Neurobiology of Depression: Road to Novel Therapeutics

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Neurobiology of Depression:

Road to Novel Therapeutics
Copyright
Contributors
1
The Classification of Depression: Embracing Phenotypic Heterogeneity in the Era of the RDoC
	Funding
	Conflict of Interest
	Acknowledgments
	References
2
The Role of Environmental and Psychosocial Factors in Depression
	Introduction
	Some Consideration of ``Depression´´
	Depressogenic Factors
	Impact of Cognitive Style
	Mechanisms Linking Psychosocial Stressors With Depression: The Centrality of Self-Esteem
	Depressogenic Stressors
	Depression Versus Grief
	The Role of Personality
	Keys and Locks: ``Swiss Cheese´´ and a Lacunae Self-Esteem
	Conclusions
	References
3
Gene-Environment Interactions and Epigenetic Mechanisms in Depression
	Introduction
	Gene x Environment Effects (Candidate Genes)
		Candidate Genes Within the Serotonergic System
	Serotonin Transporter Polymorphism (SLC6A4)
	GxE Effects in BDNF Function in MDD
	GxE Effects in HPA Dysregulation in MDD
		GxE Effects: FKBP5 Gene
		GxE Effects: CRHR1
	Epigenetic Mechanisms Modulating Environmental Effects
		Epigenetic Mechanisms Modulating Serotonin Transporter Gene Expression
		Epigenetic Mechanisms Modulating BDNF Gene Expression
		Epigenetic Mechanisms in the Regulation of Genes Within the HPA Axis
	Genome-Wide GenexEnvironment Effects
	Discussion
	References
4
Pathophysiology of Cognitive Impairment in Depression
	Executive Functioning
	Working Memory
	Memory
	References
	Further Reading
5
Anhedonia in Depression: Mechanisms, Assessment, and Therapeutics
	Introduction
	Anhedonia: A Brief Historical Context
	Anhedonia and Vulnerability to Major Depression
	Neural Mechanisms of Anhedonia and Depression
	Multifactorial Influences on Striatal Responding and Mood
	Environment
	Assessment
	Therapeutics
	Conclusions
	Conflict of Interest
	Acknowledgment
	References
6
The Neurotrophic Hypothesis of Depression Revisited: New Insights and Therapeutic Implications
	Introduction
	Brain-Derived Neurotrophic Factor (BDNF)
	Role of BDNF in the Effects of Chronic Stress
		Regulation of BDNF by Stress
		Contribution of BDNF to Stress-Evoked Cytoarchitectural Changes
		Contribution of BDNF to Stress-Induced Depressive-like Behavior
	Role of BDNF in Antidepressant Action
		Regulation of BDNF by Antidepressants
		Contribution of BDNF to Antidepressant-Evoked Cytoarchitectural Changes
		Influence of BDNF Signaling on Antidepressant-Mediated Behaviors
	Clinical Studies
		Regulation of BDNF in Depressed Patients
		Regulation of BDNF Expression in Response to Antidepressant Treatment
		BDNF Polymorphisms
	Summary
	References
7
The Monoamine Hypothesis of Depression Revisited: Could It Mechanistically Novel Antidepressant Strategies?
	The Monoamine Hypothesis
		Serotonin-Noradrenaline
			Dopamine
	Withdrawal from Antidepressants
	Conclusions
	References
8
Neuro-Immune Interactions in Depression: Mechanisms and Translational Implications
	Introduction
	The Role of Central and Peripheral Cytokines in the Pathophysiology of Depression
	Microglial Activation in Depression
	The Kynurenine Pathway and Depression
	NLRP3 Inflammasome in Depression
	Gut-Brain Axis in Depression
	Conclusion
	Acknowledgments
	References
9
The Hypothalamic-Pituitary-Adrenal Axis in Depression: Molecular Regulation, Pathophysiological Role, and Translational Im ...
