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6 Comorbid Psychiatric Illnesses 149
the potential impact of stress on depression [84]. Similarly, a study of 128
boys and girls (aged 13–19 years) in Botswana suggested the importance
of using distraction and seeking out social support to reduce the potential
impact of negative life-event stress on distress (e.g. perceived stress, sleep
problems) [85]. Therefore, it is important for clinicians to ascertain if
patients are using maladaptive coping, especially drug and alcohol use, as
this may contribute to affective distress (e.g. anxiety, depression) relative
to people who do not use illicit drugs or alcohol as a coping device [20].
It is also important to ascertain a patient’s level of social support as this
may also have implications for their mental health.
Finally, in regard to mental ill-health, it is noteworthy that the risk
factors for affective distress (e.g. anxiety, depression) are similar to the
risk factors for insomnia/impaired sleep (Chapters 2 and 7)andover-
weight/obesity (Chapter 3), and affective distress is also a risk factor for
the latter two conditions, and vice versa. That is, the risk factors and pro-
tective factors for the conditions overlap considerably with each other.
Therefore, as detailed in Chapters 7 and 9, it is possible that (i) a single
risk factor could contribute to more than a single condition (e.g. excessive
electronic device use leading to overweight/obesity and impaired sleep, in
part via physical inactivity), and (ii) two or more risk factors could interact
together to augment or attenuate the expected effects on mental health.
However, to the authors’ knowledge, few studies have examined the pos-
sible contributions of these interacting risk factors to clinical outcomes.
6.4 Causal Models for the Development
of Depression and Anxiety
Myriad different factors have been posited to contribute to the develop-
ment of depressive illness, including stressful life-events, depression vul-
nerability (e.g. maladaptive coping strategy use, high-trait anxiety), lack
of social support, impaired sleep, viral infections, chemical imbalance,
physical inactivity, cytokine activity, genetics, inadequate diet (e.g. lack
of Omega-3, too much sugar, lack of vitamin D
3
), gut dysfunction, and
circadian rhythm dysfunction,and in many cases, thesame factors are sug-
gested to underpin the development of anxiety disorders. In particular, so
150 E. Thorsteinsson and R. Brown
many theories of depression causation exist that it is difficult to reconcile
how all of them could provide a parsimonious explanation of the processes
underpinning the disorder. Further, anxiety, depression, and fatigue are
often difficult to separate in longitudinal predictive studies; thatis, depres-
sion is a strong predictor of anxiety and fatigue, and depression is strongly
predicted by anxiety and fatigue [86], suggesting that anxiety, depression,
and fatigue might also be causally related. Adding further complication, in
clinical practice, anxiety and depression may manifest only as the greater
severity of somatic complaints, including fatigue (see Chapter 8). Thus,
given the degree of overlap between the conditions (e.g. co-occurrence of
symptoms) and the likely complexity of affective disorder causation [87],
it is not surprising that the causal hypotheses for the three disorders also
tend to overlap.
However, as articulated by Borsboom and colleagues [88, 89]and
Brown and colleagues [90], many different possible pathways leading to
comorbidity are likely to exist, and the pathways occurring in a particular
person may depend on personal characteristics (e.g. life experiences, cop-
ing methods, presence of infection) and the specific life situation. Detailed
below is a brief summary of some of the dominant theories related to the
causation of affective distress, including psychosocial and biological the-
ories. Due to the extensive nature of the relevant literature, the focus here
will be on potential causes of depressed mood rather than anxiety, fatigue,
or other disorders.
6.4.1 Psychological Models
Life-event stress reliably precedes the onset of MDD and is thought to be
causally related to it [91]. The Camberwell Collaborative Depression Study
found that stressors were 2.5 times more frequent in depressed patients
than in controls, and in community samples, 80% of the depression cases
were preceded by major life-events. Thus, life stress was frequently linked
to depression diagnosis but most people did not become depressed after
experiencing amajor stressfullife-event.This result likely reflects thatsome
people have a particular vulnerability to develop depression, as detailed in
6 Comorbid Psychiatric Illnesses 151
the next section. In cases where individuals do develop depression, inter-
personal loss experiences (e.g. bereavement, separation), chronic relation-
ship stress (e.g. marital arguments), and dependent stressors (i.e. stres-
sors to which a person might have contributed such as job loss due to
unexplained absences) most consistently precede depression onset. Addi-
tionally, chronic stressors (e.g. chronic illness, marital discord) including
social disadvantage (e.g. poverty) are stronger predictors of depression
severity than acute stressors [92]. However, it is not clear exactly how
stress contributes to depression, although several factors including social
withdrawal, ruminativethinking, maladaptive coping, impairedsleep, and
stress-induced immunosuppression leading to infective illness have all
been proposed to mediate the relationship between stress and depressed
mood.
