Comorbidity of Mental and Physical Disorders

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Key Issues in Mental Health Editors: A. Riecher-Rössler, N. Sartorius Vol. 179 Comorbidity of Mental and Physical Disorders

Editors N. Sartorius R.I.G. Holt M. Maj Comorbidity of Mental and Physical Disorders Key Issues in Mental Health

Vol. 179

Series Editors

Anita Riecher-Rössler Basel Norman Sartorius Geneva Comorbidity of Mental and Physical Disorders

Volume Editors

Norman Sartorius Geneva Richard I.G. Holt Southampton Mario Maj Naples

12 figures and 20 tables, 2015

Basel · Freiburg · Paris · London · New York · Chennai · New Delhi · Bangkok · Beijing · Shanghai · Tokyo · Kuala Lumpur · Singapore · Sydney Key Issues in Mental Health Formerly published as ‘Bibliotheca Psychiatrica‘ (founded 1917)

Professor Norman Sartorius, MA, MD, PhD, Professor Richard I.G. Holt, MA, MB, BChir, FRCPsych PhD, FRCP, FHEA Association for the Improvement of Mental Health Human Development and Health Academic Unit Programmes Faculty of Medicine, University of Southampton Geneva, Switzerland University Hospital Southampton NHS Foundation Trust Professor Mario Maj, MD, PhD Southampton, UK Department of Psychiatry University of Naples Naples, Italy

Library of Congress Cataloging-in-Publication Data

Comorbidity of mental and physical disorders / volume editors, Norman Sartorius, Richard I.G. Holt, Mario Maj. p. ; cm. -- (Key issues in mental health ; vol. 179) Includes bibliographical references and indexes. ISBN 978-3-318-02603-0 (hard cover : alk. paper) -- ISBN 978-3-318-02604-7 (electronic version) I. Sartorius, N., editor. II. Holt, Richard I. G., editor. III. Maj, Mario, 1953- , editor. IV. Series: Key issues in mental health ; v. 179. 1662-4874 [DNLM: 1. Comorbidity. 2. Mental Disorders--etiology. 3. Disease--psychology. 4. Disease Management. 5. Syndrome. W1 BI429 v.179 2015 / WM 140] RC454.4 616.89--dc23 2014034031

Bibliographic Indices. This publication is listed in bibliographic services. Disclaimer. The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publisher and the editor(s). The appearance of advertisements in the book is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements. Drug Dosage. The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. © Copyright 2015 by S. Karger AG, P.O. Box, CH-4009 Basel (Switzerland) www.karger.com Printed in Germany on acid-free and non-aging paper (ISO 9706) by Kraft Druck GmbH, Ettlingen ISSN 1662–4874 e-ISSN 1662–4882 ISBN 978–3–318–02603–0 e-ISBN 978–3–318–02604–7 Contents

VII Foreword Goldberg, D. (London) XI Preface Sartorius, N. (Geneva); Holt, R.I.G. (Southampton); Maj, M. (Naples)

Background

1 Conceptual Perspectives on the Co-Occurrence of Mental and Physical Disease: Diabetes and Depression as a Model Fisher, E.B. (Leawood, Kans./Chapel Hill, N.C.); Chan, J.C.N. (Hong Kong, SAR); Kowitt, S. (Leawood, Kans./Chapel Hill, N.C.); Nan, H. (Hong Kong, SAR); Sartorius, N. (Geneva); Oldenburg, B. (Melbourne, Vic.) 15 Public Health Perspectives on the Co-Occurrence of Non-Communicable Diseases and Common Mental Disorders Oldenburg, B.; O’Neil, A.; Cocker, F. (Melbourne, Vic.) 23 Counting All the Costs: The Economic Impact of Comorbidity McDaid, D.; Park, A.-L. (London) 33 Difficulties Facing the Provision of Care for Multimorbidity in Low-Income Countries Beran, D. (Geneva)

Comorbidity of Mental and Physical Illness: A Selective Review

42 Depression, Diabetes and Dementia Rosenblat, J.D. (Toronto, Ont./London, Ont.); Mansur, R.B. (Toronto, Ont./São Paulo); Cha, D.S. (Toronto, Ont.); Baskaran, A. (Toronto, Ont./Kingston, Ont.); McIntyre, R.S. (Toronto, Ont.) 54 Cardiovascular Disease and Severe Mental Illness Holt, R.I.G. (Southampton) 66 Multiple Comorbidities in People with Eating Disorders Monteleone, P. (Salerno/Naples); Brambilla, F. (Milan) 81 Anxiety and Related Disorders and Physical Illness Kariuki-Nyuthe, C. (Ringwood East, Vic.); Stein, D.J. (Cape Town) 88 Cancer and Mental Illness Lawrence, D.; Hancock, K.J. (West Perth, W.A.); Kisely, S. (Brisbane, Qld.)

V 99 Infectious Diseases and Mental Health Müller, N. (Munich) 114 Physical Diseases and Addictive Disorders: Associations and Implications Gordon, A.J.; Conley, J.W. (Pittsburgh, Pa.); Gordon, J.M. (Springfield, Mo.)

Management of Comorbidity of Mental and Physical Illness

129 The Role of General Practitioners and Family Physicians in the Management of Multimorbidity Boeckxstaens, P.; De Maeseneer, J.; De Sutter, A. (Ghent) 137 Training Physicians at Undergraduate and Postgraduate Levels about Comorbidity Cushing, A.; Evans, S. (London) 148 The Dialogue on Diabetes and Depression African Nursing Training Programme: A Collaborative Training Initiative to Improve the Recognition and Management of Diabetes and Depression in Sub-Saharan Africa Millar, H.L. (Dundee); Cimino, L. (Indianapolis, Ind.); van der Merwe, A.S. (Stellenbosch) 157 The Challenge of Developing Person-Centred Services to Manage Comorbid Mental and Physical Illness Gask, L. (Manchester) 165 Prevention of Comorbid Mental and Physical Disorders Hosman, C. (Maastricht/Nijmegen)

Concluding Remarks

178 Conclusions and Outlook Sartorius, N. (Geneva); Holt, R.I.G. (Southampton); Maj, M. (Naples)

182 Author Index 183 Subject Index

VI Contents Foreword

The editors are to be congratulated in having ob- physical illnesses increases the probability of de- tained contributions from experts on a wide range pression: in one primary care study, patients of physical disorders in order to throw light on with a single pain were no more likely to be de- those physical disorders which have a higher rate pressed than those without pain, but with two of psychological disorders associated with them. different pains the probability of depression was Recognition and treatment of these disorders double, and with three or more pains the prob- have been shown to improve the patient’s quality ability of depression was five times higher [1] . of life, and also collaboration with the treatment Secondly, chronic physical illness carries with it regimes for their physical illness. the risk of disability, which can be very depress- Of course, the shoe can be fitted to the other ing for an adult who has previously been healthy. foot, and one can ask to what extent do particular For example, Prince et al. [2] showed that the psychological disorders have higher rates of ex- attributable fraction of disability or handicap for pected physical disorders. Both of these are valid the prediction of onset of depression among the questions, but while the second is of great scien- elderly was no less than 0.69, and Ormel et al. [3] tific interest, the first is more important from the showed similar findings in Holland. Thirdly, viewpoint of patient care. there are physical changes in some diseases In probing the reasons for these higher than which may underlie the development of depres- expected comorbidities, it is often found that sion, such as changes in the allostatic load. Al- there is no single way in which one form of lostasis refers to the ability of the body to adapt morbidity influences the other: each one exac- to stressful conditions. It is a dynamic, adaptive erbates the other, and good clinical care must process. Tissue damage, degenerative disease not be blind to the psychological disorders with (like arthritis) and life stress all increase allostat- which a particular physical disease is associated. ic load and can induce inflammatory changes This book provides examples of the various which produce substances such as bradykinin, ways in which such vicious circles establish prostaglandins, cytokines and chemokines. themselves. These substances mediate tissue repair and heal- In addition to the possible factors mentioned ing, but also act as irritants that result in periph- by the editors in their preface that may account eral sensitisation of sensory neurons, which in for the high comorbidity between psychological turn activate central pain pathways [4] . These disorders and physical illnesses, there are a are all ways in which a physical disorder can number of other possible relationships. First, produce higher than expected rates of psycho- the number of different pains caused by the logical disorders.

VII There are also psychological disorders that to atherosclerosis, and with it increased risk for antedate episodes of physical disorder, such as a both stroke and coronary artery disease. In the depressive illness. Systematic reviews of 11 pro- latter, autonomic changes in depression may spective cohort studies in healthy populations also cause ECG changes which favour develop- show that depression predicts later development ment of coronary disease. Changes in natural of coronary heart disease in all of them [5, 6] . killer cells and T-lymphocytes in depression The occurrence of a depressive episode before may lead to lowered resistance to AIDS in HIV an episode of myocardial infarction has been re- infections. Menkes and McDonald [17] have ar- ported by Nielsen et al. [7]. Three prospective gued that exogenous interferons may cause both studies have also shown that depression is an in- depression and increased pain sensitivity in sus- dependent risk factor in stroke [8–10] . In pro- ceptible individuals by suppressing tryptophan spective population-based cohort studies, de- availability and therefore serotonin synthesis. pression has been shown to predict the later de- More prosaic explanations include reduced velopment of colorectal cancer [11] , back pain physical activity in people suffering from de- [12], irritable bowel syndrome [13] and multiple pression [18] . sclerosis [14] , and there is some evidence that It is clear that relationships between the two depression may precede the onset of type 2 dia- forms of morbidity are complex and that causal betes. Prince et al. [15] argue that there is con- relationships that may be true for one physical sistent evidence for depression leading to physi- disorder may not apply to another disorder. The cal ill-health in coronary heart disease and chapters of this book bring together in one place stroke, as well as depression in pregnancy po- a comprehensive account of these comorbidities, tentially leading to infant stunting and infant and an important step has therefore been taken in mortality. a field in which there is still much to learn in the It has been hypothesised [16] that increases in future. pro-inflammatory cytokines in depression and Sir David Goldberg , Institute of Psychiatry, increased adrenocortical reactivity may also lead King’s College, London

References

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tion. Arch Gen Psychiatry 1990; 47: 239– heart disease: systematic review of pro- year period. Arch Intern Med 1998; 158:

245. spective cohort studies. BMJ 1999; 318: 1133–1138. 2 Prince MJ, Harwood RH, Blizard RA, et 1460–1467. 9 Ohira T, Iso H, Satoh H, et al: Prospec- al: Impairment, disability and handicap 6 Nicholson A, Kuper H, Hemingway H: tive study of stroke among Japanese.

as risk factors for late life depression. Depression as an aetiologic and prog- Stroke 2001; 32: 903–908.

Psychol Med 1998; 27: 311–321. nostic factor in coronary heart disease: a 10 Larson SL, Owens PL, Ford D, et al: De- 3 Ormel J, Kempen GI, Penninx BW, et al: meta-analysis of 6,362 events among pressive disorder, dysthymic disorder Chronic medical conditions and mental 146,538 participants in 54 observational and risk of stroke: thirteen-year follow

health in old people. Psychol Med 1997; studies. Eur Heart J 2006; 318: 1460– up from Baltimore Epidemiologic

27: 1065–1067. 1467. Catchment Area study. Stroke 2001; 32: 4 Rittner HL, Brack A, Stein C: Pro-algesic 7 Nielsen E, Brown GW, Marmot M: Myo- 1979–1983. and analgesic actions of immune cells. cardial infarction; in Brown GW, Harris 11 Kroenke CH, Bennett GG, Fuchs C, et al:

Curr Opin Anaesthesiol 2003; 16: 527– T (eds): Life Events and Illness. London, Depressive symptoms and prospective 533. Unwin Hyman, 1989, pp 313–342. incidence of colorectal cancer in wom-

en. Am J Epidemiol 2005; 162: 839–848.

VIII Goldberg 12 Larson SL, Clark MR, Eaton WW: De- 14 Grant I, Brown GW, Harris T, et al: Se- 16 Wichers M, Maes M: The psychoneuro- pressive disorder as a long-term ante- verely threatening events and marked immuno-pathophysiology of cytokine- cedent risk factor for incident back pain: life difficulties preceding onset or exac- induced depression in humans. Int J

a 13-year follow-up study from the Bal- erbation of multiple sclerosis. J Neurol Neuropsychopharmacol 2002; 5: 375–

timore Epidemiological Catchment Area Neurosurg Psychiatry 1989; 52: 8–13. 388.

sample. Psychol Med 2004; 34: 211–219. 15 Prince M, Patel V, Saxena S, et al: No 17 Menkes DB, McDonald JA: Interferons, 13 Ruigómez A, García Rodríguez LA, Pan- health without mental health. Lancet serotonin and neurotoxicity. Psychol

és J: Risk of irritable bowel syndrome 2007; 370: 859–877. Med 2000; 30: 259–268. after an episode of bacterial gastroen- 18 Whooley MA, de Jonge P, Vittinghoff E, teritis in general practice: influence of et al: Depressive symptoms, health be- comorbidities. Clin Gastroenterol Hepa- haviors, and risk of cardiovascular

tol 2007; 5: 465–469. events in patients with coronary heart

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Foreword IX

Preface

There is little doubt about the fact that comorbid- attention to the presence and treatment of men- ity – the simultaneous presence of two or more tal disorders in their patients. diseases – is a major challenge for health services. The neglect of comorbidity of mental and The prevalence of comorbidity has increased rap- physical illness is also linked to the fact that its idly and continues to grow for several reasons, prevalence has been, for a long time, severely un- mainly the increase in life expectancy following derestimated. This was due in part to the lack of successes in medicine and socioeconomic devel- recognition described above; however, it also re- opment. However, also playing a role are envi- flects the fact that the stigma of mental illness ronmental factors (such as air pollution), changes makes patients reluctant to speak about their in lifestyle, rapid urbanization and medical fac- mental health problems to nonpsychiatric physi- tors including iatrogenic disease and the frag- cians. Comorbidity of mental and physical ill- mentation of medical services which often result nesses often leads to a tacit collusion with patients in the late recognition of comorbid diseases and and healthcare professionals agreeing to deal with the consequent failure to treat them. the physical illness as if the mental disorder did An area of particular neglect is the comorbid- not exist. The fact that people with mental illness ity between mental and physical disorders. One are often poor and less well educated may have of the main reasons for this development is the also contributed to lesser utilization of health ser- long-standing separation of psychiatry from oth- vices that might have recorded the number and er branches of medicine. The geographic separa- frequency of comorbidity of mental and physical tion of mental health institutions from the hos- illness. pitals and departments dealing with other physi- The scant attention given to the comorbidity cal diseases is a material expression of the of mental and physical disorders is of major pub- perception that psychiatric disorders are not dis- lic health concern. The simultaneous presence of eases like others, and a consequence of this per- mental and physical diseases worsens the prog- ception is the growing distance and separation nosis of both types of disorders and increases the between psychiatry and the rest of medicine. In personal and social cost of dealing with them. practice, this has led to many psychiatrists failing Complications of the comorbid diseases become to recognize the presence of physical illness in more probable and their treatment is more com- their patients and being reluctant to provide plex. What is particularly worrisome is that co- treatment for the physical disorder when a diag- morbidity of mental and physical disorders is nosis is made. The same is true for specialists in becoming more frequent at a time when medi- other branches of medicine who pay insufficient cine is becoming increasingly fragmented into

XI super-specialties and when the numbers of gen- ready available. We invited leading experts in the eral practitioners who can follow the rapid de- field of comorbidity to participate in the produc- velopment of knowledge in the many disciplines tion of this volume. We have tried to exemplify of medicine is diminishing. issues that arise in three main areas of concern. The reasons for the high prevalence of mental The first of these are the public health aspects of and physical illness are only partially clear. To an comorbidity focusing on the ways in which co- extent this may occur because some people with morbidity can be conceptualized, on the cost that mental illness do not pay sufficient attention to comorbidity presents to society and on the inter- their bodies and do not follow elementary rules of action of comorbidity with factors stemming healthy lifestyle, hygiene and disease prevention. from the context of socioeconomic development. That many people with mental illness live in con- In the second group of chapters we assembled re- ditions of poverty and deprivation where they views of evidence that illustrate the two main ap- may be exposed to the considerable dangers of proaches to the understanding of evidence about violence and abuse might also be a part of the ex- comorbidity. For the first approach, the chapters planation. People with mental illness often abuse look at specific issues that arise in relation to co- alcohol and other drugs which expose them to the morbidity of mental disorders with disease groups health consequences of substance misuse such as of major public health importance, such as car- hepatitis and HIV infections. Although these rea- diovascular illness, cancer and infectious diseas- sons are important, they do not explain all of the es. For the second approach we examined physi- excess comorbidity. A number of biological cal comorbidity in relation to a range of mental changes seen in mental illness may also predis- and behavioral disorders, including substance pose to physical ill health, including enhanced in- abuse, eating disorders and anxiety. The message flammation or endocrine dysfunction, but genet- imbedded in this way of presenting evidence – us- ic factors are also important. We are still lacking ing one of the two approaches – is that both are longitudinal studies of comorbidity that could of- necessary: taking a position of looking at comor- fer insights into the mechanisms. The recent find- bidity from only one side may hide important is- ings on the effects of early childhood abuse on the sues and clues. The last group of chapters includes prevalence of cardiovascular diseases and on the contributions that deal with the elements of the prevalence of depression are good examples of response to the problems arising from comorbid- the gains that might result from long-term and ity – the organization of health services (especial- life-perspective studies. ly the role of the general practitioners), the train- Our main goal for this book was to assemble ing of different categories of health personnel and and present material that will help in efforts to the multisectoral engagement necessary to pre- raise awareness of the magnitude and nefarious vent comorbidity. consequences of comorbidity of mental and phys- Norman Sartorius , Geneva ical illnesses while stimulating relevant research Richard I.G. Holt , Southampton as well as the application of knowledge that is al- Mario Maj , Naples

XII Sartorius · Holt · Maj Background

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 1–14 ( DOI: 10.1159/000365522 )

Conceptual Perspectives on the Co-Occurrence of Mental and Physical Disease: Diabetes and Depression as a Model

a, b c a, b Edwin B. Fisher · Juliana C.N. Chan · Sarah Kowitt · d e f Hairong Nan · Norman Sartorius · Brian Oldenburg a Peers for Progress, American Academy of Family Physicians Foundation, Leawood, Kans., and b Department of Health Behavior, Gillings School of Global Public Health, University of North Carolina, c Chapel Hill, N.C., USA; Department of Medicine and Therapeutics, Hong Kong Institute of Diabetes d and Obesity, Chinese University of Hong Kong and Prince of Wales Hospital, and Faculty of Health and e Social Sciences, The Hong Kong Polytechnic University, Hong Kong, SAR, P.R. China; Association for the f Improvement of Mental Health Programmes, Geneva, Switzerland; School of Population and Global Health, The University of Melbourne, Melbourne, Vic., Australia

Abstract tion and management. Among these, peer support, self- Diabetes and depression provide a model for under- management and problem solving, and programs for standing the comorbidity of mental and physical disor- whole communities are promising approaches. Self- ders, as each influences the other while sharing a broad management and problem solving may also provide a range of biological, psychological, socioeconomic and coherent framework for integrating the diverse manage- cultural determinants. Diabetes and depression may be ment of tasks and objectives of those affected by diabe- viewed as: (1) categories or dimensions, (2) single prob- tes and depression and as a model for prevalent multi- lems or parts of broader categories, e.g. metabolic/car- morbidity. © 2015 S. Karger AG, Basel diovascular abnormalities or negative emotions, (3) separate comorbidities or integrated so that depression is seen as part of the comprehensive, normal clinical picture Amidst growing evidence of the bidirectional re- of diabetes, and (4) expressions of a shared, complex bio- lationship between diabetes and depression at the social propensity to chronic disease and psychological pathophysiological, clinical, behavioral, and so- distress. Interventions should reflect the commonalities cial levels [e.g. 1 ], their co-occurrence also pro- among chronic mental and physical disorders and should vides a window on a broader range of comorbidi- include integrated clinical care and self-management ties among mental health, psychological distress, programs along with population approaches to preven- and diverse chronic diseases and health condi- (Epi)genetic factors Socioeconomic deprivation Perinatal programming Low educational level

Obesigenic environment Physical illness Societal stressors Life events Biological responses (e.g. activation of stress hormonal systems dysregulation of neurotransmittors) Access to care Family/peer support

Anxiety, depression and Adverse effects of treatment Metabolic and other psychological (e.g. metabolic effects of cardiovascular distress or pathology antidepressants) or negative abnormalities emotions associated with antidiabetic treatments (e.g. insulin injection, blood glucose self-monitoring, dietary restriction)

Undesirable behaviors (e.g. low energy, binge eating, physical inactivity, poor treatment compliance, poor self care)

Comorbidities and premature mortality

Fig. 1. An example of an integrative model of diabetes and depression.

tions. Diabetes itself is an excellent model of tes and depression that recognizes how depres- chronic disease in general, and depression, with sion and stressful life events can lead to the activa- its broad range of influences, severity and inter- tion of the hypothalamic-pituitary-adrenal axis vention strategies provides an excellent model for and complex hormonal interactions in the patho- understanding psychological distress and mental genesis of metabolic disorders. These complex health problems as they interact with other as- hormonal interactions can give rise to a wide pects of health and well-being. range of metabolic and cardiovascular abnormalities which characterize diabetes and are increasingly observed in people with depression, thus Biological, Psychological and Socioeconomic threatening an increasing cycle of psychological Influences in Diabetes and Depression and physical ill health [3] . Starting with epigenetic effects of early mater- How social and psychological factors ‘get under nal care, a variety of social, psychological and bio- the skin’ to influence biological processes is cen- logical influences may interact in the etiology and tral to understanding the complexity of relation- course of both depression and diabetes, and ac- ships between mental health and chronic disease celerate the psychological and metabolic abnor- [e.g. 2 ]. Figure 1 provides a useful model in diabe- malities of each [1]. As symptoms and complica-

2 Fisher · Chan · Kowitt · Nan · Sartorius · Oldenburg

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 1–14 ( DOI: 10.1159/000365522 ) tions of diabetes increase, associated psychosocial Research has also documented associations stress and reduced coping ability may contribute between neighborhood characteristics and diabe- to depression. Additionally, the psychological tes prevalence and management. In a natural ex- burdens of diabetes treatments, such as insulin periment in the mid-1990s, the Department of injection or blood glucose self-monitoring, can Housing and Urban Development randomly as- increase negative emotions and maladaptive be- signed approximately 4,500 women with children haviors and lead to a loss of interest, low energy, living in public housing in high-poverty urban ar- abnormal eating patterns, sleep disturbance, poor eas to one of three conditions: housing vouchers treatment compliance and poor concentration. to move to low-poverty areas and receive coun- As diabetes may exacerbate depression, likewise seling, unrestricted vouchers and no counseling, evidence indicates deleterious effects of coexist- and control – no vouchers. In follow-up data ing depression on clinical status, subsequent (2008–2010), those who had been offered vouch- complications, mortality and increased health- ers for low-poverty neighborhoods were less like- care expenditures [4] . ly than controls to have BMI ≥ 35 or ≥ 40, and less Following the model in figure 1, broad social likely to have a glycated hemoglobin ≥ 6.5% (48 and economic contexts of family and social rela- mmol/mol). Those receiving the unrestricted tionships as well as organizational, economic and vouchers did not differ from controls [6] . cultural factors influence depression, diabetes A study in Quebec, Canada sheds light on spe- and other mental and physical disorders. Exam- cific neighborhood features that may be especial- ples of these are detailed in a report available at ly important. Individuals who reported their http://sph.unc.edu/profiles/edwin-b-fisher-phd/. neighborhoods as having worse physical and social order (i.e. deteriorated buildings, graffiti, noise, trash, crime and vandalism), less social co- The Breadth of Environmental Influence: hesion, and less access to services and resources Neighborhood Design and Social Isolation had greater diabetes distress including emotional burden, dissatisfaction with medical care, diffi- Illustrating the broad range of potential influenc- culty with treatment regimen, interpersonal im- es on mental and physical disorders, the next pacts and support for diabetes management. Even paragraphs provide examples of how neighbor- after controlling for confounders, such as income, hood and architectural design may influence so- education and race, these relationships remained cial relationships and health status. significant [7] . One study on housing involving older adults The complex interweaving of multiple levels of showed that architectural features such as influence results in sharp social and economic porches and stoops encouraged greater person- stratification of both diabetes and depression. to-person contact and were positively associated Failure to recognize the influence of contextual with perceived social support. These in turn factors may have at least three deleterious conse- were associated with less self-reported depres- quences. First, interventions may be less powerful sion and anxiety [5]. Other architectural fea- than they might be. Second, benefits of medical or tures, such as windows, allowed for broader ob- psychological interventions delivered to individ- servation of the surrounding area, but removed uals may be underestimated if important contex- individuals from close person-to-person contact tual moderators of their effects are not accounted and were associated with lower levels of perfor in analyses. Third, individuals may be viewed ceived social support and greater psychological as responsible for problems in a manner that con- distress [5] . stitutes a kind of ‘victim blaming’.

Co-Occurrence of Mental and Physical Disease 3

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 1–14 ( DOI: 10.1159/000365522 ) Chronic disease Genetic, epigenetic, Psychological disorder e.g. diabetes, asthma, pathophysiologic, e.g. stress, low mood, CHF, CVD psychological, social, family problems community, cultural and depression, anxiety disorder economic influences

Fig. 2. Simple model of comorbidity.

What Are We Preventing, Treating, and cation of a dimension of dysglycemia including Managing? Key Definitional and Conceptual varying degrees of insulin resistance and deficien- Issues cy that underlie manifest abnormalities in glucose metabolism. Supporting the dimensional per- In order to develop comprehensive approaches to spective, ‘graded relationships’ between depres- the effective prevention and/or management of sion and both myocardial infarction and all-cause diabetes and depression, it is necessary to clarify mortality suggest that depression ‘is best viewed just how the problems and their interrelation- as a continuous variable that represents a chronic ships are to be approached. The term ‘comorbid- psychological characteristic rather than a discrete ity’ connotes two well-defined and distinct clini- and episodic psychiatric condition’ [8] . cal entities, occurring simultaneously and each With both depression and diabetes, categori- tending to occur more frequently in the presence cal definitions may be superimposed on the di- of the other, as simply illustrated in figure 2 . How- mensional by defining the diagnostic category ac- ever, the interrelationships between diabetes and cording to a convention of some criterion score as depression may be viewed in other ways as well. in common – and changing [9] – definitions of hypertension. Additionally, the International A Dimensional versus Categorical View of Each Classification of Diseases distinguishes three cat- of Diabetes and Depression egories – mild, moderate and severe depression – Both depression and diabetes are commonly de- that also reflect the practical usefulness of the di- fined categorically with specific criteria used to mensional approach. classify individuals as having either depression or diabetes. However, an alternative to this categori- Single Problem versus Group of Problems cal definition of depression has been a dimen- In addition to the difference between viewing sional characterization of mood or dysphoria, of- problems as distinct categories or as dimensions, ten using standardized instruments such as the diabetes and depression may each be categorized popular Beck Depression Inventory which was as part of a broader class of problems: cardiomet- originally developed and validated as a measure abolic abnormalities for diabetes and negative of depressed mood, not of categorical depression. emotions for depression. For example, studies of As an example of the dimensional perspective in depression in various groups indicate high co-oc- diabetes, the success of preventing incident dia- currence of depression, anxiety and other variet- betes in high-risk subjects has led to the identifi- ies of psychological distress [10]. Similarly, stud-

4 Fisher · Chan · Kowitt · Nan · Sartorius · Oldenburg

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 1–14 ( DOI: 10.1159/000365522 ) ies in cardiovascular risk indicate the utility of pertension or hypercholesterolemia. At the popu- grouping together a set of negative emotions that lation level, however, co-prevalent problems may includes depression, anxiety, hostility and stress, share common treatment and prevention targets, and their complex interactions in pathways relat- such as healthy diet, physical activity, weight ed to cardiovascular pathogenesis [11] . Recent management and communities that encourage work in diabetes has also indicated that general them [e.g. 6] for diabetes and cardiovascular dis- measures of diabetes distress may be more closely ease, or, for negative emotions, socioeconomic related to poor metabolic control than measures well-being and communities and families that en- of depressed mood alone [12]. Parallel to the courage cooperation and satisfying relationships overlap among measures of psychological disor- among neighbors [5] . Thus, the broader catego- der and distress, hyperlipidemia, central adiposi- ries of cardiometabolic abnormalities and nega- ty and hypertension often co-occur with ‘predia- tive emotions may help guide population-wide betes’ or diabetes, leading some to refer to the prevention and treatment campaigns. At the group as comprising a ‘metabolic syndrome’ [13] . same time, their individual components are duly Whether depression and diabetes are best the focus of clinical intervention. viewed as distinct or as members of broader categories is controversial. For example, some argue Separate ‘Comorbidities’ or Depression as Part of that, however much they may co-occur, one needs Normal Clinical Picture of Diabetes to treat the individual cardiovascular and meta- Viewing diabetes and depression as part of broad- bolic problems encompassed by the term ‘meta- er groupings or syndromes may also make sense bolic syndrome’ with appropriate medications across the categories of mental health and medical for diabetes, hypertension and hyperlipidemia illness. Research such as from the Diabetes Pre- [14] . Similarly, one may argue that beyond the co- vention Program [16] raises the possibility that occurrence with anxiety, hostility and stress, de- depression is an early sign or precursor of diabe- pressed mood alone has a specific and distinctive tes. Thus, as we think of the comorbidity of dia- role with both diabetes and cardiovascular dis- betes and depression, we might consider whether ease, requiring specific treatment rather than a they are best viewed as distinct clinical entities more generalized approach. that occasionally exist together, or as components Whether diabetes or depression are best of a broader syndrome encompassing both psy- viewed as distinct entities or as parts of broader chological and physical problems. The consider- syndromes may depend on the purpose of the ation of depression as part of such a broader syn- viewing. For example, Valderas et al. [15] noted drome would not necessarily include depressive that the value of different models of comorbidity disorders with specific symptoms, courses and would vary according to the perspective taken by outcomes such as severe depressive disorders specialist, primary care, public health or health with psychotic features (DSM 296.24) or depres- services. From the perspective of clinical care of sion in typical bipolar disorders. More generally, individuals, differentiating among specific prob- the term ‘depression’ needs to be understood as lems – depression, anxiety and hostility on the referring to mood changes that may be combined one hand and diabetes, hypertension and hyper- with a large – probably larger than currently rec- lipidemia on the other – makes great sense. ognized – number of problems and syndromes, Whether with psychotherapy or psychopharma- rather than as a single entity. cology, management of depressed mood differs Table 1 depicts options to view diabetes and de- from treatment of hostility or anxiety, just as pression as: (1) distinct but comorbid conditions, medication for diabetes differs from that for hy- (2) closely related conditions with appropriately

Co-Occurrence of Mental and Physical Disease 5

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 1–14 ( DOI: 10.1159/000365522 ) Table 1. Conceptualizations of the diabetes-depression relationship and implications for treatment

Conceptualization of relationship between Approach to treatment diabetes and depression Depression as a separate clinical problem Referral for specialty care but one that complicates diabetes management, e.g. ‘There’s no way these folks can address their diabetes until we treat their depression’ Depression and diabetes as overlapping, e.g. Develop resources for psychological and psychiatric services that helping patients to set and reach goals for are closely linked to diabetes care team; include attention to increasing physical activity is good for both emotional issues in self-management programs diabetes and depression Integration: depression is part of the normal Attention to psychosocial and emotional issues is a routine part of scope of diabetes and vice versa diabetes care; clinical depression as part of a range of emotional problems in diabetes Reflecting the bidirectional nature of these relationships, obesity, metabolic syndromes, diabetes and related problems are considered as part of the management of depression

coordinated care and (3) clinical problems that Biosocial Propensity to Chronic Disease and normally and commonly co-occur, requiring inte- Psychological Distress grated care. In an integrated approach, the treat- Bringing together a number of the points illus- ment of depression becomes a routine part of dia- trated so far in this chapter, figure 3 outlines a betes care, just as foot care and yearly retinal biosocial complex of determinants of chronic dis- checks. So, too, the psychological or medical treat- ease ranging from genetic and epigenetic effects ment of depression may be expanded to address its (including those of maternal nurturance during routine metabolic and cardiovascular dimensions. early childhood) to community design. Given Consider, for example, physical activity, which is sufficient deficiencies in this complex, some kind often included in diabetes self-management and of chronic disease (diabetes, asthma, etc.) is very increasingly recognized as helpful in reducing de- likely as is some variety of appreciable psycholog- pression. When promoting physical activity in dia- ical distress or psychopathology. The particular betes self-management, one should routinely con- expression of this biosocial complex in one or an- sider reticence to engage in exercise as potentially other chronic disease and one or another type of linked to mood problems. Additionally, one should psychological problem may be hard to predict, structure goal setting and monitoring to maximize but the likelihood of at least one of each – chron- the possible benefits not only of physical activity ic disease and psychological distress – is highly itself, but also of the mood-elevating effects of likely. In a casual survey of practicing primary achieving a personal goal [17] . At the same time, care clinicians, the common response is ‘That’s promoting physical activity as part of depression half of my waiting room.’ treatment may draw added emphasis from the rec- Figure 3 raises an important point, ‘What is ognition of its value not only in increasing mood, fundamental that requires attention?’ In the sim- but also in reducing cardiovascular risks to which pler terms of figure 2 , that fundamental may be, those with depression are prone. for example, diagnosed diabetes and diagnosed

6 Fisher · Chan · Kowitt · Nan · Sartorius · Oldenburg

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 1–14 ( DOI: 10.1159/000365522 ) Chronic disease Psychological disorder e.g. diabetes, asthma, CHF, CVD e.g. depression, anxiety disorder, personality disorder

Complex of developmental, biological and psychosocial determinants communities organizations housing social networks families behavior Fig. 3. Chronic disease and early development inflammatory processes metabolism psychological disorders as epigenetics genetics expressions of a biosocial complex of influences.

depression co-occurring in a particular individu- zation of cases and strategies. Self-management al. In the more developmental, genetic terms of interventions are key components of integrative figure 3 , what is fundamental is the biosocial approaches to clinical care. They teach and pro- complex of events that make expression in diabe- mote skills for doing the things in day-to-day life tes and depression or some other varieties of that are necessary to enhance clinical status and medical and psychological morbidity highly like- well-being [21] . Diabetes self-management inter- ly. The particular choice of expressions may be ventions have been well documented as effective almost accidental or perhaps guided by some spe- in improving metabolic control [22] . Notable cific factors, but the likelihood of such expres- within the context of the present review, reports of sions is almost assured. diabetes self-management and education programs have included benefits in quality of life [23] . Integrative models have also emerged in men- Treatment: Integrative Clinical and tal health. Assertive community treatment focus- Comprehensive Population Approaches es on treating individuals with severe mental illness (schizophrenia, depression, bipolar disor- A range of pharmacologic and psychological [18] der) within the community through a team of interventions have been found to be useful for co- professionals from psychiatry, nursing and social morbid diabetes and depression. Here we high- work. Rather than providing support within hos- light those that reflect the integrative, social and pital or clinical settings, community care is pro- community perspectives suggested in the preced- vided 24 h a day, 7 days a week. Research has doc- ing pages. umented the effectiveness of assertive community treatment in reducing hospitalization days, Integrative Chronic Disease Care and inpatient psychiatric services and emergency Self-Management room visits, especially among high utilizers of Recent reports [19, 20] have documented im- healthcare services [24]. Especially pertinent to proved clinical outcomes in diabetes through in- the present volume, integrated assertive commu- tegrative care that includes team care, evidence- nity treatment models have also been used to pro- based guidelines, procedures for coordinating vide care for co-occurring physical and mental care, and registry-based monitoring and prioriti- health problems [25] .

Co-Occurrence of Mental and Physical Disease 7

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 1–14 ( DOI: 10.1159/000365522 ) Integrating such approaches to both mental peer support for depression, anxiety and other and physical disorders, Katon and colleagues [26] mental health problems included education about developed ‘collaborative care’ models that com- psychological problems and ways of coping with bined pharmacotherapy, psychotherapy, general them (e.g. deep breathing for anxiety symptoms) counseling, problem solving and support provid- as well as interpersonal therapy, and was deliv- ed by a depression care manager. They included ered by lay health counselors with back-up by pri- those with depression as well as either diabetes mary care and monthly consultations from psy- and/or elevated cardiovascular risk, and found chiatrists. Results included a 30% decrease in the that collaborative care improved treatment (as in- prevalence of depression and other common dicated by medication adjustments), clinical risk mental disorders among those with these prob- measures (glycemic control, lipids, blood pres- lems at baseline, 36% reduction in suicide at- sure), quality of life and social role disability [26] . tempts or plans, and an average of 4.43 fewer days A 2012 meta-analysis of 69 studies of collabora- with no or reduced work in the previous 30 days tive care [27] documented substantial improve- [31] , resulting in the intervention being both cost ments on a variety of indicators, including adher- saving as well as cost-effective [32] . ence to depression treatment (OR = 2.22) and re- A population-based study in the USA evalu- covery from symptoms (OR = 1.75). Such findings ated Medicaid enrollees who had made a claim have also been replicated with low-income ethnic for both community mental health and peer sup- minority patients in the USA [28] . port services. A comparison group who had made only claims for community mental health services Social Influences: Peer Support was matched by gender, race, age, urban/rural Peer supporters, also known as ‘community residence and principle diagnosis. Those who had health workers’, ‘lay health advisors’, ‘promo- received peer support were less likely to be hospi- tores’ and a number of other terms, can assist in- talized (OR = 0.766) and more likely to achieve dividuals in self-management of diabetes and crisis stabilization (OR = 1.345) [33] . prevention and management of other diseases An important impact of psychological distress [e.g. 29]. They may also provide emotional sup- in chronic disease is its role in complicating ef- port and encourage problem solving to address forts to reach and engage patients in recommend- depression and other emotional distress. Both the ed care. Peer support may be an especially effec- social isolation or lack of a confidant that often tive strategy for reaching the ‘hardly reached’ accompany psychopathology and distress [29] [34] . Asthma coaches pursuing a nondirective, and the importance of simple social contact and flexible, stage-based approach were able to en- emotional support suggest that simple, frequent, gage 89.7% of mothers of Medicaid-covered chil- affirming and pleasant contact from a supporter dren hospitalized for asthma. The coaches sus- may be especially helpful to those with emotional tained that engagement, averaging 21.1 contacts distress. per parent over a 2-year intervention. Of those In a striking cluster randomized evaluation in randomized to an asthma coach, 36.5% were re- Pakistan, ‘Lady Health Workers’ implemented a hospitalized over the 2 years compared to 59.1% cognitive-behavioral, problem-solving interven- receiving usual care (p < 0.01) [35] . tion for women who met criteria for major de- In a successful peer support intervention for pression during the third trimester of their preg- diabetes management among patients of safety nancies. Relative to controls, the intervention net clinics in San Francisco, participants were substantially reduced depression 12 months post- categorized as low, medium or high medication partum (OR = 0.23, p < 0.0001) [30] . In India, adherence at baseline. The peer support led to

8 Fisher · Chan · Kowitt · Nan · Sartorius · Oldenburg

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 1–14 ( DOI: 10.1159/000365522 ) greater reductions in glycated hemoglobin than sation of smoking in the USA [41] . Most nota- in controls across all groups, but the differential bly, declines in per capita cigarette consumption impact of peer support was greatest among those and closely associated declines in cardiovascular initially in the low adherence group [36] . In a mortality in California were attributable to a dyadic support intervention among veterans statewide campaign supported by taxes on ciga- with diabetes, improvements in blood glucose rettes that included prevention programs for measures were substantially more pronounced youth, cessation programs for adults, aggressive among those with low initial levels of diabetes counteradvertising campaigns, and communi- support (p for interaction <0.001) and those ty-based program coordination and planning with low health literacy (p for interaction <0.05) [42] . [37] . Illustrating community approaches to mental health, the German city of Nuremberg imple- Comprehensive Population Approaches to mented a multilevel 2-year community interven- Interventions for Depression and Diabetes tion to treat depression and suicide [43] . Using Community-wide health promotion programs community facilitators, the program intervened focus on populations affected or at risk. The ma- with three sectors of society: primary care physi- jor community programs aiming to prevent car- cians to provide training and awareness about de- diovascular disease [38] and encourage non- pression, the general public to raise awareness smoking [39] may provide lessons for compre- and knowledge of services, and depressed pa- hensive approaches to management of physical tients to provide support. After 2 years, the pro- and mental disorders. The North Karelia project gram found significant reductions in suicide acts in Finland addressed heightened cardiovascular and depressive symptoms, and the program was disease through a broad range of interventions. In expanded to other regions of Europe under the comparison to other parts of the country, North name ‘The European Alliance against Depres- Karelia showed impressive reductions in cardio- sion’ [43] . vascular risk factors and mortality, as well as re- How such community approaches might be ductions of cancer risk factors [38] . extended to multimorbidity of physical and men- Several characteristics appear important in the tal disorders is unclear. One might begin with be- North Karelia program. Its wide range of initia- haviors that community health promotion pro- tives included development of new treatment grams have been able to improve and that are also guidelines for hypertension and care following pertinent to diabetes and depression, such as myocardial infarction and other clinical preven- healthy diet, regular physical activity, medication tive approaches, community-based health educa- adherence, and regular clinical care, and in suc- tion and social marketing of preventive practices, cessful approaches to hypertension, such as stra- and diverse engagement of community organiza- tegically directed screening. In addition to broad tions, mass media and key businesses such as involvement of community organizations, busi- dairies, sausage factories, and food merchandis- ness and local government, intervention strate- ing groups and grocery stores to improve the gies might include: availability of healthy foods [40] . Across all inter- (1) Attention to the built environment and design ventions, great attention was given to collabora- of neighborhoods and housing to promote tive planning and implementation with local or- physical activity as well as enhance psycholog- ganizations. ical adjustment and well-being Similar lessons may be drawn from success- (2) Engaging worksites to recognize two roles ful campaigns to encourage prevention and ces- they may play: useful and socially influential

Co-Occurrence of Mental and Physical Disease 9

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 1–14 ( DOI: 10.1159/000365522 ) sites for implementation of programs, and Discussion identifying ways in which personnel policies and procedures might be improved to facili- Articulation of the roles of social and economic tate daily management of diabetes (e.g. blood factors is sometimes perceived as being in opposi- glucose monitoring, healthy diet) and to re- tion to the articulation of individual-level factors duce stress and enhance emotional as well as or clinical treatment. The intent of the broad eco- physical health logical perspective taken here is an integration (3) Community organization and social market- rather than opposition of multiple levels of expla- ing to build social capital and promote the nation. Recognition of the range of influences on kinds of community values, social interac- mental health and chronic disease will best illumi- tions and approaches to conflict resolution nate the relationships between them. Understand- that may also enhance emotional and physical ing the utilities of different perspectives on those health relationships will best guide selection of perspec- (4) Recruiting members of key audiences as peer tives that serve specific purposes. Furthermore, supporters to build links between programs integrating clinical, social and community ap- and those audiences as well as providing emo- proaches to prevention and management will best tional and tangible support to those most in meet the global burden of multimorbidities. need

New Media of Intervention: e-Learning, Clinical Implications Telehealth, Web-Based Interventions Promising results from Web-based and tele- There is often a tendency to see the world of clini- health interventions have spurred interest in cal care as separate and distinct from that of pre- new modalities for intervening with people ex- vention and population health; however, these are periencing depression and diabetes [44] . A re- overlapping. Healthy communities may enable cent systematic review of Internet support patient adherence to diabetes management and groups for individuals with depressive symp- treatment of depression. At the same time, the toms provides evidence for the role of e-health availability of quality clinical care may provide in managing depression [45] . Of the 16 studies both a channel for reaching populations as well as reviewed, a majority (62.5%) reported a positive a resource for promoting healthy lifestyles [47] . effect of Internet support on depressive symp- As discussed above, peer support may be an toms. Although only 20% of the studies used a especially promising strategy for integrating clin- control group, other randomized control trials ical and preventive as well as individual and of Internet interventions have demonstrated sta- population approaches. Peer supporters can help tistically significant reductions in depression sustain the behaviors that comprise diabetes and compared to control groups [46]. Telephone-de- depression management [29] and provide emo- livered cognitive-behavioral programs have also tional support and encourage problem solving to been successfully used with Veterans Adminis- address depression and other emotional distress tration patients in the USA to reduce depressive [30] while engaging those who otherwise fail to symptoms and improve quality of life and func- receive appropriate care [35, 48]. All of these can tioning [17]. For patients who have been ‘hardly assist in identifying and recruiting into treatment reached’ by the traditional medical care system, those with mental and physical disorders and in these new modalities offer a model for enhanced helping them take full advantage of the available patient outreach and care. resources.

10 Fisher · Chan · Kowitt · Nan · Sartorius · Oldenburg

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 1–14 ( DOI: 10.1159/000365522 ) A simple consideration that is too often unrec- cates that the benefits of cognitive behavior ther- ognized cuts across all the approaches to inter- apy for depression rest largely on the more vention outlined here. The emotional aspect is an behavioral, skill-oriented components of prob- important part of chronic disease care. Attention lem solving and ‘behavioral activation’ within to depression, emotional well-being and healthy cognitive behavior therapy [50] . Thus, problem relationships is not a secondary consideration in solving can address the management of both chronic disease care, but – based on the evidence mental and physical disorders. For example, help- [e.g. 1 ] – of central importance. In diabetes and ing individuals set objectives for increasing phys- cardiovascular disease, for example, the recogni- ical activity, take steps to accomplish those objec- tion and treatment of depression may be as im- tives, and reflect on the pleasure of reaching them portant as biological treatment targets. Further, may advance both diabetes self-management as knowledge gained by a comprehensive approach well as self-management of depression. to diabetes and depression may be highly relevant In addition to its effectiveness in both domains, to the care of other chronic diseases. Attention to an emphasis on problem solving may also provide depression, anxiety and stress disorders is likely a useful framework for providing coherence to the to have impacts on health and healthcare costs far individual’s tasks in management of mental and greater than currently appreciated. physical disorders. Organizing overall care as problem solving or self-management to achieve a healthy diet, physical activity, adherence to medi- Integrative Role of Self-Management in cations, stress management, and maintenance of Diabetes and Depression satisfying social and community engagements may provide patients a coherent framework for Self-management programs in chronic disease accommodating the changes that emerge inevita- may provide important models for approaches to bly in the natural history of chronic disease. It may mental health problems in general as well as those also avoid concerns about stigma surrounding de- which co-occur with physical disorders. Surely the pression, other forms of emotional distress or core elements of chronic disease self-manage- chronic diseases in many cultures. ment – healthy diet, physical activity, adherence to Self-management procedures emerged largely medication regimens, stress management, prob- out of research on self-control and related pro- lem solving, and cultivating family and friend sup- cesses in psychology, behavior therapy and health port – would all seem equally pertinent to the man- psychology. This might lead one to expect great agement of depression. It should also be noted that attention to self-management approaches to de- meta-analysis of interventions for depression and pression and other mental health problems that diabetes has implicated diabetes self-management psychology has traditionally addressed. Yet, while education in the metabolic benefits associated with a search of PubMed (January 13, 2014) for papers cognitive behavioral interventions [18] . with ‘self-management’ and cognates of ‘diabetes’ Within self-management, problem solving in their titles yielded 762, a parallel search for pa- may have a special role in integration of care for pers with ‘self-management’ and cognates of ‘de- depression and diabetes. Problem solving is cen- pression’ in their titles yielded only 36. When ex- tral to almost all models of self-management in panded to include mention in abstracts, results diabetes and chronic disease. At the same time, were 2,390 for ‘self-management’ with cognates of problem solving has emerged as a prominent ap- ‘diabetes’ and 567 with cognates of ‘depression’. proach to psychotherapy for depression and oth- Further, many of those mentioning depression er problems [49] . Indeed, recent research indi- were focused on self-management of other diseas-

Co-Occurrence of Mental and Physical Disease 11

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 1–14 ( DOI: 10.1159/000365522 ) es and simply included a measure of depression, the interconnected nature of behavioral health not the focus of the self-management program. It and biological problems and to bring to bear evi- should be noted that mental health researchers dence-based models for addressing them. may use other terms like ‘psychotherapy’, ‘sup- Whether through mental health, primary care, portive therapy’, and ‘bibliotherapy’ to refer to specialty care or community-based programs, in- similar services as ‘self-management’. Neverthe- dividuals should receive services that reflect the less, it appears that the combination of proactive co-occurrence of diabetes and other chronic dis- medical treatment and self-management which eases with depression and other emotional dis- constitutes the state-of-the-art in diabetes has not tress and that provide integration and continuity been fully recognized in mental health. of services for these. Integrating the clinical with Experience teaches that paradigm or conceptu- social, organizational and community approach- al shifts do not follow from rational argument as es as advocated here may offer a strong model not often as they emerge in response to events. The only for the global burdens of diabetes, depres- growing burden of diabetes, depression and other sion and other mental and physical health prob- multimorbidities may compel medicine, public lems, but also for more general prevention and health and mental health to move forward with im- healthcare in an era of aging populations, grow- proved and comprehensive interventions. Closely ing prevalence and burden of noncommunicable related to this, the pressure of healthcare costs has diseases, and normative multimorbidity . led (e.g. US Affordable Care Act) to increased emphasis on primary care and integration of chronic disease management and behavioral health. Disclosure Statement The perspectives here have substantial implications for training professionals. Beyond cover- Dr. Fisher and Ms. Kowitt are supported by the American ing chronic diseases and the behavioral health is- Academy of Family Physicians Foundation through its program, Peers for Progress, which is supported by the Eli sues that so often accompany them, training Lilly and Company Foundation, the Bristol-Myers Squibb needs to inculcate an understanding of the inte- Foundation and Sanofi US. gration of these, as they are experienced by pa- The Association for the Improvement of Mental tients and as they need to be treated by clinicians. Health Programmes, directed by Dr. Sartorius, received a grant from Eli Lilly and Company to assist in the develop- Moving down the problem list from diabetes, to ment of the Dialogue on Diabetes and Depression from joint problem, down to depression is not an ap- deliberations of which the present manuscript developed. proach to organizing clinical care that reflects the With the exception of support for travel to meetings pro- ways in which these problems emerge and func- vided through the Dialogue on Diabetes and Depression, and the support of Dr. Fisher and Ms. Kowitt by Peers for tion. One might argue that such an approach is, Progress of the American Academy of Family Physicians indeed, bad medicine. Beyond the pitfalls of poly- Foundation, the authors have collaborated in the develop- pharmacy that it engenders, it fails to recognize ment of this paper without any support for the work.

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WC, Dennison-Himmelfarb C, Handler diabetes patients. Med Care 2011; 49: CS, Hahn RA, McKnight-Eily LR, Chap- J, Lackland DT, Lefevre ML, Mackenzie 641–648. man DP, Abraido-Lanza AF, Pearson JL, TD, Ogedegbe O, Smith SC Jr, Svetkey 18 van der Feltz-Cornelis CM, Nuyen J, Anderson CW, Gelenberg AJ, Hennessy LP, Taler SJ, Townsend RR, Wright JT Stoop C, Chan J, Jacobson AM, Katon KD, Duffy FF, Vernon-Smiley ME, Jr, Narva AS, Ortiz E: 2014 evidence- W, Snoek F, Sartorius N: Effect of inter- Nease DE Jr, Williams SP: Collaborative based guideline for the management of ventions for major depressive disorder care to improve the management of de- high blood pressure in adults: report and significant depressive symptoms in pressive disorders: a community guide from the panel members appointed to patients with diabetes mellitus: a sys- systematic review and meta-analysis.

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(JNC 8). JAMA 2014; 311: 507–520. Hosp Psychiatry 2010; 32: 380–395. 28 Ell K, Katon W, Xie B, Lee PJ, Ka- 10 Hjerl K, Andersen EW, Keiding N, 19 Chan JC, So WY, Yeung CY, Ko GT, Lau petanovic S, Guterman J, Chou CP: Col- Mortensen PB, Jorgensen T: Increased IT, Tsang MW, Lau KP, Siu SC, Li JK, laborative care management of major incidence of affective disorders, anxiety Yeung VT, Leung WY, Tong PC; SURE depression among low-income, pre- disorders, and non-natural mortality in Study Group: Effects of structured ver- dominantly Hispanic subjects with dia- women after breast cancer diagnosis: a sus usual care on renal endpoint in type betes: a randomized controlled trial.

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11 Brummett BH, Boyle SH, Ortel TL, Diabetes Care 2009; 32: 977–982. Baumann LC, Mbanya JC, Rotheram- Becker RC, Siegler IC, Williams RB: As- 20 Daniel DM, Norman J, Davis C, Lee H, Borus MJ, Sanguanprasit B, Tanasugarn sociations of depressive symptoms, trait Hindmarsh MF, McCulloch DK, Wagner C: Peer support for self-management of hostility, and gender with C-reactive EH, Sugarman JR: A state-level applica- diabetes improved outcomes in interna- protein and interleukin-6 response after tion of the chronic illness breakthrough tional settings. Health Aff (Millwood)

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Organ 2012; 90: 813–821. Sumner WI, Heath AC: Cigarette smok- comes. BMC Public Health 2012; 12: 602. 33 Landers GM, Zhou M: An analysis of ing; in Raczynski J, Bradley L, Leviton L 45 Griffiths KM, Calear AL, Banfield M: relationships among peer support, psy- (eds): Health Behavior Handbook. Systematic review on internet support chiatric hospitalization, and crisis stabi- Washington, American Psychological groups (ISGs) and depression (1): do lization. Community Ment Health J Association, 2004, vol II. ISGs reduce depressive symptoms? J

2011; 47: 106–112. 40 Puska P, Nissinen A, Tuomilehto J, Sa- Med Internet Res 2009; 11:e40. 34 Fisher EB, Coufal MM, Parada H, Robi- lonen JT, Koskela K, McAlister A, 46 Glozier N, Christensen H, Naismith S, nette JB, Tang P, Urlaub D, Castillo C, Kottke TE, Maccoby N, Farquhar JW: Cockayne N, Donkin L, Neal B, Mackin- Filossof YR, Guzman-Corrales LM, Hino The community-based strategy to pre- non A, Hickie I: Internet-delivered cog- S, Hunter J, Katz AW, Worley HP, Xui vent coronary heart disease: conclusions nitive behavioural therapy for adults C: Peer support in health care and pre- from the ten years of the North Karelia with mild to moderate depression and

vention: cultural, organizational and project. Annu Rev Public Health 1985; 6: high cardiovascular disease risks: a ran- dissemination issues; in Fielding J, 147–193. domised attention-controlled trial. PLoS

Brownson RC, Green L (eds): Annual 41 Cole HM, Fiore MC: The war against One 2013; 8:e59139. Review of Public Health. Palo Alto, An- tobacco: 50 years and counting. JAMA 47 Plescia M, Groblewski M: A community-

nual Reviews, 2014, vol 35. 2014; 311: 131–132. oriented primary care demonstration 35 Fisher EB, Strunk RC, Highstein GR, 42 Fichtenberg CM, Glantz SA: Association project: refining interventions for car- Kelley-Sykes R, Tarr KL, Trinkaus K, of the California tobacco control pro- diovascular disease and diabetes. Ann

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workers on hospitalization for asthma: ease. N Engl J Med 2000; 343: 1772–1777. ress: promoting peer support for health

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Med 2009; 163: 225–232. 27(suppl 1):i62–i68. 36 Moskowitz D, Thom DH, Hessler D, 49 D’Zurilla TJ, Nezu AM: Problem-Solving Ghorob A, Bodenheimer T: Peer coach- Therapy, ed 2. New York, Springer, ing to improve diabetes self-manage- 1999. ment: which patients benefit most? J 50 Cuijpers P, van Straten A, Warmerdam

Gen Intern Med 2013; 28: 938–942. L: Behavioral activation treatments of depression: a meta-analysis. Clin Psy-

chol Rev 2007; 27: 318–326.

