Early Stages Of Bipolar Disorder Research Articles

Subfield-specific longitudinal changes of hippocampal volumes in patients with early-stage bipolar disorder.

The hippocampus is a heterogeneous structure composed of biologically and functionally distinct subfields. Hippocampal aberrations are proposed to play a fundamental role in the etiology of psychotic symptoms. Bipolar disorder (BPD) has substantial overlap in symptomatology and genetic liability with schizophrenia (SZ), and reduced hippocampal volumes, particularly at the chronic illness stages, are documented in both disorders. Studies of hippocampal subfields in the early stage of BPD are limited and cross-sectional findings to date report no reduction in hippocampal volumes. To our knowledge, there have been no longitudinal studies of BPD evaluating hippocampal volumes in the early phase of illness. We investigated the longitudinal changes in hippocampal regions and subfields in BPD mainly and in early stage of psychosis (ESP) patients more broadly and compared them to those in controls (HC). Baseline clinical and structural MRI data were acquired from 88 BPD, from a total of 143 ESP patients, and 74 HCs. Of those, 66 participants (23 HC, 43 patients) completed a 12-month follow-up visit. The hippocampus regions and subfields were segmented using Freesurfer automated pipeline. We found general baseline deficits in hippocampal volumes among BPD and ESP cohorts. Both cohorts displayed significant increases in the anterior hippocampal region and dentate gyrus compared with controls. Additionally, antipsychotic medications were positively correlated with the posterior region at baseline. These findings highlight brain plasticity in BPD and in ESP patients providing evidence that deviations in hippocampal volumes are adaptive responses to atypical signaling rather than progressive degeneration.

Resting-state Fronto-limbic Connectivity in Unipolar Depressive Patients as a Predictor for Sporadic Conversion to (Hypo)mania

IntroductionPatients with a bipolar disorder (BD) may experience one or several episodes of major depression before transitioning into a manic phase. Given that treatment with common antidepressants may exacerbate symptoms of mania in patients with BD, initial diagnosis of major depressive disorder (MDD) is a significant issue affecting BD patients. Currently, a family history of BD is used as an early identifier for BD, but as genetic factors associated with BD confer susceptibility to a wide range of psychiatric illnesses, this approach lacks specificity. Thus, there is a pressing need for a biomarker which specifically predicts development of bipolar symptoms in patients with MDD, rather than a trait vulnerability to psychiatric disorderObjectives The aim of this study is to assess alterations in fronto-limbic function that exist prior to the manifestation of the first manic episode in BD patients without familial predisposition for BD.MethodsTo identify a biomarker for conversion to BD we performed a study in a naturalistic sample of MDD patients without a familial risk for BD, which were followed for 9 years. We used a seed-based functional connectivity analysis to assess differences in resting-state fronto-limbic connectivity between MDD patients who converted to BD during the follow-up period (n = 11), and non-converting MDD patients (n = 56).ResultsClusters of significantly reduced functional connectivity were found in the fronto-limbic network of prospective converters relative to non-converters.ConclusionsFindings suggest that alterations of fronto-limbic functional connectivity during episodes of depression predate and associate with conversion to BD later in life, in the absence of familial risk. These fronto-limbic functional connectivity disturbances may be of interest for diagnosing early-stage BD, and may offer insight in the mechanisms that drive conversion in the absence of familial predisposition. Findings from this study need to be verified through large-scale longitudinal imaging studies in naturalistic cohorts of MDD patients.Disclosure of InterestNone Declared

Association of total peripheral inflammation with lower frontal and temporal lobe volumes in early-stage bipolar disorder: A proof-of-concept study

BackgroundWe previously reported that in early-stage bipolar disorder (BD), frontal and temporal lobe volume reductions were more pronounced in patients with elevated BMI and more rapidly progressive in patients with additional weight gain. Elevated BMI is a pro-inflammatory state, and inflammation may contribute to brain volume reductions in BD. However, few studies have investigated the relationship between inflammation and brain volumes. MethodsWe conducted a proof-of-concept analysis to investigate whether a composite measure of total peripheral inflammation derived from 9 cytokines predicted lower frontal and temporal lobe volumes, measured with 3 T MRI, in early-stage BD. ResultsIn 25 early-stage patients, linear regression models showed that greater total inflammation predicted lower white matter (WM) volumes in the left frontal lobe (β = −0.691, p = 0.001) and bilateral temporal lobes (left: β = −0.617, p = 0.003; right: β = −0.636, p = 0.001). Greater inflammation also predicted lower right frontal WM, although this did not survive correction for multiple comparisons (β = −0.557, p = 0.020). It did not predict frontal or temporal GM. Total inflammation was a stronger predictor of lower WM volumes than were individual cytokines. LimitationsAlthough the magnitude of the association between total inflammation and lower WM volumes was large, our sample was small. Our findings require confirmation in further studies, with samples large enough to determine whether inflammation mediates the relationship between elevated BMI and brain volumes. ConclusionsThis study supports the hypothesis that inflammation contributes to brain volume reductions in BD and suggests that total inflammatory burden best captures the impact of inflammation on the brain.

