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Comorbidity
Symptoms, Conditions,
Behavior and Treatments

Edited by
Rhonda Brown
Einar Thorsteinsson
Comorbidity
Rhonda Brown · Einar Thorsteinsson
Editors

Comorbidity
Symptoms, Conditions, Behavior
and Treatments
Editors
Rhonda Brown Einar Thorsteinsson
Research School of Psychology School of Psychology
Australian National University University of New England
Canberra, ACT, Australia Armidale, NSW, Australia

ISBN 978-3-030-32544-2 ISBN 978-3-030-32545-9 (eBook)

https://doi.org/10.1007/978-3-030-32545-9

© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature
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 Preface

Collectively, as co-authors, we have extensive clinical and research expe-

rience related to the various clinical disorders, symptoms, behaviour and
biology covered in the book. Furthermore, as research collaborators, we
can provide a unique perspective on the likely evolution and nature of
disease comorbidity, which integrates biological, medical and psycho-
logical perspectives. The book was written with an academic audience in
mind, although other interested individuals may appreciate the explora-
tion of possible mechanisms underpinning disease comorbidity. To be
clear, this is not a self-help book that reflects upon the way in which
people should live a better life or which reflects upon the way that we as
individuals live our own lives.
The stimulus for the book was research conducted by Laird
Birmingham, Rhonda Brown and others, related to low body temper-
ature and infection in anorexia nervosa patients, which later gave rise
to discussions around the possible role played by body temperature in
mediating some of the adverse health outcomes related to overweight/
obesity. However, more broadly, the co-authors have worked collec-
tively, in several different research groups, to answer the following ques-
tions related to disease comorbidity: What is causing the comorbidity

v
vi      Preface

between different medical and psychological conditions? What role (if any)
is played by the shared (or overlapping) medical and psychological
­symptoms? Or is a common factor more likely to cause the co-occurrences?
Finally, why is a similar profile of risk factors detected for a range of
different but frequently comorbid illnesses and conditions?
As argued in this book, there is a crucial need to more fully inte-
grate a broader range of comorbid illnesses and conditions, and their
often overlapping risk factors, into the same disease models; to arrive
at a more complex real-world understanding of comorbid illness causa-
tion. If such a clinical model could be developed, it might be used to
test complex hypotheses related to the evolution and nature of disease
comorbidity as well as evaluate potential new therapies.
Finally, as co-authors, we wish to thank the various researchers and
clinicians we have worked with over many years, who each have con-
tributed to the evolution of the thoughts that are collectively advanced
in this book.

Canberra, Australia Rhonda Brown

Armidale, Australia Einar Thorsteinsson
 Contents

1 Comorbidity: What Is It and Why Is It Important? 1

Rhonda Brown and Einar Thorsteinsson
1.1 What Is Comorbidity? 1
1.2 Why Is Comorbidity Important? 4
1.3 What Is the Cost of Comorbidity? 8
References 16

2 Models of Comorbidity 23
Rhonda Brown and Einar Thorsteinsson
2.1 Computational and Clinical Models
of Concurrent Symptom Development 23
2.2 Sleep, Body Temperature, and Circadian
Rhythm Function 30
References 36

vii
viii      Contents

3 Overweight/Obesity and Concurrent Disorders,

Symptoms, Behaviour, and Body Temperature 43
Rhonda Brown and Yasmine Umar
3.1 Overweight/Obesity and Comorbid Disorders 43
3.2 Overweight/Obesity, Sleep Disorders,
and Impaired Sleep 47
3.3 Overweight/Obesity, Disordered Eating, and Sleep 51
3.4 Overweight/Obesity, Disordered Eating, Sleep,
and Body Temperature 58
References 64

4 Overview of the Comorbidity Between Medical

Illnesses and Overweight/Obesity 79
Christopher J. Nolan
4.1 Medical Illnesses and Overweight/Obesity 80
4.2 Overweight/Obesity Comorbidities
and Causal Linkages 91
4.3 Lessening the Burden of Comorbid Illnesses
in Overweight and Obese Individuals 97
References 98

5 Comorbid Eating Disorders 115

C. Laird Birmingham
5.1 Anorexia Nervosa and Bulimia Nervosa 115
5.2 Eating Disorders and Medical Comorbidities 118
5.3 Eating Disorders and Anxiety and Mood Disorders 119
5.4 Can Comorbid Psychiatric Disorders Prevent
Recovery from Eating Disorders? 121
5.5 Anorexia Nervosa, Body Temperature,
Hyperactivity, and Clinical Outcomes 122
5.6 Body Warming to Treat Anorexia Nervosa,
Hyperactivity, and Exercise Addiction 124
5.7 Other Medical Treatments for Anorexia Nervosa 126
References 129
 Contents     ix

6 Comorbid Psychiatric Illnesses 139

Einar Thorsteinsson and Rhonda Brown
6.1 Comorbidity Between Anxiety and Depressive
Disorder 139
6.2 Relationships Between Stress, Depression, Anxiety,
and Impaired Sleep 143
6.3 Risk and Protective Factors for Mental Ill-Health 145
6.4 Causal Models for the Development of Depression
and Anxiety 149
References 161

