Medical Hypotheses 85 (2015) 835–841

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Medical Hypotheses
journal homepage: www.elsevier.com/locate/mehy

A biopsychosocial model of fatigue and depression following stroke

Heidi Ormstad ⇑, Grethe Eilertsen
Faculty of Health Sciences, Buskerud and Vestfold University College, Drammen, Norway

a r t i c l e i n f o a b s t r a c t

Article history: Poststroke fatigue (PSF) and poststroke depression (PSD) are both common and difficult sequelae follow-
Received 31 July 2015 ing acute ischemic stroke (AIS). Two main perspectives to explain these sequelae are the biomedical per-
Accepted 2 October 2015 spective and the psychosocial perspective. Research has shown that PSF and PSD are undoubtedly
associated with each other, although each can occur in the absence of the other. However, the nature
of the relationship is unclear. For example, do stroke patients become fatigued because of being
depressed, or do they become depressed because they are fatigued? Alternatively, is there a bidirectional
relationship between these two sequelae, with each influencing the other? We propose a biopsychosocial
model of PSF and PSD that supports the AIS-induced immune response and kynurenine pathway activa-
tion being related to fatigue but not (directly) to depression. We hypothesize that the risk of developing
depression may be reduced if the experience of fatigue is acknowledged, and then addressed accordingly.
Ó 2015 Elsevier Ltd. All rights reserved.

The biopsychosocial model
The conceptualization of a biopsychosocial model adds the
critical psychological and social factors to the more traditional, lin-
early considered biomedical model. Engel reported that ‘‘The
biopsychosocial model is a scientific model constructed to take
into account the missing dimensions of the biomedical model”
and ‘‘To the extent that it succeeds it also serves to define the edu-
cational tasks of medicine” [1]. The biopsychosocial model adds to
the biomedical model the missing psychological and social vari-
ables that are essential to effective diagnosis and treatment, and
thereby provides a more integrated, system-oriented view of
health and disease [2]. The psychosocial variables offer a more
individualistic and less mechanical approach to patient care. The
biological mechanisms underlying health and disease may be very
similar among various people, but the personal experiences, feel-
ings, and intellect, and the presence or absence of social support
add individuality to each patient [2]. Knowledge of such individual
factors could improve the comprehension of a particular patient’s
condition, and thereby facilitate interventions that are more likely
to improve both coping and well-being.
Research into poststroke fatigue (PSF) and poststroke depres-
sion (PSD) has largely had either a biomedical or a psychosocial
perspective. Based on the available research literature as well as
⇑ Corresponding author at: Faculty of Health Sciences, Buskerud and Vestfold
University College, 3045 Drammen, Norway. Mobile: +47 40215862.
E-mail address: heidi.ormstad@hbv.no (H. Ormstad).
our own research, we have aimed to develop a biopsychosocial
model of PSF and PSD that simultaneously takes into account
biomedical, psychological, and social factors.
Poststroke fatigue
Prevalence and treatment
Since no scales have been specifically advanced for measuring
PSF, it is difficult to determine its absolute prevalence. However,
a recent systematic review of nine longitudinal studies assessing
PSF found that its reported frequency ranged from 35% to 92%
[3]. This large variation in the reported frequency possibly reflects
the heterogeneity in both the included populations and the meth-
ods applied in the various studies. The review by Duncan et al. [3]
found that the fatigue symptom appears to persist for up to
36 months after stroke, and that the frequency of fatigue can either
decline or increase over time. One study showed that pathological
fatigue could become chronic so as to be present several years after
stroke onset, with a prevalence of up to 40% at 2 years after stroke
[4]. The research results related to gender differences are conflict-
ing, with some studies showing no differences between men and
women [5–7], while others have found the prevalence to be higher
among women [8–10].
A few studies have examined pharmacological, physical, and
psychological treatments for PSF. Some antidepressants have been
studied, but they were found to be ineffective at reducing

http://dx.doi.org/10.1016/j.mehy.2015.10.001
0306-9877/Ó 2015 Elsevier Ltd. All rights reserved.
