Biomarkers in Neuropsychiatry: A Primer

Contents
Biomarkers in Medicine and Psychiatry: An Overview
	1 Biomarkers in Medicine: Brief Historical Background and Updated Concepts
	2 Steps in the Development of a Candidate Biomarker
	3 Biomarkers in Psychiatry
	4 Clinical Use of Biomarkers in Psychiatry: It Is Time to Embrace the Change
	5 Final Remarks
	References
Genetic Biomarkers of Psychiatric Disorders
	1 Introduction
	2 Principles and Methods in Psychiatric Genetics
		2.1 Genome-Wide Association Study (GWAS)
		2.2 Polygenic Risk Scores
		2.3 Epigenetics
	3 Findings in Specific Disorders
		3.1 Autism Spectrum Disorder
		3.2 Bipolar Disorder
		3.3 Schizophrenia
		3.4 Suicide
		3.5 Major Depressive Disorder
	4 Clinical Applications of Genetic and Epigenetic Studies
		4.1 Pharmacogenetics
		4.2 Polygenic Risk Scores
	5 Conclusions
	References
Neurophysiological Biomarkers
	1 Introduction
	2 Methodological Strategies for Biomarker Identification and Development
		2.1 Overview of Neurophysiological and Related Neuroimaging Methods
		2.2 Brain Activation: A Framework for Developing Local-Field Biomarkers
		2.3 Network Neuroscience: A Framework for Developing Network-Level Biomarkers
		2.4 Brain Controllability Analysis: A Framework for Developing System-Level Biomarkers
	3 Preclinical and Clinical Research to Inform Neurophysiological Biomarker Development for Neuropsychiatric Disorders
		3.1 Depression
		3.2 Alzheimer’s Disease (AD)
		3.3 Stroke
	4 Conclusions
	References
Structural Neuroimaging Biomarkers in Psychiatry
	1 Introduction
	2 Structural Neuroimaging: General and Historical Aspects
	3 Structural Neuroimaging Candidate Biomarkers in Psychiatry: Current Status
		3.1 Structural Neuroimaging Findings in Mental Disorders: Similarities and Specificities
		3.2 High-Risk Population Studies
	4 Perspectives in Structural Neuroimaging Biomarkers in Psychiatry
	References
Functional Neuroimaging Biomarkers
	1 Introduction
	2 What Would Constitute an fMRI-Based Biomarker?
	3 Challenges: Why Don’t We Have Biomarkers?
		3.1 Diagnostic Challenges
		3.2 Limitations of fMRI in Development of Biomarkers
		3.3 Discussion of Challenges Applying T-fMRI to Psychiatric Symptoms/Conditions
		3.4 Discussion of Efforts with rs-fMRI and Challenges
	4 Neuropsychiatric Disorders: Current Progress
		4.1 Catatonia
		4.2 Dementia
		4.3 Epilepsy
		4.4 Multiple Sclerosis
		4.5 Parkinson’s Disease
		4.6 Traumatic Brain Injury
	5 Future Directions
	6 Conclusion
	References
PET Biomarkers in Psychiatry
	1 Introduction to PET in Psychiatry
		1.1 PET Background
		1.2 Principles of Radiotracer
	2 PET Radioligands in Alzheimer’s Disease (AD)
		2.1 Alzheimer’s Disease
		2.2 Aβ
		2.3 Tau
		2.4 Microglial Activation and Neuroinflammation
		2.5 Neurodegeneration
		2.6 Epigenetics
	3 PET Biomarkers in Schizophrenia and Psychosis
		3.1 Schizophrenia
		3.2 Dopamine
		3.3 Glutamate
		3.4 Microglial Activation
	4 PET Biomarkers in Major Depressive Disorder (MDD)
		4.1 Major Depressive Disorder
		4.2 Serotonin
		4.3 Glucose Metabolism
		4.4 Glutamate
		4.5 Monoamine Oxidase and Neuroinflammation
	5 PET Biomarkers in Bipolar Disorder (BD)
		5.1 Bipolar Disorder
		5.2 Glucose Metabolism
		5.3 Therapeutic Response Markers
	6 PET Biomarkers in Anxiety Disorders, Post-Traumatic Stress Disorder (PTSD), and Fear Dysregulation
	7 PET Biomarkers in Substance Use Disorders
		7.1 Substance Use Disorders
		7.2 Mechanisms Underlying Patterns of Drug Use
		7.3 Long-Term Neurochemical Changes in Substance Users
	8 Challenges in Using PET Biomarkers
		8.1 Introduction
		8.2 Biomarker/Radiotracer Availability
		8.3 Transdiagnostic Approach
		8.4 Study Constraints
	9 Future Applications
	10 Conclusion
	References
Digital Markers of Mental Health Problems: Phenotyping Across Biological, Psychological, and Environmental Dimensions