7 Arousal States, Symptoms, Behaviour, Sleep and Body

Temperature 179
Rhonda Brown and Einar Thorsteinsson
7.1 Arousal States and Elevated Body Temperature 179
7.2 Symptoms and Elevated Body Temperature 181
7.3 Exercise, Sleep, Affective Distress, Overweight/Obesity
and Body Temperature 191
7.4 Behaviour Linked to Impaired Sleep and Elevated Body
Temperature 197
References 202

8 Design, Statistical and Methodological Considerations:

Comorbidity 221
Einar Thorsteinsson and Rhonda Brown
8.1 Methodological Approaches 221
8.2 Statistical Approaches 228
8.3 Overlapping Risk and Protective Factors 232
8.4 Other Research and Data-Handling Approaches 234
8.5 Summary 236
References 237
x      Contents

9 Typing It All Together 241

Rhonda Brown and Einar Thorsteinsson
9.1 What Causes Comorbidity? 241
9.2 Comorbidity—Where to from Here? 248
9.3 Possible Existing, Repurposed, and Novel
Treatments for Comorbid Illness 255
References 264
 Notes on Contributors

C. Laird Birmingham, M.D. is a Specialist in Internal Medicine,

Epidemiologist and Biostatistician and a Professor of Psychiatry at the
University of British Columbia, where he was previously Professor of
Medicine. He was Leader of the BC Eating Disorders Epidemiology
Project in the Centre for Health Evaluation and Outcome Sciences
until 2008 and then Medical Director of the Woodstone Residential
Treatment Centre for Eating Disorders until December 2013. He is a
Member of the Brain Research Centre at UBC and Senior Associate
Clinician Scientist at the Children and Family Research Institute. He
has more than 40 years of experience in eating disorder research and
treatment and has 280 publications including 131 refereed articles, 23
invited chapters and 9 books. Dr. Birmingham’s research has focused on
nutrition and the brain, the effect of ambient temperature on anorexia
nervosa and the medical management of eating disorders. He is focused
now on LORETA imaging and neurofeedback of patients with disorder.
Rhonda Brown started her career as a lab-based researcher, develop-
ing an animal model for immune-mediated polyneuropathies during
her Ph.D. and exploring the overlap between neurochemical, neuroen-
docrine and immune responses to stress and infective illness, including
xi
xii      Notes on Contributors

bacterial translocation (i.e. leaky gut), during her post-doctoral fellow-

ship. She works as an Associate Professor in the Research School of
Psychology, Australian National University. She teaches health psychol-
ogy and her research examines predictive relationships between stress,
affective distress (e.g. anxiety, depression), sleep, fatigue, other symp-
toms, and illness outcomes in patients (e.g. cancer, overweight/obesity,
sleep apnoea, multiple sclerosis) and community-well individuals. She
also collaborates with other researchers to examine work-stress, burnout,
communication performance and empathy in medical staff and medical
and psychology students as well as immune function, fever response and
infection in patients with anorexia nervosa. Over the past 20-years, she
has worked extensively with each of the co-authors of this book.
Christopher J. Nolan is a clinician scientist and policy advisor in
the field of diabetes and metabolic diseases. He recently stepped
down as Director of Diabetes Services (2011–2018) and Director of
Endocrinology (2016–2018) for ACT Health to take up a new position
as Associate Dean of Research for the Medical School at the Australian
National University. He is currently a Board Member of the Australian
Diabetes Society (2018–) and an Associate Editor for Diabetologia
(2016–). He directs an active diabetes research laboratory focusing on
islet beta-cell failure in type 1 and 2 diabetes and the role of insulin
hypersecretion in metabolic syndrome and related conditions. He is a
lead investigator for the ANU Grand Challenges Project, Our Health in
Our Hands, which includes research into improving the care of people
with type 1 diabetes using a personalised medicine approach.
Einar Thorsteinsson works as Associate Professor at the University of
New England, Australia. He worked on his Ph.D., the effects of social
support on changes in cortisol and cardiovascular reactivity in response
to stressful situations, at La Trobe University in Melbourne. He was
awarded a Ph.D. in 1999 and then worked at La Trobe University in a
fire fighting decision-making lab for two years before he moved back to
focus on health psychology at the University of New England where he
has built national and international research collaborations covering
areas such as stress, social support, depression, anxiety, adolescent cop-
ing and health, and psychological well-being.
 Notes on Contributors     xiii

Yasmine Umar is a Doctoral Candidate at the Australian National

University, extensively researching the predictors of disrupted sleep,
obesity and affective distress in the general Australian population. She
has also explored the relationships between stress, infection symptoms
and chronic fatigue. She currently practises as a clinical psychologist,
specialising in youth oncology.
 List of Figures