	Stress and the Hypothalamic-Pituitary-Adrenocortical Axis
	HPA Axis Dysfunction in Major Depression
	Evidence from Animal Studies
	Translational Implications and Novel Therapeutics Targeting the HPA Axis
	References
10
Intracellular Signaling Pathways Implicated in the Pathophysiology of Depression
	Introduction
	The Role of Brain-Derived Neurotrophic Factor (BDNF) in the Pathophysiology of MDD
	The Role of Mitogen-Activated Protein Kinase (MAPK) in the Pathophysiology of MDD
	The Role of Protein Kinase B (Akt) in the Pathophysiology of MDD
	The Role of Mammalian Target of Rapamycin (mTOR) in the Pathophysiology of MDD
	The Role of Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) in the Pathophysiology of MDD
	The Role of Wnt in the Pathophysiology of MDD
	The Role of Glycogen Synthase Kinase 3 (GSK-3) in the Pathophysiology of MDD
	Conclusion
	Acknowledgments
	References
11
The Long-Lasting Neurobiological Scars of Early-Life Stress: Implications for the Neurobiology of Depression
	Introduction
	Epidemiology
	Inflammation
	Neurotransmitters and Neuroendocrinology
	Genetics and Gene-Environment Interactions
	Brain Imaging
	Electroencephalography
	Discussion
	Financial Disclosure
	References
12
Molecular, Cellular, and Circuit Basis of Depression Susceptibility and Resilience
	Introduction
	Pathological Mechanisms of Depression Susceptibility
		Rapid Regulation of Depression-Related Behaviors
		Brain-Derived Neurotrophic Factor: Contributions to Depression
		Corticotrophin-Releasing Factor-Related Basis of Depression
		A Role of HCN Channels in Regulation of Depression-Like Behaviors
		Transcriptional and Chromatin Mechanisms of Stress Susceptibility
		Inflammation and Depression
	A New Therapeutic Strategy: Targeting Mechanisms of Resilience
		Active Resilience
		KCNQ Potassium Channels as Novel Drug Targets
		Norepinephrine Mechanisms of Resilience
		Transcriptional and Chromatin Mechanisms of Resilience
	Conclusion
	Acknowledgments
	References
13
More Than a Gut Feeling: Emerging Roles of the Microbiome in the Pathophysiology and Treatment of Depression
	Overview
	The Microbiome
	Factors That Impact Microbiome Composition
	Microbiota and Depression
	Therapeutics and the Microbiota-Brain Axis
	Future Directions
	References
14
Optogenetics: Illuminating the Neural Circuits of Depression
	Optogenetic Toolbox
		Opsins
		Strategies for Targeting Opsins to Specific Cell Populations
	Circuitry Underlying Depressive-Like Behaviors in Animal Models
		Ventral Tegmental Area
		Nucleus Accumbens
		Hippocampus
		Prefrontal Cortex
		Other Limbic Areas
	Caveats and Limitations of Optogenetics
	Conclusions
	References
15
Mitochondrial Dysfunction and Oxidative Stress: Relevance to the Pathophysiology and Treatment of Depression
	About Mitochondria
	Mitochondrial Dysfunction and Major Depressive Disorder
	Oxidative Stress and Major Depressive Disorder
	Causes of Mitochondrial Dysfunction and Oxidative Stress
		Stress
		Sleep Disturbances
		Diet
			Caloric Intake and Composition
			General Nutrients
		Exercise
		Pharmaceutical Medications
		Gut Microbiota
	Summary
	References
16
Obesity and Depression: Shared Pathophysiology and Translational Implications
	Introduction
	Depression and Obesity: Two Intricate Disorders
	Mechanisms Underlying the Relationship Between Obesity and Depression
		Inflammation
		The Hypothalamic-Pituitary-Adrenal Axis
		Environmental Factors
	Translational Implications
	Conclusion
	References
17
Depression and Cardiovascular Risk: Epidemiology, Mechanisms, and Implications
	Epidemiology
		Relative Prevalence of Cardiovascular Disease Among People With Major Depressive Disorder
		Age and Sex in Relation to the Depression-Cardiovascular Link
		Impact of Depression on Subsequent CVD
		Impact of Depression and Its Treatment on Outcome of CVD
	Mechanisms
		Inflammation
		Oxidative Stress
		Hypothalamic-Pituitary-Adrenal Axis
		Serotonin and Platelets
		Autonomic Nervous System Dysfunction
	Treatment
		Omega 3 Supplementation
		Anti-Inflammatories
		Metabolism: Metformin, Orlistat, and Sibutramine
		Statins
	Conclusion
	References
18
Poststroke Depression: Pathophysiology and Treatment Strategies
	Introduction
	Risk Factors of PSD
	Diagnosis of PSD
	Screening Tools for PSD
	Mechanisms of PSD
	Treatment of PSD
	Conclusion
	Future Perspective
	Acknowledgment
	Disclosure/Conflict of Interest
	References
19
Is Depression Associated With Accelerated Aging? Mechanisms and Implications
	Introduction
		Summary
	Telomere Length in MDD
	Is Telomere Shortening Related to the Duration or the Severity of the Mood Disorders?
