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Molecular Psychiatry Dec 2023While most of the efforts to uncover mechanisms contributing to bipolar disorder (BD) focused on phenotypes at the mature neuron stage, little research has considered...
While most of the efforts to uncover mechanisms contributing to bipolar disorder (BD) focused on phenotypes at the mature neuron stage, little research has considered events that may occur during earlier timepoints of neurodevelopment. Further, although aberrant calcium (Ca) signaling has been implicated in the etiology of this condition, the possible contribution of store-operated Ca entry (SOCE) is not well understood. Here, we report Ca and developmental dysregulations related to SOCE in BD patient induced pluripotent stem cell (iPSC)-derived neural progenitor cells (BD-NPCs) and cortical-like glutamatergic neurons. First, using a Ca re-addition assay we found that BD-NPCs and neurons had attenuated SOCE. Intrigued by this finding, we then performed RNA-sequencing and uncovered a unique transcriptome profile in BD-NPCs suggesting accelerated neurodifferentiation. Consistent with these results, we measured a slower rate of proliferation, increased neurite outgrowth, and decreased size in neurosphere formations with BD-NPCs. Also, we observed decreased subventricular areas in developing BD cerebral organoids. Finally, BD NPCs demonstrated high expression of the let-7 family while BD neurons had increased miR-34a, both being microRNAs previously implicated in neurodevelopmental deviations and BD etiology. In summary, we present evidence supporting an accelerated transition towards the neuronal stage in BD-NPCs that may be indicative of early pathophysiological features of the disorder.
Topics: Induced Pluripotent Stem Cells; Neural Stem Cells; Bipolar Disorder; Humans; Cell Differentiation; Calcium Signaling; Calcium; Neurons; Neurogenesis; Organoids; MicroRNAs; Male; Transcriptome; Female
PubMed: 37402854
DOI: 10.1038/s41380-023-02152-6 -
Frontiers in Neuroscience 2023Bipolar disorder (BD) is a chronic mental disorder characterized by recurrent episodes of mania and depression alternating with periods of euthymia. Although... (Review)
Review
Bipolar disorder (BD) is a chronic mental disorder characterized by recurrent episodes of mania and depression alternating with periods of euthymia. Although environmental and genetic factors have been described, their pathogenesis is not fully understood. Much evidence suggests a role for inflammatory mediators and immune dysregulation in the development of BD. The first-line treatment in BD are mood-stabilizing agents, one of which is lithium (Li) salts. The Li mechanism of action is not fully understood, but it has been proposed that its robust immunomodulatory properties might be one of the mechanisms responsible for its effectiveness. In this article, the authors present the current knowledge about immune system changes accompanying BD, as well as the immunomodulatory effect of lithium. The results of studies describing connections between immune system changes and lithium effectiveness are often incoherent. Further research is needed to understand the connection between immune system modulation and the therapeutic action of lithium in BD.
PubMed: 37662097
DOI: 10.3389/fnins.2023.1213766 -
JAMA Psychiatry Aug 2023The association of early diagnosis and management of bipolar disorder with adolescent suicide mortality (ASM) is unknown.
IMPORTANCE
The association of early diagnosis and management of bipolar disorder with adolescent suicide mortality (ASM) is unknown.
OBJECTIVE
To assess regional associations between ASM and bipolar disorder diagnosis frequencies.
DESIGN, SETTING, AND PARTICIPANTS
This cross-sectional study investigated the association between annual regional ASM and bipolar disorder diagnosis rates in Swedish adolescents aged 15 to 19 years in January 1, 2008, through December 31, 2021. Aggregated data without exclusions reported at the regional level encompassed 585 suicide deaths, constituting 588 unique observations (ie, 21 regions, 14 years, 2 sexes).
EXPOSURES
Bipolar disorder diagnosis frequencies and lithium dispensation rates were designated as fixed-effects variables (interaction term in the case of males). An interaction term between psychiatric care affiliation rates and the proportion of psychiatric visits to inpatient and outpatient clinics constituted independent fixed-effects variables. Region and year comprised random intercept effect modifiers. Variables were population adjusted and corrected for heterogeneity in reporting standards.
MAIN OUTCOMES AND MEASURES
The main outcomes were sex-stratified, regional, and annual ASM rates in adolescents aged 15 to 19 years per 100 000 inhabitants as analyzed using generalized linear mixed-effects models.