Fig. 2.1 Symptoms, states, and behaviour that can increase

nocturnal body temperature, and if practiced at night,
thereby potentially interfere with sleep onset 30
Fig. 2.2 Original caption reads: “Diagrammatic representation
of normally entrained endogenous rhythms of core body
temperature (solid curve), plasma melatonin (dotted curve),
and objective sleep propensity (dashed curve) placed
in the context of the 24-h clock time and normal sleep
period (shaded area).” Figure is from Lack et al. [25] 31
Fig. 2.3 Original caption reads: “Fitted Fourier curves
to the control group and insomniac group mean
24-h temperature data in the constant routine relative
to subjects’ usual sleep onset times (vertical solid line).
The usual mean lights out times (LOT) for each group
are indicated as vertical dashed lines. The estimated
mean wake maintenance zone (WMZ) for each group
is indicated as shaded area.” Figure is from Morris et al. [30] 33

xv
 1
Comorbidity: What Is It and Why Is It
Important?
Rhonda Brown and Einar Thorsteinsson

1.1 What Is Comorbidity?

Comorbidity refers to any distinct clinical entity that coexists with or
occurs during the clinical course of another illness or condition [1]. In
other words, it refers to the co-occurrence of two or more distinct illnesses,
disorders or conditions in a single individual. As a result of the comorbidity,
some disorders tend to occur together more often than they occur alone.
For example, anxiety, depressed mood and impaired sleep often co-occur,
and in this instance, the co-occurrence appears to be the rule rather than
the exception [2].
In this book, the term co-occurrence is used to refer to the coexistence
of multiple symptoms (or clinical signs), whereas comorbidity specifically

R. Brown (B)
Australian National University, Canberra, ACT, Australia
e-mail: [email protected]
E. Thorsteinsson
University of New England, Armidale, NSW, Australia
e-mail: [email protected]

© The Author(s) 2020 1

R. Brown and E. Thorsteinsson (eds.), Comorbidity,
https://doi.org/10.1007/978-3-030-32545-9_1
2 R. Brown and E. Thorsteinsson

refers to the coexistence of multiple illnesses, disorders or conditions. For

simplicity, the terms illness, disease, disorder and condition will be used
interchangeably, as appropriate to the medical or psychological literatures
referenced in each chapter.
It is not possible to provide a comprehensive analysis of all comorbid dis-
orders and concurrent symptoms in this book. Nonetheless, the book rep-
resents a significant step forward in its coverage of a broad range of concur-
rent disorders including overweight/obesity, diabetes mellitus type-II, car-
diovascular disease, sleep-disordered breathing, impaired sleep/insomnia,
disordered eating (e.g. binge-eating disorder), anxiety, depression, fatigue,
anorexia nervosa and bulimia nervosa.
In contrast, prior published books on the topic have tended to examine
a limited number of comorbidities, including that between anxiety and
depression [3–10], depression and other disorders [3], comorbidity with
rheumatic disease [11], epilepsy [12], hypertension [9] and lifetime (or
non-concurrent) comorbidity [4]. However, Sartorius and colleagues [13]
have comprehensively detailed the clinical challenges of managing medical
illnesses (e.g. cardiovascular disease, cancer, infectious disease) that tend
to co-occur with mental and behavioural disorders, including substance
abuse, eating disorders and anxiety; they covered the clinical management
of the comorbidities.
In this book, a focus of attention is the comorbidity between over-
weight/obesity (or proxy measures of it, e.g. high body mass index [BMI] or
weight gain) and impaired sleep/insomnia, which is increasingly observed
in clinical practice, but as yet is not fully understood. Specifically, over-
weight/obese individuals tend to take longer to fall asleep (i.e. longer sleep
onset latency) [14], sleep for a shorter time [15, 16], and have poorer
sleep quality [17], relative to non-obese controls (or lower BMI). How-
ever, little else is known about this common comorbidity, although the
sleep problems do typically resolve once the person loses weight [18]. In
Chapter 3, this comorbidity will be discussed in greater detail as will the
links between the phenomena and certain behaviour, which may play a
causal role in contributing to the disorders. In Chapter 2, existing the-
ories that seek to explain the presence and/or development of comorbid
symptoms and disorders will be discussed.
 1 Comorbidity: What Is It and Why Is It Important? 3

Additionally, in Chapter 4, comorbidity between overweight/obesity

and diabetes mellitus type-II, sleep-disordered breathing (e.g. obstructive
sleep apnoea [OSA]) and affective distress (e.g. anxiety, depression) will
be discussed. In Chapter 6, the concurrence between anxiety, depression,
insomnia/impaired sleep, fatigue, gut pathology and gut symptoms will
be discussed. In Chapter 5, comorbidity between eating disorders (e.g.
anorexia nervosa, bulimia nervosa) and sleep problems, anxiety, depres-
sion, gut problems and hyperactivity will be examined. In Chapter 7,
symptoms/conditions (e.g. chronic pain, fatigue) that frequently co-occur
with impaired sleep, psychopathology, and other co-occurring conditions
will be briefly discussed, as will the potential role played by unhelpful
behaviour, including sleep-disrupting behaviour.
Statistically, disease comorbidity is typically evidenced by high co-
prevalence estimates between the different diagnoses; symptom concur-
rence is evidenced by moderate to high correlations between two or more
composite measures (e.g. total construct scores), using validated question-
naires [19]. Consistent with this approach, the book chapters will provide
detailed research evidence illustrating the degree of concurrence between
the aforementioned disorders and symptoms, as appropriate to the spe-
cific chapter. Further, where possible, the emphasis will be on present-
ing meta-analytic and prospective longitudinal study results, rather than
cross-sectional correlational results. That is to say, our current conception
of causality typically requires that the cause of an event must precede its’
onset in time. Only longitudinal (and experimental) study results can fulfil
that criterion, to a greater or lesser degree.
However, appreciating the nature of the temporal relationship between
two separate phenomena tells us little about the mechanism/s that under-
pin the relationship. As detailed in Chapter 2, there are few available
theories to help guide the research on disease comorbidity, and as a result,
we currently know little about the true nature of the phenomenon. Fur-
thermore, a number of statistical and methodological (e.g. measurement)
problems complicate our understanding of comorbidity, for example, by
potentially inflating the extent of the observed relationship between the
different phenomena. These methodological and statistical problems will
be discussed in more detail in Chapter 8.
4 R. Brown and E. Thorsteinsson