836 H. Ormstad, G. Eilertsen / Medical Hypotheses 85 (2015) 835–841

Fig. 1. A biopsychosocial model of fatigue and depression following stroke. This biopsychosocial model indicates that from a biological perspective, the immune response and
KYN pathway activation following AIS can predict fatigue but not (directly) depression. The acknowledgment of fatigue can facilitate the ability to cope with its symptoms,
and thus possibly diminish persistent/enforced fatigue and reduce the risk of developing (clinical) depression over time. Providing stroke survivors with acknowledgment –
which is a key to coping with the symptoms of PSF – will make it easier for them find the correct balance between rest and activity, which in our opinion is essential to
avoiding depression.

symptoms of fatigue [11,12]. A Cochrane study from 2009 evaluat- Neuroimaging

ing different interventions for PSF based on a review of three trials
found that there is currently insufficient evidence to guide the
management of PSF [13]. Since PSF is a multidimensional sequela
that is likely to have several causal factors, a multidisciplinary
approach that targets both the physical and mental features of fati-
gue is required. One recent randomized controlled trial showed
that a 12-week cognitive therapy program relieved PSF, with the
best results being obtained when cognitive therapy was aug-
mented with graded activity training [14]. However, those authors
stated that the study had several limitations and that more
research on effective treatment protocols is required.
In the abovementioned review Kutlubaev and coworkers found
that fatigue was not associated with white-matter lesions, brain
atrophy, or the pathological type of stroke, while their data on
the relationship between lesion location and fatigue were incon-
clusive [15]. The same authors subsequently studied neuroimaging
and clinical predictors of fatigue at 1 month after stroke, and
concluded that clinical observations rather than neuroimaging fea-
tures should be used to predict early PSF [9]. This conclusion was
based on 1-month PSF being associated with clinically diagnosed
posterior strokes, female gender, anxiety, and depression, but not
with poststroke neuroimaging findings.

The biomedical perspective

Kutlubaev and coworkers recently reviewed 17 studies with the
aim of identifying associations between PSF and biological factors
[15]. A meta-analysis could not be performed due to differences
in the method of fatigue assessments, the included populations,
and the study designs. The authors concluded that the biological
mechanisms of PSF are uncertain and that further studies are
required. Neuroimaging and the role of the immune system are
by far the most commonly studied biological aspects related to
PSF. Below we first summarize the neuroimaging findings before
providing further details about immunology and its possible link
to PSF.
The immunology of stroke and its relation to fatigue
There is increasing evidence that inflammation plays an impor-
tant role in acute ischemic stroke (AIS), indicating important inter-
actions between the nervous and immune systems [16,17].
Cerebral ischemia induces a strong inflammatory reaction that
involves several cell types. Numerous studies have focused on
the inflammatory reaction after an ischemic episode, and have
identified the roles played by important inflammatory signaling
molecules, mainly cytokines [18–20]. Whether postischemic
inflammatory responses are deleterious or beneficial to brain
recovery is presently unclear [19,21]. The findings of studies
 H. Ormstad, G. Eilertsen / Medical Hypotheses 85 (2015) 835–841
examining the association of the inflammatory response following
AIS with the infarct volume [22–30] and stroke subtype [30] have
been inconsistent; the roles of the cytokines involved thus remain
uncertain. The finding of significantly higher serum concentrations
of a spectrum of cytokines, both pro- and anti-inflammatory, sup-
ports the existence of an early proinflammatory response after AIS
and an early activation of endogenous immunosuppressive mech-
anisms [31]. It has been shown that high acute serum levels of glu-
cose and IL-1b and low IL1-ra and IL-9 levels may predict fatigue
after AIS, indicating that the development of PSF can be accounted
for by the proinflammatory response associated with AIS [32].
These findings were subsequently supported by a study finding
IL-1b and IL-1b/IL-10 to be significantly associated with fatigue
[33]. IL-1b as a predictor of PSF may be explained by the concept
of cytokine-induced sickness behavior, which is induced by physi-
ological concentrations of proinflammatory cytokines acting in the
brain after infection, with the symptoms being loss of appetite,
sleepiness, withdrawal from normal social activities, fever, aching
joints, and fatigue [34]. The most plausible mechanism by which
proinflammatory cytokines could induce mental fatigue is distur-
bance of glutamate signaling, which is crucial for the gathering
and processing of information within the brain. The proinflamma-
tory cytokines TNF-a, IL-1b, and IL-6 may influence the pathophys-
iology of mental fatigue via their ability to attenuate the astroglial
clearance of extracellular glutamate, the disintegration of the
blood–brain barrier, or their effects on astroglial metabolism and
the neuronal metabolic supply, thereby attenuating glutamate
transmission [35]. Further, proinflammatory cytokines may up-
regulate the indoleamine 2,3-dioxygenase (IDO)-induced kynure-
nine (KYN) pathway, as discussed below.
