Principles of CNS drugdevelopment: from testtube to patient

John Kelly

Department of Pharmacology and TherapeuticsNational University of IrelandGalwayIreland

AJohn Wiley & Sons, Ltd., Publication

Principles of CNS drug development

Principles of CNS drugdevelopment: from testtube to patient

John Kelly

Department of Pharmacology and TherapeuticsNational University of IrelandGalwayIreland

AJohn Wiley & Sons, Ltd., Publication

This edition first published 2009, � 2009 by John Wiley & Sons Ltd.

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To

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Contents

Acknowledgements xi

Preface xiii

Abbreviations xvii

1 Introduction 11.1 The global burden of CNS disease 21.2 Assessment of the global burden of disease 31.3 The prevalence of CNS disorders 51.4 Disability due to CNS disorders 51.5 Economic Costs 81.6 Concluding comments 11References 11

2 An overview of the major CNS disorders 132.1 Introduction 132.2 Overview of psychiatric disorders 172.3 Overview of neurological/neurodegenerative

disorders 312.4 Concluding comments 37References 38

3 Neurobiological substrates of CNS disorders 433.1 Introduction 433.2 Brief introduction to the principles of chemical

neurotransmission 443.3 Stages of chemical neurotransmission 473.4 Approaches to investigating CNS alterations in CNS disorders 503.5 Evidence for a neurobiological rationale for CNS disorders 533.6 Concluding comments 61References 62

4 Current pharmacological targets 654.1 Introduction 654.2 Pharmacological treatments for depression 674.3 Pharmacological treatments for schizophrenia 71

4.4 Pharmacological treatments for anxiety disorders 754.5 Pharmacological treatments for epilepsy 774.6 Pharmacological treatments for Parkinson’s disease 804.7 Pharmacological treatments for Alzheimer’s disease 824.8 Concluding comments 83References 84

5 Premarketing efficacy evaluation 875.1 Introduction 875.2 Target identification 905.3 Lead optimisation 915.4 Target validation in animal models 975.5 The use of genetically modified animals in CNS drug

development 1005.6 A selection of animal models of psychiatric disease 1015.7 A selection of animal models of neurodegenerative disease 1085.8 Which models to choose 1115.9 Clinical trials that evaluate drug efficacy 1125.10 Specific drug profiles 120References 121

6 Pharmacokinetic considerations: Absorption, distribution,metabolism and elimination 1276.1 Introduction 1276.2 What are the ‘ideal’ pharmacokinetic properties for a CNS drug? 1296.3 Absorption 1316.4 Distribution 1416.5 Metabolism 1506.6 Elimination 1586.7 Measurement of drug concentrations 1606.8 Factors that affect pharmacokinetics 1616.9 Allometric scaling 1636.10 Microdosing (Phase 0) Studies 1636.11 Dose prediction and therapeutic drug monitoring 1646.12 Stereoselectivity of metabolism of drugs 1646.13 Specific drug profiles 1656.14 Concluding comments 166References 166

7 Safety concerns 1737.1 Introduction 1737.2 Postmarketing surveillance 1747.3 Acute poisoning 1757.4 Quantification of the relative risk of fatalities from CNS drugs 1767.5 Adverse drug reactions (ADRs) 182

viii CONTENTS

7.6 Specific types of toxicity encountered with psychotropic drugs 1837.7 Safety concerns following long-term administration of CNS Drugs 1857.8 Polypharmacy 1997.9 Specific drug profiles 2017.10 Concluding comments 203References 204Websites 210

8 Preclinical and clinical safety evaluation 2118.1 Introduction 2118.2 Preclinical exploratory toxicology and safety pharmacology evaluations 2158.3 Primary and secondary pharmacology 2168.4 Safety pharmacology 2208.5 Toxicology studies required for regulatory purposes 2248.6 Clinical Studies 2388.7 Specific drug profiles 2398.8 Concluding comments 240References 241Websites 244

