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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Cariprazine in the Treatment of Bipolar Disorder: Within and Beyond Clinical Trials.

Bipolar disorder (BD) is chronic psychiatric disorder associated with significant impairment in psychosocial functioning and quality of life. Although current pharmacological treatments for BD have improved its clinical management, many patients do not achieve remission, particularly those suffering from bipolar depression. In addition, available treatments are associated with a myriad of potential adverse effects, which highlights the need for novel therapeutic agents that can be effective for both phases of the illness with a reduced side effect burden. Cariprazine is a novel antipsychotic that is a dopamine D2/D3 partial agonist with a preference for D3 receptors. In this review, we examine the pharmacological properties, clinical efficacy and tolerability profile of cariprazine in patients with BD, taking into account the latest clinical trials data. We also review post hoc analyses addressing clinically relevant subgroups and symptom domains in BD. Current evidence suggests efficacy for cariprazine 3-12 mg/day in the treatment of acute manic and mixed episodes; for bipolar depression, the efficacy of cariprazine appears to be dose-related, with doses of 1.5-3 mg/day beneficial as monotherapy. Cariprazine is overall well-tolerated by patients in both manic and depressive episodes. Its most common side effects relative to placebo include akathisia, extrapyramidal symptoms and nausea. There are no metabolic concerns reported with cariprazine use. In summary, the latest evidence suggests that cariprazine is an effective and safe treatment option for BD.

Longitudinal grey matter changes following first episode mania in bipolar I disorder: A systematic review.

BACKGROUND: While widespread grey matter (GM) changes are seen in bipolar I disorder (BD-I), it is unclear how early in the illness such changes emerge. To date there has been little synthesis of findings regarding longitudinal grey matter changes early in the course of BD-I. We conducted a systematic review to examine the evolution of GM changes in BD-I patients following the first episode of mania (FEM). METHODS: Following PRISMA guidelines, we conducted a systematic review of studies examining longitudinal changes in GM volume (GMV), cortical thickness and/or surface area in BD-I patients following FEM. We qualitatively synthesized results regarding longitudinal GM changes in BD-I patients. RESULTS: Fifteen studies met inclusion criteria, all examining GMV changes. Longitudinal ACC volume decrease following FEM was the most replicated finding, but was only reported in 4 out of 7 studies that examined this region as part of a whole brain/region of interest analysis, with 2 of these positive studies using an overlapping patient sample. The impact of episode recurrence, medications, and other clinical factors was inconsistently examined. LIMITATIONS: The literature regarding GM changes early in BD-I is highly inconsistent, likely due to heterogeneity in participant characteristics, imaging methodology/analysis and duration of follow up. CONCLUSIONS: Though there was some suggestion that structural ACC changes may represent a marker for neuroprogression following FEM, results were too inconsistent to draw any conclusions. Larger longitudinal studies examining cortical thickness/surface area, and the influence of relevant clinical factors, are needed to better understand neuroprogression in early BD-I.

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.

Efficacy of Active vs Sham Intermittent Theta Burst Transcranial Magnetic Stimulation for Patients With Bipolar Depression: A Randomized Clinical Trial.

Importance: Major depressive episodes in bipolar disorder are common and debilitating. Repetitive transcranial magnetic stimulation is well established in the treatment of major depressive disorder, and the intermittent theta burst stimulation (iTBS) protocol is replacing conventional protocols because of noninferiority and reduced delivery time. However, iTBS has not been adequately studied in bipolar disorder and, therefore, its efficacy is uncertain. Objective: To determine whether iTBS to the left dorsolateral prefrontal cortex (LDLPFC) is safe and efficacious in the treatment of acute bipolar depression. Design, Setting, and Participants: This study was a double-blind, 4-week, randomized clinical trial of iTBS targeting the LDLPFC. Two Canadian academic centers recruited patients between 2016 and 2020. Adults with bipolar disorder type I or type II experiencing an acute major depressive episode were eligible if they had not benefited from a first-line treatment for acute bipolar depression recommended by the Canadian Network for Mood and Anxiety Treatments and were currently treated with a mood stabilizer, an atypical antipsychotic, or their combination. Seventy-one participants were assessed for eligibility, and 37 were randomized to daily sham iTBS or active iTBS using a random number sequence, stratified according to current pharmacotherapy. Data analysis was performed from April to September 2020. Interventions: Four weeks of daily active iTBS (120% resting motor threshold) or sham iTBS to the LDLPFC. Nonresponders were eligible for 4 weeks of open-label iTBS. Main Outcomes and Measures: The primary outcome was the change in score on the Montgomery-Asberg Depression Rating Scale from baseline to study end. Secondary outcomes included clinical response, remission, and treatment-emergent mania or hypomania. Results: The trial was terminated for futility after 37 participants (23 women [62%]; mean [SD] age, 43.86 [13.87] years; age range, 20-68 years) were randomized, 19 to sham iTBS and 18 to active iTBS. There were no significant differences in Montgomery-Asberg Depression Rating Scale score changes (least squares mean difference between groups, -1.36 [95% CI, -8.92 to 6.19; P = .91] in favor of sham iTBS), and rates of clinical response were low in both the double-blind phase (3 of 19 participants [15.8%] in the sham iTBS group and 3 of 18 participants [16.7%] in the active iTBS group) and open-label phase (5 of 21 participants [23.8%]). One active iTBS participant had a treatment emergent hypomania, and a second episode occurred during open-label treatment. Conclusions and Relevance: iTBS targeting the LDLPFC is not efficacious in the treatment of acute bipolar depression in patients receiving antimanic or mood stabilizing agents. Additional research is required to understand how transcranial magnetic stimulation treatment protocols differ in efficacy between unipolar and bipolar depression. Trial Registration: ClinicalTrials.gov Identifier: NCT02749006.

Neurocognitive functioning in bipolar disorder: What we know and what we don't.

Introduction: This narrative review of systematic reviews and meta-analyses aims at compiling available evidence in various aspects of neurocognitive functioning in Bipolar Disorder (BD). Methods: We conducted a MEDLINE literature search and identified 38 relevant systematic reviews and metaanalyses. Results: Current evidence suggests that BD is associated with cognitive impairment across multiple domains and during all clinical states. However, there is a considerable cognitive heterogeneity within BD, which cannot be explained by clinical subtypes, and the pattern of neurocognitive impairment in BD overlaps with other psychiatric conditions such as major depression and schizophrenia. Residual depressive symptoms, poor clinical course and higher number of manic episodes may negatively impact cognitive performance, which is a major predictor of general functioning in BD. Evidence from available prospective studies does not support the notion of progressive cognitive decline in BD while some evidence exists to suggest patients may show some improvements in cognitive functioning following the first manic episode. Furthermore, a subset of patients may show premorbid cognitive abnormalities that could signal an early neurodevelopmental aetiology. Preliminary findings from small studies identify potential pro-cognitive effects of Cognitive Remediation, erythropoietin, intranasal insulin, lurasidone, mifepristone, repetitive Transcranial Magnetic Stimulation and transcranial Direct Current Stimulation in BD. Discussion: Longitudinal studies in high-risk individuals can provide a better understanding of the development and progression of neurocognitive impairment in BD. Largescale randomised control trials are needed to compare the pro-cognitive efficacy of various pharmacological and non-pharmacological interventions in different cognitive subgroups of patients at different stages of BD.

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.

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.