The IDO-induced KYN pathway in stroke and its relation to fatigue
Several proinflammatory cytokines increases the KYN/trypto-
phan (TRP) ratio in blood by up-regulating the IDO enzyme (which
catalyzes the rate-limiting step in the synthesis of KYN from TRP)
in multiple central and peripheral cell types [36,37]. This is indica-
tive of the close relationship between immune system activity and
the IDO-induced KYN pathway. Since KYN-pathway metabolites
can exhibit excitatory and oxidative neurotoxicity, but also protect
neurons from inflammatory damage and attenuate excitatory neu-
rotoxicity via NMDA receptor antagonism, overactivation of IDO in
the central nervous system might be a double-edged sword [38].
Several studies have indicated that the KYN pathway is activated
immediately after a stroke, which is related to the stroke-induced
inflammatory response, and that this IDO-induced TRP catabolism
is associated with a worse outcome [39–42]. Activity of the KYN
pathway may represent a link between inflammatory activity with
neurotoxicity and neurotransmitter dysfunction after stroke.
It has been demonstrated that TRP depletion impairs learning
and memory [43,44]. However, it is also possible that the worse
outcomes are due to the burden of neurotoxic or neuroactive
metabolites such as quinolinic acid (QA), KYN, and kynurenic acid
(KA). The production of these neuroactive metabolites has previ-
ously been associated with cognitive impairment. For instance,
the KYN/TRP ratio is elevated in Alzheimer’s disease [45], and the
KA/KYN ratio is related to Mini-Mental State Examination scores
[46]. Moreover, KA might have a protective effect on the produc-
tion of KYN and other metabolites [46], and activation of the
KYN pathway poststroke is related to cognitive impairment [47].
As far as we are aware, only one previous study has investigated
the association between PSF and the KYN pathway [48]. The find-
ings of that study indicate that stroke patients with PSF have a
lower bioavailability of TRP for serotonin (5-HT) synthesis in the
brain in the acute stroke phase. However, these patients also
appear to have greater neuroprotective potential, as indicated by
837
a higher level of KA in that phase. There are other findings that sup-
port PSF being influenced by activation of the KYN pathway. Firstly,
increased TRP breakdown has previously been associated with the
severity of fatigue in cancer [49,50]. Kurz et al. [49] suggested that
immune activation and TRP breakdown are associated with the
development of fatigue. Further, the importance of KA in fatigue
has recently been demonstrated in rodents [51]; those authors pro-
posed a KA/QA acid hypothesis for explaining central fatigue.
The psychosocial perspective of PSF: results from qualitative
research
The experiences of stroke survivors with PSF were interpreted
and synthesized by a meta-synthesis drawing on qualitative studies
published in English [52]. A computer-aided search of the PubMed,
CINAHL, PsycINFO, and Embase databases up to 2012 identified 12
studies related to the subjective experiences of PSF. A subsequent
systematic search in these databases performed in June 2015 iden-
tified only one additional new (qualitative) study [53]. A thorough
review of that study revealed that the findings support previous
assumptions about the subjective experiences of PSF.
Three main themes of the experience of PSF are (1) characteris-
tics of PSF, (2) acknowledgment of PSF, and (3) coping. The first
main theme concerns seven characteristics of PSF, of which five
have been interpreted as core characteristics that do not seem to
be influenced by the context. The other two characteristics are
interpreted as having a secondary character, and being more
responsive to the context.
The core characteristics comprise (1) lack of energy to perform
activities, (2) abnormal need for long-lasting sleep, (3) easily tired
by activity and an abnormal need for naps or rest, (4) unpre-
dictable feelings of fatigue without explanation, and (5) increased
stress sensitivity. Participants experiencing PSF reported that they
had less energy than they did prior to the stroke, and that they had
to change the priorities in their lives and give up certain activities
[53–58]. The inability to master everyday life, needing help, and
dependence on family members were prominent [55,59,60].