9 CNS drug targets in development and futureperspectives 2459.1 Introduction 2459.2 How much does it cost to develop a drug? 2479.3 Clinical drug development times 2489.4 Harmonisation between regulatory agencies 2489.5 Development of biomarkers for clinical efficacy 2499.6 Quality of life issues 2559.7 Cost-effectiveness of novel treatments 2579.8 Patient advocacy groups 2589.9 Novel targets for CNS disorders 2599.10 Targets in selected CNS disorders 2619.11 Targeting of signalling pathways 2709.12 Cardiovascular drugs in Alzheimer’s disease 2739.13 Modifying oxidative stress and inflammatory

responses 2749.14 Targeting of the amyloid-� protein in Alzheimer’s disease 2769.15 Concluding comments 278References 279

Appendices 287

Index 295

CONTENTS ix

Acknowledgements

This book has come about as a result of the significant and unselfish support of anumber of students, friends and colleagues that I’ve had the privilege to work withover the last two decades within the Department of Pharmacology and Therapeuticsin NUI, Galway.

First, I’d like to acknowledge the pivotal role that Sandra O’Brien played inmaking this book possible. Sandra’s attention to detail in preparing certain sum-mary graphs, figures and tables, and her careful proof reading of the manuscripthave been outstanding. I ought also to mention her determination in seeking thecopyright permissions that really were a test of her patience and forbearance. I hopethe experience will stand you in good stead as you embark on your PhD studies!

Thanks to the students both of our undergraduate Pharmacology and M.Sc.Neuropharmacology who have over the years been so instrumental in developingthe ideas that have formed the basis of this book.

To the staff of the Department of Pharmacology and Therapeutics, NUI, Galway,both past and present. Their acceptance and support for this project has made thetask that bit easier to face over the last two years. It has ensured that I was able tocomplete the book in a timely fashion and that those tricky deadlines were met!

A particular note of gratitude goes to Professor Brian Leonard, who brought meto Galway as a PhD student many moons ago, and to whom I’m indebted for passingon to me perhaps a little of his boundless enthusiasm for psychopharmacology andits application in the development of drugs.

Finally, a special thanks to Jo Tyszka, who copyedited the book, and to all at JohnWiley & Sons publishers, particularly to Andrea Baier, Fiona Woods, Izzy Canning,and Jon Peacock. You helped and guided me through the process of developing theidea for the book, and for enabling it to become a reality through your commitmentand professionalism at each stage until completion. Thank you!

Preface

As a society, our faith in the potential of drugs is considerable. There is a growingexpectation that there is a drug that will, if not cure, at the very least alleviate thesymptoms of each and every disease. This expectation has been brought about by thegreat advances in drug treatments that have occurred in the latter half of the 20thcentury and early 21st century in several therapeutic domains, such as in cancer, viraland other infections, and in disturbances of the endocrine, cardiovascular, respiratoryand gastrointestinal systems. In contrast, when we consider the CNS (central nervoussystem) therapeutic domain, there have been limited drug-development milestones.However, such endeavours have sometimes yielded true blockbuster CNS drugs thathave provided encouragement that pharmacological approaches can yield effectivetreatments. Moreover, they have generated huge revenues to the pharmaceuticalcompany responsible for the development of such blockbusters for the remainingduration of its patent life, following marketing. This has led to another perception insociety, which is that the pharmaceutical industry is making an inappropriately largeprofit, on the back of human suffering. Industry counters this argument by outliningthe high-risk nature of drug development, and the need to be able to invest profits infurther research and development that will generate improved pharmacological treat-ments on those currently available.

The discovery and development of a new drug can be divided into several con-secutive stages, which can vary in sequence. Regardless, the process always beginswith attempts at identifying biochemical or physiological elements that are notfunctioning properly in the disease. From such investigations, a series of ‘druggable’targets are identified, and of these, one is selected for experimental evaluations withdrug candidates. These evaluations address three broad questions:

• Does the drug candidate produce the expected therapeutic effect?

• Is the drug candidate safe?

• Does the drug candidate get to its desired target?

These questions are addressed through a long process that consists of a drug-discovery stage and a drug-development stage that is outlined in Figure P.1. At the

end of the drug discovery and preclinical development stages, a lead compoundought to have been identified which has the desirable properties, at least as far as canbe judged from in vitro (i.e. test-tube) and in vivo (i.e. laboratory animals) models.The development stage serves to evaluate whether this early promise is realised in aseries of evaluations in humans. If they do, the drug will be registered and marketed.The drug evaluation process doesn’t stop here, as an ongoing postmarketingsurveillance is conducted with a particular emphasis on verifying the safety of thedrug in the real-world situation.

