152 Current Psychiatry Reviews, 2011, 7, 152-169

Stress as a Pathophysiological Factor in Functional Somatic Syndromes

Urs M. Nater*,1, Susanne Fischer1 and Ulrike Ehlert2

1
Clinical Biopsychology, Dept. of Psychology, University of Marburg, Germany; 2Clinical Psychology & Psychother-
apy, Dept. of Psychology, University of Zurich, Switzerland

Abstract: Functional somatic syndromes (FSS) are defined by a constellation of symptoms for which after thorough
medical examination no structural pathology and no proportional tissue abnormalities can be identified. Pathophysiology
of these syndromes has remained elusive and treatment options are limited. Current research efforts acknowledge the im-
portance of stress as a potential risk factor in the manifestation and maintenance of FSS. A substantial body of research
has focused on psychological stress factors as well as alterations of the endocrine stress system (the hypothalamic-
pituitary-adrenal, HPA axis, in particular), the immune system, and the autonomic nervous system (ANS). Dysregulation
of these systems might explain some of the symptoms of FSS. In this review, we describe studies reporting stress-related
findings in three of the most prevalent and well-described FSS, i.e. chronic fatigue syndrome (CFS), irritable bowel syn-
drome (IBS), and fibromyalgia syndrome (FMS). Psychobiological processes which seem to play a role in the translation
of stress into functional symptoms and syndromes are discussed.

Keywords: Functional somatic syndromes, stress, chronic fatigue syndrome, irritable bowel syndrome, fibromyalgia syndrome.

1. FUNCTIONAL SOMATIC SYNDROMES [24], chronic whiplash syndrome [25], chronic Lyme disease
[26], the Gulf War syndrome [27], and temporomandibular
Somatic symptoms that cannot be readily explained by
joint syndrome [28]. As is evident from the individual syn-
modern medicine have become a substantial problem exert-
drome names, some FSS seem to be particularly advocated
ing significant burden on health care systems around the by specific medical specialties [8, 10]; according to this no-
world. Most health care visits are made due to common
tion, neurologists are prone to make a diagnosis of CFS,
symptoms for which no identified pathology is found [1].
rheumatologists of FMS, gastroenterologists of IBS, etc. by
Community surveys established high rates of symptoms such
focusing on prominent symptoms that are typically seen in
as headache [2, 3], fatigue [4, 5], and abdominal pain [3, 6].
the respective specialty.
Other population-based studies showed that more than 80%
of all study participants had at least one bodily symptom This observation led some researchers to propose the
causing distress [7]. Importantly, despite the high prevalence hypothesis that these syndromes were merely random ex-
of somatic symptoms, up to two-thirds of patients attending pressions of the same or similar pattern of symptoms that are
general medical clinics do not receive a biomedical explana- common to all definitions of individual FSS [29]. Studies
tion for their symptoms [8], ultimately leading to a labelling investigating concomitant diagnoses of specific FSS found
of the respective symptoms as “functional” or “medically additional evidence of overlap, e.g. between FMS and CFS
unexplained”. [30-32] or between CFS and IBS [33, 34]. In a study of pa-
tients attending a tertiary care clinic specializing in the man-
Functional somatic syndromes (FSS) are defined by a
agement of CFS, FMS, and temporomandibular joint syn-
constellation of symptoms for which after thorough medical
drome, it was reported that patients were likely to have had
examination no structural pathology and no proportional
other syndromes such as IBS, multiple chemical sensitivity,
tissue abnormalities can be identified [9-11]. Among the
and headache in their lifetime [35].
most prominent and prevalent FSS are chronic fatigue syn-
drome (CFS) [12, 13], irritable bowel syndrome (IBS) [14, However, despite considerable overlap between FSS, a
15], and fibromyalgia syndrome (FMS) [16]. However, re- variety of studies have also indicated that individual FSS
ports on other FSS are manifold: the most common syn- may present with some organ-specific symptoms and there-
drome names are: chronic pelvic pain [17], low back pain fore differ with respect to which symptoms are most promi-
[18], tension headache [19], atypical facial pain [20], nent. Robbins et al. [36], e.g., studied FSS using a latent
non-cardiac chest pain [21], multiple chemical sensitivity variable model, and the results supported the existence of
[22], the sick building syndrome [23], repetitive stress injury IBS, CFS, and FMS as discrete groups of symptoms. Further
studies were able to identify distinct FSS using similar ap-
proaches [37]. It also needs to be considered that none of the
*Address correspondence to this author at the Lichtenberg Professor of
studies mentioned above report complete overlap and 100%
Clinical Biopsychology, Department of Psychology, University of Marburg,
Gutenbergstrasse 18, 35032 Marburg, Germany; comorbidity when it comes to individual FSS diagnoses,
E-mail: [email protected] suggesting that there are patients who are suffering from

1573-4005/11 $58.00+.00 © 2011 Bentham Science Publishers Ltd.

