Drug Development in Psychiatry

Contents
About the Editors
Chapter 1: Drug Development in Psychiatry: The Long and Winding Road from Chance Discovery to Rational Development
1.1 Current Status of Psychiatric Diagnosis as a Rate-Limiting Step in Rational Psychiatric Drug Development
1.2 What Possible Changes Lie Ahead for Psychiatric Diagnoses?
1.3 The History of Current Psychiatric Drug Development: Chance Discovery and Rationale Refinement
1.4 The Future or Where to Go from Here?
1.5 The Immediate Future Which is Upbeat
References
Chapter 2: The History of Drug Development in Psychiatry: A Lesson in Serendipity
2.1 Introduction
2.2 Chlorpromazine
2.3 Monoamine Oxidase Inhibitors
2.4 Tricyclic Antidepressants
2.5 “Me Too” Drugs
2.6 Lithium
2.7 Valproate and Carbamazepine
2.8 Meprobamate and Mephenesin
2.9 LSD
2.10 Conclusion and Future Directions
References
Chapter 3: The Evolving Role of Animal Models in the Discovery and Development of Novel Treatments for Psychiatric Disorders
3.1 Introduction
3.2 Animal Models for Psychiatric Drug Discovery
3.2.1 Historical and Current Use of Animal Models for Psychiatric Disorders
3.2.2 Assessing the Validity of Animal Models
3.2.3 Types of Animal Models of Psychiatric Disorders
Major Depressive Disorder
Generalized Anxiety Disorder
Post-Traumatic Stress Disorder
Schizophrenia Spectrum and Other Psychotic Disorders
Substance-Related and Addictive Disorders
Attention Deficit Hyperactivity Disorder
3.2.4 Other Clinical Considerations to Modeling Psychiatric Disorders in Animals: Sex, Age, Ethnicity
Sex and Age Differences in Symptomatology of Psychiatric Illnesses
Sex and Age Differences in Response to Psychiatric Drugs
Sex, Age, and Ethnicity Differences in Pharmacokinetics of Psychiatric Drugs
Use of Female Animals for Drug Discovery in Psychiatric Disorders
3.3 Utility of Animal Models Throughout the Stages of Modern Drug Discovery Stages
3.3.1 Target Identification and Validation
3.3.2 High-Throughput Screening/Hit-to-Lead
3.3.3 Early-, Mid-, and Late-Lead Optimization
3.3.4 Preclinical Candidate Selection
3.3.5 Translational Animal Models for Target Occupancy and Functional Target Engagement for Psychiatric Drug Discovery
Imaging
fMRI
PET
Quantitative EEG and Event-Related Potential Measurements
3.3.6 Example of In Vivo Target Validation of the Selective M4 PAM Mechanism for the Treatment of Schizophrenia
3.3.7 Example of In Vivo Characterization of the Selective mGlu5 NAM Basimglurant Through the Late Stage Preclinical Discovery