Finally, in Chapter 9, we will tie the threads together from the vari-
ous chapters and reflect upon the most likely mechanism/s underpinning
the development of comorbidity between the aforementioned disorders.
In particular, we will discuss the likely role played by circadian rhythm
dysfunction in the development of the disorders, along with the role played
by sleep-disrupting behaviour and biological processes (e.g. elevated noc-
turnal body temperature). Finally, we will explore a broad range of novel,
existing and repurposed therapy approaches that could show utility in
treating the comorbid conditions.

1.2 Why Is Comorbidity Important?

In the twenty-first century, the tendency of patients to develop multi-
ple disorders or conditions, rather than a single medical or psychologi-
cal problem, is relatively high. For example, in a large study of 198,670
Spanish patients aged over 14 years [20], 42% had at least one chronic
condition, and the prevalence estimate for comorbidity was one-quarter
(24.5%) although the prevalence was higher in women (28.1%) than in
men (19.4%), and it increased with advancing age until 69 years, when
it stabilised. Of the 26 chronic health conditions surveyed, three distinct
comorbidity burden patterns were detected, including high comorbidity
(pattern B), intermediate comorbidity (patterns A and D) and low comor-
bidity (pattern C). Pattern B conditions included ischemic heart disease,
congestive heart failure, cerebrovascular diseases and chronic renal fail-
ure, mostly in older patients (>70 years). Pattern A conditions included
cardiac arrhythmias, hypertension (with/without complications), dia-
betes (with/without complications) and hyperlipidaemia, mostly in older
patients. Pattern D included 14 conditions, for example, obesity, osteo-
porosis, dementia, and cancer, whereas pattern C included asthma, thy-
roid disease, anxiety, depression and schizophrenia, mostly in younger
(<30 years) patients. Thus, several distinct comorbidity patterns were evi-
dent reflecting that different medical and psychological disorders tended
to cluster together, in different general practice patients.
Similarly, high comorbidity prevalence estimates have been obtained
in GP record-based studies in other countries. For example, a prevalence
 1 Comorbidity: What Is It and Why Is It Important? 5

estimate of 20% was obtained in an Australian study [21]; 29.7% had

acute and/or chronic conditions in a sample from the Netherlands [22];
and 30% had comorbid illnesses in a Spanish population-based sample
[23]. In the USA, about 25% of the population are reported to suffer from
multiple chronic conditions and this percentage increases with advancing
age [24]. Thus, it is evident that disease comorbidity is common in clinical
practice and more broadly in the global community.
Comorbidity substantially increases the burden of illness in chronic ill-
ness patients. For example, the Global Burden of Disease Study [25] eval-
uated chronic and acute illness and injury burden on patients across 188
countries (1990–2013) using years lived with disability (YLD). Globally,
from 1990 to 2013, disability rates were shown to rise, as people tended to
live longer and experienced more illness. Additionally, comorbidity preva-
lence estimates rose substantially in absolute terms and also with increasing
age; for example, the number of people with 10 or more disorders increased
by 52% over that time. Further, in total, one-third of the participants had
>5 chronic or acute illnesses, of whom 81% were <65 years of age [25].
Thus, it is evident that comorbidity occurs in younger as well as older
individuals.
However, few studies have explicitly compared the degree to which
different disorders are comorbid with each other, although higher comor-
bidity rates are reported in patients with heart (e.g. heart failure) and
cerebrovascular conditions and lower rates are reported in patients with
asthma and mental health conditions [21, 26, 27]. Nonetheless, depres-
sion is known to be a leading cause of Global Burden of Disease (GBD)
based on years lived with disability (YLD) and disability-adjusted life
years (DALYs); it may contribute to suicide and cardiovascular disease
[28]. However, expanding this examination to cover other mental health
problems including substance use/abuse and the combined effects of the
disorders is required; as the conditions are leading causes of DALY and
YLD worldwide [29]. Furthermore, as shown in a UK study, nearly one-
half (46%) of people with a mental health problem also had a chronic
physical health problem/s, whereas fewer (30%) people with a chronic
physical condition also had a mental health problem [30], suggesting that
mental ill-health is a common comorbid health problem which may have
implications for physical health.
6 R. Brown and E. Thorsteinsson