Stress and FSS Current Psychiatry Reviews, 2011, Vol. 7, No. 2 153

only one FSS. However, there might be greater overlap on a cording to this definition, stress in a given situation is under-
symptom level, i.e. it is conceivable that CFS and IBS pa- stood as the result of cognitive appraisal processes resulting
tients, although being diagnosed with only one FSS, might in an emotional, behavioral, and physiological stress re-
still suffer from similar somatic symptoms that are relevant sponse. In addition, perception and response to a stressor are
for both diagnoses. Only very few studies have looked be- influenced by previous experience, chronic ongoing adverse
yond symptom overlap or distinctive symptom patterns and experiences, and personality factors. The physiological stress
examined differences in pathophysiological factors between response comprises a complex physiological system, which
FSS. With viral infections as one controversially debated is located in both the central nervous system (CNS) and the
risk factor in the development of CFS [38], one study com- periphery of the body. The CNS stress response involves
paring CFS and IBS patients found infectious mononucleosis brain areas located in the hypothalamus and the brainstem. In
to be a specific precipitating factor in CFS but not in IBS particular, it involves inhibitory and excitatory limbic-
patients [39]. In FMS, one prominent line of research has sensitive structures. The central control of the hypothalamic-
been dedicated to study augmented pain perception in these pituitary-adrenal (HPA) axis is governed by the hypotha-
patients in combination with altered neurotransmitter balance lamic paraventricular nucleus (PVN). The purpose of these
[40] and these alterations in sensory processing have been systems is to evaluate the relevance of a stimulus for an in-
found even when controlling for negative affect [41]. In ad- dividual. Depending on the outcome, these circuits elicit an
dition to altered visceral perception, dysfunctional gastroin- appropriate hormonal response [50]. In humans, those re-
testinal motility has been subject of research efforts in IBS sponses are dependent on the cognitive appraisal processes
[42], and these mechanisms have been hypothesized to un- involved in the subjective experience of stress [51]. The pe-
derlay simultaneously occurring pulmonary dysfunctions in ripheral components include outflow from the HPA axis, the
IBS patients [43]. However, more research is needed in order efferent sympathetic-adrenomedullary (SAM) system, and
to better understand specific pathophysiological factors for components of the parasympathetic system [52-56], with the
FSS. latter two comprising the autonomic nervous system (ANS).
These systems closely interact with the immune system [57].
Taken together, the jury is still out whether the above
mentioned syndromes are artificial constructs which in fact A substantial body of research on potential alterations of
constitute one single functional somatic syndrome or the physiological stress response in FSS has focused on dys-
whether there is a variety of functional somatic syndromes regulation of the HPA axis. The HPA axis has been of pri-
that are more or less independent of each other. Clearly, fu- mary interest, because HPA axis hormones, such as cortisol,
ture research will shed further light on this question. may contribute to the peripheral and central causes of FSS
