Neurobiology of Bipolar Disorder: Road to Novel Therapeutics

Front-Matter_2021_Neurobiology-of-Bipolar-Disorder
Front matter
Copyright_2021_Neurobiology-of-Bipolar-Disorder
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Contributors_2021_Neurobiology-of-Bipolar-Disorder
Contributors
Foreword_2021_Neurobiology-of-Bipolar-Disorder
Foreword
Introduction
Some specific findings and their implications
The implications of neuroprogression for clinical therapeutics
Early intervention and prevention
A panoply of treatments are available for early intervention studies
Need for a treatment outcome network
References
Chapter-1---Tackling-the-heterogeneity-of-bipolar-disor_2021_Neurobiology-of
Tackling the heterogeneity of bipolar disorder in the era of the Research Domain Criteria (RDoC)
Introduction
The RDoC framework
Differences between RDoC and the ICD-11 and DSM-5 frameworks
Bipolar disorder
Introduction
Clinical heterogeneity
Genetic heterogeneity
Neuroimaging heterogeneity
Use of RDoC framework in bipolar disorder
Conclusion
References
Chapter-2---The-neurodevelopmental-basis-of-bipolar-_2021_Neurobiology-of-Bi
The neurodevelopmental basis of bipolar disorder: Mechanisms and implications
Introduction
Clinical and epidemiological findings
Clinical signs and features
Early development and cognitive functioning
Epidemiological findings and risk factors
Findings from postmortem, genomic, and neuroimaging studies
Postmortem studies
Genomic studies
Neuroimaging studies
Synopsis and potential mechanisms
Potential implications for future research and clinical practice
Acknowledgments
Conflict of interest
References
Chapter-3---The-neuroprogressive-nature-of-bipolar-d_2021_Neurobiology-of-Bi
The neuroprogressive nature of bipolar disorder: Mechanisms and implications
Introduction
A DSM guide to bipolar disorder
Why the neuroprogression of BD depends on the accurate and timely diagnosis by a clinician?
Mechanisms of neuroprogression of BD
Neurobiological, structural, and associated functional changes
Epigenetic changes
Molecular changes
Immune alterations and subsequent neuroinflammation
Dysregulated neurotransmission
Mitochondrial dysfunction and subsequent oxidative stress
Altered growth factors metabolism
Impaired hypothalamic-pituitary-adrenal (HPA) axis activity
Somatoprogression with neuroprogression of BD
Treatment and treatment resistance
Discussion
Conclusion
References
Chapter-4---Immune-mechanisms-in-bipolar-disorder-_2021_Neurobiology-of-Bipo
Immune mechanisms in bipolar disorder: Evidence and implications
Introduction
The association between BD, immune dysfunction, and inflammatory diseases
Evidence of the association between autoimmune disorders and BD
Evidence of the association between infections and BD
Evidence of an association between the microbiome, gut-brain axis, and BD
Peripheral inflammatory markers in the BD patients
Central nervous system inflammatory markers in the BD patients
Cerebrospinal fluid inflammatory markers in BD patients
Post mortem BD brain samples and inflammatory makers
Inflammatory molecular pathways associated with BD
Cytokines and chemokines
Oxidative stress production
Conclusions and future directions
References
Chapter-5---Mitochondrial-pathways-in-bipolar-disor_2021_Neurobiology-of-Bip
Mitochondrial pathways in bipolar disorder: Mechanisms and implications
Introduction
Defective mitochondrial metabolism and calcium levels in BD
Genetic evidence for mitochondrial dysfunction in bipolar disorder
Abnormal mitochondrial morphology and dynamics in BD
Conclusion
References
Chapter-6---Neurooxidative-and-neuronitrosative-mechan_2021_Neurobiology-of-
Neurooxidative and neuronitrosative mechanisms in bipolar disorder: Evidence and implications
Introduction
What is oxidative/nitrosative stress, what does it do?