	Potential Mediators of Telomere Shortening in Mood Disorders
		Overview
		Inflammation, Oxidation, and Increased Cell Turnover
		Stress Hormones (Cortisol and Catecholamines/Sympathetic Nervous System Activity) and Anabolic Hormones
		Effect of Psychotropic Medications on Leukocyte Telomere Length
	Telomerase Activity (TA) in Mood Disorders
		Overview
		Telomerase Activity (TA) in MDD
		Effects of Psychotropic Medication on Telomerase Activity (TA)
	Relationship of Peripheral Cell Aging Markers to the Brain
	Is Cellular Aging Preventable or Reversible?
	Summary
	References
20
Relationship Between Complicated Grief and Depression: Relevance, Etiological Mechanisms, and Implications
	Post-Loss Psychopathology
		Bereavement
		Complicated Grief
		Major Depressive Disorder
		MDD and CG: Overlapping but Distinct Disorders
	Comparing Biological and Psychological Findings in MDD and CG
		Biological Factors
		Psychological Factors
		Relationship to the Deceased and Nature of the Death
		Summary
		Reciprocal Causal Connections
	Implications for Research and Treatment
		Future Research Directions
		Treatment of Post-Loss Psychopathology
	References
21
A Neural Circuit-Based Model for Depression Anchored in a Synthesis of Insights From Functional Neuroimaging
	Introduction
	Neural Circuit Framework for Depression
	``Default Mode´´ Circuit
		Default Mode Circuit Disruptions in Depression and Anxiety
		Default Mode Circuit and Treatment Implications
	``Salience´´ Circuit
		Salience Circuit Disruptions in Depression and Anxiety
		Salience Circuit and Treatment Implications
	Affective Circuits
	Negative Valence System
		Negative Affective Circuit Disruptions in Depression and Anxiety
		Negative Affective Circuit and Treatment Implications
	Positive Affect Circuit: ``Reward´´
		Reward Circuit Disruptions in Depression and Anxiety
		Reward Circuit and Treatment Implications
	Attention Circuit
		Attention Circuit Disruptions in Depression and Anxiety
		Attention Circuit and Treatment Implications
	Cognitive Control Circuit
		Cognitive Control Circuit Disruptions in Depression and Anxiety
		Cognitive Control Circuit and Treatment Implications
	Conclusion
	References
22
Could Depression be Preventable? Evidence and Perspectives
	Why Focus on Prevention?
	Theoretical Frameworks for Prevention as Applied to Depression
		Primary Prevention
		Secondary Prevention
		Tertiary Prevention
	Summary
	References
23
Treating Depression in the Era of Precision Medicine: Challenges and Perspectives
	Introduction
	The Role of Precision Medicine
		Pharmacokinetics and Pharmacodynamics
		Genomics and MDD
		Biomarkers and MDD
		Treating Depression in the Era of Precision Medicine
		Pathways to Inform Precision Medicine in MDD
	Useful assessment tools in MDD precision medicine
		Challenges and Perspectives
	The Future of Precision Medicine-Where to From Here?