Edwin B. Fisher, PhD Department of Health Behavior Gillings School of Global Public Health University of North Carolina Box 7440 Chapel Hill, NC 27599-7440 (USA) E-Mail [email protected]

14 Fisher · Chan · Kowitt · Nan · Sartorius · Oldenburg

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 1–14 ( DOI: 10.1159/000365522 ) Background

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 15–22 ( DOI: 10.1159/000365524 )

Public Health Perspectives on the Co-Occurrence of Non-Communicable Diseases and Common Mental Disorders

a b a Brian Oldenburg · Adrienne O’Neil · Fiona Cocker a b School of Population and Global Health, The University of Melbourne, and IMPACT Strategic Research Centre, Deakin University, Melbourne, Vic., Australia

Abstract almost 90% of all deaths due to non-communica- This chapter uses a public health perspective to provide ble disease, globally. However, in recent times, an overview of the key determinants and shared path- growing support has emerged for the need for ways for the causes of non-communicable diseases and common mental disorders, such as major de- common mental disorders and their outcomes. Current pression and anxiety, to also be recognised as understandings about their co-occurrence, prevention non-communicable diseases [1] . Indeed, it is and control will be discussed, as well as the implications now very well established that these common of emerging frameworks that target modifiable risk fac- mental disorders contribute significantly to the tors. We will conclude by outlining some of the issues and global burden of disability-adjusted life years. In challenges associated with wide-scale implementation fact, when considering disability-adjusted life and scale-up of public health interventions that target years, rather than just cause of death, the so- the prevention and control of these conditions when called ‘big four’ account for only half (54%) of they co-occur in different community settings. non-communicable disease-related disability- © 2015 S. Karger AG, Basel adjusted life years, with major depression the second leading cause of disability. In response, the WHO Global Action Plan (2013–2016), devel- Current Views on the Prevention and Control oped to reduce the global burden of non-com- of Non-Communicable Diseases and Common municable diseases and preventable mortality, Mental Disorders now incorporates targets and strategies related to mental health prevention and control [2] . A shift Cardiovascular disease, type 2 diabetes mellitus, towards a model that incorporates mental and cancer and chronic respiratory disease are often physical disorders into the same constellation of referred to as ‘the big four’ non-communicable conditions also has important implications for diseases. The World Health Organization conceptualising their prevention and manage- (WHO) reports that these conditions account for ment, both as independent conditions, but even more importantly, when they co-occur. Before eases and common mental disorders. Before re- further discussing the implications of such a viewing such a framework, the shared pathways model for approaches to their prevention and that link the common mental disorders to non- control, the key determinants and pathways that communicable diseases will be described. link high prevalence non-communicable diseases to common mental disorders will be discussed. We shall particularly focus on the inter-relation- Shared Pathways for Non-Communicable ships and co-occurrence among cardiovascular Diseases and Common Mental Disorders disease, type 2 diabetes and depression. It may seem intuitive that the occurrence of depression or anxiety in those with a chronic physi- Shared Determinants for Non-Communicable cal condition exacerbates the risk of poor clinical Diseases and Common Mental Disorders outcomes. For example, after the occurrence of a life-threatening event such as acute coronary syn- When identifying population-wide prevention drome (heart attack), or symptoms and potential and control strategies for non-communicable complications of type 2 diabetes, the associated diseases, the WHO has emphasised the role of the worry and distress impair functioning, recovery lifestyle determinants of these conditions. Tradi- and/or coping ability, and the overall burden of tionally, common mental disorders have received self-management may exacerbate symptoms of relatively little attention from this perspective, depression [3] . For example, some estimates sug- and treatment options that target the modifiable gest 25–46% of people with type 2 diabetes mel- lifestyle factors known to ameliorate non-com- litus [4] or cardiac disease [5] experience symp- municable diseases have been seldom applied to toms indicative of depression. However, these common mental disorders. Jacka et al. [1] have symptoms are not just a common clinical out- argued that while contextual factors including so- come of these conditions. Major depression has cial inequity and networks, child maltreatment, emerged as a powerful and robust risk factor for and neglect clearly contribute to depression risk, both conditions in recent years [6] . While the it is important that prevention and control efforts pathways implicating depression in the patho- focus much more on those determinants with the genesis and outcomes of cardiovascular disease ‘greatest plasticity and reach’. The authors de- and/or diabetes remain unclear, they are clearly scribe a growing evidence base that identifies life- multifaceted. Psychophysiological, biobehav- style factors (e.g. physical inactivity, smoking and ioural and social influences interact to elevate the diet quality) as important determinants for the risk of cardiovascular disease and/or type 2 diabe- development of common mental disorders such tes in those with depression (both in its genesis as depression, i.e. the same lifestyle determinants and clinical course), accelerating the psychologi- already known to be important determinants of cal and cardiometabolic abnormalities of each non-communicable diseases. This evidence sug- [3]. For example, of the former, depression and gests an opportunity exists to prevent and control psychosocial stressors can lead to hypothalamic- mental and physical disorders that occur comor- pituitary-adrenal axis activation and complex bidly by using a consolidated framework in which hormonal and (auto)immuno-inflammatory in- several overlapping, modifiable risk factors, such teractions in the pathogenesis of cardiometabolic as tobacco use, unhealthy alcohol use, physical in- disorders. Such a response can elicit a host of met- activity and unhealthy diet are targeted with the abolic and cardiovascular abnormalities which potential to reduce both non-communicable dis- characterise the cardiovascular disease and diabe-

16 Oldenburg · O’Neil · Cocker

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 15–22 ( DOI: 10.1159/000365524 ) tes over-represented in people with depression. vention rather than a focus on treatment services This response can perpetuate a cycle of psycho- and management of a clinical problem. With logical and physical ill health [3] . these theoretical differences in mind, we will now Another explanation for this relationship is consider the evidence in relation to the preven- biobehavioural; the presence of shared risk fac- tion and control of comorbid non-communicable tors like smoking, obesity, poor diet or physical diseases and common mental disorders. inactivity can lead to systemic inflammation, which is common in the development of both depression [7, 8] and these systemic disorders [9] . Prevention and Control of Comorbid Physical Further, environmental and contextual factors and Mental Disorders commonly linking mental and physical disorders, including socio-economic status and social isola- To date, the evidence base for the effectiveness tion, have also been shown to increase the risk of and feasibility of real-world public health inter- all of these disorders [7, 10, 11]. Fisher et al. [3] ventions for the prevention and management of argues that these up- and downstream determi- common comorbid non-communicable diseases nants are complex in that they are interwoven at and common mental disorders is stronger for multiple levels. Failure to consider the role of people with existing conditions than for primary such factors has potentially deleterious conse- prevention or secondary prevention in those at quences with respect to the delivery and effective- ‘high risk’; we shall consider both of these. ness of public health interventions. While these consequences will be discussed further in a fol- Prevention of Comorbid Non-Communicable lowing section, we will define what is meant by Diseases and Common Mental Disorders ‘public health’ interventions before looking at As outlined in previous sections, there is sound those that exist for the prevention and control of evidence that similar lifestyle factors shown to comorbid mental and physical health disorders. precipitate the ‘big four’ non-communicable diseases are also important contributors in the development of common mental disorders. Notwith- Defining Public Health Interventions standing the complexity of factors contributing to the pathophysiology and trajectory of common The term ‘public health interventions’ can have mental disorders like depression and anxiety, this different meanings, in part because the term ‘pub- evidence suggests that modification of lifestyle lic health’ is used in different ways. First, the term behaviours as risk factors may have the potential ‘public health’, particularly ‘public health re- to ameliorate some of the risk of common mental search’, is often used as a general and very broad disorders. This rationale has underpinned recent term to be inclusive of all epidemiologic, interven- calls for a population-based approach that inte- tion and health services research. Second, it can be grates such ‘plastic’ lifestyle factors for the univer- used to imply a primary focus on the health of the sal prevention of common mental disorders [1] . public and whole populations, rather than being Recent research in this field suggests whilst the concerned with just the health and well-being of potential contribution of modifiable factors such single individuals; often this focus also includes a as social inequality, social networks, and child, particular interest in the situation as it pertains to drug and alcohol abuse to depression risk should disadvantaged individuals or groups, and/or an not be underestimated or ignored, preventive ef- emphasis on this issue globally. Third, ‘public forts should also aim to address individuals’ health’ is often taken to mean an emphasis on pre- health-related lifestyle behaviours.

Co-Occurrence of Non-Communicable Diseases and Common Mental Disorders 17

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 15–22 ( DOI: 10.1159/000365524 ) Lifestyle is a term that encompasses behav- using this approach become apparent. We shall iours related to diet, physical activity and smok- discuss the issues related to economic responsi- ing, amongst other behaviours, known to increase bility in the following section. the risk of disease and poor health. There is increasing evidence which identifies physical inac- Control and Management of Comorbid tivity as a risk factor for common mental disor- Non-Communicable Diseases and Common ders [12, 13] , with exercise shown to be effective Mental Disorders in ‘High-Risk’ Populations in treatment studies [14] . Further, some evidence Traditionally, non-communicable diseases and exists linking smoking to an increased risk of de- common mental disorders have been treated veloping common mental disorders [15, 16] . Diet uniquely and independently within the public quality has also received much attention in recent health sphere. From a systematic perspective, times in the lifestyle-mental health research field many healthcare systems are not designed to in- [17, 18] . For example, one notable study, the corporate the multidisciplinary approach required PREDIMED trial, identified a link between ad- to manage patients with co-occurring physical and herence to the Mediterranean diet, the hallmark mental disorders adequately. This is largely due to of which is the abundant use of olive oil [19] , increasingly specialised and fragmented struc- which is rich in monounsaturated fatty acids, and tures. Additionally, a range of downstream deter- reduced depression risk [20] . Results revealed a minants are likely to impede the cohesive manage- significant 40% reduction in depression risk for ment of these comorbidities, including a lack of individuals with type 2 diabetes who adhered to recognition around their high prevalence, poor the Mediterranean diet when compared with the awareness on behalf of the patient, practitioner or control group. both, and deficits in physician training. Despite these encouraging findings, evidence If we use the specific example of diabetes, a is somewhat scarce and moreover limited by un- lack of continuity of care has been shown to derpowered sample sizes or inadequate study de- translate to poorer clinical outcomes and sub- signs. However, the primary prevention of com- optimal care provision. For example, Mitchell et mon mental disorders remains a burgeoning area al. [22] provide evidence that despite greater in public health that has garnered support in re- service use, those with a mental illness are less cent years in light of data suggesting that, for the likely to be screened for diabetes, associated eye majority of people (75%), common mental disor- or foot complications, receive statins or diabetes ders manifest before the age of 24 years [21] . education, or be offered HbA1c and cholesterol Moreover, lifestyle-based strategies that target the screening. primary prevention of common mental disorders The converse is also true. Using the example of could play an important role in the subsequent heart disease, people who have been admitted to prevention of the ‘big four’ non-communicable hospital for a coronary event are unlikely to be diseases. The beneficial effects of targeting life- screened for depression. Stewart et al. [23] report style factors are likely to extend beyond that of that only 3% of clinicians in Australia perform psychological well-being to ameliorate the risk of routine screening for depression. In order to ad- non-communicable diseases, potentially produc- dress these deficiencies within healthcare sys- ing a ‘double hit’ by delaying or preventing chron- tems, models of the clinical management for co- ic disease later in the lifespan. From a well-being, morbid mental and physical disorders have been health and economic perspective, the (in)direct developed. Perhaps the most well-known is the ‘flow-on’ effects resulting from investment in the IMPACT model developed by Katon et al. [24] , primary prevention of common mental disorders which draws on evidence-based medical models

18 Oldenburg · O’Neil · Cocker

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 15–22 ( DOI: 10.1159/000365524 ) such as those described by Wagner et al. [25] These models also depend largely on local cul- (chronic care model in primary care settings) and ture, health systems, workforce and many other Lorig et al. [26] (self-management models in contextual factors and influences. community-based settings). The model of care by Katon et al. was one of the first to consider the concurrent management of depression, heart dis- Considerations for Implementation and ease and type 2 diabetes using a collaborative care Scale-Up of Prevention and Control of approach, and has been shown to be more effec- Comorbid Non-Communicable Diseases tive for chronic disease management than stan- and Common Mental Disorders dard medical care [27] . Collaborative care models emphasise the ‘up-skilling’ of practice nurses as Context case managers who aim to provide continuity of With the development and adaptation of any pub- care. This includes [24] : lic health intervention – much less one that targets • Encouraging support and effective both mental and physical disorders – one needs to communication to patients from clinicians consider particular contexts and settings. Fisher et • Utilising evidence-based guidelines to al. [3] maintains that failure to consider contex- promote patient self-management tual factors can result in a number of potentially • Monitoring risk factors deleterious outcomes. First, efficacy and/or effec- • Scheduling visits tiveness of specific interventions may be diluted. • Providing audit information Second, the benefits of interventions may be fur- Algorithms provide guidance on the direction ther underestimated should contextual modera- of care based on severity of symptoms, often us- tors remain unaccounted for in analyses. Third, ing a stepped-care approach with various health- individuals participating in these interventions care professionals based on patient need. Perhaps could be perceived as responsible for their condi- the most important characteristic underpinning tion resulting in a type of ‘victim blaming’ [3] . To this model is its operation within existing struc- this end, future opportunities exist to explore and tures of the healthcare setting, rather than amend- evaluate different approaches to increase aware- ing the healthcare structure itself. It is designed to ness and understanding of these issues in both capitalise on existing workforce and financial in- health professionals and patient populations. frastructures by refocussing the roles of the existing members and organisational structures of the Cost and Responsibility setting. There remains a need to shift the balance towards Collaborative care models have now been ex- greater investment in not only population-based trapolated to a range of other comorbidities, such prevention strategies in public health, but those as depression and coronary artery bypass grafting which incorporate attention being given to either [28] , where they have demonstrated efficacy and the increased risk or the co-occurrence of non- feasibility, and have been shown to reduce cardio- communicable diseases and common mental dis- vascular risk in elderly people with depression orders. The broader issue of responsibility must [29] . However, such models have been subject to be considered, as with the primary prevention of criticism. For example, it has been argued that any condition. Indeed, cost remains a barrier. A they have limited generalisability, require a cul- WHO report suggests a key factor underscoring tural shift in norms and roles, are too resource the traditional focus on, and preference for, cura- intensive to implement and there may be unnec- tive strategies are the short-term, tangible benefits essary overlap with other related programs [30] . as opposed to the longer pay-off periods required

Co-Occurrence of Non-Communicable Diseases and Common Mental Disorders 19

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 15–22 ( DOI: 10.1159/000365524 ) to see the effects of prevention [31] . This is par- of how to promote the health and productivity of ticularly evident as the cost of healthcare increases workers with multiple chronic illnesses is a prior- globally, thereby increasing competition for re- ity, as the impact of comorbid and multimorbid sources [31] . Because more than 80% of the mental and physical disorders is not restricted to world’s population lives in developing regions of older adults outside the workforce. the world [32] – particularly, very populous coun- Absenteeism from work is a major issue for tries, such as India, China and Indonesia, where governments across the world as it not only de- non-communicable disease risk factors continue creases productivity resulting in loss of financial to increase [33] – focus on the management of growth, but also costs governments a significant these comorbidities in so-called ‘low and middle amount of money annually to treat ill individuals, income’ countries is of particular importance. giving absenteeism a twofold economic effect [36] . Aside from the economic impact of absenteeism, there are also social benefits for adults Economic Impact of the Co-Occurrence of who participate in paid employment such as fi- Non-Communicable Diseases and Common nancial independence, a higher standard of liv- Mental Disorders: A Focus on the Workforce ing, and the potential for personal satisfaction and social acceptance [37]. Data reveal absentee- The economic impact of non-communicable dis- ism is higher amongst people with one or more eases and common mental disorders when they chronic illnesses and that employees with a occur alone is significant. However, the associ- chronic illness have higher rates of long-term ated costs, largely attributed to increased health- work disability than the general population [37] . care use and expenditure (e.g. specialist care, hos- Interestingly, one study revealed that for absen- pital care and medication) and lost productive teeism attributed to a physical illness, psycholog- time, are substantially increased when non-com- ical factors played a greater part in the decision to municable diseases and common mental disor- take a sickness absence than the physical illness ders co-occur. In most developed countries, the itself [37] . majority of people with non-communicable dis- Most of the research to date on multimorbid- eases are able to keep working, with the latest es- ity and health and social outcomes has focused on timates of workforce participation among Aus- quality of life [38] , use of medical services [39] , tralian adults with non-communicable diseases and hospitalisation and mortality [40], and has being 79% for men and 63% for women [34] . As been in clinical or primary care populations [35, a result, a substantial economic burden from 41], or selected older adult populations [41] . non-communicable diseases is borne by work- However, given that many chronic diseases affect places, in particular, lost productivity resulting healthier, working age adults [34], this focus on from absenteeism and presenteeism (working clinical populations and clinical outcomes pro- while ill) [34] . Additionally, a sizeable minority vides an insufficient evidence base for a public of employed people with non-communicable dis- health approach to the health of the workforce eases, an estimated 18% amongst Australian em- [35, 42]. Further, one recent Australian study ployees, will be managing another major health demonstrated that comorbid psychological dis- conditions such as heart disease, arthritis, de- tress causes an increased risk of productivity loss, pression, asthma, diabetes and stroke [34] , and from both absenteeism and presenteeism, for a these multimorbid disease combinations com- range of health conditions. Therefore, in terms of monly also include depression [35] . With an age- population health approaches to managing co- ing workforce globally, a greater understanding morbid non-communicable diseases and com-

20 Oldenburg · O’Neil · Cocker

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 15–22 ( DOI: 10.1159/000365524 ) mon mental disorders, an increased focus needs health programs that address the shared determi- to be on developing evidence-based guidance to nants and pathways of these disorders. Whilst some inform a reduction of the burden of common public health interventions have proven effective, chronic diseases and comorbid depression among there remains a range of contextual and economic working age adults. Specifically, this includes the factors to consider for wide-scale implementation prevention of long-term work absences and the in different settings. Specific considerations in- associated costs, generally poor outcomes of re- clude the responsibility of investment and cost return-to-work programmes, and the development covery, and a lack of awareness and action concern- of decision aids for individuals and their clini- ing comorbidity by public health and medical au- cians to help guide management of work de- thorities. Where there is not sufficient evidence for mands and resources for employers on how best either testing and/or implementing programs for to manage work attendance in employees with prevention or control, there is still an important comorbid non-communicable diseases and com- need for research that is more focused on under- mon mental disorders. standing the epidemiology and determinants of comorbid mental and physical conditions in different cultures and population groups within and be- Future Efforts in Public Health tween countries and different regions of the world.

There is a need to close the gap between the epidemic growth of common mental disorders, like Acknowledgment depression, and non-communicable diseases, such as type 2 diabetes and cardiovascular diseases, and A.O. is supported by the National Health and Medical Re- the provision of appropriate healthcare and public search Council (1052865).

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Brian Oldenburg, PhD School of Population and Global Health The University of Melbourne 207 Bouverie Street, Parkville, VIC 3010 (Australia) E-Mail [email protected]

22 Oldenburg · O’Neil · Cocker

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 15–22 ( DOI: 10.1159/000365524 ) Background

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 23–32 ( DOI: 10.1159/000365941 )

Counting All the Costs: The Economic Impact of Comorbidity

a, b a David McDaid · A-La Park a b Personal Social Services Research Unit and European Observatory on Health Systems and Policies, London School of Economics and Political Science, London , UK

Abstract This chapter provides an overview on what is This chapter provides an overview on what is known known about the economic impacts of comorbid about the economic impacts of comorbid physical and physical and mental disorders. As later chapters mental disorders. The chapter begins by briefly describ- discuss, illnesses such as psychoses, bipolar dis- ing the concept of economic cost, before going on to look order and major depression can increase the risk at different examples of the costs of comorbidity. There is of many physical health problems, including an increasing, albeit still small, number of studies that obesity, diabetes, cardiovascular disease, chronic have looked at the economic impacts of comorbid physi- obstructive pulmonary disorder and some infec- cal and mental health problems. The majority of these ex- tious diseases. Poor physical health, for instance amples are from a US context and thought must be given related to cancer or musculoskeletal health prob- on how they translate to other contexts. Nonetheless, lems, may also increase the risk of developing these studies illustrate potentially substantial costs to mental health problems such as depression and healthcare systems and society as a whole, which might anxiety-related disorders. As a result, there is be avoided through early identification of potential risk likely to be a considerable overlap in those living factors and early intervention to mitigate the effects of with long-term physical and mental health prob- comorbidity. The chapter ends by examining how infor- lems. In England, for example, it has been esti- mation on the costs of comorbidity can be used to inform mated that up to 46% of all those with mental economic arguments for investment in actions to prevent health problems also have some chronic physical or alleviate some of these morbidities, and how this evi- health problem, while 30% of those with long- dence base may be strengthened further. term physical conditions also have a mental © 2015 S. Karger AG, Basel health problem [1] . All of these comorbidities will have economic There are also ‘indirect’ costs, which focus on consequences that impact right across society. the lost opportunity to contribute to economic Some of these costs may potentially be avoidable. productivity, such as when individuals are absent Thus, there is a growing interest from policy from the labour market due to poor health or pre- makers, particularly in countries where health mature death. Productivity costs for many mental and social care spending is under great strain, disorders already account for more than 60% of about the potential importance of actions that all costs because of the low rate of participation in can effectively prevent and/or reduce the impacts employment [2]. A major reason for these costs is of comorbidity. the much higher rate of mortality due to poor This chapter therefore begins by briefly de- physical health. For instance, one study of men scribing the concept of economic cost, before go- and women with severe mental disorders in ing on to look at different examples of the costs of Denmark, Finland and Sweden reported that they comorbidity. It ends by examining how better in- lived between 20 and 15 years less than the gen- formation on the costs of comorbidity can be eral population [3] . used to inform economic arguments for invest- Other forms of productivity loss also occur. ment in actions to prevent and alleviate some of Comorbid health problems may reduce partici- these morbidities, and how this evidence base pation in school or university, potentially impact- may be strengthened further. ing on career possibilities. In fact, the long-term adverse costs to the economy due to children with mental health problems not obtaining employ- What Is Meant by Economic Cost? ment in adulthood has been one key reason for substantial policy interest in measures to help Before going further, it is worth briefly explaining support the health and well-being of children what economists mean by cost, as this is about from a very young age [4]. Family members may much more than simple monetary cost. In fact also give up some of their time from employment economists often talk about three different com- or other activities because of the need to provide ponents of cost. There may be increased direct care and support to a loved one. costs to the healthcare systems associated with the The third cost category is known as ‘intangi- management of multiple health problems, for in- ble’ because it refers to impacts that are often dif- stance if mental disorders exacerbate the risk of ficult to quantify and value. Examples include the adverse events and complications in chronic stigma associated with mental illness, communi- physical health problems or if recovery times are cable disease or physical disabilities, as well as the prolonged. This could include the salary costs of grief experienced by families as a result of an un- healthcare staff, the cost of medicines and the use expected death. of diagnostic procedures. In England it has been estimated that as much as GBP 1 in every GBP 8 spent on chronic long-term conditions is due to What Do We Already Know about the adverse outcomes arising from poor mental Economic Impacts of Comorbidity on health [1] . There may also be direct costs for the Healthcare Systems? provision of services that fall on other sectors such as social care services. In some cases there Remarkably, health economists have not focused might be additional costs falling on other sectors, much of their energies on assessing the economic such as for home modifications due to physical impact of comorbidity in any area of health, let disabilities. alone looking at the issue of mental and physical

24 McDaid · Park

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 23–32 ( DOI: 10.1159/000365941 ) Table 1. Selected examples of impact of physical comorbidity on annual healthcare costs of adults with mental disorders

Study Mental disorder Comorbid physical Relative increase in costs disorder of comorbidity (mental disorder alone = 1)a

Chwastiak et al. [5] schizophrenia obesity 1.3:1 McDonald et al. [6] schizophrenia diabetes 1.9:1 McDonald et al. [6] schizophrenia dyslipidaemia 1.8:1 McDonald et al. [6] schizophrenia hypertension 2.1:1 McDonald et al. [6] schizophrenia heart disease 1.7:1 Centorrino et al. [8] bipolar disorder metabolic disorders 2.3:1 Welch et al. [10] depression congestive heart failure 2.0:1 Welch et al. [10] depression coronary artery disease 2.1:1 Welch et al. [10] depression diabetes 2.0:1

All of the studies were from the USA. a All differences statistically significant p < 0.05.

comorbidity. This may be due to the difficulties in comes, prolong recovery time and thus exacer- attributing healthcare costs to any specific co- bate costs to healthcare systems. Some, as shown morbidity, as well as the separation of the way in in table 1 , look at the additional excess costs to the which mental and physical health services are or- healthcare system of a comorbid physical health ganised in many countries. There is, however, an problem compared to having a mental health increasing, albeit still small number of studies, problem alone, while others, as illustrated in ta- which have looked at the economic impacts of co- ble 2, focus on the additional excess costs of a comorbid physical and mental health problems. morbid mental health problem to having a physi- The majority of these examples are from a US cal health problem alone. Much of this evidence context and thought must be given on how they is from the USA, but it provides valuable insights translate to other contexts. Nonetheless, they il- on the extra costs of comorbidities in other coun- lustrate potentially substantial costs to healthcare tries, suggesting that there is the potential to avoid systems and society as a whole that might be substantial costs to healthcare systems through avoided through early identification of potential early identification and intervention. risk factors and early intervention to mitigate the Several studies focus on schizophrenia and effects of comorbidity. The next sections provide physical health problems. Analysis of healthcare an overview of some of these economic analyses, costs for more than 1,400 individuals with schizo- looking at economic impacts within and beyond phrenia who participated in the 18-month CATIE healthcare systems. trial (Clinical Antipsychotic Trials of Interven- tion Effectiveness) in the USA reported statistically significant 25% higher costs for those who Impacts on Healthcare Systems were obese [5]. Data from the US Medical Expen- diture Panel Survey of more than 571,000 indi- Comorbidities between physical and mental viduals in 2001 and 2002 found annual healthcare health problems provide major challenges to costs for people living with schizophrenia alone healthcare systems; they can worsen health out- of USD 5,990, compared with USD 11,611, 10,803,

Counting All the Costs: The Economic Impact of Comorbidity 25

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 23–32 ( DOI: 10.1159/000365941 ) Table 2. Selected examples of impact of mental comorbidity on annual healthcare costs of adults with mental disorders

Author and country Physical disorder Comorbid mental Relative increase in costs disorder of comorbidity (physical disorder alone = 1)a

Richardson et al. [25], USA asthma depression 1.5:1 Hochlehnert et al. [23], Germany cardiovascular disease depression and/or anxiety 1.5:1 Atlantis et al. [14], Australia diabetes depression 1.5:1 Le et al. [13], USA diabetes depression 1.7:1 Simon et al. [15], USA diabetes depression 1.8:1 a All differences statistically significant p < 0.05.

12,292 and 10,415 for those with comorbid diabe- sus 301 for the control cohort. Analysis of data on tes, dyslipidaemia, hypertension or heart disease, 67,000 members of a health insurance fund in respectively [6] . seven US states also suggests that 67% of total The healthcare costs of more than 31,000 older healthcare costs of bipolar disorder were related people with and without schizophrenia were ana- to the treatment of comorbid physical health con- lysed for the 10-year period from 1998 to 2008. ditions [9] . Mean healthcare costs were significantly higher Comorbid depression or anxiety disorders and in the schizophrenia group; a key driver of greater physical health problems have also been associ- healthcare costs was the significantly higher rate ated with higher levels of cost to healthcare sys- of physical health problems, including congestive tems. One US study reported that the costs of 11 heart failure (45.1 vs. 38.8%), chronic obstructive chronic health problems are significantly greater pulmonary disease (52.7 vs. 41.4%), hypothyroid- when an individual has comorbid depression. ism (36.7 vs. 26.7%) and dementia (64.5 vs. 32.1%) Costs related to diabetes, coronary artery disease [7] . and congestive heart failure were approximately Turning to bipolar disorder, in the USA the twice the costs of individuals without depression medical records (spanning 1 year) of more than [10] . 28,000 people with bipolar disorder were com- Two reviews, one with 27 [11] and the other pared with matched controls without any mental with 41 largely US-set studies [12] , looked at the health problems [8]. Those with bipolar disorder impact on healthcare resource utilisation of co- had a significantly higher prevalence of metabolic morbid diabetes and depression. Both reviews comorbidities than the general population (37 vs. consistently showed increased healthcare re- 30%). Annual healthcare costs for metabolic con- source use to manage diabetes in people with de- ditions were twice those of controls (USD 531 vs. pression. For example, in one study of more than 233). The bipolar cohort also had significantly 400,000 adults with diabetes in the USA, the costs higher overall medical service and prescription of depression increased mean annual healthcare drug costs than those of the control cohort (USD costs from USD 11,000 to 19,000 [13] , while in 12,764 vs. 3,140). Prescription medication costs Australia, health service use by people with co- for metabolic conditions were also higher, with morbid diabetes and depression was 49% higher bipolar cohort per-patient costs of USD 571 ver- compared to those with diabetes alone [14] . In

26 McDaid · Park

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 23–32 ( DOI: 10.1159/000365941 ) another US study, the healthcare costs of manag- ly higher costs in people aged 40–59 years. De- ing diabetes over a 6-month period were found to pression and comorbid obesity, heart failure or be between 50 and 75% higher in people with ma- epilepsy were associated with significantly high- jor depression than in people with diabetes alone er primary care costs in patients aged over 60 [15] . Furthermore, this study observed a signifi- years. Increases in cost ranged from GBP 269 for cant difference in the costs of managing one or people aged 40–59 years with depression and more complications of diabetes in people with cancer to GBP 2,817 in people with comorbid major depression compared to those with sub- depression and obesity aged 40–59 years. In clinical thresholds of depression. Other studies younger adults, mean additional costs related to also point to higher costs of managing complica- asthma and comorbid depression were GBP tions. In the USA, the costs of managing compli- 1,257, while comorbid diabetes and depression cations of diabetes, such as diabetic neuropathy, increased costs by GBP 2,133 in people aged in people with comorbid depression have also over 60 years. been shown to be significantly greater than in Other examples of additional costs from those without depression [16] . around the world can be identified. In Singapore, Another US study looked at the healthcare adults attending a specialist diabetes centre over a costs of more than 14,000 people with depression, 1-year period who also had depression had a 30% congestive heart failure, or both [17] . People who chance of hospitalisation compared to 10% in the also had depression had significantly higher total diabetes-alone group. They were four times more annual healthcare costs than those without: USD likely to be hospitalised for non-psychiatric con- 20,046 versus 11,956. Costs increased with the se- ditions and three times more likely to be hospital- verity of comorbidity, but mental healthcare costs ised for complications of diabetes [19] . accounted for less than 1% of total healthcare In Hungary, a survey of more than 12,000 costs. people looking at their use of health services over Outside of the USA, significantly increased a 12-month period found that those with comor- costs to healthcare systems have also been ob- bid diabetes and depression had a 2.6 times served when comorbidity involved depression. greater risk of a lengthy period of hospitalisation English data from more than 86,000 patients in and had almost double the risk of multiple hos- the General Practice Research Database were pital admissions compared to people with diabe- used to assess whether comorbidity increases tes alone [20]. Another study looked at the im- the costs of managing patients in primary care pacts of physical comorbidity on healthcare [18] . The study found that 20% of all patients costs for 65,000 people receiving primary care in had more than one chronic health problem and Spain in 2004. Individuals with a depressive dis- that all instances of comorbidity increased the order had a significantly greater number of co- costs of primary healthcare compared to the morbid conditions or risk factors, including costs of managing these conditions separately. obesity, dyslipidaemia and smoking per year Depression was found to be the most important compared to other primary care service users cost-increasing condition, significantly increas- (7.4 conditions vs. 4.3). Overall the annual costs ing costs in adult patients of all ages when co- of care were EUR 1,084 and 684 per patient in morbid with a wide range of conditions. For in- the comorbid and control populations, respec- stance, the costs of managing comorbid depres- tively [21]. In the UK, the economic impacts of sion and asthma or diabetes were greater for smoking in people with mental disorders have patients of all ages, whilst depression and co- been estimated to cost primary and secondary morbid cancer were associated with significant- care service providers GBP 720 million per an-

Counting All the Costs: The Economic Impact of Comorbidity 27

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 23–32 ( DOI: 10.1159/000365941 ) num in treating smoking-related disease. The costs – mainly productivity losses from employ- study also estimated that about a third of all cig- ment due to absenteeism, with much less discus- arettes smoked in England are smoked by people sion of poor performance at work (presenteeism); with a mental disorder. This could mean that there does not appear to be much information on there are 2.6 million avoidable hospital admis- the intangible costs of comorbidity. One review sions, 3.1 million avoidable primary care consul- looked at the impact on participation in employ- tations and 18.8 million prescriptions that can ment of people with coronary artery disease and be avoided each year [22] . mental disorders [26] . Only 13 studies were iden- In Germany, analysis at one teaching hospital tified, 10 of which focused on comorbid depres- over a 2-year period again reported that the aver- sion. The review concluded that people with co- age total costs of hospitalisation for people with morbid depression had a reduced likelihood of cardiovascular disease alone compared to those returning to work following the onset of illness with psychiatric comorbidity (largely depression (odds ratio 0.37) compared to people with coro- and anxiety disorders) differed significantly (EUR nary artery disease alone. A systematic review on 5,142 vs. 7,663). The average length of stay for pa- comorbid diabetes and depression identified 11 tients with comorbidity was 13.2 days compared studies that looked at the impacts on productivi- to 8.9 for patients with cardiovascular disease ty, but only two of these studies assigned a mon- only [23] . Furthermore, this paper highlighted etary value to productivity losses and none in- that the funding system in that hospital did not cluded losses from premature mortality or infor- fully cover the costs of comorbidity, which means mal care [12] . that patients might not receive appropriate levels Data from a cross-sectional survey of 78,000 of care. workers in Australia [27] show higher relative There is also some limited information look- risks of both absenteeism and poor functioning ing at the association between healthcare costs while at work in individuals with comorbid psy- and comorbid asthma and mental disorders. One chological distress and physical health problems systematic review found 20 studies, largely fo- compared to those with physical health problems cused on depression or anxiety disorders and only. For instance, compared to people with no asthma. It reported increased rates of hospitalisa- health problems, the risk of absenteeism from tion, emergency department visits and visits to work was 33% higher for people who were expe- primary care practitioners in people with asthma riencing psychological distress alongside obesity, and a mental disorder [24] . In the USA, a tele- and 27% higher for those who had high levels of phone survey of adolescents (aged 11–17 years) cholesterol. Rates of presenteeism were between with asthma found that those assessed to have de- 2.5 and 5 times greater in populations with co- pressive disorders as well had on average 51% morbid asthma, obesity, arthritis, diabetes and higher healthcare costs [25] . Most of these addi- high cholesterol compared with the reference tional costs were related to non-asthma and non- population. mental health-related healthcare costs. Data from the 2007 Australian National Sur- vey of Mental Health and Wellbeing (n = 8,841) have also been used to compare work functioning Impacts beyond Healthcare Systems and absenteeism rates in people with depression, cardiovascular disease, or both conditions, with a There appear to be fewer estimates of the impacts disease-free population [28] . As table 3 shows, of comorbidity beyond the healthcare system. compared to a population with neither condition, Published estimates concentrate on indirect and adjusted for various social and demographic

28 McDaid · Park

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 23–32 ( DOI: 10.1159/000365941 ) Table 3. Work participation, work functioning and disease group in Australia [28]

Disease group Full- or part-time Amount of difficulty in Number of days employment in the day to day work (full-time unable to work workforce (adjusted workers) (adjusted odds (full-time workers) odds ratio) ratio) (adjusted odds ratio)

Neither MDD or CVD 1.0 1.0 1.0 MDD only 0.8* 4.0* 1.7* CVD only 0.8* 0.9 0.9 Comorbid CVD and MDD 0.4* 10.6* 3.0*

MDD = Major depressive disorder; CVD = cardiovascular disease. * p < 0.05.

characteristics, the odds ratio for people with co- to have a prolonged absence (>10 days) from paid morbid depression and cardiovascular disease work and to be unemployed. participating in work was significantly lower at In Finland, analysis of certified sickness ab- just 0.4. This compared with odds ratios for work sence in 33,000 public sector employees reported participation of 0.8 for depression or cardiovas- that non-cardiovascular comorbid conditions cular disease only. The comorbid group were also for employees with diabetes, including depres- 10 times more likely to experience poor work sion, accounted for over 50% of excess risk of functioning compared to the healthy workforce, sickness absence [30] . A US study of a manufac- 9 times greater than for people with cardiovascu- turing company with 15,000 employees reported lar disease alone and 2.5 times greater than for 13.5 sick days per annum on average due to de- people with depression alone. Rates of absentee- pression and physical comorbidity (diabetes, ism were also significantly higher for the comor- heart disease, hypertension or back problems) bid group. compared to 6.6 and 8.8 days for those with a Data from a large Canadian survey of more physical condition or depression alone. Total than 130,000 people found (even after adjusting mean costs, including healthcare and disability, for socio-demographic characteristics, alcohol per employee with comorbidity were USD 7,906. dependence and chronic physical illness burden), This is conservative as the costs of poor perfor- that the presence of comorbid major depressive mance (presenteeism) at work were not included disorders was associated with twice the likelihood [31] . of healthcare utilisation, and increased functional Data from the UK Psychiatric Morbidity Sur- disability and work absence compared to the vey also indicate that over a year individuals with presence of a chronic physical illness without co- diabetes and depression were 7.7 and 5.3 times morbid depression [29] . Significant increases in more likely to take sick days and have their work resource use and productivity losses have also and other activities impaired by poor health com- been reported in a population survey of more pared to people with diabetes alone [32] . The than 12,000 adults in Hungary [20]. People with number of working days lost was also found to be comorbid diabetes and depression were more significantly higher in people with comorbid dia- than twice as likely to have lengthier stays in hos- betes and depression compared to diabetes alone pital (>20 days) and to have more hospital admis- in Singapore – 1.9 versus 1.4 working days lost sions. They were also more than 3 times as likely over a 3-month period [19] .

Counting All the Costs: The Economic Impact of Comorbidity 29

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 23–32 ( DOI: 10.1159/000365941 ) Strengthening the Case for Tackling One way of strengthening the evidence base in Comorbid Mental and Physical Health the short-term is to make use of economic model- Problems ling techniques to take existing data on the effectiveness of different actions to tackle comorbidity This chapter has illustrated that there are sub- and model plausible costs and benefits under dif- stantial economic costs associated with comor- ferent scenarios in different country contexts and bidity. These costs fall both within and beyond over different time periods [37] . One recent ex- healthcare systems. It is not, however, enough to ample of a modelling approach suggests that it identify these costs. Given that healthcare budget may be cost-effective to invest in group-based ac- holders have to make difficult choices on how to tions to promote better weight management in allocate scarce resources to mental health and people with schizophrenia and diabetes [38] . In other services, it is critical is to identify cost-effec- the mid to longer term it would be helpful to em- tive ways of reducing the risks or consequences of bed economic analysis, collecting data on re- comorbidity. source use, costs and economic consequences, Potentially, given the high additional costs of into evaluations of interventions to tackle comor- comorbidity, even modest success in reducing its bidity. This can facilitate better comparability prevalence may have economic payoffs. Policy across different interventions and help policymakers will want to know whether early interven- makers prioritise the way in which they allocate tion and investment in actions to protect the resources. physical health of people with mental health prob- Where mental health services are largely sepa- lems are a cost-effective use of resources, generat- rate from physical health services, the provision ing benefits not only to healthcare systems, but of seamless care for both physical and mental also more widely, perhaps reducing rates of ab- health problems becomes more difficult to senteeism from work or the need for informal achieve. Therefore, another important step may family care. They may also want to know whether be to evaluate the cost-effectiveness of different a greater focus on managing the mental health of incentives and organisational structures to en- people with chronic physical health problems is a courage a more collaborative approach to the de- cost-effective way of improving outcomes. tection and management of comorbidity; there There is a need to strengthen the evidence are often substantive silos in both the financing base, and in particular to look more at the cost- and organisation of mental health and general effectiveness of interventions outside of a US con- health services [39] . text. To date, the evidence on cost-effective ap- This chapter has illustrated that economics proaches to manage comorbidity is modest, al- can help provide powerful arguments to support though it supports investment, suggesting that a a case for tackling comorbidity. It has shown that number of cost-effective interventions are avail- there are substantial impacts both within and be- able. For instance, empirical work and modelling yond health systems linked to comorbidity. For studies focusing on comorbid diabetes and de- too long, much of these costs remained hidden; pression includes several studies that have high- this is now changing and in the future more in- lighted the cost-effectiveness of better integration formation will be available on these additional between psychological and diabetes care [33–35] . costs as well. This hopefully will provide more Only a handful of studies have considered the impetus for actions to address an issue which economic, as well as the clinical impact, of inter- leads not only to some avoidable costs to health ventions to promote and protect the physical and society, but also has profound personal hu- health of people with mental disorders [36] . man consequences.

30 McDaid · Park

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 23–32 ( DOI: 10.1159/000365941 ) References

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David McDaid, MSc, BSc Personal Social Services Research Unit, London School of Economics and Political Science Houghton Street London WC2A 2AE (UK) E-Mail [email protected]

32 McDaid · Park

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 23–32 ( DOI: 10.1159/000365941 ) Background

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 33–41 ( DOI: 10.1159/000365545 )

Difficulties Facing the Provision of Care for Multimorbidity in Low-Income Countries

David Beran Division of Tropical and Humanitarian Medicine, Geneva University Hospitals and University of Geneva, Geneva , Switzerland

Abstract infrastructure, medicine procurement and supply, acces- Low-income countries face a double burden of noncom- sibility and affordability of medicines and care, health- municable and communicable diseases, which further care workers, adherence issues, patient education and strains their limited resources. In response, the global empowerment, community involvement and positive community has prioritized four chronic noncommunica- policy environment. Primary healthcare has been pro- ble diseases and four risk factors, not including neuropsy- posed as a solution, but there are numerous barriers to chiatric disorders. Health systems play a key role in ad- implementing this. Given health system constraints, dressing the challenges of noncommunicable diseases, there is a need to shift care back to the individual and mental health and multimorbidity, but have failed to their family for managing both the medical (self-care) and tackle this effectively. Noncommunicable disease as well social aspects (e.g. stigma) of their conditions for better as noncommunicable/communicable disease multimor- outcomes. © 2015 S. Karger AG, Basel bidity cannot be managed from only a biomedical perspective, but needs to include consideration of inequality and poverty. The health systems in low-income countries Low-income countries are defined by the World are currently failing in their management of individuals Bank as countries where income per capita is with single noncommunicable diseases; therefore, when USD 1,035 or less [1] . This grouping includes 28 a person is exposed to multiple risk factors and/or has countries from sub-Saharan Africa, 5 from Asia, multiple conditions, the health system cannot cope, lead- 3 from Central Asia and 1 in the Caribbean. Be- ing to poor outcomes for individuals. Eleven elements cause of their low income, these countries spend were found to be necessary for diabetes care in low-in- on average only USD 22 per person per year on come settings, and since diabetes makes a good tracer health [2]. While traditionally it was thought that condition, these elements are presented for the issue of the burden of disease in these countries was pre- multimorbidity. They include organization of the health dominantly from communicable diseases, non- system, data collection, prevention, diagnostic tools and communicable diseases represent 80% of deaths in low- and middle-income countries [3] . Non- access to medicines and diagnostic tools, patient communicable diseases and poverty have a sym- empowerment, and coordination of different ele- biotic relationship, with poverty increasing expo- ments of the health system [6] . sure to noncommunicable disease risk factors and actual noncommunicable diseases forcing individuals and households into poverty as the bur- Multimorbidity in a Low-Income Context den of the cost of care falls on the individual in these countries [3]. Noncommunicable diseases With the number of people aged 65 years or above also impact health systems, economies and coun- projected to increase from approximately 524 tries as a whole, as every 10% increase in noncom- million in 2010 to about 1.5 billion in 2050, with municable diseases is associated with a 0.5% de- the highest increase in developing countries, the crease in economic growth. issue of multimorbidity needs to be addressed. It In September 2011, the United Nations held is estimated that 1 in 4 adults suffer from multi- its second health-related general assembly on morbidity, with most evidence coming from noncommunicable diseases after its 2001 meet- high-income countries [7] . Studies from low-in- ing on HIV/AIDS. Four diseases were prioritized come countries have found that 53.7% of people by the World Health Organization, namely car- aged above 60 years had two or more chronic diovascular diseases, cancer, chronic respiratory conditions in Bangladesh [8], 66.7% of people diseases and diabetes, which were chosen since with diabetes also had hypertension in Cameroon they contribute the largest amount to morbidity [9] and in a nationally representative sample in and mortality [4] . In 2013, the World Health Or- South Africa it was found that 29.6% had two or ganization’s noncommunicable disease global more of the following conditions: hypertension, action plan was endorsed and aims to provide a diabetes, asthma, depression, angina, stroke and guide to attain nine voluntary global targets, in- arthritis [10] . cluding the overall goal of a 25% relative reduc- Synergies to address and integrate care for tion in premature mortality from cardiovascular communicable and noncommunicable diseases disease, cancer, diabetes and chronic respiratory have not been addressed [11] . The links between disease by 2025 [4] . Although neuropsychiatric the four main noncommunicable diseases are disorders contribute an estimated 13% of the clearly established through their shared risk fac- global burden of disease [5] , they are not formal- tors and high rates of comorbidity [8, 9]. In low- ly included in the World Health Organization’s income country settings, however, there is not global noncommunicable diseases action plan. only the existence of comorbidity of noncommu- Mental health is mentioned in the context of nicable diseases, but also comorbidity of non- comprehensive care for noncommunicable dis- communicable diseases with communicable diseases needing to include ‘primary prevention, ease [12] . early detection or screening, treatment, second- The issue of multimorbidity can be linked to ary prevention, rehabilitation and palliative care the causal pathways of the diseases [13] . For ex- and attention to improving mental health’ [4] . ample, there is a link between a high burden of Health systems play a key role in addressing tuberculosis with smoking and harmful alcohol the challenges of noncommunicable diseases, use [14–16], or mental health with sexual behav- mental health and multimorbidity. The manage- ior, alcohol and tobacco use [17] . Another way of ment of these requires care be provided over a looking at multimorbidity is that having one con- long period of time, which needs the input from dition means the individual is more likely to de- a multidisciplinary team of healthcare workers, velop another [13] . For example, diabetes has

34 Beran

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 33–41 ( DOI: 10.1159/000365545 ) Table 1. The interplay of multiple risk factors and diseases

Noncommunicable Actual non- Communicable Mental health disease risk factor communicable disease disease

Noncommunicable person who smokes person with diabetes obese individual with smoking and alcohol disease risk factor and is obese who smokes HIV/AIDS consumption Actual non- person with diabetes person with diabetes people with diabetes are more communicable disease and hypertension and tuberculosis prone to depression Communicable disease person with HIV/AIDS people with HIV/AIDS more and tuberculosis likely to have mental disorders

Underlying issues include, for example, ageing and poverty.

been associated with a threefold incident risk of The challenge in low-income countries is that tuberculosis [18–20] , HIV/AIDS causes Kaposi there is a knowledge, treatment and outcome gap sarcoma and lymphoma [21] , and people with for noncommunicable diseases and multimor- HIV/AIDS are more likely to have mental disor- bidity. In Mozambique the prevalence of hyper- ders [22] . tension is 33.1%, but only 14.8% of people who It is not only the condition that may lead to have hypertension are aware they have it [27] . Of another condition, but also the treatments for those aware, 51.9% receive treatment and of those these. One particular example relevant to low-in- receiving treatment, only 39.9% are controlling come countries is the link between antiretroviral their hypertension. That means for every 100 treatment and the metabolic syndrome [18] , in- people with hypertension, only 3 know they have creased rate of cardiovascular risk factors [23] , the disease, receive treatment and have controlled diabetes [24], and other cardiac, neurological and hypertension. A nationally representative survey musculoskeletal conditions [25] . in South Africa found that despite the high preva- Finally, the last aspect is that proper manage- lence of mental disorders and related disability, ment of both conditions is necessary in order to these conditions, especially depression, were less ensure good outcomes from each disease per- likely to be treated than physical disorders [28] . spective. Good tuberculosis management is nec- Data from the World Health Organization show essary for good diabetes management, and good that between 76 and 85% of people with mental diabetes management helps ensure the success of health problems in low- and middle-income tuberculosis treatment; however, the medicines countries receive no treatment for their disorder used to treat tuberculosis may worsen blood glu- and that resources for mental health are primar- cose control [19, 20]. Management of depression ily assigned to mental hospitals [29] . is also necessary to ensure proper outcomes for The health systems in low-income countries noncommunicable diseases [26] . are currently failing in their management of indi- Addressing these situations needs to be done viduals with single conditions. Therefore, when a not only from a biomedical perspective, but also person has multiple conditions or multiple risk from a socioeconomic angle, taking into account factors for these conditions, the health system is inequalities and poverty. Table 1 details these in- not organized in a manner that can face such a terlinkages as well as the underlying issues of age- situation, which leads to poor outcomes for indi- ing and poverty. viduals.

Multimorbidity Care in Low-Income Countries 35

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 33–41 ( DOI: 10.1159/000365545 ) The Health System Barriers to Care for whereas in rural areas health services focus on a Multimorbidity in Low-Income Countries specific disease (e.g. HIV/AIDS) or selective services (e.g. maternal health) [39] . In parallel, the A health system is defined as all the ‘activities use of traditional medicine is widespread, with whose primary purpose is to promote, restore and 80% of the population in Sub-Saharan Africa re- maintain health’ [30]. Health systems have three lying on this as their primary source of care [13] , main objectives: (1) to improve the health of the which has as of yet not been integrated for the populations they serve, (2) respond to the popula- management of noncommunicable diseases. tion’s expectations and (3) provide financial pro- Although primary healthcare has been protection against the costs of ill-health [30] . moted in low-income countries, it has not been Health systems do not work in isolation of the able to address the challenge of noncommunica- other sociopolitical elements of a given country, ble disease or play a role in prevention and health and therefore different models of health systems promotion [13, 37]. Noncommunicable disease exist [31, 32] . Certain key factors that health sys- care is still the remit of specialists in specialist tems need to perform are procurement and sup- centers; for example, mental health in low-in- ply of medicines, disposables and equipment, come countries is still predominantly focused on healthcare workers in sufficient numbers and hospital care [40]. As these specialist centers are with the right skills for the given population and limited, this also causes problems for referrals disease burden, and sustainable financing and and counterreferrals. Specifically for the issue of healthcare costs that do not overburden the poor multimorbidity, the degree of overspecialization and have a financial, budgetary and regulatory may mean multiple referrals, if feasible, are made framework [31, 32] . Research into diabetes in to different specialists for the individual’s multi- low-income countries [33] found that 11 ele- ple conditions. ments were necessary for diabetes care. Diabetes When providing care for a person both over a makes a good tracer condition for health systems, long period of time and with multiple conditions, from which the lessons learnt can be applied to another element the health system needs to pro- other chronic conditions [34–36] . vide is data collection. Data are needed at all levels The first element is organization of the health of the health system in order to inform policies, system. Currently, health systems in low-income medicine procurement, and staffing and individ- countries are not organized to manage noncom- ual care. However, there is a general lack of qual- municable disease, let alone individuals with ity health information systems in many low-in- multiple conditions, and are more focused on income countries [37]. At the level of the individual, fectious diseases [37] . Many health system re- poor use of patient records means that previous sponses in low-income countries for HIV/AIDS consultations or other conditions are not taken and tuberculosis have focused on vertical pro- into account, thus leading to an unstructured grams only addressing these specific conditions monitoring of clinical care [37] . There is also a and not tackling all the challenges faced by indi- lack of a recall system to ensure continuity of care viduals in the health system [38] . Although these [38] . In terms of studies, very few have looked at have shown some success, they fail to take a per- the issue of multimorbidity in low-income coun- son-centered focus and do not manage all the tries except for the issue of HIV/AIDS and tuber- conditions the individual may have, but only the culosis. one that is being funded, leading to fragmenta- Another area where studies are lacking from tion of healthcare [39]. This fragmentation also low-income countries and which is important for exists because care in urban areas is hospital based the issue of multimorbidity is prevention. As

36 Beran

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 33–41 ( DOI: 10.1159/000365545 ) mentioned previously, primary healthcare in cation of needs, efficient procurement, efficient low-income countries does not fulfill its role in distribution, rational prescription and proper terms of prevention and health promotion [33] . compliance [43] . This is linked to lack of training, human resourc- Mental health is an example highlighting the es and culturally appropriate materials to ensure challenge of medicine procurement and supply wider knowledge of noncommunicable disease with such issues as prescription regulations, avail- and their risk factors in these settings. For exam- ability and use of certain treatments, and limited ple, asthma and chronic respiratory disease are expenditure (low-income countries spend 10 underrecognized, underdiagnosed, undertreated times less than lower-middle and 1,547 less than and insufficiently prevented. With one of the high-income countries, respectively) [40] . Ulti- main risk factors in low-income countries being mately, all of these factors impact the affordabil- the use of biomass fuel, local healthcare workers ity and accessibility of medicines. Accessibility is need the knowledge about these conditions in linked not only to distribution, but also to where their specific context to enable them to play a pre- the individual lives, with urban areas having bet- ventive role and not only provide care [41] . The ter access than rural areas. In terms of affordabil- World Health Organization has also developed ity, government policies will impact this; for ex- ‘best buys’ for noncommunicable diseases for the ample, insulin is free in Nicaragua, while individ- four common risk factors (tobacco use, harmful uals have to pay for this in Mali because of the use of alcohol, unhealthy diets and physical inac- government policy of cost recovery [43] . Generic tivity) and for cardiovascular disease, diabetes medicines to treat noncommunicable disease and cancer [42]. However, many low-income were found to be less available than medicines for countries lack the capability of implementing, en- communicable conditions in both the public forcing and sustaining these. (36.0 vs. 53.5%) and private sectors (54.7 vs. As prevention also includes screening mea- 66.2%) [44]. Specifically, antiasthmatic inhalers sures, diagnostic tools and infrastructure are were available to 30.1% in the public sector and to needed. However, health infrastructure is poor at 43.1% in the private sector. In terms of affordabil- all levels of the health system with, for example, ity, it has been found that 1 month of treatment 19 and 39% of primary healthcare facilities in for coronary heart disease costs 18.4 days’ wages Tanzania and Senegal, respectively, having access in Malawi while for insulin in Mali the annual to electricity, water and sanitation [13]. In addi- cost represented 38% of per capita gross domestic tion, basic equipment is lacking in these facilities product [43, 45] . These conditions also place a and access to diagnostic tools for diabetes has huge financial burden on countries, with diabetes been seen to be poor in low-income countries care representing 5% of the total budget for the [43]. There are also financial constraints for the Ministry of Health in Nicaragua and insulin rep- individual if they need to pay for the test as well resenting 10% of the total medicines budget in as budget limits that impact a prescribers’ ability Mozambique [43] . to ask for certain tests [38] . An essential element of the health system is Besides diagnostic tools and infrastructure, healthcare workers. Issues of availability, rational health systems need to be able to procure and use and training need to be addressed [46] . Low- supply medicines to manage multimorbidity. income countries face a severe shortage of health- Looking at the issue of insulin in low-income care workers and the human resources present countries, a variety of factors impact its procure- are inequitably distributed [13] . Specifically for ment and supply, such as budget allocation for mental health in the Africa region of the World medicines, adequate buying procedures, quantifi- Health Organization, there is significant varia-

Multimorbidity Care in Low-Income Countries 37

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 33–41 ( DOI: 10.1159/000365545 ) tion in the number of psychiatrists, ranging from descriptions for this condition including super- more than 10 per 100,000 to fewer than 1 per natural causes. The health system may provide 100,000 [47] . There is also a low focus of these the majority of aspects that a person with a non- human resources on community care [40] . Over- communicable disease requires; however, the all, this problem is linked to an internal and ex- burden of care falls on the individual and their ternal ‘brain drain’ with doctors preferring the family as the majority of the time spent manag- private over public sector, urban over rural areas, ing a noncommunicable disease is done outside and tertiary levels of care versus primary care of the health system [51] . [48] . In addition, this internal brain drain to non- Adherence is impacted by education about the governmental organizations specifically in the condition and the financial burden of care. In area of HIV/AIDS has impacted the availability low-income countries, patient education is lack- of health professionals, e.g. 50% of medical ing for noncommunicable disease and there is graduates in Uganda were found to be working still a large financial burden of care. In a system- for an HIV-related nongovernmental organiza- atic review of adherence to cardiovascular medi- tion [49] . cations in resource-limited settings, Bowry et al. It is important to define the role of different [52] found that poor adherence was due to these cadres of healthcare workers in managing non- factors as well as negative perceptions about med- communicable disease and the role of specialists, icines and their side effects. such as in the initiation of treatment versus fol- Community involvement and patient associa- low-up and continuation of treatment and how tions can play a role in patient education and em- this is linked to treatment guidelines that are powerment, thereby impacting adherence, with adapted to the local context or include the best the proper support from the health system. Many clinical evidence. Another issue is actual training types of patient organizations (e.g. diabetes asso- and how this training currently focuses on clini- ciations) exist, with varying roles, such as advo- cal management of certain diseases and not the cacy, training for patients and healthcare work- issue of multimorbidity. Current training of ers, and acting as a support group for patients and health professionals, especially doctors, does not families, as well as being a provider of care [53] . include the preventive role they can play. The 2011 Mental Health Atlas [40] found that Patient education is lacking both as health 39% of low-income countries had associations professionals are not trained in this area, have compared with 80% of high-income countries. It very little time for this, and also lack the materi- is not only the number of these organizations that als and the means to deliver this. In addition, the is important, but also that many of them focus on view of certain diseases may impact how health specific diseases, such as cancer societies, diabetes professionals educate and empower their pa- associations, etc. tients. For example, in some settings people with Overall, the health system elements described mental health problems are shackled and beaten above need to be present and supported by a pos- because of traditional beliefs about the causes of itive policy environment. In low-income coun- these conditions [47]. Therefore, issues of stig- tries, there is a large reliance on external funding ma also need to be addressed not only for indi- for specific disease programs [13] . Due to this it viduals with these conditions, but also in the was found that 30% of countries do not have a wider community. There is also the issue of us- specified budget for mental health [47] . In paral- ing Western concepts of disease. For example, lel, in order to address the issue of noncommuni- Patel et al. [50] while studying depression in cable disease properly, a multisectorial approach Zimbabwe found a variety of presentations and is needed that not only includes the health sector,

38 Beran

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 33–41 ( DOI: 10.1159/000365545 ) but also education, trade and agriculture [33] . For An innovative approach to addressing the is- mental health there is also a need to include police sue of noncommunicable diseases in low-income and judicial systems. Although many low-income countries was a Twinning project between Diabe- countries have started to develop national non- tes UK (UK-based diabetes association) and communicable disease plans, these fail to recog- Mozambique [55] . This project showed that by nize the true issue of multimorbidity and include taking a systematic approach to developing dia- mental health [54] . In low-income countries, only betes care, including activities addressing all 11 48.7% of countries have a mental health policy in elements presented above, it was able to improve comparison to 77.1% of high-income countries healthcare worker knowledge, access to medi- [40] . cines and the government’s response not only to diabetes, but also all noncommunicable diseases [56] . Conclusion In looking at lessons from low-income countries in improving access to psychological treat- There is both the need to address prevention and ments, Patel et al. [57] found that the two main the wider determinants of noncommunicable barriers were a lack of human resources and the disease as well as ensuring access to affordable acceptance of the treatments proposed in differ- care [37] . Primary healthcare has been proposed ent sociocultural contexts. The human resource as a solution to address this challenge as it enables challenge in low-income countries will not be a shift in focus to managing the individual and solved quickly, and with the rising burden of not the specific condition; however, there are nu- noncommunicable disease and multimorbidity, merous barriers to delivery of noncommunicable solutions need to be found. Specifically looking disease interventions and not all noncommuni- at mental health, Petersen et al. [58] propose cable disease interventions, due to their complex- task-shifting to nonspecialists. These nonspecial- ity, can be integrated in primary healthcare. This ists need to shift the power back to the individual is even more relevant for multimorbidity where- and their family, and have informed and active by the complexity of the individual may mean individuals in their own care who are able to have that primary healthcare does not have the human a partnership with their healthcare providers and resource capacity to manage this. [59] . Each level of the health system has a role to One lesson from HIV/AIDS that may be useful play in multimorbidity prevention and manage- for multimorbidity is to involve local communi- ment, and thus needs certain materials and hu- ties actively [60]. As chronic diseases are mainly man resources to be available. Also, a certain lev- managed outside the formal health system, indi- el of organization and coordination between dif- viduals need the skills to be able to care for them- ferent levels of the health system and different selves. Parallel to the ageing population, commu- sectors within the same institution (inpatient and nity-based care is necessary. This will of course outpatient services, pharmacy, laboratory, etc.) require trained healthcare workers to be involved, need to be in place for patient management and but by involving civil society, traditional healers referral. Guidelines need to be developed and and other groups, the issues of knowledge and used as well as data to ensure efficient and effec- stigma can effectively be addressed, ensuring bet- tive care and help define referral pathways from ter management, medically and socially, and different levels of the health system to avoid over- therefore better outcomes for people with multi- use of hospital care and ensure prompt referral to ple conditions. specialists only when needed.