Drug discovery and development involves the utilisation of a series of experi-ments that requires the deployment of a vast array of resources. These experimentseach have a specific aim and utilise relevant and appropriate models that are aimedat providing an answer to the three questions raised above, at different stages in thedevelopment process. Thus, it can be viewed as an evidence-based decision-makingprocess, which, at crucial points, will determine whether a particular compound willproceed to the next stage, with the ultimate stage being the conduction of a Phase III

Duration(Years)

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Figure P.1 The stages of drug discovery and development. IND¼ investigational new drug;NDA¼ new drug application.

xiv PREFACE

trial, i.e. an experiment investigating the benefit of the test drug against no treat-ment (placebo) and a comparator compound (if such exists).

The purpose of this book is to explore the process by which drugs are developedto treat CNS disorders and it is divided into three sections. The first section consistsof four chapters and aims to set the scene, by using six CNS disease areas, drawnfrom psychiatric diseases (bipolar and unipolar depression, anxiety disorders andschizophrenia) and neurological/neurodegenerative diseases (epilepsy, Alzheimer’sdisease and Parkinson’s disease). The first chapter describes the global burden thatCNS disorders represent, whilst the second chapter provides a brief description ofthese major CNS disorders, from the perspective of the criteria that need to befulfilled, and the different rating tools that have been developed to identify thosepatients suffering from such CNS disorders. Chapter 3 describes the theories thathave been proposed for the aetiology of CNS disorders, which have to date largelycentred upon changes in central chemical neurotransmission. The section is con-cluded by describing the current pharmacological approaches for the treatment of aselection of CNS disorders.

The second section describes the CNS drug development process in detail, andalso consists of four chapters. The first of these concentrates on the methods that areused to identify the therapeutic benefit of a candidate drug, beginning at the earliestpreclinical models, progressing through more elaborate animal models, and ulti-mately to clinical evaluation involving Phases I, II and III, which will determinewhether the promise of preclinical examination is realised in patients. Chapter 6covers the area of pharmacokinetics (i.e. the processes by which the drug isabsorbed, distributed, metabolised and eliminated), which tends to accompanythe efficacy evaluation of a candidate drug, and similarly involves a range ofpreclinical and clinical investigations. These investigations help to answer thequestion as to whether the candidate drug has the desired pharmacokinetic profile,most particularly whether it penetrates the brain in appropriate concentrations. Thefinal two chapters cover the safety aspects of CNS drugs. The first of these chaptersinvestigates the safety concerns that currently are to the forefront of CNS drugdevelopment, whilst the second chapter examines the methodologies that have beendeveloped to address these concerns in preclinical evaluation.

The final section consists of a single chapter that examines the challenges faced indeveloping CNS drugs of the future. This chapter examines some of the importantemerging strategies that are having or will have a considerable impact on CNS drugdevelopment. In addition a selection of the novel therapeutic targets that arecurrently being evaluated are presented, either preclinically or clinically in fourCNS disorders, namely depression, schizophrenia, Alzheimer’s disease andParkinson’s disease. These diseases have been selected, as they probably representthose in the CNS arena into which the greatest amount of research and developmentis currently being carried out. This book is intended to provide the reader with anoverview of a multifaceted, challenging and constantly evolving process.