	References
24 Neurobiological Aspects of Functional Recovery in Major Depressive Disorder
	Introduction
	Functional Recovery in MDD
		Depressive Symptoms Mediating Functional Recovery
	Neurobiology of Fatigue and Cognitive Dysfunction
		Monoamines
		Hypothalamic-Pituitary-Adrenal (HPA) Axis and Neuroinflammation
		Neural Circuitry
	Effects of Antidepressants on Specific Symptoms
	Summary
	References
25
Diet and Depression: From Epidemiology to Novel Therapeutics
	Background and Historical Context
	Epidemiological Evidence for the Association Between Diet and Depression
	Limitations
	Novel Therapeutic Interventions for Mental Illness
		Introduction
		Whole-of-Diet Interventions
		Vitamins and Minerals
		Amino Acids
		Herbal Interventions
			St John´s Wort
			Saffron
			Curcumin
			Kava
		Omega 3 Fatty Acids
		Probiotics
		Limitations
			Lack of Long-Term Efficacy and Safety Data
			Lack of Dose Finding and Response Interventions
			Lack of Data on Predictors of Treatment Response
	Chapter Summary and Future Directions
	References
26
Physical Activity and Exercise as a Treatment of Depression: Evidence and Neurobiological Mechanism
	Introduction
	Defining Physical Activity and Exercise
	Relationship Between Physical Activity, Sedentary Behavior, and Depression
	Mechanisms Underpinning the Relationship Between PA and Incident Depression
	Relationship Between Cardiorespiratory Fitness and Incident Depression
	Exercise as a Treatment for Depression
	The Effects of Exercise in People With MDD Goes Beyond Depressive Symptoms
	Adherence and Adverse Events From Exercise in Depression
	Potential Neurobiological Mechanisms
	Conclusion
	References
27
Antidepressants and Suicidality-Controversies and Possible Mechanisms
	Brief History
	Investigating Causality
	Causality Assessments Based on Individual Case
	The Role of Randomized Controlled Clinical Trials in Adverse Event Research
	Ascertainment Bias
	Lack of Clinical Trials Powered to Differentiate Between Depressive Suicidality and AISIB
	Clinical Trials of Antidepressants Will Show Different Relative Risks of Suicidality Depending on the Population Studied
	Generalizing to Clinical Populations
	Did the Black Box Warning Increase Suicides?
	Mechanisms of Action
		Activation Syndrome
		Activation Syndrome and Akathisia
		Activation Syndrome and Mania
		Emotional Blunting
		Antidepressant Drug Withdrawal
	Future Directions
	Conclusions
	References
28
Altered GABAergic Function, Cortical Microcircuitry, and Information Processing in Depression
	Introduction
		Cortical Microcircuits (CMs): Functional Units of the Cortex
		Excitation Inhibition Balance (EIB): Importance to Healthy Brain Functioning
		Relevance of EIB Changes to Network Activity of the Depressed Brain
	Evidence of GABA Deficits From Clinical Studies
		CSF GABA Levels in MDD
		Plasma Levels of GABA in MDD
		GABA Measured by 1H-MRS: A Window into the Living Brain
		TMS-EMG: Measuring the Functionality of the GABA System
		Summary of Clinical Evidence
	Postmortem Evidence of GABA Deficits
		GABA Deficits in Postmortem MDD Brains: Replication and Extension of Clinical Findings
		SST-Neuron Dysfunction as a Key Contributing Pathological Substrate of MDD and Other Psychiatric Disorders
	Insights From Animal Models
		SST Neurons Are Causally Involved in Depressive-Like Behavior and Are Selectively Vulnerable to Dysfunction
	Functional Effects of SST Pathology
		Other Relevant Contributors to EIB
	Implications for Novel Treatments
	Summary and Future Directions
	References
29
Biomarker-Based Treatment Selection: A Precision Medicine Approach for Depression
	Introduction
	Clinical Trials-Personalized Medicine in Depression
		Pharmacogenomics
			Monoamine Availability
			Antidepressant Availability
			Inflammation, Neurogenesis, and HPA Axis Activity
		Protein/mRNA Biomarkers
		Physiological Biomarkers (EEG)
		Neuroimaging Biomarkers
		Limitations
		Concluding Remarks
	References
30
Implications of Pharmacogenomics in Depression Pathophysiology and Treatment
	Introduction
	Pharmacogenetics and Depression Pathophysiology