Feelings of overwhelming tiredness include both mental and
physical tiredness, and many stroke survivors perceive that they
never get sufficient continuous sleep [53,58]. This abnormal tired-
ness and abnormal need for long-lasting sleep have been found in
several studies [58,61–63]. Stroke survivors are easily tired by
activities [53,57,60,62,63] and report an unusual need for rest after
even a short period of working. In many cases napping and resting
become part of their daily routines [57,58,63].
A characteristic of PSF is that it manifests without any specific
reason [54,64], and may affect the relationships of stroke survivors
since they cannot offer plausible explanations for their feelings.
The unpredictability of the experienced fatigue can cause insecu-
rity [55], and this results in frustration among stroke survivors
due to the uncontrollable effect of the fatigue [61]. Irritability,
impaired stress tolerance, and sensitivity to sound and light have
been commonly reported, which illustrates how fatigue is accom-
panied by increased stress sensitivity [55,61,63,65].
The themes considered to be additional distressing characteris-
tics of PFS [52] (a complicated invisibility and undefined condition) as
well as the two main themes of lack of acknowledgment and coping
with PSF are further described in the section entitled ‘‘Psychosocial
perspectives: nonbiomedical studies supporting the model.”
Poststroke depression
Prevalence and treatment
A recent systematic review found a pooled prevalence of
depression at any time point after stroke of 29%, with prevalence
838 H. Ormstad, G. Eilertsen / Medical Hypotheses 85 (2015) 835–841
rates of 28%, 31%, 33%, and 25% at <1 month, 1–6 months,
6–12 months, and >1 year poststroke, respectively [66]. In spite
of considerable heterogeneity between studies, as well as method-
ological limitations in a substantial number of them, a recent
meta-analysis has shown that selective serotonin-reuptake inhibi-
tors (SSRIs) may improve dependence, disability, neurological
impairment, anxiety, and depression after stroke [67]. However,
well-designed clinical trials are still needed in order to determine
whether or not SSRIs should be given routinely to stroke patients.
The biomedical perspective
While there has been widespread research on PSD over the past
few decades, the etiology of this condition remains unclear. The
most frequently cited mechanism has probably been the proin-
flammatory cytokine hypothesis of PSD, in which an increased pro-
duction of proinflammatory cytokines in response to stroke is
considered to cause the widespread activation of IDO and the sub-
sequent depletion of serotonin [68,69].
The immunology of stroke and its relation to depression
Many researchers have suggested that immune dysregulation is
important in the pathophysiology of major depression [34,70–74].
A role for cytokines in depressive disorder appears reasonable;
however, two meta-analyses found that the cytokine levels in
major depressive disorder (MDD) are uncertain [75,76]. A recent
clinical study of the cytokine profile in MDD revealed elevation
of a broader spectrum of cytokines than previously described
[77]. Recovery from depression was found to be associated with
the levels of most of the measured cytokines returning to normal
levels, strongly supporting that a complex network of cytokines
is involved in the pathophysiology of MDD.
Of particular relevance to the present study is whether cytoki-
nes play a role in PSD. Ormstad and coworkers found no associa-
tion between the serum levels of cytokines and PSD [78], thereby
providing no support for a causal immunological etiology for
PSD, as had previously been suggested for PSF in the same study
sample [32], which suggests that the mechanism underlying PSD
has a different origin. The sickness-behavior model of Dantzer
et al. [34] is relevant in this context since it suggests that depres-
sive disorders develop from cytokine-induced sickness behavior
only in vulnerable patients [79]. A review of clinical studies in
which patients were treated continuously with recombinant
cytokines found that depression is a late phenomenon that devel-
ops over a background of early-appearing sickness behavior [80].
Further, incorporating this feature in animal models of
inflammation-associated depression has verified that alterations
of brain serotoninergic neurotransmission do not play a major role
in its pathogenesis. As discussed by Dantzer and coworkers, this is
in contrast to the activation of IDO, which could generate neuro-
toxic metabolites. Since glutamate signaling is crucial for informa-
tion processing within the brain and plays an essential role in the
brain metabolism of glutamate, alterations in glutamate transmis-
sion may play a role in fatigue, as mentioned above. Since QA can
act as an agonist to the glutamatergic receptor, increased IDO
activity may lead to alterations in brain serotonin neurotransmis-
sion and disturbed glutamatergic activity.