symptoms, such as pain and fatigue. For example, glucocor-
2. STRESS AS AN UNDERLYING MECHANISM FOR
ticoid deficiency is associated with symptoms of fatigue,
FUNCTIONAL SOMATIC SYNDROMES?
malaise, somnolence, myalgia, and arthralgia [58]. Cortisol
The attempt to understand FSS has spurred a variety of is pleiotropic and exerts its effects through ubiquitously dis-
research activity during the past few decades. Two major tributed intracellular receptors. It affects glucose production,
approaches have emerged, i.e. search for biomarkers and fat metabolism, inflammatory responses, cardiovascular re-
biological explanations, and development of explanatory sponsiveness, and central nervous system and immune func-
models using psychosocial variables [44]. After a long his- tioning [59, 60]. As is evident from numerous studies, the
tory of dichotomy in research paradigms, recent research has above mentioned symptoms also reflect alteration of the im-
started focusing on combining these two approaches. With mune system via inflammatory cytokines, such as interleukin
the advent of the biopsychosocial model in medicine current (IL)-6 or interleukin 1 beta (IL-1b) [61], which are thought
research efforts acknowledge both the influence and con- to reflect disease activity, and are potent stimulators of the
comitants of biological and psychosocial factors in explain- endocrine stress axis [62]. In turn, the interaction between
ing the patients’ somatic symptoms. HPA axis and immune system is mediated by both the sym-
pathetic and the parasympathetic branches of the ANS. In the
Particularly, the importance of stress as a potential risk following sections, we will describe studies reporting stress
factor in the manifestation and maintenance of FSS has been related results in three of the most prevalent FSS, i.e. CFS,
highlighted in recent years, and the psychobiological proc- IBS, FMS. Particularly, findings on psychological stress ex-
esses assumed to play a role in the translation of stress expe- periences, as well as alterations in HPA axis, ANS, and im-
rience into functional symptoms and syndromes have been mune system in these three FSS will be briefly summarized.
examined [45]. Stress is a multi-faceted phenomenon and With this summary, we aim to describe the importance of
may precipitate, exacerbate, and perpetuate physical symp- stress and elucidate the role of stress as a pathophysiological
toms [46, 47]. Conservative estimates suggest that stress factor in both etiology and maintenance of FSS.
accounts for approximately 30% of the overall costs of ill-
ness and accidents, totaling 0.5–3.5% of the gross domestic
2.1. Chronic fatigue Syndrome
product across Western nations [48]. These figures make
stress and its prevention an important enterprise for science 2.1.1. Definition
and society. The most commonly used definition of stress is
Chronic fatigue syndrome (CFS) is defined by: 1) clini-
the transactional definition of stress as 'a particular relation-
cally unexplained, persistent or relapsing fatigue of at least 6
ship between the person and the environment that is ap-
months’ duration that is not the result of ongoing exertion, is
praised by the person as taxing or exceeding his or her re-
not substantially alleviated by rest, and results in substantial
sources and endangering his or her well-being' [49]. Ac-
154 Current Psychiatry Reviews, 2011, Vol. 7, No. 2 Nater et al.