PREFACE xv

Abbreviations

5-HT Serotonin (5-hydroxytryptamine)A� Amyloid � proteinACC Anterior Cingulate CortexACh AcetylcholineAChE AcetylcholinesteraseACTH AdrenocorticotrophinAD Alzheimer’s diseaseADLs Activities of Daily LivingADME Absorption, Distribution, Metabolism and EliminationADR Adverse Drug ReactionAED Antiepileptic DrugAMPA �-amino-3-hydroxy-5-methyl-4-isoxazole propionic acidAMPT �-methyl-p-tyrosineANS Autonomic Nervous SystemAPP Amyloid Precursor ProteinAUC Area Under the CurveBACE 1 �-site amyloid-cleaving enzyme 1BBB Blood-brain barrierBDNF Brain-Derived Neurotrophic FactorBDZ BenzodiazepineBHK Baby Hamster KidneyBPD Bipolar DisorderBPRS Brief Psychiatric Rating ScalecAMP Cyclic Adenosine MonophosphateCATIE Clinical Antipsychotic Trials of Intervention EffectivenessCBP CREB Binding ProteinCGI Clinical Global Impression ScaleCHO Chinese Hamster OvaryCLOGD Calculated octanol/water partition coefficientCNS Central Nervous SystemCNV Copy-Number VariationCOMT Catechol-O-methyl transferaseCOX Cyclo-oxygenase

CRF Corticotrophin Releasing FactorCSF Cerebrospinal fluidCss Steady-state concentrationCT Computerized TomographyCUtLASS Cost Utility of the Latest Antipsychotic Drugs in SchizophreniaCVS CardiovascularCYP Cytochrome p450DA DopamineDAD Disability for Dementia Rating ScaleDALYs Disability-Adjusted Life YearsDAT Dopamine TransporterDLB Dementia with Lewy bodiesDSM Diagnostic and Statistical Manual of Mental DisordersDTI Diffusion Tensor ImagingDZP DiazepamEEG ElectroencephalographyEh Hepatic extractionEMEA European Medicines AgencyEPM Elevated Plus MazeEPS Extrapyramidal SymptomsFDA Food and Drug AdministrationFDG [18F]fluoro-2-deoxy-D-glucoseFGA First Generation AntipsychoticFIH First-In-HumanfMRI Functional Magnetic Resonance ImagingFTD Frontotemporal DementiaFTI Fatal Toxicity IndexGABA g-aminobutyric acidGBD Global Burden of DiseaseGIT GastrointestinalGLP Good Laboratory PracticeGPCR G-protein-coupled receptorGRPD General Practice Research DatabaseGSK-3 Glycogen Synthase Kinase-3H&Y Hoehn and Yahr Rating ScaleHAD Hospital Anxiety and Depression ScaleHAM-A Hamilton Anxiety Rating ScaleHAM-D Hamilton Depression Rating ScaleHEK Human Embryonic KidneyhERG human ether a-go-goHR-QoL Health-Related Quality of LifeICD International Classification of Diseases

xviii ABBREVIATIONS

ICH International Conference on HarmonizationILAE International League Against EpilepsyIND Investigational New DrugITT Intention To TreatKi Inhibitory constantKO KnockoutLI Latent InhibitionLOCF Last Observation Carried ForwardmAChR Muscarinic receptorMADRS Montgomery-Asberg Depression Rating ScaleMAO Monoamine OxidaseMAOI Monoamine Oxidase InhibitorMAS Bech-Rafaelsen Mania ScaleMDD Major Depressive DisordermGluR Metabotropic glutamate receptorMIST Metabolites in Safety TestingMMSE Mini Mental State ExamMRI Magnetic Resonance ImagingMRS Magnetic Resonance SpectroscopyMTC Mesiotemporal CortexNA NoradrenalinenAChR Nicotinic receptorNARI Selective Noradrenaline Reuptake InhibitorNBRA Nonbenzodiazepine Receptor AgonistNDA New Drug ApplicationNICE National Institute for Health and Clinical ExcellenceNMDA N-methyl-D-aspartateNOEL No Observed Effect LevelNPI Neuropsychiatry Inventory Rating ScalePANSS Positive and Negative Syndrome ScalePCP PhencyclidinePD Parkinson’s diseasePDUFA Prescription Drug User Fee ActPET Positron Emission TomographyP-GP P-glycoproteinpKa Ionization constantPoC Proof of ConceptPPI Prepulse InhibitionPTSD Post-Traumatic Stress DisorderQSAR Quantitative Structure-Activity RelationshipRCB Rodent Cancer BioassayrCBF Regional Cerebral Blood Flow