Only some people who experience a major stressful life-event will go on
to develop depression,suggesting thatdepression vulnerability plays a role in
the developmentof depression. However,there aremyriad different poten-
tial vulnerabilities that could predispose a person to develop depression,
as detailed in the psychological literature, including maladaptive coping
strategy use (e.g. avoidant coping), inherited personality traits/disorders
(e.g. borderline personality disorder, dysthymia), developmental factors
(e.g. in utero stress), social modelling (e.g. child learns to respond exces-
sively to stress from parent), and genetic or other biological factors [93].
Thus, it is unclear exactly what the vulnerability might entail. Neverthe-
less, it is noteworthy that a strong predictor of depressed mood is a prior
history of a mental health condition and/or a family history of one [94–
96].The relationship may indicate that there is a genetic or biologicalbasis
for the disorder, but it is equally plausible the family members shared the
same disadvantaged social environment, were exposed to the same stres-
sors, and/or that they respondedto stressful situations in a similar manner.
In contrast, the Tripartite Mode [97, 98] proposes that the comorbidity
between anxiety and depression may be partly explained by a common
negative affect which is shared by anxiety and depression. However, a
review [97] of the model suggests that anxiety is clinically dissociable from
depressed mood, given that anxiety is principally linked to hyper-arousal
whereas depression is linked to low-positive affect. Such an assertion is
152 E. Thorsteinsson and R. Brown
supported by the results of a 3-month follow-up study, in which high-
depression levels werepredicted by negative affect, whereas lowdepression
was predicted by positive affect with resilience mediating the effects to
some degree [99]. Thus, it is possible that anxiety and depression have a
common causation, but it is likely that separate processes may underpin
the expression of these affective symptoms.
The provision of adequate social support and satisfaction with support
is known to predict better mental health outcomes (e.g. better wellbeing,
fewer affective symptoms), whereas inadequate support (or the percep-
tion of inadequate support) predicts worse mental health (e.g. depression
severity) [100]. This is paralleled by results indicating that better physical
health (including better medical outcomes in medical patients) is linked
to adequate socialsupport, whereas worse physical health is linked to inad-
equate social support (i.e. loneliness and social isolation) [101], or at least
the perception of it. The literature is mostly comprised of cross-sectional
research studies; thus, it is unclear whether inadequate support adversely
impacts on health, if health adversely impacts on social supports, or if
both are likely to be true. Nevertheless, there are several theories of social
support (e.g. stress-bufferinghypothesis) [102] which broadly suggestthat
the provisionof social support can protect an individualfrom experiencing
distress.
Similarly, social isolation is reported to increase a person’s morbidity
rate [101] although research on the topic is limited. It and feeling lonely
are strongly related to depressed mood [103], though loneliness may be a
better predictor than social support, where loneliness irrespective of social
support levels predicts levels of depression [103], but more studies are
needed to enable modelling any bidirectional relationships that might
exist with depression predicting lack of social support and loneliness. It is
not difficult to appreciate that feeling lonely will tend to worsen a person’s
thinking and mood, and that they may not feel much like socialising
when they are feeling depressed. Interestingly, as detailed in Chapter 7,
social exclusion has been linked to feeling colder [104]andadropinbody
temperature that is associated with feeling cold [105], whereas enhancing
a person’s perception of warmth increases social proximity and feelings of
closeness [106]. Thus, social isolation and an actual or perceived lack of
support may contribute to the development of depressed mood.
6 Comorbid Psychiatric Illnesses 153
In a similar vein, Martin Seligman has proposed that the current global
depression epidemic is partly fuelled by socio-cultural changes that have
occurred in modern society. For example, he suggests that our culture
of individualism, the self-esteem movement, and the collapse of com-
munal society structures have resulted in a lack of connectedness, fewer
roles/responsibilities, social isolation, and lack of life meaning, which has
likely increased the risk of developing a mental health problem. His recent
books (e.g. Learned Optimism)[107] have focused on learning how to
become more optimistic and achieving authentic happiness and flourish-
ing, in part, by focusing on the acquisition of character strengths (e.g.
persistence, courage) that can help to buffer against feelings of distress
that could lead to depressed mood [108, 109].