RESULTS
Female adolescents were diagnosed with bipolar disorder almost 3 times more often than male adolescents (mean [SD], 149.0 [19.6] vs 55.3 [6.1] per 100 000 inhabitants, respectively). Median regional prevalence rates of bipolar disorder varied over the national median by a factor of 0.46 to 2.61 and 0.00 to 1.82 in females and males, respectively. Bipolar disorder diagnosis rates were inversely associated with male ASM (β = -0.00429; SE, 0.002; 95% CI, -0.0081 to -0.0004; P = .03) independent of lithium treatment and psychiatric care affiliation rates. This association was replicated by β-binomial models of a dichotomized quartile 4 ASM variable (odds ratio, 0.630; 95% CI, 0.457-0.869; P = .005), and both models were robust after adjusting for annual regional diagnosis rates of major depressive disorder and schizophrenia. No such association was observed in females.
CONCLUSIONS AND RELEVANCE
In this cross-sectional study, lower suicide death rates in adolescent males was robustly associated with regional diagnosis rates of bipolar disorder at an estimated magnitude of approximately 4.7% of the mean national suicide death rate. The associations could be due to treatment efficacy, early diagnosis and management, or other factors not accounted for.
Topics: Humans; Male; Adolescent; Female; Bipolar Disorder; Sweden; Depressive Disorder, Major; Cross-Sectional Studies; Suicide; Lithium
PubMed: 37223908
DOI: 10.1001/jamapsychiatry.2023.1390 -
Cureus Oct 2023This conversation with ChatGPT explores the use of lithium in pregnancy for bipolar disorder, a topic of significant importance in psychiatry. Bipolar disorder is...
This conversation with ChatGPT explores the use of lithium in pregnancy for bipolar disorder, a topic of significant importance in psychiatry. Bipolar disorder is characterized by extreme mood swings, and its prevalence varies globally. ChatGPT provides valuable information on bipolar disorder, its prevalence, age of onset, and gender differences. It also discusses the use of lithium during pregnancy, emphasizing the need for individualized decisions, close monitoring, and potential risks and benefits. However, it is essential to note that ChatGPT's responses lack specific references, raising concerns about the reliability of the information provided. Further research is needed to quantify the correctness and dependability of ChatGPT-generated answers in the healthcare context.
PubMed: 37933339
DOI: 10.7759/cureus.46548 -
European Psychiatry : the Journal of... Aug 2023Affective disturbances in schizophrenia and bipolar disorder may represent a transdiagnostic etiological process as well as a target of intervention. Hypotheses on...
BACKGROUND
Affective disturbances in schizophrenia and bipolar disorder may represent a transdiagnostic etiological process as well as a target of intervention. Hypotheses on similarities and differences in various parameters of affective dynamics (intensity, successive/acute changes, variability, and reactivity to stress) between the two disorders were tested.
METHODS
Experience sampling method was used to assess dynamics of positive and negative affect, 10 times a day over 6 consecutive days. Patients with schizophrenia ( = 46) and patients with bipolar disorder ( = 46) were compared against age-matched healthy controls ( = 46).
RESULTS
Compared to controls, the schizophrenia group had significantly more intense momentary negative affect, a lower likelihood of acute changes in positive affect, and reduced within-person variability of positive affect. The bipolar disorder group was not significantly different from either the schizophrenia group or the healthy control group on any affect indexes. Within the schizophrenia group, level of depression was associated with weaker reactivity to stress for negative affect. Within the bipolar disorder group, level of depression was associated with lower positive affect.
CONCLUSIONS
Patients with schizophrenia endured a more stable and negative affective state than healthy individuals, and were less likely to be uplifted in response to happenings in daily life. There is little evidence that these affective constructs characterize the psychopathology of bipolar disorder; such investigation may have been limited by the heterogeneity within group. Our findings supported the clinical importance of assessing multiple facets of affective dynamics beyond the mean levels of intensity.