	1 Introduction
	2 What Are Digital (Bio)Markers?
	3 Ethical Issues and Acceptability of Digital Biomarkers
	4 Sensors and Devices Used to Generate Digital Biomarkers
		4.1 Sensors
		4.2 Tracking Interactions with Devices
		4.3 Implantable and Ingestible Devices
	5 Applications of Digital Markers
		5.1 Assessment of Patients in Clinical Care
		5.2 Evaluation and Delivery of Mental Health Interventions
		5.3 Population Mental Health and Psychopathology
		5.4 Barriers to Implementation
	6 Current Challenges and Future Directions
	References
Staging Biomarkers in Psychiatry
	1 Introduction
	2 Staging of Bipolar Disorder
		2.1 Neuroimaging
		2.2 Inflammatory and Neurotrophic Biomarkers
	3 Staging of Major Depressive Disorder
		3.1 Inflammatory and Neurotrophic Biomarkers
		3.2 Neuroimaging
	4 Staging of Post-Traumatic Stress Disorder
		4.1 Neuroimaging
		4.2 Inflammatory Biomarkers
	5 Schizophrenia
		5.1 Inflammatory and Neurotrophic Biomarkers
			5.1.1 Neuroimaging
	6 Conclusion
	References
Biomarkers of Delirium and Cognitive Impairment
	1 Introduction
	2 Candidate Biomarkers
		2.1 Inflammatory Biomarkers
		2.2 Neuroendocrine Biomarkers
		2.3 Biomarkers of Neurodegenerative Diseases and Delirium
		2.4 Neurotransmitter Activity
		2.5 Behavioral Biomarkers and Risk Assessment
		2.6 Neuroimaging Biomarkers
		2.7 Electroencephalogram (EEG)
	3 Conclusion
	References
Fluid-Based Biomarkers of Alzheimer’s Disease
	1 Introduction
	2 Cerebrospinal Fluid (CSF) Markers of Alzheimer’s Disease
	3 Blood-Based Biomarkers of Alzheimer’s Disease
	4 Final Remarks
	References
Neuroimaging Biomarkers in Alzheimer’s Disease and Related Disorders
	1 Introduction
	2 Neuroimaging Biomarkers
		2.1 MRI Regional Brain Volume
		2.2 Metabolism
		2.3 Perfusion Imaging
		2.4 Amyloid Imaging
		2.5 Tau Imaging
		2.6 Inflammation Imaging
	References
Biomarkers of Cognitive Decline and Dementia in Down Syndrome
	1 Introduction
	2 Cognitive Markers
	3 Biomarkers of Amyloid Pathology
		3.1 CSF and Plasma Markers
		3.2 Neuroimaging
	4 Biomarkers of Tau Pathology
		4.1 CSF and Plasma Markers
		4.2 Neuroimaging
	5 Biomarkers of Neurodegeneration
		5.1 CSF and Plasma Markers
		5.2 Neuroimaging
	6 Biomarkers of Inflammation and Oxidative Stress
	7 Biomarkers of Cerebrovascular Disease
	8 Genes and Protein Expression
		8.1 Amyloid Precursor Protein (APP) Gene
		8.2 Apolipoprotein E (ApoE)
	9 Conclusion
	References
Biomarkers of Schizophrenia
	1 Introduction
	2 Genetic Biomarkers
	3 Neuroimaging Biomarkers
		3.1 Predictors for Transition to Psychosis
		3.2 Diagnosis
		3.3 Treatment Response
	4 Peripheral Markers
		4.1 Immune Markers
		4.2 Oxidative Stress
	5 Cognitive Markers
	6 Discussion
	References
Biomarkers for Bipolar Disorder
	1 Introduction
	2 Neuroimaging
	3 Genetics
	4 Peripheral Markers
		4.1 HPA Axis Markers
		4.2 Neurotrophic Markers
		4.3 Immune Markers
		4.4 Oxidative Stress
		4.5 Metabolic Markers
	5 Cognitive Markers
	6 Circadian Markers
	7 Discussion
	References
Biomarkers in Anxiety Disorders
	1 Introduction
	2 Generalized Anxiety Disorder
		2.1 Structural Brain Morphology – Structural Magnetic Resonance Imaging Studies in Generalized Anxiety Disorder
		2.2 Structural Brain Morphology – in Generalized Anxiety Disorder
		2.3 fMRI in Generalized Anxiety Disorder
			2.3.1 Resting-State fMRI
			2.3.2 Emotional Dysregulation fMRI
			2.3.3 Emotional Reactivity – Facial Affect and Image Processing
			2.3.4 Emotional Reactivity – Verbal and Imagery Stimulus
			2.3.5 Cognition and Emotion
			2.3.6 Treatment Studies
		2.4 Neurochemical Biomarkers in Generalized Anxiety Disorder
	3 Panic Disorder
		3.1 Structural Brain Morphology – Structural Magnetic Resonance Imaging Studies in Panic Disorder