3.4 Future Innovations for Animal Models in Psychiatric Drug Discovery
3.4.1 RDoC Framework for Clinical to Preclinical Translational Studies for New Animal Model Development
3.4.2 Novel Technologies Enabling Development of Animal Models
Novel Genetic Approaches
Novel Techniques to Study Neurocircuitry Abnormalities in Psychiatric Disorders
Optogenetics and dLight Signaling Strategies
DREADDs
GCaMP
Novel High-Throughput Behavioral Screening Technologies
3.5 Summary and Future of Animal Models in Psychiatric Drug Discovery
References
Chapter 4: Discovery and Development of Monoamine Transporter Ligands
4.1 Introduction and Overview of Monoamine Transporters
4.2 Therapeutic Relevance of MATs
4.3 Structural Insights and Transport Mechanism
4.4 Central Binding Site Versus Allosteric Binding Sites in MATs
4.5 Medicinal Chemistry of MAT Ligands
4.5.1 Structure-Activity Relationship Studies of DAT Ligands
4.5.2 Structure-Activity Relationship Studies of SERT Ligands
4.5.3 Structure-Activity Relationship Studies of NET Ligands
4.6 Conclusion
References
Chapter 5: Drug Development for New Psychiatric Drug Therapies
5.1 The Drug Development Pathway
5.1.1 Pathway Overview
5.1.2 Drug Development Costs
5.1.3 Regulatory Overview
5.1.4 Types of Drug Therapies
New Molecular Entities
Generics
5.2 Preclinical Drug Development Phase
5.2.1 Characterization
5.2.2 Developing a Formulation Prototype
5.2.3 In Vitro-in Vivo Testing
5.2.4 Pharmacokinetic-Pharmacodynamic (PK-PD) Analysis
Animal Models
5.2.5 Mutagenicity
5.2.6 Toxicology Considerations
5.2.7 Regulatory Pathway: Preclinical to Clinical Trials
5.2.8 Investigational New Drug (IND) Application
5.3 Clinical Development Phase
5.3.1 Phase I Clinical Trials
5.3.2 Phase II Clinical Trials
5.3.3 Phase III Clinical Trials
5.3.4 Pediatric Considerations
5.4 Regulatory Review Process
5.4.1 Regulatory Pathway: Clinical Trials to Commercialization
5.4.2 NDA Review and Approval
5.4.3 Abbreviated NDAs
5.4.4 Advisory Committees
5.4.5 Expedited Review Programs
5.4.6 Prescription Drug Labeling Information
5.5 Phase IV Activities
5.5.1 Phase IV Clinical Trials
5.5.2 Monitoring Adverse Effects
5.5.3 Phase IV Health Outcomes/Quality of Life
5.6 Bioethical Issues
5.7 Conclusions
References
Chapter 6: Post-Approval Research in Drug Development: Priorities and Practices
6.1 Priorities
6.2 Regulatory Commitments
6.3 Further Clinical Considerations
6.4 Payer Considerations
6.5 Decisions: What Gets Studied?
6.6 Practices
6.7 Conclusions
References
Chapter 7: Discovery of New Transmitter Systems and Hence New Drug Targets
7.1 Introduction
7.1.1 Limitations in Psychiatric Drug Development
7.1.2 Neurotransmitter Systems
7.1.3 Genetic Basis for Drug Discovery
7.1.4 Timeline from Discovery to Approval
7.2 Orexin Pathway
7.2.1 Orexin Neurotransmitters and Receptors
7.2.2 Mechanism of Action
7.2.3 Role of Orexin in CNS Diseases
7.3 History of Dual Orexin Receptor Antagonists
7.3.1 Almorexant
7.3.2 SB-649868
7.3.3 Lemborexant
7.3.4 Filorexant
7.4 Suvorexant
7.4.1 Mechanism of Action
7.4.2 Clinical Trial Results
7.5 Targeted Drug Development
7.6 Conclusions
References
Chapter 8: Reverse Engineering Drugs: Lorcaserin as an Example
8.1 Introduction
