Comorbidity Symptoms, Conditions, Behavior and

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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