Integrity of cerebellar tracts associated with the risk of bipolar disorder

This study examined the structural brain differences across individuals of different BD stages and the risks of developing bipolar disorder (BD) associated with these brain differences. A total of 221 participants who were recruited from the Guangzhou Brain Hospital and the community were categorized into four groups: NC (healthy control) (N = 77), high risk (HR) (N = 42), ultra-high risk (UHR) (N = 38), and bipolar disorder (BD) (N = 64) based on a list of criteria. Their demographics, clinical characteristics, and diffusion magnetic resonance imaging (dMRI) data were collected. ANCOVA results showed that the HR group had significantly reduced mean diffusivity (MD) (p = 0.043) and radial diffusivity (RD) (p = 0.039) of the left portico-ponto-cerebellar tracts when compared with the BD group. Moreover, logistic regression results showed that the specific diffusivity measures of cerebellar tracts (e.g., cortico-ponto-cerebellar tract), particularly the RD and MD revealed differences between groups at different BD stages after controlling for the covariates. The findings suggested that specific diffusivity (RD and MD) of cerebellar tracts (e.g., cortico-ponto-cerebellar tract) revealed differences between groups at different BD stages which is helpful in detecting the trajectory changes in BD syndromes in the early stages of BD, particularly when the BD syndromes start from HR stage.

Thyroid hormones disturbances, cognitive deficits and abnormal dynamic functional connectivity variability of the amygdala in unmedicated bipolar disorder

ObjectiveAccumulating evidence suggests that hypothalamus-pituitary-thyroid (HPT) axis dysfunction is relevant to the neuropsychological and pathophysiology functions of bipolar disorder (BD). However, no research has investigated the inter-relationships among thyroid hormones disturbance, neurocognitive deficits, and aberrant brain function (particularly in the amygdala) in patients with BD. Materials and methodsData of dynamic resting-state functional connectivity (rs-dFC) were gathered from 59 patients with unmedicated BD II during depressive episodes and 52 healthy controls (HCs). Four seeds were selected (the bilateral lateral amygdala and the bilateral medial amygdala). The sliding-window analysis was applied to investigate dynamic functional connectivity (dFC). Additionally, the serum thyroid hormone (free tri-iodothyronine (FT3), total tri-iodothyronine (TT3), free thyroxin (FT4), total thyroxin (TT4) and thyroid-stimulating hormone (TSH)) levels, and cognitive scores on the MATRICS Consensus Cognitive Battery (MCCB) in patients and HCs were detected. ResultsThe BD group exhibited increased dFC variability between the left medial amygdala and right medial prefrontal cortex (mPFC) when compared with the HC group. Additionally, the BD group showed lower FT3, TT3, and TSH level, higher FT4 level, and poorer cognitive score. Moreover, a significant negative correlation was observed between the dFC variability of the left medial amygdala-right mPFC and TSH level, or reasoning and problem solving of MCCB score in BD group. Multiple regression analysis showed that the TSH level × dFC variability of the medial amygdala-mPFC was an independent predictor for cognitive processing speed in BD group. ConclusionsThis study revealed patients with BD II depression had excessive variability in dFC between the medial amygdala and mPFC. Moreover, both HPT axis dysfunction and abnormal dFC of the amygdala-mPFC might be implicated in cognitive impairment in the early stages of BD.

Altered Risk-Taking Behavior in Early-Stage Bipolar Disorder With a History of Psychosis.