Oxidative stress markers in BD
DNA/RNA damage
RNA damage
DNA/RNA damage in BD
DNA repair
DNA repair and BD
OS/NS, DNA/RNA damage, and treatment of BD
Future directions
References
Chapter-7---Mechanisms-underpinning-neurocognitive-_2021_Neurobiology-of-Bip
Mechanisms underpinning neurocognitive dysfunction in bipolar disorder
Brain imaging and electrophysiological correlates of cognitive functioning in BD
Functional MRI studies and cognitive functions in BD
Resting-state fMRI studies and cognitive functions in BD
Cognitive evoked-related potentials in BD
DTI studies and cognitive functions in BD
Volumetric and cortical thickness and cognitive functions in BD
Summary of the relationship between brain imaging and electrophysiological studies and cognition in BD
Neurobiological and genetic correlates of cognitive impairment in BD
Oxidative stress, neurochemical abnormalities, and cognitive functions in BD
Neuronal integrity, glutamate, and cognition in BD
Inflammation and cognitive functions in BD
Hypothalamic-pituitary-adrenal axis and neurocognition in BD
Neurotrophic factors, neurocognition, and BD
Genetic factors and cognitive impairment in BD
Summary
Medical comorbidities, substance abuse, iatrogenic factors, and cognitive impairment in BD
Metabolic syndrome, obesity, cardiovascular risk factors, and cognition in BD
Antipsychotics and cognitive impairment in BD
Comorbid alcohol and substance use disorders and cognitive impairment in BD
Summary
Mechanisms underlying cognitive impairment in BD
Abnormal neurodevelopment and cognitive impairment in BD
Interaction of neurodevelopmental abnormalities, aging, and medical comorbidities in BD. Is there a non-BD-related cognitiv ...
Might there still be a neurodegenerative subtype of BD in a minority of the patients?
Conclusion
References
Chapter-8---The-biological-basis-of-predomina_2021_Neurobiology-of-Bipolar-D
The biological basis of predominant polarity
Introduction
Bipolar disorders prevalence and clinical course
The origins of predominant polarity
Conceptualization and operationalization of predominant polarity
Prevalence of predominant polarity
Predominant polarity across international diagnostic criteria and clinical guidelines
Machine learning for precision psychiatry applied on predominant polarity
Clinical implications of predominant polarity
Sociodemographic correlates of predominant polarity
Diagnosis and predominant polarity
Specific symptoms and predominant polarity
Age of onset and first episode polarity
Suicidality and predominant polarity
Mixed episodes in predominant polarity
Undetermined predominant polarity
Substance use disorders and predominant polarity
Association with cooccurring mental disorders
Rapid cycling and predominant polarity
Seasonality and predominant polarity
Cognition and predominant polarity
Functioning and predominant polarity
Follow-up studies on polarity
The endophenotype of temperaments and predominant polarity
Treatment implications of predominant polarity
Pharmacological treatment and predominant polarity
Psychological treatment and predominant polarity
Neurobiology of predominant polarity
Genetic base of predominant polarity
Neuroradiology of predominant polarity
Discussion
References
Chapter-9---The-evolution-of-animal-models-for-_2021_Neurobiology-of-Bipolar
The evolution of animal models for bipolar disorder
Introduction
Animal model of bipolar disorder induced by amphetamine
Animal model of bipolar disorder induced by OUA
Animal model of bipolar disorder induced by sleep deprivation
Genetic models
References
Chapter-10---Alteration-in-circadian-rhythms-in-bipol_2021_Neurobiology-of-B
Alteration in circadian rhythms in bipolar disorder: Mechanisms and implications
Circadian rhythms
Circadian clock genes and bipolar disorder
Circadian rhythms and bipolar disorder
Melatonin
Hypothalamic-pituitary-adrenal axis
Body temperature
Sleep
Chronotype
Saesonality
Circadian rhythms and inflammation in bipolar disorder
Circadian rhythms and metabolic alterations in bipolar disorder
Sleep, connetomics, and bipolar disorder
Circadian rhythms and drug therapy in bipolar disorders
Chronotherapy
Conclusion
References
Chapter-11---Genetic-factors-in-the-etiology-of_2021_Neurobiology-of-Bipolar
Genetic factors in the etiology of bipolar disorder
Genome-wide association studies
Structural variants: Exome sequencing and copy number variants
Quantitative trait loci: Convergent genomic analyses
Polygenic risk scores
Future directions
References
Chapter-12---Pharmacogenomics-of-bipolar-di_2021_Neurobiology-of-Bipolar-Dis
Pharmacogenomics of bipolar disorder
Introduction
Candidate gene studies
Lithium salts
Other mood stabilizers
Atypical antipsychotics
Genome-wide association studies: From pharmacogenetics to pharmacogenomics
Post-GWAS: Polygenic risk score and functional approaches
Discussion
References
Chapter-13---Blood-brain-barrier-s-interplay-with-periphe_2021_Neurobiology-
Blood-brain barrier’s interplay with peripheral and central inflammation as a pathophysiological mechanism of bipolar disor ...
