Behavioral Neurobiology of Schizophrenia and Its Treatment

Preface

Contents

Contributors

Part I: Function, Outcome and Treatmentin Schizophrenia

Assessing Function and Functional Outcome in Schizophrenia

1 Introduction

1.1 Functional Dimensions

1.2 Recent Reviews and Overviews of Measures of Functioning in Schizophrenia

2 Construct Validity

2.1 Functional Outcome as an Experiential Process

2.2 Environmental Moderators of the Functional Dimensions

3 Ecological Validity

3.1 Verisimilitude and Veridicality

3.2 Observation in Naturalistic Environments

4 Conclusion

References

Antipsychotics and Metabolics in the Post-CATIE Era

1 Introduction

2 Sources of Cardiovascular Risk

3 The Cardiovascular and Metabolic Risk Profile of Subjects Entering the CATIE Schizophrenia Trial

4 The Impact of Antipsychotic Treatment on Cardiovascular and Metabolic Outcomes in the CATIE Schizophrenia Trial

4.1 Metabolic Outcomes

4.2 Framingham Cardiovascular Risk

4.3 Outcomes with Novel Biomarkers

5 The Post-CATIE Era

5.1 Clinical Conclusions

5.2 Hypotheses on Schizophrenia and Metabolic Risk, and Adiposity-Independent Drug Effects

6 Conclusions

References

Pharmacological Strategies for Enhancing Cognition in Schizophrenia

1 Introduction

2 Cholinergic Agents

2.1 Cholinesterase Inhibitors

2.2 Nicotine, Nicotinic Receptor Agonists, and Muscarinic Receptor Agonists

3 Glutamatergic Agents

3.1 Glycine Allosteric Modulators

3.2 AMPA Receptor Modulators

3.3 Phosphodiesterase 5 Inhibitors

3.4 NMDA Receptor Antagonists

4 Gamma-Aminobutyric Acid Modulating Agents

5 Dopaminergic Agents

5.1 Indirect Dopamine Agonists

5.2 Atomoxetine and Amantadine

5.3 Selective Dopamine Agonists

6 Modafinil

7 Other Agents

8 Conclusions

References

Treatment Implications of the Schizophrenia Prodrome

1 Introduction

1.1 Early Identification of Psychotic Illness

1.2 Duration of Untreated Psychosis: Individual and Public Health Concern

1.3 Identifying and Predicting Risk for Psychotic Illnesses

1.4 Review of Treatment Studies in the Psychotic Prodrome

1.5 Nonpharmacologic Interventions

1.6 Psychopharmacologic Interventions

1.7 Pharmacologic Potential for Neuroprotection

1.8 Preliminary Treatment Recommendations

1.9 Ethical Implications

1.10 Development of Clinical Staging Criteria

1.11 Recommended Treatment Guidelines

1.12 General Summary

References

Antipsychotic Drug Development

1 Introduction

2 Dopamine D2 Receptors: Antagonism, Inverse Agonism, and Partial Agonism

3 Dopamine D3 Receptors: Cognition and ``Optimized Antagonism´´ at D3 Versus D2 Receptors

4 Serotonin 5-HT2A Receptors: Dopamine Brakes

5 Serotonin 5-HT1A Receptors: Dopamine Accelerators

6 Serotonin 5-HT2C Receptors

7 Serotonin 5-HT7 Receptors

8 Glutamatergic Receptors: NMDA and mGluR

9 Glycine Agonists

10 Receptors That Mediate Side Effects

11 Conclusion

References

Antipsychotic Dosing and Drug Delivery

1 Background

2 History

3 Dopamine Hypothesis

4 D2 Mechanism of Antipsychotic Medication

5 Clozapine

6 Genesis and Interpretation of ``Atypicality´´

7 Current State of Affairs

8 Dosing

8.1 Chlorpromazine Equivalents

8.2 Other Contributions (Non-D2) to Efficacy