Altered risk-taking propensity is an important determinant of functional impairment in bipolar disorder. However, prior studies primarily assessed patients with chronic illness, and risk-taking has not been evaluated in the early illness course. This study investigated risk-taking behavior in 39 euthymic early-stage bipolar disorder patients aged 16–40 years who were treated within 3 years from their first-episode mania with psychotic features and 36 demographically-matched healthy controls using the Balloon Analog Risk Task (BART), a well-validated risk-taking performance-based paradigm requiring participants to make responses for cumulative gain at increasing risk of loss. Relationships of risk-taking indices with symptoms, self-reported impulsivity, cognitive functions, and treatment characteristics were also assessed. Our results showed that patients exhibited significantly lower adjusted scores (i.e., average balloon pumps in unexploded trials) (p = 0.001), lower explosion rate (p = 0.007) and lower cumulative scores (p = 0.003) than controls on BART, indicating their suboptimal risk-taking performance with increased propensity for risk aversion. Risk-taking indices were not correlated with any symptom dimensions, self-reported impulsivity, cognitive functions or antipsychotic dose. No significant difference was observed between patients with and without antipsychotic medications on self-reported impulsivity or any of the BART performance indices. This is the first study to examine risk-taking behavior in early-stage bipolar disorder with history of psychosis and indicates that patients displayed altered risk-taking with increased risk aversion compared with controls. Further research is needed to clarify longitudinal trajectory of risk-taking propensity and its relationships with psychosis and functional outcome in the early stage of bipolar disorder.

Prevalence and 5-year trend of incidence for medical illnesses after the diagnosis of bipolar disorder: A nationwide cohort study.

Medical comorbidities are prevalent in patients with bipolar disorder. Evaluating longitudinal trends of the incidence of medical illnesses enables implementation of early prevention strategies to reduce the high mortality rate in this at-risk population. However, the incidence risks of medical illnesses in the early stages of bipolar disorder remain unclear. This study investigated the incidence and 5-year trend of medical illnesses following bipolar disorder diagnosis. We identified 11,884 patients aged 13-40 years who were newly diagnosed as having bipolar disorder during 1996-2012 and 47,536 age- and sex-matched controls (1:4 ratio) who represented the general population from Taiwan's National Health Insurance Research Database. We estimated the prevalence and incidence of individual medical illnesses yearly across the first 5 years after the index date. The adjusted incidence rate ratio was calculated to compare the occurrence of specific medical illnesses each year between the bipolar disorder group and control group using the Poisson regression model. Apart from the prevalence, the adjusted incidence rate ratios of most medical illnesses were >1.00 across the first 5-year period after bipolar disorder diagnosis. Cerebrovascular diseases, ischaemic heart disease, congestive heart failure, other forms of heart disease, renal disease and human immunodeficiency virus infection exhibited the highest adjusted incidence rate ratios during the first year. Except for that of renal disease, the 5-year trends of the adjusted incidence rate ratios decreased for cerebrovascular diseases, cardiovascular diseases (e.g. ischaemic heart disease, other forms of heart disease, and vein and lymphatic disease), gastrointestinal diseases (e.g. chronic hepatic disease and ulcer disease) and communicable diseases (e.g. human immunodeficiency virus infection, upper respiratory tract infection and pneumonia). Incidence risks of medical illnesses are increased in the first year after bipolar disorder diagnosis. Clinicians must carefully evaluate medical illnesses during this period because the mortality rates from medical illnesses are particularly high in people with bipolar disorder.

Peripheral biomarkers to predict the diagnosis of bipolar disorder from major depressive disorder in adolescents.

The onset of bipolar disorder (BD) occurs in childhood or adolescence in half of the patients. Early stages of BD usually present depressive episodes, which makes it difficult to be distinguished from major depressive disorder (MDD). Objective biomarkers for discriminating BD from MDD in adolescent patients are limited. We collected basic demographic data and the information of the first blood examination performed after the admission to psychiatry unit of BD and MDD inpatients during 2009-2018. We recruited 261 adolescents (aged from 10 to 18), including 160 MDD and 101 BD. Forward-Stepwise Selection of binary logistic regression was used to construct predictive models for the total sample and subgroups by gender. Independent external validation was made by 255 matched patients from another hospital in China. Regression models of total adolescents, male and female subgroups showed accuracy of 73.3%, 70.6% and 75.2%, with area under curves (AUC) as 0.785, 0.816 and 0.793, respectively. Age, direct bilirubin (DBIL), lactic dehydrogenase (LDH), free triiodothyronine (FT3) and C-reactive protein (CRP) were final factors included into the models. The discrimination was well at external validation (AUC = 0.714). This study offers the evidence that accessible information of common clinical laboratory examination might be valuable in distinguishing BD form MDD in adolescents. With good diagnostic accuracies and external validation, the total regression equation might potentially be applied to individualized clinical inferences on adolescent BD patients.