The IDO-induced KYN pathway in stroke and its relation to depression
It has been demonstrated that TRP depletion is associated with
major depression [81–83], supposedly as a result of a decrease in
serotonin turnover in the brain. The IDO-induced activation of
the KYN pathway has been studied in MDD for several years, but
there have been inconsistent reports regarding the KYN pathway
activity in MDD. One recent study found that IDO activation was
not associated with depressive symptoms, which does not support
the hypothesis that MDD depressive episodes are associated with
elevated activity in the KYN pathway [84]. This suggests that the
pathophysiology underlying depressive episodes in common
MDD differs from that of interferon-induced depression.
As far as we are aware, only two studies have examined the
relationship between peripheral blood KYNs and PSD symptoms
in stroke patients [33,48]. None of these studies found IDO-
induced activation of the KYN pathway associated with depressive
symptoms. Interestingly, and supporting our ideas, Bensimon and
coworkers identified a proinflammatory bias specifically in
patients with mild depressive symptoms and which was associated
with PSF.
A recent review by Anderson and coworkers concluded that
immune-inflammatory pathways, may at least partially explain
the occurrence of physiosomatic symptoms in depression, somati-
zation, or myalgic encephalomyelitis/chronic fatigue syndrome,
and thus also the clinical overlap of these disorders [85].
The relationship between PSF and PSD
As discussed above, PSF and PSD are common but often over-
looked symptoms that may develop after stroke, both of which
have highly negative impacts on the quality of life, daily activities,
and rehabilitation of patients. Further, PSF and PSD are two gener-
ally related, although independent sequelae of stroke [78,86,87].
However, the nature of the relationship is unclear. For example,
do stroke patient become depressed as a result of being fatigued
or do they become fatigued as a result of being depressed? Alterna-
tively, is there a bidirectional relationship between these two
sequelae, with each influencing the other? In addition, what are
the biological mechanisms underlying these relationships?
Possible biomedical mechanisms to be included in a model
As discussed above, there is increasing evidence that inflamma-
tion plays an important role in AIS, which would indicate the pres-
ence of important interactions between the nervous and immune
systems. The results presented in this paper support that the AIS-
induced immune response and IDO activation that follows AIS can
predict PSF but not PSD. This notion is supported by the findings
indicating that stroke patients with PSF have a lower bioavailability
of TRP for serotonin synthesis in the brain in the acute stroke phase.
However, they also appear to have greater neuroprotective potential
during that phase. In contrast to PSF, no predictors of PSD has been
found [33,48], indicating that separate mechanisms underlie fatigue
and depression. Analogous discrepancies have also been found in
cancer; the observed co-occurrence of fatigue and depression in
cancer patients has led to a proposed common pathophysiological
mechanism involving serotonin regulation, while two studies did
not support this hypothesis [88,89].
It is possible that PSD differs from clinical depression and that
the development of clinical depression may be avoided if the expe-
rience of fatigue is taken into account; that is, if the patient accepts
the presence of fatigue and applies appropriate coping mecha-
nisms [48]. Stroke patients reportedly have relatively low Beck
Depression Inventory (BDI) scores, with most of them being classi-
fied as low intensity according to the BDI-II manual [48]. The idea
that PSD differs from clinical depression is supported by a recent
study finding that the pattern of symptoms was less severe in
PSD than in major depression [90]. This idea, which is supported
by the biomedical studies discussed above, is in our opinion further
supported by the qualitative research literature in the field as dis-
cussed below.
 H. Ormstad, G. Eilertsen / Medical Hypotheses 85 (2015) 835–841
Psychosocial perspectives: nonbiomedical studies supporting the
model
PSF represents a complicated experience of a hidden dysfunc-
tion [55,58]. This has been called ‘‘the invisible handicap,” which
was considered to be less legitimate than other forms of handicap,
and induced a fear of what other people would think when they
were always tired [61]; some participants in that study expressed
a wish to replace the invisible fatigue with a visible physical hand-
icap. Being misinterpreted and not being taken seriously increased
the uncertainty about and struggle with understanding and defin-
ing the fatigue being experienced [55].