Taken together, it appears that comorbidity is present in at least one-

quarter to one-third of the population, including in general practice
patients. Furthermore, comorbidity prevalence estimates have significantly
increased over time and they tend to increase with advancing age, as do dis-
ability prevalence estimates [31]. Thus, as the global population ages, the
extent to which we will be affected by comorbid disease burden is expected
to substantially rise, although a substantial proportion of younger people
are also affected by comorbidities. Therefore, there is an urgent need to bet-
ter understand the nature of disease comorbidity and its likely causation,
so that effective multi-modal therapies can be developed (or re-purposed)
to treat the individual patients who have multiple comorbid illnesses.
Comorbidity tends to be associated with impaired daily functioning
and low health-related quality of life (QOL), including the physical and
mental health components of QOL [23]. More broadly, chronic illness
patients often experience severe and/or debilitating symptoms; will likely
undertake fear-provoking, painful or otherwise demanding investigations
and treatments; experience a high degree of uncertainty related to the
condition/s and their treatment; and about one-quarter of them will go
on to develop clinically significant psychological distress. Adherence may
also be reduced due to such severe symptoms and painful and demanding
treatments reducing the efficiency of treatment and increasing costs. Even
without a psychological disorder, patients will still need to psychologically
adjust to their illness, which will require them to regulate their thoughts,
feelings and behaviour; acquire new skills to manage their psychologi-
cal symptoms; adopt a new lifestyle of self-care; establish collaborative
relationships with their healthcare team/s; and, even then, sub-clinical
affective distress (e.g. anxiety, depression) may occur [32]. Nevertheless,
the impact of multiple different comorbid disorders (e.g. disability) tends
to be greater than for a single disorder, as are the costs associated with it
(e.g. financial, personal), as discussed in detail below.
However, despite the high prevalence of comorbidity and its con-
siderable impact on individual patients, most medical and psychologi-
cal researchers have tended to focus on single disorders or conditions,
rather than (or in addition to) disorders that coexist with them; irrespec-
tive of whether the subjects are medical patients, psychological clients or
community-derived non-clinical samples. For example, researchers may
 1 Comorbidity: What Is It and Why Is It Important? 7

investigate the relationship between certain risk factors (e.g. physical inac-
tivity) and depressed mood, without examining their relationship to other
coexisting symptoms (e.g. impaired sleep, fatigue), despite the common
propensity of depression to coexist with anxiety [33], impaired sleep [34]
and fatigue [33, 35]. However, many researchers will at least statistically
control for the potential effects of the concurrent symptoms. For exam-
ple, they may assess the predictive relationship between risk factors and
depressed mood, and partial out the effects of anxiety on the outcome mea-
sure, to obtain a purer estimate of the risk factor–depression relationship.
Such an approach can assist researchers to better understand the extent
to which particular risk factors and depressed mood are related, but this
approach potentially ignores the possibility that anxiety is functionally
related to depression via a number of possible mechanisms, as discussed
in Chapter 6.
Additionally, few theories of disease comorbidity exist to help guide the
comorbidity research. Specifically, as discussed in detail in Chapter 2, there
are few available clinical theories with any utility in explaining the way
in which different-but-related disorders and symptoms are likely to coex-
ist and the mechanisms by which they will develop. Such a theoretical
model would greatly assist researchers and clinicians to better understand
the likely complex causal relationships that exist between different risk
factors, medical illnesses and psychological disorders; it might also facili-
tate the evidence-based co-treatment of different comorbid disorders and
conditions.
However, most existing therapies have not been designed to treat
different-but-related disorders. Nor have they been examined for their
utility in treating coexisting conditions. Similarly, clinical practice guide-
lines and disease management programs typically focus on single diseases
but fail to take comorbidities into account; instead, they tend to deal with
the disorders as if they are isolated clinical entities [36]. Thus, there is
a clear need to update the clinical practice guidelines and patient man-
agement approaches to take disease comorbidity into account, especially
in the case of highly comorbid disorders and conditions. Furthermore,
there is a need to develop and evaluate novel (or repurposed) evidence-
based therapies to more effectively treat the aforementioned comorbid
conditions.
8 R. Brown and E. Thorsteinsson

However, as discussed in Chapter 9, there appear to be few novel ther-

apies on the horizon that might remedy the comorbidities; there is no
clarity as to whether existing therapies could be used to concurrently treat
comorbid illnesses or if a sequenced approach to therapy might work best.
Nevertheless, there are a few notable exceptions: for instance, cognitive
behavioural therapy (CBT) can effectively treat depressed mood, fatigue,
insomnia/sleep problems and eating disorders; and there are disorder-
specific variants of CBT to treat depression [37], fatigue [38], insomnia
(CBT-I) [39] and eating disorders (CBT-E) [40]. However, the CBT pro-
tocols do not generally provide any detail about the way in which the
comorbid disorders should be managed together, either concurrently or
sequentially, in a single individual. Additionally, antidepressants have been
used to treat sleep problems in patients with depressed mood, but the
findings are typically mixed, with some studies showing that the drugs
can improve insomnia [41], whereas others show the drugs may worsen
insomnia [42]. Thus, there is a clear need to systematically review the effi-
cacy of antidepressant use in treating insomnia. A Cochrane review that
began in 2013 found that there was little evidence for the effectiveness of
SSRIs in treating impaired sleep and any apparent improvements in sleep
quality were short-lived, although the findings were only preliminary as
insufficient studies could be sourced to examine this issue [43].