Détection et intervention précoce auprès des jeunes avec trouble bipolaire émergent : où en sommes-nous ?

Bipolar disorder (BD) is one of the most disabling chronic illness for which the delay in diagnosis and access to adequate care is about 10 years, with many consequences such as numerous comorbidities, greater illness severity and resistance to treatments. Building on advances in early intervention in psychosis, optimizing the detection of patients with BD and intervening early is essential to improve their prognosis. Identifying risk factors for BD would allow earlier detection of the target population with the aims of: (1) preventing the development of the disease, (2) delaying its onset and (3) improving the course through more timely treatment. We conducted a narrative review of the literature of the past 30 years on risk factors of BD and synthetising the concepts of at-risk of BD mental state, the staging model and associated interventions. These concepts are illustrated by a clinical case with and without early intervention highlighting the challenges of early intervention in BD and the scientific data currently available of use to the clinician (both general practitioners and psychiatrist). In addition to genetic and environmental risk factors (early trauma, substance use, etc.), vulnerability markers (cyclothymic or hyperthymic temperament, cluster B personality disorder) can guide the clinician towards the detection of at risk of BD mental state syndrome consisting of attenuated symptoms of hypomania, mood lability, early depressive episode with psychotic, severe or atypical characteristics. The delay in access to care attributable to the absence of “help-seeking”, to self-stigmatization, or to unrecognized diagnoses (misdiagnosis with personality disorders or substance use disorders) weighs down the prognosis leading, as episodes cumulate over time, to incomplete remission of episodes with residual symptoms and significant functional decline. The use of validated tools and careful coordination of the various actors are assets for the early identification of subjects at-risk of transition to BD. Following the staging model, targeted primary prevention interventions (e.g., promotion of good sleep hygiene, stress management strategies) for at-risk individuals should be offered by general practitioner or other front-line mental health professionals (e.g., psychologist, nurse); early secondary prevention (for stage 1) should be provided by general psychiatric or general medicine services. Although no official guidelines for early intervention for BD are available yet, experts opinions are multiplying and supporting an integrated approach that maximizes young patient engagement. These integrated approaches aiming at symptomatic and functional improvement combine effective psychopharmacology and psychosocial interventions, including cognitive- behavioral therapy, approaches based on social rhythm, psychoeducation, relapse prevention, social and vocational recovery and family interventions. The scarcity of studies on the early stages of bipolar disorder limits the predictive value of risk factors and at-risk syndromes which remain to be validated. Prospective controlled studies are warranted to improve the prevention efforts and effective early treatment of bipolar disorder.

Mitochondrial Alterations in Fibroblasts of Early Stage Bipolar Disorder Patients.

This study aims to evaluate whether mitochondrial changes occur in the early stages of bipolar disorder (BD). Using fibroblasts derived from BD patients and matched controls, the levels of proteins involved in mitochondrial biogenesis and dynamics (fission and fusion) were evaluated by Western Blot analysis. Mitochondrial membrane potential (MMP) was studied using the fluorescent probe TMRE. Mitochondrial morphology was analyzed with the probe Mitotracker Green and mitophagy was evaluated by quantifying the co-localization of HSP60 (mitochondria marker) and LC3B (autophagosome marker) by immunofluorescence. Furthermore, the activity of the mitochondrial respiratory chain and the glycolytic capacity of controls and BD patients-derived cells were also studied using the Seahorse technology. BD patient-derived fibroblasts exhibit fragmented mitochondria concomitantly with changes in mitochondrial dynamics and biogenesis in comparison with controls. Moreover, a decrease in the MMP and increased mitophagy was observed in fibroblasts obtained from BD patients when compared with control cells. Impaired energetic metabolism due to inhibition of the mitochondrial electron transport chain (ETC) and subsequent ATP depletion, associated with glycolysis stimulation, was also a feature of BD fibroblasts. Overall, these results support the fact that mitochondrial disturbance is an early event implicated in BD pathophysiology that might trigger neuronal changes and modification of brain circuitry.

Adjuvant psychotherapy in early-stage bipolar disorder: A protocol for systematic review and meta-analysis.