	Pharmacogenetics and Depression Treatment
	Pharmacogenetic Decision-Support Tools
	Future Direction
	Conclusion
	References
31
Novel Neuromodulatory Approaches for Depression: Neurobiological Mechanisms
	Introduction
	Mechanisms of Action
	Clinical Efficacy
	Neurobiological Mechanisms of NIBS in Depression
		Molecular Mechanisms
			Neurotransmitters
			Genetics and Neurotrophins
			Neuroendocrine System
		Electrophysiology
		Neuroimaging
	Conclusion
	References
32
Electroconvulsive Therapy for Depression: Neurobiological Mechanisms
	Introduction
	Methodological Differences Between MRI Techniques
		Structural
		Functional
		MRS
		Additional Considerations
	Brain Changes Related to ECT
		Medial Temporal Lobe
		Anterior Cingulate Cortex
		Other Regions
	Clinical and Methodological Considerations
	Conclusion
	References
33
Deep Brain Stimulation: Mechanisms Underpinning Antidepressant Effects
	Introduction
		Clinical Studies
		Preclinical Studies
			Behavioral Effects
			Neurobiological Effects
	Conclusions
	References
34
Novel Therapeutic Targets for Major Depressive Disorder
	Introduction
	Inflammatory Pathway
		TNF-α Antagonists (Infliximab)
		IL-6 Antagonists (Sirukumab)
		NSAIDs (ASA, Celecoxib)
		Natural Anti-Inflammatory Agents (Omega-3 Polyunsaturated Fatty Acids, Curcumin)
		Tetracycline Antibiotics
	Oxidative and Nitrosative Stress
		N-acetyl Cysteine
	Hypothalamic-Pituitary-Adrenal Axis
		Cortisol Synthesis Inhibitors (Metyrapone and Ketoconazole)
		Oxytocin
		Endogenous Neurosteroids (Pregnenolone and Dehydroepiandrosterone)
	Glucose Metabolism
		Incretins (GLP-1, Gliptins)
		Insulin Sensitizers (Pioglitazone)
		Insulin
	Bioenergetics and Mitochondrial Modulators
		Creatine
	One-Carbon Cycle and the Endogenous Creation of Monoamines
		S-Adenosyl-Methionine and l-Methyl-Folate (Potentially Broad Mechanism of Action)
	Neurotrophin Signaling
		Erythropoietin
	Glutamatergic System
		High-Trapping Glutamatergic Modulators (Ketamine, Esketamine, and (2R,6R)-Hydroxynorketamine)
		NMDA Receptor Antagonists (Nitrous Oxide, Dextromethorphan)
		Subunit-Specific NMDA Receptor Antagonists (CP-101,606, CERC-301, d-Cyclosporine, Rapastinel, Sarcosine)
		mGlu Receptor Modulators (Basimglurant)
		Glutamate Modulators (Riluzole, Lithium)
	Opioids
		MOR Modulators (Buprenorphine and Samidorphan)
		KOR Antagonists (CERC-501)
	Cholinergic System
		Antimuscarinic Agents (Scopolamine)
		Nicotinic ACh Receptor Antagonists (Mecamylamine, Varenicline)
	Other
		Silexan
	Conclusion
35
The Search for Rapid Acting Antidepressants: Research Synthesis and Perspectives
	Introduction
	Time Course of Monoaminergic Antidepressant Therapy
	Time Course of Electroconvulsive Therapy
	Sleep Deprivation
	Ketamine and Other NMDA Targeting Drugs
	Glutamate Targeting Drugs
	GABA and Serotonin Targeting Drugs
	Psilocybin
	Conclusion
	References
36
Pediatric Depression
	Epidemiology and Definitions
	Risk and Protective Factors
	Genetic and Biological Influences on Environmental Risks
	Family Studies
	Twin Studies
	Twin Studies of Continuity Over Time
	Intergenerational Studies
	Prevention
	Molecular Genetic Findings
	Treatment
	Conclusion
	References
37
Depression in Women
	Introduction
	Organizational Effects: Genetics and Genomics
		5-HTTLRP and MAOA
		FKBP5
		PACAP
	Organizational Effects: Early Life Environment
		Prenatal
		Postpartum
	Adolescence: Where Genetics and Organization Meet Activation
	Adulthood: Exposure to Cyclic Sex Steroids and Stress
		Premenstrual Dysphoric Disorder
		Postpartum Depression
		Major Depressive Disorder
	Cumulative Exposures, Hormone Withdrawal, and Aging
	Conclusions
	References
38
Advances in the Neurobiology of Late-Life Depression
	Introduction
	Clinical Presentation of Late-Life Depression: Does Age of Onset Matter?
	Inflammatory Changes in LLD
	Adhesion Molecules
	Neuroendocrine Changes in LLD
	Neurotrophic Factors in LLD
	Other Peripheral Biomarkers in Late-Life Depression
	Amyloid and Tau Pathology in LLD
	Conclusions
	References
Index
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