8.2 Overview of CNS Disorders and Drug Development
8.3 Approaches to Drug Development
8.4 Reverse Engineering
8.5 History of Seratonin Receptors
8.6 5HT2 Receptor Agonists
8.7 Lorcaserin
8.8 Reverse Engineering in Drug Discovery
8.9 Conclusions
References
Chapter 9: Back to the Future of Neuropsychopharmacology
9.1 Breakthrough Discoveries in the Past: What Made Them Possible?
9.2 The Schizophrenic Mouse 1.0: How It Was Done in the Past
9.3 The Schizophrenic Mouse 2.0: Reverse Engineering Approaches
9.4 Redefining the Use of Animal Models in Neuropsychiatric Drug Discovery
9.4.1 Lesson 1: Do Not Expect a Mouse with Schizophrenia
9.4.2 Lesson 2: Understand Drug-Target Interactions
9.4.3 Lesson 3: Be Confident in the Data
9.4.4 Lesson 4: Adopt Transparent and Open Science Practices
References
Chapter 10: Targeted Treatments for Fragile X Syndrome
10.1 Introduction: Overview of Fragile X Spectrum Disorders Including the Full Mutation and FXS and Premutation Disorders
10.2 Animal Models Guiding Targeted Treatments
10.2.1 KO Mouse Model and Drosophila Model for FXS
10.2.2 Downside of Animal Models
10.3 FMRP Deficits and Pathways that Are Dysregulated in the Absence of FMRP
10.4 Symptomatic Treatments for FXS
10.4.1 Stimulants and Alpha Agonists
10.4.2 Antidepressants
10.4.3 Antipsychotics
10.4.4 Mood Stabilizers
10.5 mGluR5: The Failed Translation of Preclinical Success
10.5.1 Target Supported by Theory
10.5.2 mGluR5 Human Trials
10.6 Targeted Treatments Not Yet FDA Approved
10.7 Targeted Treatments Available Currently
10.7.1 Minocycline
10.7.2 Metformin
10.7.3 Cannabidiol (CBD)
10.8 Lessons Learned
10.8.1 Easier to Cure the Mouse than the Human
10.8.2 How to Avoid a Placebo Effect
10.8.3 Quantitative Outcome Measures Are a Necessity
10.8.4 Measuring Cognition with the NIH Toolbox
10.8.5 New Language Outcome Measures
10.8.6 Multimodality Treatment Can Be Synergistic
10.8.7 Earlier Treatments Can Build a Better Brain
10.9 Summary
10.10 Definitions/Assessments
References
Chapter 11: The Difficult Path to the Discovery of Novel Treatments in Psychiatric Disorders
11.1 Is There a Problem with the Discovery of New Therapeutics for Psychiatric Disorders?
11.1.1 Why Are Most Drugs for Psychiatric Disorders Similar?
11.2 Drug Discovery
11.2.1 Defining Drugs and the Limitations of Therapeutic Benefit
11.2.2 The Process of Drug Discovery
11.2.3 The Economics of Drug Discovery and Development
11.3 The Unique Problems of CNS Drug Discovery in General and Psychiatric Drug Discovery in Particular
11.3.1 Why Is CNS Drug Discovery Difficult?
11.3.2 The Complicated Landscape of Psychiatric Drug Discovery
11.3.3 Schizophrenia Spectrum as a Disorder and a Drug Target
11.4 How Can We Move Psychiatric Drug Discovery Forward?
11.4.1 Biomarkers in Psychiatry
11.5 New Approaches in Drug Discovery for Schizophrenia
11.6 Conclusions
References
Chapter 12: Biomarkers in Psychiatric Drug Development: From Precision Medicine to Novel Therapeutics
12.1 Introduction
12.2 Conclusion
References
Chapter 13: The Role of fMRI in Drug Development: An Update
13.1 Introduction
13.1.1 fMRI Definitions
Data Acquisition Paradigms for fMRI
Data Analysis Paradigms for fMRI
13.1.2 Drug Development Definitions
Definition of “Biomarker”
