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Frontiers in Neuroscience 2023Bipolar disorder (BD) is characterized by extreme mood swings ranging from manic/hypomanic to depressive episodes. The severity, duration, and frequency of these... (Review)
Review
Bipolar disorder (BD) is characterized by extreme mood swings ranging from manic/hypomanic to depressive episodes. The severity, duration, and frequency of these episodes can vary widely between individuals, significantly impacting quality of life. Individuals with BD spend almost half their lives experiencing mood symptoms, especially depression, as well as associated clinical dimensions such as anhedonia, fatigue, suicidality, anxiety, and neurovegetative symptoms. Persistent mood symptoms have been associated with premature mortality, accelerated aging, and elevated prevalence of treatment-resistant depression. Recent efforts have expanded our understanding of the neurobiology of BD and the downstream targets that may help track clinical outcomes and drug development. However, as a polygenic disorder, the neurobiology of BD is complex and involves biological changes in several organelles and downstream targets (pre-, post-, and extra-synaptic), including mitochondrial dysfunction, oxidative stress, altered monoaminergic and glutamatergic systems, lower neurotrophic factor levels, and changes in immune-inflammatory systems. The field has thus moved toward identifying more precise neurobiological targets that, in turn, may help develop personalized approaches and more reliable biomarkers for treatment prediction. Diverse pharmacological and non-pharmacological approaches targeting neurobiological pathways other than neurotransmission have also been tested in mood disorders. This article reviews different neurobiological targets and pathophysiological findings in non-canonical pathways in BD that may offer opportunities to support drug development and identify new, clinically relevant biological mechanisms. These include: neuroinflammation; mitochondrial function; calcium channels; oxidative stress; the glycogen synthase kinase-3 (GSK3) pathway; protein kinase C (PKC); brain-derived neurotrophic factor (BDNF); histone deacetylase (HDAC); and the purinergic signaling pathway.
PubMed: 37592949
DOI: 10.3389/fnins.2023.1228455 -
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 -
Molecular Psychiatry Jul 2023The difference between chronological age and the apparent age of the brain estimated from brain imaging data-the brain age gap (BAG)-is widely considered a general...
The difference between chronological age and the apparent age of the brain estimated from brain imaging data-the brain age gap (BAG)-is widely considered a general indicator of brain health. Converging evidence supports that BAG is sensitive to an array of genetic and nongenetic traits and diseases, yet few studies have examined the genetic architecture and its corresponding causal relationships with common brain disorders. Here, we estimate BAG using state-of-the-art neural networks trained on brain scans from 53,542 individuals (age range 3-95 years). A genome-wide association analysis across 28,104 individuals (40-84 years) from the UK Biobank revealed eight independent genomic regions significantly associated with BAG (p < 5 × 10) implicating neurological, metabolic, and immunological pathways - among which seven are novel. No significant genetic correlations or causal relationships with BAG were found for Parkinson's disease, major depressive disorder, or schizophrenia, but two-sample Mendelian randomization indicated a causal influence of AD (p = 7.9 × 10) and bipolar disorder (p = 1.35 × 10) on BAG. These results emphasize the polygenic architecture of brain age and provide insights into the causal relationship between selected neurological and neuropsychiatric disorders and BAG.
Topics: Humans; Child, Preschool; Child; Adolescent; Young Adult; Adult; Middle Aged; Aged; Aged, 80 and over; Depressive Disorder, Major; Genome-Wide Association Study; Mental Disorders; Brain; Bipolar Disorder
PubMed: 37165155
DOI: 10.1038/s41380-023-02087-y -
Molecular Psychiatry Nov 2023According to the operational diagnostic criteria, psychiatric disorders such as schizophrenia (SZ), bipolar disorder (BD), major depressive disorder (MDD), and autism...