ABBREVIATIONS xix

rCBV Regional Cerebral Blood VolumeRIMA Reversible Inhibitor of MAO-ARNS Reactive Nitrogen SpeciesROS Reactive Oxygen SpeciesS&E Schwab and England Rating ScaleSERT Serotonin TransporterSGA Second Generation AntipsychoticSNP Single-Nucleotide PolymorphismSNpc Substantia Nigra pars compactaSNRI Serotonin/Noradrenaline Reuptake InhibitorSPECT Single-Photon Emission Computerized TomographySSRI Selective Serotonin Reuptake InhibitorSTAR*D Sequenced Treatment Alternatives to Relieve DepressionSTEP-BD Systematic Treatment Enhancement Program for Bipolar DisorderTCA Tricyclic AntidepressantTDM Therapeutic Drug MonitoringTdP Torsades de PointesUPDRS Unified Parkinson’s Disease Rating ScaleVd Volume of distributionWHO World Health OrganizationYLD Years Lost to DisabilityYLL Years lost to premature mortalityYMRS Young Mania Rating Scale

xx ABBREVIATIONS

1Introduction

Diseases of the central nervous system (CNS) are of an enormous diversity. They canrange from diseases that are present from an early stage of life to those that areprimarily of a later-age onset. For a long time, CNS disease was labelled andstigmatised by society, with it being believed that the sufferers were possessed bydemons or evil spirits, or that it was the consequence of some personality deficit orweakness in the afflicted individual. In the nineteenth and early twentieth century,the prevailing attitudes resulted in the committing of many mentally ill individualsto asylums. Such attitudes were hard to shift, and residues of them are still apparent.The alterations in attitudes to mental health and its treatment can most vividly beseen with the remarkable reduction in the population suffering from mental illnessin long-term residential care (Figure 1.1), and consequential growth in the treat-ment of patients within their communities (Manderscheid et al., 2009). The processof deinstitutionalization and psychiatric reform gathered momentum after WorldWar II, originally in the United States and UK, but gradually spread across the world(Novella, 2008). The consequences were that, in the United States, there was a peakin the number of residents in the mid 1950s. This peak coincides with the introduc-tion of the first pharmacological treatments for psychosis and depression. Sincethen, after nearly 50 years of decline, the resident population in psychiatric institu-tions is beginning to stabilise at around 50,000, with a modest rise even being seen in2005, which may be due to a number of factors, including demographic age-relatedand ethnic changes, as well as pressures on the provision of community services(Manderscheid et al., 2009).

The major challenge in the pharmacological treatment of disorders of the brain isthat they have a greater complexity than most other diseases or conditions. Forexample, most other diseases have a well-defined biological origin, from which drug

Principles of CNS drug development: from test tube to patient John Kelly

� 2009 John Wiley & Sons, Ltd

treatments that are mechanistically driven can be developed. For example, Type 1diabetes mellitus is a disease where there is a deficiency of the pancreatic hormone,insulin. The function of this hormone is to facilitate the uptake of the glucose fromthe blood and into the tissues. The consequences of a lack of this hormone are thatthe levels of glucose in the blood rise to a potentially life-threatening level, and thetissues of the body are starved of glucose, the major source of energy. The bodyresponds by having to utilise other sources of energy (such as breaking down proteininto amino acids), resulting in the wasting aspects of the disease. Administration ofinsulin in a fashion that mimics the natural secretory patterns will result in anormalisation of plasma glucose levels by removing glucose from the blood and aconsequent amelioration of the symptoms of the disease. If only things could be sostraightforward in the pharmacological treatment of CNS disease!

1.1 The global burden of CNS disease

Assessing the burden that disease places on a society is an enormous challenge, butone that is vitally necessary to allow governments to gauge the magnitude of healthproblems that they currently face, as well as trying to make reasonable predictionsabout the shifting nature of these health problems into the future, i.e. in the absenceof any interventions on their part. Most diseases that are not the result of eitherinfections or cancer can be considered to be ‘incurable’. This means that the goal oftherapy involves treating the symptoms, without being able to cure the underlyingbiological changes that are present in the sufferer of the disease. Using our earlierexample of insulin treatment for Type 1 diabetes mellitus, this pharmacologicaltreatment strategy will allow the patient to live a largely normal life with little

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Figure 1.1 Changes in resident population in psychiatric institutions in the United Statesduring the twentieth century. (Adapted from Manderscheid et al., 2009. Copyright � 2009,Vendome Healthcare.)