1.3 What Is the Cost of Comorbidity?

Disease comorbidity is associated with a range of economic, societal and
personal costs. Economic costs can include the direct costs to the health-
care system of managing multiple health problems (e.g. prolonged recov-
ery time); direct costs to other sectors (e.g. provision of social care); and,
indirect costs such as the lost opportunity to contribute to economic pro-
ductivity (e.g. reduced workforce participation or participation in school,
etc.). The full economic costs of comorbidity are largely unknown, especially
the estimates of the impact beyond the healthcare system; in this case, the
estimates are mostly of indirect costs, including productivity losses due to
under-employment resulting from absenteeism [44].
 1 Comorbidity: What Is It and Why Is It Important? 9

Nevertheless, it is broadly appreciated that the financial costs of man-

aging two different chronic disease patients, one with diabetes and the
other with heart disease, will be higher than the cost of managing a single
patient with comorbid heart disease and diabetes [45]. This disparity is
due to the need to duplicate certain aspects of services provision to each
individual patient (e.g. administrative costs, clinic attendance), indicat-
ing that there are likely to be potential per capita cost savings associated
with the treatment of patients with comorbidity. However, a single patient
with comorbid illness may require additional health resources (e.g. more
time with the doctor, longer hospital stay) and longer and more intense
treatments, relative to two different patients with a single chronic condi-
tion. As detailed below, relatively few studies have compared the economic
costs of managing multiple comorbid disorders with the uncomplicated
presentation and treatment of single disorders.
However, the costs associated with managing comorbid mental health
disorders (e.g. anxiety disorders, depressive illness) and related conditions
(e.g., sleep problems) are known to be high. For example, at any one
time, about 2% of the Australian population is reported to be affected
by a serious mental health condition; in financial terms, this translates
into an annual societal cost of AU$15 billion in Australia and NZ$3.1
billion in New Zealand [46]. However, the full costs of managing the
separate conditions tend to be underestimated due to the omission of
costs related to the patients’ other comorbidities [47]. Further, a recent
US study showed that if a patient was hospitalised for a non-mental health
condition (i.e. heart failure), the cost was significantly higher if they had a
comorbid mental health condition (e.g. depression); that is, the additional
costs of depression ranged from US$1844 to US$7763 per patient per
psychiatric diagnosis, and it likely resulted in a longer hospital stay [48].
Thus, despite the lack of specific research, it is evident that the financial
costs of managing comorbid mental and physical health problems are high.
Similarly, sleep problems represent a significant cost to the individual
and the wider community, including the cost of therapy and costs asso-
ciated with work-related injuries, motor vehicle accidents and losses to
productivity due to sleep disorders [49]. For example, in four US corpora-
tions, workers who had insomnia and/or insufficient sleep syndrome had
significantly lower productivity, workplace performance and work safety
10 R. Brown and E. Thorsteinsson

outcomes than those without a sleep disorder; the loss to productivity due
to sleep problems was estimated at $1967 per employee annually [50].
Similarly, the costs linked to sleep problems in Australia are estimated to
be about $5.1billion per annum, but again, the value excludes the costs
of managing people’s other comorbid conditions [49]. However, Deloitte
Access Economics and the Australian Sleep Health Foundation computed
the direct and indirect costs of several sleep disorders including insomnia,
OSA and restless leg syndrome (RLS), using 2010 data [51]. The indirect
costs of treating OSA included managing any comorbid hypertension,
vascular disease, depression and related motor vehicle and workplace acci-
dents. In total, the sleep disorders cost about AU$818 million which
included sleep disorder treatment ($274 million), treatment of other dis-
orders caused by the sleep problem ($544 million), and non-financial
costs of the disorders, including lost productivity ($3.1 billion/year) [51],
although some researchers have argued that the full costs were underesti-
mated, due to the use of overly conservative prevalence estimates for OSA,
RLS and insomnia [49].
Thus, it is apparent that the financial costs of managing comorbid
illnesses are high. It is certainly higher than the cost of managing the
uncomplicated presentation of a single disorder. However, relatively few
studies have examined the direct and indirect costs of disease comorbid-
ity. Nevertheless, the costs of comorbidity will likely vary depending on
the type and extent of the comorbidities. For example, common disorders
(e.g. insomnia, obesity) will tend to cost the most to manage, in terms of
the total health sector costs. Similarly, conditions that tend to co-occur
the most will tend to contribute more to the costs of managing other dis-
orders; for example, sleep problems are more strongly linked to depressed
mood than anxiety disorders; and [35, 52] thus, the costs of sleep-related
comorbidity will tend to be greater in patients with depressed mood than
in those with a comorbid anxiety disorder.
In contrast, chronic pain is more strongly linked to anxiety than depres-
sion, and so the economic costs of managing anxiety may be higher than
the costs of managing depression in chronic pain patients. For example,
nearly one-half (43.9%) of a sample of Spanish patients with chronic
widespread pain reported anxiety and whereas only one-quarter (27%)
reported depression [53]. Taken together, the results suggest that the costs
 1 Comorbidity: What Is It and Why Is It Important? 11