Objective:There is no systematic review or meta-analysis to evaluate the efficacy of adjuvant psychotherapy in early-stage bipolar disorder. Therefore, the goal of this meta-analysis is to examine the evidence supporting psychotherapy as an efficacious approach to treating bipolar disorder.Methods:Seven electronic databases including Web of Science, Embase, PubMed, Wanfang Data, Scopus, Science Direct, Cochrane Library were searched in March 2021 by two independent reviewers. Data extraction was performed independently, and any conflict was resolved before final analysis. Only randomized clinical trials were included in this study. The trial entails 1 primary outcome measure (relapse) and several secondary outcome measures: time to relapse, relapse rate, days missed at work/school (record, interview), and social functioning level. The risk of bias assessment of the included studies was performed by 2 authors independently using the tool recommended in the Cochrane Handbook for Systematic Reviews of Interventions.Results:We hypothesized that combined psychotherapy and pharmacological interventions would be superior to pharmacological interventions alone regarding the time to relapse into a manic or depressive episode.Conclusion:This study expects to provide credible and scientific clinical evidence for the efficacy and safety of combined psychotherapy and pharmacological interventions in the treatment of bipolar disorder.OSF registration number:10.17605/OSF.IO/ZGS6W

Brain-derived neurotrophic factor levels in newly diagnosed patients with bipolar disorder, their unaffected first-degree relatives and healthy controls.

Brain-derived neurotrophic factor (BDNF), which facilitates neuroplasticity and synaptogenesis, may be decreased in bipolar disorder, but has not been systematically investigated in people with newly diagnosed bipolar disorder and unaffected first-degree relatives. To compare BDNF levels in patients with newly diagnosed bipolar disorder, their unaffected first-degree relatives and healthy controls. The study investigated plasma BDNF levels in patients (n = 371) with newly diagnosed bipolar disorder, their unaffected first-degree relatives (n = 98) and healthy controls (n = 200) using enzyme-linked immunosorbent assay. We further investigated associations between BDNF levels and illness-related variables and medication status. BDNF levels were found to be 22.0% (95% CI 1.107-1.343) higher in patients with bipolar disorder compared with healthy controls (P < 0.001) and 15.6% higher in unaffected first-degree relatives compared with healthy controls (95% CI 1.007-1.327, P = 0.04), when adjusting for age and gender. Further, BDNF levels were positively associated with duration of illness at a trend level (P = 0.05), age (P = 0.001) and use of anti-epileptic medication (P = 0.05). These findings suggest that BDNF levels are not decreased in the early stages of bipolar disorder and in unaffected first-degree relatives contrasting with prior findings during later stages of the illness.

Gene Expression of Inhibitory Receptors and Immune Regulatory Molecules in Polarized Macrophages Derived from Early- and Late-Stage BD Patients

Background: Bipolar disorder (BD) has been associated with increased levels of peripheral inflammatory mediators and neuroinflammation. Previously, we observed different immune responses in macrophages of BD patients at different stages of the disorder. Thus, we aimed to further evaluate the regulation of immune response in BD by quantifying the expression of immune checkpoint receptors and respective ligands, as well as molecules involved in regulation and transcription of inflammatory mediators in polarized macrophages of early and late stages individuals with BD. Methods: qRT-PCR was performed to analyze the expression of TLR1, TLR6, PD-1, NFKB1, PD-L1, PD-L2 and TIM-3 in samples of proinflammatory M1 or M(IFNγ+LPS) and anti-inflammatory M2 or M(IL-4) macrophages derived from peripheral blood mononuclear cells (PBMCs) of euthymic BD patients (n=16), classified as early-stage BD (BD-E, n=9) and late-stage BD (BD-L, n=7) - according to Functional Assessment Short Test (FAST) - and healthy controls (HC, n=10). Results: M(IL-4) from BD-E showed higher expression levels of NFKB1 and PD-L1 in comparison to HC (p<0.05), while BD-L only had higher expression levels of PD-L1 compared to HC (p<0.05). No statistical differences were found between groups for the expression levels of TLR1, PD-L2 and TIM-3 in M(IL-4) phenotype, while expression levels remained unchanged in M(IFNγ+LPS) for all markers. TLR6 and PD-1 did not show PCR amplification in both macrophage phenotypes. Conclusion: Our findings suggest an immunological regulation acting as a compensatory mechanism by M2 anti-inflammatory macrophages at an early stage of BD, although decreased regulation in these cells seems to be observed at late stages of the disorder. We hypothesize that such alterations are possibly due to chronic low-grade inflammation during the course of BD, resulting in the ‘exhaustion’ of macrophage response. However, further investigation is required to comprehend better the role of immune regulatory mechanisms in the disorder. Funding Information: This work was supported by the FIPE-HCPA (Project Number 150396) and National Council for Scientific and Technological Development (CNPq, Brazil; Project Number PQ 302382/2019-4); and BA is a scholarship recipient from CNPq, Brazil. Declaration of Interests: None to declare. Ethics Approval Statement: All participants provided written informed consent before their inclusion, and this study was approved by the Institutional Review Board of Hospital de Clinicas de Porto Alegre (HCPA, Project Number 150396).

