasidone for depressive symptoms in depression with MFs. Divalproex may also be efficacious for acute mania with MFs. The few extant maintenance studies suggest that divalproex and olanzapine may have long-term efficacy in those with index MFs or for the prevention of MFs, respectively. The existing evidence suggests that clinicians consider atypical antipsychotics and divalproex for treating acute mixed presentations. However, adequately powered treatment trials-and studies of maintenance and neurostimulation therapies-are needed. Additionally, data-driven techniques to identify relevant symptom clusters may help improve our conceptualization of mixed presentations.

Lithium vs valproate in the maintenance treatment of bipolar I disorder: A post- hoc analysis of a randomized double-blind placebo-controlled trial.

OBJECTIVE: Lithium and valproate are commonly used either in monotherapy or in combination with atypical antipsychotics in maintenance treatment of bipolar I disorder; however, their comparative efficacy is not well understood. This study aimed to compare the efficacy of valproate and lithium on mood stability either in monotherapy or in combination with atypical antipsychotics. METHODS: We performed a post hoc analysis using data from a 52-week randomized double-blind, placebo-controlled trial, that recruited 159 patients with recently remitted mania during treatment with lithium or valproate and adjunctive atypical antipsychotic therapy. Patients were randomized to discontinue adjunctive atypical antipsychotic at 0, 24 or 52 weeks. RESULTS: No significant differences in efficacy were observed between valproate and lithium (hazard ratio: 0.99; 95% confidence interval: [0.66, 1.48]) in time to any mood event. Valproate with 24 weeks of atypical antipsychotic was significantly superior to valproate monotherapy in preventing any mood relapse (hazard ratio: 0.46; 95% confidence interval: [0.22, 0.97]) while lithium with 24 weeks of atypical antipsychotic was superior to lithium monotherapy in preventing mania (hazard ratio: 0.27; 95% confidence interval: [0.09, 0.85]) but not depression. CONCLUSION: Overall, this study did not find significant differences in efficacy between the two mood-stabilizing agents when used as monotherapy or in combination with atypical antipsychotics. However, study design and small sample size might have precluded from detecting an effect if true difference in efficacy existed. Further head-to-head investigations with stratified designs are needed to evaluate maintenance therapies.

Neuroprogression and episode recurrence in bipolar I disorder: A study of gray matter volume changes in first-episode mania and association with clinical outcome.

OBJECTIVES: Bipolar I disorder (BD-I) is associated with gray matter volume (GMV) alterations in neural regions important for emotional regulation. Reductions found in patients with multiple episodes are not seen at illness onset, suggesting that changes occur with illness progression, although no prospective studies to date have examined this. In the present study, we assessed GMV at baseline and one year following a first manic episode, examining the impact of episode recurrence on the trajectory of change. METHODS: A total of 41 recently remitted first manic episode patients with BD-I and 25 healthy subjects (HS) underwent 3T magnetic resonance imaging at baseline and one year later. Using voxel-based morphometry, we compared GMV change between HS, patients who experienced a recurrence of a mood episode (BDrecurr ), and patients in sustained remission (BDwell ). RESULTS: The GMV change from baseline to one year did not differ significantly between HS and the full BD-I group or BDwell and HS. However, the BDrecurr group had greater GMV loss than HS in left frontal and bilateral temporal regions, and BDwell patients involving bilateral frontal, temporal and left parietal regions. CONCLUSIONS: GMV change early in the course of BD-I is associated with clinical outcome, such that neuroprogression found in patients who experience a recurrence of a mood episode is not seen in those with sustained remission. These findings have important implications for the treatment of BD-I as they suggest that prevention of recurrence might minimize neuroprogression of the disease, possibly requiring a multipronged early intervention approach to achieve this goal.

Cannabidiol as a Treatment for Mood Disorders: A Systematic Review.