Multimorbidity Care in Low-Income Countries 39

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 33–41 ( DOI: 10.1159/000365545 ) References

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David Beran, MSc, PhD Division of Tropical and Humanitarian Medicine Geneva University Hospitals and University of Geneva Rue Gabrielle-Perret-Gentil 6, CH–1211 Geneva 14 (Switzerland) E-Mail [email protected]

Multimorbidity Care in Low-Income Countries 41

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 33–41 ( DOI: 10.1159/000365545 ) Comorbidity of Mental and Physical Illness: A Selective Review

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 42–53 ( DOI: 10.1159/000365529 )

Depression, Diabetes and Dementia

a, d a, f, g a, b Joshua D. Rosenblat · Rodrigo B. Mansur · Danielle S. Cha · a, e a–c Anusha Baskaran · Roger S. McIntyre a b Mood Disorders Psychopharmacology Unit (MDPU), University Health Network, Institute of Medical c d Science, and Department of Psychiatry and Pharmacology, University of Toronto, Toronto, Ont. , Schulich e School of Medicine and Dentistry, Western University, London, Ont. , and Centre for Neuroscience Studies, f Queen’s University, Kingston, Ont. , Canada; Interdisciplinary Laboratory of Clinical Neuroscience (LINC) and g Program for Recognition and Intervention in Individuals in At-Risk Mental States (PRISMA), Department of Psychiatry, Federal University of São Paulo, São Paulo , Brazil

Abstract flammatory pathway, hypothalamic-pituitary-adrenal Depression, diabetes and dementia are three disorders axis dysregulation, monoamine changes and lowering of associated with staggering morbidity and mortality neurotrophic support to the CNS. Stress and psychosocial worldwide. The association between depression and dia- determinants of health may also be key mediators in how betes has been well established. Furthermore, both de- these systems interact. The involvement of several path- pression and diabetes have been shown to increase the ways may present new potential drug targets for the incidence of dementia individually and synergistically. treatment and prevention of dementia using a lifetime The metabolic-brain axis appears to be a key mediator approach. Systemic and intranasal insulin, oral diabetic connecting depression, diabetes and dementia. Brain re- medications, exercise, dietary changes, bariatric surgery gions important for cognition and emotional regulation and improved screening practices with early treatment may be damaged by the effects of hyperglycemia and of depression and diabetes all show promise in the treat- insulin resistance. Indeed, insulin resistance and de- ment and prevention of comorbid depression, diabetes creased insulin in the central nervous system (CNS) re- and dementia. © 2015 S. Karger AG, Basel sults in decreased intracellular glucose levels in frontal and subcortical regions, neurotoxicity, decreased neuroplasticity, decreased signaling, decreased synaptic con- Depression has been recognized by the World nectivity and disturbances in neural circuitry. The afore- Health Organization (WHO) as one of the lead- mentioned changes may be attributable to brain ing causes of disability worldwide, affecting an bioenergetics wherein there is a bias toward energy con- estimated 350 million people globally [1] . De- servation. The insulin pathway also has a bidirectional in- pression has also been identified as a risk factor teraction with amyloid-β oligomer formation, one of the and poor prognostic indicator for several medi- hallmarks of Alzheimer’s disease. As well, depression may cal comorbidities including, but not limited to, further facilitate neural circuit damage through the in- metabolic disorders such as diabetes, metabolic syndrome and obesity [2] . According to WHO Mechanisms Linking Depression, Diabetes estimates, diabetes, which now affects more than and Dementia 350 million people globally, will be the seventh leading cause of death by 2030 [3] . Moreover, de- Evidence from preclinical and clinical studies has pression and diabetes have a well-established suggested several potential mechanisms connect- link as numerous investigators have shown a bi- ing diabetes, depression and dementia. Essential directional association between these disorders to this discussion is the recognition that the neu- [4] . Both depression and diabetes have been in- ral networks implicated in cognitive and emo- dependently associated as risk factors for the de- tional function and dysfunction have significant velopment of cognitive impairment and demen- overlap, as shown in figure 1 [15] , which is central tia [5, 6] . Furthermore, depression and diabetes to the observed interactions between cognition have been recognized as having a synergistic ef- and mood. It has been amply documented that fect in increasing the risk for dementia above and cognitive dysfunction and changes in mood are beyond the effects that depression or diabetes key symptoms that have been observed to appear would have on the risk of developing dementia together in individuals diagnosed with major de- independently. More specifically, comorbid type pressive disorder [6, 16]. Therefore, the observed 2 diabetes mellitus and major depressive disor- symptoms of Alzheimer’s disease and major de- der have been documented to increase the inci- pressive disorder may be associated with a spec- dence of Alzheimer’s disease greatly later in life trum of structural and functional changes of [7] . shared neural circuits of the frontal and subcorti- Alzheimer’s disease is the leading cause of de- cal regions [6, 16] . Likewise, the epidemiological mentia, the sixth leading cause of mortality and observation and proposal of major depressive dis- the third most costly disease in the USA [8–10] . order as a prodrome of Alzheimer’s disease may It is progressive in nature and is ultimately fatal be indicative of progressive damage to these neu- [10] . Currently, available treatments are only pal- ral circuits with repeated major depressive epi- liative as there are no agents that have been sodes [6, 13, 16] . shown to have disease-modifying properties In addition, central to the discussion of mech- [11]. Therefore, primary prevention represents a anisms involved in diabetes, depression and de- priority research vista for identifying and target- mentia is the bidirectional relationship of the ing modifiable risk factors of Alzheimer’s dis- body’s metabolic milieu and neural circuitry ease. Modifiable risk factors that are addressed in [17] . Pathologic metabolic processes may dam- this review are type 2 diabetes and major depres- age these foregoing neural circuits. Evidence for sive disorder. such damage to neural circuits is shown through The overarching aim of this review is to review impaired cognition and altered brain connectiv- the potential pathophysiologic mechanisms ity in people with diabetes, independent of vas- which may account for this observed association cular pathology, as demonstrated through func- between Alzheimer’s disease, type 2 diabetes and tional imaging techniques, such as electroen- major depressive disorder. There is also a brief cephalography, magnetoencephalography and discussion about preventative and therapeutic functional magnetic resonance imaging [18, 19] . options with particular emphasis on a lifetime ap- The damage to frontosubcortical circuits by proach to dementia. Evidence for the association metabolic pathology, namely diabetes, insulin between diabetes, depression and dementia has resistance, and obesity, may thus impair cogni- been extensively reviewed and can be found else- tion and affect mood [18, 20] . where [7, 12–14] .

Depression, Diabetes and Dementia 43

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 42–53 ( DOI: 10.1159/000365529 ) Parietal/occipital Hippocampal Cingulate visual association formation areas

Dorsolateral Posterior parietal Motor structures prefrontal cortex heteromodal area

Ventromedial Amygdala complex Inferior temporal prefrontal visual association cortex areas

Fig. 1. The neural basis of cognitive and emotional processes. Reprinted with permission from Wood and Grafman [15] .

Impaired Central Insulin and Glucose Supply olfactory bulb, cerebral cortex, substantia nigra, Insulin, produced by the pancreas, enters the basal ganglia, hippocampus and amygdala [25] . blood stream allowing for its systemic circulation As such, altered insulin levels and signaling, as and systemic effects [21] . To enter the central ner- seen in type 2 diabetes, may have important CNS vous system (CNS), blood-borne insulin is trans- consequences. ported across the blood-brain barrier via a satu- Type 2 diabetes is characterized by hypergly- rable, receptor-mediated process [15]. Once in cemia, insulin resistance with compensatory hy- the CNS, insulin may exert a plethora of impor- perinsulinemia, and subsequent pancreatic de- tant effects, including, but not limited to, promot- compensation, resulting in hypoinsulinemia at ing glucose uptake in specific regions, neurogen- later stages, unless treated [21] . Preliminary evi- esis, neuroplasticity, synaptic strengthening and dence indicates that the blood-brain barrier insu- preventing neurodegeneration [22, 23]. CNS in- lin transporters may be downregulated in chron- sulin and glucose have also been proposed to be ic hyperinsulinemia [15] and that, consequen- an important modulator of the reward system tially, CNS insulin levels may be decreased and appetite [24] . [26–28] . As previously discussed, CNS insulin is The previous understanding that insulin had an important signaling molecule in numerous no effect on the brain has now been abolished CNS processes. Therefore, in the setting of type 2 with the discovery of insulin receptors in numer- diabetes where CNS insulin has been decreased ous brain regions [25]. Notably, insulin receptors because of blood-brain barrier receptor down- have been identified in regions involved with cog- regulation, several deleterious effects may ensue nition and emotion including the hypothalamus, [23, 26] .

44 Rosenblat · Mansur · Cha · Baskaran · McIntyre

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 42–53 ( DOI: 10.1159/000365529 ) The simplest deleterious effect to conceptual- atrophy. In keeping with this hypothesis, imaging ize is a decrease in intracellular glucose, second- and postmortem studies have found hippocam- ary to decreased CNS insulin levels, as certain pal atrophy in type 2 diabetes, major depressive brain regions, notably the medial temporal lobe disorder and Alzheimer’s disease [32] . and hippocampus, have insulin-dependent glucose uptake [26]. GLUT4 receptors in the hippo- Bioenergetics campus have been shown to facilitate insulin-de- Numerous energetically ‘expensive’ processes are pendent glucose uptake [29] . In type 2 diabetes continually occurring in the brain. These energet- animal models of insulin resistance, there is de- ically intensive processes include, but are not lim- creased glucose uptake in the hippocampus [26] . ited to, maintenance of an electrochemical gradi- Therefore, metabolically active CNS tissue im- ent in cells, neurogenesis, cellular depolarization portant for cognition and emotion receive subop- and repolarization, synaptogenesis, and release timal levels of glucose and thus may have subop- and reuptake of neurotransmitters [33, 34] . In ad- timal function. dition, brain topology studies have shown that CNS insulin not only increases glucose uptake higher functioning neural circuits have a greater in particular regions, but also acts as a growth fac- volume and length of connections, and as such, tor through its downstream effects. In brief, in vi- are even more energetically expensive [35] . tro studies and animal models have shown that To support these processes, the brain, while when insulin binds its receptor, the phos- representing only 2% of total body mass, con- phoinositide-3 kinase pathways are activated, sumes 25% of the body’s available glucose [34] . which promotes the production and release of Furthermore, Peters et al. [24] hypothesized that several growth factors including brain-derived the ‘selfish brain’ ensures adequate energy for it- neurotrophic factor (BDNF) and vascular endo- self through modulating appetite, prioritizing glu- thelial growth factor [30] , thereby promoting cose supply to the brain above other organs and neuronal survival, synaptogenesis and dendritic decreasing energy demands. In support of this hy- arborisation [23] . Similarly, long-term potentia- pothesis, empirical data have shown that carbohy- tion cascades, important for learning and memo- drate intake is increased in humans after a stress- ry, are promoted by insulin [26] . Indeed, animal ful intervention (a model shown to increase brain models have shown a strong trophic effect of in- energy consumption by 10–15%) [36, 37]. In ad- sulin on hippocampus size and benefits in cogni- dition to postintervention changes in food con- tion and memory [22, 23, 26, 27, 31] . Further- sumption, participants had increased blood glu- more, in animal models, inhibiting the binding of cose with a blunted insulin response. Since brain insulin to hippocampal cells has a marked nega- glucose uptake is largely insulin independent, this tive effect on hippocampus size and function (as pattern is indicative of a preferential bias of brain manifested through impaired memory) [26, 31] . glucose uptake relative to other organs when brain Taken together, insulin acts as a growth factor energy demands are increased [37] . and mediator of glucose uptake in the hippocam- Low CNS insulin and intracellular glucose lev- pus and other areas of emotion and cognition, els, as seen in type 2 diabetes with downregulated promoting the health of these neural circuits. blood-brain barrier insulin transport and insulin Therefore, insulin resistance may lead to de- resistance, may lead to the perception of low en- creased CNS insulin levels, leading to decreased ergy availability and thus may trigger down- hippocampal glucose uptake and decreased stream mechanisms to conserve energy [24, 38] . growth factor signaling, which may lead to im- To conserve energy, neurogenesis is prevented as paired neurogenesis and ultimately hippocampal it requires great consumption of energy [24, 29,

Depression, Diabetes and Dementia 45

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 42–53 ( DOI: 10.1159/000365529 ) 39]. Animal models of type 2 diabetes have re- thermore, insulin degrading enzyme levels are reported that N-methyl- D -aspartate (NMDA) sig- duced in type 2 diabetes animal models [14, 18] . naling for the purpose of long-term potentiation Moreover, insulin has been shown to modulate is inhibited as it too is energetically expensive amyloid-β removal, reduce amyloid-β load and [40] . prevent pathogenic binding of amyloid-β [28, 43] . Ultimately, energy deficits perceived by the The interaction between insulin and amyloid-β brain (e.g. lowered CNS insulin and glucose in the is bidirectional. More specifically, accumulating case of type 2 diabetes) may negatively impact amyloid-β can bind to insulin receptors and neuroplasticity, optimal neural circuitry and thus downregulate insulin signaling, thus impairing optimal function [24, 29, 39]. In keeping with this neurogenesis and function through the previous- view, when the frontosubcortical regions are ly discussed mechanisms [45]. The foregoing bi- forced to reduce energy expenditure by allocating directional interaction may perpetuate a deleteri- resources to less demanding neural circuits, the ous positive feedback loop whereby insulin resis- domains of mood and cognition may be impaired tance promotes increased amyloid-β and to conserve energy in times of perceived energy amyloid-β induces further insulin resistance [26] . depletion [17, 24, 38] . Furthermore, chronic per- This loop may provide another reason for the ceived bioenergetic depletion may lead to chronic high prevalence of Alzheimer’s disease in people and progressive impairment of these circuits [17] . with type 2 diabetes [26] . Taken together, comorbid mood and cognitive symptoms, commonly observed and reported in Neuroplasticity, Inflammation, Oxidative Stress epidemiological studies as the co-occurence of and the Hypothalamic-Pituitary-Adrenal Axis major depressive disorder and Alzheimer’s dis- Neuroplasticity is the brain’s ability to change in ease, may represent late-stage bioenergetic bias. response to environmental stimuli [46]. The in- More specifically, older individuals with type 2 di- ability of the brain to change at a molecular, cel- abetes experience years of brain insults resulting lular, structural and ultimately functional level from glycemic dysregulation and aberrant insulin is an important cause of impaired cognition and levels, affecting neuroplasticity and neural func- mood. Diabetes and depression have been tion, leading to bioenergetic bias towards energy shown to impair neuroplasticity through the in- conservation rather than higher functioning [17] . flammatory pathway, oxidative stress, depletion of neurotrophic factors and hypothalamic-pitu- Insulin-Amyloid Pathway itary-adrenal (HPA) axis derangement, leading Another mechanism whereby hyperinsulinemia to impaired neurogenesis, impaired long-term with insulin resistance and low CNS insulin may potentiation and neurotoxicity [47, 48] . impact function is through the insulin-amyloid A proinflammatory state has been shown to be pathway. Amyloid-β protein oligomers have been associated with stress (physical, emotional, psy- strongly implicated in the pathoetiology of Al- chological), inflammatory medical comorbidities zheimer’s disease [41]. What induces amyloid-β (infection, obesity, diabetes, metabolic syndrome, oligomer formation is not yet fully understood; autoimmune diseases, cardiovascular disease) however, a strong interaction between amyloid-β and psychiatric comorbidities (mood disorders, and insulin has been identified [41, 42] . Notably, anxiety disorders, psychotic disorders) [49] . The insulin and amyloid-β compete for the same de- cytokines produced, most notably TNF-α, IL-6 grading enzyme, namely, insulin degrading en- and IL-1β, in this proinflammatory state have zyme, thereby indirectly affecting each other’s been associated with ‘sickness behavior’ includ- systemic and central concentration [43, 44] . Fur- ing depressive symptoms of lethargy, anhedonia

46 Rosenblat · Mansur · Cha · Baskaran · McIntyre

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 42–53 ( DOI: 10.1159/000365529 ) and cognitive decline [49] . The downstream ef- Brain-Derived Neurotrophic Factor fects of the proinflammatory state include de- Low levels of BDNF are commonly observed in rangement of monoamine levels, pathologic mi- people with type 2 diabetes, impaired glucose tol- croglial cell dysfunction, increased oxidative erance, major depressive disorder and Alzheim- stress, HPA axis activation and structural changes er’s disease [58]. This observation may suggest of the subcortical regions, all of which may lead to another common mechanism of pathogenesis of decreased neuroplasticity and dysfunctional these diseases. For example, during a major de- emotional and cognitive processing [50] . pressive episode, hippocampal 5-HT2A receptors More specifically, proinflammatory cytokines are upregulated, which may lead to decreased have been shown to cause tryptophan depletion BDNF and a subsequent decrease in hippocampal and increased serotonin turnover, both well- volume [59] . Moreover, BDNF is one of the known causes of altered mood and cognition downstream targets of insulin receptor activation [51] . Increased oxidative stress also accompanies [30]. Therefore, in the setting of insulin resistance the elevated metabolic rate induced by a proin- where signaling is diminished, BDNF levels are flammatory state, thus increasing cellular damage also lower [26] . The low levels of BDNF, as seen at the molecular level ultimately leading to neuro- in both type 2 diabetes and major depressive dis- toxicity [51] . order, may thus increase vulnerability to hippo- Also implicated in the inflammatory pathway campal dysfunction and atrophy secondary to in- are microglial cells, the macrophages of the CNS. adequate growth factor stimulation [26, 31, 60] . Microglial cells are important for normal brain function and synaptic pruning; however, in a Monoamine Changes chronic inflammatory state, microglial cells may The monoamine pathway has been the primary induce high levels of neural death through patho- therapeutic target of major depressive disorder logic synaptic pruning leading to impairment of for decades. Causes of monoamine derangement the cognitive and mood neural circuits [52, 53] . are numerous, including the previously discussed The proinflammatory state is also associated inflammatory pathway [49] and CNS insulin [26] . with activation of the HPA axis leading to hyper- Monoamines, notably serotonin, norepinephrine cortisolemia as well was impaired HPA negative and dopamine, are now also being recognized as feedback through decreased glucocorticoid re- having significant roles in cognition [61] . For ex- ceptor expression, translocation and signaling ample, serotonin receptors are found abundantly [54] . Of note, diabetes and depression as well as in cognitive regions such as the hippocampus, stress all have the ability to activate the HPA axis, prefrontal cortex and septum, where they play an inducing hypercortisolemia [54, 55] which leads important role in cognition, most notably cre- to further hyperglycemia and thus to poorer con- ation of episodic memories as evidenced by tryp- trol of diabetes and increased insulin require- tophan depletion studies [62] . Norepinephrine ments [21] . Chronic exposure to high levels of plays a significant role in alertness and arousal, cortisol can also cause neurotoxicity in the hip- thus affecting cognitive function in the domains pocampus, leading to impaired cognition and of working memory, memory consolidation, at- mood symptoms [56]. This neurotoxic effect is tention and executive function [61] . Dopamine amplified in the presence of insulin resistance levels are also salient to cognition, motivation and [26] . Notably, cortisol has also been implicated in the reward system [63] . In sum, the monoamine altering metabolism of amyloids and may thus ex- system can be altered by depression and type 2 hibit pro-Alzheimer’s disease properties through diabetes and has large effects on both cognition the amyloid mechanism as well [57] . and emotion. Therefore, it may provide another

Depression, Diabetes and Dementia 47

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 42–53 ( DOI: 10.1159/000365529 ) pathophysiologic nexus to account for the interplay between depression, diabetes and cognitive Stress impairment [61] . Inflammation

Microbiota-Gut-Brain Axis Many decades ago, the vast and dynamic ecosys- tem of the gut microbiota was hypothesized to af- Peripheral Brain function

fect mental health; however, only recently has this metabolism/ Humoral factors (emotion, idea been revisited [64]. Currently, there is only energy cognition, expenditure memory, limited evidence for the bidirectional interaction (glucose, insulin) learning, reward, between the gut and the CNS, but interest across motivation) the fields of psychiatry, neurology, gastroenterology and endocrinology is increasing [65] . Preclin- ical evidence suggests that this interaction may Fig. 2. Role of humoral factors in normal and pathologi- provide mechanisms whereby the gut microbiota cal nexus between peripheral metabolism and brain may induce metabolic, behavioral, mood and functions. Reprinted with permission from Kaidanovich- cognitive changes [65]. This field is still in its in- Beilin et al. [17] . fancy but is being implicated as an etiologic factor in dictating eating habits, BDNF levels, HPA axis activity, inflammation and oxidative stress, all of zheimer’s disease [67]. Microangiopathic chang- which are important factors in the mechanisms of es may be linked with amyloid-β oligomer forma- affective and cognitive dysfunction, as previously tion [68]. The proposed mechanism and evidence discussed [64, 65]. In brief, the gut may have bi- in support of the microangiopathy-cognitive-af- directional communication with the brain to infective connection have been reviewed elsewhere duce behaviors that increase the risk of diabetes [66, 67, 69] . as well as may be the nidus of a chronic inflammatory state which may induce sickness behav- Common Psychosocial Determinants ior, hypercholesterolemia, hyperglycemia, hyper- A separate but not mutually exclusive explana- cortisolemia and ultimately neural damage, af- tion of the connection between diabetes, depres- fecting cognitive and emotional function [64, 65] . sion and dementia may be due to the psychosocial risk factors that are shared by these disease pro- Microangiopathy cesses [17] . Epidemiological studies provide evi- Microvascular (nephropathy, neuropathy, reti- dence for low socioeconomic status, childhood nopathy) and macrovascular (stroke, myocardial adversity, medical comorbidities, addiction and infarction) complications of diabetes are well es- psychiatric comorbidities as being common risk tablished in the literature [21]. Moreover, it has factors for type 2 diabetes and major depressive now been well-established that the brain has in- disorder [70–72]. Therefore, one potential expla- creased susceptibility to microvascular disease, nation for the observed association may be com- independent of the presence of large vessel dis- mon etiologic factors [17]. As shown in figure 2, ease, in people with diabetes [66] . Postmortem both common biological and psychosocial factors and imaging analyses has revealed these microan- may be creating a pathological nexus between pe- giopathic changes to be associated with the devel- ripheral metabolism and brain function. Taken opment of depression, cognitive impairment and together, certain life circumstances may predis- dementia, particularly vascular dementia and Al- pose individuals to the development of both type

48 Rosenblat · Mansur · Cha · Baskaran · McIntyre

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 42–53 ( DOI: 10.1159/000365529 ) 2 diabetes and major depressive disorder, which cases worldwide [74] . Similarly for type 2 diabe- could synergistically damage the neural circuits tes, appropriate therapy achieving adequate gly- of emotion and cognition, thereby increasing the cemic, lipid and blood pressure control has been risk of cognitive impairment and dementia [17] . shown to decrease the risk of cognitive impairment, Alzheimer’s disease and vascular dementia [75, 76] . Taken together, screening for major de- Implications for Treatment and Prevention pressive disorder in people with type 2 diabetes and vice versa would thus have clear benefits for As shown, numerous mechanisms may be in- early detection and treatment for both condi- volved in the interaction of diabetes, depression tions while reducing the risk of developing Al- and dementia, and may present new therapeutic zheimer’s disease [77] . targets. Therefore, in this section, the focus will be From a public health perspective, exercise placed on selected new and novel therapeutic and and a healthy diet have been promoted because preventative options that target components of of their positive impact on cardiovascular health the mechanisms previously discussed. Emphasis [78] . Evidence consistently documents the im- will be placed on (1) the benefit of early detection portance of exercise and a healthy diet and their and treatment of major depressive disorder and impact on diabetes, depression and dementia diabetes, (2) the importance of lifestyle modifica- [14, 79–83] . For example, exercise has been tions, namely exercise and dietary changes, and shown repeatedly to have a positive effect on (3) novel metabolic therapeutic options which mood and cognition in individuals with depres- hold promise for improving mood and cognition sion [32, 83] . Likewise, among individuals with in the context of major depressive disorder, type Alzheimer’s disease, exercise has been shown to 2 diabetes and Alzheimer’s disease. improve mood and cognition both in the short As previously discussed, no disease-modify- and long term [80, 81] . In type 2 diabetes, life- ing agents are currently identified for Alzheim- style management has long been a part of first- er’s disease [10] . Therefore, prevention through line therapy with clear effects on cognition, risk factor modification has been a focus of Al- mood and Alzheimer’s disease prevention [10, zheimer’s disease research and public health ef- 84, 85]. Therefore, lifestyle management should forts [10, 73] . Understanding the pathophysiol- also be emphasized from a mental health per- ogy of Alzheimer’s disease as occurring over a spective, rather than only for its cardiovascular lifetime, rather than only in old age when symp- benefits. toms begin to manifest, is essential to this pre- From a pharmacologic perspective, increasing ventative approach. Epidemiologic and mecha- interest has been developing for the use of dia- nistic data strongly suggest both depression and betic medications for improvement of mood and diabetes to be modifiable risk factors of Alzheim- cognition. For example, recent studies have been er’s disease. Therefore, screening programs to al- conducted investigating the role of insulin in low for early detection and treatment of both ma- mood and cognition [22]. As previously dis- jor depressive disorder and type 2 diabetes may cussed, CNS insulin plays a key role in brain func- be extremely helpful in the prevention of Al- tion, and CNS insulin levels are reduced in people zheimer’s disease. Indeed, evidence suggests that with Alzheimer’s disease [27]. Intravenous ad- an estimated 10–15% of Alzheimer’s disease cas- ministration of insulin has been investigated for es are attributable to depression and a 25% re- its effects on cognition and emotion. Several induction in depression prevalence would result in vestigators have shown that in both human and approximately 830,000 fewer Alzheimer’s disease animal models, intravenous insulin administra-

Depression, Diabetes and Dementia 49

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 42–53 ( DOI: 10.1159/000365529 ) tion can increase hippocampal neural activity and Bariatric surgery produces vastly improved improve mood and cognition (most reproducibly glycemic control and significant sustained re- declarative memory) in the short and long term duction in weight far beyond the effects of med- [86, 87]. However, concerns of the systemic ef- ical therapy alone [95–97]. This significant im- fects and risks, namely hypoglycemic events, were provement in diabetic control, in theory, may a limiting factor to their wider promotion [88, decrease the risk of depression and cognitive im- 89] . Therefore, interest has shifted to intranasal pairment later in life by preventing neural de- insulin administration, whereby insulin directly generation from the previously described mech- enters the CNS, bypassing the blood-brain barri- anisms. However, to the authors’ knowledge, er, presumably via the olfactory and trigeminal there have been no studies to assess the effect of nerves [88, 89]. Intranasal administration has bariatric surgery on mood, cognition and risk of been shown to increase the level of insulin in the Alzheimer’s disease development. Therefore, CNS while not affecting the systemic concentra- this effect may be an interesting topic for future tion of insulin or glucose [88–90] . Furthermore, research. in human and animal studies, intranasal insulin has been shown to improve mood and cognition reproducibly in healthy, obese and Alzheimer’s Conclusion disease subjects [91]. Moreover, intranasal insulin has benefited disparate measures of neurocog- Several mechanisms have been proposed to ac- nition in adults with bipolar disorder, a group count for the well-documented association be- highly susceptible to cognitive dysfunction [92] . tween diabetes, depression and dementia. The Oral diabetic medication, particularly thia- metabolic-brain axis appears to be a key media- zolidinediones and incretins have also produced tor connecting these conditions. Brain regions interesting results. Pioglitazone, a thiazolidinedi- important for cognition and emotional regula- one, is an insulin sensitizer that has been shown tion may be damaged by the effects of hypergly- to also have effects on cognition [87, 93] . Indeed, cemia and insulin resistance. Indeed, a decreased cognitive improvements as well as a reduction in insulin effect and thus decreased intracellular the development of Alzheimer’s disease have glucose levels in frontal and subcortical regions been observed in people with type 2 diabetes results in neurotoxicity, decreased neuroplasti- treated with pioglitazone [87, 93]. Incretins, gas- city, decreased signaling and decreased synaptic trointestinal hormones which delay gastric emp- connectivity resulting in an overall effect of dys- tying and increase insulin release from the pan- functional neural circuits. Major depressive dis- creas, have also shown great promise to treat met- order may further facilitate neural circuit dam- abolic, cognitive and affective symptoms age through the inflammatory pathway, HPA simultaneously [22, 94] . In a recent review by Mc- axis deregulation, monoamine changes and low- Intyre et al. [94], the positive effects of incretins, ering of central BDNF levels. Stress and psycho- specifically glucagon-like peptide-1, were dis- social determinants of health may also be key me- cussed. In brief, glucagon-like peptide-1 may im- diators and etiologic factors in these interactions. prove glycemic control, improve cognition and Taken together, several mechanistic pathways mood, and decrease the risk of Alzheimer’s dis- may be involved, presenting new potential drug ease through its neuroprotective effects, ability to targets for the treatment and prevention of de- reduce amyloid-β load and through promotion of mentia using a lifetime approach. Systemic and long-term potentiation and neuroplasticity [22, intranasal insulin, insulin sensitizers, incretins, 94] . exercise, dietary changes, bariatric surgery, im-

50 Rosenblat · Mansur · Cha · Baskaran · McIntyre

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 42–53 ( DOI: 10.1159/000365529 ) proved screening and early treatment practices of ture reviewed here shows great promise for fur- type 2 diabetes and major depressive disorder ther studies of the metabolic-brain axis which have all been implicated for potential use in the could revolutionize the understanding, treat- treatment and prevention of dementia. Further ment and prevention of cognitive and affective research is most definitely indicated as the litera- disorders.

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Depression, Diabetes and Dementia 53

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 42–53 ( DOI: 10.1159/000365529 ) Comorbidity of Mental and Physical Illness: A Selective Review

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 54–65 ( DOI: 10.1159/000365531 )

Cardiovascular Disease and Severe Mental Illness

Richard I.G. Holt Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, University Hospital Southampton NHS Foundation Trust, Southampton , UK

Abstract Cardiovascular disease is the leading cause of People with schizophrenia or bipolar disorder have in- mortality worldwide, accounting for approxi- creased morbidity and shortened life expectancy com- mately 30% of all deaths. Similarly, mental illness pared with the general population. The prevalence of is also common, affecting 1 in 10 people at any many physical illnesses is increased in people with se- one time. A degree of comorbidity is therefore to vere mental illness and accounts for around three quar- be expected but it is clear that mental illness oc- ters of all deaths; cardiovascular disease is the most curs more commonly among people with cardio- common cause of death. The increased prevalence of vascular disease than expected and vice versa [1] . cardiovascular disease is explained, at least in part, by The relationship between cardiovascular dis- increased rates of traditional cardiovascular risk factors ease and mental illness is complex and bi-direc- including diabetes, dyslipidaemia, obesity and smok- tional, with mental illness being both a cause and ing, but mental illness is an independent risk factor for consequence of cardiovascular disease. For exam- cardiovascular disease and mortality. Despite national ple, cross-sectional studies have shown that the and international guidance and an increasing aware- prevalence of depression is increased in people ness of physical health issues in people with severe with cardiovascular disease with up to 40% of mental illness, the level of screening for and manage- people having either major or minor depression ment of cardiovascular risk factors remains poor. While following a myocardial infarction [2] . Further- there are additional challenges in managing cardiovas- more, longitudinal studies indicate that depres- cular risk in people with severe mental illness, the prin- sion increases the risk of myocardial infarction, ciples are similar to those in the general population. A coronary heart disease, cerebrovascular disease multidisciplinary approach involving healthcare profes- and other cardiovascular diseases by up to 2-fold sionals within psychiatry, general practice and medical in both men and women, independent of other specialties as well as and clear patient pathways are risk factors [3, 4], and increases mortality follow- needed to reduce the health inequalities experienced ing a myocardial infarction [5, 6]. Similarly, anxi- by people with severe mental illness. ety is an independent risk factor for incident cor- © 2015 S. Karger AG, Basel onary heart disease and cardiac mortality [7] . Table 1. Estimated prevalence of modifiable cardiovascular risk factors in people with schizophrenia and bipolar disorder, and relative risk compared with the general population (adapted from De Hert et al. [10])

Modifiable risk factor Schizophrenia Bipolar disorder prevalence relative risk pre valence relative risk

Smoking 50–80% 2–3 54–68% 2–3 Dyslipidaemia 25–69% ≤5 23–38% ≤3 Diabetes 10–15% 2–3 8–17% 1.5–3 Hypertension 19–58% 2–3 35–61% 2–3 Obesity 45–55% 1.5–2 21–49% 1–2 Metabolic syndrome 37–63% 2–3 30–49% 2–3

This chapter, however, will review the associa- older than 50 years [9]. While the morbidity and tion between severe mental illness (schizophrenia mortality associated with cardiovascular disease and bipolar disorder) and cardiovascular disease have fallen in the general population over the last as an example of this complex relationship. It will 20 years, these benefits have not been shared by explore the reasons for the comorbidity and the people with severe mental illness, which has led to steps needed to reduce cardiovascular disease in a widening health inequality gap. people with severe mental illness. Severe mental illness is associated with a 3-fold increased risk of premature death and shortened life expectancy by Aetiology of Cardiovascular Disease in Severe approximately 10–20 years [8]. Although suicide Mental Illness accounts for the highest relative risk of mortality, being up to 20-fold more common than the gen- There are numerous reasons for the increased eral population, a range of physical illnesses oc- rate of cardiovascular disease in people with se- curs more frequently in people with severe men- vere mental illness, including an increased preva- tal illness and which are the cause of approxi- lence of modifiable cardiovascular risk factors, mately three quarters of all deaths, with such as obesity, smoking, diabetes and dyslipi- cardiovascular disease being the most common daemia (table 1 ), as well as intrinsic biological cause of death [8] . changes that occur during psychosis [10] . Not only do modifiable cardiovascular risk factors occur more commonly, but they appear at a young- Epidemiology of Cardiovascular Disease in er age; in the US Clinical Antipsychotic Trials of Severe Mental Illness Intervention Effectiveness (CATIE), over a quarter of men with schizophrenia, aged 20–29 years, Cardiovascular morbidity and mortality are in- at baseline had metabolic syndrome, a proxy for creased approximately 2- to 3-fold in people with cardiovascular risk, compared with fewer than severe mental illness [8]. The relative risk is more 10% in the general US population [11]. The im- markedly increased in younger individuals with plication of this finding is that healthcare profes- severe mental illness, in whom the prevalence of sionals need to pay attention to cardiovascular cardiovascular disease is 3.6-fold higher com- risk factor management in people with severe pared with a 2.1-fold increase in people who are mental illness from diagnosis.

Cardiovascular Disease and Severe Mental Illness 55

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 54–65 ( DOI: 10.1159/000365531 ) Obesity of physical activity and social and urban depriva- The global prevalence of obesity has increased tion experienced by those with schizophrenia dramatically over the last three decades, driven by may contribute further to the increased obesity changes in diet and physical activity. These de- rates. mographic changes appear to have affected people with severe mental illness to a greater extent Diabetes than the general population as studies that pre- It is estimated that between 10 and 15% of people date the 1980s did not consistently report higher with severe mental illness have diabetes [10] . The rates of obesity in those with severe mental illness onset occurs on average 10 years earlier, with [12] . By contrast, more recent studies have shown women appearing to have a greater risk of diabe- that obesity is approximately 2-fold more com- tes than men [15] . Type 1 diabetes is not in- mon in people with schizophrenia or bipolar dis- creased and so the 2- to 3-fold excess is explained order. The mean baseline BMI in the CATIE by an increase in type 2 diabetes. The prevalence study was 29.7 kg/m2, with 37% of men and 73% of undiagnosed diabetes is also considerably of women having central obesity as defined by a higher in people with schizophrenia than the waist circumference in excess of 102 and 88 cm, general population with as many as 70% of cases respectively. being undiagnosed. This may reflect a reluctance Obesity occurs early in the natural history of of people with severe mental illness to volunteer schizophrenia with a significant proportion of symptoms and the overlap between some symp- people with first-episode psychosis being over- toms of diabetes and mental illness, leading to weight prior to any treatment. Weight gain less screening in people with severe mental ill- frequently occurs rapidly following treatment ness. initiation. Seventeen per cent of people with Like obesity, the rates of diabetes may be in- schizophrenia in the European First Episode creased because of lifestyle factors, but there is Schizophrenia Trial were overweight at baseline also evidence of a genetic link between the two prior to treatment and 37–86% had gained more conditions. There is a high prevalence of meta- than 7% of their initial body weight during the bolic abnormalities in the first degree relatives of first year of treatment, depending on medica- people with severe mental illness, and between 17 tion choice [13] . and 50% of people with schizophrenia have a Body composition is also altered in people family history of type 2 diabetes [15] . Although with severe mental illness; higher waist-to-hip ra- these findings may result from shared familial en- tios and increased visceral fat have been found vironment, genome-wide association studies even in people with first episode psychosis; other have suggested a shared genetic linkage between studies have not replicated these findings, but severe mental illness and diabetes [16] . note marked weight gain and increasing girth during treatment with antipsychotic medication Dyslipidaemia and Hypertension [12] . A meta-analysis including 11 papers on dyslipi- The cause of obesity in people with schizo- daemia showed that the major lipid abnormalities phrenia includes genetic and lifestyle factors as seen in people with severe mental illness are low- well as illness and treatment effects. Individuals er levels of HDL cholesterol and hypertriglyceri- with schizophrenia are more likely to consume a daemia, although not all studies have shown this diet that is rich in fat and refined carbohydrates [17] . By contrast, total cholesterol was not higher while containing less fibre, fruit and vegetables in people with severe mental illness. Overall, dys- than the general population [14] . The lower levels lipidaemia is reported in 25–69% of people with

56 Holt

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 54–65 ( DOI: 10.1159/000365531 ) severe mental illness. The same meta-analysis in- treatment, albeit at a slower rate. There is a hi- cluded 12 papers on hypertension and found a erarchy of weight gain between second-genera- non-significant 11% increase in the prevalence of tion antipsychotics, with clozapine and olanzap- hypertension (1.11, 95% CI: 0.91–1.35) [17] . ine being associated with the greatest weight gain, but no agent should be considered as Smoking weight neutral. There is an intermediate risk of Smoking rates are high in people with severe weight gain with quetiapine and risperidone, mental illness (50–80%). In the USA, 68% of 689 while aripiprazole, amisulpride and ziprasidone schizophrenia patients who took part in the have little effect on weight. Some first-genera- CATIE study were smokers compared to 35% of tion antipsychotics, for example chlorproma- age-matched controls. In the UK general popula- zine, and other psychotropic medications, such tion, 20% of men and 19% of women are current as certain antidepressants, are also associated smokers, but the odds of people with schizophre- with a high risk of weight gain. nia being current smokers are 5.3 times higher Predicting weight gain with treatment is diffi- and the odds are greater for men than women at cult because there is marked inter-individual 7.2 and 3.3, respectively [18]. People with severe variation in treatment-induced weight change. mental illness are also heavier smokers both in Other factors associated with weight gain are terms of total number of cigarettes smoked and younger age, lower initial BMI, family history of amount of smoke inhaled. obesity, concomitant cannabis use and a tendency to overeat at the time of stress [12] . The best Intrinsic Biological Changes in Severe Mental predictor of long-term weight gain is the change Illness in the first 4–6 weeks of treatment, emphasising Severe mental illnesses are associated with a num- the need for regular weight measurement during ber of biological changes that affect intermediate the early phase of treatment. metabolism and consequently cardiovascular risk The relationship between antipsychotics and [15] . These include hypothalamic-pituitary-adre- diabetes is complex because of the long natural nal axis dysfunction, manifesting as subclinical history of diabetes and the potential confounding hypercortisolism and blunted diurnal cortisol effects of other diabetes risk factors in people rhythm, altered immune function (e.g. altered cy- with severe mental illness [19] . The earliest case tokine expression) and altered platelet function. report linking antipsychotics with diabetes was in 1956 when a man developed haemolytic anaemia and diabetes 2 weeks after stopping chlorproma- Antipsychotic Medication and Cardiovascular zine [20] . Since then, cases of diabetes and dia- Disease betic ketoacidosis have been seen in people receiving various first- and second-generation an- There are concerns that antipsychotics may tipsychotics [19]. Although these studies provide contribute to cardiovascular risk by inducing evidence of causality, particularly when the glu- weight gain and worsening lipid profile and cose was measured before treatment initiation blood glucose. Weight gain is the most common and where the diabetes entered remission after side effect seen with second-generation antipsy- treatment discontinuation, the small numbers chotics, affecting between 15 and 72% of pa- make it difficult to determine whether these are tients [12] . Most weight gain occurs early in isolated cases or whether they can be extrapolat- treatment, but patients may continue to gain ed to the wider body of people receiving antipsy- weight for at least 4 years after the initiation of chotic medication.

Cardiovascular Disease and Severe Mental Illness 57

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 54–65 ( DOI: 10.1159/000365531 ) A large number of pharmaco-epidemiologi- ziprasidone, but a similar increase as clozapine cal studies have indicated that people receiving [24] . antipsychotics have a higher prevalence of dia- Overall it appears that there is a causative link betes than the general population and that peo- between antipsychotics and diabetes, but the risk ple receiving second-generation drugs have a is probably low and the majority of people receiv- slightly increased risk of diabetes compared ing antipsychotics will not develop diabetes as a with those receiving first-generation drugs. result of their medication [19] . One meta-analysis found that the relative risk Antipsychotic treatment is also associated of diabetes in those prescribed a second-gener- with increases in LDL cholesterol and triglycer- ation antipsychotic was 32% (15–51%) higher ides and decreased HDL cholesterol. In a meta- than those receiving a first-generation antipsy- analysis of 48 studies comparing different sec- chotic. There was, however, considerable varia- ond-generation antipsychotics, olanzapine pro- tion between studies [21] , and a further system- duced a greater increase in total cholesterol than atic review of cohort studies found no consis- aripiprazole, risperidone and ziprasidone, but no tent difference in diabetes risk between differences with amisulpride, clozapine and que- second-generation antipsychotics either as a tiapine were seen [24] . These differences may re- group when compared with first-generation an- flect the propensity to weight gain, but there may tipsychotics or between individual drugs [22] . be other direct mechanisms as hypertriglyceri- Over the last decade, randomised controlled daemia may occur following treatment despite trials reporting treatment-emergent diabetes only modest weight gain. have begun to appear in the literature. A system- The effect of antipsychotics on blood pressure atic review of 22 of these trials found no consis- is variable; although weight gain may lead to intent significant difference in treatment-emergent creased blood pressure, this may be offset by ad- glucose abnormalities between antipsychotics, ei- renergic blockade by the antipsychotics [17] . ther when compared with other antipsychotics or Overall it appears that many antipsychotics with placebo [23]. However, caution is needed have an adverse effect on cardiovascular risk fac- when interpreting this analysis as the primary tors. However, it is important to understand that aim of many of these studies was to assess anti- these are surrogate markers and may not translate psychotic efficacy rather than metabolic side ef- into increased cardiovascular events and mortal- fects, and as such are underpowered to address ity. Indeed, the opposite is suggested by several this issue. The reporting of metabolic data was in- large epidemiological studies. A UK study of over consistent and duration of many studies was too 46,000 people found that while exposure to first- short to assess diabetes risk. Furthermore, several generation antipsychotics, particularly high dos- studies have shown small increases in glucose es, was associated with excess cardiovascular concentration in people receiving second-gener- mortality, this increase was not seen in people re- ation antipsychotics during the studies, which ceiving second-generation antipsychotics [9] . may translate into meaningful differences in the Similarly in a large Finnish study of 66,881 people rate of diabetes over the many years that people with schizophrenia, total mortality was lowest in with severe mental illness take antipsychotics individuals receiving clozapine and olanzapine, [24] . A more recent meta-analysis comparing the with no difference in cardiovascular mortality be- metabolic side effects of different second-genera- tween drugs [25]. A more recent Finnish study tion antipsychotics found that olanzapine pro- examining the impact of the first- and second- duced a greater increase in glucose than amisul- generation antipsychotics on mortality in people pride, aripiprazole, quetiapine, risperidone and with first-onset schizophrenia found that the use

58 Holt

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 54–65 ( DOI: 10.1159/000365531 ) Table 2. Recommended screening based on currently available guidelines

Baseline 2–3 months Annual Target

Medical history to include ✓✓ ✓ family history, ethnicity, smoking, alcohol, diet, exercise

Height ✓ Weight1 ✓ Every week during first ✓ BMI <25 kg/m2 6–8 weeks of treatment and at every clinic visit thereafter, but at least quarterly

Blood pressure ✓✓ ✓<140/90 mm Hg Glucose2 ✓✓ ✓Fasting glucose <6.0 mmol/l Non-fasting glucose <7.8 mmol/l

Glycated haemoglobin3 ✓✓ ✓<6.0% (42 mmol/mol) if no history of diabetes; target should be individualised for people with diabetes but likely 6.5–7.5% (47–58 mmol/mol)

Lipid profile4 ✓✓ ✓Total cholesterol <5.0 mmol/l, <4.0 mmol/l if established CVD or diabetes LDL-cholesterol <3.0 mmol/l, <2.0 mmol/l if established CVD or diabetes 30% reduction in patient starting statins

Electrocardiogram ✓✓ ✓To assess QTc interval

1 Additional information can be obtained by measuring waist circumference; target men <94 cm, women <80 cm. Lower values should be sought in people from non-white European populations. 2 Either a fasting or non-fasting sample can be used. Fasting samples are more reproducible, but may be logistically more difficult to obtain. A formal 75-gram oral glucose tolerance test is only needed rarely. 3 Note glycated haemoglobin may be normal in situations where there is a rapid onset of diabetes and so is less suited to the 2- to 3-month sample. 4 Either a fasting or non-fasting sample can be used. Fasting samples are needed to assess LDL cholesterol and triglycerides, but cardiovascular risk can be calculated using the total:HDL cholesterol ratio which is largely unaffected by eating.

of second-generation antipsychotics, especially Screening for Cardiovascular Risk Factors clozapine, olanzapine and quetiapine, was associated with reduced risk of all-cause mortality in The increased prevalence of cardiovascular dis- people with schizophrenia [26]. By contrast, ease and its modifiable risk factors in people with first-generation antipsychotics, specifically le- severe mental illness provides a strong rationale vomepromazine, thioridazine and clorprothix- to screen for cardiovascular risk factors. Screen- ene, were associated with increased risk of all- ing should begin prior to the onset of treatment cause mortality and levomepromazine with an or as soon as is reasonably possible, 2–3 months increased likelihood for cardiovascular death. As later to assess the acute metabolic effects of the these studies are both observational, there may be antipsychotics, and thereafter on an annual basis other explanations or confounders underlying unless significant treatment changes are contem- the results [25, 26] . plated (table 2 ).

Cardiovascular Disease and Severe Mental Illness 59

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 54–65 ( DOI: 10.1159/000365531 ) Cardiovascular risk assessment should include psychiatrists which showed that US Food and a detailed medical history to assess risk factors, Drug Administration guidelines and a joint posi- physical examination to include weight and blood tion statement of the American Psychiatric Asso- pressure, a blood test to assess lipids and glycae- ciation, American Diabetes Association and North mia, and an electrocardiogram [10] . It is known American Association for the Study of Obesity had that waist circumference is more closely associat- no effect on screening rates for diabetes [32] . There ed with cardiovascular disease than BMI, but in is a lack of clarity among mental healthcare profes- some settings, such as within the UK primary care, sionals about whose responsibility physical health there has been reluctance to undertake this mea- screening is [33] . In some countries, such as the surement. The close correlation between weight UK, the responsibility for screening is placed with- and waist circumference for most of the popula- in primary care [28] . This may be appropriate be- tion would suggest that while additional informa- cause many people with mental illness have fre- tion may be obtained from a waist measurement, quent contact with their primary care doctor and weight is a pragmatic and practical alternative. primary care doctors have all the skills and training A fasting blood sample is required to interpret a to address this issue. However, some people with full lipid profile, but a non-fasting sample is accept- severe mental illness only see their mental health able where logistical difficulties prevent the patient team and under this circumstance it is important from attending in a fasting state. The sensitivity and the screening occurs in this setting. It is clear that specificity for diabetes, particularly if the glucose good communication is needed between primary measurement is combined with glycated haemoglo- care and mental health teams to ensure that the bin, does not differ greatly and most 10-year cardio- patient does not fall between the two settings. vascular risk engines use the total and HDL choles- Mental healthcare professionals have also ex- terol, which are largely unaffected by eating. Al- pressed concern about their lack of understanding though it may be easier to obtain a non-fasting about what should be measured and when and sample, clinicians should not assume that patients how to interpret the results [33] . Lack of access to with severe mental illness are unable to attend fasted necessary equipment may be a further barrier. as several studies have shown that this is feasible [27] . It is well recognised that people with severe mental illness are less likely to take advantage of Current Screening Practises health screening [34] and health services. Since to Despite clear guidance from both national and in- a large extent care is not offered unless requested, ternational bodies [10, 28–30] , it is clear that people with severe mental illness may be disadvan- many people with severe mental illness are not taged. The Disability Rights Commission has high- being screened for cardiovascular risk factors. In lighted that instead of receiving holistic care, many an audit of 50 in-patients and 50 out-patients people with mental illness describe how their phys- with severe mental illness in Hampshire, UK, ical illnesses are overshadowed by the mental ill- documented evidence that blood pressure had ness, with healthcare professionals concentrating been measured was found in only 32% of case on the latter to the detriment of the former [35] . notes, and glucose (16%), lipids (9%) and weight (2%) were assessed even less frequently [31] . This Assessment of Cardiovascular Risk was despite a high prevalence of metabolic syn- Cardiovascular risk is usually assessed by the use drome in these patients and a significant number of locally relevant risk engines. These have not at high risk of cardiovascular disease. been validated in people with severe mental ill- The effectiveness of national guidelines and ness who are typically younger, have higher blood campaigns has been questioned by a study of US pressure and are more likely to smoke than the

60 Holt

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 54–65 ( DOI: 10.1159/000365531 ) populations used to derive cardiovascular disease showed that those taking bupropion with co-in- risk scoring systems, such as Framingham and terventions (group therapy alone or in combina- QRISK. As traditional risk factors only partially tion with nicotine replacement therapy) for up to explain the excess cardiovascular disease seen in 12 weeks were 3 times more likely to be abstinent people with severe mental illness, it is possible 6 months after starting treatment, compared with that these traditional risk engines may underesti- those taking a placebo [39] . Bupropion, however, mate cardiovascular risk in people with severe is contraindicated in people with bipolar disor- mental illness. However, pending further re- der. Varenicline may also improve smoking ces- search, they provide a guide for the initiation of sation rates in people with schizophrenia, but primary preventative measures. there have been reports of suicidal ideation and behaviours from people on varenicline.

Managing Cardiovascular Risk Factors Obesity The pessimism surrounding treatment of obesity While there are additional challenges in ensuring in people with severe mental illness has been chal- that the person with severe mental illness under- lenged by a number of recent observational stud- stands the aims and rationale for treatment, caries and randomised controlled trials of lifestyle diovascular risk factor management is essentially and pharmacological interventions. A recently along similar lines to the general population. published meta-analysis of non-pharmacological interventions in people with schizophrenia has Smoking shown that these led to a mean reduction in Healthcare professionals should provide smokers weight of 3.12 kg over a period of 8–24 weeks with information about the risks of smoking and [40] . In addition, there were commensurate re- encourage them to quit. Interventions for smoking ductions in waist circumference and improve- cessation range from basic advice to pharmaco- ments in other cardiovascular risk factors. The therapy coupled with either individual or group benefits of these programmes were seen irrespec- psychological support. Smokers with schizophre- tive of the duration of mental illness treatment, nia are less likely to quit than the general popula- whether the intervention was delivered to an in- tion, with one meta-analysis reporting the smok- dividual or in a group setting, whether the inter- ing cessation rate for people with schizophrenia to vention was based on cognitive behavioural ther- be 9% compared with 14–49% in the general popu- apy or a nutritional intervention, or whether it lation (OR 0.19, 95% CI: 0.14–0.24) [18] . This low- was designed to promote weight loss or prevent er rate is partly attributable to an increased sever- weight gain. Out-patient interventions appeared ity of nicotine dependence, fewer attempts to stop more effective than in-patient settings. The meta- smoking, lower motivation to quit and less access analysis acknowledges a number of limitations of to interventions [36, 37]. However, the rates of the trials, including the small numbers of partici- smoking cessation in people with schizophrenia pants and the lack of long-term follow-up. Most can be increased with appropriate support [38] . studies do not extend beyond 12 weeks and hence The three main pharmacotherapies are nico- their applicability to the long-term nature of tine replacement therapy, the antidepressant bu- schizophrenia remains uncertain. The few studies propion and the nicotinic receptor partial agonist reporting long-term effects suggest that these varenicline. Of these, bupropion is both safe and may be persistent after the end of the programme effective in increasing the rates of abstinence in for up to 1 year, but others suggest that long-term people with schizophrenia. A meta-analysis behaviour change is difficult to achieve [41] .

Cardiovascular Disease and Severe Mental Illness 61

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 54–65 ( DOI: 10.1159/000365531 ) There are several longer-term observational were not imposed on patients by healthcare pro- studies of the effects of weight management professionals, but were chosen by the participants grammes. Menza et al. [42] showed that a 52- themselves. Furthermore, many of the initial week multimodal weight control programme led health behaviours, such as high intake of sugary to significant improvements in weight, BMI, gly- carbonated beverages, were readily amenable to cated haemoglobin, blood pressure, levels of exer- change. The stepwise change made the process cise and nutritional knowledge in 20 of the 31 simple, achievable and sustainable. participants who completed the programme. An- Several pharmacological agents have been tried other study of 33 people with schizophrenia in to reverse or prevent antipsychotic-induced weight Taiwan demonstrated a mean 3.7 and 2.7 kg re- gain [45] . No drug has been found to be particu- duction in body weight after 6 months and 1 year, larly effective, but a recent systematic review respectively, following a 10-week multimodal showed that there was preliminary evidence that weight control program [43] . A long-term metformin may attenuate weight gain in both (8 years) observational study of a group interven- adult and adolescent patients taking second gen- tion demonstrated that further weight loss is eration antipsychotics [46] . The review included achievable with ongoing support [44]. In this 14 articles, 8 of which were double-blind, placebo- study of well-motivated patients, there was a pro- controlled studies. The studies lasted 8–16 weeks gressive statistically significant reduction in mean and used doses ranging from 500 to 2,550 mg daily. weight and BMI throughout the follow-up with Most of these studies showed a modest reduction no suggestion of a plateau. The mean weight loss in weight with metformin (approx. 1 kg), while was approximately 10% at 1 year (approx. 10 kg), those treated with placebo gained weight. Where it with 61% achieving a 7% weight loss. By the end was measured, insulin resistance appeared to im- of the programme, 92% (n = 130) had lost some prove in those treated with metformin. The review weight. The only predictor of weight loss was the concluded that although there was no clear sub- number of sessions attended; gender, age, diag- stantial evidence that metformin, as an adjuvant to nosis and treatment were not related to weight second generation antipsychotic use, will decrease loss. This suggests that an intervention of greater weight gain and improve metabolic effects, the re- intensity or stronger focus may be needed in peo- sults are encouraging and additional studies of ple with severe mental illness compared with the longer duration were recommended. general population. Although previous studies have suggested that lifestyle interventions are Dyslipidaemia hard to maintain in people with schizophrenia Although target levels of total cholesterol and LDL without support [41] , there may be other factors cholesterol are the same as the general population that contributed to the achieved weight loss in (<5.0 and <3.0 mmol/l, respectively), tighter goals this clinic. The model of care offered a multimod- of <4.0 and <2.0 mmol/l may be appropriate for al programme that incorporated nutrition, exer- individuals with established cardiovascular disease cise and some degree of behavioural interven- or diabetes. No cardiovascular disease outcome tions on the premise that weight management trials with statins have been performed specifically should not be viewed in isolation and is best com- in people with severe mental illness, but these bined with a holistic approach to lifestyle man- drugs are as effective in lowering total and LDL agement. The clinic first utilised a group ap- cholesterol as the general population [47] . Fur- proach as a pragmatic low cost way forward, but thermore, there is no evidence that lipid-lowering the group setting and peer support was also ap- medication is associated with suicide or traumatic preciated by many participants. Lifestyle changes deaths in people with severe mental illness.