2 CH1 INTRODUCTION

outward signs of the disease. However, if the insulin treatment were to bediscontinued at any time during their life, the symptoms of the disease wouldre-emerge; thus, diabetes mellitus is a lifelong disease whose symptoms can becontrolled pharmacologically.

CNS disorders can be thought to be of a similar nature. Bipolar disorder, epilepsyand schizophrenia are CNS disorders that have usually presented during childhoodor adolescence and are lifelong illnesses. Depression and anxiety disorders can alsobe of a lifelong nature, but can be precipitated at any stage, and may be of a transientnature, i.e. an episode occurring during one’s life with no further recurrence.Alzheimer’s and Parkinson’s disease are typically of a late onset in life. There aresome CNS disorders that are absolutely 100% genetically determined, which havebeen inherited and programmed to manifest themselves at a certain age, such asHuntington’s disease and some genetic forms of Alzheimer’s and Parkinson’sdiseases. Cerebrovascular stroke is a condition that afflicts the brain (it can beconsidered as analogous to an ischaemic attack of the heart), due to a specificcardiovascular event, and as such is the only condition that afflicts the brain,where the cause can be defined. However, the damage that occurs in the immediateaftermath of such a cerebrovascular event (i.e. the ‘therapeutic window’) means thatthe scope for pharmacological intervention is limited to this period.

1.2 Assessment of the global burden of disease

As mentioned earlier, assessment of the magnitude of disease plays a vital role inmaking decisions and formulating policy on health issues. To this end, the WorldHealth Organization (WHO) produced its first Global Burden of Disease (GBD)study in 1990, where it acquired statistics on the incidence of more than 100 diseasesand injuries, examining the morbidity and mortality associated with these diseasesfrom a global, but also regional, perspective. An update of this GBD study has takenplace for 2004 (WHO, 2008). In this study, CNS disorders come under the umbrellaterm ‘neuropsychiatric disorders’ and for convenience can be divided into threebroad categories:

• Psychiatric conditions: Unipolar depressive disorders; bipolar affective disorder;schizophrenia; post-traumatic stress disorder; obsessive–compulsive disorder;panic disorder; insomnia

• Neurological/neurodegenerative conditions: Epilepsy; Alzheimer’s disease andother dementias; Parkinson’s disease; multiple sclerosis; migraine

• Substance abuse conditions: Alcohol-use disorders; drug-use disorders.

1.2 ASSESSMENT OF THE GLOBAL BURDEN OF DISEASE 3

The total number of deaths from any cause has been estimated worldwide to havebeen nearly 59 million in 2004. Of these, 2.1% (or 1.26 million) were attributed toneuropsychiatric disorders. The breakdown of these deaths by CNS disorder type isdepicted in Figure 1.2.

From a burden perspective, the report uses various measures. These include thesum of years lost to premature mortality (YLL), the years lost to disability (YLD), andthe disability-adjusted life years (DALYs), which we will discuss further later. Thereport has ranked diseases and conditions according to the magnitude of the disabilityassociated with them. These disability classes are summarised in Table 1.1 and range

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Figure 1.2 Estimates of global deaths caused by CNS disorders, 2004. Alzheimer’s diseasealso includes other dementia types. Within the ‘Other’ category, unipolar depressive dis-orders (15 000), schizophrenia (30 000) and multiple sclerosis (17 000) are the main con-tributors. (Data derived from WHO (2008).)

Table 1.1 Disability classes for certain CNS disorders

Disability class Severity weight Example

I 0.00–0.02 Stunting due to malnutritionII 0.02–0.12 Amputated fingerIII 0.12–0.24 AnginaIV 0.24–0.36 Congestive heart failure, Parkinson’s diseaseV 0.36–0.50 Mild mental retardation, bipolar disorderVI 0.50–0.70 Blindness, Alzheimer’s disease and other dementiasVII 0.70–1.00 Terminal stage cancer, active psychosis, severe depression

The severity weights range from 0 (perfect health) to 1 (death). They represent an average for each condition,

which itself can potentially span several (if not all) disability classes. (Taken from WHO (2008).)