8.2.1 Potential Benefits of Continuous Infusion

8.2.2 Alternative Hypothesis

9 Adherence

9.1 Background and Clinical Perspective

9.1.1 Adherence Rates

9.1.2 Relapse Rates as a Function of Adherence

9.1.3 Causes of Poor Adherence

9.2 Development of Depots

9.2.1 Clinical Studies and Meta-Analyses Comparing Depots to Oral Administration

9.2.2 Barriers to Creating Depots for More Agents

9.3 Development of Polymer-Based Microsphere Systems to Overcome Limitations of Chemistry

9.4 Potential Extension to Implants

9.4.1 Biodegradable Versus Nonbiodegradable

Nondegradable

Biodegradable Systems

9.4.2 PLGA/PLA

9.4.3 Poly(epsi-Caprolactone)

9.4.4 Drug Release Mechanisms

9.4.5 Erosion

9.4.6 Diffusion

9.4.7 Advantages

Duration

Reversibility

9.4.8 Limitations

Physical Drug Characteristics

Stability of the Molecule in a Physiological Environment

Ethical Considerations

Extension to Other Areas

9.5 Transdermal Delivery Systems

9.5.1 Potential Benefits

9.5.2 Passive Systems

9.5.3 Active Iontophoretic Systems

9.5.4 Limitations

9.6 Barriers to Development of Novel Delivery Systems

9.6.1 Long Clinical Trial Length

9.6.2 Inclusion of Controls in Studies of 6-Month Exposure to Antipsychotic Medications

9.6.3 Placebo Arm in Patients for Length of Time Needed to Truly Test a 6-Month Delivery System

10 Summary and Conclusions

References

Part II: Experimental measures of brain functionand dysfunction in schizophenia

Functional Brain Imaging in Schizophrenia: Selected Results and Methods

1 Introduction

2 Critical Regions

2.1 Positive Symptoms

2.1.1 Spontaneous Presentation

2.1.2 Brain Activation Studies

2.1.3 Comments

2.2 Negative Symptoms

2.2.1 Studies of Uncontrolled Mental State

2.2.2 Studies of Brain Activation: Working Memory

2.2.3 Summary and Comments

3 Brain Systems

3.1 Functional Connectivity

3.2 Summary and Comments

4 Final Comments and Emerging Trends

References

Neurochemical Imaging in Schizophrenia

1 Introduction

2 Brief Overview of Neurochemical Imaging Techniques

3 Imaging Neurotransmitter Systems

3.1 Dopamine

3.1.1 Striatal DA Parameters

D2 Receptors

Baseline Striatal D2 Receptor Density

DA Release: Pharmacological Challenge Studies

Baseline DA Release

Striatal D1 Receptors

Dopamine Transporters

DA Synthesis

3.1.2 Extrastriatal Dopamine

D2 Receptors

Extrastriatal D1 Receptors

3.2 Serotonin

3.2.1 5-HT2A Receptors

3.2.2 5-HT1A Receptors

3.2.3 Serotonin Transporters

3.3 Gamma-Aminobutyric Acid

3.4 N-Methyl-d-Aspartic Acid and Glutamate

4 Occupancy Studies (Pharmacological Studies)

4.1 DA Receptor Occupancy

4.1.1 D2 Receptor Occupancy

Implications for Treatment

4.1.2 D1 Receptor Occupancy

4.2 Serotonin Occupancy

4.2.1 5-HT2A Receptor Occupancy

4.2.2 5-HT1A Receptor Occupancy

5 Future Directions

References

A Selective Review of Volumetric and Morphometric Imaging in Schizophrenia

1 Introduction

2 Limbic/Paralimbic Regions

3 Prefrontal Cortical Regions

4 Caudate Nucleus

5 Neocortical Temporal Lobe

6 Conclusion

References

Neurophysiological Measures of Sensory Registration, Stimulus Discrimination, and Selection in Schizophrenia Patients