62 Holt

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 54–65 ( DOI: 10.1159/000365531 ) Diabetes rithms as the general population, with recom- The treatment of diabetes in people with severe mended target blood pressure levels of <140/90 mental illness should follow currently available mm Hg. Patients should be advised to reduce treatment algorithms, although oral antidiabetes smoking and salt intake. European and UK agents that induce less weight gain may have ad- guidelines emphasise the need to choose antihy- vantages given the high prevalence of obesity in pertensive agents best suited to the individual pa- people with severe mental illness [48] . The addi- tient’s needs as the achieved blood pressure is tional challenges of managing comorbid diabetes more important than the agent used to achieve and mental illness, however, require close collabo- this. ration between mental and diabetes services. As hyperglycaemia is associated with an increased risk of diabetes complications, neuropathy, reti- Conclusion nopathy and nephropathy, glycaemic targets should be determined for each individual with dia- The increased rates of cardiovascular disease in betes. The precise target is dependent on a number people with severe mental illness provide a clini- of factors including disease duration, risk of hypo- cal imperative to screen and manage cardiovascu- glycaemia, life expectancy and comorbidities in- lar risk factors with a systematic approach. In the cluding macrovascular disease as well as patient at- past, the physical health needs of people with se- titude and resources; however, glycated haemoglo- vere mental illness have largely been ignored, cre- bin targets between 6.5 and 7.5% (48–58 mmol/ ating significant heath inequalities. Contrary to mol) would be usual [48] . expectation, individuals with severe mental ill- Prevention of diabetes is also an important ness are as motivated about their physical health consideration as lifestyle intervention pro- as the rest of the population, but often lack aware- grammes involving dietary modification, weight ness and fail to prioritise physical well-being [50] . loss and increased physical activity have been Providing a supportive environment in which shown to reduce the incidence of type 2 diabetes cardiovascular risk factors can be managed sys- [49] . As these programmes share many features tematically is likely to have a significant impact with lifestyle weight loss programmes used in on cardiovascular morbidity and mortality in people with severe mental illness, it is hoped that people with severe mental illness. the programmes may also lead to diabetes prevention, although this has not been formally assessed. Metformin may also be considered [10] . Disclosure Statement

Hypertension Professor Holt has lectured on cardiovascular risk in peo- The management of hypertension in severe men- ple with severe mental illness for Sanofi-Aventis, Eli Lilly, tal illness should follow the same treatment algo- Otsuka, Lundbeck and Bristol-Myers Squibb.

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Prof. Richard I.G. Holt, MA, MB, BChir, PhD, FRCP, FHEA Human Development and Health Academic Unit, Faculty of Medicine University of Southampton, University Hospital Southampton NHS Foundation Trust IDS Building (MP887), Tremona Road, Southampton SO16 6YD (UK) E-Mail [email protected]

Cardiovascular Disease and Severe Mental Illness 65

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 54–65 ( DOI: 10.1159/000365531 ) Comorbidity of Mental and Physical Illness: A Selective Review

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 66–80 ( DOI: 10.1159/000365532 )

Multiple Comorbidities in People with Eating Disorders

a, b c Palmiero Monteleone · Francesca Brambilla a b Department of Medicine and Surgery, University of Salerno, Salerno , Department of Psychiatry, c University of Naples SUN, Naples , and Department of Psychiatry, San Paolo Hospital, Milan , Italy

Abstract eating behavior often resulting in dramatic con- Eating disorders, including anorexia nervosa and bulimia sequences for the physical health of patients. nervosa, are complex psychiatric diseases characterized Anorexia nervosa is characterized by restricted by severe disturbances in eating behavior, often resulting eating, obsessive fears of being fat and the volun- in dramatic consequences for the physical health of pa- tary pursuit of thinness with an inability to tients. Even though appearing after the beginning of an maintain a normal healthy body weight. Despite eating disorder and therefore not representing their pri- increasing emaciation and a body weight below mary cause, physical impairments play an important role 85% of the ideal, individuals with anorexia are in the development of psychopathology, its course and dissatisfied with the perceived size and shape of prognosis, and in the most severe cases may also repre- their body, and engage in unhealthy behaviors to sent a significant threat to the patient’s life. They contrib- perpetuate weight loss or prevent weight gain. ute, together with suicide, to the high mortality of pa- There are two subtypes of anorexia nervosa: an- tients with eating disorders. Indeed, anorexia nervosa has orexia nervosa binge-eating/purging subtype, the highest mortality of any psychiatric diagnosis, esti- where patients engage in binge-eating/purging mated at 10% within 10 years of diagnosis, while mortal- behaviors, and anorexia nervosa restricting sub- ity for bulimia nervosa is lower, occurring at approximate- type, where patients exclusively restrict their ly 1% within 10 years of diagnosis. With a few exceptions, food intake. the physical complications resolve with the recovery of Bulimia nervosa is characterized by recurrent body weight and the discontinuation of aberrant eating episodes of uncontrolled binge eating coupled and purging behaviors. The burden of physical complica- with inappropriate compensatory behaviors, tions demands prompt clinical consideration and appro- such as vomiting, laxative abuse, food restriction priate treatment. © 2015 S. Karger AG, Basel and/or excessive exercising, in order to prevent weight gain due to the patient’s pathological fear of becoming fat. Generally, because of the inges- Eating disorders, including anorexia nervosa tion of some food in the course of bingeing, peo- and bulimia nervosa, are complex psychiatric ple with bulimia nervosa have a normal body diseases characterized by severe disturbances in weight. Anorexia and bulimia are perhaps the most Brittle hair and eyelashes and loss of hair and intriguing combinations of psychological and eyebrows are present in people with both sub- physical pathology. Even though appearing after types of anorexia nervosa, while the skin is often the beginning of an eating disorder and therefore covered by a fine, down-like hair known as ‘la- not representing their primary cause, physical nugo’, growing especially on the face, superior lip, comorbidity plays an important role in the devel- back, arms and legs. Fragile nails and a dystrophic opment of psychopathology, its course and prog- aspect of the skin, which is dry and scaling, pale nosis, possibly through the essential contribution or yellowish like old paper or brownish like dirt that nutritional alterations typical of these dis- because of cornification, occur because of nutri- eases exert on the brain biochemical function. tional deficiencies and starvation-linked hypo- The physical complications observed in eating thyroidism that develops early in the disease. The disorders have been considered a consequence of yellowish color of the skin is partly due to the hy- nutritional derangements because of the similar- percarotenemia, which is typically observed in ities with the alterations observed in simple star- people with anorexia in contrast to involuntary vation. People with bulimia are not starving, but starvation when hypocarotenemia is characteris- the loss of food from vomiting or use of laxatives, tic. In people with anorexia, the phenomenon is the biased selection of macro-/micronutrients linked to the excessive consumption of carrots, typical of the bingeing episodes, and the alterna- pumpkins and similar yellowish vegetables, but tion of gorging and severe dieting might lead to possibly also to an acquired defect in the absorp- malnutrition, resulting in some of the adverse ef- tion, use or metabolism of carotene. Skin thick- fects of simple starvation. What remain uncer- ness and median collagen content are significant- tain are the mechanisms by which starvation ly reduced. Spontaneous cuts are frequently ob- during anorexia and malnutrition with bulimia served at the corners of the lips and near the nails. induces and maintains the physical complica- The presence of skin trauma and calluses on tions of the syndromes. In particular, it is unclear the dorsal surface of hands, secondary to using why some patients show the full spectrum of the hands as an instrument to induce vomiting, is physical complications while others with a very characteristic and was first described in 1979 by similar psychopathological picture do not. More- Russell (Russell sign) [7]. The lesions appear in over, it is not clear what influence is exerted by people with anorexia nervosa binge-eating/purg- peripheral physical complications on the course, ing subtype, and can be anywhere on the dorsum response to treatments and prognosis of eating of the hand, but more frequently at the metacar- disorders. These problems must be addressed in pophalangeal joint of each finger. They rapidly the future. progress to hyperpigmentation of the calluses and This chapter provides a brief review of the scarring. It has been reported that these lesions most common physical complications occurring may disappear in the later course of the disease, as in patients with eating disorders [1–5] ( table 1 ). many patients train themselves to vomit reflex- ively. Poor wound healing is frequent. Facial dermatitis, seborrheic dermatitis and acne are occa- Alterations of Skin and Related Organs sionally observed. Peripheral edema, especially pretibial, may oc- In both subtypes of anorexia nervosa, cutaneous cur in 20% of people with anorexia mostly of the alterations occur as a consequence of starvation, restrictive subtype, often during the refeeding self-induced vomiting and abuse of purging drugs phase. A mild form may occur in people with the [6, 7] . restrictive subtype of anorexia without a clear etio-

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 66–80 ( DOI: 10.1159/000365532 ) Table 1. The most common physical complications of eating disorders

Anorexia nervosa Skin and related organs: yellow-orange dry and dystrophic skin (especially on the palmar surfaces of hands and on the plantar surfaces of feet), lanugo hair, especially on the face and on the back, brittle falling out hair, Russell’s sign Oral cavity: tooth enamel erosion, caries, gingivitis, salivary gland hypertrophy Gastrointestinal system: gastroesophageal reflux disease, esophagitis, delayed gastric emptying, esophageal erosions and ulcers, hepatomegaly, fatty liver disease, constipation, hemorrhoids, rectal prolapse Cardiovascular system: bradycardia, hypotension, tricuspid and mitral valve prolapse, arrhythmias caused by electrolyte abnormalities, electrocardiographic alterations (low voltage, prolonged QRS and QT interval, T wave and ST segment depression, T wave inversion), reduced cardiac output Skeletal system: osteopenia, osteoporosis, muscle wasting, bone fractures Metabolic changes: hypoglycemia, hypothermia, dehydration, hypercholesterolemia, ketosis, ketonuria, hyperuricemia, hypoproteinemia, metabolic alkalosis Electrolyte alterations: hypochloremia, hypokalemia, hyponatremia, hypomagnesemia, hypophosphatemia

Hematologic changes: vitamin B12 and/or iron deficiency anemia, neutropenia

Endocrine system: amenorrhea, lower T3, hypercortisolism, high GH and reduced IGF-I Bulimia nervosa Skin and related organs: dry and dystrophic skin, Russell’s sign, peripalpebral petechiae, conjunctival hemorrhages, perioral ulcerations Oral cavity: tooth enamel erosion, caries, gingivitis, salivary gland hypertrophy Gastrointestinal system: gastritis, esophagitis, esophageal erosions and ulcers, gastroesophageal reflux, dysphagia and odynophagia, inflammations of the colon, hepatomegaly, fatty liver disease Electrolyte alterations: hypokalemia Cardiovascular system: bradycardia, hypotension, cardiac arrhythmias

logical cause in those with normal plasma proteins, platelet number and increased capillary vessel and in particular albumin levels. A more severe permeability. With repeated vomiting, subcuta- form is associated with purging and chronic laxa- neous emphysema of the neck has been described, tive abuse, which leads to marked hypoprotein- in some cases associated with spontaneous pneu- emia and subsequent lowering of plasma osmotic momediastinum. pressure and passage of fluids from the vascular Stable erythema, linked to the abuse of phenol- tree into tissues. This severe form of edema is rap- phthalein-containing laxatives or ipecac, has been id in onset and may lead to life-threatening shock, reported in people with anorexia. Cutaneous al- renal infarction and cardiovascular collapse due to terations linked to vitamin deficiency, including an inability to maintain fluid volume [1] . scurvy or pellagra, have been infrequently report- In people with the binging subtype of anorex- ed. More frequent are signs of self-injury, such as ia, vomiting strain may lead to the appearance of excoriated acne and erythema ab igne. cutaneous petechiae, especially on the face, and In bulimia, lesions of the skin, hair and other an- hemorrhage of the conjunctiva, possibly linked to nexes are similar to those observed in anorexia, fragility of venous and capillary walls, reduced only occurring less frequently [8] . The most fre-

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 66–80 ( DOI: 10.1159/000365532 ) quent alteration is the Russell sign, which is due to The oral alterations reported for the binging self-induced vomiting. Peripheral edema may be subtype of anorexia are also present in bulimia seen although less frequently than in anorexia, pos- nervosa [10]. Most of the dental problems are re- sibly due to the loss of electrolytes through vomit- lated to the frequent vomiting resulting in enam- ing and the relative poor consumption of proteins el injury and dental caries, which may also be in- in these patients. Subcutaneous emphysema may duced by the ingestion of large amounts of carbo- be present secondary to recurrent severe vomiting hydrates. Enamel biopsies (postmortem) reveal a strain. Signs of self-injury are frequent. preserved thickness of the surface, with normal hardness measurements suggesting that oral hygiene and use of fluoride may minimize the ero- Oral Pathology sive effect of vomiting on tooth enamel. Sialade- nitis is extremely frequent in bulimia, and is often Dental caries is frequent in anorexia, being related related to hyperamylasemia. The phenomenon to starvation in the restricting type and to both has been attributed to excessive food intake and a vomiting and excessive carbohydrate intake in the reflex stimulation of the glands during vomiting. bingeing-purging type [9] . There is delayed formation and missing tooth enamel, as well as erosion (perimolysis) of the maxillary lingual surfaces, es- Gastrointestinal Complications pecially of the anterior teeth. A frequent oral pathology is angular cheilosis, a stomatitis character- The esophagus is frequently affected in both types ized by pallor and maceration of the mucosa at the of anorexia nervosa. Pathologies include stenosis, corners of the mouth, which may result in painful esophagitis (which causes epigastric or substernal linear fissures and consequent scars. It is mostly burning pain radiating to the jaw or down both observed in the binging subtype of anorexia, and is arms), erosions and ulcers of the gastroesopha- caused by the caustic effect of regurgitated gastric geal junction and esophageal rupture. These le- acid content, but may also be an expression of an sions are due mostly to vomiting, the frequently underlying vitamin deficiency, especially of ribo- spastic motility of the esophagus and a neuropa- flavin (B2 ) and pyridoxine (B6 ) – in this case being thy linked to vitamin deficiencies. Superior mes- seen also in the restrictive subtype of anorexia. enteric artery syndrome occurs frequently in an- Gingival health is impaired in anorexia, pos- orexia [11] . sibly due to the chronic irritation produced by the In the restrictive type of anorexia, gastric vol- regurgitated gastric acid content, often associated ume is normal or reduced, the wall’s smooth mus- with painful pharyngeal erythema. Hypertrophy cle is atrophic and atonic, and antral mobility is of the salivary glands (sialadenosis) is common in abnormally low; gastric emptying is always slow the binging subtype of anorexia, again linked to and delayed for solid food and hypertonic liquids repeated vomiting, with occlusion of the salivary [11] . These abnormalities are partly responsible ducts by fragments of nondigested food. Gener- for the postprandial early feeling of gastric fullness ally the hypertrophy is painless, mostly bilateral, and the very frequent belching observed in people and more frequent in the parotids, which may en- with anorexia. Complications secondary to bing- large up to five times their normal size. The hy- ing in the bulimic type of anorexia include gastric pertrophy of the glands may be more evident in dilatation, which is rarely associated with rupture. the case of concomitant masseteric hypertrophy, During refeeding, gastric bloating and other especially present in people with the binging sub- nonspecific abdominal discomforts usually per- type of anorexia affected by bruxism [10] . sist. Complaints of esophageal reflux may occur

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 66–80 ( DOI: 10.1159/000365532 ) even without self-induced vomiting, and is gener- probably due to reduced intragastric pressure for ally secondary to diminished competence of the a given volume and a lower gradient between the gastroesophageal sphincter. stomach and duodenum. Rectal prolapse has been Gastritis and pyloric erosions are not frequent, reported to occur secondary to constipation, laxa- but dilatation of the proximal duodenum and je- tive abuse, overzealous exercise and increased in- junum are frequently reported. Gastric perfora- tra-abdominal pressure from forced vomiting. tion is a rare complication of the restrictive type of anorexia. Constipation, mostly due to the drastically re- Hepatic and Pancreatic Pathology duced caloric intake, constantly follows weight loss in anorexia, and is generally worsened by the In both types of anorexia nervosa, deficiencies of abuse of laxatives. Abdominal pain is generally many specific food components may lead to he- diffuse but without tenderness. Decreased colonic patic abnormalities, including hepatomegaly, in- transit and pelvic floor dysfunction occur in un- creases in serum concentrations of lactate dehy- dernourished people with anorexia, and normal- drogenase, aspartate and alanine transaminase, ize after refeeding. Colonic lesions are mostly sec- and reduction of cholinesterase and plasma pro- ondary to chronic constipation and laxative abuse. teins. Diffuse liver steatosis may be observed in Inflammation, atony and dilatation and the so- the most severe forms of the disorder, occasion- called cathartic colon characterized by thinness, ally evolving in cirrhosis and disappearing with atrophy and superficial ulcers of the mucosa, re- refeeding. Lower than normal plasma concentra- tention cysts and mononuclear infiltration of the tions of glutathione are observed, with higher submucosa are very frequent observations. Occa- than normal levels of homocysteine, glycine and sionally, ischemic necrosis of the segmental ileum glutamine, which points to a decreased utilization and cecum has been reported, possibly resulting of these amino acids for glutathione synthesis and from poor blood supply linked to severe malnutri- an impairment of transsulfuration [15] . tion and dehydration. Rectal prolapse occurs, pos- Morphological and functional pancreatic ab- sibly due to constipation or increased intra-abnormalities are frequent in both types of anorex- dominal pressure from forced vomiting [12] . ia, sometimes persisting long after recovery [16] . Esophagitis, disordered esophageal motility Morphological changes include atrophy with re- including lower than normal esophageal sphinc- duced acinar cells and zymogen granules, inter pressure, relaxed sphincter pressure, reduced creases of fibrous interstitial tissue, cystic dilata- mean esophageal body contraction and ampli- tion of pancreatic ducts and diffuse calcification. tude, altered waveform morphology, and reduced The most specific functional abnormality is a re- progression occur infrequently in bulimia nervo- duction of pancreatic enzyme secretion. Amylase sa, while gastroesophageal reflux, dysphagia and and elastase-1 serum concentrations, specific in- odynophagia are often observed [13] . dices of pancreatic dysfunction, are increased. Gastric capacity is generally increased in rela- Pancreatitis may be present, but occurs more fre- tion to the frequency and severity of the binging quently during refeeding. Amylase levels are gen- and the amount of daily food intake [14] . The sen- erally elevated, correlating with vomiting fre- sation of maximal fullness occurs sooner than the quency. The occurrence of pancreatitis may be maximally tolerated gastric pain, which is mostly facilitated by the duodenal stasis followed by du- reduced. Intragastric pressure reached at maxi- odenal-pancreatic reflux. mum tolerance is normal. Gastric emptying is Similar alterations may be present in bulimia slower in bulimia nervosa than in normal subjects, nervosa [16] .

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 66–80 ( DOI: 10.1159/000365532 ) Cardiovascular Complications riod, a too rapid weight gain may lead to congestive heart failure and arrhythmias, possibly relat- Cardiovascular abnormalities occur in up to 87% ed to hypophosphatemia occurring during the of people with anorexia [17] . They include sinus first weeks of nutritional rehabilitation. bradycardia and much less frequently tachycar- Hypotension, both systolic and diastolic, of dia, ventricular arrhythmia resulting from elec- less than 90/60 mm Hg occurs in up to 85% of trolyte disturbances, lower than normal heart rate people with anorexia [20], usually as a result of variation between supine and standing posture, chronic volume depletion and orthostatic chang- lower than normal ratios of low- and mid-fre- es resulting in frequent bouts of dizziness and oc- quency to high-frequency power (which may rep- casionally frank syncope. Decreased thickness of resent a balance between the activities of the car- ventricular walls, with consequent decreased diac sympathetic symptoms), cardiac failure, re- myocardial contractility and subsequent hypovo- duced atrial and left ventricular volume, reduced lemia and reduction of cardiac cavities concur to mean cardiac output, and reduced mean ascend- decrease blood pressure. ing aortic velocity. Bradycardia of less than 60 People with bulimia may show some of the beats/min during the day and around 30 beats/ cardiovascular changes seen in anorexia nervo- min at night, related to an energy-conserving sa, but these are much less frequent and less se- slowing of the metabolic rate, is possibly linked to vere [21] . A slightly longer mean QT has been vagal hypertonus. Heart rate variability correlates reported. Hypotension is very uncommon in inversely with BMI [18] . this disorder. Arrhythmias due to electrolytic As reported in simple starvation, electrocar- disturbances may occur in people with severe diographic alterations occur frequently in people purging behaviors. with both types of anorexia [19] . They are represented by low voltage, prolonged Q time, increased QT dispersion, longer QRS intervals, a Pulmonary Disease shift to the right of the QRS axis, diminished amplitude of the QRS complex and T wave, depres- Pulmonary alterations do not occur frequently in sion of the ST tract, inversion of the T wave, oc- anorexia nervosa [22] , but can occur as a conse- casional U waves linked to hypokalemia and hy- quence of vomiting or refeeding phenomena. pomagnesemia, and premature atrial and Pneumomediastinum has been observed in the ventricular heart beats. Ventricular tachyarrhyth- bulimic subtype of anorexia with and without mias, however, are less frequent. The inversion of vomiting. The pathology is due to alveolar rupture the T wave and the prolonged Q time, which in- and subsequent tracking of air along perivascular creases the risk of tachyarrhythmias, prevail in planes to the mediastinum and subcutaneous area. people with the bingeing subtype of anorexia, Subcutaneous emphysema is diagnosed by palpa- with more severe hypokalemia and hypomagne- tion of the skin overlying the thorax, which reveals semia. Sometimes, however, electrocardiograph- a ‘crunchy’ sensation, and is also heard over the ic impairments occur also in people without evi- pericardium being synchronous to systole. During dent electrolytic alterations, possibly linked to hy- rapid refeeding, pulmonary edema may result pertonus of the central autonomic system. Most from congestive heart failure with dyspnea, or- of the electrocardiographic changes are revers- thopnea and paroxysmal nocturnal dyspnea. On ible, often improving rapidly with correction of examination, dullness to percussion of the lung electrolytic disturbances and a return to normal fields and crackles or wheeze on auscultation may nutrition and hydration. During the refeeding pe- be found.

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 66–80 ( DOI: 10.1159/000365532 ) Pulmonary alterations are infrequent in buli- and differs from that observed in simple starva- mia nervosa [22], and are linked mainly to vomit- tion, which is represented by a mix of type I and ing and ingestion of the material in the lungs or II fiber atrophy. Electromyographic studies have to a rapid increase in intra-alveolar pressure with revealed increased polyphasic potentials parallel alveolar rupture and pneumomediastinum. Pul- to increases in plasma creatinine-phosphokinase monary edema due to congestive heart failure is concentrations. Possible causes of this myopathy generally observed only in long-lasting and ex- are the reduced total body potassium levels and tremely severe cases. caloric and protein deficiency, together with increased physical activity. No muscular alterations have been reported in people with bulimia. Renal Disease When anorexia has its onset in childhood, patients have reduced skeletal growth, resulting in Impaired renal function occurs in 70% of starving short stature. Bone accretion and maturation, people with anorexia, with alterations of glomer- characteristic of adolescence, are generally re- ular filtration rate and concentration capacity, tarded, and bone maturation may even totally acute or chronic renal failure, increased blood cease during active phases of the disease [24] . urea, pitting edema, hypokalemic nephropathy, Treatment and weight restoration induce a pyuria, hematuria, and proteinuria. An increased growth catch-up, which, however, does not reach risk of urolithiasis has been noted, possibly linked the expected growth rate. Around a quarter to a to a combination of high dietary oxalate intake third of people with anorexia suffer from osteo- (from tea, spinach, rhubarb, almonds and cashew porosis, represented by reduced peak bone mass, nuts), chronic dehydration, low urinary excretion decreased mineral density, decreased total body and purging. Hypokalemic nephropathy due to mineral content, pathological fractures and verte- the chronic abuse of diuretics or laxatives may oc- bral collapse. These alterations correlate with ill- cur. This pathology can lead to chronic renal fail- ness duration and BMI. It is not clear whether ure with polyuria, polydipsia and increased se- strenuous weight-bearing exercise can improve rum creatinine concentration. High serum levels bone density in people with anorexia. Osteoporo- of uric acid have been seen and along with in- sis and osteopenia also occur in men with anorex- creased creatinine are considered a poor prog- ia, but with greater severity than in women. Bilat- nostic feature of the disease [22] . eral osteonecrosis of the talus has been reported Renal impairment is not frequent in bulimia in anorexia [25] . nervosa [22] , unless the pathology is extremely Increased bone fractures are also observed in severe; in such cases, abnormalities similar to an- bulimia, although less frequently than in anorex- orexia are seen. ia. It is unknown whether the phenomenon is related to osteoporosis (which generally has not been demonstrated in bulimia) or to increased Musculoskeletal Abnormalities behavioral impulsivity [26] .

The most common alterations of the muscular system observed in people with anorexia are mus- Hematological Changes cular weakness, hypotonia and atrophy, which become evident when starvation is markedly se- In two thirds of patients with anorexia, neutro- vere [23] . A primary myopathy with prominent penia and reduced monocytes occur, with white atrophy of type II fibers is the major abnormality blood cell numbers lower than 5,000/mm3 . Rel-

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 66–80 ( DOI: 10.1159/000365532 ) ative lymphocytosis and multilobular polymor- inversely correlated with the degree of weight phonuclear leukocytes are very frequently seen. loss. Glucose ingestion results in prolonged insu- This alteration could result from bone marrow lin peaks [28] . hypoplasia and its gelatinous transformation Lipid alterations occur in 50% of people with with markedly reduced cell production. Gelati- anorexia, with hypercholesterolemia linked to an nous transformation and cellular necrosis de- increase in LDL cholesterol and elevated fasting rive from insufficient medullar nutrition, the free fatty acid concentration [29] . The cholester- former occurring when the caloric deficiency ol alteration does not correlate with thyroid dys- develops gradually and the latter when the star- function, severity of weight loss, type of food vation is acute and extremely rapid, or when consumption, vomiting or laxative abuse. It may other threatening events (e.g. a severe infection) be related to diminished activity of the occur concomitantly. People with anorexia may 5-α-reductase enzyme system. Decreased con- have bone marrow suppression secondary to centrations of n–6 polyunsaturated fatty acids excessive consumption of phenolphthalein- have been found. Plasma levels of HDL choles- containing laxatives. The alteration disappears terol, VLDL cholesterol and triglycerides are with normal nutrition and weight recovery [23, normal or increased. 27] . Hypercholesterolemia has been observed in Anemia, usually of the normochromic and bulimia [1] . normocytic type with preserved hemoglobin, is People with anorexia generally have a re- observed in at least one third of people with an- duced concentration of total blood proteins orexia [27]. Occasionally, macrocytic anemia [15] . In particular, globulin levels, more than may be observed, with elevated mean cell volume albumin, are lower than normal. Muscular due to vitamin B 12 deficiency. Acanthocytosis, a mass destruction, typical of the disease, is re- disorder of the red blood cell membrane, is also sponsible for protein catabolism. Dehydration, observed and is likely linked to abnormalities of hypovolemia, diminished plasma renal flow cholesterol metabolism. Iron deficiency anemia and diminished glomerular filtration induce an occurring in anorexia may be normochromic increase of serum urea. Reduced urinary excre- when hemoglobin is above 11 g/dl, or microcytic, tion of methylhistidine, a specific index of hypochromic and with anisocytosis when hemo- muscular catabolism, has been observed. Very globin is below 11 g/dl. Thrombocytopenia has low albumin levels seem to be highly predictive been described in nearly one third of people with of death. Reduced blood levels of the essential anorexia. Purpura and petechiae are infrequent in amino acids, threonine, valine, isoleucine, leu- anorexia. cine, and normal or reduced tryptophan levels People with bulimia do not seem to have sig- (including normal or reduced tryptophan to nificant hematological abnormalities. neutral amino acid ratio) have been reported. The tryptophan/neutral amino acid ratio seems to be higher in people with anorexia who are Metabolic Changes actively exercising. Uric acid is often elevated as an expression of strenuous physical activity In anorexia, glucose metabolism is impaired and, combined with starvation resulting in muscle even though glucose concentration may be low- destruction. normal, the glucose response to a glucose toler- No significant protein alterations have been ance test is diabetic-like or flat. Insulin and gluca- observed in bulimia nervosa. gon concentrations are normal or reduced, and

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 66–80 ( DOI: 10.1159/000365532 ) Electrolyte and Vitamin Alterations and 24,25-dihydroxyvitamin concentrations are reduced while vitamin D-binding protein values In anorexia, electrolytic alterations occur fre- are normal. quently as a consequence of starvation and malnutrition, vomiting, and laxative and diuretic abuse, with ensuing fluid depletion and hypovo- Endocrine Consequences lemia [30, 31] . Hypokalemia, hypochloremia and hypochloremic metabolic alkalosis with in- Hypothalamic-Pituitary-Gonad Axis creased pCO2 are the most frequently observed Amenorrhea is the most frequent clinical endo- alterations. Phosphate and calcium concentra- crine alteration occurring in underweight wom- tions are generally normal, but vomiting, diar- en with anorexia, and has long been considered rhea and abuse of diuretics may result in severe a key criterion for the diagnosis of anorexia [34, hypophosphatemia, which may also be seen dur- 35] . Only recently has it been excluded from the ing refeeding as a result of transfer of phosphate definition of the disorder in the fifth edition of into cells for phosphorylation of glucose and for the Diagnostic and Statistical Manual of Mental protein synthesis. A quarter of people with an- Disorders, since it has been recognized that orexia [32] develop hypomagnesemia, refractory menstruation may still occur even in severely hypocalcemia caused by increased urinary cal- malnourished patients or, on the contrary, it cium excretion with renal calculi production, may be absent even when body weight is nor- and hypokalemia, which return to normal after mal. Hypogonadotropic hypogonadism with re- magnesium replacement. Iron deficiency and duced secretion of luteinizing hormone (LH), decreased total iron-binding capacity may oc- follicle-stimulating hormone (FSH), estrogens cur, generally as a consequence of a lack of iron- and progesterone are at the basis of amenorrhea. rich foods. Zinc is low in plasma, urine and tis- In the acute phase of anorexia, circadian gonad- sues linked to the duration and severity of the otropin secretion is similar to that of the prepu- disease, and zinc deficiency is due to starvation, bertal stage, with secretory pulses almost com- reduced intestinal absorption of the metal or in- pletely absent during the day and occasionally creased excretion through sweating. Zinc defi- present at night. The hypothalamic-pituitary- ciency per se induces anorexia with related gonad (HPG) axis response to the administra- weight loss, delayed growth and sexual develop- tion of the gonadotropin-releasing hormone ment, depressed mood, loss of taste, hair loss, (GnRH) results in low or absent secretion of LH and skin alterations resembling those of anorex- and FSH (with a preponderance of the FSH re- ia. All metal alterations normalize after nutri- sponse over the LH), as occurs before pubertal tional rehabilitation. maturation. Since estrogens are synthesized Hypercarotenemia, normal plasma levels of from androgens in the fat tissue and exert a pos- vitamin A binding protein and retinol-binding itive feedback on hypothalamic GnRH secre- protein are observed especially in the restrictive tion, a critical minimum amount of fat tissue subtype of anorexia following severe starvation seems to be necessary for normal HPG axis and weight loss [33]. Riboflavin and pyridoxine functioning [36] . Therefore, in low-fat tissue pa- deficiencies have been reported. Vitamin B 12 and tients with anorexia, a lack of aromatization of folate concentrations in blood are generally low. androgens to estrogens, with a consequent hy- Vitamin B 12 and vitamin C-related pellagra and poestrogenemia is probably responsible for scurvy have been infrequently reported. Blood HPG axis dysfunction. However, since in some 25-hydroxyvitamin D, 1,25-dihydroxyvitamin women amenorrhea precedes weight loss or per-

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 66–80 ( DOI: 10.1159/000365532 ) sists after the recovery of body weight [37] , fac- mone (TRH) is normal. Paradoxical responses tors other than weight changes may be involved to both GnRH and GHRH have been detected in in the HPG axis dysfunction, including the ex- the acute phase of the disease [41] . aggerated physical activity of some women with Normal, decreased or increased baseline pro- anorexia. Indeed, in female athletes, menstrual lactin levels can be observed in people with buli- dysfunction has been found to correlate with the mia, with a prolactin response to TRH that is gen- intensity of physical exercise rather than with fat erally normal [41] . mass. Men with anorexia nervosa are characterized Hypothalamic-Pituitary-Thyroid Axis by low levels of testosterone and LH, but normal In acutely ill patients with anorexia, triiodothy- response of the HPG axis to the administration of ronine (T3 ) levels are lower than normal, re- GnRH [38, 39]. Moreover, the exocrine testis versed T3 (rT 3) levels (which are biologically in- function seems to be preserved as suggested by active) are increased, and thyroxine and thyroid- the occurrence of normal blood concentrations of stimulating hormone (TSH) levels are normal inhibin B, which is a marker of gonadal exocrine [42] . The lower T 3 levels have been attributed to activity [39] . Therefore, in men with anorexia a reduced peripheral deionization of thyroxine nervosa, malnutrition seems to have less impact with a simultaneous increased formation of rT3 , on the gonadal axis. which delineates a ‘low T3 syndrome’. This rep- Oligomenorrhea or amenorrhea occur in al- resents a metabolic adaptation to the chronic re- most half of women with bulimia [35] , especially duction in caloric intake since it decreases rest- when there is a chronic course of bulimic ating energy expenditure [43] . In spite of the re- tacks. Normal or decreased levels of plasma go- duced secretion of T3 , TSH is not increased in nadotropins, with reduced circadian pulsatility, acutely ill patients with anorexia. This could be and diminished concentrations of estrogens and due to the fact that during low-energy expendi- progesterone may be observed. LH secretion is ture, a reduction in endogenous metabolic pro- more deranged in its amplitude than in the fre- cesses occurs in all cells of the organism, includ- quency of secretory pulses, and the LH response ing pituitary thyrotropes, which respond as if the to GnRH is normal or even enhanced. These ir- low T3 levels are sufficient for metabolic needs; regularities have been ascribed to food deficien- in such a condition, TSH secretion does not in- cy and especially to protein malnutrition. In ad- crease. Even if TSH secretion is unaltered in an- dition, since binging episodes increase plasma orexia, its central regulation is deranged. The prolactin levels, it is possible that repeated hy- TSH response to exogenous TRH is delayed and perprolactinemia could impair HPG axis activi- sometimes lower than normal. Finally, atrophy ty due to the inhibitory action of this hormone of the thyroid gland may occur in underweight on GnRH release. people with anorexia. This alteration has been related to the low insulin-like growth factor-I Hypothalamic-Prolactin Axis (IGF-I) levels since thyroid size is clearly influ- Normal baseline concentrations of prolactin are enced by this peptide. generally observed in people with anorexia, even Basal thyroxine and T3 concentrations are pre- though slightly reduced or increased plasma lev- served in people with bulimia, even though low els may be found [40]. Normal diurnal and in- circulating T 3 levels have been observed. Baseline creased nocturnal concentrations of prolactin concentrations of TSH are mostly normal in bu- have been observed in acutely ill patients. The limia, whereas the TSH response to TRH can be prolactin response to thyrotropin-releasing hor- found to be either normal, blunted or delayed [1] .

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 66–80 ( DOI: 10.1159/000365532 ) Hypothalamic Growth Hormone-IGF-I Axis administration. Moreover, it has been shown that In emaciated people with anorexia, plasma levels the recombinant human GH in people with an- of growth hormone (GH) are increased and the orexia achieves medical and cardiovascular sta- plasma concentration of IGF-I and GH-binding bility more rapidly [47] . protein is reduced [44] . The concentration of the Normal or increased GH levels with a normal IGF-binding proteins, especially that of the IGF- circadian rhythm are reported in people with bu- binding protein-3, is reduced during starvation, limia, while circulating IGF-I is reduced [1] . although increased levels of circulating IGF- binding proteins resulting in a decrease of free Hypothalamic-Pituitary-Adrenal Axis IGF-I have also been reported [45] . In under- Abnormalities of the hypothalamic-pituitary-ad- weight people with anorexia, the decreased IGF- renal (HPA) axis are frequently present in people I production increases GH secretion because of with anorexia, including increased plasma levels diminished negative feedback. Concomitantly, of cortisol with normal blood concentrations of primary or secondary hypothalamic or suprahy- adrenocorticotropic hormone (ACTH), and in- pothalamic changes may further affect GH pro- creased urinary cortisol levels in the acute phase duction. Increased GH levels correlate negatively of the disease [48]. The circadian rhythm of with the amount of calories ingested and de- ACTH is well preserved, but plasma cortisol con- crease with improved nutritional intake even be- centrations are higher than normal throughout fore significant weight recovery has taken place. the day and have an increased number and ampli- Since GH-binding protein represents the GH re- tude of cortisol secretory bursts, especially during ceptor extracellular domain, its reduced blood the middle afternoon when values of the hor- levels mirror a reduced sensitivity to GH. The mone should be at their lowest point. These data decrements of IGF-I and GH-binding protein in suggest that the HPA axis in the acute phase of severely undernourished people with anorexia, anorexia is hyperactive. Dynamic studies of HPA an expression of a resistance to GH, are probably axis function tend to demonstrate that hypotha- the reason why GH hypersecretion in these indi- lamic and/or suprahypothalamic alterations may viduals does not result in acromegalic symptom- cause the higher than normal activity of the axis atology. [49]. Indeed, most people with anorexia cannot The hypothalamic GH-IGF-I axis dysregula- suppress cortisol production during the dexa- tion may contribute to the development of osteo- methasone suppression test; the cortisol respons- penia since IGF-I has a trophic effect on the bone. es to ACTH stimulation are enhanced while the In prepubertal subjects, the ‘resistance’ to GH ACTH response to corticotropin-releasing factor may be one of the causes for the growth delay or (CRF) is reduced/normal in underweight individ- cessation persisting following treatment, result- uals with anorexia [50] . Since these alterations re- ing in a final height lower than that genetically vert with the recovery of body weight, they are determined [46] . Recombinant human IGF-I or considered a consequence of malnutrition, al- GH have been used in people with anorexia to though this is controversial [51]. In experimental prevent bone loss or bone fractures, and to facili- animals, CRF provokes anorexia, increased phys- tate a more rapid metabolic recovery. Recombi- ical activity and reduced sexual behavior, which nant human IGF-I in severely osteopenic women would support a role for this peptide in the devel- with anorexia increases bone turnover markers in opment and/or maintenance of some anorexic the short term, leading to amelioration of bone symptoms. Clinically, it is intriguing that the hy- density after 9 months, with the latter effect being percortisolemia of people with anorexia never potentiated by concomitant oral contraceptive leads to the development of Cushingoid features.

76 Monteleone · Brambilla

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 66–80 ( DOI: 10.1159/000365532 ) The adrenal glands also secrete androgen de- Table 2. Main signs and symptoms of the physical com- hydroepiandrosterone (DHEA) and DHEA sul- plications of anorexia and bulimia nervosa fate (DHEAS) under the regulation of the CRF- Anorexia nervosa ACTH system. Evidence for a decreased produc- Signs tion of both DHEA and DHEAS in underweight Hypothermia people with anorexia has been widely reported, Bradycardia (<60 beats/min) with a dissociation in the adrenal secretion be- Hypotension (<90 mm Hg systolic pressure) Dry skin tween cortisol and androgen similar to that ob- Brittle hair served in the pubertal stage of sexual maturation Brittle nails [52] . This suggests that people with postpubertal Hair loss acute anorexia may regress to a prepubertal secre- Yellow-orange dry and dystrophic skin (especially on the palmar surfaces of hands and on the plantar tory aspect of the reproductive axis (see below), surfaces of feet) also affecting the HPA androgen system. This re- Lanugo hair duction, together with the increase in cortisol lev- Edema (ankles, around eyes) els, leads to decreased DHEA to cortisol and Cardiac murmur (caused by mitral prolapse) Symptoms DHEAS to cortisol ratios similar to that occurring Amenorrhea in the pubertal stage of sexual maturation [53] . Fatigue In people with bulimia, HPA axis activity is Faintness only slightly altered, with morning plasma corti- Dizziness sol concentrations either normal or increased, Abdominal pain Sensation of fullness while urinary excretion of free cortisol and 17-hy- Polyuria droxycorticosteroids as well as cortisol responses Cold intolerance to CRF or ACTH are normal. The most widely Constipation reported alteration of the HPA axis in bulimia is Polydipsia the nonsuppression of cortisol to a dexametha- Bulimia nervosa sone challenge in 20–60% of patients, without sig- Signs Russell’s sign (calluses on knuckles) nificant correlations with severity and chronicity Salivary gland hypertrophy of the illness, concomitant depressive symptoms, Tooth enamel erosion or previous history of anorexia. This alteration Perioral ulcerations disappears after successful treatment of bulimia, Petechiae and is not predictive of treatment outcome [54] . Lanugo hair Hematemesis (vomiting of blood) Edema (ankles, around eyes) Abdominal bloating Conclusions Dysregulated heart beat Symptoms Dysregulated menses In people with eating disorders, physical compli- Heart palpitations cations are very common and usually occur as Esophagus burning pain consequences of nutritional derangements sec- Abdominal pain ondary to aberrant eating and abnormal com- Abdominal bloating Faintness pensatory behaviors. In the most severe cases, Constipation or diarrhea these complications represent a significant Hands and feet swelling threat to the patient’s life. In emaciated people Sensitive teeth with anorexia, especially in those who vomit and/or abuse diuretics and laxatives, immediate

Somatic Complications in Eating Disorders 77

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 66–80 ( DOI: 10.1159/000365532 ) risks come from electrolytic perturbations and Although, with a few exceptions, physical starvation-induced cardiovascular and renal complications resolve with the recovery of body complications. These complications may lead to weight and the discontinuation of aberrant be- the development of severe arrhythmias and sud- haviors, they contribute, together with suicide, to den death. Individuals with a chronic course of the high mortality of patients with eating disor- anorexia are exposed to consequences of the ders. Indeed, anorexia has the highest mortality of progressive impairment in bone density, which any psychiatric diagnosis, estimated at 10% with- increases the likelihood of pathological frac- in 10 years of diagnosis, and is the leading cause tures. On the other hand, some of the somatic of death in young females 15–24 years of age. alterations occurring in the acute phase of an- Mortality for bulimia is approximately 1% within orexia seem to have a protective effect. Indeed, 10 years of diagnosis. It is important to remember in emaciated people with anorexia, the impaired that even if most of the physical complications of function of the reproductive axis and the re- eating disorders do not represent life-threatening duced activity of thyroid gland aim to preserve conditions, they increase the patients’ burden of residual energy stores for vital functions and re- suffering, impair their quality of life and, there- duce basal metabolic needs. fore, need clinical consideration and appropriate In bulimia, physical complications are less se- treatment. Therefore, psychiatrists who have pa- vere and occur less frequently than in anorexia. tients with anorexia nervosa and bulimia nervosa Therefore, they rarely represent a serious threat should be alerted to identify those signs and to the patient’s life. The most harmful complica- symptoms that express malnutrition-related tions are represented by esophageal and/or gas- physical complications ( table 2 ) and collaborate tric ruptures, secondary to the massive ingestion with medical experts who specialize in the treat- of food in the course of binge episodes, and car- ment of physical alterations. This will ensure the diac arrhythmias induced by severe electrolytic simultaneous correction of psychopathological imbalance following vomiting and diuretic or lax- and physical aberrations in order to obtain a full ative abuse. and fast recovery from the diseases.

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Palmiero Monteleone, MD Department of Medicine and Surgery University of Salerno Via S. Allende, IT–84081 Baronissi, Salerno (Italy) E-Mail [email protected]

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 66–80 ( DOI: 10.1159/000365532 ) Comorbidity of Mental and Physical Illness: A Selective Review

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 81–87 ( DOI: 10.1159/000365538 )

Anxiety and Related Disorders and Physical Illness

a b Catherine Kariuki-Nyuthe · Dan J. Stein a Eastern Health Outer East Mobile Support and Treatment Service, Ringwood East, Vic. , Australia; b Department of Psychiatry and Mental Health, University of Cape Town, Cape Town , South Africa

Abstract deed, these anxiety and related disorders occur Anxiety and related disorders are the most prevalent frequently with a range of general medical disor- mental disorders in the general population. There is a ders [4, 5], including gastrointestinal disease [6] , strong bidirectional association between anxiety and re- pulmonary disease [7, 8] , cardiovascular disease lated disorders and co-occurring general medical condi- [9], endocrine disorders [10] , dermatological dis- tions. The co-occurrence of anxiety and related disorders orders [11] and cancer [12] , as well as neuropsy- and general medical conditions is associated with signif- chiatric disorders such as chronic pain [13, 14] , icant impairment, morbidity and economic costs. At the migraines [15] , dementia [16] and Parkinson’s same time, recognition of anxiety and related disorders disease [17] . In this chapter we review the epide- in people with medical illness may be challenging when miology of comorbid anxiety and related disor- comorbid with physical illness due in part to overlap in ders and physical illness, the growing evidence of symptomatology. Furthermore, there is a relatively lim- a bidirectional relationship between these sets of ited evidence base of randomized controlled trials in this conditions [18] and relevant randomized con- population. Additional work is needed to improve screen- trolled trials in this area. ing for anxiety and related disorders in medical illness, to enhance diagnosis and assessment, and to optimize treatment. © 2015 S. Karger AG, Basel Epidemiology

Anxiety and related disorders are the most com- Anxiety disorders, obsessive-compulsive and re- mon psychiatric disorders worldwide, with a lated disorders, and trauma- and stressor-related 12-month prevalence worldwide of between 4 disorders are the most prevalent psychiatric dis- and 20% [2] . The onset of anxiety and related disorders in the general population [1, 2] , with gen- orders usually happens in childhood or adoles- eralized anxiety disorder the most common anxi- cence, with many individuals first presenting ety disorder in primary care populations [3] . In- with physical symptoms in primary care settings Table 1. Common medical conditions associated with anxiety

Endocrine disorders diabetes mellitus [32], thyroid disease [10], catecholamine-secreting pheochromocytoma Gastrointestinal peptic ulcers [27], celiac disease [33], irritable bowel syndrome [26] disorders Musculoskeletal disorders fibromyalgia/chronic fatigue syndrome [34], arthritis [35] Neurological disorders migraines [15], epilepsy, neurodegenerative illness [17] Cardiorespiratory disease asthma [30], angina [25], chronic obstructive pulmonary disease [7], mitral valve prolapse [36], cystic fibrosis [8], obesity [24, 37, 38] Chronic pain burns [14], cancer [12] Infectious disease HIV [39], tuberculosis [39]

[4]. Anxiety and related disorders are prevalent conditions associated with anxiety symptoms throughout life [19–22]. Furthermore, while the and disorders. prevalence of comorbid anxiety and related disor- The co-occurrence of anxiety and general ders in those with chronic medical illness is not as medical conditions is associated with significant well studied as depression in medical conditions, impairment, morbidity and economic costs [36, studies which have been done indicate it is as 40–42]. For example, in a study of almost 500 common [22–25] . A large cross-sectional study medically ill persons diagnosed with anxiety dis- demonstrated that generalized anxiety disorder orders, those with posttraumatic stress disorder, was the most prevalent anxiety disorder in pri- panic disorder and social anxiety disorder were mary care settings [3] . found more likely to be frequent consumers of Systematic reviews have established that anxi- healthcare, and to remain unable to maintain ety disorders are particularly prevalent in gastro- their roles and responsibilities, including work intestinal disorders, pulmonary disease, cardio- [43] . Medical comorbidities with anxiety disor- vascular disease, endocrine disease and cancer, as ders have also been shown to elevate suicide risk well as neuropsychiatric disorders such as chron- [44] . Adequate management of anxiety symp- ic pain and migraines. In irritable bowel syn- toms can improve outcomes of physical ill-health, drome, up to 95% of patients have generalized and reduce the use of healthcare resources [4, 45] . anxiety disorder or panic disorder [26] . Similar- In addition, some work suggests that quality of ly, panic disorder and generalized anxiety disor- life and functional ability may be improved with der were more prevalent in those with peptic ul- optimal treatment of comorbid general medical cer disease [27] . In asthma, anxiety disorders oc- and anxiety disorders [46–48] . cur in at least 25% of patients [28, 29] . In multiple studies of adolescents and adults with asthma, the prevalence of panic disorder and agorapho- Etiology bia is almost three times that of the general population [30, 31]. Another anxiety disorder that co- There is a growing body of evidence for a strong occurs with respiratory illness is generalized anx- bidirectional association between anxiety and re- iety disorder [31] . Table 1 outlines medical lated disorders and co-occurring general medical

82 Kariuki-Nyuthe · Stein

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 81–87 ( DOI: 10.1159/000365538 ) conditions [14, 29, 49] . On the one hand, medical conditions. A medical condition can be sufficient disorders may lead to fears about diagnosis, hos- enough to be a stressor for an individual to de- pitalization, painful procedures and a foreshort- velop an adjustment disorder, and in some cases ened lifespan, while certain medical disorders even posttraumatic stress disorder. Secondly, may be linked physiologically to the development anxiety symptoms may overlap with symptoms of of anxiety and related disorders [50] . On the oth- an underlying medical disorder; thus, since pa- er hand, anxiety and related disorders may lead to tients with cancer may have insomnia and fatigue, vulnerability for various medical conditions. conditions such as generalized anxiety disorder There may also be underlying factors that con- are overlooked. Similarly, medications used in the tribute to susceptibility for both anxiety disorders treatment of physical disorders may lead to anxi- and physical conditions [51] . ety symptoms [20, 49, 58] . There is ongoing work to determine the pre- In a patient with anxiety symptoms, a range of cise nature of the relationships between anxiety different diagnoses can be considered. Table 2 disorders and physical illness in a number of ar- tabulates the main features of key anxiety and re- eas. Thus, in irritable bowel syndrome, it has been lated disorders. Posttraumatic stress disorder is suggested that infection or inflammation of the the anxiety and related disorder that is most com- gastrointestinal tract lead to anxiety [29] , while in monly associated with gastrointestinal, cardiac, asthma it has been postulated that increased par- endocrine, chronic pain, migraines and Parkin- tial pressure of carbon dioxide is responsible for son’s disease [14, 22]. Symptoms of generalized panic attacks [52] . On the other hand, neurotrans- anxiety disorder arguably most closely resemble mitter disturbances and hypothalamic-pituitary- those of many general medical conditions, par- adrenal axis dysfunction have been postulated to ticularly in the older population [20]. Panic disor- play a key role in explaining how anxiety symp- der may, however, mimic a number of physical toms and disorders lead to medical illnesses [53] . illnesses. Indeed, a broad range of different anxi- The common underlying factors that may ety and related disorders have been associated contribute to both anxiety disorders and comor- with various physical illnesses. bid physical illness have also received ongoing study. Genetic factors may, for example, predispose to both general medical conditions and anx- Management iety disorders [54, 55] . In the World Mental Health Surveys, there were strong relationships Early identification of anxiety symptoms and dis- between early adversity and subsequent onset of orders in individuals with chronic illness is im- both anxiety disorders and various physical dis- portant in determining better outcomes for indi- orders, including chronic spinal pain, chronic viduals with both sets of disorders [60–62] . The headache, heart disease, asthma, diabetes and hy- therapeutic alliance and collaboration between pertension [56, 57] . medical professionals may contribute to successful management of symptoms [50]. There is, however, a paucity of robust evidence in the treat- Clinical Features ment of chronically ill patients with comorbid anxiety and related disorders [51] . Recognition of anxiety disorders in people with Cognitive behavioral therapy has been un- medical illness can be challenging for several rea- dertaken in a number of studies of individuals sons. Firstly, anxiety symptoms are an under- with medical illness and anxiety and related dis- standable response to the diagnosis of medical orders. A systematic review of 32 psychotherapy

Anxiety and Related Disorders and Physical Illness 83

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 81–87 ( DOI: 10.1159/000365538 ) Table 2. Anxiety and related disorders commonly seen in medically ill adult patients [14, 59]

Generalized anxiety characterized by a pervasive and excessive worry about everyday life events; this disorder worry is difficult to control and is accompanied by somatic symptoms which impair the individual’s functioning Specific phobia characterized by excessive, irrational and persistent fear of specific objects, situations or activities such as heights, flying and spiders Social anxiety disorder characterized by an intense and excessive fear of scrutiny and humiliation in social situations which then leads to avoidance of these situations, or development of panic attacks when the situations are endured Panic disorder characterized by recurrent unexpected panic attacks described as discrete events in which the individual experiences symptoms that peak within a few minutes and resolve spontaneously, coupled with anticipatory anxiety about future panic attacks Posttraumatic disorder a disorder in which the individual experiences a traumatic event; the disorder is then characterized by recurrent distressing re-experiencing phenomena, increased arousal, persistent avoidance of reminders and stimuli associated with the event, and negative cognitions and mood Hypochondriasis characterized by preoccupation with having a severe disease; the individual cannot be reassured despite medical investigations Obsessive-compulsive characterized by recurrent intrusive distressing thoughts or images (obsessions) disorder which are neutralized by some other thought or repetitive mental act/behavior (compulsions) Substance/medication- characterized by anxiety symptoms which are directly related to the physiological induced anxiety disorder effects of a substance or medication Adjustment disorder characterized by a time-limited, maladaptive anxiety response to an identifiable with anxiety stressor Separation anxiety characterized by excessive, developmentally inappropriate anxiety upon separation disorder of the child from the home or from significant attachment figures Anxiety disorder not diagnosed when the individual’s symptoms are severe and distressing but do not otherwise specified meet diagnostic criteria for any other anxiety disorder

trials in patients with irritable bowel syndrome Behavioral strategies in anxiety disorders and and anxiety disorders indicates the efficacy of comorbid medical illnesses include biofeedback, cognitive behavioral therapy in reducing somat- relaxation training and meditation [68, 69] . Two ic distress [63–65] . A systematic review of 20 randomized controlled trials examining the ef- studies of cognitive-behavioral interventions in fects of biofeedback in the management of asth- nearly 3,000 participants found that they may be ma [69] , and another two randomized controlled effective in the management of HIV-/AIDS-as- trials looking at relaxation therapy showed a re- sociated anxiety [66]. Cognitive behavioral ther- duction in the use of bronchodilator agents and apy has also been shown to reduce anxiety symp- improved quality of life [70] . toms and distress in patients with cardiac disease Hypnotherapy and interpersonal therapy are and anxiety in one randomized controlled trial other treatment modalities showing promise in [67] . the management of pain related to procedures for

84 Kariuki-Nyuthe · Stein

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 81–87 ( DOI: 10.1159/000365538 ) cancer therapies [71, 72] , but rigorous studies are cious in the treatment of some anxiety and related lacking in this area [14, 64] . disorders [50], but its metabolic, cardiac and au- In patients with physical illness and anxiety tonomic side-effect burden should be taken into and related disorders, there are relatively few ran- consideration. domized controlled trials to guide treatment choices. Thus, medications should be selected based on studies of efficacy in anxiety disorders, Conclusion and on minimizing adverse events and drug-drug interactions. The selective serotonin reuptake in- Anxiety and related disorders are frequently co- hibitors sertraline, citalopram and escitalopram morbid with chronic medical conditions. There is have relatively few adverse events and are safe in growing understanding of the bidirectional rela- interaction with other agents [73]. The serotonin- tionships between these sets of disorders. Recog- noradrenaline reuptake inhibitors venlafaxine nition can be delayed due to the similarity of pri- and duloxetine have the potential advantage of mary anxiety symptoms and anxiety secondary to being beneficial for pain symptoms, but venlafax- general medical conditions. Pharmacotherapy ine has the disadvantage of requiring blood pres- management can be effective, but clinicians need sure monitoring [74] . Drugs such as mirtazapine to be aware of the side-effect burden of psycho- and the tricyclic antidepressants may be effica- tropics in medical conditions as well as potential cious in the treatment of some anxiety disorders, drug-drug interactions. There is a growing data- but carry a significant side-effect profile and may base of studies of cognitive-behavioral therapy have worrisome drug-drug interactions [74] . showing efficacy in individuals with anxiety dis- Benzodiazepines and sedative-hypnotic agents orders and comorbid medical illness. Further may be helpful for anxiety symptoms, but should work is needed to improve screening for anxiety be used cautiously due to concerns of dependence and related disorders in medical illness, to en- [6] . The second-generation antipsychotic que- hance diagnosis and assessment, and to optimize tiapine is anxiolytic at low doses, and is effica- treatment.