Individualized identification of first-episode bipolar disorder using machine learning and cognitive tests

Identifying cognitive dysfunction in the early stages of Bipolar Disorder (BD) can allow for early intervention. Previous studies have shown a strong correlation between cognitive dysfunction and number of manic episodes. The objective of this study was to apply machine learning (ML) techniques on a battery of cognitive tests to identify first-episode BD patients (FE-BD). Two cohorts of participants were used for this study. Cohort #1 included 74 chronic BD patients (CHR-BD) and 53 healthy controls (HC), while the Cohort #2 included 37 FE-BD and 18 age- and sex-matched HC. Cognitive functioning was assessed using the Cambridge Neuropsychological Test Automated Battery (CANTAB). The tests examined domains of visual processing, spatial memory, attention and executive function. We trained an ML model to distinguish between chronic BD patients (CHR-BD) and HC at the individual level. We used linear Support Vector Machines (SVM) and were able to identify individual CHR-BD patients at 77% accuracy. We then applied the model to Cohort #2 (FE-BD patients) and achieved an accuracy of 76% (AUC=0.77). These results reveal that cognitive impairments may appear in early stages of BD and persist into later stages. This suggests that the same deficits may exist for both CHR-BD and FE-BD. These cognitive deficits may serve as markers for early BD. Our study provides a tool that these early markers can be used for detection of BD.

Adjuvant psychotherapy in early-stage bipolar disorder: study protocol for a randomized controlled trial

BackgroundBipolar disorders are serious illnesses with a chronic course and a high rate of relapse. Typically, bipolar disorders onset during adolescence or early adulthood, with patients experiencing significant personal and social costs as a consequence of their illness. Despite this, to date, there is limited (controlled) evidence regarding the effectiveness of psychotherapy during the critical stages of the disorder (e.g., early onset). Some preliminary studies suggest that targeted, tailored early interventions in particular may improve disease prognosis. The proposed study examines the effectiveness of group psychotherapy on relapse prevention, global adaptive functioning, and neuropsychological functioning in early-stage bipolar disorder.MethodsIn this multicenter randomized controlled trial (RCT), 300 patients with bipolar disorder are randomized to one of two group psychotherapies: Specific Emotional-Cognitive Therapy (SECT; intervention group) or Emotion-Focused Supportive Therapy (EFST; active control group). Each therapy comprises of a total of 48-h sessions (delivered once a month) over a period of 4 months. Assessments take place at baseline (t1); 6 months follow-up, i.e., post-intervention (t2); 12 months follow-up (t3); and 18 months follow-up (t4), whereby 18 months follow-up is the primary time point of interest.DiscussionThe goal of this study is to test the effects of an innovative, specific group therapy relative to an active control condition in terms of rates of relapse, global functioning, and neuropsychological functioning. Pending the outcomes of the trial, it will be possible to establish a firm evidence base for accessible group psychotherapy adjuvant to routine psychiatric care for individuals with bipolar disorder.Trial registrationUSA: ClinicalTrials.gov NCT02506322. Registered on 19 December 2014; Germany: German Clinical Trials Register DRKS00006013. Registered on21 May 2015

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

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). 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. 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. 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.