Introduction
From systemic inflammation to neuroinflammation in BD
Systemic inflammation in bipolar disorder
Neuroinflammation in bipolar disorder
Conclusion
Impact of neuroinflammation in the physiopathology of BD
Hypothalamic-pituitary-adrenal axis dysregulation
Serotonin metabolism dysregulation
Impaired neurogenesis
Astrocytes activation
Blood-brain barrier dysfunction as a central physiopathological mechanism of BD
The blood-brain barrier at the interface between systemic and central inflammation
BBB dysfunction in bipolar disorder
Conclusion
References
Chapter-14---Induced-pluripotent-stem-cells-as-tools-to-in_2021_Neurobiology
Induced pluripotent stem cells as tools to investigate the neurobiology of bipolar disorder and advance novel therapeutic d ...
Generation of human stem cell models of disease: Reprogramming technology
Developmental phenotypes observed in bipolar disorder patient iPSC models
Characterizing lithium responsiveness using reprogrammed cells from bipolar disorder patients
Leveraging bipolar disorder hiPSC model phenotypes for target identification and drug discovery
Integration of iPSC models with mouse model studies
ANK3 mouse and human iPSC models
CACNA1C mouse and reprogrammed models
Development of mouse/hiPSC chimeric models
Integration of human neuropathology with hiPSC models
Integration of human genetics with hiPSC models
Closing the translation loop to elucidate the neurobiology of bipolar disorder
Acknowledgments
Conflict of interest
References
Chapter-15---Bipolar-disorder-as-a-gliopa_2021_Neurobiology-of-Bipolar-Disor
Bipolar disorder as a gliopathy
What are glial cells?
Evidences from total glia studies
Evidence from astrocyte studies
Evidence from microglia studies
Evidence from oligodendrocyte studies
Future studies: Using hiPSC and cerebral organoids to understand the role of glia cells on the disease development, progres ...
References
Chapter-16---Molecular-imaging-findings-in-bip_2021_Neurobiology-of-Bipolar-
Molecular imaging findings in bipolar disorder
Introduction
Translocator protein imaging
n -Acetylaspartate magnetic resonance imaging spectroscopy in bipolar disorder
Serotonin transporter imaging in bipolar disorder
Radioligands available for imaging serotonin transporters
Findings of altered 5-HTT binding in bipolar disorder
Molecular imaging to monitor therapeutics applied in bipolar disorder
Aripiprazole occupancy
Lithium concentration assessment with magnetic resonance spectroscopy
Conclusions
References
Chapter-17---Structural-neuroimaging-findings-in_2021_Neurobiology-of-Bipola
Structural neuroimaging findings in bipolar disorders
Introduction
Circuits of mood regulation according to animal and lesion studies
Postmortem studies in mood disorders
Structural neuroimaging in bipolar disorders
Computed tomography
Magnetic resonance imaging
Region of interest and voxel-based morphometry approaches
Bipolar disorder in comparison with healthy controls
Bipolar depression and comparison between unipolar and bipolar disorders
Bipolar type I versus bipolar type II
Bipolar disorder in comparison with schizophrenia
Putative factors contributing to morphometric changes
Conclusion
References
Chapter-18---Epigenetic-mechanisms-of-bipola_2021_Neurobiology-of-Bipolar-Di
Epigenetic mechanisms of bipolar disorder
Introduction
Genetic alterations of BD
Epigenetic mechanisms
Epigenetic alterations in BD
DNA methylation alterations in BD
Histone modifications in BD
miRNA alterations in BD
Future directions and perspectives
Conclusions
References
Chapter-19---Bipolar-disorder-and-cardiovascular-dys_2021_Neurobiology-of-Bi
Bipolar disorder and cardiovascular dysfunction: Mechanisms and implications
Introduction
Cardiovascular risk factors, disease, and mortality
Excess cardiovascular mortality
Psychotropic medication use and cardiovascular disease
Cardiovascular disease and mood