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Dan J. Stein, BSc (Med), MBChB, FRCPC, FRSSAf, PhD, DPhil Department of Psychiatry and Mental Health, University of Cape Town Anzio Road, Rondebosch 7700 Cape Town (South Africa) E-Mail [email protected]

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 81–87 ( DOI: 10.1159/000365538 ) Comorbidity of Mental and Physical Illness: A Selective Review

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 88–98 ( DOI: 10.1159/000365541 )

Cancer and Mental Illness

a a b David Lawrence · Kirsten J. Hancock · Stephen Kisely a Telethon Kids Institute, Centre for Child Health Research, The University of Western Australia, b West Perth, W.A. , School of Medicine, The University of Queensland, Brisbane, Qld. , Australia

Abstract Overview of Excess Mortality and Mental Over many years, it has been shown that cancer repre- Illness sents a significant proportion of excess mortality for people with mental illness. In this chapter, we probe this re- It is well known that people with mental illness lationship in more detail, and examine the progression have higher mortality rates and reduced life ex- of factors that play a role in this finding. Against expecta- pectancy compared to people without mental ill- tions, people with mental illness are no more likely to ness. Our own work using record linkage systems develop cancer, even though they have higher exposure in Western Australia has shown that the gap in to major risk factors including smoking, drug and alcohol life expectancy for people with and without men- use, and obesity. However, even though people with tal illness has increased since 1985, to 12 years for mental illness are just as likely to be diagnosed with can- women and 16 years for men, principally because cer, they are more likely to die from it. The reasons for improvements in life expectancy for the general this are multifactorial, including lower rates of routine population have not extended to people with cancer screening (either because it is not recommended mental illness [1] . or people with mental illness do not follow through on While mental illness is associated with an in- the recommendation to do so), the increased length of creased risk of suicide, much of the excess mortal- time it takes to be diagnosed after presenting with symp- ity associated with mental illness is actually due to toms, more advanced stage at diagnosis including meta- common physical health conditions, in particular static cancer at diagnosis, and reduced likelihood of cardiovascular disease, respiratory diseases and surgical intervention. We discuss the complexities asso- cancer [1, 2]. With a particular focus on cancer – ciated with providing medical care for people with co- the topic of this chapter – we have previously re- morbid psychiatric disorders and the difficulties faced ported that cancer diagnosis rates are comparable both by people with mental illness and the people who between people with and without mental illness; provide them with medical care. at the same time, however, not only is case fatality © 2015 S. Karger AG, Basel after a cancer is diagnosed substantially worse in 100

Patients (%) Patients 40

Psychiatric patients, male 20 WA population, male Fig. 1. Survival since diagnosis of all Psychiatric patients, female cancers by contact with mental WA population, female health services. WA = Western 0 Australia. Reproduced with 0 1234567 permission from JAMA Psychiatry Time since cancer diagnosis (years) [3] .

people with a history of mental illness, but sur- The Evolution of Mental Illness and Cancer vival times are also much shorter (fig. 1 ) [2–4] . In Research order to reduce the excess mortality attributable to cancer, it is important to understand the un- Study of the relationship between poor physical derlying factors as to why people with mental ill- health and high mortality in people with mental ness have worse case fatality associated with can- illness has a long history. In 1841, William Farr cer. There are obvious and immediate avenues to [5] reported to the Royal Statistical Society on examine, in particular whether lifestyle factors mortality within the major asylums in England. place people with mental illness at greater risk of At that time, high mortality was principally as- developing cancer. For instance, are they less like- cribed to infectious diseases and the generally ly to participate in cancer screening activities, poor conditions within asylums. Around the leading to differences in how soon diagnoses are same time, the Commissioners in Lunacy were made and therefore presenting with more ad- established to oversee the conditions and care vanced disease? Do people with mental illness re- provided in asylums and workhouses in England. ceive differential treatment once they are diag- The commissioners were among the first to note nosed? Are they more likely to reject lifesaving that in spite of the general poor health of people treatments or not comply with aftercare require- with mental illness, cancers were not often seen, ments? All of these factors may go some way to and they suggested in their 1909 report that peo- developing a more rounded understanding of ple with mental illness may have a certain immu- why people with mental illness experience greater nity to cancer [6] . With the dawn of the com- cancer mortality. In this chapter we address each puter age, new methods of research in mental of these questions, reviewing the evidence as to illness became viable. The Oxford Record Link- where the greatest discrepancies lie and which as- age Study, established in the 1960s, was the first pects of cancer diagnosis and treatment deserve study to undertake a systematic analysis of the further attention. association between physical health problems

Cancer and Mental Illness 89

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 88–98 ( DOI: 10.1159/000365541 ) and mental illness, using administrative data Since then, there have been numerous studies on from mental health services in the Oxford region cancer mortality and mental illness, and most [7] . At that time, the main question of interest studies published in the last decade have found was whether an association between a physical higher standardised mortality ratios associated illness and a mental illness could reveal some- with cancer [3, 4, 14–17]. However, these find- thing about the aetiology of both conditions. ings have not always been consistent, and have The relationships between cancer and schizo- varied according to the years of study, the men- phrenia and between rheumatoid arthritis and tal illness and type of cancer examined, and the schizophrenia have received particular attention study populations and methodologies that each [8] . The strong negative correlation between study used. For example, the results of earlier these conditions led to hypotheses that there studies typically found no excess mortality at- might be specific genes involved in the aetiology tributable to cancer [18–21], and in some cases of these diseases. lower standardised mortality ratios were ob- As more data were accumulated over time and served [22, 23] . the pattern of association between schizophrenia and cancer was observed to be more complex, more nuanced hypotheses were advanced. These Incidence and Case Fatality Rates included the idea that certain neuroleptic drugs may have a tumour-suppressing effect, that this There is considerable research demonstrating effect may vary depending on the stage of cancer that people with mental illness engage more fre- during neuroleptic treatment, that the effect may quently in behaviours that are associated with vary depending on cancer morphology, or there cancer risk. For example, people with mental ill- may be an interaction between neuroleptics, lev- ness have higher rates of smoking and smoke els of specific hormones and genetic susceptibility more cigarettes on average [24] , and despite to certain types of tumours [9–12]. However, to wanting to quit smoking find it much harder date this line of investigation has not led to any than people without mental illness to do so [25] . significant advance in the understanding of the Drug and alcohol addiction is also more com- aetiology or treatment of either schizophrenia or mon in people with mental disorders [26] , and cancer. many psychiatric disorders are treated with medications which, in addition to other lifestyle and diet factors, result in increased incidence of obe- Cancer and Excess Mortality sity [27] . Additionally, a common side effect of antipsychotic medications is hyperprolactinae- While much of the early research focussed on mia, an excess of the hormone prolactin. Hyper- the possibility of people with mental illness be- prolactinaemia is also associated with an in- ing at reduced risk for developing cancer, the creased risk of breast cancer in women [28] , and possibility that cancer may be a cause of excess possibly prostate cancer in men [29] , though oth- mortality was first reported by Katz et al. [13] in ers have noted that hyperprolactinaemia is also 1967, who found that cancer mortality amongst associated with hypogonadism, which may be psychiatric patients in New York was higher protective against breast and prostate cancer than in the general population, though only for [30] . patients with shorter periods of hospitalisation. Because of these lifestyle and medication side- Patients with psychiatric hospital stays of more effect risk factors, it may seem reasonable to hy- than 10 years had lower cancer mortality rates. pothesise that increased exposure to these cancer

90 Lawrence · Hancock · Kisely

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 88–98 ( DOI: 10.1159/000365541 ) risk factors would cause more cancers in people duces incidence of cancer in people with mental with mental illness. If this were the sole reason for illness. Some exceptions are apparent, for exam- worse cancer mortality, then we would expect ple a systematic review of the incidence of breast that people with mental illness would be at great- cancer amongst women with schizophrenia er risk of developing cancer, and as such we would found that while the incidence rates of breast see an increased incidence of cancer amongst peo- cancer varied across the studies, those with larger ple with mental illness. Despite the high rates of samples and better quality indicators found high- exposure to demonstrated carcinogens in people er rates of breast cancer in women with schizo- with mental illness, there is in fact no clear evi- phrenia [42] . A possible explanation for this dence that people with mental illness are more finding, if true, may relate to the increased likeli- likely to develop cancer, or at least be any more hood of hyperprolactinaemia for people who are likely to be diagnosed with cancer. Studies that administered antipsychotic medication. Howev- have examined both cancer incidence and mor- er, we have not observed any increase in breast tality in populations of people with mental illness cancer in women with severe mental illness in indicate that cancer incidence rates for people our own work in Western Australia and Nova with mental illness are generally comparable with Scotia [2–4] . the rest of the population, though this pattern ap- Brain tumours are a notable exception to the pears to depend on the type of cancer and the se- finding that the incidence of cancer is compa- verity of mental illness. Many studies have found rable in psychiatric and general populations. A that cancer rates are lower amongst people with number of studies have identified higher rates of schizophrenia in particular [31–34] . However, brain cancer diagnosis following diagnosis of not all studies have found this pattern amongst mental illness. A likely explanation for this find- people with schizophrenia [15] , and as such, this ing is the general difficulty of diagnosing brain pattern for people with schizophrenia may reflect cancers, and the common early presentation of methodological or cohort differences [35] . While brain cancer sufferers with symptoms of mental some studies have found an increased incidence distress including depression and memory im- of smoking-related cancer, such as lung cancer, in pairment. This may lead to people with brain tu- people with mental illness [36, 37] , the over- mours being referred for mental health treat- whelming majority of studies that examine psy- ment prior to the diagnosis of their tumour [2, chiatric disorders, other than schizophrenia, have 43] . found no increased risk of cancer incidence in psychiatric populations [3, 4, 15, 36, 38–41] . In addition, people with severe mental illness do not Factors Related to Higher Case Fatality have a greater incidence of melanoma, but have worse case fatality even though melanoma is a Less studied than cancer incidence, but more cancer that cannot be attributed to concurrent consistent in its findings, is the higher case fatal- lifestyle factors such as diet, drugs, alcohol or to- ity following cancer diagnosis in people with co- bacco, as it is mainly related to childhood sun ex- morbid mental illness. This has been consistently posure [3] . reported from a number of large record linkage In the case of cancers that are associated with and cohort studies including our own record risk factors such as smoking, alcohol and other linkage work using the populations of Western drugs, comparable rates of cancer incidence in Australia and Nova Scotia [3, 4]. This worse case people with and without mental illness may im- fatality from time of diagnosis deserves addition- ply some other, as yet unknown, factor that real focus and attention. Here we examine the can-

Cancer and Mental Illness 91

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 88–98 ( DOI: 10.1159/000365541 ) cer screening rates for people with mental illness The question of why people with mental illness and further treatment discrepancies that occur may receive less cancer screening remains unre- following diagnosis. solved. For instance, some research points to the possibility that people with mental illness are less Screening Rates likely to be offered screening for cervical, breast, Another possible explanation for the comparable prostate or colorectal cancer by their primary rate of cancer diagnosis in people with mental ill- physicians [54] , or if screening is recommended, ness despite high exposure to known carcinogens are less likely to adhere to recommended screen- is the hypothesis that cancers do occur more fre- ing [55]. In their systematic review, Lord et al. quently in people with mental illness, but are less [56] identified the relationship with the primary likely to be detected because of lower rates of care physician as perhaps the most important fac- screening and access to general healthcare. As life tor to explain deficits in receipt of cancer screen- expectancy is substantially reduced in people with ing and other preventive health measures. They mental illness, and mortality from other causes of note that proactive contact from the primary care death is substantially higher, more people with physician, and the use of peer support workers, mental illness who have cancer may die before are two interventions where there is some evi- that cancer is diagnosed. To date, the results dence to support their effectiveness in boosting about the extent to which people with mental ill- screening rates. ness receive routine cancer screening have been mixed. For example, in a study of privately in- Delay to Diagnosis and Stage of Cancer at sured women with, and without, claims for men- Diagnosis tal illness, women with a mental disorder were Differences in screening rates aside, there is a significantly less likely to receive mammography, growing body of literature documenting other particularly women with more severe disorders disparities in cancer treatment for people with [44]. Similar patterns have been observed in other mental illness, including the length of time it studies with different populations of patients takes to be diagnosed with cancer after presenting [45–48], though others have found that women with symptoms. In a study of patients with oe- with mental illness were more likely [49] , or at sophageal cancer, O’Rourke et al. [57] found that least equally likely, to receive mammography cancer patients who had a DSM-IV diagnosed [50] . In a narrative review of 17 studies examining psychiatric comorbidity waited a median of 90 the uptake of screening services by people with days between reporting symptoms and receiving mental illness, Happell et al. [51] showed a 20– a diagnosis, compared to 35 days for patients 30% reduced likelihood of breast, cervical and without mental illness. They were also more like- colorectal cancer screening for patients with se- ly to have advanced disease at the time of diagno- vere mental illness in the majority of studies. The sis (37 vs. 18%) and also had a decreased likeli- pattern was most commonly observed for people hood of receiving surgical therapy (38 vs. 59%). In with more severe disorders, with up to a 60% re- other research, the proportion of people with can- duced likelihood [52]. Taken together, the evi- cer who had metastases at presentation was sig- dence suggests that people with mental illness are nificantly higher in psychiatric patients (7.1 vs. less likely to receive preventive cancer screening 6.1%), though larger gaps were observed for spe- services than those without [53] . As a result, can- cific types of cancer [3] . For example, for people cers may be more advanced by the time the diag- with breast cancer the difference was 6.3 vs. 4.5%, nosis is made, with poorer outcomes associated and lung cancer 0.6 vs. 0.2%. No differences in with the delay in diagnosis. rates of cancer with metastases were found for

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Patients (%) Patients 20

Psychiatric patients, male WA population, male 10 Psychiatric patients, female Fig. 2. Time from diagnosis to WA population, female surgical removal of the tumour by contact with mental health services. 0 WA = Western Australia. 0 30 60 90 Reproduced with permission from Time since cancer diagnosis (days) JAMA Psychiatry [3] .

other sites. Though statistically different, these colorectal resections occurred less frequently for difference rates are small in absolute terms, and patients who were diagnosed with dementia, af- cannot account for the significantly larger differ- fective psychoses, other psychoses and depres- ences in case fatality for cancer patients. These sion. Psychiatric patients also received 10.3 ses- patterns, reinforced by findings from another re- sions of chemotherapy on average, compared to cent study [58] , suggest that the elevated mortal- 12.1 for the general population, and were less ity associated with cancer is unlikely to be primar- likely to receive radiotherapy for breast cancer ily the result of the cancer being more advanced (2.6 vs. 4.1%), colorectal cancer (1.6 vs. 3.9%) and by the time it is diagnosed. uterine cancer (13.0 vs. 21.1%). To summarise, although the cancer incidence in psychiatric pa- Medical Care after Diagnosis: Surgical tients is no higher than in the general population, Intervention psychiatric patients are more likely to have me- There are apparent disparities in other ongoing tastases at diagnosis and less likely to receive spe- treatment options, including rates of surgical in- cialised interventions. Together, these may ex- tervention and the time it takes to get to surgery. plain the greater case fatality found in people In our recent work using the Western Australian with a psychiatric disorder. Data Linkage System [3] , psychiatric patients had Though our focus here has been on cancer a reduced likelihood of surgery after diagnosis outcomes for people with a prior history of men- for all types of cancer, and for those who did have tal illness, for many people, the onset of mental surgery, the length of time between cancer diag- illness can occur following cancer diagnosis and nosis and surgery was longer (see fig. 2 for treatment [59] , particularly post-traumatic trends). Men were less likely to have a colorectal stress disorder and depressive and anxiety disor- resection, and women were less likely to have ders. Research indicates that people with comor- surgery for colorectal, breast and cervical cancer. bid diagnoses of cancer and mental illness have The psychiatric diagnosis also mattered – poorer outcomes and greater difficulty adhering

Cancer and Mental Illness 93

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 88–98 ( DOI: 10.1159/000365541 ) to treatment regimens [60, 61]. In this respect, been noted in the literature [65, 66] . First, there issues surrounding treatment disparities apply is the long established separation of mental and to all people with mental illness, irrespective of physical healthcare, with many mental health their psychiatric history prior to a cancer diag- service users not receiving ongoing physical nosis. However, different types of mental illness healthcare, and many psychiatrists reluctant to offer different challenges to people with mental diagnose and treat physical health conditions. illness and to the practitioners who treat them, Additionally, stigma is seen as a major issue in and the types of mental illness that arise follow- the equitable delivery and access to general ing the development of cancer are somewhat healthcare. Unfortunately, mental illness can narrower in scope than the range of illnesses that rob people of aspects of personality that others develop over a lifetime. Research that compares find most endearing, and even among health treatment outcomes for people whose onset of professionals there are many who find it diffi- mental illness was before or after cancer may of- cult to provide the same level of concern and fer further insights as to why disparities occur. support to people with mental illness. Also, the way that healthcare is delivered in developed countries generally results in greater benefit to Comorbidities and Challenges for Health and those who have the best understanding of health Mental Healthcare Providers conditions and the healthcare system. People with mental illness may also have limited means People with mental illness who also have physical to pay for healthcare or might not be covered by health problems are often more likely to be among health insurance. Many mental illnesses are as- the more complex cases with multiple presenting sociated with cognitive impairments and disad- symptoms and problems. For example, in a small- vantages that can impact people’s ability to scale review of 29 people with schizophrenia and maximise their use of healthcare options. These lung cancer [62], potentially curable cancers were include smaller support networks and impacts identified in 17 individuals, with 5 of the 17 re- on motivation, concentration, assertiveness and ceiving less than best practice care. Issues that re- communications ability. In some cases these sulted in disparities in care included other physi- deficits have been used as justification not to cal comorbidities that complicated the treatment provide health interventions. For instance, and ethical issues with patients not consenting to some cancer surgeries are highly invasive and invasive treatments. Irrespective of the presence debilitating, and pose substantial demands dur- of mental illness, patients with complex needs ing recuperation. Similarly, chemotherapies and who have multiple comorbidities have worse out- other more experimental drug treatments can comes and are more poorly served by standard have significant side effects and exact a toll on medical care [63]. With the high level of speciali- the patient. sation now required to deliver high-quality The issue of obtaining informed ethical con- healthcare for any condition, it is clear that few sent to risky treatments or treatments with sub- healthcare providers are well equipped to deal ef- stantial side effects also requires sensitive consid- fectively with diverse and challenging health eration. Some people with mental illness require problems simultaneously [64] . a higher level of support to understand the impli- Equitable access to healthcare has become an cations of treatments, which may require more important focus of research in the gaps in phys- time commitment from the practitioner. Compli- ical health outcomes associated with mental ill- ance with aftercare may also require a higher lev- ness, and a number of contributing issues have el of support. However, in the same way that

94 Lawrence · Hancock · Kisely

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 88–98 ( DOI: 10.1159/000365541 ) physical disability is not a valid reason for not illness and valuing the contribution people with a providing access to healthcare, any cognitive or history of mental illness make to their communi- behavioural impairment associated with mental ties [71, 72] . This has led to a much greater focus illness should be recognised as a component of on the human cost of the high physical comorbid- the illness that deserves support. ity associated with mental illness, the wasted life Finally, another aspect of medical care for peo- seen in the substantial gaps in life expectancy ple with both mental illness and cancer is end-of- [73] . life palliative care, which shares some similarities Mental illnesses are common, and people with the recovery model of mental healthcare that with mental illness suffer a disproportionate is based on respect, dignity, and valuing both life burden associated with physical illness, includ- and the individual [67]. Results from limited re- ing higher mortality from cancer. Bringmann et search on this issue have been contradictory. al. [74] estimate that up to one third of cancer Some work suggests that people with severe men- patients have a psychiatric history. As such, tal illness may be less likely to receive palliative dealing with comorbid mental illness is a signif- care [67] . In contrast, our own preliminary work, icant component of cancer care. Though people using data from the Western Australian Data with mental illness may not be at any higher risk Linkage System for the period 1988–2007, indi- than anyone else for developing cancers, the cates that people with a history of mental illness clearly worse outcomes once cancer is diagnosed who were dying of cancer received the same level highlight the role that preventive and treatment and duration of palliative care prior to death as services are likely to play in reducing these dis- the general population, with an average of 19 days parities. There is insufficient research at present of palliative care [unpubl. data]. In spite of the to definitively identify the contribution that in- challenges that people with mental illness may dividual issues make to the overall gaps in out- pose to palliative care environments, they may es- comes, but it is highly likely that a range of fac- pecially benefit from such care when making dif- tors contribute. Further research into ways to ficult end-of-life decisions or deal with significant improve health service delivery to people with pain, as they are less likely to have strong person- comorbid mental health problems is required. It al support networks [67] . Again, the issue of stig- appears that reduced access to screening, delays ma and the cognitive and behavioural conse- in diagnosis, differential access to and uptake of quences of mental illness can affect the way peo- treatment options, and impacts of other comor- ple are received and treated in the palliative care bidities may all play a role. Clearly, these issues environment [68, 69] . are not straightforward to resolve as shown by the lack of major progress anywhere in the world. There is a small and developing evidence Conclusions base supporting some directions for improving physical healthcare for people with mental ill- With significant advances in the treatment and ness, although none of this literature is specific understanding of mental illness, and large-scale to cancer. These include variations on the theme change in mental health service delivery to com- of more holistic care models including multidis- munity-based care, there have been significant ciplinary teams and co-location, use of peer sup- shifts in treatment goals and expectations. There porters and addressing stigma in the healthcare are now effective treatments available for most profession [66]. mental health conditions [70] , and a major focus of mental healthcare is on recovery from mental

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David Lawrence, PhD Telethon Kids Institute Centre for Child Health Research, The University of Western Australia PO Box 855, West Perth, WA 6872 (Australia) E-Mail [email protected]

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 88–98 ( DOI: 10.1159/000365541 ) Comorbidity of Mental and Physical Illness: A Selective Review

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 99–113 ( DOI: 10.1159/000365542 )

Infectious Diseases and Mental Health

Norbert Müller Department of Psychiatry and Psychotherapy, Ludwig-Maximilian University Munich, Munich , Germany

Abstract psychiatric disorders are discussed as examples for im- Emil Kraepelin, the founder of modern psychiatric clas- munomodulating treatment approaches in psychiatric sification, and the Nobel laureate Julius Wagner von Jau- disorders. Further immunotherapies used in Tourette’s regg highlighted the role of infections and the immune syndrome or pediatric autoimmune disorders associated system in psychiatric disorders. It is well known that infec- with streptococci are highlighted as further examples for tions can trigger various psychiatric syndromes and influ- such a therapeutic approach. © 2015 S. Karger AG, Basel ence the course of psychiatric disorders. Psychiatric symptoms during virulent infections, often presenting as encephalitis or meningitis, normally are diagnosed as Humans are constantly being assaulted by infec- mental disorders due to a general medical condition. On tious agents. Fortunately, we have evolved a com- the other hand, an expanding research field underpins plex process, the immune response, to help fight the view that infections and activation of the immune sys- and clear infection [1]. The immune response tem may play a causative role in major psychiatric disor- evoked by an infectious agent may or may not ders such as schizophrenia or major depression. Also in generate clinical symptoms, depending on the ex- other psychiatric syndromes, such as Tourette’s syn- act type and degree of response. Infectious dis- drome, inflammation – partially based on infections – is eases are well known to provoke psychiatric involved. For this mild smoldering inflammatory process, symptoms. As early as 1890, Emil Kraepelin, one the ‘mild (chronic) encephalitis’ concept was developed. of the founders of modern psychiatry, described In this chapter, findings related to immune activation and during an influenza epidemic 11 cases of psychi- inflammation in schizophrenia, major depression and To- atric disorders that presented with different urette’s syndromes as examples for this concept are de- symptoms such as depressed mood, a paranoid scribed. Moreover, encouraging results from randomized and hallucinatory syndrome, involuntary move- clinical trials in schizophrenia and major depression ments, cognitive deterioration, and a delirious showing a benefit of anti-inflammatory therapy in these state [2]. Later, Kraepelin postulated in his pro- Table 1. Diagnostic criteria DSM-IV: psychopathological states due to a general medical condition

293.0 Delirium due to a general medical condition Dementia due to a general medical condition 294.0 Amnestic disorder due to a general medical condition 293.8x Psychotic disorder due to a general medical condition 293.83 Mood disorder due to a general medical condition 293.89 Anxiety disorder due to a general medical condition Sexual dysfunction due to a general medical condition 780.5x Sleep disorder due to a general medical condition

grammatic essay ‘Objectives and methods of psy- disturbances. An example is ‘sickness behavior’ as chiatric research’ to make the immunological de- a model for depressive disorder, as described be- fense and adaption system a focus of psychiatric low. research [3, 4]. There are also numerous descriptions of an association between chronic inflammation of the central nervous system (CNS) and The ‘Sickness Behavior’ Model in Major psychopathological states [5] . For example, symp- Depression toms of depression and schizophrenia have been described in a certain form of multiple sclerosis ‘Sickness behavior’, the reaction of an organism to [6] . The same is true for viral CNS infection with infection and inflammation, is well established as a herpes simplex virus types 1 [7] and 2 [8, 9] and model for depression in animals and humans [21, measles [10] . Autoimmune processes, such as 22] . The model is based on the observation that in- poststreptococcal disorders, lupus erythematodes creased levels of proinflammatory cytokines, such and scleroderma, may present primarily as a psy- as tumor necrosis factor-α (TNF-α) and interleu- chopathological syndrome [11–18]. This line of kin-6 (IL-6), are associated with depressive-like evidence led to the concept of ‘mild encephalitis’ behavior in animals, including decreased drive and [19] . motivation, lack of energy and appetite, tiredness, In modern diagnostics, psychiatric symptoms and weight loss. The involvement of cytokines in coexisting with severe infections are diagnosed as the regulation of sickness behavior in humans has ‘mental disorders due to a general medical condi- been studied by administering the bacterial endo- tion’. Infections can cause a broad spectrum of toxin lipopolysaccharide to healthy volunteers psychiatric symptoms, e.g. delirium, psychotic [23] . Levels of anxiety, depression and cognitive disorder or mood disorder (table 1 ) [20] . impairment were found to be related to the levels Factors influencing the psychiatric presenta- of circulating cytokines [23, 24] . tion of infections are the subject of intense re- The findings of these studies, together with the search and might include the pathogen, individu- sickness behavior model, have led to the hypoth- al medical history and locus of infection. Infec- esis that ‘cytokines sing the blues’, i.e. cytokines tions of the CNS, such as meningitis and and a proinflammatory immune state are in- encephalitis, are believed to be more commonly volved in the pathogenesis of major depression associated with psychiatric symptoms than those [25, 26]. This view is supported by recent litera- of the peripheral organs, although peripheral in- ture showing signs of a proinflammatory immune fections are also well known to cause psychiatric state in major depression.

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 99–113 ( DOI: 10.1159/000365542 ) Table 2. Components of the innate and adaptive immune system

Component Innate Adaptive

Cellular Monocyte macrophages T and B cells Granulocytes Natural killer cell γ-/δ-cells Humoral Complement, APP, mannose- binding lectin Antibody

Components and Functions of the Immune sponse. While TNF-α mainly activates the type 1 System response, IL-6 activates the type 2 response, including antibody production. Anti-inflammato- The innate immune system, which includes nat- ry cytokines such as IL-4 and IL-10 help to ural killer cells and monocytes, for example, as downregulate the inflammatory immune re- the first barrier against infection, is phylogeneti- sponse (table 2 ). cally the oldest part of the immune system. The adaptive immune response with the antibody- producing B lymphocytes and the T lympho- The Proinflammatory Immune State in Major cytes (helper T cells) is the pathogen- and anti- Depression gen-specific component of the immune system. Cytokines regulate all cellular components of Elevated plasma concentrations of C-reactive the immune system and are involved in both the protein (CRP) are a common marker of an in- innate and the adaptive immune response. Help- flammatory process. CRP levels have been repeat- er T cells are of two types: T helper 1 (Th-1) and edly observed to be higher in people with depres- 2 (Th-2). Th-1 cells produce the characteristic sion than in healthy controls, for example in se- ‘type 1’ activating cytokines such as IL-2 and verely depressed in-patients [28], and high CRP interferon-γ. However, since not only Th-1 cells, levels have been found to be associated with the but also certain monocytes/macrophages (M1) severity of depression [29]. Higher CRP levels and other cell types, produce these cytokines, have also been found in both men [30, 31] and this type of immune response is called the type 1 women [32, 33] in remission after a depressive immune response. The humoral, antibody-prostate. In a sample of older healthy persons, CRP ducing arm of the adaptive immune system is levels and IL-6 levels were predictive of cognitive mainly activated by the type 2 immune response. symptoms of depression 12 years later [34] . In Th-2 and certain monocytes/macrophages (M2) comparison to acute inflammatory diseases, such produce mainly IL-4, IL-10 and IL-13 [27] . An- as pneumonia, however, the CRP increase is other terminology system differentiates cyto- slight. kines as being proinflammatory and anti-in- Characteristics of immune activation in ma- flammatory. Proinflammatory cytokines such as jor depression include increased numbers of cir- TNF-α and IL-6 are primarily secreted from culating lymphocytes and phagocytic cells, up- monocytes and macrophages, and activate other regulated serum levels of markers of immune ac- cellular components of the inflammatory re- tivation, higher serum concentrations of positive

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 99–113 ( DOI: 10.1159/000365542 ) Table 3. Examples for immune markers reflecting immune activation in major depression

Disease-related markers Markers for antidepressant Markers for response to immune response related therapy IL-6 [124] IL-6 [28, 105] IL-6 [105] TNF-α [41] Quinolinic acid CRP [106] CRP [28, 29] [Müller et al., unpubl. data] TNF-α [106] Neopterin [47] TNF-α [125] TNFR1 [106, 126] TNFR2 [106] Kynurenine/tryptophan [Müller et al., unpubl. data] Kynurenine/quinolinic acid [Müller et al., unpubl. data]

acute phase proteins coupled with reduced levels Infections and Autoimmune Disorders as Risk of negative acute phase proteins, and increased Factors for Major Depression release of proinflammatory cytokines such as IL- 1β, IL-2, TNF-α and IL-6 (through activated The results of a prospective population-based macrophages) and interferon-γ (through acti- Danish register study in 3.6 million people born vated T cells) [35–41]. Interferon-α is well docu- between 1945 and 1996 support the view that an mented to induce severe depressive symptoms, infection or autoimmune disease significantly in- including suicidality, in about one third of pa- creases the risk of a depressive disorder. Partici- tients [42]. Different research groups [43–45] pants were followed up from 1977 to 2010, for a have described increased numbers of peripheral total of 78 million person-years. All people diag- mononuclear cells in major depression, and, in nosed with an affective disorder according to accordance with findings of increased mono- ICD-8, ICD-9 or ICD-10 and at least one in- or cytes and macrophages, an increased level of ne- outpatient hospital contact due to an affective dis- opterin, a marker for activated macrophages, order (including bipolar disorder) were included. has also been described [46–49]. The role of cel- Every previous hospital contact due to an autoim- lular immunity, cytokines, and the innate and mune disorder or infection (apart from HIV/ adaptive immune systems in depression has AIDS) was then recorded. Over 91,000 cases of af- been recently reviewed [50, 51]. Table 3 summa- fective disorder were identified, of which approx- rizes several examples for immune markers in imately 30,000 had previously been diagnosed major depression. with infection and >4,000 with an autoimmune Although immune activation is well estab- disease. The results show that hospitalization for lished in major depression and infections are infection significantly increased the risk for later well known to trigger depressive symptoms, mood disorder by 63% [incidence rate ratio (IRR) the association between infection and major 1.63 (95% CI: 1.61–1.66)] and hospitalization for depression has not been properly studied. In autoimmune disease significantly increased it by contrast, the etiology of immune activation in 45% [IRR 1.45 (95% CI: 1.39–1.52)]. Both risk fac- major depression is the subject of intense re- tors interacted and increased the risk to an IRR of search. 2.35 (95% CI: 2.25–2.46). The findings do not support the hypothesis that primarily CNS infections

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 99–113 ( DOI: 10.1159/000365542 ) result in later symptoms of mood disorders as, for blunted type 1 and (compensatory) increased example, the risks were higher for hepatitis infec- type 2 cytokine pattern have been repeatedly ob- tion [IRR 2.82 (95% CI: 2.58–3.08)] than for sepsis served in people with unmedicated schizophrenia or CNS infections. Interestingly, the risk for mood [55] . Recently published reviews on the imbal- disorder increased with the proximity of time to ance of types 1 and 2 and pro- and anti-inflamma- the infection, with the highest risk within the first tory immune systems as well as innate immunity, year [IRR 2.70 (95% CI: 2.60–2.80)] [52] . Since including the monocytic system, in schizophrenia only infections and autoimmune disorders result- have indicated that an inflammatory process ing in a hospital contact were recorded, the risk plays an important role in the pathophysiology of for a mood disorder might be higher when all in- (at least) a subgroup of people with schizophrenia fections are considered. [56, 57] . Over the last five decades, research on the neu- robiology of schizophrenia has focused over- Infection and Autoimmunity Presenting with whelmingly on disturbances of dopaminergic Symptoms of Schizophrenia neurotransmission [58] . A disturbance of the dopamine system is clearly involved in the patho- There are numerous descriptions of an associa- genesis of schizophrenia, although the mecha- tion between (chronic) inflammation of the CNS nism is unclear and antipsychotic antidopami- and schizophrenia [5] . For example, symptoms of nergic drugs still show unsatisfactory therapeutic schizophrenia have been described in the enceph- effects. alitic form of multiple sclerosis [6] , in viral CNS IL-1β, which can induce the conversion of rat infection with herpes simplex virus types 1 [7] mesencephalic progenitor cells into a dopaminer- and 2 [8], and measles [10] , and also in autoim- gic phenotype [59–61], and IL-6, which is highly mune processes such as poststreptococcal disor- effective in decreasing the survival of fetal brain ders [11–14], lupus erythematodes and scleroder- serotonergic neurons [62], seem to have an im- ma [15–18] . Schizophreniform symptoms in pri- portant effect on the development of the neu- mary infectious diseases are diagnosed according rotransmitter systems specifically involved in to DSM-IV as a mental disorder due to a general schizophrenia, although the specificity of these medical condition (whereas in earlier times the cytokines is a matter of discussion. Maternal im- diagnosis was ‘organic brain disorder’). However, mune stimulation during pregnancy increased we do not know whether schizophreniform the number of mesencephalic dopaminergic neu- symptoms are ‘secondary’ to an infection or auto- rons in the fetal brain, and the increase was prob- immune process or the infection is a comorbid ably associated with a dopaminergic excess in the condition in a person with a ‘primary’ diagnosis midbrain [63]. Persistent pathogens might be key of schizophrenia. factors that drive imbalances of the immune reaction [18] . Nevertheless, many questions remain unanswered about how immunity and immune Inflammation and the Effect on pathology in virus infections interact in order to Neurotransmission in Schizophrenia show clinical symptoms [64] . Much evidence indicates that a lack of gluta- Signs of inflammatory degradation products have matergic neurotransmission, mediated via been described in schizophrenic brain tissue [53] NMDA antagonism, is a key mechanism in the and in the cerebrospinal fluid of about 50% of pathophysiology of schizophrenia [65] . Kynuren- people with schizophrenia [54] . Furthermore, a ic acid, the only NMDA receptor antagonist

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 99–113 ( DOI: 10.1159/000365542 ) COX-2 inhibition Tryptophan Modulating cytokine production

IDO PGE2

Kynurenic Serotonin Melatonin KAT Kynurenine acid Proinflammatory (Depletion in depression) = NMDA antagonist cytokines (e.g. IFN-ǅ, TNF-į, IL-6) IDO IDO (Ȝ in schizophrenia CNS) KMO Anti-inflammatory cytokines (e.g. IL-4) f50HKYM f5MoHKYM 3-OH-Kynurenine (neurotoxic)

Quinolinic acid Neurodegeneration + = NMDA-R agonist apoptosis (Ȝin depression)

Fig. 1. The enzyme indoleamine 2,3-dioxygenase (IDO) is activated by proinflammatory cytokines [and prostaglandin E2 (PGE2 )] and inhibited by anti-inflammatory cytokines. IDO degrades kynurenine, serotonin and melatonin, and influences the concentrations of these neuroactive metabolites and neurotransmitters. The enzyme KMO [kynurenine 3-monooxygenase (identical with kynurenine 3-hydroxylase)] drives the metabolism to the neurotoxic metabolite quinolinic acid. The enzyme KAT (kynurenine aminotransferase) drives the metabolism to kynurenic acid.

known to occur naturally in the human CNS [66] , [74] or in other groups of people with schizophre- is one of at least three neuroactive intermediate nia [75] . Increased neopterin values are to be products of the kynurenine pathway. In schizo- mentioned here again [76] . Antipsychotic medi- phrenia, a predominant type 2 immune response cation, however, affects kynurenine metabolites inhibits the enzyme indoleamine 2,3-dioxygen- and has to be regarded as an interfering variable ase, resulting in an increased production of kyn- [74, 75, 77] . urenic acid and consequently in NMDA receptor antagonism [65, 67]. The recent finding of NMDA receptor antibodies in about 10% of patients with Infection as a Possible Pathogenetic Factor in acute and unmedicated schizophrenia is especial- Schizophrenia ly interesting in this regard (fig. 1 ). Findings regarding kynurenic acid in schizo- The proposed involvement of immune activation phrenia vary. Elevated kynurenic acid has mainly and inflammation in the pathogenesis of schizo- been described in the cerebrospinal fluid [68–70] phrenia has led to the hypothesis that infectious and in the brains of people with schizophrenia agents may be involved. Many recent studies have [71, 72] , as well as in animal models of schizo- focused on members of the virus family of Her- phrenia [73] . However, no increased kynurenic pesviridae [78] , Borna virus [79] , intracellular acid levels have been described in the peripheral bacteria like Chlamydia [80] and the protozoan blood of people with first-episode schizophrenia organism Toxoplasma gondii [81] . The roles of

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 99–113 ( DOI: 10.1159/000365542 ) Cytomegalovirus and T. gondii have been stressed schizophrenia for many years, but the results have for many years [82] . These agents are the focus of been inconsistent due to reasons such as interfer- research because of their ability to establish persis- ing factors not being controlled for. Antibody lev- tent infections within the CNS and the occurrence els are associated with the medication state, a of neurological and psychiatric symptoms in some finding which partly explains earlier controver- individuals infected with these agents [83] . sial results. In one of our own studies, people with The group of Danish researchers mentioned schizophrenia had higher titers of different patho- above performed a study in schizophrenia similar gens than controls, a phenomenon that we call the to their study in affective disorders [127]. They ‘infectious index’. found that severe infections and autoimmune Prenatal immune activation – regardless of disorders also additively increased the risk of whether it is triggered by infection – is an impor- schizophrenia and schizophrenia spectrum distant risk factor for schizophrenia. In humans, in- orders. However, this large-scale study did not creased maternal levels of the proinflammatory confirm infections in the parents, including intra- cytokine IL-8 during pregnancy were shown to uterine infections, as definite risk factors. Despite increase the risk for schizophrenia in the off- its large scale, the study’s sensitivity was not very spring, whatever the reason for the increase in IL- high because only infections associated with a 8. Moreover, increased maternal IL-8 levels in contact to a Danish hospital were recorded, pregnancy were also significantly related to de- meaning that the risk factors which were identi- creased brain volume, leading to lower volumes fied may only have been the ‘tip of the iceberg’. of the right posterior cingulum and the left ento- Animal models of schizophrenia show that rhinal cortex, and higher volumes of the ventri- stimulation of the maternal immune system by cles in the offspring with schizophrenia (fig. 2 ). viral agents leads to typical symptoms in the offspring. Evidence for pre- or perinatal exposure to infections as a risk factor for schizophrenia has Cyclooxygenase-2 Inhibition as an Example of been obtained not only from animal models, but an Anti-Inflammatory Therapeutic Approach also from studies with various viruses in humans. in Schizophrenia and Major Depression Increased risk for schizophrenia in the offspring was also observed after respiratory infections or An immune-based therapeutic approach for psy- genital or reproductive tract infections. T. gondii chiatric disorders was first proposed decades ago infection in mothers was also described to be a when the Nobel laureate Julius Wagner von Jau- risk factor. Interestingly, recent animal research regg developed a vaccination therapy for psycho- showed that stressful events in later stages of life ses [85] . He treated patients successfully with vac- (during puberty, an especially vulnerable phase in cines derived from attenuated Mycobacterium tu- life) unmask latent neuropathological conse- berculosis , Plasmodium malariae or Salmonella quences of prenatal immune activation [84] . This Typhi, all of which stimulate a type 1 immune re- animal model might explain the delay between an sponse [86]. This therapy showed the best results early inflammation and the onset of schizophre- in syphilis infection, but Wagner von Jauregg also nia years later. administered the vaccination therapy for other Both infections before birth and infections, psychiatric disorders. After the introduction of particularly of the CNS, during later stages of penicillin and as a consequence of the overwhelm- brain development increase the risk for later ing success of the neurotransmitter approach in schizophrenia. Antibody titers against viruses psychiatry, the therapeutic vaccination approach have been examined in the sera of people with was not pursued further. In the past decade, the

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 99–113 ( DOI: 10.1159/000365542 ) Environmental factors Immunogenetics (e.g. infectious pathogens)

Immune function/inflammation Stress

Serotonin Tryptophan NMDA Dopamine noradrenaline Kynurenine Glutamate

Neuro- Neuro- degeneration Psychopathology protection

Antipsychotics Immunotherapy Antidepressants

Fig. 2. Pathoetiological model of psychiatric disorders with special emphasis on the influence of infections, inflammation and the immune system. Besides other environmental factors such as stress (chronic stress depletes the immune response), pathogens are an important factor. Immune genes are involved in psychiatric disorders. The activation or inhibition of the immune response influences the noradrenergic, serotonergic, dopaminergic and glutamatergic neurotransmission and the (neuroprotective and/or neurotoxic) tryptophan/kynurenine system, and through these mechanisms contributes to the psychopathology of psychiatric disorders. Anti-inflammatory drugs show beneficial effects in disorders such as schizophrenia or major depression.

emerging limitations of the neurotransmitter ap- nounced in cognition [89]. The efficacy of thera- proach for pathogenetic research have resulted in py with a COX-2 inhibitor seems most pro- increased interest in other therapeutic approach- nounced in the first years of the schizophrenia es, including the possible use of modern anti-in- disease process [90, 91] . A recent study also found flammatory agents in schizophrenia [87] . The cy- a beneficial effect of acetylsalicylic acid in schizo- clooxygenase-2 (COX-2) inhibitor celecoxib was phrenia spectrum disorders [92]. A recent meta- studied as an add-on to risperidone in a prospec- analysis on the use of nonsteroidal anti-inflam- tive, randomized, double-blind study of acute ex- matory drugs in schizophrenia found a signifi- acerbation of schizophrenia; patients receiving cant benefit of add-on treatment with nonsteroidal celecoxib had a statistically significant better out- anti-inflammatory drugs on positive and negative come and showed an increase in the type 1 im- symptoms and on the total symptomatology over mune response [88] . The clinical effects of COX-2 all studies [93] . A second meta-analysis on the inhibition in schizophrenia are especially pro- same topic, but based on a broader database,

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 99–113 ( DOI: 10.1159/000365542 ) found a benefit only in the early stages of the dis- in 50 patients with major depression also showed ease, in particular in first manifestations of schizo- a significantly better outcome with the COX-2 in- phrenia [94] . hibitor celecoxib plus fluoxetine than with fluox- COX-2 inhibitors also showed interesting ef- etine alone [104]. A similar result was obtained fects in animal models of depression. Treatment with a celecoxib add-on approach to sertraline in with the COX-2 inhibitor celecoxib, but not with major depression [105, 106]. A meta-analysis on a COX-1 inhibitor, prevented the dysregulation the use of COX-2 inhibitors in major depression of the hypothalamic-pituitary-adrenal axis, in found an overall benefit of celecoxib add-on ther- particular the increase of cortisol, one of the key apy [107] . biological features associated with depression Interestingly, etanercept, which blocks the in- [95, 96] . This effect was expected because prosta- teraction of TNF-α with the TNF-α cell surface glandin E 2 , which stimulates the hypothalamic- receptors, showed a highly significant antidepres- pituitary-adrenal axis in the CNS [97], is inhibit- sant effect [108] . A study with another TNF-α re- ed by COX-2 inhibition. The functional effects of ceptor blocker, infliximab, found no overall ben- IL-1 in the CNS, which include sickness behavior, efit in treatment-resistant patients with major de- were also shown to be antagonized by treatment pression, but did find a benefit in those with with a selective COX-2 inhibitor [98] . higher levels of inflammatory markers, such as COX-2 inhibitors also affect the CNS seroto- CRP, TNF-α or soluble TNF receptors [106] . nergic system, either directly or via CNS immune Although those preliminary data have to be in- mechanisms. In a rat model, treatment with rofe- terpreted cautiously and further research is need- coxib was followed by an increase of serotonin in ed to evaluate the therapeutic effects of COX-2 the frontal and temporoparietal cortex [99] . inhibitors in major depression, the results are en- COX-2 inhibitors would be expected to show a couraging for further studies on the inflammato- clinical antidepressant effect since a lack of sero- ry hypothesis of depression and the pathogenesis, tonin is one of the main factors in the pathophys- course and therapy of the disease. iology of depression. The antidepressant action of COX-2 inhibitors may be mediated through inhibition of IL-1 and IL-6 release. In the depression Childhood Infections: A Common Cause for model of bulbectomized rats, a decrease in hypo- Mental Disorders? thalamus cytokine levels and a change in behavior have been observed after chronic celecoxib treat- Maternal infection during pregnancy and child- ment [100] . In another animal model of depres- hood infections are risk factors for later schizo- sion, however, the mixed COX-1/COX-2 inhibi- phrenia, especially in combination with stress tor acetylsalicylic acid showed an additional anti- during puberty [84, 109] . Furthermore, infections depressant effect by accelerating the antidepressant in later life are risk factors for both major depres- effect of fluoxetine [101] . In an open-label pilot sion [52] and schizophrenia [110] . In major de- study in humans, acetylsalicylic acid also acceler- pression, an inflammatory process seems to play ated the antidepressant effect of fluoxetine and a role in a subgroup of patients, but no specific increased the response rate to monotherapy with infectious pathogens have been described. Stress fluoxetine in depressed nonresponders [102] . A and other environmental factors may contribute significant therapeutic effect of the COX-2 inhib- to the proinflammatory state. For example, ani- itor celecoxib in major depression was also found mal models indicate that early life separation is in a randomized, double-blind pilot add-on study associated with increased cytokine levels and pas- [103]. Another randomized, double-blind study sive behavior [111] and that early childhood stress

Infectious Diseases and Mental Health 107

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 99–113 ( DOI: 10.1159/000365542 ) disrupts the regulation of innate immune resis- criticism that the postinfectious syndrome might tance to a challenge (lipopolysaccharide, viral in- present with behavioral symptoms or comorbidi- fection), resulting in enhanced immunological ties other than tics and obsessive-compulsive and behavioral responses to immune activation symptoms. Exploratory studies aiming to identify in animals [112]. In people with depression, ear- clinical or cognitive features that could discrimi- ly-life stress is associated with enhanced inflam- nate PANDAS from other pediatric obsessive- matory responsiveness to stress [113] . Moreover, compulsive and tic disorders have presented a relationship between early childhood stress, in- methodological limitations and are therefore inflammatory markers and depression in adult pa- conclusive. Given the uncertainties regarding the tients has been described [114, 115] . Overall, clinical definition of PANDAS, it is not surprising studies indicate that stress and adverse events in that the evidence for a postinfectious, immune- childhood seem to be risk factors for an inflam- mediated pathophysiology has to be further elu- matory state in adulthood. cidated and specified [122] . However, therapeutic studies based on the PANDAS concept have shown that immunomodulating therapies, such The Concepts of Pediatric Autoimmune as intravenous γ-immunoglobulin or plasma- Neuropsychiatric Disorder Associated with pheresis, have highly significant advantages com- Streptococcal Infections, Pediatric Infection- pared to placebo [123] . Triggered Autoimmune Neuropsychiatric The conceptual and terminological heteroge- Disorder and Pediatric Acute-Onset neity discussed above reflects the difficulties not Neuropsychiatric Syndrome as Infectious only of postinfectious (auto-)immune syn- Disorders Presenting as (Neuro-) Psychiatric dromes, but also of infection- and immune-medi- Symptoms ated disorders in psychiatry in general: the pathophysiological process is not fully elucidated, spe- There are further examples for the involvement of cific mechanisms still need to be explored and infections in psychiatric disorders. Pediatric au- further scientific efforts are necessary. On the toimmune neuropsychiatric disorder associated other hand, similar to the neurotransmitter-cen- with streptococcal infections (PANDAS) mani- tered biological approach in psychiatry in which fests with tics, Tourette’s syndrome and/or obses- therapies were developed first and biological ex- sive-compulsive symptoms [116], and is a conse- planations came later, effective therapeutic ap- quence of streptococcal infection. However, not proaches are on the way and may provide post only Streptococcus but also other infectious agents hoc validation of the discussed concepts. such as Borrelia burgdorferi [117] or Mycoplasma pneumoniae [118, 119] may directly or indirectly cause this syndrome. Therefore, the concept of Conclusions pediatric infection-triggered autoimmune neuropsychiatric disorder, a postinfectious syndrome The possible influences of infection and immune not restricted to streptococcal infection, was in- processes on the pathogenesis of major psychiat- troduced [116, 120]. The broader concepts of pe- ric disorders resulting in inflammation have long diatric acute-onset neuropsychiatric syndrome been neglected. Increasing evidence for a role of [121] and childhood acute neuropsychiatric syn- proinflammatory cytokines in major depression dromes, which define a much broader clinical and schizophrenia, the strong influence of pro- spectrum encompassing etiologically diverse en- and anti-inflammatory cytokines on the trypto- tities, were recently proposed to overcome the phan/kynurenine metabolism and – related to

108 Müller

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 99–113 ( DOI: 10.1159/000365542 ) that mechanism – the influence of cytokines on model’ of schizophrenia – a condition sine qua the glutamatergic neurotransmission support the non in schizophrenia, it is also a confounding fac- view that infection, psychoneuroimmunology tor for research of the immune system and in- and inflammation rightly should be a focus of flammatory processes. psychiatric research. This view is fostered by the These considerations show that further re- results of (immuno-) genetic findings and the ex- search is needed to clarify the role of infection and hibited therapeutic effects of anti-inflammatory of the immune system in psychiatric disorders. drugs in schizophrenia and major depression. On Recent results encourage placing further empha- the other hand, it is possible that immunological sis on this fascinating field. Therapeutic studies, research in patients may be susceptible to arte- including meta-analyses, support the view that facts; interfering variables such as medication, therapeutic progress based on anti-inflammatory smoking, stress, sleep and others play an impor- and/or immunomodulating approaches are not tant role and cannot always been controlled. This only of theoretical interest, but may have an im- can be shown by the example of stress: stress is portant clinical impact and might lead to a para- not only – according to the ‘vulnerability-stress- digm change in psychiatric therapy.

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chiatr Scand 2014; 129: 163–179. 97 Song C, Leonard BE: Fundamentals of patients with major depressive disor- 88 Müller N, Riedel M, Scheppach C, psychoneuroimmunology. Chicester, J der: randomized double-blind placebo-

Brandstätter B, Sokullu S, Krampe K, Wiley and Sons, 2000. controlled study. J Affect Disord 2012;

Ulmschneider M, Engel RR, Möller HJ, 98 Cao C, Matsumura K, Ozaki M, Wata- 141: 308–314. Schwarz MJ: Beneficial antipsychotic nabe Y: Lipopolysaccharide injected 106 Raison CL, Rutherford RE, Woolwine effects of celecoxib add-on therapy com- into the cerebral ventricle evokes fever BJ, Shuo C, Schettler P, Drake DF, Ha- pared to risperidone alone in schizo- through induction of cyclooxygenase-2 roon E, Miller AH: A randomized con-

phrenia. Am J Psychiatry 2002; 159: in brain endothelial cells. J Neurosci trolled trial of the tumor necrosis fac-

1029–1034. 1999; 19: 716–725. tor antagonist infliximab for 89 Müller N, Riedel M, Schwarz MJ, Engel 99 Sandrini M, Vitale G, Pini LA: Effect of treatment-resistant depression: the RR: Clinical effects of COX-2 inhibitors rofecoxib on nociception and the sero- role of baseline inflammatory bio-

on cognition in schizophrenia. Eur Arch tonin system in the rat brain. Inflamm markers. JAMA Psychiatry 2013; 70:

Psychiatry Clin Neurosci 2005; 255: 149– Res 2002; 51: 154–159. 31–41. 151. 100 Myint AM, Steinbusch HW, Goeghe- 107 Na KS, Lee KJ, Lee JS, Cho YS, Jung 90 Müller N: COX-2 inhibitors as antide- gan L, Luchtman D, Kim YK, Leonard HY: Efficacy of adjunctive celecoxib pressants and antipsychotics: clinical BE: Effect of the COX-2 inhibitor cele- treatment for patients with major de- evidence. Curr Opin Investig Drugs coxib on behavioural and immune pressive disorder: a meta-analysis.

2010; 11: 31–42. changes in an olfactory bulbectomised Prog Neuropsychopharmacol Biol Psy-

91 Müller N, Krause D, Dehning S, Musil R, rat model of depression. Neuroimmu- chiatry 2014; 48: 79–85.

Schennach-Wolff R, Obermeier M, nomodulation 2007; 14: 65–71. 108 Tyring S, Gottlieb A, Papp K, Gordon Möller HJ, Klauss V, Schwarz MJ, Riedel 101 Brunello N, Alboni S, Capone G, Bena- K, Leonardi C, Wang A, Lalla D, Wool- M: Celecoxib treatment in an early stage tti C, Blom JM, Tascedda F, Kriwin P, ley M, Jahreis A, Zitnik R, Cella D, of schizophrenia: results of a random- Mendlewicz J: Acetylsalicylic acid ac- Krishnan R: Etanercept and clinical ized, double-blind, placebo-controlled celerates the antidepressant effect of outcomes, fatigue, and depression in trial of celecoxib augmentation of amis- fluoxetine in the chronic escape deficit psoriasis: double-blind placebo-con-

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 99–113 ( DOI: 10.1159/000365542 ) 109 Meyer U, Schwarz MJ, Müller N: In- 116 Swedo SE, Leonard HL, Garvey M, 122 Macerollo A, Martino D: Pediatric au- flammatory processes in schizophre- Mittleman B, Allen AJ, Perlmutter S, toimmune neuropsychiatric disorders nia: a promising neuroimmunological Dow S, Zamkoff J, Dubbert BK, Lougee associated with streptococcal infec- target for the treatment of negative/ L: Pediatric autoimmune neuropsychi- tions (PANDAS): an evolving concept. cognitive symptoms and beyond. Phar- atric disorders associated with strepto- Tremor Other Hyperkinet Mov (N Y)

macol Ther 2011; 132: 96–110. coccal infections: clinical description 2013; 3: pii: tre-03–167-4158-7. 110 Benros ME, Mortensen PB, Eaton of the first 50 cases. Am J Psychiatry 123 Perlmutter SJ, Leitman SF, Garvey MA,

WW: Autoimmune diseases and infec- 1998; 155: 264–271. Hamburger S, Feldman E, Leonard HL, tions as risk factors for schizophrenia. 117 Riedel M, Straube A, Schwarz MJ, Wil- Swedo SE: Therapeutic plasma ex-

Ann NY Acad Sci 2012; 1262: 56–66. ske B, Müller N: Lyme disease present- change and intravenous immunoglob- 111 Hennessy MB, Schiml-Webb PA, Mill- ing as Tourette’s syndrome. Lancet ulin for obsessive-compulsive disorder

er EE, Maken DS, Bullinger KL, Deak 1998; 351: 418–419. and tic disorders in childhood. Lancet

T: Anti-inflammatory agents attenuate 118 Müller N, Riedel M, Forderreuther S, 1999; 354: 1153–1158. the passive responses of guinea pig Blendinger C, Abele-Horn M: To- 124 Maes M, Bosmans E, Calabrese J, pups: evidence for stress-induced sick- urette’s syndrome and mycoplasma Smith R, Meltzer HY: Interleukin-2 ness behavior during maternal separa- pneumoniae infection. Am J Psychia- and interleukin-6 in schizophrenia and

tion. Psychoneuroendocrinology 2007; try 2000; 157: 481–482. mania: effects of neuroleptics and

32: 508–515. 119 Müller N, Riedel M, Blendinger C, mood stabilizers. J Psychiatr Res 1995;

112 Avitsur R, Sheridan JF: Neonatal stress Oberle K, Jacobs E, Abele-Horn M: 29: 141–152. modulates sickness behavior. Brain Be- Mycoplasma pneumoniae infection 125 Hestad KA, Tonseth S, Stoen CD,

hav Immun 2009; 23: 977–985. and Tourette’s syndrome. Psychiatry Ueland T, Aukrust P: Raised plasma

113 Pace TW, Mletzko TC, Alagbe O, Mus- Res 2004; 129: 119–125. levels of tumor necrosis factor alpha in selman DL, Nemeroff CB, Miller AH, 120 Allen AJ, Leonard HL, Swedo SE: Case patients with depression: normaliza- Heim CM: Increased stress-induced study: a new infection-triggered, auto- tion during electroconvulsive therapy.

inflammatory responses in male pa- immune subtype of pediatric OCD and J ECT 2003; 19: 183–188. tients with major depression and in- Tourette’s syndrome. J Am Acad Child 126 Müller N, Schwarz MJ, Riedel M: COX-

creased early life stress. Am J Psychia- Adolesc Psychiatry 1995; 34: 307–311. 2 inhibition in schizophrenia; in Eaton

try 2006; 163: 1630–1633. 121 Macerollo A, Martino D: Pediatric au- WW (ed): Medical and Psychiatric 114 Zeugmann S, Quante A, Heuser I, toimmune neuropsychiatric disorders Comorbidity over the Course of Life. Schwarzer R, Anghelescu I: Inflamma- associated with streptococcal infec- Washington, American Psychiatric tory biomarkers in 70 depressed inpa- tions (PANDAS): an evolving concept. Publishing, 2006, pp 265–276. tients with and without the metabolic Tremor Other Hyperkinet Mov (N Y). 127 Benros ME, Nielsen PR, Nordentoft M,

syndrome. J Clin Psychiatry 2010; 71: 2013 Sep 25;3. pii: tre-03-167-4158-7. Eaton WW, Dalton SO, Mortensen PB: 1007–1016. Autoimmune diseases and severe in- 115 Zeugmann S, Quante A, Popova-Zeug- fections as risk factors for schizophre- mann L, Kossler W, Heuser I, Anghe- nia: a 30-year population-based regis-

lescu I: Pathways linking early life ter study. Am J Psychiatry 2011;168: stress, metabolic syndrome, and the 1303–1310. inflammatory marker fibrinogen in depressed inpatients. Psychiatr Danub

2012; 24: 57–65.