1 Introduction

1.1 Automatic and Attention Dependent Processes

1.2 Event-Related Potentials

1.3 The Oddball Paradigm

1.4 Basic Processes

2 N1 ERP

2.1 N1 Deficits in Schizophrenia

2.2 N1 Stability, Reliability, and Heritability

3 MMN ERP

3.1 MMN Deficits in Schizophrenia

3.2 MMN Stability, Reliability, and Heritability

4 P300 ERP

4.1 P300 Deficits in Schizophrenia

4.2 P3 Stability, Reliability, and Heritability

5 Discussion

References

Eye Tracking Dysfunction in Schizophrenia: Characterization and Pathophysiology

1 Introduction

2 Components of the Smooth Pursuit Eye Tracking Response

3 Characterization of ETD

4 Pathophysiology of ETD

4.1 Behavioral Evaluations of the Contribution of Motion Processing to ETD

4.1.1 Psychophysical Judgment Studies of Motion Perception

4.1.2 Saccadic Studies of Motion Perception

4.1.3 Pursuit Initiation Studies

4.2 Extraretinal Processes in Pursuit

4.3 Neuroimaging of Pursuit and Component Processes

5 Association Between Genetic Polymorphisms and ETD

6 Summary

References

Prepulse Inhibition of the Startle Reflex: A Window on the Brain in Schizophrenia