6.4.2 Biological Models
Stress-related immune suppression, which increases the risk of an infection,
is posited to underpin the development of depression. Psychological stress
typically results in stress hormone release (e.g. cortisol) that can poten-
tially suppress immune system functioning, thereby potentially increasing
a person’s susceptibility to infection [110–113], which may then result in
depressed mood. Depression is also linked to immune suppression and
an increased risk of infection, especially pneumonia and upper respiratory
tract infection [114]. Findings from a meta-analysis of 38 depression-
immune studies[115] suggest thatclinical depression isalso reliably linked
to impaired immune functioning, with the strongest associations found
in older people and inpatients. Depressed people are also more likely to
develop an infection and stay unwell for longer [116]. In older individ-
uals, the number of depressive symptoms was positively associated with
plasma Interleukin-6 levels contributing to increased inflammation and
inflammation-related health problems [117]. Furthermore, viral and bac-
terial infections are known to precede or co-occur with depressed mood,
and depressionis associatedwith thesubjective feelingof infection, fatigue,
gastrointestinal upset, autonomic arousal [118], and more frequent infec-
tions [116], including specific viral [119–121] and bacterial infections
[118], relative to healthy controls. Thus, an infection or its effects (e.g.
154 E. Thorsteinsson and R. Brown
cytokine response to infection) may contribute to depressed mood. How-
ever, a recent meta-analysis [122] showed that statistically significant asso-
ciations only existed between depression and Borna disease virus, herpes
simplex virus-1, varicella zoster virus, Epstein–Barr virus, and Chlamy-
dophila trachomatis. Thus, there is preliminary evidence suggesting that
depressed moodcould be induced byviral and other infections. The mech-
anisms bywhich this conditionmight develop areexamined below, includ-
ing the effects of fever/elevated body temperature (BT), brain inflamma-
tion, and cytokine secretion.
An elevated BT and circadian rhythm dysfunction have been posited
to underpin the development of depressed mood. For example, positive
affect is related to the normal circadian rhythm of core BT [90], whereas
its dysregulation is linked to affective disorders including depressed mood
[90]. For example,several studieshave shownthat BT(including nocturnal
BT) is higher in depressed individuals, relative to healthy controls [90],
which results in a flatter and delayed circadian rhythm of core BT and a
phase delay in the sleep-wake cycle, as well as an early morning increase in
BT, which is linked to early morning wakening [90]. Additionally, several
hallmark features of depressed mood are suggestive of circadian rhythm
dysfunction, including elevated nocturnal BT, phase advance in the core
BT rhythm (e.g. peak cortisol and melatonin levels occur later at night),
early morning wakening which is preceded by an early increase in BT,
diurnal changes in mood, circannual rhythm of mood, and changes in
sleep architecture (e.g. short REM latency) [90]. As detailed in Chapter 2,
when a person’s BT fails to rapidly fall in the evening, because of processes
that oppose it (e.g. elevated BT related to depressed mood), this could
potentially result in impaired sleep, specifically the inability to fall asleep.
However, as detailedbelow,the elevated BT in depressedindividuals might
alternatively be explained by other biological processes.
Rausch and colleagues [123] suggest that the BT changes in depressed
individuals provide supportfor the inflammatory model of depression,which
posits that depressed mood is caused by activation of the inflammatory
response system. For example, an elevated BT could indicate a fever
response in depressed people, which may be due to infection. Consis-
tent with this theory, antidepressants (e.g. selective serotonin reuptake
inhibitors [SSRIs]) have been shown to exert anti-inflammatory effects;
6 Comorbid Psychiatric Illnesses 155
that is, reducing the release of nitric oxide andpro-inflammatory cytokines
(e.g. interferon-
γ
, tumour necrosis factor-
α
[TNF-
α
], and interleukin-6
[IL-6]), all of which are detected in the sera and brains of depressed indi-
viduals [124, 125]. Furthermore, anti-inflammatory compounds such as
aspirin have been shown to reduce depressive symptoms, either taken
alone, taken for their anti-platelet effects or to reduce the risk of myocar-
dial infarction [126] orin combination with SSRIs, relativeto SSRIs alone
[127] However, there are other possible explanations of the elevated BT
and abnormal cytokine secretion in depressed people. As mentioned in
Chapters 7 and 9, cytokines are also released in response to exercise [128],
physical stress [129], cold [130], and heat stimulation [131, 132], and the
cytokine responses to fever/infection are largely indistinguishable from
those secreted in response to overheating/heat stroke, stress/autonomic
arousal, and exercise/physical activity [132–134]. Thus, there are pro-
cesses other than infection, such as autonomic arousal and overheating
(or an elevated BT), which could alternatively explain the BT changes in
depressed individuals.