OBJECTIVE: To review the current evidence for efficacy of cannabidiol in the treatment of mood disorders. METHODS: We systematically searched PubMed, Embase, Web of Science, PsychInfo, Scielo, ClinicalTrials.gov , and The Cochrane Central Register of Controlled Trials for studies published up to July 31, 2019. The inclusion criteria were clinical trials, observational studies, or case reports evaluating the effect of pure cannabidiol or cannabidiol mixed with other cannabinoids on mood symptoms related to either mood disorders or other health conditions. The review was reported in accordance with guidelines from Preferred Reporting Items for Systematic reviews and Meta-Analyses protocol. RESULTS: Of the 924 records initially yielded by the search, 16 were included in the final sample. Among them, six were clinical studies that used cannabidiol to treat other health conditions but assessed mood symptoms as an additional outcome. Similarly, four tested cannabidiol blended with Δ-9-tetrahydrocannabinol in the treatment of general health conditions and assessed affective symptoms as secondary outcomes. Two were case reports testing cannabidiol. Four studies were observational studies that evaluated the cannabidiol use and its clinical correlates. However, there were no clinical trials investigating the efficacy of cannabidiol, specifically in mood disorders or assessing affective symptoms as the primary outcome. Although some articles point in the direction of benefits of cannabidiol to treat depressive symptoms, the methodology varied in several aspects and the level of evidence is not enough to support its indication as a treatment for mood disorders. CONCLUSIONS: There is a lack of evidence to recommend cannabidiol as a treatment for mood disorders. However, considering the preclinical and clinical evidence related to other diseases, cannabidiol might have a role as a treatment for mood disorders. Therefore, there is an urgent need for well-designed clinical trials investigating the efficacy of cannabidiol in mood disorders.

Caring for youth with co-occurring substance use and severe psychiatric disorders: diagnostic challenges and clinical implications.

Appropriate interventions for psychiatric conditions that commonly emerge during adolescence and early adulthood play a crucial role in modifying both acute risks as well as long-term outcomes. Substance use disorder is a common comorbidity during the early stages of mood and psychotic disorders that further heightens acute risks and is considered a negative prognostic factor. New presentations of mood and psychotic symptoms with co-occurring substance use are inherently challenging to formulate due to the uncertainty surrounding the relative impact of multiple intrinsic and extrinsic factors. Given such uncertainty, it is natural for clinicians to rely on heuristics to guide assessment and management. These heuristics however may bring about premature diagnostic closure by favouring the primacy of substance use, which in turn can result in a missed window of opportunity for a timely and appropriate intervention. We caution clinicians against over-attributing early symptoms of mood and psychotic disorders to substances use alone.

Les interventions appropriées pour les troubles psychiatriques qui apparaissent communément durant l'adolescence et le début de l'âge adulte jouent un rôle essentiel dans la modification tant des risques aigus que des résultats à long terme. Le trouble d'utilisation de substances est une comorbidité commune durant les premières phases des troubles de l'humeur et psychotiques qui hausse davantage les risques aigus et est considéré comme un facteur pronostic négatif. Les nouvelles présentations des symptômes de l'humeur et psychotiques avec un trouble concomitant d'utilisation de substances sont intrinsèquement difficiles à formuler en raison de l'incertitude entourant l'effet relatif de multiples facteurs intrinsèques et extrinsèques. Devant cette incertitude, il est naturel pour les cliniciens d'employer l'heuristique pour guider l'évaluation et la gestion. Ces heuristiques peuvent toutefois provoquer la clôture d'un diagnostic prématuré en favorisant la primauté de l'utilisation de substances, qui à son tour peut entraîner une fenêtre d'opportunité manquée pour une intervention ponctuelle et appropriée. Nous mettons en garde les cliniciens contre l'attribution excessive des symptômes précoces de l'humeur et des troubles psychotiques à la seule utilisation de substances.

Patient Characteristics and Positive Outcomes Associated With a Novel Youth Inpatient Program for Concurrent Disorders.

ABSTRACT: Concurrent substance use and mental health disorders in youth are a major public health concern and require specialized and comprehensive services. In this paper, a novel inpatient tertiary care facility serving youth aged 13 to 18 with significant concurrent substance use and mental health issues is introduced. The development of this unit was prompted by the opioid overdose crisis in British Columbia and serves as the third concurrent disorders unit in Canada catered specifically to an adolescent population. From its opening in 2017, preadmission and postadmission data from each patient was gathered with the aim of providing a robust image of the serviced patient population as well as the efficacy of this service model. Patients admitted to this program had significantly higher quality of life ( d = 0.65) and significantly lower suicidality ( d = 0.86) at discharge, compared with at admission. Patients identifying as female had significantly lower quality of life, higher suicidality, and higher prevalence of adverse childhood events compared with patients identifying as male. Results from this program evaluation outline the efficacy of a novel concurrent disorders program for youth while further providing an overview of clinical and relevant demographic characteristics from an underanalyzed patient population.

Evidence of factors influencing delays in the diagnosis and treatment of bipolar disorder in adolescents and young adults. Protocol for a systematic scoping review.