1 Background of PPI Studies

2 Prepulse Inhibition Deficits in Schizophrenia Spectrum (and Other) Patients

3 Sex, Symptoms, Cognitive, and Functional Correlates of PPI Deficits in Schizophrenia Patients

4 Pharmacological Studies of PPI in Human Subjects Relevant to Schizophrenia

4.1 Dopamine

4.2 Nicotine

5 Antipsychotic Medications in Schizophrenia Patients

6 Genomic Influences on PPI in Schizophrenia

7 Summary and Future Directions

References

Neurocognition in Schizophrenia

1 Introduction

2 General Intellectual Functioning

3 Attention

4 Processing Speed

5 Executive Functioning

6 Learning and Memory

7 Language

8 Visual Perceptual/Constructional Skills

9 Fine Motor Skills

10 Social Cognition

11 Deficits Among Populations at Risk and Endophenotypes

12 Longitudinal Studies of Neuropsychological Deficits

13 Future Directions of Research

References

Animal Models of Schizophrenia

1 Introduction

2 Criteria Used to Validate Animal Models

2.1 Reliability

2.2 Face Validity

2.3 Predictive Validity

2.4 Construct Validity

2.5 Etiological Validity

3 Modeling Schizophrenia in Animals

4 Behavioral Measures by Symptom Group

4.1 Positive Symptoms

4.2 Negative Symptoms

4.2.1 Progressive Ratio Breakpoint Studies

4.2.2 Intracranial Self-Stimulation

4.3 Cognitive Symptoms

4.3.1 Attentional Dysfunction

5-Choice Serial Reaction-Time Task

Sustained Attention Task

4.3.2 Executive Function

Attentional Set-Shifting Task

4.3.3 Working Memory

Radial Arm Maze

Odor Span Task

4.3.4 Visual Learning and Memory

Morris Water Maze

Novel Object Recognition Task

4.4 Sensorimotor Gating Paradigms

4.4.1 Prepulse Inhibition

4.4.2 Auditory Gating

4.5 Latent Inhibition

5 Experimental Manipulations for Animal Models of Schizophrenia

5.1 Dopaminergic Agonist Models

5.1.1 Acute Models

5.1.2 Repeat Administration Models

5.2 Glutamatergic Antagonist Models

5.2.1 Acute Models

5.2.2 Repeated Dosing Models

5.3 Serotonergic Agonist Models

5.4 Cholinergic Antagonist Models

5.5 Lesion Models

5.6 Genetic Models for Schizophrenia

5.6.1 Schizophrenia as a Genetic Disease

5.6.2 Candidate Susceptibility Genes for Schizophrenia

Human Genetic Linkage and Association

Neuregulin-1

Dysbindin

Cytogenetic Studies

Disrupted in Schizophrenia 1

COMT

NPAS3

5.7 Candidate Genes from Animal Models

5.7.1 Sp4

5.7.2 Copy Number Variation

5.7.3 Chromosome 22q11 Deletion

5.7.4 Chromosome 15q13.3 Deletion

5.8 Transgenic Mouse Models

5.8.1 Neuregulin

5.8.2 Dysbindin

5.8.3 DISC1

5.8.4 COMT

5.8.5 CHRNA7

6 Conclusions

References

Models of Neurodevelopmental Abnormalities in Schizophrenia

1 Neurodevelopmental Models of Schizophrenia

1.1 Developmental Theory of Schizophrenia

1.2 Animal Models of Developmental Hypothesis

2 Behavioral Measures

2.1 Spontaneous and Drug-Induced Locomotor Activity

2.2 Gating Deficits

2.3 Attention

2.4 Cognitive Deficits

2.5 Social Interaction

3 Epidemiologic-Based Developmental Manipulations

3.1 Viral and Immune-Activating Models of Schizophrenia

3.1.1 Prenatal Viral Exposure

3.1.2 Prenatal PolyI:C Exposure

3.1.3 Prenatal LPS Exposure

3.1.4 Role of Cytokines in Prenatal Immune Models

3.1.5 Neonatal Immune Activation

3.1.6 Discussion of Immune Models

3.2 Maternal Malnutrition

3.2.1 Prenatal Protein Deficiency

3.2.2 Prenatal Vitamin D Deficiency

3.3 Obstetric Complications

3.3.1 Cesarean Section

3.3.2 Perinatal Hypoxia

3.3.3 Placental Insufficiency

3.4 Prenatal/Postnatal Stress

3.4.1 Prenatal Stress

3.4.2 Maternal Deprivation

3.5 Postweaning Social Isolation

3.5.1 Isolation Rearing: Neuroanatomical Abnormalities

3.5.2 Isolation Rearing: Behavioral Abnormalities

3.5.3 Discussion of Isolation-Rearing Model

4 Heuristic Neurodevelopmental Models

4.1 Neonatal Ventral Hippocampal Lesion Model

4.1.1 Neonatal Ventral Hippocampal Lesion Model: Behavioral Studies

4.1.2 Neonatal Ventral Hippocampal Lesion Model: Neuropathological Studies

4.1.3 Conclusions for nVH Lesion Model

4.2 Prenatal Toxin

4.3 Postnatal/Neonatal NMDA Antagonists

5 Discussion

References

Part III: Neural substrates of schizophrenia

Prefrontal Cortical Circuits in Schizophrenia

1 Introduction

1.1 Working Memory Impairments and Dorsolateral Prefrontal Cortex Circuitry

2 Pathology of DLPFC Circuitry in Schizophrenia

2.1 Abnormalities in Pyramidal Neuron Anatomy and Glutamatergic Signaling

2.2 Abnormalities in GABA Signaling

2.3 Alterations in the Dopamine Neurotransmitter System

2.4 Pathophysiological Consequences of Altered DLPFC Circuitry on Cognitive Functioning in Schizophrenia

3 Cortical Circuitry Alterations Beyond the DLPFC

4 Cannabis Use and Schizophrenia

4.1 Clinical Effects of Cannabis Use in Schizophrenia

4.2 Potential Impact of Cannabis Use of Altered Neurotransmitter Systems in Schizophrenia

4.3 Endogenous Cannabinoid System and Schizophrenia

5 From Pathology to New Therapeutic Approaches

References

Thalamic Pathology in Schizophrenia

1 Introduction

2 The Thalamus Is Uniquely Suited to Modulate Signals Passing to the Cortex

3 Syndromes of Thalamic Dysfunction and Their Relevance to Schizophrenia

4 Postmortem Evidence: Structural Changes

5 Postmortem Evidence: Neurochemical Changes

6 Evidence from Neuroimaging

6.1 Lower Thalamic Volume Is Frequently Seen in Schizophrenia: Changes May Be Localized to the MDN, the Anterior Nuclei, and the Pulvinar