Topics: Humans; Schizophrenia; Bipolar Disorder; Emotions; Ecological Momentary Assessment; Patients
PubMed: 37544924
DOI: 10.1192/j.eurpsy.2023.2438 -
Pushing the Frontiers: Optogenetics for Illuminating the Neural Pathophysiology of Bipolar Disorder.International Journal of Biological... 2023Bipolar disorder (BD), a disabling mental disorder, is featured by the oscillation between episodes of depression and mania, along with disturbance in the biological... (Review)
Review
Bipolar disorder (BD), a disabling mental disorder, is featured by the oscillation between episodes of depression and mania, along with disturbance in the biological rhythms. It is on an urgent demand to identify the intricate mechanisms of BD pathophysiology. Based on the continuous progression of neural science techniques, the dysfunction of circuits in the central nervous system was currently thought to be tightly associated with BD development. Yet, challenge exists since it depends on techniques that can manipulate spatiotemporal dynamics of neuron activity. Notably, the emergence of optogenetics has empowered researchers with precise timing and local manipulation, providing a possible approach for deciphering the pathological underpinnings of mental disorders. Although the application of optogenetics in BD research remains preliminary due to the scarcity of valid animal models, this technique will advance the psychiatric research at neural circuit level. In this review, we summarized the crucial aberrant brain activity and function pertaining to emotion and rhythm abnormities, thereby elucidating the underlying neural substrates of BD, and highlighted the importance of optogenetics in the pursuit of BD research.
Topics: Animals; Humans; Bipolar Disorder; Optogenetics; Central Nervous System
PubMed: 37781027
DOI: 10.7150/ijbs.84923 -
Journal of Affective Disorders Nov 2023Bipolar disorder (BD) is a severe psychiatric illness with an increasing prevalence worldwide. Although the pathological mechanism of and pharmacological interventions... (Review)
Review
Bipolar disorder (BD) is a severe psychiatric illness with an increasing prevalence worldwide. Although the pathological mechanism of and pharmacological interventions for BD have been extensively investigated in preclinical and clinical studies, a scientometric analysis of the developmental trends, interdisciplinary frontiers, and research hotspots in this field has not yet been conducted. Therefore, we performed a comprehensive scientometric review of 55,358 published studies on BD over the past two decades (2002-2021) to identify the most frequently used keywords and explore research hotspots and trajectories. The present findings revealed the main distribution, knowledge structure, topic evolution, and emerging topics of BD research. Analysing the risk factors, pathogenesis, key brain regions, comorbid conditions, and treatment strategies for BD contributed to understanding of the aetiology, progression, and treatment of this disorder. These findings provided substantial support for continued research in this area.
Topics: Humans; Bipolar Disorder; Risk Factors
PubMed: 37595897
DOI: 10.1016/j.jad.2023.08.069 -
Biological Psychiatry Jan 2024Whereas genetic variants influencing total amygdala volume have been identified, the genetic architecture of its distinct nuclei has yet to be explored. We aimed to...
BACKGROUND
Whereas genetic variants influencing total amygdala volume have been identified, the genetic architecture of its distinct nuclei has yet to be explored. We aimed to investigate whether increased phenotypic specificity through nuclei segmentation aids genetic discoverability and elucidates the extent of shared genetic architecture and biological pathways with related disorders.
METHODS
T1-weighted brain magnetic resonance imaging scans (N = 36,352, 52% female) from the UK Biobank were segmented into 9 amygdala nuclei with FreeSurfer (version 6.1). Genome-wide association analyses were performed on the entire sample, a European-only subset (n = 31,690), and a generalization (transancestry) subset (n = 4662). We estimated single nucleotide polymorphism-based heritability; derived polygenicity, discoverability, and power estimates; and investigated genetic correlations and shared loci with psychiatric disorders.
RESULTS
The heritability of the nuclei ranged from 0.17 to 0.33. Across the whole amygdala and the nuclei volumes, we identified 28 novel genome-wide significant (p < 5 × 10) loci in the European analysis, with significant en masse replication for the whole amygdala and central nucleus volumes in the generalization analysis, and we identified 10 additional candidate loci in the combined analysis. The central nucleus had the highest statistical power for discovery. The significantly associated genes and pathways showed unique and shared effects across the nuclei, including immune-related pathways. Shared variants were identified between specific nuclei and autism spectrum disorder, Alzheimer's disease, Parkinson's disease, bipolar disorder, and schizophrenia.
CONCLUSIONS
Through investigation of amygdala nuclei volumes, we have identified novel candidate loci in the neurobiology of amygdala volume. These nuclei volumes have unique associations with biological pathways and genetic overlap with psychiatric disorders.