4 CH1 INTRODUCTION

in severity across seven levels. The first disability class is a relatively modest form ofdisability that would have little impact on an individual’s quality of life. However, theseventh disability class is one that is so severely disabling that it can be considered tobe, at its most extreme, life-threatening. With regard to CNS disorders, it can be seenthat they have a representation in several of the more severe disability classes. Thus,using this particular classification system, we can see that certain CNS disorders areextremely disabling, some of which are on a par with the terminal stages of cancer.

1.3 The prevalence of CNS disorders

Table 1.2 consists of the prevalence of certain CNS disorders across the world, andalso in its regions. It can be seen that depression (i.e. unipolar depression) is themost prevalent CNS disorder worldwide, followed by epilepsy, bipolar disorder,schizophrenia, Alzheimer’s disease and Parkinson’s disease.

1.4 Disability due to CNS disorders

1.4.1 YLD as an indicator of extent of disability

As part of the GBD 2004 study, WHO has prepared a table of the 10 leading causes ofdeath, broken down by gender, from which the CNS disorders that are representedare depicted in Table 1.3. As can be seen, three neuropsychiatric (namely unipolardepression, schizophrenia and bipolar disorder) conditions are represented in thetop 10 leading causes of years lost due to disability, with unipolar depression beingranked first, irrespective of gender. When broken down according to gender, theYLD due to unipolar depression is much greater in females than in males. Overall,neuropsychiatric conditions are the most important single cause of disability across

Table 1.2 Global and regional prevalence (millions) of certain CNS disorders

Disorder World Africa America E. Med Europe S.E. Asia W. Pacific

Depression 151.2 13.4 22.7 12.4 22.2 40.9 39.3BPD 29.5 2.7 4.1 2.1 4.4 7.2 8.9Schizophrenia 26.3 2.1 3.9 1.9 4.4 6.2 7.9Epilepsy 40.0 7.7 8.6 2.8 4.1 9.8 7.0AD 24.2 0.6 5.0 0.6 7.6 2.8 7.4PD 5.2 0.2 1.2 0.2 2.0 0.7 1.0Alcoholdisorders

125.0 3.8 24.2 1.1 26.9 21.5 47.3

BPD¼ bipolar disorder; AD¼Alzheimer’s disease and other dementias; PD¼ Parkinson’s disease. (Takenfrom WHO (2008).)

1.4 DISABILITY DUE TO CNS DISORDERS 5

all regions of the world population aged 15 or over. There are other CNS conditionsthat are represented, but only in one of the genders. For example, alcohol-usedisorders are the second most important cause of YLD in males, whilstAlzheimer’s disease and other dementias are ranked 10th in the female category.

Another way in which the YLDs have been examined is by dividing the world intoeither low/middle-income countries or high-income countries (Table 1.4). Here, wecan see that unipolar depression is still the major cause of YLD irrespective ofincome, but that schizophrenia and bipolar disorder are more prevalent in low-andmiddle-income countries, whilst Alzheimer’s disease and other dementias are the4th leading cause of YLD in high-income countries; alcohol abuse is high up the listof YLDs for both categories.

1.4.2 DALYs

According to WHO (2008), measuring the incidence, prevalence and YLD donot themselves give an accurate depiction of the burden placed upon societyby disease. They have developed the concept of the disability-adjusted life year

Table 1.3 CNS disorders that are amongst the leading global causes ofYLD in 2004

Cause Total YLD Male Female

Unipolar depression 65.3 24.3 (1) 41.0 (1)Schizophrenia 16.3 8.3 (5) 8.0 (6)Bipolar disorder 14.4 7.3 (7) 7.1 (8)

The figures are expressed in millions. YLD¼ years lost due todisability. Numbers in bracketsare the ranking of the disorder within the particular gender. (Taken from WHO (2008).)

Table 1.4 CNS disorders that are leading causes of YLD according to relative wealth ofcountries

Low/middle-income countries High-income countries

Cause YLD Cause YLD

Unipolar depression (1) 55.3 Unipolar depression (1) 10.0Alcohol-use disorders (4) 18.4 Alcohol-use disorders (3) 3.9Schizophrenia (6) 14.8 Alzheimer/other dementias (4) 3.7Bipolar disorder (8) 12.9 Drug-use disorders (10) 1.7

The figures are expressed in millions. YLD¼ years lost due to disability. Numbers in brackets are the rankingof the disorder within the top 10 causes. (Taken from WHO (2008).)