In related research, prolonged stress and depression have been shown
to be related to brain changes (e.g. reduced cerebral blood flow, reduced
cerebral metabolism, structural abnormalities). In particular, using fMRI,
depression was shown to be linked to reduced cerebral blood flow [135],
and using positron emission tomography, cerebral metabolism was shown
to be reduced in the prefrontal cortex and hippocampus [136]. Paralleling
the changes, post-mortem brain size in depressed people has been shown
to be reduced (i.e. atrophy) [137] and there is reduced connectivity and/or
atrophy in the hippocampus, anterior cingulate, orbital cortex, and dorso-
lateral and subgenual prefrontal cortex in depressed patients [137–139].
However, the processes underpinning these brain changes are not exactly
clear, although it is likely that the brain atrophy in MDD patients occurs
secondary to brain inflammation [140–142]. This interpretation is con-
sistent with prior research showing that patients receiving cytokine ther-
apy can develop depressive symptoms [143, 144], experimentally induced
inflammation can promote mood deterioration in healthy subjects [145],
elevated inflammatory markers predict poorer response to antidepressant
therapy, and depressed patients who are non-responsive to antidepressant
therapy show persistently elevated inflammation [146].
156 E. Thorsteinsson and R. Brown
Similar to the inflammatory model of depression, the cytokine theory
of depression posits that depression may be induced by inflammation that
occurs secondary to cytokine secretion [118]. Cytokines are proteins that
are secreted by most immune cells to enable communication between
them; not unlike neurotransmitters and neuromodulators in the nervous
system, such that cytokines can bind to specific receptor sites on the exter-
nal surface of immune cells,thus aiding in immune system defence against
invading pathogens[147, 148]. In recent years, cytokines havebeen linked
to various illnesses including rheumatoid arthritis [149], inflammatory
bowel disease [150], cardiovascular disease [151], diabetes [152], and also
mental healthconditions such as psychosis [153] and obsessivecompulsive
disorder [154]. Specifically, the cytokine theory of depression posits that
the inflammatory response system can be activated via external (e.g. infec-
tion) or internal stressors (e.g. cortisol, psychosocial stressors), to result
in the production of pro-inflammatory cytokines and oxidative processes
(e.g. nitric oxide, super oxide) that directly damage proteins, membranes,
and genes, ultimately resulting in depression [118]. Consistent with the
theory, is the abovementioned research showing that antidepressants (e.g.
SSRIs) have anti-inflammatory effects [124, 125, 155, 156], and anti-
inflammatory compounds (e.g. aspirin) can improve depressive symptoms
[126, 127]. Alternatively, it could be possible that the changes in brain
function are a reflection of circadian rhythm dysfunction, although so far
the hypothesis has not been examined.
Finally, perturbations in the gut –brain axis are suggested to underpin
the development of depression. The GBA facilitates bidirectional com-
munication between the nervous system (e.g. via the vagus nerve), neu-
rotransmitters produced in the gut (e.g. serotonin, gamma-aminobutyric
acid [GABA]), and the immune system [157],anditislinkedtoabout
1 kg of bacteria in the digestive tract [158]. For example, patients with
MDD showed elevated antibodies to infection (IgM and IgA responses
to lipopolysaccharide [LPS]), which is a toxin in the cell wall of gram-
negative bacteria (e.g. Salmonella and Escherichia coli species). Patients
also experienced frequent subjective feelings of infection, fatigue, GIT
symptoms, and autonomic arousal [118]. Taken together, the results sug-
gest that leaky gut (i.e. physical disruption or increased permeability of
the intestinal tract) which gives rise to bacterial translocation (i.e. escape
6 Comorbid Psychiatric Illnesses 157
of indigenous bacterial flora from GIT to sterile extra-intestinal sites;
e.g. liver, mesenteric lymph nodes, bloodstream) may explain the phe-
nomenon. Simply put, bacterial translocation from the gut is known to
result in the systemic release of pro-inflammatory cytokines, which could
provide an ongoing source of cytokine secretion to fuel the depressed
person’s brain inflammation [118].