A persistent finding in the aforementioned meta-analysis [52]
was the lack of knowledge about fatigue. Although it is difficult
to describe in exact terms, PSF differs from the types of fatigue
experienced prior to a stroke [56,57,61,63]. The participants in
the study of Flinn and Stube [63] reported that health professionals
minimized the importance of PSF, while other stroke survivors
pointed out that fatigue was seldom discussed during hospitaliza-
tion, and thus they did not anticipate that it would form part of
their illness trajectory [58,64]. Similarly, another study found that
stroke survivors were not informed about the signs of fatigue and
possible coping techniques to overcome fatigue [57]. This limita-
tion of knowledge seemed to hinder the acquisition of a real sense
of fatigue as a phenomenon, thereby leaving it as an undefined
condition.
The second main theme in the meta-synthesis [52] was the con-
sistent finding that acknowledgment of PSF from significant others
has a major impact on the ability to cope with PSF. How stroke sur-
vivors, their families, and health workers understand fatigue seems
to influence whether fatigue is acknowledged as a part of the
recovery process. The lack of acknowledgment is a recurrent issue,
and we interpreted this as being an additional burden for many
stroke survivors. According to Flinn and Stube [63], stroke sur-
vivors expend considerable mental energy searching for validation
of their fatigue, while Carlsson et al. [55] stated that their study
participants ‘‘tried to hide their condition from people around
them” (p. 1377) since they felt that other people made negative
evaluations about their fatigue. A lack of initiative or the presence
of fatigability is often interpreted as laziness, and stroke survivors
consider that others have unreasonable expectations because they
are unable to see and understand their condition [55]. While sleep
and rest during the day have been acknowledged as being accept-
able in the early phase, such needs can cause irritation later in the
illness trajectory [63]. It is common for stroke survivors them-
selves and their families to not know how long the fatigue could
be expected to last [63]. Families make their own assumptions
about the duration, and when the fatigue persists beyond this
phase it can result in disagreements within the family. Some stroke
survivors report that others perceive their fatigue as being illegit-
imate and unacceptable [57], while White et al. [58] reported that
mood changes are influenced by a sense of stigma related to
fatigue.
Regarding the third theme [52] of coping with PSF, we hypoth-
esize that lack of acknowledgment is important to how stroke sur-
vivors cope with fatigue. The synthesizing process revealed two
main coping patterns: (1) struggling to cope and (2) taking the fati-
gue into account. Considerable mental energy and concern have
been devoted to searching for validation of fatigue and ‘‘accept-
able” coping techniques [61,63]. A frequent theme has been the
need for rest or sleep. Some stroke survivors resist sleeping as
much as possible, and many of them report that napping during
the day has become part of their daily routine, although they often
feel guilt about it [63]. Several studies have found fatigue to be a
major source of frustration and guilt among stroke survivors
[58,61,63]. When stroke survivors experience that their family
839
undermines the different methods that they use to cope with fati-
gue, the survivors can interpret this as their family not accepting
these coping strategies. These findings suggest the necessity of dis-
cussing rest as an appropriate and necessary coping strategy for
PSF. It was found that the response of fatigue symptoms to rest
was better for stroke patients than for patients with multiple scle-
rosis [91]. Interestingly, Young et al. [53] reported a patient who
slept not only because of the fatigue but also as an escape from
the condition. If this situation is considered to reflect a bodily mes-
sage, as a call for complete rest, sleep should be accepted as a man-
agement strategy for coping with PSF in certain patients. In our
opinion, health workers should be able to answer questions about
good resting in the same way as they answer questions about what
is good training. The recovery of stroke patients would probably
benefit from taking both training and rest into account, since rest-
ing does not necessarily conflict with the training dimension in
recovery. Health workers should therefore help stroke survivors
to find the individualized balance between these two dimensions.
Social support and the acknowledgment of PSF have also been
found to be important in quantitative research [92]. Those authors
found that patients with elevated fatigue severity scores had lower
social support, and they argued that family and friends can play an
important role in helping to identify and reinforce successful fati-
gue management strategies, and in providing ongoing social
support.
Based on the above observations, we hypothesize (1) that PSD
differs from clinical depression and (2) that the risk of developing
clinical depression post stroke can be reduced if the experience of
PSF is acknowledged and taken into account. Based on these
assumptions, we interpret lack of acknowledgment, undermined
coping strategies, and frustration and guilt as contributors to mood
disturbance, and possibly also to clinical depression over time. The
notion that fatigue can lead to depression is supported by Young
et al. [53], who wrote ‘‘As a result, the experience of fatigue and
subsequent role loss was felt to contribute to mood disturbance
rather than, conversely, fatigue being a somatic manifestation of
depression.”