According to the operational diagnostic criteria, psychiatric disorders such as schizophrenia (SZ), bipolar disorder (BD), major depressive disorder (MDD), and autism spectrum disorder (ASD) are classified based on symptoms. While its cluster of symptoms defines each of these psychiatric disorders, there is also an overlap in symptoms between the disorders. We hypothesized that there are also similarities and differences in cortical structural neuroimaging features among these psychiatric disorders. T1-weighted magnetic resonance imaging scans were performed for 5,549 subjects recruited from 14 sites. Effect sizes were determined using a linear regression model within each protocol, and these effect sizes were meta-analyzed. The similarity of the differences in cortical thickness and surface area of each disorder group was calculated using cosine similarity, which was calculated from the effect sizes of each cortical regions. The thinnest cortex was found in SZ, followed by BD and MDD. The cosine similarity values between disorders were 0.943 for SZ and BD, 0.959 for SZ and MDD, and 0.943 for BD and MDD, which indicated that a common pattern of cortical thickness alterations was found among SZ, BD, and MDD. Additionally, a generally smaller cortical surface area was found in SZ and MDD than in BD, and the effect was larger in SZ. The cosine similarity values between disorders were 0.945 for SZ and MDD, 0.867 for SZ and ASD, and 0.811 for MDD and ASD, which indicated a common pattern of cortical surface area alterations among SZ, MDD, and ASD. Patterns of alterations in cortical thickness and surface area were revealed in the four major psychiatric disorders. To our knowledge, this is the first report of a cross-disorder analysis conducted on four major psychiatric disorders. Cross-disorder brain imaging research can help to advance our understanding of the pathogenesis of psychiatric disorders and common symptoms.
Topics: Humans; Depressive Disorder, Major; Autism Spectrum Disorder; Bipolar Disorder; Mental Disorders; Cerebral Cortex; Magnetic Resonance Imaging
PubMed: 37596354
DOI: 10.1038/s41380-023-02224-7 -
American Journal of Human Genetics Dec 2023We examined more than 97,000 families from four neurodevelopmental disease cohorts and the UK Biobank to identify phenotypic and genetic patterns in parents contributing...
We examined more than 97,000 families from four neurodevelopmental disease cohorts and the UK Biobank to identify phenotypic and genetic patterns in parents contributing to neurodevelopmental disease risk in children. We identified within- and cross-disorder correlations between six phenotypes in parents and children, such as obsessive-compulsive disorder (R = 0.32-0.38, p < 10). We also found that measures of sub-clinical autism features in parents are associated with several autism severity measures in children, including biparental mean Social Responsiveness Scale scores and proband Repetitive Behaviors Scale scores (regression coefficient = 0.14, p = 3.38 × 10). We further describe patterns of phenotypic similarity between spouses, where spouses show correlations for six neurological and psychiatric phenotypes, including a within-disorder correlation for depression (R = 0.24-0.68, p < 0.001) and a cross-disorder correlation between anxiety and bipolar disorder (R = 0.09-0.22, p < 10). Using a simulated population, we also found that assortative mating can lead to increases in disease liability over generations and the appearance of "genetic anticipation" in families carrying rare variants. We identified several families in a neurodevelopmental disease cohort where the proband inherited multiple rare variants in disease-associated genes from each of their affected parents. We further identified parental relatedness as a risk factor for neurodevelopmental disorders through its inverse relationship with variant pathogenicity and propose that parental relatedness modulates disease risk by increasing genome-wide homozygosity in children (R = 0.05-0.26, p < 0.05). Our results highlight the utility of assessing parent phenotypes and genotypes toward predicting features in children who carry rare variably expressive variants and implicate assortative mating as a risk factor for increased disease severity in these families.
Topics: Child; Humans; Virulence; Parents; Family; Autistic Disorder; Bipolar Disorder
PubMed: 37979581
DOI: 10.1016/j.ajhg.2023.10.015 -
Psychiatric Comorbidities and Schizophrenia in Youths With Attention-Deficit/Hyperactivity Disorder.JAMA Network Open Nov 2023The association between attention-deficit/hyperactivity disorder (ADHD) and schizophrenia has received increased attention; however, evidence on the association between...
IMPORTANCE
The association between attention-deficit/hyperactivity disorder (ADHD) and schizophrenia has received increased attention; however, evidence on the association between psychiatric comorbidities and subsequent schizophrenia in patients with ADHD is limited.
OBJECTIVE
To investigate the risk of being diagnosed with schizophrenia in children and adolescents with ADHD considering the presence of psychiatric comorbidity.
DESIGN, SETTING, AND PARTICIPANTS
This was a population-based, retrospective cohort study using the Health Insurance Review and Assessment claims database from January 1, 2007, to December 31, 2019. Participants were children and adolescents aged 5 to 19 years who received an ADHD diagnosis between January 1, 2010, and December 31, 2018, in the nationwide claims data of Korea. Data were analyzed from January 2010 to December 2019.
INTERVENTIONS OR EXPOSURES
The presence of psychiatric comorbidity was assessed from diagnosis records within 1 year before ADHD diagnosis. Comorbidities were further categorized according to the number of comorbidities and specific comorbid disorders.