Prof. Dr. med. Dipl.-Psych. Norbert Müller Department of Psychiatry and Psychotherapy Ludwig-Maximilian University Nussbaumstrasse 7, DE–80336 Munich (Germany) E-Mail [email protected]

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 114–128 ( DOI: 10.1159/000365543 )

Physical Diseases and Addictive Disorders: Associations and Implications

a–c a, b d Adam J. Gordon · James W. Conley · Joanne M. Gordon a b Center for Health Equity Research and Promotion (CHERP) and Mental Illness Research, Education, and c Clinical Center (MIRECC), VA Pittsburgh Healthcare System, Division of General Internal Medicine, University d of Pittsburgh School of Medicine, Pittsburgh, Pa. , and Biomedical Sciences, Missouri State University, Springfield, Mo., USA

Abstract substances, co-occurring or incident physical health con- Increasingly, the identification, assessment and treat- ditions associated with substance use may present a sub- ment of unhealthy use of alcohol and other drugs often stantial healthcare cost to the individual as well as to the occur within general medical settings. Within this cli- healthcare system at large, resulting in a debilitating mate, there is a growing awareness of the physical effects strain on often limited time and resources. connected to acute or chronic use of substances of abuse. © 2015 S. Karger AG, Basel By examining these associations and their purported biological causative mechanisms, greater clinical attention – in the form of screening, identification and treatment – to Alcohol and illicit drug use and related use disor- co-occurring medical conditions as well as to the use of ders impact mental, physical and environmental illicit substances itself may be possible. In this review, we health. Identification and treatment of addictive examine recent peer-reviewed literature regarding three disorders are the responsibility of all healthcare substances of abuse (cocaine, marijuana and opioids) providers. Currently, the education and training and their direct associations with physical disorders. We of healthcare professionals to address co-occur- group the association of diseases based on organ sys- ring physical and mental health conditions asso- tems and critically examine the literature regarding the ciated with alcohol and illicit drug use and related evidence to supporting those associations and causative use disorders may not be a focus of medical edu- mechanisms. There is good evidence to support the as- cation and training. Because they have not been sociation of cocaine, marijuana and opioid use with a va- exposed to sufficient undergraduate or graduate riety of physical health conditions. Unfortunately, while medical education regarding screening, assess- the causative evidence of these associations is prelimi- ment, and treatment of alcohol and illicit drug nary, we could conclude that the use of these substances use, providers may feel inadequately equipped to can incite a host of medical illnesses or complicate their engage the complex intersection between mental treatment. When combined with societal, mental health and physical health presented by ongoing alcohol and public health harms associated with the use of illicit and substance use. In some countries, a concerted effort has been undertaken in primary care to ed- Immune System ucate generalist healthcare providers about addiction and alcohol and illicit drug-related physi- Cocaine cal and medical health disorders [1–4] . While An increasing body of evidence, both from clini- much attention has been devoted to physical con- cal epidemiological and laboratory studies, points ditions resulting from alcohol use [5–8], less at- to an association between cocaine use and an al- tention has been directed to the associations be- tered innate immune response that involves a de- tween physical conditions and other illicit drug crease in monocyte expression of several cyto- use [9, 10] . kines [11]. As a weak agonist for sigma receptors, A pressing need exists for better understand- cocaine has also been found to alter cytokine re- ing among healthcare providers of the serious lease from both proinflammatory and anti-in- health and healthcare implications of illicit sub- flammatory T cells [12] . These studies suggest stance abuse, particularly for physical health con- that cocaine use can have a direct effect on the ditions. The purpose of this review is to examine innate immune system and thus increase the like- the co-occurring and comorbid relationships be- lihood of greater risk for infectious diseases. tween major drugs of abuse and physical illness. Adulterants in cocaine, specifically levamisole, Similar to previous efforts, we examined the re- which is found in more than half of the cocaine in cent peer-reviewed literature regarding evidence the USA [13] , has a direct effect on the immune of the associations of illicit substance use on system. Leukopenia (especially neutropenia), physical health conditions [9, 10] . We investigat- agranulocytosis and vasculitis have been associ- ed the literature to detail physical health issues ated with levamisole. associated with the use of three of the most common substances of abuse (cocaine, marijuana Marijuana and opioids). While physical illnesses associated Despite strong evidence that cannabinoid type 2 with use of other broad categories of drugs of receptors are found predominantly on cells in- abuse, such as stimulants and hallucinogens, may volved in immunity and inflammation and can mirror the health effects of cocaine (stimulants) decrease activity of immune cells [14], no link has or marijuana (hallucinogens), for simplicity and been shown between marijuana use and hemato- brevity we concentrated our review on only co- poietic or lymphatic disorders. caine, marijuana and opioids. Although each substance may invite risk of physical illness due Opioids to the nature of taking the substance (e.g. injec- Some of the opioids, including fentanyl, metha- tion or inhalation), or social and environmental done, loperamide and β-endorphin, have been problems associated with use (e.g. risky sexual found to increase the levels of interleukin-4 (IL-4) practices, trauma or other criminal activity), we in human type 2 T cells while other opioids, such as concentrated our review on the direct associa- morphine and buprenorphine decrease the levels tions between the substance in question and of IL-4 [15] . However, a study of male long-term physical health. For many of these associations, daily opium users in Iran did not show a change in we examined purported pathophysiological rea- IL-4 levels compared to controls [16] , although sons for the association with physical ill-health. there were higher levels of other cytokines associ- Thus, we provide a brief description of physical ated with either cellular or humoral immunity health conditions related to use of these three (interferon-γ, IL-10 and IL-17), indicating that substances, organized according to generalized some opioids have an effect on the immune re- bodily systems. sponse and the ability to react to infectious agents.

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 114–128 ( DOI: 10.1159/000365543 ) Infection of cocaine compared to those who used amphetamines, lysergic acid diethylamide (LSD) or Cocaine methaqualone [27] . Besides the effect of cocaine on the innate immune system, cocaine use can increase the risk of infec- Marijuana tions through risky behavior associated with drug There appears to be a link between marijuana use use, e.g. unprotected sex, multiple sexual partners, and some cancers in long-term users. However, needle sharing and contaminated drug parapher- many studies are hampered by selection bias, nalia. Unhealthy living conditions and malnutri- small sample size, lack of adjustment for concur- tion can also influence the risk for infections. rent tobacco use and other problems. Marijuana use has been linked to bladder cancer [28] , cancer Marijuana of the head and neck [29, 30] , and lung cancer Marijuana users may be more vulnerable to infec- [31–33]. Marijuana use has also been associated tion than the general public. Combined with can- with testicular germ cell tumors [34–36] . Smoked nabinoids’ suppression of the inflammatory re- marijuana tar contains carcinogens similar to sponse and natural immunity [17] , marijuana use those found in cigarettes [37] , and while studies may promote greater susceptibility and decreased are still inconclusive, it is reasonable to suspect resistance to a wide array of infections. The com- that marijuana smoking may contribute to other mon practice of shared or communal use of cancers as well, including oral and pharyngeal bongs, pipes and marijuana cigarettes may fur- cancer. ther promote transmission of airborne and fluid- based diseases, such as tuberculosis [18, 19] . Among other diseases for which marijuana use Hematopoietic Disorders has been correlated with infection are Neisseria meningitidis [20, 21], oral candidiasis [22, 23] and Cocaine sexually transmitted disease [24] . As well, mari- Cocaine has a role in coagulopathy. Recent re- juana users with chronic hepatitis C may be at search has found that use of cocaine increases von greater risk of developing steatosis and fibrosis in Willebrand factor release from the endothelium the liver [25, 26] . [38] . An increase in plasma von Willebrand factor can enhance platelet aggregation and throm- Opioids bus formation, leading to increased risk for sys- Use of opioids is often associated with risky be- temic thrombi in large and small vessels. Cocaine havior, thus increasing the likelihood of being in- use is associated with thrombi formation in coro- fected by human immunodeficiency virus (HIV), nary stents [39] and atherosclerotic lesions and hepatitis B and C, and other sexually transmitted total thrombus occlusion in the main coronary pathogens. Intravenous use of opioids can in- arteries in long-term cocaine users [40] . crease the risk of cellulitis and endocarditis. Marijuana A determination has yet to be made regarding Cancers whether cannabis arteritis is a distinct and separate disease from the thromboangiitis obliterans Cocaine seen in cigarette smokers. Over 50 cases of can- There appears to be an increased risk of develop- nabis arteritis have been reported since 1960 in ing non-Hodgkin’s lymphoma in frequent users marijuana users who did not smoke tobacco [41] ,

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 114–128 ( DOI: 10.1159/000365543 ) and cases of arteritis have been described in regu- tributed to cocaine use. Cocaine users may also lar marijuana users who were moderate users of be more susceptible to developing coronary ar- tobacco [42]. Cannabis arteritis may contribute tery aneurysm [46] . Compared to a control group to juvenile peripheral obstructive arterial disease of individuals with similar cardiovascular risk, [41] . In addition, arteriographic studies have 30.4% of cocaine users (mean age 44 years) had found distal abnormalities similar to thromboan- coronary artery aneurysms, compared to only giitis obliterans, with changes in the architecture 7.6% in a control group. Although rare, postpar- of the vasa nervorum [42] . tum coronary artery dissection has been reported in a 25-year-old woman who had been using cocaine [47] . Arrhythmias, in addition to tachycar- Cardiovascular Disease dia, may occur in cocaine users and have been attributed to ischemia and electrolyte imbalance. Cocaine However, cocaine sequestration in myocytes may The surge of catecholamines in the plasma soon interfere with calcium storage and release and after use of cocaine can cause significant diffuse normal excitation and contraction, thus predis- and focal coronary vasospasm. Additionally, the posing the heart to lethal arrhythmias [48] . Oxi- increase in heart contractility and heart rate and dative stress and direct myocardial toxicity has resultant high blood pressure can cause cardiac been suggested as another reason for the myocar- ischemia, vasospasm and infarction. Cocaine-re- dial cell death associated with ischemia and acute lated endothelin-1 release from the endothelium myocardial infarction in cocaine users [49] . Car- and alterations in platelet aggregation and for- diac oxidative stress occurs soon after cocaine mation of vessel thrombi can contribute to the enters the vascular system, leading to myocyte increased risk of acute myocardial infarction in dysfunction and an increase in the number of in- cocaine users. Young cocaine users may experi- flammatory cells in the heart. ence chest pain, ischemia, arrhythmias and acute myocardial infarction. Atherosclerotic lesions Marijuana are not primarily associated with cocaine-related Marijuana use has already been associated with infarcts [43] . However, myonecrosis and coro- some clinical cardiovascular issues, specifically nary stenosis is often found in cocaine users with heart palpitations, orthostatic hypotension and previous infarctions. Asymptomatic cocaine us- acute increase in heart rate [50, 51] . Long-term ers may have significant cardiac disease (myocar- users may experience an increase in heart rate, dial dysfunction, tissue edema or fibrosis) [44] potentially resulting in cardiac ischemia and the and cocaine-users may have a higher risk than arrhythmic effects of the catecholamines [52] . nonusers in developing silent acute myocardial These users may delay pursuing medical help in infarction. The young age of cocaine users may response to the pain normally associated with be a survival benefit for those who experience a ischemia because of marijuana’s effect as an anal- resuscitated cardiac arrest [45] . Compared to gesic and dissociative agent, further exacerbating noncocaine users, cocaine users often survive the damage over time. There are competing data re- arrest without neurological sequelae. However, garding marijuana and mortality risk with acute the likelihood of young cocaine users experienc- myocardial infarction. While marijuana has been ing a nonfatal acute myocardial infarction was shown to increase the risk of acute myocardial in- higher than those who were not cocaine users. farction within an hour of use when compared to Twenty-five percent of nonfatal acute myocardi- nonsmokers [53] , a longitudinal study taken over al infarction in 18- to 45-year-olds has been at- the course of 15 years did not find an increased

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 114–128 ( DOI: 10.1159/000365543 ) risk of acute myocardial infarction in users [54] . caine [60] . Lesions can include ischemic and Furthermore, no statistically significant associa- necrotic changes to the mucosa, perichondri- tion has yet been found between marijuana use um, nasal septum (including perforation), hard and general mortality [55]. It should be noted that and soft palate, and sinuses. Lacrimal duct ob- marijuana users often have other cardiovascular struction and destruction of the nasal turbi- risk factors, such as higher alcohol and overall ca- nates may also be seen. Because similar lesions loric intake, which increase postmyocardial in- may be seen in patients with granulomatosis, farction mortality in those individuals with coro- sarcoidosis and lymphoma, diagnosis can be nary heart disease [56] . difficult, particularly since antineutrophil cytoplasmic antibody tests may be positive in all of Opioids these conditions. Sniffling, nasal crusts, nose- Cardiovascular effects of opioids include some bleeds and sinus problems are common prob- risk of infective endocarditis (associated with in- lems in cocaine users who may also have burns travenous opiate use) and cardiac arrhythmias, to their upper airway. Depressed hearing and especially long QT syndrome and torsades de diminished sense of smell have also been re- pointes. Long QT syndrome is a condition asso- ported. ciated with an abnormal gene coding for a protein component of myocardial cell potassium- Marijuana voltage gated channels that is important in repo- Similar to tobacco, marijuana smoking increases larization, resulting in a lengthening of the the risk of a number of oral diseases and disor- depolarization/repolarization cycle [57] . Other ders, including xerostomia, tooth decay, peri- risks for long QT syndrome include hypokale- odontitis, severe gingivitis and mucosal abnor- mia. Long QT syndrome can lead to the develop- malities [23], as well as leukoedema and traumat- ment of torsades de pointes, a potentially lethal ic ulcers of the mouth [61] . It should be noted that ventricular arrhythmia. In a randomized trial it is not yet clear whether the higher incidence of comparing the rate-adjusted QT length (QTc) in caries and periodontal disease in marijuana opioid-dependent subjects, the QTc increased in smokers is a direct effect of use or a byproduct of those subjects treated with the opioids levometh- attendant poor hygiene [62] . adyl (21%) and methadone (12%), but not in those treated with buprenorphine [58] . Signifi- Opioids cant risk factors for the development of a pro- A recent article suggests that nasal mucosal ne- longed QTc in individuals on methadone main- crosis found in a small number of patients is re- tenance therapy include the presence of conges- lated to heroin snorting [63] . tive heart failure and other cardiac disease, elevated HbA1c and use of cocaine [59] . Conges- tive heart failure and poor glycemic control in- Respiratory Disease crease the risk for mortality. Cocaine Bronchial and lung dysfunction in cocaine us- Oral, Ear, Nose and Throat Disorders ers include cough, black sputum, hemoptysis and chest pain [9] . Some studies have reported Cocaine an exacerbation of asthma symptoms in those Midline nasal and oral destructive lesions are who smoke crack cocaine [64] and a higher in- significant complications of insufflation of co- cidence of out-of-hospital asthma deaths [65] .

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 114–128 ( DOI: 10.1159/000365543 ) Although crack cocaine users are less likely to infants [80] can occur with fentanyl use in pro- have hemoptysis, respiratory distress and ab- cedural events, but can also occur with illegiti- normal pulmonary function tests than those mate use of the drug. participants who use tobacco [66], cocaine users are more likely to have an increase in alveolar macrophages and endothelin-1 (a po- Gastrointestinal Disorders tent vasoconstrictor) in bronchial alveolar la- vage samples, suggesting that microvascular Cocaine injury is associated with heavy crack cocaine Cocaine use has been implicated in ischemic dis- smoking. ease of the digestive system, with ischemia and/or infarction being reported in the mesentery vessels Marijuana [81], and occlusive disease of the small and large Studies suggest that marijuana users are at an el- bowel [82]. Frequently, the onset of abdominal evated risk of experiencing increased mucus pro- pain is in temporal proximity to use of either duction as well as symptoms of chronic bronchi- crack or intravenous cocaine. The mortality rate tis [67–70]. Cannabis may also be an allergen for associated with ischemic colitis has been found to some [71]. A recent report found that forensic be higher in cocaine users than noncocaine users laboratory workers handling hashish or marijua- [83] . na for 16–25 years developed marijuana hypersensitivity [72]. Others may be at risk for develop- Marijuana ing an allergy to the drug. A number of articles, including a case series [84] , have been published on cases of chronic marijua- Opioids na users who were diagnosed with cannabinoid Respiratory depression is a major adverse effect hyperemesis, characterized by cyclical, chronic of many of the opioids and can cause death in vomiting and severe abdominal pain, and often users. As many as 58% of the deaths related to accompanied by a compulsion to take hot baths drug abuse in Ontario, Canada, between 2006 or showers. The authors report that discontinu- and 2008 were related to opioid use, with over ing marijuana use causes symptoms to dissipate one third of these associated with oxycodone use and further assert that the illness is often under- [73] . Respiratory depression and death may also diagnosed and underreported. occur with opioid use in neonates, the elderly and obese, and those with cardiopulmonary disease. Opioid respiratory depression has also Hepatobiliary Disease been reported in noncancer patients using methadone or transdermal fentanyl for chronic pain Cocaine [74]. Other opioid-related respiratory condi- Hepatotoxicity in cocaine users is likely the result tions have also been reported. Use of methadone of direct toxicity mediated by oxidative stress and was found to be associated with sleep apnea in a mitochondrial dysfunction occurring during me- study of 392 patients using the opioid for chron- tabolism of cocaine [85]. It is likely that cocaine- ic pain [75, 76] . Exacerbation of asthma symp- induced oxidative cell stress leads to cell damage, toms can occur in heroin users [77, 78] , possibly fibrosis and abnormal liver function. This mecha- associated with histamine release by the opioid. nism also occurs in the kidney and many body Aspiration pneumonia is also associated with systems, including the cardiovascular, central opiate use. Chest wall rigidity in adults [79] and nervous, immune and reproductive systems [86] .

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 114–128 ( DOI: 10.1159/000365543 ) Metabolic, Nutritional and Endocrine Marijuana Disorders Glomerular, interstitial and renal vascular disease may all be associated with marijuana use [90] , Marijuana though that link is not definite [91] . Marijuana Although some research has shown that overac- may contribute to male infertility [92] , decrease tivity of cannabinoid receptors may lead to ab- spermatogenesis and circulating testosterone lev- dominal obesity, dyslipidemia and hyperglyce- els [93] , and has been linked to inhibited orgasm mia [87] , there is little clinical evidence that mar- and painful sex [94] . ijuana use is associated with development of diabetes mellitus or hyperlipidemia. Opioids A recent study found that morphine use can ac- Cocaine celerate chronic kidney disease [95] . Glomerular While cocaine use has not been found to have an podocytes appear to be affected by morphine-in- effect on the development of diabetes mellitus, duced oxidative stress, leading to albuminuria cocaine use has been shown to increase the risk of and renal dysfunction. diabetic ketoacidosis and for hospitalization of recurrent diabetic ketoacidosis [88] . Noncompli- ance with the therapeutic regimen is thought to Female Reproductive System be a contributing factor in diabetic ketoacidosis. Cocaine Genital ulcer disease and pelvic inflammatory dis- Renal and Male Urogenital Disorders ease have been reported in women who use cocaine. Both conditions are likely due to sexually transmit- Cocaine ted diseases associated with risky behavior and un- The risk for rhabdomyolysis and acute renal fail- protected sex, as well as immune dysfunction. ure is significant for those who use cocaine. Co- caine has direct toxic effects on skeletal muscle Marijuana and, along with severe vasoconstriction, can cause There is a potential link between female infertility muscle ischemia and release of myoglobin and and marijuana, either as a lone agent or in concert other cell contents from damaged cells [89] . Myo- with other illicit substances [96] . A case control globin is freely filterable in glomeruli, but accu- study found that women who used marijuana with- mulates in the distal tubules, resulting in obstruc- in 1 year of attempting to conceive were not likely tion. The effect of vasoconstriction on the renal to become pregnant [97] . Additionally, marijuana vessels by cocaine, and a possible direct toxic ef- users are six times more likely to develop Tricho- fect of cocaine and myoglobin on renal tissue, monas vaginalis infections than nonusers [98] . contributes to the development of acute renal failure. However, with aggressive therapy, almost 80% of the individuals survive and most recover Pregnancy adequate renal function. Genital ulcer disease found in male cocaine us- Cocaine ers is generally related to unprotected sex and A comparison of 18 studies describing pregnancy contact with partners with sexually transmitted complications found increased risk for preterm diseases and immune dysfunction associated with labor, placenta abruptio, fetal death, placenta pre- cocaine use. via and spontaneous abortion [9] . Infants of co-

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 114–128 ( DOI: 10.1159/000365543 ) caine-using mothers are more at risk for de- found predominantly on the lower extremities, creased weight and length than infants of nonco- but can also develop on the face and ears. Leuko- caine users. Infants of cocaine-using mothers penia and neutropenia may be seen, and labora- were also found to be more at risk for transient tory tests for antineutrophil cytoplasmic antibod- atrial and ventricular arrhythmias than infants of ies can be positive, suggesting an immune reac- noncocaine-using mothers [99] . At birth, neo- tion. Thrombotic vasculopathy and small-vessel nates may experience some autonomic dysregula- vasculitis may be found on skin biopsies. Levam- tion, but withdrawal symptoms are generally isole contamination in cocaine often contributes minimal [100]. Cocaine is not likely to be a direct to the development of these skin lesions. fetal teratogen, although some evidence exists for alteration of cerebral development [101] . Neurological Disorders Marijuana Young women using marijuana during pregnan- Cocaine cy may often have infants with low birth weight The major harms associated with cocaine abuse and decreased length. However, a direct link to of the nervous system are related to cerebrovascu- these consequences as a result of marijuana use is lar disease. Cocaine users are at risk for develop- unclear. Often lack of prenatal care, social prob- ment of subarachnoid hemorrhage associated lems or poor economic conditions may be associ- with ruptured aneurysms, ischemic stroke and ated with these infant outcomes. hemorrhagic stroke [105]. Compared to nonusers, cocaine users are more likely to experience Opioids an aneurysm rupture and less likely to survive As seen with other drugs of abuse, use of opioids subarachnoid hemorrhage than nonusers. Isch- during pregnancy can have detrimental effects on emic strokes are also seen in cocaine users and newborns, including low birth weight and length. may be associated with hypertension, vasospasm, Often, infants are exposed in utero to a number of arteritis and increased platelet aggregation [106] . drugs, including cocaine, heroin, cannabinoids and Cocaine users with ischemic stroke are often benzodiazepines, and their related side effects. younger than nonusers and are more likely to Newborns of opioid-using mothers are particularly smoke tobacco. Morbidity and mortality are sim- at risk for neonatal abstinence syndrome, which ilar in both cocaine users and nonusers. Seizures typically occurs within the first 3 days of life [102] . may also occur after cocaine use, especially in Methadone and buprenorphine have both been women, when high doses are used, with chronic used to manage opioid dependence in pregnant use of cocaine, and in users previously experienc- women. In the newborn, buprenorphine appears to ing seizures [107] . be less likely to alter cardiac function and produces fewer severe side effects than methadone [103] . Marijuana Use of marijuana has been associated with vascular disease in the central nervous system, with Dermatologic Disorders several cases of ischemic strokes documented in recent literature [108–110], including a study Cocaine finding increased risk of stroke in marijuana us- Cutaneous vasculopathy is a dermatologic condi- ers [111]. Marijuana use may increase the risk of tion seen in cocaine users, especially in women the movement disorder tardive dyskinesia [112] . [104] . Retiform rashes with purpuric plaques are In a study of the incidence of tardive dyskinesia in

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 114–128 ( DOI: 10.1159/000365543 ) a group of people with chronic schizophrenia, ure and midline destructive lesions of the face and women and older patients who smoked marijua- oral cavity, are strongly associated with cocaine na while taking antipsychotic drugs were more use. Although no other significant musculoskel- likely to develop repetitive and involuntary move- etal disorders have been reported with cocaine ments than other patients. Links between mari- use, the inclusion of levamisole in cocaine has the juana and transient amnesia [113] , ataxia [114] , potential of leading to untoward rheumatic con- propriospinal myoclonus [115] and spasticity sequences [122] . [116] have yet to be fully explored.

Opioids Conclusion Opioids are often abused because of their stimula- tory effects on the nervous system. However, in In this review, we relate the recent literature re- large doses, opioids can have a detrimental effect garding the physical health associations of the use on the central nervous system and can lead to de- of three drugs of abuse (cocaine, marijuana and lirium and coma. Hydromorphone, on the other opioids) and a variety of physical illnesses (ta- hand, can cause neuroexcitation, as reported in a ble 1 ). The use of cocaine, marijuana and opioids study of 156 hospice patients receiving the drug has been shown to impart a plethora of physical while in an inpatient setting [117]. An increased illnesses, many with purported and examined risk of hydromorphone-induced neuroexcitation pathophysiological mechanisms. While associa- was associated with large doses and longer dura- tions of these conditions are known, the causative tion of drug use, increased age of the patient, and rationales for these conditions are less known. increased serum creatinine. Symptoms often as- More research is certainly needed to examine sociated with hydromorphone-induced neuroex- causation of these drugs with physical illness. It citation include tremor, myoclonus and agitation. may be that when more people use certain drugs Cognitive dysfunction is also commonly seen (e.g. legalization of marijuana and increase in opi- [118] . Spongiform leukoencephalopathy is a rare oid prescription drug misuse), their related phys- sequela of inhalation of heated heroin smoke. In ical health conditions will become more readily one study, postmortem findings in 4 patients with apparent. spongiform leukoencephalopathy showed signifi- For the clinician, our findings that use of illicit cantly higher numbers of apoptotic cells in both substances, namely cocaine, marijuana and opi- the cerebellum and corpus callosum [119] . Cere- oids, have some evidence in the peer-reviewed lit- bral vacuolar degeneration was also found, par- erature of physical health consequences may not ticularly around microvessels. Sequelae include be a surprise. Clinicians often treat patients who hydrocephalus and cerebellar swelling [120] . Al- use illicit substances and often appreciate the del- though rare or possibly underreported, seizures eterious social and environmental harms associ- can occur with opioid use, including generalized ated with this use. Often, patients who use illicit tonic-clonic seizures and status epilepticus [121] . substances have co-occurring mental health conditions and these are readily appreciated by clinicians. However, what may be less known are the Musculoskeletal Disease physical health conditions that may be directly attributable to use of illicit substances. Certainly, we Cocaine found that significant evidence exists of a myriad As previously mentioned, two musculoskeletal of physical health conditions that may be directly conditions, rhabdomyolysis with acute renal fail- attributable to illicit substance use.

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 114–128 ( DOI: 10.1159/000365543 ) Table 1. Conditions clinicians are likely to see with use of three commonly abused substances

System Cocaine Marijuana Opioids

Immune altered cytokine release leading to no association with altered altered cytokine function; system increased risk of infections; leukopenia, immunity, inflammation increased risk of altered agranulocytosis, vasculitis associated cellular, humoral immune with additive levamisole response Infection increased due to risky behavior, higher risk for Neisseria, increased risky behavior unhealthy living conditions, malnutrition Candida, sexually associated with HIV, hepatitis transmitted diseases, B and C, other sexually chronic hepatitis C with transmitted disease; liver steatosis, fibrosis intravenous use and increased cellulitis, endocarditis Cancer increased risk of non-Hodgkin’s increase risk of bladder lymphoma cancer, cancer of head and neck, lung; testicular germ cell cancer; oral and pharyngeal cancer Hematopoietic increased risk of coagulopathy (VWF), cannabis arteritis disorders thrombus formation; atherosclerotic (thromboangiitis lesions, thrombi in systemic, main obliterans); peripheral coronary arteries obstructive arterial disease Cardiovascular high blood pressure, cardiac ischemia, cardiac palpitations, infective endocarditis; disease vasospasm, infarction; increased orthostatic hypotension, arrhythmias including long systemic vessel thrombi, AMI, silent tachycardia; increased risk QT-syndrome, torsades de infarct; arrhythmias; coronary aneurysms of silent AMI and infarct pointes; congestive heart soon after use; coexisting failure cardiac risk factors Oral, ear, nose, midline nasal, oral destructive lesions xerostomia, periodontitis, mucosal necrosis in heroin throat disorders with insufflation, positive ANCA test; gingivitis, mucosal lesions, snorters sinus disease; upper airway burns ulcers Respiratory bronchial, lung dysfunction, cough, increased mucus respiratory depression and disease hemoptysis, chest pain; exacerbation of production, signs and death (oxycodone), asthma symptoms; increased symptoms of chronic particularly in neonates, microvascular injury bronchitis; increased risk elderly, obese, those with for marijuana allergy cardiopulmonary disease; increased sleep apnea; exacerbation of asthma symptoms (heroin); aspiration pneumonia; chest wall rigidity Gastrointestinal mesenteric ischemia, infarction, cannabinoid hyperemesis, disorders occlusive disease of small and large often associated with bowel; increased risk of death from compulsion for hot bath or ischemic colitis shower Hepatobiliary liver fibrosis, abnormal liver function disease secondary to oxidative stress Metabolic, increased risk of diabetic ketoacidosis possible abdominal nutritional, secondary to noncompliance to obesity, dyslipidemia, endocrine treatment regime hyperglycemia disorders

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 114–128 ( DOI: 10.1159/000365543 ) Table 1. Continued

System Cocaine Marijuana Opioids

Renal, male increased risk of rhabdomyolysis, acute glomerular, interstitial, acceleration of chronic renal urogenital renal failure; genital ulcer disease renal vascular disease; disease associated with disorders secondary to unprotected sex possible infertility with oxidative stress decreased spermatogenesis and testosterone; erectile dysfunction Female genital ulcer disease, pelvic infertility; increased risk of reproductive inflammatory disease Trichomonas infection system Pregnancy increased risk of preterm labor, placenta decreased birth length and decreased birth length and abruptio, fetal death, placenta previa, weight weight; high risk for neonatal spontaneous abortion; transient atrial abstinence syndrome and ventricular arrhythmias; decreased birth length and weight Dermatologic cutaneous vasculopathy (retiform rash, disorders purpuric plagues); leukopenia, neutropenia; small vessel disease; positive ANCA test; thrombic vasculopathy Neurological cerebrovascular disease (ischemic, cerebrovascular disease delirium, coma; neuro- disease hemorrhagic stroke); aneurysm rupture, (ischemic stroke); increased excitation (hydromorphone); subarachnoid hemorrhage; seizures risk for tardive dyskinesia; cognitive dysfunction; transient amnesia; ataxia; spongiform propriospinal myoclonus, leukoencephalopathy (heated spasticity heroin smoke); seizures Musculoskeletal rhabdomyolysis with acute renal failure; disease midline destructive lesions (face, oral cavity); rheumatoid findings with levamisole

AMI = Acute myocardial infarction; ANCA = antineutrophil cytoplasmic antibody; VWF = von Willebrand factor.

Clinicians, particularly general practitioners tive approach for assessing and treating these or primary care providers, should screen and as- physical health conditions associated with illicit sess for illicit substances among their patients. If use may be valuable, as patients who use illicit they identify a patient who uses an illicit sub- substances may not seek medical care, and cer- stance, our review of literature relates that they tainly may not establish longitudinal healthcare should consider evaluating for physical health services, such as a general practitioner or primary conditions associated with that use. Even mental care provider. In addition, attention in healthcare health providers should consider assessing for professional schools and training programs re- these physical health conditions, as patients with garding the association of illicit substances and illicit substances may not seek care with a general physical health may be warranted. In sum, physi- practitioner or primary care provider. A proac- cal health conditions associated with use of illicit

124 Gordon · Conley · Gordon

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 114–128 ( DOI: 10.1159/000365543 ) drugs is a significant concern for all patients who sociations to physical illness, but due to the route use illicit substances and should be a concern for of exposure. While we critically examined the lit- their healthcare providers as well as healthcare erature, much of the literature examines associa- provider educators. tions rather than causations, or exists in the form This review has significant limitations related of case reports, case series or descriptive studies. to our approach which should temper overreach- Conclusions regarding the specificity and strength ing or generalizing our findings. We reviewed of the association with drugs of abuse and physi- only the recent (over the last 2 decades) peer-re- cal illness should be tempered unless there is evi- viewed literature, and only that which was pub- dence of biological mechanisms to support the as- lished in English. It may be that some published sociation. studies remained undiscovered in the process of Despite these limitations, drugs of abuse un- our electronic review. We did not cover other il- questionably cause physical health effects. Some licit drugs of abuse, but much of the literature on of the diseases connected to cocaine, marijuana amphetamines is similar to the literature on co- and opioid use possess strong evidence of disease caine and much of the literature on hallucinogens association. These diseases are often serious, re- is similar to the literature on marijuana. We did sulting in a significant burden on healthcare sys- not examine the behavioral, mental health, social tems to finance, treat or support long-term man- and environmental problems that afflict persons agement of these conditions. All healthcare pro- who use substances of abuse, and we did not con- viders should be aware of these associations and centrate this review on the associations made discuss these associations with patients who use through the route of drug administration (e.g. in- these substances. By doing so, illicit use, as well as crease in hepatitis C and HIV through injections the physical harm and diseases associated with of illicit drugs) as these were not direct drug as- that use, may be diminished or even eliminated.

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Adam J. Gordon, MD, MPH Center for Health Equity Research and Promotion, CHERP: 151-C, VA Pittsburgh Healthcare System University of Pittsburgh School of Medicine University Drive C Pittsburgh, PA 15240-1001 (USA) E-Mail [email protected]

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 114–128 ( DOI: 10.1159/000365543 ) Management of Comorbidity of Mental and Physical Illness

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 129–136 ( DOI: 10.1159/000365544 )

The Role of General Practitioners and Family Physicians in the Management of Multimorbidity

a, c, d a, c, d b–d P. Boeckxstaens · J. De Maeseneer · A. De Sutter a b c Community Health Centre ‘Botermarkt’ and Community Health Centre ‘Rabot’, Department of Family d Medicine and Primary Health Care and International Center for PHC and Family Medicine, Ghent University, Ghent , Belgium

Abstract The Epidemiological Transition towards The rising prevalence of chronic conditions also implies People with Multiple Chronic Conditions a rise in multimorbidity. Comorbid diseases are important because they influence the diagnostic process, the Due to the aging of the population and the rising therapeutic approach, the effect of the treatment and prevalence of chronic diseases, the number of ultimately the patient’s outcome. Most studies on chron- people suffering from more than one disease will ic diseases have focused on patients with a single condi- continuously increase. Anderson et al. [1] have tion and the evidence on how to manage coexisting reported that in the general population, 50% of chronic diseases is lacking. Moreover, most health sys- those aged over 65 years have at least 3 chronic tems have been developed to tackle diseases through conditions, and 20% of those aged over 65 years vertical disease-oriented programs. This chapter dis- have at least 5 chronic conditions. The lack of cusses the challenges of multimorbidity (including men- comparability between studies precludes giving tal illness) from a primary care perspective and the role an overall estimate on the prevalence of multi- of family physicians or general practitioners in the man- morbidity since this is very dependent on the way agement of multimorbidity. Strong primary care sys- multimorbidity is measured [2, 3]. However, re- tems can enable a comprehensive approach to multi- gardless of the measure used, the prevalence of morbidity, shifting the paradigm from ‘disease multimorbidity is high and will rise further. This orientation’ towards ‘goal orientation’. is especially the case in older persons, where mul- © 2015 S. Karger AG, Basel timorbidity will become the rule rather than the exception in clinical care. The comorbidity of gradient for every age group, with multimorbid- mental and physical disorders is the least well re- ity being more prevalent in the most deprived searched, with many studies excluding patients groups [10], while deprivation is frequently linked with psychiatric comorbidity, despite the mental to depressive symptoms. comorbidity creating important challenges for Moreover, from the patients’ perspective, the clinical management. distinction between index diseases and comorbid diseases is often irrelevant because the impact of diseases on their lives crosses the boundaries of General Practice: From a Comorbidity to a individual diseases. In fact, as indicated in one of Multimorbidity Perspective the latest reviews on COPD and comorbidities [4], whatever the underlying mechanism of co- In the 1980s and 1990s, the focus of chronic care morbidities, the personal, clinical, prognostic and was on single diseases. Comorbidity was includ- therapeutic impact on the patient asks for a shift ed as a MeSH term for the first time in 1989. Most from comorbidity to multimorbidity. research on the coexistence of chronic diseases originated from fundamental research and focused on the underlying mechanisms of comor- How Does the Health System Address bidities. In the case of chronic obstructive pul- Patients with (Several) Chronic Conditions monary disease (COPD), abundant comorbidity Today? research has indicated that selected comorbidities, such as atherosclerotic disease, depression, In recent years, not only Western countries, but chronic kidney disease and cognitive impair- also developing countries, have started ‘chronic ment, are found more frequently among people disease management programs’ [11, 12] in order with COPD [4–7] . The same applies for diabetes, to improve care for long-term chronic condi- rheumatoid arthritis and many other diseases for tions. A recent survey of ‘chronic disease manage- which comorbidities have been documented. ment’ in 10 European countries illustrated that The term ‘multimorbidity’ was introduced in disease-management programs in most countries the 1990s and is not yet a MeSH term. It is impor- are organized around a single chronic condition, tant to distinguish the concepts of comorbidity e.g. diabetes, sometimes focusing on subgroups and multimorbidity [8]. Comorbidity always im- within a specific chronic disease, e.g. disease- plies an index disease, whereas multimorbidity is management programs that only include people defined as any co-occurrence of medical condi- with type 2 diabetes [12]. Incentives have been tions within a person. From the perspective of defined in order to stimulate both patients and primary healthcare, the construct of multimor- providers to adhere to guidelines. This develop- bidity is particularly relevant because general ment has led to important results, e.g. in process practitioners deal with the broad spectrum of dis- and (biomedical) outcome indicators defined by eases affecting these patients and do not necessar- the UK Quality and Outcomes Framework [13] . ily put one disease or body system at the forefront. Moreover, the ‘chronic disease management’ ap- When it comes to mental illness, Gunn et al. [9] proach has led to an acceleration of task-shifting clearly demonstrated that the number of (physi- from physicians to nurses, dieticians and health cal) chronic conditions is directly related to the educators. presence of depressive symptoms [9] . Moreover, Disease-management programs also have in- as is the case for most chronic conditions, in pa- creased the attention given to interventions that tients with multimorbidity there is a clear social improve the knowledge and skills of patients in

130 Boeckxstaens · De Maeseneer · De Sutter

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 129–136 ( DOI: 10.1159/000365544 ) dealing with their chronic condition, e.g. self- According to the guidelines, Jennifer is faced management of diabetes. Despite some criticism with a lot of tasks: joint protection, aerobic exercise, regarding equity [14, 15], the sustainability of the muscle strengthening, a range of motion exercising, quality of improvement and comprehensiveness self-monitoring of blood glucose, avoiding environmental exposure that might exacerbate COPD, wear- versus a reductionist nature of the programs [16] , ing appropriate foot wear, limiting intake of alcohol these programs in general have received positive and maintaining body weight. She has to receive pa- feedback from providers, patients and politicians. tient education regarding diabetes self-management, However, the continuous development of single- foot care, osteoarthritis and the COPD medication disease programs may also entail a growing mis- delivery system training. Her medication schedule match between the needs of people living with includes 11 different drugs, with a total of 20 admin- multimorbidity and the resources offered by a istrations a day. The clinical tasks for the general health system that increasingly focuses on dis- practitioner in relation to this patient include vacci- ease-defined care. nation, blood pressure control at all clinical visits, evaluation of self-monitoring of blood glucose, foot examination, laboratory tests, and psychological assessment and support in episodes of depression. Why Primary Care? Moreover, referrals are needed for physiotherapy, retinal examination, pulmonary rehabilitation and Although much has been learned from vertical psychotherapy. disease-oriented programs, better outcomes Jennifer lives independently at home, with some could be reached by addressing diseases through help from her youngest daughter, Elisabeth. I visit her an integrated approach in a strong primary care regularly and each time she starts by saying: ‘Doctor, system. An example is Brazil, where therapeutic you must help me’. Then a succession of complaints coverage for HIV/AIDS reaches almost 100%, and unwell feeling follows. Sometimes it has to do with her heart, another time with lungs, then the hip and which is far higher than HIV/AIDS programs in sometimes depression. Each time I suggest – accord- other countries with less robust primary care. ing to the guidelines – all sorts of examinations that do Vertical disease-oriented programs for HIV/ not improve her condition. Her requests become more AIDS, malaria, tuberculosis and other infectious and more explicit, while my feelings of powerlessness, diseases encourage duplication and the inefficient inadequacy and irritation increase. Moreover, I have use of resources. They produce gaps in the care of to cope with guidelines that are contradictory: for patients with multimorbidity [17, 18] and cause COPD she sometimes needs corticosteroids, which al- inequity for patients who do not have the ‘right’ ways worsens her diabetes control. The adaptation of disease [19] . Horizontal primary care provides the medication for the blood pressure (once too high, once too low) does not meet with her approval, nor the opportunity for integration and addresses the does my interest in her HbA1C and lung function test problem of inequity, providing access to the care results. for all health problems, thereby avoiding ‘inequity by disease’ [20] .

How Can We Build an Evidence Base for The Case of Jennifer Multimorbidity?

Jennifer is 75 years old. Fifteen years ago she lost her hus- Clinical decisions must be based on adequate band. She has been a patient at the practice for 15 years knowledge of diseases (medical evidence), but at now. She has been through a difficult medical history: hip replacement surgery for osteoarthritis, hypertension, type the same time they must take into account pa- 2 diabetes, COPD and episodes of depression. tient-specific aspects of medical care (contextual

Managing Multimorbidity in Primary Care 131

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 129–136 ( DOI: 10.1159/000365544 ) evidence) and efficiency and equity (policy evi- agement of multimorbidity to the personal cir- dence) [21] . As far as medical evidence is con- cumstances of these patients, such as vitality, per- cerned, in primary healthcare we are confronted sonal preferences and socioeconomic conditions. with the tension between the results of actual They stressed the importance of tailoring care to clinical research on the one hand and the needs the individual and trying to understand the of daily clinical practice on the other hand. As meaning of illness for a person. A personal pa- the case of Jennifer illustrates, questions arise tient-doctor relationship and continuity of care about which evidence to follow in the case of were considered major facilitators in the man- multimorbidity. Treatment according to the agement of multimorbidity, and the presence of guidelines for one condition (corticosteroids for mental health problems was regarded as a com- COPD) may interfere with the guidelines for an- plicating factor. In order to build a useful and rel- other (glycemic control in type 2 diabetes). evant evidence base for multimorbidity, there is There is a lot of evidence available on the man- a need to explore new generic ways and para- agement of COPD and type 2 diabetes for peo- digms to approach patients with multimorbidity ple younger than 75 years and without comor- which allow tailoring care to focus on the needs, bidity, but there is little, if any, evidence about goals and expectations of each individual patient how to treat a 75-year-old woman who has both [26–28] . disorders. This problem implies a need for research on the effectiveness of diagnostic and therapeutic From Problem-Oriented Towards interventions that take into account these as- Goal-Oriented Care pects of patients in primary care. The challenge of multimorbidity illustrates the lack of appro- Jennifer eventually said, ‘Doctor, I want to tell priate evidence. Most available evidence to you what really matters to me. On Tuesday and treat chronic diseases has been collected in sin- Thursday, I want to visit my friends in the neigh- gle-disease trials, often excluding patients with borhood and play cards with them. On Saturday, comorbid diseases. A possible solution to tack- I want to go the supermarket with my daughter. le the evidence gap for multimorbidity may be And for the rest of the week, I want to be left in to engage in the development of randomized peace. I do not want to continually change the clinical trials or guidelines on patients with therapy anymore, especially not having to do this specific combinations of diseases [22, 23] . and to do that’. In the conversation that followed, However, a practice-based cross-sectional anal- it became clear to me how Jennifer had formu- ysis of the medical records of 543 patients aged lated the goals for her life. At the same time I felt over 65 years in primary care has shown that challenged to identify how the guidelines could patients with multimorbidity have complex and contribute to the achievement of Jennifer’s goals. unique combinations of problems [24]. I have enjoyed visiting Jennifer ever since. I know The low prevalence of disease combinations at what she wants and how much I can (merely) the practice level will hamper the usefulness of contribute to her life. randomized trials and guidelines for providers. Jennifer’s case clearly illustrates the need for Moreover, many of the strongest associations a paradigm-shift for chronic care: from problem show a contribution of a psychiatric problem or oriented to goal oriented. In 1991, Mold et al. a social problem which demands a tailored ap- [27] recognized that the problem-oriented mod- proach. Luijks et al. [25] showed that general el, which focuses on the eradication of disease practitioners agreed on the need to adapt man- and the prevention of death, is not well suited to

132 Boeckxstaens · De Maeseneer · De Sutter

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 129–136 ( DOI: 10.1159/000365544 ) the management of chronic illness. Therefore, The International Classification of Function- they proposed a goal-oriented approach that en- ing (ICF) [30] might become as important as courages each individual to achieve the highest the International Classification of Diseases possible level of health, which is defined by the (ICD), as it draws a conceptual framework in individual instead of the health system. This which different domains of human functioning represents a more positive approach to health- are defined. These domains are classified from care, characterized by a greater emphasis on in- an eco-, bio- and psychosocial viewpoint by dividual strengths and resources. What really means of a list of body functions and structures, matters for patients is their ability to function and a list of domains of activity and participa- (functional status) and social participation. tion. As an individual’s functioning and disabil- Goal-oriented care assists an individual in ity depends on the context, the ICF includes a achieving their maximum individual health po- list of environmental factors and the concept of tential in line with their individually defined personal factors in its framework. The ICF is goals. Exploring the goals of patients will re- part of the ‘Family of International Classifica- quire adequate communication with patients to tions’ (FIC) and meets the standards for health- allow providers to explore and elicit personal related classifications as defined by the World goals. At a practice level, providers should in- Health Organization (WHO). Although the creasingly pay attention to goal-oriented care ICD has a dominating role in healthcare data and provide an atmosphere of open communi- management, the WHO aims to reach the same cation attentive and supportive to patients who level with the ICF, a classification that defines should be encouraged to introduce their own functional status irrespective of the underlying goals in clinical decision-making. health condition.

The Need for New Types of Evidence Implications for the Health System

In order to understand the goals of the patients At a policy level, healthcare systems should be- better, new research frameworks and research come more attentive to goal-oriented care and disciplines will be needed. This will require in- support providers to engage in the labor-inten- put from disciplines that contribute to the un- sive process of goal-oriented care. This will re- derstanding of provider-patient interaction quire both a fundamental reflection on time man- such as medical philosophy, sociology and an- agement, task delegation and payment systems. thropology. Research methods will have to shift Family physicians should be encouraged to pro- from purely quantitative (randomized clinical vide less and longer proactive patient contacts in- trials) towards qualitative approaches looking stead of more and shorter reactive consultations. at understanding through in-depth interviews Practice nurses and other primary care providers and focus groups. We will have to look for re- should be increasingly encouraged to engage in search tools and approaches that explore sub- chronic care. Moreover, taking into account the jective determinants of well-being, and not only social gradient, with deprived patients being biomedical measurements. In the new research more prone to multimorbidity [31, 32] , social designs, patients with multimorbidity will be workers should be included in the team approach. the rule (instead of an exclusion criterion) and The current focus on fee for (technical) services complexity will be embraced instead of avoided does not seem well suited to a goal-oriented ap- [29] . proach in healthcare.

Managing Multimorbidity in Primary Care 133

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 129–136 ( DOI: 10.1159/000365544 ) Multimorbidity, Goal-Oriented Care and build an individual care plan together with the Equity patient. Through continuity of care, the general practitioner can be attentive to the fact that goals When implementing goal-oriented care, there of patients can change over time as the context may be a threat to equity, as the way goals are changes. This approach will, however, require formulated by patients might be determined by more focus on the individual patient-provider a number of factors including social class. More- interaction and on appropriate communication over, integrating the patient’s context implies skills to facilitate goal definition and patient em- the risk of taking the context for granted; people powerment. living in poverty will generally have been obliged Other primary care providers, such as nurses, to take on lower expectations in terms of quan- physiotherapists, occupational therapists, social tity and quality of life than well-educated people. workers, dieticians and others, also have invalu- Therefore, ‘goal-oriented medical care’ could able insights into the patients’ situation, which contribute to an increase in social inequities in should be integrated in the care for the patient. health. Therefore, the primary care team should Shared decision-making, starting with patient engage in an approach of intersectoral action for goals and involving the patient and other care health (interacting with sectors like employ- providers, will avoid gaps in the process and en- ment, housing and education) and address the courage empowerment of the patient. Especially social determinants and ‘upstream causes’ of ill in a context of multimorbidity, there is a need health. for a shift from ‘chronic disease management’ towards ‘participatory patient management’, with the patient at the center of the process. The Role of the General Practitioner Moreover, as definition of ‘goals’ may often be in the Management of Patients with related to values, the providers in the primary Multimorbidity care team will have to act as reflective practitioners that contribute to reconcile individual and The role of the general practitioner in the man- community health requirements. It is clear that agement of multimorbidity is situated at differ- this process will require more time investment ent levels. The general practitioner is the pro- at first, e.g. to engage in a goal-setting encounter vider with a comprehensive view on both the with the patient; however, in the long term, biomedical and personal health status of the pa- goal-oriented care might prove to be more rel- tient. They are in the frontline to detect the evo- evant, effective and efficient, and require less lution from ‘single disease’ to ‘comorbidity’ and time spent on targets not of interest to that indi- ‘multimorbidity’ in individual patients, and are vidual patient. able to integrate disease-specific guidelines to At the meso-level, general practitioners may the personal situation of the patient. They are have an important ‘signaling’ role in order to able to define medical priorities and integrate document and draw attention to problems of in- them with the personal goals and preferences of equity. Institutions for health professionals’ ed- the patient, thereby supporting a timely shift ucation are challenged to train providers that from ‘problem orientation’ to ‘goal orientation’. are not only ‘experts’, or excellent ‘profession- The general practitioner can be involved in the als’, but also ‘change agents’ [33] who continu- facilitation of ‘goal definition’ by the patients ously improve the health system and question and is well placed to integrate these goals in clin- the relevance of knowledge and care. General ical decision-making for multimorbidity and practitioner education will have to provide the

134 Boeckxstaens · De Maeseneer · De Sutter

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 129–136 ( DOI: 10.1159/000365544 ) needed support and training of providers and At the macro-level, this will also require dialogue the coordination of the different primary care and communication methodologies between the organizations. General practitioners should be health sector and persons in need of healthcare as able to reflect on the equitable distribution of well as with other stakeholders within the society resources, taking into account social determi- involved in healthcare at the practice, research and nants, on the organization of the healthcare ser- policy levels in order to guarantee the essential char- vices and the features of the health system in or- acteristics of an effective health system including der to tailor care to this growing group of com- relevance, equity, quality, cost-effectiveness, sus- plex patients. tainability, people-centeredness and innovation.

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J. De Maeseneer, MD, PhD Department of Family Medicine and Primary Health Care Ghent University, UZ-6K3 De Pintelaan, 185 BE–9000 Ghent (Belgium) E-Mail [email protected]

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 129–136 ( DOI: 10.1159/000365544 ) Management of Comorbidity of Mental and Physical Illness

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 137–147 ( DOI: 10.1159/000365598 )

Training Physicians at Undergraduate and Postgraduate Levels about Comorbidity

a b Annie Cushing · Sandra Evans a b Clinical and Communication Skills Unit, Institute of Health Sciences Education, and Department of Psychiatry, Barts and The London School of Medicine and Dentistry, St. Bartholomew’s Hospital, Queen Mary, University of London, London , UK

Abstract Physical and mental comorbidity has not been This chapter addresses the importance of training on co- well addressed in medical education, especially in morbidity and the principles of learning. It covers the systems-based curriculum designs. Increasing methods and structuring of such training, the content on specialisation of healthcare delivery also threat- which it is based, and what is known in the field. It includes ens integrated managemant. Training is impor- illness versus disease management, holistic approaches, tant for a commitment to understanding comor- patient and doctor roles regarding shared decision-mak- bidity from the start of clinical training about pa- ing, adherence and self-management, polypharmacy, in- tient care. For clinical practice to develop, it terprofessional and team communication, and effective requires active engagement, adjustments in daily consultation and communication skills. We highlight working and broader support from the health- methods which are learner-centred, aiming at active en- care system [1] ( fig. 1 ). gagement in a collaborative endeavour with the trainer. The crowded curriculum in medicine puts We emphasise the need to recognise the broader sys- each discipline in competition with one anoth- tems’ factors which support or undermine integration of er over what is most important for the first- learning into everyday practice. Training should address year medical student, foundation trainee or in- cognitive (knowledge), emotional and motivational (at- tern to know. The only way to cover the mate- titudes), and behavioural (skills) elements of learning. rial adequately and ensure an appropriate Whilst undergraduates will need more didactic elements attitude towards patient care is to work coop- and proscribed activities, postgraduate training benefits eratively and in an interdisciplinary manner. from flexibility to the learners’ working context. Training From the outset, we need to model ways of in- the trainers is an important component of an education tegrating mental and physical health care strategy so that teachers use a learner-centred approach knowledge so that students will see their pa- consistent with the patient-centred consultation model tients in a way which allows them to feel con- needed to manage comorbidity. © 2015 S. Karger AG, Basel fident in both spheres. Chronic Care Model

Community Health systems Resources and policies Organisation of healthcare Self- Delivery Clinical Decision management system information support support design systems

Informed, Prepared, Productive activated proactive interactions patient practice team

Fig. 1. A model for managing long- Improved outcomes term conditions [42].