Stress has been shown to be linked to intestinal mucosal dysfunc-
tion (e.g. gut bacterial infection) and extreme stressors (e.g. burns injury,
surgery) are reported to induce bacterial translocation [159, 160]. Thus,
the translocation of intestinal bacteria (and associated toxins) could pro-
vide a mechanism by which the aforementioned brain inflammation
occurs [161], and this could be linked to the presence of inflamma-
tory bowel disease or irritable bowel syndrome [162]. However, results
of two animal studies suggest that ‘stress-induced bacterial translocation’
is unlikely toexplain the relationship between gutdysfunction and depres-
sion. Ando and colleagues [163] showed that short-term restraint in mice
induced the translocation of indigenous gram-positive bacteria only in
a small proportion of mice, but translocation of gram-negative bacte-
ria did not occur, although it did induce short-lived increases in plasma
corticosterone and brain amine metabolism. In contrast, bacterial translo-
cation occurred more slowly and it persisted after HPA axis and neuro-
chemical responses had dissipated. However, when mice were infected
with Salmonella typhimurium, spontaneous translocation did occur, and
plasma cortisone,interleukin-6, andbrain catecholamineand indoleamine
metabolism were elevated. Similarly, Dunn and colleagues [164]showed
that restraint stress did not reliably induce bacterial translocation, except
in the presence of gut bacterial infection, whereas normal neurochemi-
cal responses to restraint occurred in germ-free rats. Taken together, the
results suggest that bacterial translocation is linked to activation of the
HPA axis and brain amine metabolism, similar to the effects of restraint
stress, but the latter effects cannot be explained by thepresence of bacterial
translocation.
Finally, in regard to gut–brain axis dysfunction, medically unexplained
GIT symptoms are known to be linked to anxiety and depression. If a
person has one or more GIT symptoms, they are at twice the risk of
158 E. Thorsteinsson and R. Brown
experiencing MDD and three-times more likely to experience panic dis-
order oragoraphobia; and the risk ofpsychopathology increases with more
GIT symptoms, relative to their prevalence in the general population (e.g.
25–40%) [165]. Anxiety is most frequently linked to GIT symptoms,
especially nausea, heartburn, constipation, upper dysmotility, and diar-
rhoea [166, 167]. Similarly, impaired sleep is common in patients with
gastrointestinal problems, as is anxiety and/or depressed mood, and the
latter statesare thoughtto disruptsleep whichleads tofurther gastrointesti-
nal symptoms [168]. Gut dysfunction (e.g. lack of microbial diversity, gut
inflammation, leaky gut) is also thought to be linked to schizophrenia and
bipolar disorder [169–171], whereas the presence of certain pathogenic
gut bacteria and gut symptoms are linked to ASD [172].
In contrast, probiotics may moderate the effects of stress on the gut,
possibly via a reduction in stress-reactivity and reduced HPA axis and
SNS functioning, to lead to an improvement in depression [173]. A sys-
tematic review [174] of 10 RCTs (clinical and non-clinical) suggests that
there is preliminary support for probiotics reducing anxiety and depres-
sion symptoms [174], similar to the results of an RCT study [175]in
which probiotics administered to 40 patients with MDD over 8-weeks
led to reduced depression levels (Hedges’ g = 0.73) [175]. However, the
use of probiotics has not been shown to improve schizophrenia outcomes
[176]. Finally, a poor diet has b een shown to be linked to depressed mood
and it is thought to be causally related to it, whereas a better diet (e.g.
Mediterranean diet) may improve depression levels [177], although few
studies have examined diet in regard to depression [178]. Thus, it appears
that gut health and diet may also contribute to mental health, although
this is a relatively new area of research enquir y.
6.4.3 Integrated Models of Depression Causation
Myriad different socio-psychological and biological factors are posited to
contribute todepressive disorderdevelopment, including stressors,depres-
sion vulnerability (e.g. high-trait anxiety), lack of social support, impaired
sleep, viral infections, chemical imbalance, physical inactivity, cytokine