MAIN OUTCOMES AND MEASURES
Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% CIs, examining the association between psychiatric comorbidities and the risk of being diagnosed with schizophrenia. Furthermore, the occurrence of psychiatric comorbidity during the follow-up period was explored among patients without psychiatric comorbidity at baseline.
RESULTS
A total of 211 705 patients with newly diagnosed ADHD were included. A total of 157 272 patients (74.3%) were male, and the age of 5 to 9 years showed the highest distribution (115 081 patients [54.4%]). Patients with psychiatric comorbidity had a significantly higher risk of being diagnosed with schizophrenia than those without (adjusted HR, 2.14; 95% CI, 2.05-2.23). The association between schizophrenia and psychiatric comorbidity became progressively greater with the increasing number of comorbidities. Several individual psychiatric disorders showed an association with development of schizophrenia, with ASD, intellectual disability, tic disorder, depression, and bipolar disorder being the top 5 disorders most associated. Furthermore, 3244 patients (73.8%) without psychiatric comorbidities experienced the emergence of other psychiatric disorders before schizophrenia occurrence.
CONCLUSIONS AND RELEVANCE
In this retrospective cohort study involving children and adolescents with ADHD, the presence of psychiatric comorbidity in patients with ADHD was associated with an increased risk of being diagnosed with schizophrenia, with an increased risk observed in multiple comorbidities and a wide variety of comorbidities. These findings highlight the significance of assessing and managing psychiatric comorbidities in patients with ADHD to decrease subsequent schizophrenia risk and allow for early intervention.
Topics: Child; Humans; Adolescent; Male; Female; Schizophrenia; Attention Deficit Disorder with Hyperactivity; Retrospective Studies; Comorbidity; Bipolar Disorder
PubMed: 38032637
DOI: 10.1001/jamanetworkopen.2023.45793 -
BMC Psychiatry Nov 2023The timings of reproductive life events have been examined to be associated with various psychiatric disorders. However, studies have not considered the causal pathways...
BACKGROUND
The timings of reproductive life events have been examined to be associated with various psychiatric disorders. However, studies have not considered the causal pathways from reproductive behaviors to different psychiatric disorders. This study aimed to investigate the nature of the relationships between five reproductive behaviors and twelve psychiatric disorders.
METHODS
Firstly, we calculated genetic correlations between reproductive factors and psychiatric disorders. Then two-sample Mendelian randomization (MR) was conducted to estimate the causal associations among five reproductive behaviors, and these reproductive behaviors on twelve psychiatric disorders, using genome-wide association study (GWAS) summary data from genetic consortia. Multivariable MR was then applied to evaluate the direct effect of reproductive behaviors on these psychiatric disorders whilst accounting for other reproductive factors at different life periods.
RESULTS
Univariable MR analyses provide evidence that age at menarche, age at first sexual intercourse and age at first birth have effects on one (depression), seven (anxiety disorder, ADHD, bipolar disorder, bipolar disorder II, depression, PTSD and schizophrenia) and three psychiatric disorders (ADHD, depression and PTSD) (based on p<7.14×10), respectively. However, after performing multivariable MR, only age at first sexual intercourse has direct effects on five psychiatric disorders (Depression, Attention deficit or hyperactivity disorder, Bipolar disorder, Posttraumatic stress disorder and schizophrenia) when accounting for other reproductive behaviors with significant effects in univariable analyses.
CONCLUSION
Our findings suggest that reproductive behaviors predominantly exert their detrimental effects on psychiatric disorders and age at first sexual intercourse has direct effects on psychiatric disorders.
Topics: Humans; Female; Genome-Wide Association Study; Mendelian Randomization Analysis; Bipolar Disorder; Schizophrenia; Attention Deficit Disorder with Hyperactivity
PubMed: 37915018
DOI: 10.1186/s12888-023-05203-y -
Psychiatry Research Sep 2023Bipolar disorder (BD) is a chronic and severe psychiatric disorder associated with significant medical morbidity and reduced life expectancy. In this study, we assessed...