6 CH1 INTRODUCTION

(DALY) which ‘can be thought of as a measurement of the gap betweencurrent health status and an ideal situation where everyone lives into oldage, free of disease and disability’ (WHO, 2008). The DALY is a combinationof the YLL (years of life lost due to premature death) and the YLD (equivalenthealthy life years lost through living in states of less than full health due todisease and injury). When the DALYs are calculated, unipolar depressivedisorders are ranked third in total number, with 65 million DALYs, withonly lower respiratory infections (94.5 million DALYs) and diarrhoeal diseases(72.8 million DALYs) being ranked ahead of them. This list is dominated byinfectious diseases, birth and congenital abnormalities, and injuries of one type oranother. When middle-income and high-income countries are considered, uni-polar depressive disorders are the leading cause of DALYs, with Alzheimer’sdisease and other dementias coming 4th in high-income countries. When lookinginto the future, it is predicted that unipolar depressive disorders will be theleading cause of DALYs worldwide by 2030. The estimated global DALYs forneuropsychiatric disorders for 2004 have been estimated at 200 million (approx13% of the total DALYs). The breakdown of these DALYs according to diseasetype is depicted in Figure 1.3.

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Figure 1.3 Global DALYs estimate for neuropsychiatric disorders, 2004. Data are the 2004estimates for disability-adjusted life years (DALYs) adapted from WHO (2008). Within the‘Other’ category are insomnia (3623), post-traumatic stress disorder (3468), Parkinson’sdisease (1710) and multiple sclerosis (1527)

1.4 DISABILITY DUE TO CNS DISORDERS 7

1.4.3 Regional distribution of DALYs

The three categories of neuropsychiatric conditions (namely psychiatric, neurolo-gical/neurodegenerative and substance abuse) have been summarised in Table 1.5,according to regional distribution. The total number of DALYs for each region areroughly in keeping with their population, but when subdivided into differentcategories reveal some regional differences in prevalence. For example, substance-abuse disorders have a lower prevalence of DALYs in Africa and south-east Asia, anda greater prevalence in the Americas and Europe than would be expected based onpopulation. Also, psychiatric disorders have a greater prevalence in south-east Asia,whilst neurological/neurodegenerative disorders are more prevalent in Europe andthe Americas.

1.5 Economic Costs

As well as the burden of CNS disease being expressed in terms of years lost due to earlymortality, morbidity or disability, there have also been attempts to calculate theeconomic burden, i.e. the financial costs of the disease. The measures used haveproven to vary enormously from one study to another due to marked differences inthe study design and cost model utilised. For example, some studies have generatedfigures based purely on calculating the direct costs of the disorder, i.e. in its treatment.

Table 1.5 Regional distribution of DALYs for neuropsychiatric disorders

RegionPopulation(millions)

TotalNeuropsych.DALYs(thousands)

Psychiatric(thousands)

Neuro/Neurodegen.(thousands)

Subst. Abuse(thousands)

World 6437 177 659 115 652 29 960 32 047Africa 738 (11%) 15 611 (9%) 10 935 (9%) 2948 (10%) 1728 (5%)S.E. Asia 1672 (26%) 47 228 (27%) 35 032 (30%) 6692 (22%) 5504 (17%)Americas 874 (14%) 29 974 (17%) 17 437 (15%) 5274 (18%) 7263 (23%)E. Med. 520 (8%) 13 568 (8%) 9834 (9%) 1790 (6%) 1944 (6%)Europe 883 (14%) 26 412 (15%) 14 340 (12%) 5703 (19%) 6369 (20%)W. Pacific 1738 (27%) 44 866 (25%) 28 074 (24%) 7553 (25%) 9239 (29%)

Data derived from WHO (2008). The DALYs for a range of CNS disorders have been divided into psychiatric,

neurological/neurodegenerative and substance abuse. The percentage of the total for each category is in

brackets.

8 CH1 INTRODUCTION