Our students and trainees are embarked upon Educational Theories, Principles and a trajectory of life-long learning. We describe Implications for Training how this occurs, including brief coverage of theories of adult learning and how these inform train- Important and influential educationalists of our ing design and techniques. Examples of model time, including Kolb [4], Schon [5], Dewey [6] programmes, including the use of communica- and Vygotsky [7] , have addressed conditions of tion skills training and other forms of active expe- effective learning. Kolb’s learning cycle explains riential learning, are included. All learners have to how learning takes place when (1) having a con- be convinced that their efforts are worthwhile, re- crete experience, followed by (2) observation of alistic and manageable, and will bring about de- and reflection on that experience leads to (3) for- sired outcomes. Good practice demonstrated by mation of abstract concepts (analysis) and gen- excellent teachers and practitioners is a strong eral principles (conclusions) which are then (4) positive influence. Clinicians and lecturers need used to test hypotheses in future situations. All to model respect for the psychological aspects of four stages are needed, although one can enter at illness. The power of the role model in learning is different points and no one stage is an effective well documented and so engagement of faculty by learning procedure on its own. Schon’s work on training the trainers and postgraduate education the reflective practitioner powerfully shows that is essential for transformative learning and incor- learners need to be processing information and poration into clinical practice. Not surprisingly feelings while developing insight and responding therefore, the shift from paternalism to partner- to changing situations. ship in the doctor-patient relationship is best mir- Dewey [6] emphasised the importance of the rored by a shift to a more collaborative trainer- emotional element in learning. Negative emo- trainee relationship. Training and new skills/ap- tions, such as extreme anxiety, will act as barriers proaches must be supported and reinforced by to engagement in learning. Trainers must estab- the clinical environment, otherwise formalised lish a supportive, whilst appropriately ‘challeng- learning is not sustained [2, 3] . ing’, approach to the educational event. Feedback

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 137–147 ( DOI: 10.1159/000365598 ) Table 1. Examples of learners’ needs

Pass the assessment Manage time in consultation – get there quicker Be able to deal with the situation if they ‘take the lid off it’ Helpful strategies, skills, examples of questions and phrasing A good history and diagnosis Not miss pathology Develop a management plan Work without all the information and ‘mine for data’ Manage uncertainty Patient safety Satisfied patient Connect patients to other healthcare professionals/refer/support

should always be linked to what one is trying to (3) Pitch training to the level and context of the achieve, so goals of the consultation need to be learner clarified and agreed [8, 9]. Feedback framed in (4) Ensure feedback and include follow-up action terms of what is effective and examples of any plans missed opportunities are conducive to useful Undergraduates have limited clinical experi- learning. Emotional involvement is a key feature ence and will benefit from an approach which of learning. The feedback conversation is central involves more teaching, coaching and real pa- and includes checking how the learner is feeling, tients or problem-based learning scenarios in- preferably in a small, supportive group setting corporating comorbidity. Involving the ‘pa- [10] . Learners then need to set goals for imple- tient’s voice’ and expert patients in education is menting their learning, based on a collaborative memorable and helps students and trainees un- evaluation of the importance of and confidence in derstand patients’ particular expertise [12] . Stu- being able to apply the new knowledge and behav- dents are strongly motivated by assessment iour. Vygotsky highlights: ‘the distance between rather than seemingly distant clinical practice; the actual developmental level as determined by therefore, assessments such as objective struc- independent problem solving and the level of po- tured clinical examinations should incorporate tential development as determined through prob- identification of comorbidity. Online resources lem solving under adult guidance…’ [ 7 , p. 86]. with case studies, video clips and principles of Designing learning activity pitched at a level in practice help the novice develop an understand- order to challenge without overwhelming the ing [13] . Early years’ experience of meeting pa- learner should: tients and carers using reflective learning as- (1) Consider the learners’ agenda ( table 1 ), the pa- signments and progressing to role-play utilising tients’ agenda (‘what I want doctors to help me actors, particularly for more complex consulta- with’), the trainers’ agenda (evidence-based tions, provides a vertical integration in a cur- practice) and the service agenda (the pragmat- riculum. ic approach) Postgraduate learners bring their own clinical (2) Make it real by designing training character- experience. Incorporating their particular situa- ised by relevance, experience, activity and tions maximises relevance and engages motiva- learner-centredness [11] tion. From their own reflections in identifying

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 137–147 ( DOI: 10.1159/000365598 ) Patient presents unwell Disease: Illness: Biopsychosocial perspective Skills Patient perspective Listening History Rapport Ideas Physical examination Empathy Concerns investigations Question style Expectations Clarifying Feelings Signposting Effects on life Summarising Explaining Negotiating Differential diagnosis Shared decision-making Understanding the patient

Integration management plan

Fig. 2. Disease-illness framework and patient-centred communication. Adapted from McWhinney [15] .

the challenges of these interactions, they can The Biopsychosocial Disease-Illness Model and practice new strategies in role-play and receive Patient-Centred Care constructive feedback. Good postgraduate train- In 1989, McWhinney [15] described the disease- ing programmes develop skills for working in illness framework and the need to explore both partnership by involving patients with long-term biomedical and psychosocial information to un- conditions as co-facilitators alongside trainers derstand the patient and his/her situation ( fig. 2 ). [14] . The patient’s experience and beliefs are hugely significant, although historically often neglected because a patient’s views and expectations will af- Training Goals fect adherence to medications and the actions he/ she takes regarding lifestyle changes. Discussing Training needs to incorporate some explanation raised glycated haemoglobin levels with a patient of comorbidity and the potentially dangerous im- distracted by depression about having diabetes is plications of not identifying it within the consul- unhelpful. Engaging patient understanding and tation. As it will inevitably require more effort ini- managing his/her healthcare in collaboration tially on the clinician’s part to explore comorbid- with the physician will have better outcomes ity, conviction and skills are needed. Training [16] . outcomes include (1) acceptance of the biopsy- As one patient explained, ‘You’re always hop- chosocial model of health and awareness of issues ing there will be a cure, which is why you end up in comorbidity, (2) knowledge of what to manage being so depressed, when there isn’t one… . and how, and what to refer, and (3) communica- Within secondary care in particular, there’s still tion and interpersonal skills. too much emphasis on treatment rather than self-

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 137–147 ( DOI: 10.1159/000365598 ) management’ (Shani Evans, 2008) [14] . Students suggest a misdiagnosis and even the possibility of need to recognise that partnership between pa- medically unexplained symptoms. tients and clinicians in a co-creating health rela- Physical manifestations of psychological dis- tionship is essential both for patients’ well-being tress are well understood, such as dry mouth or and tackling escalating costs of care [17] . tachycardia when anxious. Some symptoms are less obviously associated with a trauma. They Issues in Comorbidity: The Dialectic between the may convey meaning unknown to the sufferer Physical and the Mental and require more careful history taking to eluci- The curriculum needs to include the following date. six themes which should cover the basic under- Medically unexplained symptoms are not so standing of comorbidity for students and junior easy to understand on the surface, but may be trainees. simpler to demonstrate clinically. In a simulated clinical setting, for example, by exploring psycho- (1) The Interdependence of Mind and Body: social information students can easily be encour- How the Psychological Can Impact the Physical aged to divine the likely association of headaches and Vice Versa in a person whose partner has just died of a brain A psychological understanding and a framework tumour, or one who complains of memory prob- of illness and the emotional responses to it are vi- lems when stressed and exhausted from looking tal to a well-functioning and quality health ser- after their elderly mother who has Alzheimer’s vice. This perspective becomes increasingly perti- disease. The common factor here is encouraging nent as survival from disorders that used to be students’ curiosity and getting them to ask appro- life-threatening becomes more commonplace. priate questions. Exploring a symptom can be lik- Diabetes, HIV and renal disease are a few exam- ened to detective work. ples of diseases that cannot be cured but can be How can we engage students and trainees ful- managed; and yet the psychological effect of a ly in the current governmental commitment to long-term disorder that will change lives and im- offer ‘parity of esteem’ as in the USA for mental poverish expectations is also important. Students health issues as for physical ones [18] ? We need must learn the goals after survival include reduc- medical schools to collaborate with psychiatry ing suffering, increasing emotional well-being, and psychology departments in order to ensure pain control, functional ability and vitality. A cli- that the psychological perspective becomes part nician teacher’s role includes sharing awareness of teaching all systems and permeates across of common psychiatric comorbidities and how to most aspects of training. Psychiatry is not just a manage them in a patient-centred way. discipline like medicine or surgery: it is also a way of understanding pathological processes (2) Presentations of Illness That Can Confound that engages the medical model, but also views Diagnosis patients from their own psychological and social Medical students and young doctors have to perspective. Especially valuable can be educa- struggle with large amounts of new knowledge tional methods bringing together specialists and tend to prefer clear facts that are easy to di- from different fields of medicine and surgery gest. As their learning progresses they will be able (gastroenterology, cardiology, gynaecology, pri- to recognise when patients’ presentations do not mary care, psychologists, psychiatrists) in clini- follow the usual pattern of a disease profile. Dis- cal forums to discuss patients, encouraging the crepancies in symptoms or repeat presentations skills needed to communicate effectively and by the same person who is not getting better may manage care [19]. Similar methods in under-

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 137–147 ( DOI: 10.1159/000365598 ) graduate teaching from multispecialist groups at greater risk of an adverse drug reaction and are are needed to prevent development of negative more likely to suffer from the prescribing cascade attitudes towards patients with medically unex- [22] . Medication for physical illness can cause plained symptoms [20] . mental health symptoms and conversely drugs taken for mental health problems may cause (3) Risk Factors for Mental Health Difficulties in physical symptoms and predispose to physical Physical Illness: Particularly Long-Term disease. How students will be guided to consider Conditions these issues and how to approach them requires Some physical health conditions often go hand in teaching faculty who are committed to an inte- hand with a psychiatric morbidity. A common grated way of viewing health. example is one of anxiety and depression experienced with severe breathing problems [21] . Stu- (4) Learners’ Own Physical and Mental Health: dents starting their clinical attachments will often Knowing One’s Self and Being Aware of come across such patients who may be the subject Assumptions and Judgments of their first clerking. In a medical school focused Being aware of one’s own views and reactions to on clinical skills and listening and attending to a other people’s misfortunes is essential to enable patient’s agenda, the student may be struck by the learners to behave in a non-partisan, professional worries and concerns of patients with asthma or manner that does not seek to judge but merely to bronchitis. Their task may be to take a history and inform. Knowing something about the nature then examine the patient physically. They will and management of addictions is also enormous- also ask about the impact of illness on the per- ly important when deciding on the best course of son’s life. They will understand that work may be action in the treatment of physical problems in limited, exercise impossible and enjoyment cur- people with substance misuse, alcoholism or ad- tailed. Managing long-term conditions holistical- diction (e.g. liver failure). Religious and cultural ly can have a significant positive effect on pa- diversity among patients and students will influ- tients’ mental health and quality of life. If psychi- ence understanding, personal attitudes and com- atry is integrated into teaching from the outset munication. (including how to perform a mental state exami- Mental health problems may remain uncov- nation), students may feel able to ask about mood ered for patients whose doctors do not explore symptoms as a result and even enquire about sui- this aspect of the patient’s psychosocial history cidal thoughts. Fostering an understanding of [23] . Whilst patients may drop cues from de- these principles and supporting learners who are meanour or language, they are less likely to raise commonly anxious about asking such potentially these worries directly. Doctors commonly use upsetting questions is a key goal of educators. Stu- distancing tactics such as focusing only on bio- dents adjust to knowing that patients with psychi- medical facts, premature reassurance or jollying atric symptoms can be on medical wards and not patients along rather than pursue cues, and thus just in a psychiatry setting. They also learn that miss significant mental health problems. Key psychiatric symptoms are commonplace, associ- communication skills are associated with in- ated with physical conditions and treatable if rec- creased disclosure. Teaching learners to observe ognised. demeanour, note speech quality, listen, allow si- The importance of understanding the inter- lence and express empathy are particularly im- relationship of conditions and the medications portant. Skills training helps the healthcare pro- used to treat them are also crucial. Patients dis- fessional to engage the patient and discuss with pensed medications from multiple providers are them their ideas, concerns and expectations in

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 137–147 ( DOI: 10.1159/000365598 ) conjunction with addressing biomedical facts ers must be skilled in facilitating such situations [24] . and be prepared to listen and support students who Mental illness carries stigma. Those most at are upset or having difficulties. Preferably they will risk of this way of thinking are the medical stu- have received training in role-play methods using dents and doctors themselves. Students often fear ground rules for safety. a mental health diagnosis because of ignorance, stigma and a belief that it will prevent their quali- (5) Risk Factors for Physical Health Difficulties fying as a doctor [25]. Stress, one of our biggest in People with Mental Illness difficulties in busy, demanding and responsible Depressed people are less likely to be able to man- jobs, can cause much physical and mental ill age their illness, medications or lifestyle changes health. Sometimes alleviated by alcohol use, which [16, 17]. Difficulties exercising and keeping fit are may become a problem in itself, it is more danger- often associated with feeling unmotivated, anx- ous when we fail to recognise it in ourselves. ious about facing the world or being indifferent to Students and trainees can experience distress- one’s own future. Drugs used in treating psychot- ing situations in their own lives as well as in clinic disorders often cause weight gain, induce dia- ical practice. A curriculum which includes teach- betes mellitus and risk heart disease. Enabling ing about stress, its impact on doctors and the students to discover these issues early on in their available support services enables students and training through talking to patients with chronic trainees to recognize when this may be an issue mental health problems, and their families, also and where to get help. encourages a more compassionate and thought- Experiential learning is also powerful. For ex- ful view of the complexity of psychiatric disorder. ample, clinical skills training combining the ability Interestingly, there is some evidence that al- to ‘break bad news’ sensitively while attempting to though the coexistence of depression and multi- understand the unique perspective of the person ple physical conditions is associated with in- with a particular physical or indeed ‘mental illness’ creased illness burden, such patients benefit most diagnosis is one learning strategy that is used [26] . from the Chronic Disease Self-Management Pro- Role-playing the clinician can be very helpful in grams, and students and trainees should learn that one is exposed to a range of affects from the about these approaches [28] . simulated patient and one learns how to manage each. If students are asked to play the patient as well (6) Consultation Skills to Identify and Plan as the doctor, this adds a power to the scenario, but Management for Comorbidity can be challenging. These methods can really assist Goals for the consultation include an open, respect- medical students and trainees to empathise. Exer- ful, empathic, accurate and constructive consulta- cises such as having a conversation whilst breath- tion based on both the patient’s and doctor’s agen- ing through a straw to simulate the experience of da, focussing on gathering relevant biomedical and someone with chronic obstructive pulmonary dis- psychosocial information and shared decision- ease (COPD) [Kim C, pers. commun., 2013] and making. The very important therapeutic function the ‘hearing voices’ audiotaped exercise used to il- of the consultation, in and of itself, is well known. lustrate the experience of patients with psychosis To operationalise the disease/illness and [27] help learners imagine the lived experience of shared decision/partnership care, a number of disability and appreciate of the patients’ suffering. consultation guides for skills training have been By being in the patients’ ‘shoes’, the potential con- developed [29–31]. These frameworks define the sequences of a doctor choosing to listen attentively skills that, when used in context, are known to be or maintaining distance can be understood. Train- helpful. Particularly important are listening (and

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 137–147 ( DOI: 10.1159/000365598 ) silence), observing non-verbal cues, listening to problems are. If the doctor overly controls the na- quality of speech and responding to cues using ture of information gained and the type of infor- empathic reflection. mation the patient gives, an inadequate problem definition may occur. Skills are needed to pick up on cues, create trust and gain an accurate compre- Training Issues hensive history, and these skills can be taught [33] .

Barriers to Identifying Comorbidity Whilst clinicians may be aware of comorbidity, Teaching Consultation and Communication they can also feel time pressured and powerless to Skills manage the problems, as well as lack confidence or strategies to deal with all the issues, and thus act to Communication skills training promoting patient- avoid being overwhelmed by a variety of patient centred approaches in clinical consultations is best needs. Training must take account of the fact that designed on a blended learning skills-based and at- clinicians may control and limit the interview as a titude development approach with incorporation way of avoiding emotional difficulties [32] . of peer support using a variety of training tech- Comorbidity may mean that patients are al- niques [32, 34–36] . Group problem-solving discus- ready seeing, or will need to see, other members sions on how to respond to comorbidity and practi- of the healthcare team. Accessing and transfer- cal management planning addresses learners’ con- ring patient information between healthcare pro- cerns about ‘taking the lid off’ problems and not viders is not easy where multiple information sys- having confidence or strategies to tackle them. tems of patients’ data exist. If clinicians see only Without this, application in practice will be com- problems and no ways of efficiently dealing with promised [36] . Case studies, such as those below these, they may be reticent to explore comorbid- can be used to discuss goals for a consultation, ity and may focus narrowly or exclusively on the practical management strategies and to practice primary presenting problem. Similarly, students communication skills. and trainees need to have a strategy of how to re- Case Study 1 spond. These can include listening attentively, ac- Mr. Peters, 58 years of age, was admitted through the ac- knowledgement of the problem and advocacy by cident and emergency department with acute shortness of offering, with the patient’s permission, to talk to breath, and is now on intravenous antibiotics. He has a the doctor or attending physician. Trainees may 5-year history of COPD and has had three chest infections already this year. Mr. Peters had smoked 20 cigarettes a in addition be able to offer simple advice, help pa- day for 40 years, but has now cut down. COPD is signifi- tients to problem solve, book a longer appoint- cantly affecting his life. ment and refer to colleagues. Without plans for The patient’s ideas: ‘My lungs are damaged from what to do next, students and trainees will likely working on the buses, exhaust fumes in the garage and not ask about comorbidity. Training should in- stress. I know smoking is bad but helps with stress and corporate strategies for the next steps. I’ve cut down but not quit.’ The patient’s concerns: ‘My breathing is bad and I can’t do much or go far. I retired early on health Skills for Patients and Clinicians to Understand grounds and miss my mates. I’m worried about all the Each Other hospital admissions, but staff are wonderful, I feel safer The doctor-patient interaction is recognised as in hospital and enjoy the company.’ one of unequal power which brings with it a num- The patient’s expectations: ‘I want the doctor to ber of challenges for open communication. Pa- give me a stronger drug to help breathing. He’ll prob- tients frequently hint rather than say what their ably ‘‘have a go at me’’ again about quitting smoking.’

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 137–147 ( DOI: 10.1159/000365598 ) Two years later, Mr. Peters, has become increasingly most successful [24, 35, 37] . More pragmatic isolated, rarely goes out, is now having panic attacks courses include three consecutive small group about his COPD, cannot sleep and often wakes in the sessions of 3–4 h each, a week or more apart, with night to use his nebulizer. When he cannot breathe his practice between sessions [38]. As with patients, wife phones an ambulance. He is scared he is dying and changing clinicians’ habits is difficult and has to his wife feels distraught and does not know how to cope. start with a belief in the importance and achiev- Case Study 2 ability of the changes. Action plans for imple- Erica Johnson is a 31-year-old woman of African-Carib- mentation in practice, subsequent review of suc- bean parentage. She developed schizophrenia in her mid- cess and troubleshooting closes the training loop 20s. Although compliant with treatment, a depot antipsy- [4] . chotic medication for the past 3 years and no hospital admissions, her general health is suffering. She has gained a lot of weight and is now morbidly obese, has developed type II diabetes and has raised blood pressure. Her self- New Models of Learning esteem is at an all-time low and she feels depressed. Her general practitioner notices that recent blood tests suggest her diabetes is not well controlled. Some educationalists have called for a broadening The general practitioner is mainly concerned about of concepts of education, away from the conven- her diabetes. He sees that Erica is overweight but is un- tional pedagogy in medicine where learning is an sure whether there is enough time to tackle this prob- individual enterprise, to a collective activity [39, lem today and feels unsure about the potential impact 40]. Clinicians do not work alone and their ac- on her mental health. tions are determined by many external factors. Erica is desperately unhappy about her weight. She Just as patients have a psychosocial world, so do feels low and miserable, is lonely, and feels unattract- clinicians, and the influence it has on working ive. She wants a family, but has no confidence to find practice should be recognised. The whole culture herself a boyfriend. Erica wants to give up the injec- and materiality of the workplace environment af- tions which she feels are the cause of her problems. fects the daily interactions and practice patterns [1, 41] . An electronic record, for example, that in- Summary cludes or does not include a section on whether Role-play provides a powerful and effective teach- comorbidity has been screened for will affect ing tool. The participant has space for self-reflec- practitioners’ behaviour and should be included tion and comment followed by feedback from the in training about consultations. Such systems’ en- actor and facilitator. Using video, a recording can ablers and barriers need to be recognised for be played back so that particular points in the in- training to be real and credible. Observing prac- teraction can be identified. Feedback is vital with tice ‘in situ’ strengthens both learners’ and teach- the opportunity to then repeat any aspects since ers’ abilities to engage with performance in prac- an experience of success in doing something dif- tice. As communication within teams is essential ferently consolidates learning. and liaison and referrals are important, team learning is to be promoted.

Training Course Designs Conclusions Intensive experiential postgraduate courses con- sisting of a 2- or 3-day programmes with a group This chapter has addressed the importance of size of no more than 8 participants, involving vid- training for patient-centred consultations on co- eoing and delivered by expert facilitators, are morbidity and principles of learning to guide the

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 137–147 ( DOI: 10.1159/000365598 ) methods and structuring of such training. A spi- a learner-centred approach consistent with the ral curriculum is advocated with interdisciplinary holistic patient-centred consultation model. With teaching, using a variety of educational methods training that addresses issues of comorbidity, and incorporating identification and manage- communication skills and the ability to plan man- ment of comorbidity into summative assess- agement in a shared decision-making approach, ments. our students and trainees will be better prepared Training the trainers is an important compo- for the reality of high-quality, modern practice in nent of an education strategy so that teachers use whichever field they work.

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Prof. Annie Cushing, PhD, FDSRCS (Eng), BDS (Hons) Clinical and Communication Skills Unit, Institute of Health Sciences Education Barts and The London School of Medicine and Dentistry, St. Bartholomew’s Hospital, Queen Mary, University of London London EC1A 7 BE (UK) E-Mail [email protected]

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 148–156 ( DOI: 10.1159/000365599 )

The Dialogue on Diabetes and Depression African Nursing Training Programme: A Collaborative Training Initiative to Improve the Recognition and Management of Diabetes and Depression in Sub-Saharan Africa

a b c H.L. Millar · L. Cimino · A.S. van der Merwe a b Mental Health Directorate, The Carseview Centre, Dundee , UK; International Center for Intercultural c Communication, Indiana University, Indianapolis, Ind. , USA; Division of Nursing, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch , South Africa

Abstract tice new skills to recognise and manage comorbid condi- The Dialogue on Diabetes and Depression (DDD) is an tions. This programme is an example of a unique and in- international collaborative effort to address the prob- novative educational effort regarding comorbidity with a lems related to the comorbidity of depression and diabe- practical clinical approach. It enables nurses to screen, tes. The Association for the Improvement of Mental recognise and treat diabetes and depression in Sub-Sa- Health Programmes, a Swiss-based NGO, established the haran Africa by promoting a patient-centred collabora- DDD to raise awareness, coordinate research, develop tive approach model with early recognition and manage- training materials, and organise scientific meetings and ment of these comorbid conditions in order to improve training courses. The DDD developed the Diabetes and outcomes and life expectancy in this population. Depression African Nursing Training Programme in col- © 2015 S. Karger AG, Basel laboration with the International Council of Nurses to address identified needs of nurses in Sub-Saharan Africa to whom the delivery of primary healthcare often devolves. The Dialogue on Diabetes and Depression An international faculty of experts delivered the educa- (DDD), established in 2007, is an international tional programme to nurses from seven countries in Sub- collaborative initiative addressing research and Saharan Africa and involved over 175 participants, most healthcare needs related to the comorbidity of di- of whom have responsibility for the education or in-ser- abetes and depression [1]. Together with the In- vice training of nurses. Participants appreciated the pro- ternational Council of Nurses, the DDD em- gramme – especially the opportunity to enhance their barked on a capacity-building programme, focus- knowledge of these two common disorders and to prac- sing on nurse training in seven countries in Sub- Saharan Africa. The programme aimed at ‘train- ence a higher burden of infectious and chronic ing the trainers’ to increase capacity in frontline diseases [7, 8] . healthcare staff to recognise and manage these Contemporary evidence demonstrates that ef- comorbid conditions and to enhance the ability of fective treatment of depression in people with di- nurses to promote and enact educational pro- abetes depends on a multidisciplinary collabora- grammes of this nature within their own health- tive approach to optimise a comprehensive pack- care systems. age of care ensuring the best outcomes in terms of physical and mental well-being [9, 10] . Interna- tional programmes have been introduced to man- Background age diabetes in a range of settings, most notably those by the International Diabetes Federation Thomas Willis, a 17th-century English physi- (IDF) [11] . cian and anatomist described the association be- Within well-integrated healthcare services, tween depression and diabetes, noting that dia- programmes have been developed for the effec- betes appeared more frequently in those who tive treatment of depression. By contrast, holistic suffered life traumas or long-term sorrow [2] . programmes to manage people with comorbid Contemporary epidemiological studies suggest depression and diabetes are not yet well estab- that at least one third of this population suffer lished despite the evidence available for treating from depression [3, 4] and up to 45% of those this specific comorbidity [12] . The quality of var- with diabetes have depressive symptoms not ious conceptual frameworks varies depending on amounting to the ICD diagnosis of depressive the personnel available and the resources within disorders [5] . Additionally, those suffering from the healthcare system. The preparation and train- depression are at an increased risk of developing ing of healthcare professionals to deal with such diabetes [6]. Studies now clearly point to a bidi- comorbid conditions is limited, and this situation rectional relationship between diabetes and de- is probably exacerbated within more deprived pression, which is complex in terms of the patho- and challenging healthcare systems where both fi- genesis, pathophysiology and psychological nancial and human resources are more limited mechanisms. Evidence from high-income coun- and where deep-rooted layers of stigma and ste- tries suggests that depression with diabetes is as- reotyping exist. As a result, the fragmentation of sociated with socio-economic status, marital sta- services with poor accessibility may lead to inad- tus, physical activity and chronic somatic diseas- equate care pathways, lack of seamlessness and a es. Psychosocial factors may impact on the delay in any meaningful interventions. This may relationship between socio-economic status and culminate in more complications and overall a depression in people with diabetes, including so- worse prognosis and clinical outcomes for those cial isolation, poor social support, limited cop- presenting with these two comorbid conditions ing ability and burden of work. Overall studies [13, 14]. It is often the case that mental healthcare have shown an inverse relationship, i.e. the risk professionals feel unable to provide adequate ser- for depression in diabetes is higher with lower vices for the physical health of the mentally ill socio-economic status. However, the relation- population; however, the reverse is also probably ship may vary depending on the socio-economic true [15] due to training inadequacies and lack of context of the particular country. In low-income experience. countries, a higher socio-economic status is gen- Another challenge in dealing with the com- erally associated with higher levels of chronic plexity of chronic comorbid conditions is the disease risk factors, whilst the poor often experi- need for a range of skills and the expertise of a

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 148–156 ( DOI: 10.1159/000365599 ) multicondition collaborative care approach by a of organisations including support from the Lun- multidisciplinary team working together across dbeck Institute and the International Council of specialities, clinics and distances [10] . The patient Nurses, which represents nursing associations with comorbid conditions presents with complex from 135 countries and is made up of more than challenges requiring education to enhance en- 13 million nurses worldwide. The International gagement in self-care management to achieve op- Council of Nurses works to ensure high quality in timal outcomes. This is especially important in nursing care and the advancement of nursing areas of the world where access to care systems is knowledge, and promotes the nursing profession challenged with limited capacity and skill mix. as a competent workforce worldwide. To initiate programmes addressing multimor- A steering group was set up that included rep- bidity, it was decided to select a commonly occur- resentatives from the DDD, the International ring comorbidity and to use the experience gained Council of Nurses, Lundbeck Institute and inter- to design other programmes managing multi- national experts to support the implementation morbidity in general. Both diabetes and depres- of the project. The group used a logic model sion are common disorders with increasing inci- framework to steer the project work within stipu- dences and are associated with a high cost burden lated timeframes. The logic model focuses on to society. Both disorders are relatively easy to di- achieving planned actual change and has been ex- agnose and have recognised effective treatments tensively used in planning, application and evalu- which have had an impact on reducing the stigma ation of a range of programmes [16–19]. It forces associated with them. careful reflection on the relationships between Nurses are an essential part of the interdisci- outcomes (short and long term), the rationale and plinary team and were selected for this training assumptions within the unique context of the programme because of their broad reach and po- programme to be delivered with the necessary ac- tential impact on care for patients with such con- tions and resources required to achieve such out- ditions. Nurses are the largest group of healthcare comes. Immediate and direct outputs versus professionals in most low- and middle-income long-term impacts are also outlined. countries, and are at the critical interface with pa- The steering group provided the leadership for tients and their carers. This scenario was consid- the design and rollout of the DDD African Nurse ered especially pertinent for Africa. Hence, the Training Programme. The first series of training aim of the programme was to strengthen the sessions included nurses from five countries in nurses’ core competencies in the assessment and Africa, namely South Africa, Uganda, Botswana, management of patients with comorbid diabetes Lesotho and Swaziland. The steering group re- and depression. The programme adopted a train- convened after this first set of sessions to review the-trainer approach – empowering nurses to feedback and to further fine-tune the programme train others and to enact countrywide and local to meet the needs of nurses and patients in clinical programmes that address healthcare problems practice. They then conducted a second set of related to comorbidity. training sessions in Ethiopia and Kenya. The IDF recommended local diabetes educators from South Africa and Kenya to participate in the Programme Rollout workshops to strengthen local knowledge and relevance of the skills and to assist in understanding The African Nurse Training Programme on Dia- local attitudes and values. betes and Depression was a collaborative effort In planning the educational curriculum, the co-ordinated by the DDD and engaged a number steering group was mindful of the importance of

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 148–156 ( DOI: 10.1159/000365599 ) the context of the African countries and consid- In reflecting on the outcomes as stated by the ered political, economic, social and psychological logic model, the following challenges presented factors when designing the programme. The themselves in the designing and planning of the steering group also considered how the diagnosis programme. and treatment of diabetes or depression, or both, needed to fit into different cultural value systems Develop Core Competencies and Capacity in the and social practices. The complex status of the Field healthcare system and the seemingly poor inte- Teaching the management of a patient with co- gration of mental and physical healthcare in many morbid conditions presented a unique education- of the countries required careful consideration. It al challenge because the relevant skills and knowl- was also recognised that there might be limited edge had to be imparted to groups of nurses who integration between primary and secondary care were either from a mental health or a general systems as well as a lack of integration between nursing background. It was important to inte- the medical and nursing competency frameworks grate the new knowledge and skills with the base- in such a multiprofessional initiative. line of knowledge and skills that the nurses had in The nurses who participated in the programme their area of expertise. A questionnaire was sent were exposed to a total of ten educational mod- to prospective participants in advance to establish ules. Interactive sessions included role-play, in- baseline knowledge and clinical practices. The terviewing and assessment, self-management, data from this survey assisted in informing the and train-the-trainer guidance to implement the development of the theoretical and applied con- programme and deal with the environment. The tent. Comprehensive slide sets, narratives and International Faculty Steering Group prepared fact sheets were prepared to provide the necessary the educational materials in a modular format documentary support for all participants, and with each participant receiving a binder contain- emphasis was placed on interactive teaching and ing the programme outline, module outline, nar- learning practices, such as through the use of case ratives, fact sheets, instruments and tools, and studies and role-plays to strengthen critical think- evaluation forms. The content used the evidence- ing and problem-solving skills. based integrated approach to the recognition and The selection of the participants in the courses management of diabetes and depression with the was given careful attention because it was expect- most up-to-date literature in the field. ed that the nurses participating in the course The co-ordinators of each of the workshops would become ambassadors for the programme, promoted an interactive and participatory teach- drivers of initiatives for better care of patients ing and learning approach including opportuni- with comorbid diseases and trainers – using the ties for role-play, assessment and interviewing educational material provided as a resource and under their supervision. The last session in each basis. of the programmes focused on the development of an action plan for the participant to ensure a Facilitate Change in the Environment focus on changes in clinical practice and a com- The steering group considered the rollout of the mitment by each nurse to meet their goals and programme and public involvement as important expected outcomes from the course. The Interna- aspects of the programme. In most cases, a repre- tional Council of Nurses monitors these action sentative of the DDD preceded the arrival of the plans and the steering group use them for ongo- faculty to the country to meet the organisers from ing evaluation of the impact of the programme on the national nursing association and to make con- the practice of these nurses. tact with policy makers, patient and family organ-

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 148–156 ( DOI: 10.1159/000365599 ) isations, and key contacts in the media. The DDD and how they applied to diabetes and depression. representative organised interaction with local Context-specific strategies were discussed, espe- government officials and senior healthcare advi- cially in relation to personal and public cam- sors, and considered them as critical to assist in or paigns and collaborative actions. It is, however, a facilitate policy change. The faculty members also challenge to change the way healthcare users with assumed the roles of advocates, participating in comorbid disease are perceived, assessed and local media opportunities (including local radio treated. These challenges are even more pro- and television interviews) and discussions with nounced in lower income countries, in less-effec- local politicians. Where feasible, the national tive healthcare systems and in the presence of nursing associations invited important stake- stigmatisation and stereotyping. holders and the media to public meetings where patients told their own stories, seamlessly integrating their personal experiences of, for exam- Workshop Implementation and Evaluation ple, stigma, assessment and treatment. Within the programme, the faculty made par- A total of 175 clinical nurse practitioners and ticipants aware of their own responsibilities nurse educators were trained in the six work- working in the field of diabetes and depression. shops held in South Africa, Botswana, Swaziland, They encouraged them to consider the potential Uganda, Ethiopia and Kenya. The DDD, the In- barriers hindering the patients’ commitment to ternational Council of Nurses and the Lundbeck changes in lifestyle as well as engagement with Institute provided the logistical support for the self-help and treatment. They advocated reflec- identification of participants and organisation of tion on their own clinical practice and the need to workshops. The International Council of Nurses embrace evidence-based competencies. The or- worked closely with local nursing organisations ganisation of the workshops with their unique ex- to identify and select nurses representing a range posure to international experts, well-designed of educational and healthcare settings. The Inter- material, and contemporary teaching and learn- national Council of Nurses accredited the working strategies was intended to make a difference shops and provided each participant with a for- in the lives of all concerned. The sessions promot- mal certificate of completion. As follow-up, each ed networking as a strong conduit to address participant developed an action plan to guide quality issues by encouraging collaborative work them in the incorporation of the new knowledge in groups, organisations and within the regional and skills into their practice. political structures. The steering group developed an evaluation instrument that addressed the outcomes of each Address Issues of Stigma in the Diagnosis of module and items related to the teaching meth- Diabetes and Depression ods. The latter items were kept constant to facili- The course placed particular importance on the tate ease of use. Participants evaluated each item recognition of the role of stigma in the manage- using a Likert scale with 5 being the highest or ment of comorbidity [20]. Although stigmatisa- best scoring. An opportunity for open-ended re- tion was not addressed in a specific module, the sponses was also provided for each module and a faculty and participants within the group work final part of the evaluation instrument allowed explored the realities of stigma from avoidance of the participants to reflect on the workshop as a recognition to management of the comorbid con- whole. ditions. It was important to discuss the stigmati- The system of formal participant feedback was sation issues within the wider cultural context explained to participants at the start of the pro-

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 148–156 ( DOI: 10.1159/000365599 ) gramme. At the time of writing this chapter the first through new partnerships and community 146 sets of evaluation forms were received, but in- capacity building dividual item responses varied from 106 to 146 be- It was meaningful that the participants high- cause of various factors. Survey Monkey software lighted specific skills and tools in their feedback. was used to analyse the quantitative data whilst the The demonstration and introduction of the Pa- qualitative responses were transcribed and catego- tient Health Questionnaire (PHQ9) for the as- rised, and themes developed from the data. sessment of depression was considered useful for their practical clinical setting [21]. The participants considered the PHQ9 ‘wonderful and will Results be embraced’. The nominal group technique [22, 23] as adapted by the educational expert in the The participants’ overall evaluation of the work- steering group was viewed as meaningful for en- shop was positive with mean scores not lower hancing group participation. Motivational inter- than 4.69 of a maximum of 5. Participants espe- viewing was considered an essential technique to cially appreciated the useful exchange of knowl- be included in future nursing curricula. edge, values and skills, and considered the public event an important achievement. The qualitative responses echoed these positive results with clear Discussion reference to the value of and approach to the workshops. Participants considered the work- Participants and facilitators considered the first shops to be ‘eye opening’ and ‘straightforward’ – phase of this project as successful and the feed- appreciating the presence and approach used by back guided the final phase of the programme experts throughout. The quality of the organisa- that incorporated the above. The integration of tion was also highlighted. training about the two conditions of depression Within the first rollout, participants made a and diabetes within the context of comorbidity number of recommendations that resonated well was challenging and this series of workshops pro- with the experience and expressed opinions of the vided valuable pointers on how to achieve this ef- steering group. These included: fectively. It was clear that nurses and most other • Provision of further support and monitoring healthcare professionals still undergo training of actions, such as drug fact sheets, that emphasises systems-based or disease-orient- conversation maps and the involvement of ed models. The comorbidity framework provides local multidisciplinary teams in further new insights and ways of thinking and implemen- training tation – both in education and clinical practice • Introduction of even more interactive work [10]. This model encourages multiprofessional such as role-plays and group work working with case management, a structured • Refining some workshop material, the flow of management plan and enhanced interprofession- certain modules and time allocation for the al communication. There is now growing evi- modules on diagnosis and assessment of dence that collaborative care can successfully im- depression in people with diabetes prove depression and diabetes outcomes with • Fine-tuning of the workshop evaluation cognitive behaviour therapy enhancing diabetes format and the management of post- self-management, reducing diabetes morbidity, workshop expectations improving stability and treating depression effec- • Identification of barriers to change and tively. In addition, other risk factors, such as low- mechanisms to deal with such; mostly density lipoprotein and cholesterol levels as well

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 148–156 ( DOI: 10.1159/000365599 ) as high blood pressure, can be better controlled by evant healthcare professionals, but also those in a adoption of this person-centred collaborative position to restructure the health system and del- model of care [9]. Rushton et al. [24] confirmed egate responsibilities appropriately. Subsequent the need for health professionals to rethink how skill and knowledge training of other primary to manage patients with multiple healthcare con- and secondary healthcare professionals would be ditions, given that the care environment itself re- necessary and is recommended as a follow-up to mains fragmented. nurse training. Additional resources and the It was clear to the steering group that the selec- commitment of the trained trainers to cascade tion of participants for such programmes should the learning from the African Nurse Training be more focused and differentiated; for example, Programme to other new and practicing nurses there is a need to focus more on nurse educators will be essential to the institutionalisation of the in future programmes and to provide a variety of concepts and the broad-scale benefits to affected modules to meet the needs and backgrounds of patients. different groups at different times. It was also ac- The International Council of Nurses and the knowledged that multiprofessional collaboration national nursing associations should prioritise is critical and that specific sessions and applied the further dissemination of the knowledge and exercises are needed to drive home the complexi- skills from the African Nurse Training Pro- ties of comorbid disease assessment and treat- gramme by establishing regional centres of excel- ment. lence to institutionalise the concepts and maximise their adoption in nursing practice. The programme as designed forms a good Limitations of the Programme baseline to be adapted for other healthcare professionals and multiprofessional groups. Such a Being the first round of this type of programme, rollout would provide further strength to the ini- it was considered important to provide partici- tiative to better manage and support patients with pants with an evaluation form for each module comorbid conditions. Material would also be and one for the overall workshop. The feedback coded for use as half day, full day or 2.5 days – de- provided valuable insights to the steering group, pending on participant needs, timeframe and re- but it is acknowledged that data collection instru- sources available. ments of this nature tend to elicit more subjective To further support this aim, an integrated responses. The Likert scale is relatively easy to manual, which will serve as a comprehensive ref- use, but suffers from traditional concerns such as erence, is in process. This manual will also in- participant honesty, interpretation of the scale, clude guidelines for logistical and other arrange- feeling-bias and (in this case) a laborious analysis ments of such a programme, pre-workshop mate- process. It is, however, important to note that the rial and action plans. Heuristic hints for the qualitative data provided by participants corre- development of good case studies, role-plays and sponded well with the Likert-type scale findings. other teaching and learning activities would provide further guidance. Another action relates to the strengthening of Next Steps in Comorbidity Training multiprofessional, and especially nursing, research relating to comorbidity within Africa. An Organising the delivery of services in such a way example would be PhD and Masters research that collaborative and coordinated care is possi- projects that strengthen care outcomes for pa- ble requires the buy-in of not only the other rel- tients with comorbid disease.

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 148–156 ( DOI: 10.1159/000365599 ) Conclusions • Expert faculty members: Professor N. Sartorius (President AIMHIP, Switzerland), Professor R. Holt (UK, Endocrinology and Diabetology), Dr. H.L. Using the comorbidity of disease framework as a Millar (UK, Consultant Psychiatrist) and Dr. legitimate springboard for redesigning both for- Tesfamicael Ghebrehiwet (Consultant in Nursing mal and informal educational programmes is and Health Policy, ICN) warranted, feasible and acceptable. The frame- • Expert academic and technical facilitators: Dr. J. Hayes (USA, Psychiatry), Larry Cimino (USA, work rings true to the clinical challenges of medi- Programme Director), André Joubert (Director, cine in the 21st century, with the increasing prev- Lundbeck Institute) and Marianne Helwigh alence of comorbidity and how patients present (Operational Manager, Lundbeck Institute) in healthcare systems. Stigmatisation remains a • Regional experts: Professor S. Rataemane (University serious concern in many cultural contexts, and of Limpopo, Pretoria, South Africa), Dr. S. Bahendeka (IDF Uganda) and Dr. I. Westmore good research and clinical work that addresses (Consultant Psychiatrist, South Africa) this issue directly and indirectly within a comor- • IDF educators: B. Majikela-Dlangamandla (South bidity of disease framework would contribute to Africa) and A. Jalang’o (Kenya) equitable access and better-quality healthcare. • The International Diabetes Federation (IDF) • The Dialogue on Diabetes and Depression (DDD) Further follow-up of the participants’ progress • The Association for the Improvement of Mental from the African experience in relation to chang- Health Programmes (AIMHP) es in clinical practice will help to inform and op- • International Council of Nurses (ICN) timise the benefits of such future programmes. • The Lundbeck Institute Given the positive African experience, the faculty • Eli Lilly and Company • The World Federation for Mental Health (WFMH) is better equipped and more confident in their • The University of Southampton Faculty of Medicine ability to deliver such comorbidity programmes • The School of Nursing, Faculty of Health Sciences, in other culturally challenging environments. University of the Free State, South Africa • Democratic Nursing Organisation of South Africa (DENOSA) • Ethiopian Nurses Association (ENA) Acknowledgements • Lesotho Nursing Association • National Nursing Association of Kenya (NNAK) The authors would like to acknowledge the important • Nursing Association of Botswana contributions and/or support of the following entities • Swaziland Nurses Association and/or persons: • Uganda Nurses and Midwives Union (UNMU)

References

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niano. Oxford, 1674. emotional problems in patients with Am J Psychiatry 2010; 167: 496–497. 3 Anderson RJ, Freedland KE, Clouse RE, diabetes: comparison of screening char- 8 Leone T, Coast E, Narayanan S, et al: Lustman PJ: The prevalence of co-mor- acteristics of depression questionnaires, Diabetes and depression comorbidity bid depression in adults with diabetes. measurements of diabetes-specific emo- and socio-economic status in low and

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Med 2010; 363: 2611–2620. 2011; 10: 138–151. 20 Weiss MG, Ramakrishna J, Somma D: 11 International Diabetes Federation Clini- 16 Schreirer MA: Getting more bangs for Health-related stigma: rethinking con-

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Dr. H.L. Millar Mental Health Directorate, The Carseview Centre 4 Tom McDonald Ave Dundee, Scotland DD2 1NH (UK) E-Mail [email protected]

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 157–164 ( DOI: 10.1159/000365600 )

The Challenge of Developing Person-Centred Services to Manage Comorbid Mental and Physical Illness

Linda Gask Centre for Primary Care, Institute of Population Health, University of Manchester, Manchester , UK

Abstract morbidity, and the challenges posed by comor- This chapter considers the difficulties posed by the direc- bidity of physical and mental health problems in tion in which healthcare has developed across the world, particular. At the heart of this challenge is the in particular problems arising from fragmentation and need for us not to lose sight of the needs of the specialisation of care provision. There has been an in- person who is seeking help for his/her ailments, creasing recognition of the need for improved systems from the macro-level of designing healthcare of primary care; however, there is no universal model of systems to the micro-level of interaction be- provision, and barriers to the management of physical tween doctor and patient within the consulting and mental comorbidity can be identified in primary care room. settings. Models of collaborative care which derive from the Chronic Care Model have shown some promise in management of comorbidity. In order to improve out- The Fragmentation of Healthcare comes for people who present with comorbid and multimorbid health problems, healthcare professionals in all Heath systems are increasingly fragmented. Even settings will need to acquire a range of specific skills. the British National Health Service, which histor- These include being able to explore the impact of physi- ically has a strong orientation to primary care, has cal and mental health problems on the patient, and the become less integrated in the way it delivers care. negotiation of patient-centred goals. At the organisational level this is reflected in an © 2015 S. Karger AG, Basel ever-increasing number of different ‘providers’ being ‘commissioned’ to deliver care – some profit-making, some not-for-profit – and each one of Other chapters in this book have described the them requiring an army of administrative staff nature and magnitude of the problems facing (and not a few lawyers) to negotiate the detailed healthcare in addressing the problem of multi- contracts, performance management and financial arrangements that go with them. Hospitals to their own specific area of expertise. The psy- are moving to take over and develop community chiatrist John sees never seems to know what resources such as services for older people to in- blood tests his doctor has done recently for his tegrate them ‘vertically’, but in doing so loosen diabetes, which is not well controlled at the mo- the ‘horizontal’ ties they have with other services, ment, and says that their computer systems ‘don’t the most important of these being primary care. talk to each other’. Nobody seems to be able to Within primary care, a payment-for-perfor- help him prioritise one appointment above an- mance system called the ‘Quality and Outcomes other if they clash and he cannot make it to both; Framework’ rewards doctors according to criteria attending all of them is a great deal of work [3] , based on single diseases rather than management sometimes rather like a full-time job. When he of multimorbidity [1] . missed an appointment once, he was discharged Take for instance John, who is 58 years old and from a clinic and his general practitioner had to has multiple health concerns, diabetes, coronary re-refer him. He no longer works, but he does not heart disease, arthritis and severe depression fol- think he would be able to anyway, as all this ‘self- lowing the death of his wife. In the past he went management’ takes so much time. to his general practitioner when he did not feel It sometimes feels to John as though nobody is well, but now he does not know where he should actually interested in finding out what is worrying go. There seem to be far more doctors at the prac- him about his health in the midst of all this fre- tice than there used to be, but he does not seem to netic yet increasingly fragmented ‘provider’ activ- know any of them very well, and it seems harder ity. He muddles through somehow. His daughter to see the same doctor each time than it once was. is worried about him, but she is not sure which According to the practice website, the doctors doctor is the right person to tell and neither is now have particular expertise in certain diseases John. (such as diabetes or coronary heart disease). Does that mean he should go and see different doctors for each problem? He is called in for appoint- The Consequences of Specialisation and ments with the practice nurse to review how he is Fragmentation doing with his diabetes as she works her way through the patients on the diabetes register. Next There is nothing unusual about John’s story. In week he may be asked to come in for a different some countries his story would even be more review appointment for his cardiovascular dis- complex as he might also have to become in- ease, generated by another disease register to volved in discussion with insurance companies meet the needs of reporting in the Quality and about the cost of his care. John has access to more Outcomes Framework. John’s experience is of be- scientifically informed healthcare than at any pe- ing ‘under surveillance’ and ‘monitored’ [2] rath- riod in the past. Yet the expansion in specialist er than being an active participant in care. The information which has been generated has come practice has put up a sign saying it is now run by without an improvement in our ability to inte- Angel Healthcare Providers for the NHS. Are not grate this knowledge optimally to meet John’s they a commercial company? personal needs. The World Health Organisation In addition to these ‘review’ appointments at (WHO) [4] has drawn attention to this character- the general practitioner practice, he has outpa- istic trend that is shaping health systems today: tient appointments with specialists at the hospital • A disproportionate focus on specialist, every now and then, for his mental health and ar- tertiary care, or ‘hospital centrism’: in thritis, but each doctor he sees pays attention only member countries of the Organisation of

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 157–164 ( DOI: 10.1159/000365600 ) Table 1. The consequences of fragmentation inefficiency: the most fragmented healthcare systems in the world are also the most expensive (adapted from Stange [6])

Ineffectiveness spending more on the parts, such as through narrowly focussed pay-for-performance schemes does not improve the whole Inequality in a fragmented healthcare system people fall between a patchwork of ‘safety nets’ and specific barriers to access (e.g. for ethnic minority groups) are not addressed Commoditisation disease management programmes support narrow evidence-based care rather than integrated care; patients become ‘customers’ and doctors become ‘providers’ Commercialisation healthcare becomes ‘market driven’ De-professionalisation professionals become technicians delivering a narrow slice of care De-personalisation and both patients and professionals are unhappy with their experience of the system dissatisfaction

Economic Cooperation and Development cal, scientifically sound and socially acceptable (OECD), the 35% growth in the number of methods and technology at a cost the community doctors between 1990 and 2005 was driven by and country can afford’. a nearly 50% increase in specialists compared Numerous studies from multiple countries with a 20% rise in general practitioners [5] have shown that when systems are organised • Fragmentation as a result of the around primary care, outcomes are better with multiplication of specialist programmes and improved equity and lower costs. For example, projects built around ‘priority programmes’ when people have a primary care doctor as op- focussed on single-disease control posed to a specialist as their personal physician, • The pervasive commercialisation of their mortality risk drops by nearly 20% and their healthcare in unregulated healthcare systems costs are about one third less [7] . The WHO views the development of primary In an editorial article in Annals of Family Med- healthcare as one of the key challenges for health icine , Kurt Stange [6] highlighted the conse- system reform [4]. More than 30 years after the quences of our increasingly specialised and frag- Alma Ata Declaration, the vision of primary care mented healthcare systems (table 1 ). For the perfor all has yet to be achieved, but according to son with multimorbidity, the primary care Gunn et al. [9] the generalist holds the key to pro- professional, doctor or nurse, is a key person in viding truly personalised care (p. 111): helping them to navigate an increasingly complex landscape [7] . A fundamental role of the generalist is to balance the biotechnical with the biographical. The generalist must know and understand how each life story and so- The Importance of Primary Care cial context are constantly influencing and being influenced by physical and emotional health. To achieve the balance between the biotechnical and biographical as- The Alma Ata Declaration [8] defined primary pects of each interaction, the generalist must have the care thus: ‘the role of primary health care as the skills to reach a mutual understanding of the priorities local, universally available, essential, first point of and challenges that individual patients face when man- contact with the health system, based on practi- aging their health.

Person-Centred Services for Comorbidity 159

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 157–164 ( DOI: 10.1159/000365600 ) This very personal model of care is neverthe- ally a person may feel that, in wanting to raise less greatly challenged by the forces such as those ‘personal’ issues, there is a sense that the profes- described above [1] , which seek to fragment the sional is trying to dismiss the severity of physical process and provision of care in the belief that symptoms or talk about issues which do not seem this will lead to improved quality of care [10] . In- to the patient to be relevant to the problem they novations such as the Quality and Outcomes present. This is something we have particularly Framework in the UK focus on single diseases observed when patients present with what seem rather than multimorbidity, and solely on dis- to the doctor to be ‘medically unexplained symp- ease-centred outcomes rather than also taking toms’ [12] ; however, in a recent study of the im- into consideration the patient’s goals. This is par- plementation of a new model of care for depres- ticularly problematic when managing people sion and cardiovascular disease, uncertainty was with complex comorbid and multimorbid condi- also raised by some patients (and professionals) tions [1] . about how much they wanted physical and men- Across the world, providers of primary care tal healthcare to be more integrated [13] . We have include not only doctors who have received spe- also noted that both primary care doctors, osten- cific vocational training in family medicine (in- sibly providing holistic care for the person, and cluding general internal medicine and general patients with long-term conditions may collude paediatrics in some countries such as the USA), to avoid discussing emotional problems, prefer- but also non-physician primary care providers ring instead to keep to the ‘safer ground’ of phys- (such as nurses and physician assistants). Non- ical health and ‘normalising’ the distress associ- primary care physicians, in particular gynaecolo- ated with conditions, such as diabetes and cardio- gists but also other specialists including psychia- vascular disease, rather than daring to try and trists, may also provide patient care services that raise the possibility that this might be ‘depression’ are usually delivered by primary care physicians. [14] . These form significant barriers to both de- These may focus on particular needs related to tecting and managing emotional problems in the care such as prevention or chronic care, but they setting of long-term conditions and mean that do not provide these services in the context of professionals need to work hard to engage people comprehensive, first contact and continuing care sensitively in talking about their emotional prob- which is what characterises family medicine. lems (see below). Nevertheless, it is crucial that such specialists Similar barriers occur in the detection and have a basic understanding of the diseases that are management of physical illness in people with comorbid with those in which they specialise; for long-term mental health problems. Many people example, the need for psychiatrists to understand with severe and enduring mental illness do not the role played by cardiovascular disease in the feel stigmatised when receiving treatment in the excess mortality and morbidity of people with a setting of primary care [15], but some undoubt- diagnosis of severe and enduring mental illness edly do [16] . In the UK, a significant minority do [11] . not attend their general practitioner for the rou- However, a crucial challenge faced by those tine physical health checks for which general seeking to develop services for comorbid physical practitioners are now financially rewarded. The and mental health problems is that patients them- degree to which people with severe mental illness selves vary in how much they want to share their receive equivalent physical healthcare to the gen- emotional problems with those caring for their eral population from either primary care [17] or physical health problems. Mental health prob- alternatively within mental health services [18] lems still carry significant stigma, and addition- remains debatable.

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 157–164 ( DOI: 10.1159/000365600 ) Table 2. Elements of collaborative care (adapted from Gunn et al. [30])

Multiprofessional approach to patient care provided by a case manager working with the family doctor under weekly supervision from specialist mental health medical and psychological therapies clinicians A structured management plan of medication support and brief psychological therapy Scheduled patient follow-ups Enhanced interprofessional communication of patient-specific written feedback to family doctors via electronic records and personal contact

Developing Novel Models of Care for intervention with a choice of starting with psy- Comorbidity and Multimorbidity chotherapy or pharmacotherapy, to a primary care population yielded an effect size of − 0.292 In recent years, numerous disease-management (95% CI: −0.429 to −0.155, n = 1,133) for depres- programs, incorporating clinician interventions sion outcomes. This is a moderate effect size, but (education, feedback, reminders) and/or patient the studies were based on community samples interventions (education, reminders, financial in- with few exclusion criteria (unlike studies of psy- centives), to improve quality of care and out- chotherapies based in specialist settings), indicat- comes for people with long-term conditions have ing this effect size could potentially be attained on been described in the literature. These programs, a population scale. The authors concluded by say- the best known of which is the Chronic Care ing, ‘improvement of the general medical condi- Model developed by Wagner et al. [19] in Seattle, tion including glycemic control is likely to require have been developed and extensively evaluated simultaneous attention to both conditions.’ for single conditions, but less commonly for dis- Reviewing the literature on the content of eases in combination. A recent systematic review these complex interventions, Piette et al. [23] sug- of complex interventions for patients with multi- gested an effective organisational management morbidity identified 10 randomised controlled strategy for diabetes and depression should in- trials, of which only 3 provided data on mental clude all the following elements: (1) systematic health outcomes [20] . identification of patients with diabetes and de- However, there is now a growing body of lit- pression and quality-of-care reviews, (2) proac- erature on interventions for comorbid diabetes tive patient monitoring between outpatient en- and depression. The Chronic Care Model in- counters, (3) intensive efforts to co-ordinate formed the development of collaborative care ( ta- treatment across clinicians, (4) increased access ble 2 ) which has been extensively evaluated for to cognitive-behavioural or related therapies ad- the management of depression [21, 22] . dressing patients’ depressive symptoms and dia- A recent meta-analysis of 14 randomised con- betes self-care, and (5) an emphasis on promoting trolled trials of interventions for depression in the physical activity to address both depressive symp- setting of diabetes with a total of 1,724 patients toms and physiologic dysregulation. [22] showed that treatment was effective in terms Katon et al. in the TEAMcare study [ 24 ] have of reduction of depressive symptoms, but the ef- now both successfully addressed multimorbidity fect on glycaemic control was substantially small- and improved physical and mental health outer. Collaborative care (utilising the components comes. A specially trained and supported case described below), which provided a stepped care manager was employed to ‘treat to target’ both

Person-Centred Services for Comorbidity 161

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 157–164 ( DOI: 10.1159/000365600 ) Table 3. Key skills for managing people with comorbid physical and mental health problems

Sensitively engaging the patient in discussing their worries and concerns Finding out about the patient’s problems Exploring the impact of physical and mental health problems on the patient (and on each other) Eliciting health beliefs Clarifying and negotiating the patient’s goals (and how these relate to their healthcare including self-management of chronic illness) Motivating the patient to achieve their goals Developing a therapeutic plan with the patient through shared decision-making Employing simple psychological strategies (e.g. behavioural activation and problem solving) to help the person to achieve their goals

depression and other chronic disease-related out- systems where the general practitioner works comes in the primary care setting, achieving sig- alone without any additional person who might nificant improvements in both. The TEAMcare take the role of the ‘case manager’. In these set- nurse was integrated into primary care and super- tings a more traditional approach to ‘collabora- vised weekly by a psychiatrist and primary care tive care’ of developing the skills of the general physician. The intervention improved glycaemic practitioner in systematically following-up peo- control, lipid profile, systolic blood pressure and ple with common chronic conditions with the depression symptoms compared to usual primary support and supervision of specialists may still be care. the way forward [27] . Implementing collaborative care into routine In the USA the concept of the ‘patient-centred practice poses challenges. In the USA, the medical home’ is a delivery system and re-im- IMPACT model for depression care in older peo- bursement reform that aims to reduce care frag- ple with comorbid physical health problems has mentation and other inefficiencies associated been implemented in a range of healthcare sys- with chronic disease management. Its supporters tems across the country [25] , and this has also describe four ‘cornerstones’ that serve as the con- been highly influential internationally. Major ceptual foundation for a successful medical changes (including re-allocation of resources) are home: (1) engaging patients actively in medical needed to implement disease management and decision-making and enhancing their access, (2) collaborative care models, and investment in clin- incorporating evidence-based processes of care ical electronic information systems is essential into practice, (3) adopting new payment struc- [26] . Re-designed systems and care pathways tures that reimburse care activities occurring must implement more frequent follow-up and outside the traditional office visit and (4) en- routine monitoring of outcomes by case manag- hanced primary care [28] . There is increasing ers, promote integration of specialists into prima- recognition of the crucial role that primary care ry care to provide supervision and support, and has in providing both mental healthcare for peo- develop self-management systems for patients ple with chronic illness and physical healthcare and professionals. There are also problems in de- for people with severe mental illness in the ‘med- livering such complex interventions in healthcare ical home’ [29] .