reduction in previous levels of occupational, educational, 2.1.4. Findings on ANS and CFS
social, or personal activities, and 2) concurrent occurrence of
A number of studies have examined the involvement of
at least 4 accompanying symptoms (unusual post-exertional
the autonomic nervous system (ANS) in the pathophysiology
malaise, unrefreshing sleep, significant impairment in mem-
of CFS based on the observation that many CFS symptoms
ory/concentration, headache, muscle pain, joint pain, sore
throat and tender lymph nodes) [13]. are also observed in conditions of known dysautonomia,
including disabling fatigue, dizziness, diminished concentra-
tion, tremulousness, and nausea [101]. Numerous studies
2.1.2. Findings on Psychological Stress and CFS
have found evidence of increased occurrence of orthostatic
Several studies suggest that stress plays an important role intolerance, which includes development of symptoms upon
in CFS [63] (see Table 1). For example, one study showed assuming and maintaining upright posture [102-107]. How-
that the physical symptoms of CFS were exacerbated by the ever, results are not consistent, with some studies finding no
stress inflicted on people by Hurricane Andrew [64], and differences between CFS and control groups regarding or-
CFS patients appear more likely to report histories of stress- thostatic symptoms [108-111]. Another line of research in
ful life events compared to controls [65-70]. Stressful life the study of ANS alterations in CFS has focused on cardio-
events assessed in these studies usually included events such vascular autonomic measures. Many studies have found in-
marriage, problems with a relationship, family illness, mov- creased heart rate measures in CFS both at rest and due to
ing, financial problems, job-related troubles, death of friends challenge [108, 112-117]. This is in accordance with other
or relatives etc. Also, one study found that about 15% of studies showing low vagal tone [112, 118-120] and a general
CFS patients had posttraumatic stress disorder (PTSD), sympathetic overactivity [105, 121, 122]. However, there are
which reflects an aberrant response to extreme stress [71]. also reports on decreased heart rate in response to exercise
[123] or mental stress [124], or no differences between CFS
Recent findings from retrospective and prospective studies
and healthy controls at all [104, 121, 124]. A previous study
indicate that stress experienced prior to manifestation of CFS
[125] has shown increased salivary alpha-amylase (which is
(e.g. early life stress or self-reported stress assessed about 20
thought to reflect sympathetic activation) activity in CFS
years earlier) may predict the risk for developing CFS [72-
patients compared to healthy controls, both at baseline and
74]. However, other studies did not find higher levels of ex- after a psychosocial stress test in the laboratory.
posure to childhood trauma when comparing people suffer-
ing from CFS to healthy controls [75, 76]. Only one study 2.1.5. Findings on Immune SYSTem and CFS
has examined psychological responses to acute stressors in
Other studies have indicated signs of immune disturbance
CFS, but found no noticeable differences between patients
in patients with CFS, especially in the form of elevated
and healthy controls [77].
proinflammatory cytokine levels [126, 127], such as IL-6
and tumor necrosis factor (TNF)-alpha [90, 128, 129]. Con-
2.1.3. Findings on HPA Axis and CFS
sistent with these findings, increased in vitro inflammatory
A wealth of information has accumulated on both basal cytokine release has been reported in stimulated peripheral
and challenge outcomes of endocrine functioning in CFS blood mononuclear cells of CFS patients [130]. Other indi-
[78-80]. In a seminal study by Demitrack and colleagues, ces of cytokine-mediated immune alterations that have been
low levels of cortisol in 24-hour urine of CFS patients were reported in patients with CFS include increased levels of
found in comparison to healthy controls [81]. These findings autoantibodies, decreased natural killer cell activity, high
were among the first to suggest hypoactivity of this axis in levels of type 2 cytokine-producing cells, activated T lym-
CFS. Subsequent studies of basal HPA axis found similar phocytes, CD19+ B cells, neopterin (a marker of activated
results. Some studies reported on lower cortisol levels after cell-mediated immunity) and activated complement [131-
awakening in comparison to healthy controls [82-85], which 134]. In addition, alterations in the gene expression involved
is of particular interest considering the notion that altered in immunity have been detected [135].
awakening cortisol levels are associated with increased stress
levels [86-88]. Furthermore, a generally reduced diurnal 2.1.6. Summary
fluctuation of salivary cortisol in CFS compared to healthy
Although the reported results are somewhat contradict-
controls was observed [89, 90]. However, other studies
ing, the overall picture may be summarized as a high preva-
found no difference in salivary cortisol concentrations be-
lence of subjective stress experiences, accompanied by rela-
tween CFS and healthy controls [91, 92]. Insight from phar-
tive hypoactivity of the HPA axis, and an increased activity
macological challenge studies testing specific levels of HPA
of both the ANS and immune systems in CFS patients. These
axis regulation indicates enhanced feedback sensitivity [92-
alterations might potentially be able to explain at least some
95], increased adrenocortical sensitivity to adrenocortico-
of CFS symptomatology [58]. Interestingly, only very few
tropic hormone (ACTH), and a reduced maximal cortisol
studies so far have examined acute stress reactivity in CFS
response compared to normal subjects [81, 96], with non-
patients. What is more, no study so far has been concomi-
significant findings being reported also [97, 98]. Clearly,
tantly measuring parameters from multiple stress systems.
findings point toward relative hypocortisolism in CFS. Re-
Considering the intricate relationships between biological
cent findings from psychotherapeutic trials have shown that
stress systems, research is needed incorporating a multidi-
hypocortisolism may be reversed after successful implemen-
mensional measurement approach and studying responses to
tation of cognitive-behavioral therapy (CBT) [99], and that it
acute stressors.
may be predictive of a poor response to CBT [100].
Stress and FSS Current Psychiatry Reviews, 2011, Vol. 7, No. 2 155