BACKGROUND: Bipolar Disorder (BD) is a complex psychiatric condition that typically manifests during late adolescence and early adulthood. Over the past two decades, international studies have reported that BD often goes unrecognized and untreated for several years, which can lead to negative clinical and functional outcomes. However, the components of delay in the diagnosis and treatment of BD and various factors influencing those components have not been systematically explored. OBJECTIVES: The scoping review described in this protocol aims to map the existing literature on potential factors that influence delays in the treatment of BD in adolescents and young adults, in order to identify the knowledge gaps and future research and policy priorities. METHODS: This protocol for a systematic scoping review will be reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline (PRISMA-ScR). We will search the electronic databases of MEDLINE (OVID), EMBASE, PsycINFO and CINAHL for peer-reviewed primary research articles published in academic journals. Grey literature will not be explored due to resource limitations. A conceptual framework based on the Model of Pathways to Treatment by Scott and colleagues was used as a foundation for our search and extraction strategy to ensure all components of delay and potential factors influencing each component are explored. Two independent reviewers will screen the references retrieved by the literature search and select relevant studies based on our inclusion criteria. The data from included studies will be synthesized into a narrative summary, and implications for future research, practice and policy will be discussed. DISCUSSION: To the best of our knowledge, this will be the first scoping review to explore the potential factors that influence delays in the treatment of BD in adolescents and young adults. We intend to disseminate the review results through academic conferences and publication in a peer-reviewed journal.

The CANMAT and ISBD Guidelines for the Treatment of Bipolar Disorder: Summary and a 2023 Update of Evidence.

Bipolar disorder is a complex and heterogeneous psychiatric condition that affects more than 2% of the population. The assessment and treatment of bipolar disorder can be a challenge for clinicians, given its clinical complexity and the rapidly changing treatment landscape with the growing range of treatment options that are becoming available for various phases of the illness. To help clinicians navigate the complexity involved in the assessment and management of bipolar disorder, the guidelines of the 2018 Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) synthesized the evidence on the efficacy, safety, and tolerability of treatments for bipolar disorder and translated it into first-, second-, and third-line treatment recommendations. The main objective of this contribution is to provide clinicians with a summary of the 2018 CANMAT/ISBD guideline recommendations with the addition of any new evidence for the treatment of bipolar disorder across the lifespan.

New Pharmacologic Approaches to the Treatment of Bipolar Depression.

Depression is the most commonly experienced mood state over the life span in individuals with bipolar disorder (BD) and is the primary driver of functional impairment and suicidality in BD. Despite this, there are few effective treatments for BD depression, with only a handful of atypical anti-psychotics and inconsistent evidence for traditional mood stabilizing agents. There have been few major 'breakthroughs' in the treatment of BD depression, and until recently, few agents that work via novel mechanisms of action to exert therapeutic effects. Here, we review treatments for BD depression which are emergent or on the horizon. Included are new atypical anti-psychotics, glutamate modulators (ketamine and cycloserine/lurasidone), neurosteroid modulators (zuranolone), anti-inflammatories and mitochondrial modulators, cannabidiol (CBD) and psilocybin. New atypical anti-psychotics lumateperone and cariprazine have demonstrated efficacy in large-scale, placebo-controlled, double-blind randomized controlled trials (RCT) in treatment of BD depression. Non-racemic amisulpride showed potential therapeutic benefit in one RCT which requires replication. Three small RCTs examined the efficacy of intravenous ketamine in BD depression and showed rapid antidepressant and anti-suicidal effects after a single infusion. Anti-inflammatory and mitochondrial modulators show inconsistent evidence for efficacy. There are currently no adequately powered RCTs of zuranolone, psilocybin or CBD in BD depression to support their use. While there are potentially efficacious, mechanistically novel agents on the horizon, they require further study and validation. Further investigation on how these agents may impact specific subgroups of patients will also advance the field.

Transitioning to bipolar disorder: A systematic review of prospective high-risk studies.

PURPOSE OF REVIEW: Bipolar disorder is a highly heritable condition, which can progress from an asymptomatic period in at-risk individuals to a potentially debilitating illness. Identifying individuals who are at a high risk of developing bipolar disorder may provide an opportunity for early intervention to improve outcomes. The main objective of this systematic review is to provide an overview of prospective studies that evaluated the incidence and predictors of transitioning to bipolar disorder among high-risk individuals. RECENT FINDINGS: Twenty-three publications from 16 cohorts were included in the final review. Most studies focused on familial high-risk groups, while others either used clinical or a combination of clinical and genetic risk factors. The follow-up length was from 1 to 21 years and the rate of conversion to bipolar disorder was between 8 and 25% among different studies. Overall, the results suggest that a combination of genetic and clinical risk factors; namely, subthreshold (hypo)manic symptoms and elevated depressive symptoms, may be required to optimally predict conversion to bipolar disorder. SUMMARY: The concept of high-risk for bipolar disorder is still in its infancy. Further discussions are needed to work towards an expert consensus on the high-risk criteria for bipolar disorder, taking into account both clinical and genetic risk factors.

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.