CVD across bipolar subtypes and mood states
Cardiovascular risk factors and mood
Elevated CVD risk in other psychiatric populations
Early indicators of central and peripheral vascular dysfunction
Noninvasive vascular imaging
Arterial stiffness
Retinal photography
Cerebral blood flow
Inflammation, oxidative stress, and endothelial dysfunction
Harnessing the vascular-bipolar link to inform novel treatment approaches
Optimization of traditional cardiovascular risk factors
Cerebral blood flow as a putative treatment target
Targeting endothelial function
Aerobic exercise
Conclusion
References
Chapter-20---At-risk-mental-states-for-bipola_2021_Neurobiology-of-Bipolar-D
At-risk mental states for bipolar disorder
Introduction
Clinical overview
Neuroimaging
Structural neuroimaging
Spectroscopy neuroimaging
Functional neuroimaging
Clinical treatment of at-risk youth
Risk factors and risk assessment for manic conversion
Discussion
References
Chapter-21---Allostatic-load--Implications-for-the-path_2021_Neurobiology-of
Allostatic load: Implications for the pathophysiology, evolution, and treatment of bipolar disorder
Introduction
The hypothalamic-pituitary-adrenal axis and cortisol dysregulation in bipolar disorder
Oxidative stress and bipolar disorder
Inflammation/immunity and bipolar disorder
Metabolic dysregulation in bipolar disorder
Allostatic load and cognition in bipolar disorder
Cardiovascular markers and bipolar disorder
Clinical implications
Conclusion
References
Chapter-22---Bipolar-disorders--obesity--and-metaboli_2021_Neurobiology-of-B
Bipolar disorders, obesity, and metabolic disturbances: Mechanisms and implications
Introduction
Mortality and metabolic disturbances in bipolar disorders
Metabolic syndrome and bipolar disorders
Prevalence of metabolic disturbances in bipolar disorders
Neurobiological mechanisms of metabolic syndrome in bipolar disorder
Intrinsic factors
Shared genetic vulnerability between MetS and BD
Central and peripheral immune, metabolic, and endocrine dysregulations
The hypothalamic-pituitary-adrenal (HPA) axis role in MetS in BD
The inflammatory and immune system role in MetS in BD
Dopamine and MetS in BD
Gut-brain axis alteration influence in MetS in BD
Specific symptoms and MetS in BD
Sleep disorders and MetS in BD
Psychological factors and MetS in BD
Extrinsic factors
Psychopharmacology and MetS in BD
Prevalence of MetS in drug-naïve BD
Antipsychotics and MetS in BD
Mood stabilizers and MetS in BD
Combined antipsychotic-mood stabilizers and MetS in BD
Antidepressants and MetS in BD
Psychiatric and nonpsychiatric comorbidities linked to MetS in BD
Lifestyle factors and medical care in BD
Clinical implications of metabolic disturbances in the course of bipolar disorder
Bipolar depression and MetS
Cognition and neuroimaging and metabolic disturbances in BD
MetS and clinical outcomes in BD
Obesity and clinical outcomes in BD
Dyslipidemia and clinical outcomes in BD
Diabetes, impaired glucose metabolism, and clinical outcomes in BD
Blood hypertension and clinical outcomes in BD
Management of MetS in BD
The unmet needs of MetS in BD: Current situation, guidelines, and general recommendations
Smoking assessment and treatment
MetS management in BD
Overweight and obesity management in BD
Dyslipidemia management in BD
Hypertension management in BD
Hyperglycemia management in BD
Final remarks
References
Chapter-23---The-microbiota-gut-brain-axis-and-_2021_Neurobiology-of-Bipolar
The microbiota-gut-brain axis and bipolar disorder
Introduction
The microbiota-gut-brain axis
The neuroendocrine pathway
The gut immune system
The neural pathway
Epithelial barrier, dysbiosis and leaky gut
The influence of gut microbiota on behavior and cognition
MGBA and bipolar disorder
Microbiota in BD relatives
Therapeutic implications
Probiotics
Antibiotics
Prebiotics
Dietary intervention
Fecal transplantation
Impact of psychotropic treatment in microbiota