Topics: Humans; Female; Male; Genome-Wide Association Study; Autism Spectrum Disorder; Brain; Bipolar Disorder; Amygdala; Genetic Predisposition to Disease; Genetic Loci; Polymorphism, Single Nucleotide
PubMed: 37391117
DOI: 10.1016/j.biopsych.2023.06.022 -
Journal of Affective Disorders Nov 2023It remains unclear how adverse childhood experiences (ACE) and increased genetic risk for bipolar disorder (BD) interact to influence BD symptom outcomes. Here we...
BACKGROUND
It remains unclear how adverse childhood experiences (ACE) and increased genetic risk for bipolar disorder (BD) interact to influence BD symptom outcomes. Here we calculated multiple psychiatric polygenic risk scores (PRS) and used the measures of ACE to understand these gene-environment interactions.
METHOD
885 BD subjects were included for analyses. BD, ADHD, MDD and SCZ PRSs were calculated using the PRS-CS-auto method. ACEs were evaluated using the Children Life Event Questionnaire (CLEQ). Participants were divided into groups based on the presence of ACE and the total number of ACEs. The associations between total ACE number, PRSs and their interactions were evaluated using multiple linear and logistic regressions. Secondary analyses were performed to evaluate the influence of ACE and PRS on sub-phenotypes of BD.
RESULTS
The number of ACEs increased with the ADHD PRS. BD participants who had ACEs showed an earlier age of BD onset and higher odds of having rapid cycling. Increased BD PRS was associated with increased odds of developing psychotic symptoms. Higher ADHD PRS was associated with increased odds of having rapid cycling. No prediction effect was observed from MDD and SCZ PRS. And, we found no significant interaction between ACE numbers and any of the PRSs in predicting any selected BD sub-phenotypes.
LIMITATIONS
The study was limited by sample size, ACE definition, and cross-sectional data collection method.
CONCLUSIONS
The findings consolidate the importance of considering multiple psychiatric PRSs in predicting symptom outcomes among BD patients.
Topics: Child; Humans; Bipolar Disorder; Adverse Childhood Experiences; Cross-Sectional Studies; Risk Factors; Gene-Environment Interaction
PubMed: 37643680
DOI: 10.1016/j.jad.2023.08.116 -
Psychological Medicine Aug 2023There is significant heterogeneity in cognitive function in patients with bipolar I disorder (BDI); however, there is a dearth of research into biological mechanisms...
BACKGROUND
There is significant heterogeneity in cognitive function in patients with bipolar I disorder (BDI); however, there is a dearth of research into biological mechanisms that might underlie cognitive heterogeneity, especially at disease onset. To this end, this study investigated the association between accelerated or delayed age-related brain structural changes and cognition in early-stage BDI.
METHODS
First episode patients with BDI ( = 80) underwent cognitive assessment to yield demographically normed composite global and domain-specific scores in verbal memory, non-verbal memory, working memory, processing speed, attention, and executive functioning. Structural magnetic resonance imaging data were also collected from all participants and subjected to machine learning to compute the brain-predicted age difference (brainPAD), calculated by subtracting chronological age from age predicted by neuroimaging data (positive brainPAD values indicating age-related acceleration in brain structural changes and negative values indicating delay). Patients were divided into tertiles based on brainPAD values, and cognitive performance compared amongst tertiles with ANCOVA.
RESULTS
Patients in the lowest (delayed) tertile of brainPAD values (brainPAD range -17.9 to -6.5 years) had significantly lower global cognitive scores ( = 0.025) compared to patients in the age-congruent tertile (brainPAD range -5.3 to 2.4 yrs), and significantly lower verbal memory scores ( = 0.001) compared to the age-congruent and accelerated (brainPAD range 2.8 to 16.1 yrs) tertiles.
CONCLUSION
These results provide evidence linking cognitive dysfunction in the early stage of BDI to apparent delay in typical age-related brain changes. Further studies are required to assess how age-related brain changes and cognitive functioning evolve over time.
Topics: Humans; Child, Preschool; Child; Adolescent; Bipolar Disorder; Neuropsychological Tests; Cognition; Brain; Executive Function; Memory, Short-Term
PubMed: 35875930
DOI: 10.1017/S0033291722002136