6.2 Medication Effects

6.3 Studies at the Onset of Psychosis, and Longitudinal Data

6.4 Imaging Studies in Relatives of Subjects with Schizophrenia

6.5 Other Types of Neuroimaging (fMRI, PET, SPECT, DTI)

6.6 The Limitations of Neuroimaging: Why the Conflicting Results?

7 Thalamic Pathology in Schizophrenia: Clinical Correlates

8 Dysfunction in Thalamocortical Circuits

References

Hippocampal Pathology in Schizophrenia

1 Introduction

2 The Human Hippocampus

3 The Hippocampus in Neuropsychiatric Disorders

4 Models of Hippocampal Dysfunction in Schizophrenia

5 Evidence of Hippocampal Dysfunction in Schizophrenia

5.1 Hippocampal Volume Change in Schizophrenia

5.2 Hippocampal Neurons in Schizophrenia

5.2.1 Hippocampal Neuron Number

5.2.2 Glutamatergic Neurotransmission

5.2.3 GABAergic Neurons

5.2.4 Other Neurotransmitters

5.3 Genetic Mechanisms of Hippocampal Pathology in Schizophrenia

5.4 Hippocampal Function and Schizophrenia

5.4.1 Hippocampal Activity at Rest in Schizophrenia

5.4.2 Hippocampal Activity and Cognitive Function in Schizophrenia

6 Animal Models

7 Critical Review of Findings and Directions for Future Studies

References

Integrative Circuit Models and Their Implications for the Pathophysiologies and Treatments of the Schizophrenias

1 Introduction

2 Distributed Neural Dysfunction: The ``Hole´´ Thing Is Wrong

3 Now That We Know This, What Do We Ask?

3.1 Primary Versus Secondary?

3.2 Clinical Correlates?

3.3 Different Etiologies?

3.4 Risk Markers?

3.5 Which Target?

4 Where Does This Lead Us?

4.1 The Fourth Option

4.2 Old News, New Urgency

5 Conclusion

References

Part IV: Genetic and molecular substratesof schizophrenia

Experimental Approaches for Identifying Schizophrenia Risk Genes

1 Introduction

2 Linkage Mapping

3 Association Mapping

4 Identifying Genes Through Structural Chromosomal Variations

5 Re-Sequencing

References

Epigenetics of Schizophrenia

1 Introduction

2 Histone Modifications and DNA Methylation

3 Findings in Schizophrenia Postmortem Brain

4 Reproducibility of Epigenetic Alterations in Schizophrenia Postmortem Brain

5 Cellular Specificity of Epigenetic Markings

6 Epigenetic Markings in Brain: How Stable?

7 Implications for the Neurobiology of Schizophrenia

8 Chromatin Remodeling and Antipsychotic Medication

9 Synopsis and Outlook

References

Molecules, Signaling, and Schizophrenia

1 Introduction

2 AKT1 Gene and the AKT/GSK3beta Signaling Pathway

2.1 Neuronal Plasticity

2.2 Dopamine Signaling

2.3 GSK3beta Signaling

3 PPP3CC Gene and the Calcineurin Signaling Pathway

3.1 Dopamine Signaling

3.2 Transcriptional Regulation

3.3 Synaptic Plasticity and Neurotransmission

3.4 Nitric Oxide Signaling

3.5 Vesicle Trafficking

3.6 Cytoskeletal Phosphorylation

4 DISC1 Gene and the cAMP and GSK3/Wnt Signaling Pathways

4.1 Disc1 and cAMP Signaling

4.1.1 PDE4 and Psychiatric Disorders

4.1.2 Adenylyl Cyclase and Psychiatric Disorders

4.1.3 cAMP-Dependent Downstream Signaling and Schizophrenia

Dopamine Signaling

EPAC-Mediated Signaling

4.2 Disc1 and GSK3beta Signaling

5 General Summary

References

Index