(and disability) associated with chronic widespread pain, which is often

concurrent with anxiety, depression and sleep problems, is higher than
the costs of managing matched control patients who do not have chronic
widespread pain [53]. The specific costs associated with managing other
comorbid disorders (e.g. diabetes mellitus type-II) will be described in
greater detail in the relevant book chapters.
Disease comorbidity has been shown to be associated with shorter life
expectancy. For example, the risk of myocardial infarction increases four—
fivefold in the presence of depressive symptoms, even after controlling for
medical factors [54]. Similarly, patients with comorbid depressed mood
and overweight/obesity [55], diabetes [56, 57] and insomnia (i.e. sleep
duration) [58] are more likely to experience an earlier than expected death.
Depression comorbidity also increases the mortality risk in patients with
high mortality illnesses such as OSA [59, 60] and anorexia nervosa [61],
although there is a lack of research on OSA [62]. Similarly, the high
mortality rate in schizophrenia patients has been shown to be at least
partly attributable to comorbid cardiovascular disease and cancer [63]; a
recent meta-analysis that evaluated studies from 25 countries confirmed
this pattern, showing that the high mortality rates linked to schizophrenia
were largely attributable to the presence of comorbid conditions [64].
Similarly, the Royal Australian and New Zealand College of Psychiatrists
[46] reported that comorbidity of a mental and physical health condition
reduced life expectancy in men and women. Patients with anxiety and/or
depression were at greater risk of all-cause mortality and risk of death from
specific illnesses, probably due to the ill-effects of the comorbid physical
health condition/s (e.g. cardiovascular disease, diabetes) [65]. In addition,
hospital inpatients with depressive symptoms are more likely to experience
readmission or increased mortality risk, relative to patients without depres-
sive symptoms [66]. Similarly, using data from the US National Health
Interview Survey (1999–2011), Pederson and colleagues [66] showed that
people with anxiety/depression were likely to die an average 7.9 years ear-
lier and had a doubled mortality risk and risk of hospital readmission,
relative to non-anxious and depressed controls [66]. Finally, in a study of
>5 million US military veterans, of whom 850,000 were depressed, high
baseline depression was linked to a 17% increased risk of all-cause mor-
tality and specific increases in mortality due to heart disease, respiratory
12 R. Brown and E. Thorsteinsson

illness, cerebrovascular disease, accidents, diabetes, nephritis, influenza,

Alzheimer’s disease, septicaemia, suicide, Parkinson’s disease and hyper-
tension [65]. Thus, it is evident that comorbidity between a mental health
and physical health condition is linked to a shorter life expectancy. Specific
details of the mechanisms that may underpin the elevated mortality risk
in patients with comorbid illnesses will be discussed in greater detail in
the relevant book chapters.
Comorbidity is also typically linked to substantial disability. Disability
can limit a person’s ability to function adequately in their current environ-
ment, either mentally or physically [67]; this can adversely impact upon
multiple different aspects of their daily life. For example, a person with
diabetic retinopathy may develop permanent vision impairment and this
may interfere with their ability to perform daily domestic duties (e.g. cook-
ing), care for children and/or do paid work, unless accommodations can
be made in the workplace. Specifically, disabilities such as mobility and
cognitive impairment often result in a change in the patients’ work status,
including withdrawal from work, reducing work hours and/or changing
the type of work performed, for example, as seen in patients with multi-
ple sclerosis [68]. Furthermore, disease comorbidity can limit a person’s
capacity for self-care [32], suggesting that patients with multiple comorbid
disorders may struggle to manage the different illnesses and deal with the
extent of their disabilities. According to 2012 figures, about 4.2 million
Australians were affected by a disability, and compounding this issue, the
unemployment rate was 9.4% among disabled individuals, compared to
4.9% in those who were not disabled [69]. Thus, disability is common in
the community, although it is unclear just how much of this is related to
comorbid disease burden.
In particular, comorbidity between mental and physical health condi-
tions has been shown to more than double the odds that a person will
suffer from severe disability [70]. Several large mental health surveys have
shown that when mental health conditions are compared to physical health
conditions, the mental health conditions are more likely to predict severe
disability burden; specifically, the odds of experiencing a severe disability
were greater (more than additive) in patients with a mental and physi-
cal health condition/s [70]. Further, comorbidity between psychological
 1 Comorbidity: What Is It and Why Is It Important? 13