Conclusions and future directions
References
Chapter-24---The-hypothalamic-pituitary-adrenal-a_2021_Neurobiology-of-Bipol
The hypothalamic-pituitary-adrenal axis in bipolar disorder
Introduction
Hypotalamic-pituitary-adrenal (HPA) axis and stress response
Bipolar disorder and HPA dysfunction
Gene polymorphism and HPA dysregulation in BD
Clinical and therapeutic implications
Conclusions
References
Chapter-25---From-intracellular-signaling-pathways-to-_2021_Neurobiology-of-
From intracellular signaling pathways to neural circuit dysfunction in bipolar disorder
Introduction
Mechanism of action of mood stabilizers
Cellular models
Blood cells
Olfactory epithelium
Transmitochondrial cybrids
iPS cell-derived neurons
Postmortem brain analysis
Genetics
Genome-wide association studies (GWAS)
Whole exome/genome sequencing
Syndromic bipolar disorder due to Mendelian diseases
Darier’s disease
Wolfram disease
Mitochondrial disease
Search for neural circuit dysfunction using animal models
Top hit genes of GWAS
CACNA1C
ANK3
Genes of Mendelian diseases implicated in bipolar disorder
ATP2A2 (Darier’s disease) and WFS1 (Wolfram disease)
POLG and ANT1 (mitochondrial diseases)
Implications of the findings in the pathophysiology of bipolar disorder
PVT and serotonergic neurons
Hyperactivity of emotion-related circuitry
Conclusion
References
Chapter-26---The-impact-of-early-life-stress-in-the-deve_2021_Neurobiology-o
The impact of early-life stress in the development and course of bipolar disorder: Mechanisms and implications
Introduction
Early-life stress
Neurobiological mechanisms
Hypothalamic-pituitary-adrenal axis [25]
Sympathetic nervous system
Serotonin system
Oxytocin system
Immune system [46]
Brain development, structure and connectivity [27, 57, 58]
Early-life stress and bipolar disorder: Clinical and psychopathological dimensions
Maternal stress, prenatal medical illnesses, and obstetric complications
Different types of trauma on BD
Childhood trauma and dimensions of psychopathology
Genetic × environment
Ankyrin-3 (ANK-3)
5-HTTLPR
BDNF
HPA-related genes
Neuroinflammation
Kindling hypothesis
Treatment and future developments: Conclusion
References
Chapter-27---Bipolar-disorder-and-accelerated-aging-_2021_Neurobiology-of-Bi
Bipolar disorder and accelerated aging: Shared mechanisms and implications
Introduction
Biomarkers of biological aging
Bipolar disorders as an illness of accelerated aging
Brain aging
Oxidative stress
Senescent cells and inflammaging
Telomere length and epigenetic clock
New therapeutic avenues
References
Chapter-28---Suicidal-behaviors-in-bipolar-d_2021_Neurobiology-of-Bipolar-Di
Suicidal behaviors in bipolar disorder
Epidemiology and risk factors
Exploring suicidal behavior: Most relevant theories upon suicide
Interventions for suicidal behaviors
Conclusions
References
Chapter-29---Older-age-bipolar-disorder_2021_Neurobiology-of-Bipolar-Disorde
Older-age bipolar disorder
Introduction
Epidemiology and clinical features
Clinical features
Psychiatric and medical comorbidity
Cognition
Neuroimaging
Biological therapies
Late-life mania
Late-life bipolar depression
Psychosocial therapies
Conclusions
References
Chapter-30---Biomarkers-for-bipolar-disor_2021_Neurobiology-of-Bipolar-Disor
Biomarkers for bipolar disorder
Introduction
Peripheral biomarkers
The hypothalamic-pituitary-adrenal axis
Brain-derived neurotrophic factor and inflammatory markers
Oxidative stress markers
Neuroimaging
Structural neuroimaging
Functional neuroimaging
Metabolomics, proteomics, and machine learning
Conclusion
References
Chapter-31---The-mechanisms-of-action-of-lithium_2021_Neurobiology-of-Bipola
The mechanisms of action of lithium in bipolar disorder
Introduction
Genes and genomes
Genetics and genomics
Gene expression
Pathway analysis
Signal transduction
Mitochondria and endoplasmic reticulum
Human-induced pluripotent stem cells