Bipolar disorder (BD) is a chronic and severe psychiatric disorder associated with significant medical morbidity and reduced life expectancy. In this study, we assessed accelerated epigenetic aging in individuals with BD using various DNA methylation (DNAm)-based markers. For this purpose, we used five epigenetic clocks (Horvath, Hannum, EN, PhenoAge, and GrimAge) and a DNAm-based telomere length clock (DNAmTL). DNAm profiles were obtained using Infinium MethylationEPIC Arrays from whole-blood samples of 184 individuals with BD. We also estimated blood cell counts based on DNAm levels for adjustment. Significant correlations between chronological age and each epigenetic age estimated using the six different clocks were observed. Following adjustment for blood cell counts, we found that the six epigenetic AgeAccels (age accelerations) were significantly associated with the body mass index. GrimAge AgeAccel was significantly associated with male sex, smoking status and childhood maltreatment. DNAmTL AgeAccel was significantly associated with smoking status. Overall, this study showed that distinct epigenetic clocks are sensitive to different aspects of aging process in BD. Further investigations with comprehensive epigenetic clock analyses and large samples are required to confirm our findings of potential determinants of an accelerated epigenetic aging in BD.
Topics: Humans; Male; Bipolar Disorder; Epigenesis, Genetic; Aging; DNA Methylation; Smoking
PubMed: 37542794
DOI: 10.1016/j.psychres.2023.115373 -
Journal of Affective Disorders Oct 2023Cognitive deficits are a core feature of bipolar disorder (BD) that persist during the euthymic phase and affect global functioning. However, nowadays, there is no... (Review)
Review
BACKGROUND
Cognitive deficits are a core feature of bipolar disorder (BD) that persist during the euthymic phase and affect global functioning. However, nowadays, there is no consensus on the optimal tool to capture cognitive deficits in BD. Therefore, this review aims to examine the psychometric properties of tools commonly used to assess cognitive functioning in BD.
METHODS
Literature search was conducted on PubMed and Web of Science databases on August 1, 2022 and on April 20, 2023, yielding 1758 de-duplicated records. Thirteen studies fulfilled the inclusion criteria and were included in the review.
RESULTS
All tools examined showed acceptable-to-good psychometric properties suggesting that both brief cognitive screeners and comprehensive batteries may be appropriate for detecting or monitoring cognitive changes in BD.
LIMITATIONS
Methodological differences between the included studies precluded a direct comparison of the results. Further research is needed to investigate the psychometric properties of cognitive tools that assess also affective and social cognition.
CONCLUSIONS
The tools examined appear sensitive enough to distinguish between BD patients with versus without cognitive deficits, however, an optimal tool has not yet been identified. The applicability and clinical utility of the tools may depend on multiple factors such as available resources. That said, web-based instruments are expected to become the first-choice instrument for cognitive screening as they can be applied on a large scale and at an affordable cost. As for second-level assessment instruments, the BACA shows robust psychometric properties and tests both affective and non-affective cognition.
Topics: Humans; Bipolar Disorder; Psychometrics; Neuropsychological Tests; Cognition; Cognitive Dysfunction
PubMed: 37331381
DOI: 10.1016/j.jad.2023.06.026 -
Journal of Neural Transmission (Vienna,... Sep 2023Mood disorders such as major depressive disorder (MDD) and bipolar disorder (BD) are often resistant to current pharmacological treatment. Therefore, various alternative... (Review)
Review
Mood disorders such as major depressive disorder (MDD) and bipolar disorder (BD) are often resistant to current pharmacological treatment. Therefore, various alternative therapeutic approaches including diets are, therefore, under investigation. Ketogenic diet (KD) is effective for treatment-resistant epilepsy and metabolic diseases, however, only a few clinical studies suggest its beneficial effect also for mental disorders. Animal models are a useful tool to uncover the underlying mechanisms of therapeutic effects. Women have a twice-higher prevalence of mood disorders but very little is known about sex differences in nutritional psychiatry. In this review, we aim to summarize current knowledge of the sex-specific effects of KD in mood disorders. Ketone bodies improve mitochondrial functions and suppress oxidative stress, inducing neuroprotective and anti-inflammatory effects which are both beneficial for mental health. Limited data also suggest KD-induced improvement of monoaminergic circuits and hypothalamus-pituitary-adrenal axis-the key pathophysiological pathways of mood disorders. Gut microbiome is an important mediator of the beneficial and detrimental effects of diet on brain functioning and mental health. Gut microbiota composition is affected in mood disorders but its role in the therapeutic effects of different diets, including KD, remains poorly understood. Still little is known about sex differences in the effects of KD on mental health as well as on metabolism and body weight. Some animal studies used both sexes but did not find differences in behavior, body weight loss or gut microbiota composition. More studies, both on a preclinical and clinical level, are needed to better understand sex-specific effects of KD on mental health.
Topics: Animals; Female; Male; Diet, Ketogenic; Depressive Disorder, Major; Bipolar Disorder; Epilepsy; Models, Animal
PubMed: 36943505
DOI: 10.1007/s00702-023-02620-x