13.1.3 Theoretical Schema for Utilizing fMRI for Biomarkers in Drug Development
Preclinical Phase
Early-Phase Human Studies
Late-Phase Human Studies
13.1.4 Current Regulatory Status of fMRI Biomarkers
13.2 What Is Required of Any fMRI Biomarker?
13.2.1 Reproducibility and Modification by the Pharmacological Agent
13.2.2 Well-Defined Measurement Characteristics
13.2.3 Prespecification of Acquisition and Analysis Steps
13.2.4 Real-World Applicability (Diverse Centers, Diverse Technologists)
13.2.5 Rigorous Quality Control
13.3 What Can fMRI Biomarkers Do Currently?
13.3.1 Change in Response to Acute and Chronic Administration of Certain Drugs
13.3.2 Identify Converging Mechanisms of Drug Response Across Drugs
13.3.3 Support Translation Between Preclinical and Clinical Studies
13.4 What Are the Challenges in Developing fMRI Biomarkers?
13.4.1 Lack of Agreed-Upon Concise Readouts from fMRI Exams
13.4.2 Poor Replication of Effects at the Individual Level
13.4.3 Poor Replication of Effects at the Group Level
13.4.4 A Replication Crisis?
13.4.5 Lack of Full Understanding of Molecular Modifiers of the fMRI Signal
13.4.6 Lack of Full Understanding of Real-World Confounders/Best Practices for Participant Preparation, Etc.
13.4.7 Lack of Understanding of Relationships Among Dose, fMRI Signals, and Clinical Outcomes
13.4.8 Lack of Established Protocols for fMRI-Informed Participant Screening, Stratification, Trial Enrichment
13.5 How to Overcome the Challenges
13.5.1 Form Public–Private Partnerships to Fund fMRI Method Development and Validation Studies
13.5.2 Develop Infrastructure for Sharing Clinical Trial Data Without Exposing Sponsors or CROs to Legal Risks
13.5.3 Establish an Ongoing, Regular Conference on fMRI in Clinical Trials
13.5.4 Strengthen Publishing of All fMRI Validation Studies, Positive or Negative; Strengthen fMRI Method Reporting  Standards
References
Chapter 14: Monoamine Oxidase B (MAO-B): A Target for Rational Drug Development in Schizophrenia Using PET Imaging as an Example
14.1 General
14.2 Experimental Materials and Methods
14.2.1 Eligibility Criteria
14.2.2 Literature Search
14.2.3 Study Selection
14.2.4 Data Extraction
14.2.5 Study Identification
14.3 Review of Studies
14.3.1 Postmortem Findings (Table 14.1)
14.3.2 Preclinical Findings in MAO-B Knock-Out Mice (Table 14.2)
14.3.3 Peripheral Findings (Table 14.3)
14.3.4 Genetic Findings
14.3.5 PET Findings: Review of Human MAO-B Studies (Table 14.4)
14.4 Conclusion and Clinical Translation
References
Chapter 15: Genomics in Treatment Development
15.1 Pharmacogenomics and Drug Development
15.2 Genomics and Drug Development
15.3 Epigenetic Targets of Drug Development
15.3.1 Epigenetic Modifications: General Aspects
15.3.2 Epigenetic Modifications: Role in Psychiatric Disorders
15.3.3 Epigenetic Pharmacotherapy
15.4 Conclusion
References
Chapter 16: Increased Inflammation and Treatment of Depression: From Resistance to Reuse, Repurposing, and Redesign
16.1 Introduction
16.2 Increased Inflammation in Depression: Sources, Symptoms, and Role in Treatment Resistance
16.2.1 Inflammation in Depression: Causes and Consequences
16.2.2 Increased Inflammation and Antidepressant Treatment Response
16.2.3 Relationships Between Inflammation and Symptom Domains
16.2.4 Inhibition of Inflammation in Depression and Symptom Specificity
16.3 Inflammation Effects on the Brain and Behavior
16.3.1 Impact of Inflammation on Reward and Motor Regions and Circuits
16.3.2 Impact of Inflammation on Regions and Circuits for Fear, Anxiety, and Emotional Processing
16.3.3 Endogenous Inflammation and Circuit Dysfunction in Patients with Depression
16.4 Treatment Targets for Depressed Patients with Increased Inflammation
16.4.1 Compounds That Increase Dopamine Synthesis, Synaptic Availability, and Receptor Signaling
16.4.2 Therapies That Target Glutamate Transmission
16.4.3 Therapies That Affect the Immune System
16.5 Summary and Translational Conclusions
References
Chapter 17: Experimental Medicine Approaches in Early-Phase CNS Drug Development
17.1 The Evolving Landscape in Early-Phase Clinical Trials in CNS
17.1.1 Challenges with Traditional Approach to Phase 1 Trials
17.1.2 Evolution of Phase 1 Study Designs and Concepts
17.1.3 Early Inclusion of Patients into the Phase 1 Study
17.1.4 Incorporating Biomarkers into the Phase 1 Clinical Development Plan
17.2 Leveraging Experimental Medicine to Support Early Decision-Making in Early-Phase Trials
17.2.1 NIMH Research Domain Criteria (RDoC) Framework and the “Fast-Fail” Initiative
17.2.2 Incorporating RDoC and Fast-Fail Concepts: A Proof-of-Mechanism Study
17.3 Biomarker Technologies in Ph1 Studies to Support PoM
17.3.1 Electrophysiologic Biomarkers in Early-Phase CNS Drug Development
Quantitative Electroencephalography (QEEG)
Event-Related Potentials (ERP)
Polysomnography (PSG)
17.3.2 Neuroimaging Biomarkers in Early-Phase CNS Drug Development
Positron Emission Tomography (PET)
Magnetic Resonance Imaging (MRI)
17.4 An Example of PoM Studies Supporting the Early Clinical Development Plan
17.4.1 Development of Takeda’s TAK-063, Selective Phosphodiesterase 10A (PDE10A) Inhibitor for Schizophrenia
References
Index