Protein and proteomics
Neurotransmitters
Monoamines
Glutamate
Circadian rhythm
Endocrine systems
Cytokines and immune system
Brain chemistry, structure, and functions
Brain chemistry
Gray matter
Global volume
White matter
Brain functions
Conclusion
References
Chapter-32---Is-there-a-biosignature-for-lithium-respo_2021_Neurobiology-of-
Is there a biosignature for lithium response in bipolar disorder? Evidence and implications
Introduction
Biosignature of lithium response
Neuroimaging biomarkers
Peripheral biomarkers
Genetic biomarkers
Conclusion and outlook
References
Chapter-33---Physical-activity-and-exercise-in-the-pat_2021_Neurobiology-of-
Physical activity and exercise in the pathophysiology and treatment of bipolar disorder
Introduction
Definitions
Epidemiology
Physical activity and bipolar disorder
Physical activity and mental health
Physical activity and cognitive health
Physical activity and physical health
Sedentary behavior and bipolar disorder
Mechanisms
Barriers and facilitators
Conclusion
References
Chapter-34---Noninvasive-neuromodulatory-approach_2021_Neurobiology-of-Bipol
Noninvasive neuromodulatory approaches for bipolar disorder
Introduction
Noninvasive brain stimulation
Repetitive transcranial magnetic stimulation (rTMS)
Deep repetitive transcranial magnetic stimulation (dTMS)
Transcranial direct current stimulation (tDCS)
The use of neuromodulation techniques in treatment of the bipolar disorder
Depressive episodes
RTMS
Deep TMS
TDCS
Manic episodes
TMS
tDCS
Conclusion
References
Chapter-35---Novel-therapeutic-drug-targets-for_2021_Neurobiology-of-Bipolar
Novel therapeutic drug targets for bipolar disorder
Introduction
Challenges in BD drug development
Identifying novel drug targets in BD
Novel neurotransmitter targets
Ketamine and the glutamate system
Scopolamine and the cholinergic system
Buprenorphine and the opioid system
Melatonin, orexin, and the sleep-wake cycle
Nonneurotransmitter systems
Antiinflammatories, antioxidants, and related systems
Antidiabetics and the insulin pathway
Probiotics and the gut-brain
Concluding remarks
References
Chapter-36---The-treatment-of-bipolar-disorder-in-the-e_2021_Neurobiology-of
The treatment of bipolar disorder in the era of precision psychiatry: Challenges and opportunities
Background
Clinical trials in the era of precision psychiatry
Biomarker-stratified design within a traditional randomized controlled trial: Retrospective design
Biomarker-stratified design: Prospective design
Enriched by biomarker randomized controlled trial design
Randomized controlled trial design of a biomarker strategy
Umbrella trial design and basket trial design
Promising biomarkers for response to treatment in bipolar disorder: Where do we stand?
Peripheral blood-based biomarkers
Brain-derived neurotrophic factor (BDNF)
Inflammatory and immunological biomarkers
Neuroimaging
Genetic predictors of response to treatment
Future directions
References
Chapter-37---Intracortical-myelination_2021_Neurobiology-of-Bipolar-Disorder
Intracortical myelination
Myelin
Neurobiology of oligodendrocytes
Intracortical myelin
Myelin and bipolar disorder
White matter abnormalities in bipolar disorder
Gray matter and cortical changes in BD
Intracortical myelin in BD
The trajectory of intracortical myelination
Cognition and intracortical myelination
Modulation of intracortical myelin
Conclusion
References
Chapter-38---The-impact-of-psychotropic-drugs-on-brain_2021_Neurobiology-of-
The impact of psychotropic drugs on brain functionality and connectivity in bipolar disorder
Introduction
Effects of pharmacologic treatment on brain activity and connectivity in BD
Effects of specific classes of medication on brain activity/connectivity in BD
Conclusions and future perspectives
Acknowledgments
References
Index_2021_Neurobiology-of-Bipolar-Disorder
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