CCL11 levels in drug-naive bipolar patients: The role of sex and smoking status

• Changes in CCL11 levels may not be involved in the early stages of bipolar disorder. • Demographic and lifestyle factors may drive changes in CCL11 levels in young adults. • Tobacco use and male sex may be associated with higher CCL11 levels in young adults. It has been reported that patients with bipolar disorder (BD) present changes in peripheral levels of the inflammatory cytokine CCL11, particularly at latestages. The aim of this study is to evaluate CCL11 levels in a population-based sample of drug-naive young adults. This is a cross-sectional study nested to a large population-based study. 29 drug-naive young adults with BD and 29 controls selected from this cohort were matched for sex, age, and years of education. The diagnosis of psychiatric disorders was performed using the Mini International Neuropsychiatric Interview PLUS. Serum levels of CCL11 were measured using sandwich-ELISA. Independent samples T-test was used to assess differences between groups regarding CCL11 levels. Multivariate linear regression analyses were used to evaluate the effect of independent factors on CCL11 levels. There were no demographic differences between individuals with BD and controls. No significant differences were found regarding CCL11 levels between groups. The final multivariate model showed that the variables that remained independently associated with higher CCL11 levels were male sex (B:41.41 [CI95%: 15.66 - 67.15], p = 0.002) and tobacco use (B:22.71 [CI95%: 1.28 - 44.15], p = 0.038). The present study suggests that there is a possible influence of sex and tobacco use on CCL11 levels, as male sex and smoking status were associated with higher CCL11 levels in our sample. It also suggests that peripheral levels of CCL11 may not be involved in the pathophysiology of BD at early stages of the disorder.

Depression Preceding Diagnosis of Bipolar Disorder.

This paper focuses on depression that precedes an onset of manifest bipolar disorder as early stage bipolar disorder. First, we review how to pragmatically identify the clinical characteristics of patients presenting with an episode of depression who subsequently go on to develop episodes of mania or hypomania. The existing literature shows a strong consensus: accurate identification of depression with early onset and recurrent course with multiple episodes, subthreshold hypomanic and/or mixed symptoms, and family history of bipolar disorder or completed suicide have been shown by multiple authors as signs pointing to bipolar diagnosis. This contrasts with relatively limited information available to guide management of such “pre-bipolar” (pre-declared bipolar) patients, especially those in the adult age range. Default assumption of unipolar depression at this stage carries significant risk. Antidepressants are still the most common pharmacological treatment used, but clinicians need to be aware of their potential harm. In some patients with unrecognized bipolar depression, antidepressants can not only produce switch to (hypo)mania, but also mixed symptoms, or worsening of depression with an increased risk of suicide. We review pragmatic management strategies in the literature beyond clinical guidelines that can be considered for this at-risk group encompassing the more recent child and adolescent literature. In the future, genetic research could make the early identification of bipolar depression easier by generating informative markers and polygenic risk scores.

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.

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). 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. 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. 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.

T56. RISKY DECISION-MAKING IMPAIRMENT IN EARLY-STAGE PSYCHOTIC BIPOLAR DISORDER

BackgroundPrevious research suggests that bipolar disorder may be associated with increased risk-taking / impulsivity. Risky decision-making paradigm is an objective, performance-based measure which has been increasingly applied in bipolar disorder research examining. Nonetheless, literature focused only on chronically ill samples, with illness chronicity, clinical heterogeneity and prolonged medication exposure being potential confounding factors of study results. The current study aimed to explore whether patients with early-stage psychotic bipolar disorder (BDP) exhibit impaired risky decision-making relative to healthy controls, using a well-validated, widely-applied experimental paradigm of Balloon Analogue Risk Task (BART).MethodsThirty-nine patients with early-stage BDP (defined by having received psychiatric treatment for first-episode BDP within 3 years since service entry) and 36 demographically matched healthy controls were recruited. BART was administered to examine risky decision-making performance. Deliberative risky behavior was operationalized as the willingness to inflate balloons as each pump was accompanied by an extra point gained in the temporary repository or balloon explosion. Three performance-based indices (adjusted score, explosion rate and cumulative score) were derived and analyzed.ResultsThere were no significant differences between patients and controls in age, gender and educational levels. Independent samples t-tests illustrated that patients had significantly lower adjusted score (t = -3.45, p = .001, d = .791), explosion rate (t = -2.75, p = .007, d = .631) and cumulative score (t = -3.07, p = .003, d = .714) in BART compared to controls. Similar findings were obtained when comparison analyses were restricted to patients who were treated with antipsychotic medications at the time of study assessment (n = 30). No significant correlations between BART performance-based indices and measures of clinical and treatment variables were found in patient sample.DiscussionOur results demonstrated that early-stage BDP patients displayed suboptimal risky decision-making compared with controls. Abnormal risky decision-making observed in the euthymic state of patients in early stage of bipolar disorder suggests that such impairment might represent a trait factor in the disorder. Further prospective research is warranted to clarify the longitudinal course of risky decision-making impairment in bipolar disorder.