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Report 2008: Primary Care – Now More their doctors? Qualitative analysis of Schizophr Res 2011; 129: 104–110. than Ever. Geneva, WHO, 2008, p 10. potential barriers to reattributing medi- 18 Lawrence D, Kisely S: Inequalities in 6 Stange K: The problem of fragmentation cally unexplained symptoms. J Gen In- healthcare provision for people with

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2012; 10:CD006525. illnesses. N Engl J Med 2010; 363: 2611– Quality, 2010. 22 van der Feltz-Cornelis CM, van der Nuy- 2620. 29 Croghan TW, Brown JD: Integrating en J, Stoop CH, Chan J, Jacobsen AM, 25 Unützer J, Powers D, Katon W, Langs- Mental Health Treatment Into the Pa- Katon W, Snoek F, Sartorius N: Effect of ton C: From establishing an evidence- tient Centered Medical Home. (Prepared interventions for major depressive dis- based practice to implementation in by Mathematica Policy Research under order and significant depressive symp- real-world settings: IMPACT as a case Contract No. HHSA290200900019I

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Linda Gask, PhD, FRCPsych Centre for Primary Care, Institute of Population Health 5th Floor Williamson Building, University of Manchester Oxford Road, Manchester M13 9PL (UK) E-Mail [email protected]

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 165–177 ( DOI: 10.1159/000365601 )

Prevention of Comorbid Mental and Physical Disorders

Clemens Hosman Emeritus Professor of Mental Health Promotion and Prevention, Maastricht University, Maastricht, and Radboud University Nijmegen, Nijmegen , The Netherlands

Abstract As is extensively discussed and evidenced in this This chapter aims to explore the possibilities of prevent- book, comorbidity of mental and physical disor- ing comorbid mental and physical disorders. It presents ders is a common phenomenon among patients a framework of optional preventive strategies based on in physical and mental healthcare, as well as in four explanatory models of comorbidity and six strategic populations. Comorbidity with physical illnesses, dimensions. Addressing common early risk factors is particularly chronic physical illnesses, is reported discussed as one of these preventive strategies. Some especially for depression and anxiety disorders. examples of evidence-based prevention programs are This is in line with conclusions from the WHO presented that might contribute to prevention of comor- World Mental Health Surveys in 18 countries, the bidity, needs for further research are discussed, and rec- results of which are presented in Global Perspec- ommendations are presented for policy makers and prac- tives on Mental-Physical Comorbidity in the WHO titioners to improve the perspectives for preventing World Mental Health Surveys (2009) [1] . This in- mental and physical comorbidity. So far, preventing men- ternational cross-sectional study measured the tal disorders and preventing physical disorders have prevalence of mental and physical comorbidity been highly separated fields. It is recommended that during the year preceding data collection. Pooled both fields should broaden the range of baseline and out- across 18 surveys in developed and developing come indicators and include longitudinal designs to un- countries, odds ratios (ORs) between 1.8 and 3.3 derstand the long-term broad-spectrum outcomes of were found for depression and dysthymia, and for preventive interventions better. Future policy plans and different anxiety disorders in people with chronic practices in physical and mental health should be more pain conditions (arthritis, spinal pain, headache); focused at preventing comorbidity, and enhance related among those with a heart disease, the ORs fell in expertise among policy-makers and practitioners. Finally, the range of 1.9–2.7 [2] . Averaged across coun- it is argued that the preventive approach of comorbidity tries, the WHO study found that 36.9% of those should be broadened to ‘smart clusters’ of highly related with a depressive or anxiety disorder also suffered mental, physical and social problems, with the last pos- from a physical disorder. Prospective studies have sibly referring to important common risk factors. shown that mental disorders could precede the © 2015 S. Karger AG, Basel onset of chronic physical disorders, but also that chronic physical disorders could precede the mendations for policy makers and practitioners onset of mental disorders [3] . Mental and physi- to improve the perspectives for preventing co- cal comorbidity represents a high burden to soci- morbidity. eties, as is illustrated by a recent Australian report on comorbidity. In 2007, almost 12% of Australians aged 16–85 had a mental disorder Developments in Preventing Mental Disorders and a physical condition at the same time [4] . Comorbidity of mental disorders with physi- Although the idea of preventing mental illness cal disorders and comorbidity in general por- was introduced more than 100 years ago, sci- tends a poorer outcome for the patients and high- ence-based prevention has a history of around er economic costs [2]. This includes poorer clini- 30–40 years. Over the last decades, much prog- cal course, higher risk of chronicity, disability, ress has been made in understanding the risk additive work-loss, poorer quality of life and and protective factors for mental disorders, mortality, as well as more healthcare utilization, which has been translated into a wide range of poorer treatment adherence and reduced treat- prevention programs. Prevention and health ment success [5–7] . All of these outcomes stress promotion, also in the mental health domain, the need to invest in prevention of comorbid dis- have emerged internationally as a significant orders. If effective prevention strategies were im- multidisciplinary field of science and practice, plemented, such an investment could result in a with a range of peer-reviewed scientific journals tremendous reduction in human suffering, utili- and specialized university departments and re- zation of treatment services and huge cost savings search centers in most continents. Currently, a in healthcare and social security. wide range of science- and practice-based pre- Although the bulk of studies on comorbidity vention programs are available. Thousands of date from after 2000, there were studies on mental controlled studies and a large range of system- and physical comorbidity in the 1980s and 1990s atic reviews and meta-analytic studies have been [8–11] . By the 19th and 20th centuries, most published showing that prevention programs mental hospitals had wards devoted to the treat- targeting mental health can generate a wide ment of physical illness of patients admitted be- range of positive outcomes [12–15]. These in- cause of mental illness. From the 1970s, a DSM- clude strengthening protective factors (e.g. so- based assessment on the link between mental and cial-emotional skills, parenting competence, ear- physical diseases became an essential part of clin- ly parent-child interaction, coping with parental ical diagnosis. Given this history, it is striking that death and loss) and reducing the number of risk there are very few publications on the prevention factors (e.g. child maltreatment, insecure attach- of comorbidity. Most of the current literature is ment, early externalizing problems, bullying, almost exclusively focused on improving treat- substance use). There is also cumulative evi- ment for patients who already suffer from comor- dence of reductions in the onset of depression bid mental and physical illness. [16] , anxiety symptoms and disorders [17, 18] , This chapter aims to explore the possibility of eating disorders [19] , externalizing problems preventing comorbid mental and physical disor- and conduct disorders [20–22] , and substance ders. It presents a theory-based framework of op- use problems [23] . Some randomized longitudi- tional preventive strategies, describes examples of nal studies have found significant effects even up evidence-based prevention programs that might to 15 and 40 years later. A growing number of contribute to prevention of comorbidity, identi- economic evaluations of such programs have fies further research needs and presents recom- also provided evidence of their potential cost-ef-

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 165–177 ( DOI: 10.1159/000365601 ) fectiveness, especially early childhood programs tal disorders prevention are highly separated. [24] . Even in cases where risk factors are addressed with To date, evidence-based prevention programs a potential broad-spectrum outcome, testing their are internationally exchanged, disseminated and impact on the onset of both mental and physical implemented, and supported by online interna- illnesses is exceptional. Most disorder prevention tional and national databases that are freely acces- programs in mental health are targeted at prevent- sible to policymakers and practitioners. Given the ing a single disorder (e.g. depression). steadily growing availability of effective preven- To understand how to prevent physical and tion programs and the awareness of the enor- mental comorbidity and to measure if interven- mous human and economic burden of mental tions are effective in preventing comorbidity, we disorders, it is likely that investments in prevent- first need to understand what comorbidity means, ing and treating mental disorders will become how we can differentiate between types of comor- more balanced during this century. bidity and what the causal processes are underly- In spite of these promising developments, ing comorbidity. major challenges exist in preventing mental disorders and promoting mental health. First, reviews and meta-analyses have shown that on av- Types of Comorbidity erage the effect sizes of prevention programs are small to moderate albeit significant, mostly Comorbidity can be defined at an individual level ranging between 0.15 and 0.40. Meta-analyses and at a population level, paralleling a clinical and have also shown large differences in effect sizes a public health approach. This is a relevant dis- between programs, ranging from highly effec- tinction as prevention encompasses both preventive to showing no effect and in some cases even tive treatment and public health actions. Clini- negative effects. This emphasizes the urgent cians in physical and mental healthcare are chal- need for program improvement and knowledge lenged to identify the risk of comorbidity in on the moderators and principles of effective- individual patients and to act accordingly to pre- ness. Secondly, owing to the use of labor-inten- vent comorbidity. This requires widening clinical sive methods in many programs, low levels of assessment and treatment to address the risk of implementation and poor resources and infra- multiple disorders in the physical and mental structure for prevention, the population reach of health domains, and, if needed, to involve other these preventive interventions is still marginal. clinical disciplines. This contrasts with the much wider implemen- Preventing comorbidity at the population lev- tation and public reach of programs aimed at re- el requires a public health way of thinking [26] . ducing the risk of chronic physical diseases such This includes population-based assessment, as those on reducing risk behaviors (e.g. smok- finding groups at high risk of comorbidity, iden- ing, substance use, consuming unhealthy food, tifying risk and protective factors, taking policy risky driving) and environmental risk factors measures, initiating intervention programs to re- (e.g. air pollution, safe cars and roads, quality of duce the risk of disorders and comorbidity, and food). rigorously testing their efficacy and effectiveness. Finally, although Kessler and Price [25] already As discussed in the next section, interventions in 1993 advocated for investment in the preven- could range across a wide spectrum of optional tion of comorbidity in psychiatric disorders, pre- preventive strategies that could start before the vention research has only marginally addressed onset of a primary disorder and even before this issue. The fields of physical diseases and men- birth.

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 165–177 ( DOI: 10.1159/000365601 ) A distinction is commonly made between con- ample might not reflect the sequential onset of current comorbidity and sequential comorbidity. two comorbid disorders, but age-related manifes- Concurrent comorbidity refers to a situation in tations of a similar underlying long-term depres- which a person has two or more disorders at the sive disorder. same time or at least during the same period. In The distinction between concurrent and se- such cases, taking timely action to prevent the on- quential comorbidity is less transparent than it set of both disorders would be the most desirable looks at first sight. Concurrent refers to the co- approach. This is only possible when both disor- occurrence of two disorders during a specific ders have evidence-based common risk or protec- period of measurement, which could be the tive factors that are measurable and malleable preceding week, month or year. In the case of a during the antecedent period. For instance, grow- chronic physical disease, the onset of a reactive ing empirical support exists for serious childhood depression might follow months after the onset adversities as a risk factor for both mental disor- of a chronic heart disease. When their illness ders and chronic physical diseases [1, 27] . Serious periods (prevalence) overlap, they could be motor vehicle accidents with life-threatening ex- considered as concurrent diseases, but as se- periences represent another example, as they quential comorbidity when we use onset as the could result in both serious physical injuries and criterion. As primary prevention aims to re- a posttraumatic stress disorder among survivors. duce onset of diseases, the onset criterion is of The many successful measures that have been ad- more strategic value as it offers more informa- opted in recent decades to reduce serious traffic tion on possible causal sequences and timing of accidents have likely prevented many physical preventive interventions and their outcomes. diseases or disability as well as comorbid post- The onset of a primary disease could then be traumatic stress disorders. used as a trigger for interventions to prevent Sequential comorbidity refers to the onset of a the onset of a related secondary disease. Fur- secondary disease that is significantly associated ther, when the secondary disorder is likely to with or influenced by an already existing primary start during the episode of the primary disor- disease. A well-known example of sequential co- der, it is most practical that clinicians integrate morbidity within the mental health domain is the efforts to prevent a secondary disorder in their relation between child anxiety disorders and ado- treatment of the primary disorder. Finally, even lescent major depression. In their longitudinal when sequential comorbidity is established, community study, Wittchen et al. [28] found that how disorders are related remains an impor- in the case of comorbidity, anxiety disorders tant question. Theory-based prospective stud- mainly precede the onset of major depression. ies are needed to establish if the onset of the The ORs for later onset of depression ranged second disorder is mediated by the features and from 2.5 for specific phobia to 3.7 and 3.8 for pan- outcomes of the primary disorder, or a delayed ic disorder and agoraphobia. The time delay be- result from a common risk factor. tween the onset of the two related disorders could be short (e.g. a month or a year) or might even extend over one or more decades. The develop- Four Explanatory Models ment of sequential comorbidity could encompass longitudinal pathways from the start of life into Most research on comorbidity is targeted at in- late adulthood [28]. It should be stressed, how- creasing the knowledge on prevalence and conse- ever, that anxiety symptoms might be an expres- quences of comorbidity, and on early detection sion of child depression, which means that the ex- and appropriate treatment. The causes of comor-

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 165–177 ( DOI: 10.1159/000365601 ) bidity are studied much less [7] . For prevention medication. Preventive interventions could aim policies and programs, the latter type of studies are to reduce or compensate for these mediating out- crucial, as preventive interventions typically aim comes. In the bidirectional model, two disorders to influence causes of diseases to lower the risk of and their outcomes are assumed to reinforce each onset. Designing an effective prevention approach other’s development and chronic course. In this to mental and physical comorbidity is only possi- case, preventive interventions could address me- ble when we have insight into the underlying caus- diating outcomes of both disorders. Finally, in the al mechanisms. For this reason, this section is fo- accidental comorbidity model comorbid disorders cused on understanding how multiple diseases are considered to be a random phenomenon, with could be related and how risk and protective fac- no evidence of mutual influence or common tors might contribute to comorbidity. Next, we causes. Each disorder is assumed to have an inde- present a comprehensive framework of optional pendent causal trajectory. The prevention of both preventive strategies to reduce comorbidity. disorders would require the implementation of To describe how and why disorders could be separate primary preventive interventions, each related, we differentiate between four models: (1) addressing a different disorder. common antecedent model, (2) sequential comorbidity model, (3) bidirectional comorbidity model and (4) accidental comorbidity model. Strategies to Prevent Comorbidity The common antecedent model assumes that common, broad-spectrum factors influence the To prevent comorbid mental and physical ill- onset of multiple disorders, irrespective of wheth- ness, one could choose from different interven- er the onset and prevalence of these disorders is tion scenarios. Each strategy is defined by the co-occurring or separated over time. For child- combination of choices on a range of target- hood adversities (e.g. child abuse and neglect, pa- and strategy-related dimensions that roughly rental mental illness, parental death and divorce), represent the ‘what-who-why-when frame- especially in the case of an accumulation of child- work’. This framework of choices is composed hood adversities, extensive evidence exists for a of six dimensions: wide range of long-term negative outcomes such (1) Target. This dimension concerns choices as increased risk of depression, conduct disor- such as ‘Which combination of comorbid disorders, drug and alcohol abuse, low self-esteem, ders is targeted?’, ‘Which of them should be pre- poor emotional competence, risky sexual behav- vented?’ and ‘The mental disorder, physical dis- ior, suicidal behavior, and adult-onset asthma, order, or both?’. obesity and hypertension [1, 3] . (2) Target population. Should the target popu- The sequential comorbidity model presumes lation be chosen through universal, selective or that features and outcomes of a primary disorder indicated prevention? This refers to a choice or its treatment increase the onset of a secondary about the width and level of risk of the targeted disorder. Examples of factors that mediate the population. Universal prevention targets whole causal relationship between both disorders are se- populations, selective prevention targets groups rious stress experiences resulting from the prima- at risk and indicated prevention targets persons ry disorder (e.g. pain, psychotrauma, physical or groups at high risk when they show subclinical disability, dependency, unemployment, social symptoms that might grow into a diagnosable isolation), harmful coping behaviors (e.g. smok- disorder. Targeted persons or groups could be at ing, alcohol use, inactivity), negative social reac- risk of the primary disorder, the secondary disor- tions (e.g. social stigma) or negative side effects of der or both. Identifying persons at high risk re-

Prevention of Comorbid Mental and Physical Disorders 169

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 165–177 ( DOI: 10.1159/000365601 ) quires the use of risk assessment tools that are still when a common risk or protective factor emerg- poorly developed in psychiatry. es and the most sensitive period during which (3) Factors. Which evidence-based risk or such a factor could be influenced. For instance, protective factors are targeted? This concerns es- research outcomes suggest that maternal de- pecially the choice between addressing common pression, anxiety and chronic stress during causal factors or disorder-specific factors. Com- pregnancy and early child maltreatment may re- mon factors are shared by multiple disorders, sult in a disturbed emotional brain and stress- also called broad-spectrum factors. Disorder- response system (HPA axis) in childhood that is specific factors could be related to either a physi- associated with long-term vulnerability to men- cal disorder or a comorbid mental disorder. Risk tal disorders and weakened immunity against factors for depression include, for instance, a pa- chronic diseases. This points to the need to start rental mental illness, negative cognitive style, se- preventive interventions as early as during preg- rious loss experiences, physical illnesses (e.g. dia- nancy and infancy. betes, stroke, cardiac disease, loss of hearing), (5) Provider . Who will provide the preventive poverty and exposure to childhood traumas, intervention and from which setting? This could while parental care, secure attachment, coping be general practitioners, public nurses, mental skills, social-emotional competence and social health professionals, medical specialists in hospi- support are considered to protect against depres- tals, public health professionals, health educators, sion. Several of these factors (e.g. poverty, child- or peers and experts-by-experience. It is highly de- hood maltreatment, secure attachment, social sirable to integrate prevention in the work of all of support) can also be considered as broad-spec- these disciplines. Related to this is the choice be- trum factors. There is growing evidence that high tween providing preventive support integrated in risk is not just defined by single risk factors, but the treatment process (e.g. following a stepped by the number of accumulating risk factors [28– care model) or by a referral to separately provided 30] ; reducing this number by targeting the most prevention programs. malleable factors might be a cost-effective strat- (6) Method . This concerns the choice of inter- egy to prevent disorders. vention methods and theories and principles of (4) Timing. This refers to choices concerning change. Evidence-based prevention programs use when to intervene. In the case of sequential co- a wide variety of intervention methods, such as morbidity, the options are to provide a preven- home-visiting, parenting education, school- tive intervention prior to, during or after a pri- based programs, group-based courses, internet- mary disorder, or prior to the secondary disor- based interventions, self-help books, support der. For instance, some studies suggest that groups, individual counseling and preventive depression in children, adolescents and young medication. These methods make use of different adults increases the risk of adult obesity [31, 32] . mechanisms of change to influence causal factors, To lower the risk of secondary obesity, one such as providing information, feedback, model- could aim to prevent depression in adolescents, ing, competence training, emotional support and treat first episodes of depression effectively, pre- biological agents, as well as through environmen- vent relapses, educate people with depression tal changes. about healthy lifestyles, or detect and treat early Figure 1 offers an overview of six alternative eating problems among those with chronic de- prevention strategies (PS) that could contribute to pression. When common factors are targeted, a the prevention of comorbidity-based on combina- choice needs to be made about when to inter- tions of choices at the target, target population, vene along the life span. This will depend on factor and timing dimensions. Preventive inter-

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 165–177 ( DOI: 10.1159/000365601 ) Disorder C Life span

Common factors Disorder B

Specific Prodromal Mediating Prodromal factors symptoms Disorder A factors symptoms Disorder D

PS1 PS2 PS3 PS4 PS5 PS6

Fig. 1. Model of strategies to prevent comorbidity across the developmental trajectory and targeted at common or disorder-specific factors.

ventions could start during pregnancy and infan- reduce comorbidity, but some examples will cy to influence the development of common risk show that effective preventive actions might be and protective factors early in life or during child- possible. hood and adolescence (PS1). Other interventions are targeted at disorder-specific risk factors (PS2) Preventing Child Abuse and Neglect and prodromal or subclinical symptoms preced- The first example concerns the prevention of ing the primary disorder (PS3), at effective treat- early child abuse and neglect, earlier identified ment of the primary disorder (PS4), reducing neg- as a broad-spectrum risk factor for both mental ative outcomes of the primary disorder or its treat- disorders and chronic physical diseases. In their ment (PS5), and addressing specific risk factors Lancet review on interventions to prevent child and subclinical symptoms of secondary disorders maltreatment in 2009, Macmillan et al. [33] con- (PS6). cluded that some home-visit programs have shown significant results in controlled trials. Ef- fective programs include among others the Promising Evidence-Based Preventive Nurse-Family Partnership program that was Programs evaluated in three randomized controlled trials across different US regions [34] . The program Following the strategic framework, many avail- uses trained nurses that visit low-income first- able evidence-based prevention programs time mothers during pregnancy and infancy, might be useful as components of an integral many of whom are single mothers or who have approach to reduce comorbidity, although they to cope with other life stressors. The nurses offer were not developed originally for this purpose. parent education, promote a healthy lifestyle, We do not have the opportunity here to review help the mothers to develop supportive relation- all prevention programs that might be useful to ships, and link them to appropriate health and

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 165–177 ( DOI: 10.1159/000365601 ) social services. The studies showed a wide vari- tered child abuse and less child maltreatment in- ety of positive outcomes, including healthier juries [35, 36] . The program is currently imple- maternal diets and less smoking, 75% fewer pre- mented in a wide range of countries around the term deliveries, less irritable and fussy babies, a world. large drop in cases of child maltreatment, fewer emergency visits and less injury requiring medi- Selected and Indicated Prevention of Depression cal examination, higher IQ among children of Most intervention programs that aim to prevent smoking mothers, and shorter periods of mater- the onset of depression make use of cognitive-be- nal dependency on social welfare. Fifteen years havioral treatment principles to educate at-risk later, children from the intervention group individuals to challenge negative beliefs, enhance showed dramatically less exposure to child abuse positive thinking, and strengthen their problem over this period, and lower levels of adolescent solving and social skills. A wide variety of such substance abuse, arrests and convictions than programs have been standardized for adolescents, children from the control condition. Several adults and elderly. The best known are the Coping other home-visit programs were not successful with Depression Course and the Penn Resilience in reducing child maltreatment. Likely condi- Program. These types of programs are provided in tions for successful programs are a theory base, different formats such as group-based courses, use of trained professionals (nurses) and safe- self-help books in combination with telephone guarding program fidelity during implementa- support and as internet-based programs. Each of tion. Also starting home-visiting during preg- these formats can easily be provided by physical nancy might have significantly contributed to and mental health services or by national insti- the success of the Nurse-Family Partnership tutes or nongovernmental organizations in the program. case of internet-based programs. Several reviews Two other types of programs have shown sig- and meta-analyses across a large range of con- nificant benefits in randomized trials, as reported trolled trials have shown that these programs are by Macmillan et al. [33] . In the Safe Environment effective in reducing depression-prone risk fac- for Every Kid (SEEK) program, pediatric resi- tors and depressive symptoms in different age dents were trained to identify family problems groups, including older adults [37, 38] . Face-to- and to link families to a social worker if needed. face, internet-based and self-help formats were all Families served by these trained residents showed found to be effective. A meta-analysis of 19 ran- fewer child-protection service reports, fewer in- domized controlled trials that tested the impact of stances of medical neglect, and less harsh punish- selected and indicated depression prevention pro- ment reported by parents, although the results grams found an average 22% reduction in the on- were only marginally significant. Triple P is an set of depressive episodes as a result of participa- Australian multicomponent program on positive tion in comparison to the incidence in the control parenting that addresses both universal and tar- groups [17] . One randomized controlled trial test- geted populations of parents, using a wide variety ed the integration of preventive interventions in a of educational methods (e.g. group work, mass stepped care mental health service model for el- media, books, lectures). The results across 48 derly with an elevated level of depressive symp- controlled studies showed significant reductions toms [39] . Implementation of this prevention-ori- in ineffective parenting and depression among ented stepped care model resulted in a 50% reduc- parents and less behavioral problems among their tion in incident depression or anxiety among children, and in one large randomized trial across elderly people aged 75 years or older, which was 18 US counties around 1 in 5 less cases of regis- sustained over 24 months.

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 165–177 ( DOI: 10.1159/000365601 ) Healthy Lifestyle Programs the interplay of biological, behavioral and social While chronic physical illnesses increase the forces along the life span, and how the develop- risk of secondary mental disorders, such as de- ment of mental and somatic disorders is inter- pression and anxiety disorders, one might ex- twined. pect that public health efforts to prevent physi- The growing knowledge on the narrow rela- cal illnesses might also result in a lower inci- tionships between mental and physical disorders dence of secondary mental disorders. For challenges the current practice in prevention re- instance, meta-analyses and systematic reviews search of treating the mental and physical disease have shown that the risk of type 2 diabetes and domains as completely separated fields. As a con- cardiovascular disease can be reduced through sequence, in current prevention studies in the behavioral counseling to promote physical ac- physical and mental health domains, major op- tivity and a healthy diet [40–42]. No insight ex- portunities are missed to understand possible ists, however, on the impact of such programs at broad-spectrum effects of prevention programs the onset of secondary depression among those that surpass the originally targeted domain. It is at risk. likely that both programs could contribute to outcomes in the other domain – outcomes that have remained undetected so far. Breaking Challenges for Research through the borders between both domains could also open research on innovative approaches This exploratory paper has revealed a range of where prevention programs from both domains weaknesses in current knowledge and challenges could be combined to create a higher level of ‘col- for future prevention research. These challenges lective impact’. For instance, under what condi- concern both the development of basic knowl- tions could lifestyle programs contribute to the edge on the causal mechanisms of comorbidity, prevention of depression and anxiety? How can and the need to understand what works and how depression prevention and mental health pro- to prevent comorbidity. motion programs be combined with lifestyle ed- The first challenge is to better understand ucation in order to reduce smoking and obesity what common risk and protective factors and more effectively? shared developmental trajectories are in the etiol- To understand the relationship between men- ogy of mental disorders and chronic physical distal and physical processes and disorders better, it eases. The science of developmental psychopa- is necessary to broaden the range of baseline and thology could serve as a great source for such outcome indicators in prevention studies. In knowledge as this field is typically multidisci- prevention studies primarily targeting common plinary in nature and studies complex and long- mental disorders, more physical health indica- term etiological trajectories. The aim is to under- tors should be added, and likewise, mental health stand the spectrum of long-term mental and indicators should be added to studies primarily physical outcomes of common early risk factors targeting physical disorders. Currently, it is com- (multifinality) as well as the different etiological mon practice in trials targeted at the prevention paths toward a similar disorder (equifinality). Its of a specific disorder to measure at baseline only multidisciplinary nature facilitates the integra- the presence of that disorder to exclude those tion of knowledge from genetic and epigenetic, with the disorder from participation in the trial. biological, neurological, psychological and social It is, however, likely that many included subjects research. This cross-fertilization of research ap- had other disorders in the preceding year or at proaches offers great opportunities to understand baseline that remained unnoticed. Including a

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 165–177 ( DOI: 10.1159/000365601 ) Table 1. Policy- and practice-based strategies to prevent comorbidity of mental and physical disorders

Policy-based Addressing comorbidity issues in health and mental health policies as well as in prevention and health promotion policies, and enhancing integrated approaches that address ‘smart clusters’ of multiple health and social problems Special focus on prevention and health promotion policies at reducing common early risk factors (e.g. childhood adversities) and strengthening protective factors (e.g. emotional resilience) Reducing the barriers between health and mental health policies, and between healthcare and mental healthcare Define quality standards in care for addressing prevention of comorbidity Making evidence-based preventive interventions more accessible through international and national databases Safeguarding professional and financial resources for prevention of comorbidity Investing in research and development of effective interventions to prevent comorbidity Practice-based Adoption of risk assessment practices in primary health services and pediatric care for early identification of common risk factors Training practitioners in risk assessment and interventions to prevent comorbidity in different stages of the life span Enhancing integrated practices that address related health, mental health and social problems

wider set of health and mental health indicators Challenges for Policy and Practice could offer more insight into the impact of prevention trials on comorbidity, as well as in the The analysis and findings presented in this chap- impact of comorbid disorders on the outcomes ter show that a wide range of policy- and prac- of prevention trials. tice-based strategies are possible to prevent co- Lastly, it would be desirable to combine the morbidity, as illustrated in table 1 . This should use of a wider spectrum of outcome indicators have implications for the work of individual with longitudinal research designs in prevention physical and mental health practitioners, as well studies. Many prevention and mental health pro- as for national and local public health and pre- motion programs address early risk and protec- vention policies. tive factors (e.g. child maltreatment, parenting, Recognizing the interrelatedness of mental social and emotional resilience) that might be re- disorders with chronic physical diseases, and the lated to a broad spectrum of mediating or long- role of common risk and protective factors, fu- term health outcomes. Studies that measure only ture policy plans should be more focused at in- short-term outcomes will likely undervalue the tegrated approaches, addressing mental and potential spectrum of effects of a prevention pro- physical outcomes simultaneously. Currently, gram. prevention of mental disorders still occupies a In conclusion, a major issue for the future re- marginal and undervalued position in public search agenda is to study what the potential of health policies and health budgets worldwide. current evidence-based programs in the mental Finding opportunities for shared preventative health domain is to prevent comorbidity, to im- and health promotion approaches might open prove both physical and mental health, and to new perspectives for preventing mental disor- learn how physical and mental health are related ders. It will offer better opportunities to expand along the lifespan. the reach in the population. It will also offer op-

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 165–177 ( DOI: 10.1159/000365601 ) portunities to increase the resources and profes- physical comorbidity. The public health and pre- sional capacity to implement prevention for vention approaches in the future should not be mental health. This will be more likely when ev- targeted at single disorders one by one, but at so- idence shows that preventive interventions in called ‘smart clusters’ of highly related social, the mental health domain are successfully tar- mental and physical problems, especially those geting risk and protective factors that also have clusters that concentrate in low-income coun- an impact on the development of chronic physi- tries, problem areas, disadvantaged communities cal diseases. Given the growing knowledge of the or populations at high risk for an accumulation of impact of stress and depression on the function- problems. This challenges health and public ing of the immune system, such a perspective is health managers, health promoters, nongovern- not imaginary. mental organizations, community leaders, citizen To make practitioners and local health and groups, private companies, policy makers and mental health services more willing and capable politicians to sit together and communicate about to address the prevention of comorbidity, their an effective integral preventive approach to such expertise in preventative strategies and interven- clusters of problems. In such a comprehensive ap- tions needs to be expanded. This initially re- proach, multiple social measures and preventive quires making prevention and comorbidity a interventions could be combined in a comple- standard element in the training of general prac- mentary way, where the collective impact is larger titioners, nurses, psychiatrists, psychologists and and has a broader spectrum than could be social workers. Secondly, the knowledge and ac- achieved by stand-alone interventions and pro- cessibility of available evidence-based preventa- grams. Such a smart cluster and integral approach tive interventions need to be increased. This could be concentrated at crucial stages of the life could be facilitated by easily accessible databases span, such as a ‘healthy start in life’ to facilitate of effective prevention programs as these are al- children growing up in healthy, safe and caring ready available in some countries, such as the environments that enhance their physical, mental USA, the Netherlands, Norway and Germany. and social resilience, and immune systems, and By establishing an international network of such will contribute to less mental, physical and social databases, international exchange of new evi- problems during their adolescence and adult- dence-based programs and best practices could hood. Integrating a focus on the social determi- be improved. nants in a mental health approach is in line with Finally, this book is devoted to the relationship the core messages of the recent WHO Compre- between mental and physical disorders. There are hensive Mental Health Action Plan 2013–2020 good reasons, however, to assume that the rela- [43] . tionship between both types of problems is caused In conclusion, the field of mental health and or at least reinforced by existing social problems, physical health should become more integrated, such as poverty, unemployment, discrimination, which would make working on the prevention of domestic violence, war-related traumas, housing comorbidity a normal phenomenon instead of an problems, poor social networks, social isolation exception. In the end it will be the well-being of and social stigma. Such social circumstances the person that will gain most from it. could be considered as common risk factors or even as the ‘root of the roots’. For this reason, the message of this book is that the single disorder approach to address mental-physical comorbidity should be expanded to focus on social-mental-

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 165–177 ( DOI: 10.1159/000365601 ) Concluding Remarks

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 178–181 ( DOI: 10.1159/000365606 )

Conclusions and Outlook

a b c Norman Sartorius · Richard I.G. Holt · Mario Maj a Association for the Improvement of Mental Health Programmes, Geneva , Switzerland; b Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, c University Hospital Southampton NHS Foundation Trust, Southampton , UK; Department of Psychiatry, University of Naples, Naples , Italy

Abstract is frequent in the population and its prevalence The reviews of evidence presented in the chapters of this grows with age and with successes of medicine volume lead to several conclusions and four recommen- saving lives (but not curing diseases) [Rosenblat dations. The prevalence and incidence of comorbidity of et al., pp. 42–53; Holt, pp. 54–65; Monteleone and mental and physical disorders are high and likely to grow. Brambilla, pp. 66–80; Kariuki-Nyuthe and Stein, The problems of comorbidity are not the simple addition pp. 81–87; Lawrence et al., pp. 88–98; Müller, pp. of problems related to the diseases involved, as they 99–113; Gordon et al., pp. 114–128]. Second, co- worsen the prognosis of all diseases involved to a signifi- morbidity does not simply add problems related cantly greater extent. At present there is no clear strategy to one disease to those of the other: by and large of action concerning comorbidity at the primary, second- the simultaneous presence of several diseases ary or tertiary levels of healthcare or in the local, provin- makes the prognosis of all the diseases involved cial, national or international decision-making systems. worse, their complications more frequent and The evidence presented in the book also allows the for- their treatment more complicated [Fisher et al., mulation of recommendations concerning the training of pp. 1–14; Oldenburg et al., pp. 15–22]. Third, no healthcare staff and the organization of healthcare. To medical discipline has a clear strategy of action support the changes proposed and to evaluate their ef- required when a disease that does not belong to fects it will be necessary to strengthen research concern- its special field of interest accompanies one that is ing comorbidity and seek ways of sharing experience ob- within the domain of their specialty. Fourth, the tained by the use of different models of care catering to current trend of super-specialization and frag- the needs of people with comorbid illnesses. mentation of medicine may make matters worse © 2015 S. Karger AG, Basel unless appropriate action is taken promptly [Fisher et al., pp. 1–14]. Fifth, primary healthcare professionals (e.g. general practitioners or family Several conclusions emerge from the chapters physicians) are aware of the problems related to that have been included in this volume. First, co- comorbidity because they encounter them even morbidity between mental and physical disorders more frequently than other medical specialists; however, most have not received specific training tionally invited to serve as teachers of health in the use of skills that might be central in dealing professional students. with comorbidity [Boeckxstaens et al., pp. 129– The distinction of psychological reactions to 136; Cushing and Evans, pp. 137–147; Gask, pp. being ill and mental disorders in a strict sense is 157–164]. also a problem. Many of those surrounding the The material presented also indicates direc- patient – professional and nonprofessional car- tions of future work at different levels. First, it ers – are ready to dismiss the notion that the is clear that changes in the delivery of education patient they have before them has a depressive of healthcare personnel are urgently needed illness that requires specific treatment, prefer- [Cushing and Evans, pp. 137–147; Millar et al., ring to explain the symptoms in ‘logical’ terms pp. 148–156; Gask, pp. 157–164]. This is true for as the reaction of patients who were told that all categories of healthcare professionals includ- they have a serious illness and that they have to ing nurses, medical assistants, general practitio- live with it. Occasionally both the patient and ners and specialists, at both undergraduate and the doctor realize that a mental disorder as well postgraduate levels. Problem-based learning as a physical illness is present, but they are unit- was seen as an educational method that would ed in a tacit collusion about the presence of the lead to a better understanding of the problems mental illness which they hope will vanish once and solutions and that would be in harmony the treatment of the physical illness has been with the environment in which the patient lives successfully completed and therefore focus on and the service operates. Unfortunately, the the treatment of the physical illness only. This training materials that were produced by spe- way of proceeding is also seen and emulated by cialists, who were to lead problem-based learn- the medical students who in later years of their ing as well as the implementation of the train- training often learn by imitating the behavior of ing, have neglected, to a large degree, the co- more experienced general practitioners or other morbidity of mental and physical disorders. The specialists. education of healthcare personnel in institu- A second line of recommendations that could tions which are usually uneasy federations of be made concerns in-service training of doctors specialized departments did not help in devel- and other health personnel. The two examples oping an attitude of dealing with illnesses fully given in the chapters by Cushing and Evans [pp. aware of the person who suffers from that ill- 137–147] and Millar et al. [pp. 148–156] concern ness and possibly from various other ills and the in-service training of nurses and general problems. Teachers of the disciplines are usu- practitioners. In the chapter by Cushing and Ev- ally specialists knowledgeable in their own field ans, which describes the training of senior nurs- and somewhat distant or even possibly disdain- es and nurse trainers in African countries, the ful of other specialists and matters with which participants are cited as saying they found it use- they deal. In many parts of the world, family ful to discuss how to organize their service in a physicians are rarely invited to train medical manner that would facilitate the management of students and other students of health profes- problems arising for people with comorbid de- sions. By contrast, in the UK general practitio- pression and diabetes because they have not ners are invited to teach increasingly often and been trained in ways in which this should be it is to be hoped that this will soon happen else- done. Bearing in mind that in the countries from where. Carers who often have a vast array of ex- which the nurses attending the course came, and periences in dealing with comorbid chronic where nurses are the backbone of health service, mental and physical diseases are only excep- it is clear that the training of nurses about the

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Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 178–181 ( DOI: 10.1159/000365606 ) ways in which their service should be organized er the universities will be in a position to play the is a neglected priority in the effort to provide ap- role of being leaders in research which is of pub- propriate care to people who have the misfor- lic health importance will to a large extent de- tune of suffering from more than one illness at pend on the support of their governments – the same time [Beran, pp. 33–41; Millar et al., pp. which unfortunately in recent times they have re- 148–156]. Family physicians seem to be clear fused to provide. about the need to see the patients in their total- Finally, in addition to the recommendations ity and to pay attention to all of their ills; there on funding of research and reorientation of train- is, however, no consensus about the ways in ing, a fourth recommendation could be directed which this type of approach to the patients they to the search for opportunities to study and test see can best be supported by referral and feed- the most appropriate models of service for people back arrangement within the health system as a with comorbid mental and physical disorders. In whole [Boeckxstaens et al., pp. 129–136]. the 19th century, mental hospitals were obliged A third recommendation that could be for- to have wards for inpatients who in addition to mulated concerns funding. At present a consid- their mental disorder also had a physical illness. erable proportion of research funding is chan- These wards were usually run by specialists in in- neled through institutions which deal with a sin- ternal medicine who in the course of time ac- gle disease or a group of diseases. This is the quired considerable experience and knowledge principle on which the National Institutes of about mental disorders. In the early 20th century Health in the USA as well as many funding agen- a new category of super-specialists came into ex- cies in other countries have been constructed. istence – the liaison psychiatrists who often, in Some of the major foundations fund various addition to their postgraduate education in psy- types of research, but even there a major part of chiatry, also had attended postgraduate courses the funding follows a call for proposals on a sin- in internal medicine. To an extent, the existence gle disease or disease group. There are very few of this group is a sad admission of the fact that the calls for proposals on comorbidity and even few- vast majority of psychiatrists was not willing or er that would specifically invite applications for able to deal with physical illness in their patients. research on comorbid mental and physical disor- This refusal to perform all that undergraduate ders [Hosman, pp. 165–177]. Universities, which and postgraduate education gave to these doctors should, if true to their mission, fund research on has not been typical for other specialties; for ex- topics of major public health importance and ample, there are no liaison surgeons, liaison der- could therefore be expected to fund research on matologists or liaison ophthalmologists although comorbidity, are increasingly adopting the strat- these specialists, among others, often deal with egy of making a good part of their living from patients who have a mental disorder as well as a overhead charges to projects which have been dermatological illness or problems with their funded by someone else and only rarely provide eyes. Liaison psychiatry and ‘general hospital their researchers funds for projects that would psychiatry’ are clearly not the best way to a solu- express the universities’ public health mission. It tion of the comorbidity problem and therefore might therefore be recommended that universi- there is an urgent need to develop service models ties take it upon themselves to fund research and that will be better suited to meet the needs of peo- other work related to comorbidity at least until it ple with comorbid illnesses and to provide train- dawns on the other agencies that comorbidity ing in ways of doing it. should be at the center of their interest rather than being seen as a confounding factor. Wheth-

180 Sartorius · Holt · Maj

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 178–181 ( DOI: 10.1159/000365606 ) Recommended Reading

Glassman A, Maj M, Sartorius N: Depression Katon W, Maj M, Sartorius N: Depression Leucht S, Burkard T, Henderson JH, Maj M, and Heart Disease. Hoboken, Wiley- and Diabetes. Hoboken, Wiley-Black- Sartorius N: Physical Illness and Schizo- Blackwell, 2010. well, 2010. phrenia: A Review of the Evidence. Gordon AJ: Physical Illness and Drugs of Kissane DW, Maj M, Sartorius N: Depres- Cambridge, Cambridge University Abuse: A Review of the Evidence. Cam- sion and Cancer. Hoboken, Wiley- Press, 2007. bridge, Cambridge University Press, Blackwell, 2011. O’Hara J, McCarthy J, Bouras N: Intellectual 2010. Kurrle S, Brodaty H, Hogarth R: Physical Disability and Ill Health: A Review of the Comorbidities of Dementia. Cambridge, Evidence. Cambridge, Cambridge Uni- Cambridge University Press, 2012. versity Press, 2010.

Prof. Norman Sartorius, MA, MD, PhD, FRCPsych President, Association for the Improvement of Mental Health Programmes 14, Chemin Colladon CH–1209 Geneva (Switzerland) E-Mail [email protected]

Conclusions and Outlook 181

Sartorius N, Holt RIG, Maj M (eds): Comorbidity of Mental and Physical Disorders. Key Issues Ment Health. Basel, Karger, 2015, vol 179, pp 178–181 ( DOI: 10.1159/000365606 )

Author Index

Baskaran, A. 42 Gask, L. 157 McIntyre, R.S. 42 Beran, D. 33 Goldberg, D. VII Millar, H.L. 148 Boeckxstaens, P. 129 Gordon, A.J. 114 Monteleone, P. 66 Brambilla, F. 66 Gordon, J.M. 114 Müller, N. 99

Cha, D.S. 42 Hancock, K.J. 88 Nan, H. 1 Chan, J.C.N. 1 Holt, R.I.G. XI, 54, 178 Cimino, L. 148 Hosman, C. 165 Oldenburg, B. 1, 15 Cocker, F. 15 O’Neil, A. 15 Conley, J.W. 114 Kariuki-Nyuthe, C. 81 Cushing, A. 137 Kisely, S. 88 Park, A.-L. 23 Kowitt, S. 1 De Maeseneer, J. 129 Rosenblat, J.D. 42 De Sutter, A. 129 Lawrence, D. 88 Sartorius, N. XI, 1, 178 Evans, S. 137 Maj, M. XI, 178 Stein, D.J. 81 Mansur, R.B. 42 Fisher, E.B. 1 McDaid, D. 23 van der Merwe, A.S. 148

182

Subject Index

Accidental comorbidity model 169 Anxiety disorders Adaptive immunity, overview 101 differential diagnosis 83, 84 Addiction, see specific substances epidemiology 81, 82 Adrenocorticotropic hormone, eating disorder management 84, 85 effects 76, 77 physical illness comorbidity African Nursing Training Programme, see Dialogue etiology 82, 83 on Diabetes and Depression management 86 Alcoholism, comorbidity of non-communicable overview 82 diseases and mental disorders 16, 114, 115 Alzheimer’s disease, see Dementia Bidirectional comorbidity model 169 Anorexia nervosa Bipolar disorder endocrine consequences cardiovascular disease comorbidity adrenocorticotropic hormone 76, 77 antipsychotic medication effects on physical corticotropin-releasing factor 77, 78 disease 57–59 dehydroepiandrosterone 77 epidemiology of cardiovascular disease follicle-stimulating hormone 74 comorbidity 55 growth hormone 76 etiology of cardiovascular disease insulin-like growth factor-I 76 comorbidity luteinizing hormone 74 diabetes 56, 57 prolactin 75 dyslipidemia 56 thyroid hormone 75 hypertension 56 oral pathology 69 obesity 56 overview 66 smoking 57 physical complications management of cardiovascular risk cardiovascular complications 71 diabetes 63 electrolytes and vitamins 74 dyslipidemia 62 gastrointestinal complications 69, 70 hypertension 63 hematologic changes 72, 73 obesity 61, 62 hepatic and pancreatic pathology 70 smoking 61 metabolic changes 73 overview 54, 55 musculoskeletal abnormalities 72 screening for cardiovascular risk 59–61 prospects for study 77, 78 economic impact of comorbidity 26 pulmonary disease 71, 72 Brain-derived neurotrophic factor renal disease 72 insulin-induced release 45 skin and hair alterations 67–69 levels in diabetes, depression and dementia table 68 comorbidity 47, 50

183 Bulimia nervosa dyslipidemia 56 endocrine consequences hypertension 56 adrenocorticotropic hormone 76, 77 obesity 56 corticotropin-releasing factor 77, 78 smoking 57 dehydroepiandrosterone 77 management of cardiovascular risk follicle-stimulating hormone 74 diabetes 63 growth hormone 76 dyslipidemia 62 insulin-like growth factor-I 76 hypertension 63 luteinizing hormone 74 obesity 61, 62 prolactin 75 smoking 61 thyroid hormone 75 overview 54, 55 overview 66 screening for cardiovascular risk 59–61 physical complications global burden 15, 34, 54 cardiovascular complications 71 substance abuse risks 117 electrolytes and vitamins 74 Child abuse, prevention 171, 172 gastrointestinal complications 69, 70 Chronic obstructive pulmonary disease, comorbidity hematologic changes 72, 73 case study 131 hepatic and pancreatic pathology 70 overview 130 metabolic changes 73 Cocaine musculoskeletal abnormalities 72 cancer risks 116 prospects for study 77, 78 cardiovascular disease risks 117 pulmonary disease 71, 72 dermatologic disorders 121 renal disease 72 ear, nose and throat disorders 118 skin and hair alterations 67–69 female reproductive system effects 120, 121 table 68 gastrointestinal disorders 119 Bupropion, smoking cessation 61 hematopoietic disorders 116 hepatobiliary disease 119 Cancer immune system effects 115 global burden 15, 34 infection risks 116 mental illness comorbidity metabolic, nutritional and endocrine case fatality factors disorders 120 diagnosis delay and cancer stage at musculoskeletal disease 122 diagnosis 92, 93 neurological disorders 121 screening rates 92 overview of effects 123, 124 surgery 93, 94 renal and male urogenital disorders 120 challenges for healthcare providers 94, 95 respiratory dysfunction 118, 119 incidence and case fatality rates 90, 91 Common antecedent model 169 mortality excess 89–91 Comorbidity, see also specific diseases research evolution 89, 90 costs, see Economic impact, comorbid mortality 88, 89 non-communicable diseases and mental substance abuse risks 116 disorders Cardiovascular disease low-income countries, see Low-income countries bipolar disorder or schizophrenia comorbidity models 168, 169 antipsychotic medication effects on physical prevention of mental disorders 166, 167 disease 57–59 prevention epidemiology of cardiovascular disease evidence-based programs 171–173 comorbidity 55 policy challenges 174, 175 etiology of cardiovascular disease comorbidity research challenges 173, 174 diabetes 56, 57 strategies 169–171

184 Subject Index primary care, see Patient-centered care, Primary insulin-amyloid pathway 46 care microangiopathy 46 public health intervention, see Public health monoamine neurotransmitters 47, 48 intervention neuroimaging studies 43 recommendations 178–180 neuroplasticity 46 training, see Dialogue on Diabetes and Depression, psychosocial determinants 48, 49 Training overview 42, 43 types 167, 168 diabetes association Concurrent comorbidity 168 biosocial propensity to chronic disease and Congestive heart failure, economic impact of stress 6, 7 comorbidity 27 dimensional versus categorical view 4 Corticotropin-releasing factor, eating disorder integrative model 2, 3, 7 effects 77, 78 neighborhood design and social isolation Cost, see Economic impact influences 3 Cyclooxygenase-2, inhibitor therapy for schizophrenia separate comorbidity or depression as part of and depression 105–107 normal diabetes 5, 6 single problem versus group of problems 4, 5 Dehydroepiandrosterone, eating disorder effects 77 treatment Dementia, diabetes and depression comorbidity comprehensive population approaches 9, 10 clinical implications 49–51 integrative chronic disease care and self- mechanisms management 7, 8, 11, 12 bioenergetics 45, 46 peer support 8–10 brain-derived neurotrophic factor levels 47, 50 Web-based and telehealth interventions 10 gut microbiota 48 economic impact of comorbidity 25, 27 hypothalamic-pituitary-adrenal axis 47, 50 infection and autoimmune disease as risk impaired central insulin and glucose supply 44, factors 102, 103 45, 49 inflammatory immune state 101, 102 inflammation 46, 47 non-communicable disease risk factor 16, 42 insulin-amyloid pathway 46 prevention 172 microangiopathy 46 sickness behavior model 100 monoamine neurotransmitters 47, 48 Developing countries, see Low-income countries neuroimaging studies 43 Diabetes type 2, see also Dialogue on Diabetes and neuroplasticity 46 Depression psychosocial determinants 48, 49 antipsychotic medication effects 57, 58 overview 42, 43 cardiovascular disease Depression, see also Dialogue on Diabetes and management 63 Depression risk in severe mental illness 56, 57 cyclooxygenase-2 inhibitor therapy 105–107 diabetes and dementia comorbidity diabetes and dementia comorbidity clinical implications 49–51 clinical implications 49–51 mechanisms mechanisms bioenergetics 45, 46 bioenergetics 45, 46 brain-derived neurotrophic factor levels 47, brain-derived neurotrophic factor levels 47, 50 50 gut microbiota 48 gut microbiota 48 hypothalamic-pituitary-adrenal axis 47, 50 hypothalamic-pituitary-adrenal axis 47, 50 impaired central insulin and glucose impaired central insulin and glucose supply 44, 45, 49 supply 44, 45, 49 inflammation 46, 47 inflammation 46, 47 insulin-amyloid pathway 46

Subject Index 185 microangiopathy 46 global examples 27, 28 monoamine neurotransmitters 47, 48 schizophrenia 25, 26 neuroimaging studies 43 incentive for treatment 30 neuroplasticity 46 Employment, impact of comorbid non-communicable psychosocial determinants 48, 49 diseases and mental disorders 20, 21, 28, 29 overview 42, 43 diabetes association Family of International Classifications 133 biosocial propensity to chronic disease and Follicle-stimulating hormone, eating disorder stress 6, 7 effects 74 dimensional versus categorical view 4 integrative model 2, 3, 7 Glucagon-like peptide-1, neuroprotection 50 neighborhood design and social isolation Growth hormone, eating disorder effects 76 influences 3 Gut microbiota, diabetes, depression and dementia separate comorbidity or depression as part of comorbidity role 48 normal diabetes 5, 6 single problem versus group of problems 4, 5 Human immunodeficiency virus, low-income treatment countries 34–36, 38, 39 comprehensive population approaches 9, 10 Hyperlipidemia, see Dyslipidemia integrative chronic disease care and self- Hypertension, cardiovascular disease management 7, 8, 11, 12 management 63 peer support 8–10 risk in severe mental illness 56 Web-based and telehealth interventions 10 global burden 15, 34 IMPACT model 18, 162 Dialogue on Diabetes and Depression Infection background 148–150 childhood infections and mental disorders 107, limitations 154 108 prospects in comorbidity training 154, 155 depression rollout 150–152 infection as risk factor 102, 103 workshop implementation and evaluation 152, inflammation 101, 102 153 sickness behavior model 100 Dyslipidemia schizophrenia antipsychotic medication effects 58 infection as risk factor 104, 105 cardiovascular disease infection presenting as 103 management 62 inflammation and effect on risk in severe mental illness 56 neurotransmission 103, 104 eating disorders 73 substance abuse risks 116 screening 60 Inflammation depression association 101, 102 Eating disorders, see Anorexia nervosa, Bulimia schizophrenia and neurotransmission 103, 104 nervosa therapeutic targeting in schizophrenia and Economic impact, comorbid non-communicable depression 105–107 diseases and mental disorders Innate immunity, overview 101 cost categories 24 Insulin, diabetes, depression and dementia employment 20, 21, 28, 29 comorbidity healthcare system burden impaired central insulin and glucose supply 44, bipolar disorder 26 45, 49 congestive heart failure 27 insulin-amyloid pathway 46 depression 25, 27 Insulin-like growth factor-I, eating disorder effects 76 difficulty of study 24, 25 International Classification of Functioning 133

186 Subject Index Low-income countries PANDAS 108 definition 33 Panic disorder, see Anxiety disorders health system limitations 36–39 Patient-centered care local immunity involvement 39 care model development for comorbidity and multimorbidity overview 34, 35 multimorbidity 161, 163 Luteinizing hormone, eating disorder effects 74 collaborative care elements 161 fragmentation of healthcare 157, 158 Marijuana physician training 140, 141, 163 cancer risks 116 Phobia, see Anxiety disorders cardiovascular disease risks 117, 118 PREDIMED trial 18 ear, nose and throat disorders 118 Pregnancy, substance abuse effects 120, 121 female reproductive system effects 120, 121 Primary care gastrointestinal disorders 119 fragmentation of healthcare hematopoietic disorders 116, 117 consequences of specialization and immune system effects 115 fragmentation 158, 159 infection risks 116 overview 157, 158 metabolic, nutritional and endocrine general practitioner role in multimorbidity disorders 120 management 134, 135 neurological disorders 121, 122 goal-oriented care 132, 134 overview of effects 123, 124 importance 159, 160 renal and male urogenital disorders 120 overview 131 respiratory dysfunction 119 patient-centered care, see Patient-centered care Medical school, see Training, medical students about Prolactin, eating disorder effects 75 comorbidity Public health intervention Multimorbidity comorbid non-communicable diseases and mental concept 130 disorders evidence base 131–133 control in high-risk populations 18, 19 general practitioner role in management 134, economic impact 20, 21 135 implementation and scale-up of programs goal-oriented care 132, 134 context 19 implications for health system 133 cost and responsibility 19, 20 low-income countries 34, 35 prevention 17, 18 prospects 21 Obesity definition 17 antipsychotic medication effects 57 cardiovascular disease Respiratory disease management 61, 62 global burden of chronic disease 15, 34 risk in severe mental illness 56 smoking, see Smoking Obsessive-compulsive disorder, see Anxiety disorders substance abuse and dysfunction 119 Opioids cardiovascular disease risks 118 Schizophrenia ear, nose and throat disorders 118 cardiovascular disease comorbidity immune system effects 115 antipsychotic medication effects on physical infection risks 116 disease 57–59 neurological disorders 122 epidemiology of cardiovascular disease overview of effects 123, 124 comorbidity 55 pregnancy effects 121 etiology of cardiovascular disease comorbidity renal and male urogenital disorders 120 diabetes 56, 57 respiratory dysfunction 119 dyslipidemia 56

Subject Index 187 hypertension 56 Thyroid hormone, eating disorder effects 75 obesity 56 Tobacco, see Smoking prevalence 55 Training, medical students about comorbidity smoking 57 barriers in comorbidity identification 144 management of cardiovascular risk communication skills diabetes 63 case studies 144, 145 dyslipidemia 62 consultation 144, 145 hypertension 63 patients 144 obesity 61, 62 course designs 145 smoking 61 educational theories and learning models 138– overview 54, 55 140, 145 screening for cardiovascular risk 59–61 goals cyclooxygenase-2 inhibitor therapy 105–107 biosocial disease-illness model and patient- economic impact of comorbidity 25, 26 centered care 140, 141 infection consultation skills 143, 144 pathogenesis 104, 105, 107, 108 illness presentation and confounded presenting as 103 diagnosis 141, 142 inflammation effects on neurotransmission 103, interdependence of mind and body 141 104 risk factors Separation anxiety, see Anxiety disorders mental illness in physical illness 142 Sequential comorbidity 168 physical illness in mental illness 143 Sequential comorbidity model 169 self-awareness and judgment 142, 143 Smoking overview 137, 138 cardiovascular disease management 61 Vascular endothelial growth factor, insulin-induced risk in severe mental illness 57 release 45 comorbidity of non-communicable diseases and mental disorders 16 Substance abuse, see specific substances

188 Subject Index Key Issues in Mental Health Editors: A. Riecher-Rössler, N. Sartorius ISSN 1662–4874

176 Attention-Deficit Hyperactivity Disorder (ADHD) in Adults Editors: W. Retz, Homburg/Saar; R.G. Klein, New York, N.Y. VIII + 192 p., 9 fig., 18 tab., hard cover, 2010. ISBN 978–3–8055–9237–6

177 Neurocognition and Social Cognition in Schizophrenia Patients Basic Concepts and Treatment Editors: V. Roder, Bern; A. Medalia, New York, N.Y. XII + 178 p., 16 fig., 1 in color, 11 tab., hard cover, 2010. ISBN 978–3–8055–9338–0

178 Violence against Women and Mental Health Editors: C. García-Moreno, Geneva; A. Riecher-Rössler, Basel XII + 180 p., 5 fig., 9 tab., hard cover, 2013. ISBN 978–3–8055–9988–7

179 Comorbidity of Mental and Physical Disorders Editors: N. Sartorius, Geneva; R.I.G. Holt, Southampton; M. Maj, Naples XII + 188 p., 12 fig., 20 tab., hard cover, 2015. ISBN 978–3–318–02603–0

This publication presents evidence about the magnitude and severe consequences of comorbidity of mental and physical illnesses from a personal and societal perspective. Leading experts address the huge burden of comorbidity to the affected individual as well as the public health aspects, the costs to society and interaction with factors stemming from the context of socioeconomic developments. The authors discuss the clinical challenge of managing cardiovascular illnesses, cancer, infectious diseases and other physical illness when they occur with a range of mental and behavioral disorders, including substance abuse, eating disorders and anxiety. Also covered are the organization of health services, the training of different categories of health personnel and the multidisciplinary engagement necessary to prevent and manage comorbidity effectively. The book is essential reading for general practitioners, internists, public health specialists, psychiatrists, cardiologists, oncologists, medical educationalists and other health care professionals.