disorders has consistently been shown to be related to poorer progno-

sis and greater therapeutic demands from patients [71]. Taken together,
the results suggest that patients with comorbid health problems are more
likely to experience disability, poorer prognosis, and have more complex
health needs than patients with a single disorder, especially if they have a
concurrent medical and psychological problem/s.
Importantly, disability is described as a societal phenomenon inasmuch
as it is typically defined in terms of the extent to which it impairs a
person’s engagement with activities, including work, and the extent and
nature of their social interactions [72]. Thus, the effects of disability will
tend to extend beyond the individual to include their family unit, friends
and social network, and its effects may change over time. For example,
a patient may withdraw from their social network while they are unwell,
but if their health improves, they may need to rebuild the network and/or
make new friends or contacts. Alternately, a spouse may need to take over as
the primary breadwinner or give up work to care for the patient, resulting
in a loss of family income, financial stress and tension related to changes
in family roles and responsibilities and the broader redefinition of social
roles. Thus, it is apparent that comorbid disease burden has important
implications for the broader community, including the possibility that
the affected individual will prematurely withdraw from or reduce their
engagement with important aspects of their world. For example, a person
may need to withdraw from work and/or their social network due to
disability, and additionally, they may become stigmatised because of the
illness or the disability.
Stigma involves labelling an individual or group therefore setting them
apart from others. In nations such as Australia, stigmatised groups typi-
cally include people who are disabled, Indigenous, LGBTQI, unemployed,
homeless, poor, asylum seekers and those with mental health conditions.
Stigma is known to potentially lead to health inequality [73]; the more
a person (or population) is stigmatised, the more likely they are to suffer
disadvantage, although it has not been examined in regard to comorbidity.
Nevertheless, a review examining the mental health of Australian home-
less youth has suggested that homelessness is linked to increased suicidal
behaviour, the presence of psychiatric disorders and psychological distress
[74].
14 R. Brown and E. Thorsteinsson

Thus, it is apparent that comorbidity is associated with considerable per-

sonal costs to individual patients, including the physical and psychological
impacts of the conditions. For example, they will likely experience multi-
ple physical and/or psychological symptoms; need to undertake multiple
different therapies, each of which may need to be taken at a different time
of day or under different conditions (e.g. before meals); need to attend
multiple different therapy appointments at different locations, at con-
siderable personal cost; and need to work with multiple different health
practitioners to co-manage their conditions. As a result, the burden of
comorbidity and its treatment is likely to interfere with a patient’s ability
to lead a normal life, derive a sense of personal control and psychological
well-being and maintain important social relationships and social roles
(e.g. parent, worker). Furthermore, certain aspects of the illnesses (e.g.
severity, disability, prognosis, treatment) may increase the likelihood that
they will experience stress, affective distress (e.g. anxiety, depression), grief
and possibly other comorbid conditions (e.g. sleep disorder).
In particular, patients with several different-but-related conditions may
spend many hours seeing various healthcare professionals, each of whom
will separately evaluate and treat the medical and psychological problems,
in an uncoordinated way. For example, a patient with comorbid over-
weight/obesity, binge-eating disorder, diabetes mellitus type-II, OSA and
depressed mood may variously be managed by an obesity clinic, endocri-
nologist, sleep apnoea clinic and clinical psychologist; they may separately
participate in weight loss and exercise programs and be prescribed dia-
betes medication, continuous positive airway pressure (CPAP) therapy
and cognitive behavioural therapy. As mentioned above, this uncoordi-
nated approach to patient care can represent a substantial burden to indi-
vidual patients and their families; for example, it may interfere with their
capacity to earn a living or fulfil important social roles as well adding to
the financial costs of caring for the patient.
Finally, as mentioned in Sect. 1.2, most healthcare services are currently
ill-equipped to treat patients with multiple comorbid conditions [75]. In
most clinical settings, patients tend to be prescribed a single treatment
plan for each separate condition, rather than a single coordinated ther-
apy plan for individual patients. Each treatment plans will typically be
administered by a different medical team or allied health professional;
 1 Comorbidity: What Is It and Why Is It Important? 15

there is often little communication between the staff, and between health-
care workers and patients [76]. Similarly, in some poor countries, there is
a lack of healthcare providers who have expertise in managing common
comorbid illnesses (e.g. HIV/AIDS and tuberculosis) using an integrated
treatment plan which takes into account the interactions between the dif-
ferent diseases [77]. Furthermore, where clinical practice guidelines exist
for the treatment of comorbidities, they have typically been found to be
less than adequate and may potentially increase the burden to patients
[78].
Thus, it is clear that patients with substantial comorbid illness burden
require an integrated therapy approach, which separately (and together)
addresses each medical and psychological condition. For example, a patient
could receive multiple co-therapies together or sequential therapies that
are co-managed in individual patients, although few comorbidity ther-
apy protocols currently exist. Nevertheless, multidisciplinary treatment
approaches will likely have utility in optimally managing a person’s comor-
bid illnesses, as they tend to permit the provision of coordinated evidence-
based therapy, using co-therapy or sequential therapy protocols.
Multidisciplinary care typically involves patients attending a central
location to see a number of medical and/or allied health staff involved in
their care. Clinicians can communicate with each other about the pre-
cise sequencing of the prescribed evidence-based care and the manage-
ment of the related problems (e.g. therapy side effects, affective distress).
For example, a breast cancer patient may undergo surgery, chemotherapy
and/or radiotherapy, as sequenced by the treatment team, using established
sequential therapy protocols that minimise side effects and maximise the
clinical response to therapy. Her psychological condition can also be man-
aged in the same clinic by allied health staff in coordination with the
medical team. Unfortunately, multidisciplinary care approaches have, for
the most part, not been utilised in the treatment of comorbid illnesses,
except in diabetes patients, who are sometimes managed in the multidisci-
plinary care setting; in which case, diabetes and comorbid conditions (e.g.
depressed mood) can be concurrently treated, as discussed in Chapter 4.
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