		3.2 Structural Brain Morphology – in Panic Disorder
		3.3 fMRI in Panic Disorder
			3.3.1 Resting-State fMRI in PD
			3.3.2 Emotional Processing fMRI in PD
			3.3.3 Treatment fMRI Studies
		3.4 Physiological Biomarkers
			3.4.1 Respiratory Patterns and Carbon Dioxide (CO2) Sensitivity
			3.4.2 Heart Rate Variability
		3.5 Neurochemical Biomarkers in PD
	4 Social Anxiety Disorder
		4.1 Structural Brain Morphology – Structural Magnetic Resonance Imaging Studies in Social Anxiety Disorder
		4.2 Structural Brain Morphology – White Matter (WM) and Structural Connectivity – Diffusion-Weighted Magnetic Resonance Imaging (DW-MRI) in Social Anxiety Disorder
		4.3 fMRI in Social Anxiety Disorder
			4.3.1 Resting-State fMRI in SAD
			4.3.2 Task-Based fMRI in SAD
			4.3.3 Treatment fMRI Studies
		4.4 PET and SPECT in Social Anxiety Disorder
		4.5 Neurochemical Biomarkers in Social Anxiety Disorder
	5 Final Considerations
	References
Biomarkers in Obsessive-Compulsive Spectrum Disorders
	1 Introduction
	2 Neuroimaging Biomarkers
		2.1 OCD Diagnosis
		2.2 OCD Treatment Response
		2.3 Obsessive-Compulsive Spectrum Disorders
	3 Neuroinflammatory Biomarkers
	4 Discussion
	References
Sleep Disorders: Identifying Biomarkers and Clinical Applications
	1 Introduction
	2 What We Are Looking For
	3 Where We Are
		3.1 Sleep Disorders and Insufficient Sleep
		3.2 Sleep Loss and Excessive Daytime Sleepiness
		3.3 Obstructive Sleep Apnea
		3.4 Insomnia Disorder
		3.5 REM Sleep Behavior Disorder
		3.6 Willis-Ekbom Disease
		3.7 Narcolepsy
		3.8 Circadian Phase Disorders
	4 Conclusions and Perspectives
	References
Biomarkers in Substance Use Disorder
	1 Introduction
	2 Nicotine
		2.1 Genetic/Epigenetic
		2.2 Cellular/Molecular
		2.3 Peripheral Systems
		2.4 Neuroimaging
		2.5 Cognitive-Behavioral/Psychometric
	3 Alcohol
		3.1 Genetic/Epigenetic
		3.2 Cellular/Molecular
		3.3 Peripheral Systems
		3.4 Neuroimaging
		3.5 Cognitive-Behavioral/Psychometric
	4 Psychostimulants
		4.1 Genetic/Epigenetic
		4.2 Cellular/Molecular
		4.3 Peripheral Systems
		4.4 Neuroimaging
			4.4.1 Positron Emission Tomography (PET) and Magnetic Resonance Spectroscopy (MRS)
			4.4.2 Diffusion Tensor Imaging (DTI)
			4.4.3 Functional Magnetic Resonance Imaging (fMRI)
			4.4.4 Electroencephalogram (EEG)
		4.5 Cognitive-Behavioral/Psychometric
	5 Opioids
		5.1 Genetic/Epigenetic
		5.2 Cellular/Molecular
		5.3 Peripheral Systems
		5.4 Neuroimaging
			5.4.1 Neurophysiology
			5.4.2 MRI
			5.4.3 PET
		5.5 Cognitive-Behavioral/Psychometric
	6 Summary and Future Directions
	References
Biomarkers of Traumatic Brain Injury and Related Neuropsychiatric Symptoms and Disorders
	1 Introduction
	2 Neuropsychiatric and Cognitive Symptoms Associated with TBI
		2.1 Depression
		2.2 Anxiety Disorders
		2.3 Posttraumatic Stress Disorder
		2.4 Bipolar Disorder and Mania
		2.5 Cognitive Impairment
		2.6 Apathy and Anhedonia
		2.7 Aggression
		2.8 Impulsivity
	3 TBI-Related Biomarkers for Neurobehavioral Symptoms and Disorders
		3.1 Blood Biomarkers
		3.2 Cerebral Spinal Fluid Biomarkers
		3.3 Neuroimaging Biomarkers
	4 Conclusion
	References
Biomarkers in Psychiatry: Conceptual and Methodological Challenges
	1 Introduction
	2 Biomarker Discovery
	3 Biomarker Validation and Implementation
	4 Perspectives
	References
Ethical Issues Related to Biomarkers in Psychiatry
	1 Introduction
	2 From the Bioethics Dawn to Values-Based Medicine
	3 Ethical Concerns with Biomarkers
		3.1 The Case of Neuroimaging
		3.2 The Case of Alzheimer’s Disease
		3.3 Children and Adolescents
	4 Mental Health and Primary Mental Disorders Particularities
	5 Conclusion
	References
Index