Drug Development in Psychiatry

Description

The book reviews clinical trial methodology as it pertains to drug development in psychiatry. The reader will understand the process of drug development in psychiatry from discovery through marketing with the help of clinically relevant examples. The reader will appreciate the history of drug development in psychiatry dating back to the era of serendipitous discovery and culminating in an era of new and highly focused targets. Readers will understand how drug development in psychiatry has changed and adapted with the discovery of novel mechanism of action drugs. Novel drugs and disease targets have changed the way developers and regulatory agencies think about clinical trial methodology. The book elucidates how biomarkers, genetics and advances in neuroscience and neuroimaging have influenced drug development approaches, which will ultimately change the practice of psychiatry. The book will be broken down into the following sections: a.        Prior to the 1960s - Drug discovery by chance observation b.       The last 50 years – refined targeting of CNS drugs without the discovery of mechanistically new drugs c.       The future – the discovery and development of mechanistically new drugs. The examination of new targets, genetics and biomarkers.  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