Our idea is further supported by theories such as ‘‘the struggle
for recognition” [93], as well as the research findings for other sim-
ilar conditions. The theory of recognition is beyond the scope of
this paper, so instead we discuss our idea in the light of research
on somatization, or so-called medically unexplained symptoms
(MUS) [85]. Although stroke is a well-diagnosed neurological dis-
ease, PSF is not. As discussed above, stroke survivors experience
PSF as an undefined condition since they have not been adequately
informed about the signs of fatigue and possible coping techniques
[57]. It is also interesting to note that we previously found fatigue
to be more severe among patients with so-called cryptogenic
stroke; that is, with radiologically unconfirmed infarctions [32].
We hypothesize that a diagnosis of ‘‘unconfirmed” stroke reflects
a lack of acknowledgment of patients, which generates a feeling
of uncertainty and speculation, not unlike the situation for MUS.
MUS, or somatization, constitute a symptom cluster character-
ized by ‘‘psychosomatic” symptoms, including fatigue, malaise,
autonomic symptoms, hyperalgesia, intestinal hypermotility, and
peripheral neuropathy [85]. van Eck van der Sluijs and coworkers
examined the prevalence and incidence rates of mood, anxiety,
and substance-use disorders in groups with explained physical
symptoms (PHY) alone, MUS alone, and combined MUS and PHY
compared to a no-symptoms reference group in the general popu-
lation [94]. They found that MUS were associated with the highest
prevalence rates of mood and anxiety disorders, and that combined
MUS and PHY were associated with the highest prevalence of
substance-use disorder and with a higher incidence rate of mood
disorder (odds ratio of 2.9). Those authors considered that their
findings supported further research into possible methods for
840 H. Ormstad, G. Eilertsen / Medical Hypotheses 85 (2015) 835–841
improving recognition and early intervention in subjects with
combined MUS and PHY. In our opinion, a stroke survivor experi-
encing fatigue is a typical example of a person suffering from com-
bined PHY and MUS.
Nettleton [95] reported on a qualitative interview-based study
of 18 neurology outpatients in England who were living with
MUS, and provided very stimulating reflections and discussions
that support our hypothesis. The findings reflect the difficulties
of living with uncertainty, and dealing with legitimacy and a resis-
tance to psychological explanations of their suffering. A thematic
analysis of the interview data identified three related issues:
‘‘morality,” ‘‘chaos,” and ‘‘ambivalence.” Nettleton attempted to
provide a sociology-based explanation of the emergent themes
by drawing on sociological and cultural analyses of risk and the
body, drawing on Bauman’s concept of ambivalence [96] to suggest
that the very processes associated with more precise ‘‘problem-
solving” and ‘‘classification” actually generate even more uncer-
tainty and anxiety. We agree with Nettleton’s opinion that society
does not readily give people permission to be ill in the absence of
an ‘‘accepted” abnormal pathology or physiology, and moreover
that ‘‘other people” and indeed society more generally is uncom-
fortable with or can even be fearful of such anomalies. Nettleton
reminds us that biomedical classifications are social constructs
that have the symbolic effect of stabilizing identity and restoring
coherence [97].
Conclusion
By allowing for a more integrated, system-oriented view of
health and disease, a biopsychosocial model should add to the
biomedical perspective the missing psychological and social vari-
ables that are essential to effective diagnosis and treatment. The
biopsychosocial model presented herein (see Fig. 1) indicates that
from a biological perspective, the immune response and IDO acti-
vation following AIS can predict fatigue but not (directly) depres-
sion. However, stroke survivors may also develop (clinical)
depression over time. The importance of acknowledging PSF
should not be overlooked, since this can facilitate the ability to
cope with the symptoms of fatigue, and thus possibly reduce the
risk of developing (clinical) depression over time. Providing stroke
survivors with acknowledgment – which is a key to coping with
the symptoms of PSF – will make it easier for them find the correct
balance between rest and activity, which in our opinion is essential
to avoiding depression.
Conflicts of interest
The authors declare that there are no conflicts of interest.
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