Table 1. Psychological Stress in CFS

Subjects CFS As- Psychiatric Assess- Medical Assessment Stress Assessment Setting Findings
sessment ment

(Masuda, 10 CFS CDC 1988 Self-Rating Depres- Cornell Medical Index Questions on work Japan Subjects suffering from chronic fatigue
Nozoe, Montgomery sion Scale situation reported more occupational stress than
24 chronic Diagnosis by physical Recruitment of
Matsuyama, true-false controls
fatigue examination and labora- Social Readjustment employees
& Tanaka, tiredness tory screening Rating Scale CFS patients had more life event stresses
14 controls Cross-sectional
1994) scale Self- than fatigued subjects, which in turn had
study design
developed
more life events stresses than healthy
questionnaire
controls
on fatigue

(Lutgendorf 49 CFS CDC 1988 Symptom Checklist Diagnosis by physical Exposure to hurricane USA Relapse was more probable among
et al., 1995) Chronic 90R examination Andrew Referral from subjects with higher exposure

Fatigue tertiary care Physical symptoms of CFS were exacer-

Immune Cross-sectional bated in this group and impairment was
Dysfunction higher
study design
Symptoms

Questions on
symptoms

Relapse
score

Sickness
Impact
Profile

(MacDonald 47 CFS CDC 1988 Beck Depression Diagnosis by physical History of sexual abuse USA CFS subjects and controls did not differ
et al., 1996) Inventory examination and labora- regarding a history of sexual abuse
47 controls Visual Life events in the year Minnesota Regional
tory screening
analogue Psychiatric interview preceding illness onset Chronic Fatigue They did not differ regarding life stress in
scale on Syndrome Research the year before the onset of CFS
Self-Rating Depres-
fatigue Program Registry
sion Scale
Cross-sectional
Symptom Checklist
study design
90R

(Reyes 25 CFS CDC 1988 No details reported Diagnosis by physical Interview on life events USA CFS patients with a gradual illness onset
et al., 1996) examination and labora- were more likely to report histories of
47 controls Metropolitan
tory screening stressful life events compared to subjects
Atlanta CFS Sur-
veillance Registry with a sudden illness onset and controls

Cross-sectional
study design

(Salit, 1997) 134 CFS CDC 1988 No details reported Diagnosis by physical List of events (and Canada Stressful events were very common in the

35 controls Questions on examination and additional self-reported Referral from year preceding the onset of CFS compared

symptoms laboratory screening ones) in the year pre- primary care to controls
ceding illness onset
Cross-sectional
study design

(Theorell, 46 CFS CDC 1994 No details reported Diagnosis at recruitment Social Readjustment Sweden Excess prevalence of negative life events
Blomkvist, 46 controls Visual site Rating Scale (modified) Recruitment at a during the quarter year preceding the
Lindh, & onset of CFS was found
analogue CFS outpatient
Evengard,
scale on clinic
1999) symptoms
Cross-sectional
study design

(Fiedler 35 veterans CDC 1994 Quick Diagnostic Diagnosis by physical Childhood Traumatic USA No differences in traumatic experiences
et al., 2000) with CFS and Interview Schedule examination and labora- Events Scale during childhood were found
Short-form Persian Gulf War
co-morbid Health Structured Clinical tory screening Combat Exposure Scale Registry Measures of self-reported combat stress
psychiatric Survey 36 Interview for DSM- significantly differentiated healthy veter-
Psychiatric Epidemiol- Cross-sectional
disorder
IV II ogy Research Interview study design ans from both groups with CFS
23 veterans – Life Events Scale The fatigued group with comorbid psychi-
with CFS and
atric disorder experienced more life events
no co-morbid
six months after the war
psychiatric
disorder

45 healthy
veterans
156 Current Psychiatry Reviews, 2011, Vol. 7, No. 2 Nater et al.

Table 1. Contd….

Subjects CFS As- Psychiatric Assess- Medical Assessment Stress Assessment Setting Findings
sessment ment

(Gaab 21 CFS CDC 1994 Beck Depression Diagnosis by physical Exposure to a psycho- Germany No differences were found between
et al., 2002) 20 controls CFS inter- Inventory examination and labora- social stressor (Trier Recruitment via a patients and controls in their appraisal of
view Composite Interna- tory screening Social Stress Test) self-help organiza- the Trier Social Stress Test

Multidimen- tional Diagnostic Primary appraisal and tion

sional Interview secondary appraisal Cross-sectional
Fatigue Hamilton Rating scale study design
Inventory Scale for Depression
Oxford Symptom Checklist
criteria 90R
Sickness
Impact
Profile

(Sundbom, 13 CFS CDC 1994 Psychiatric assess- Diagnosis by physical Paykel’s list of events Sweden The group with CFS reported significantly
Henningsson, 19 conver- ment examination and labora- (modified) Referral from more negative life events prior to the
Holm, sion disorders tory screening tertiary care onset of their illness than controls
Soderbergh, patients Cross-sectional
& Evengard,
13 controls study design
2002)

(Hatcher & 64 CFS Health and Present State Exami- Diagnosis by physical Life Events and Diffi- UK Patients with CFS were more likely to
House, 2003) 64 controls Fatigue nation 9 examination and labora- culties Schedule Referral from experience severe events and difficulties
Rating Scale tory screening Interview on dilemmas tertiary care in the 3 months and 1 year prior to onset
Oxford of their illness than controls
Cross-sectional
criteria study design Thirty percent of patients were experienc-
ing dilemmas 3 months prior to illness
onset

(Heim et al., 43 CFS CDC 1994 Davidson PTSD Diagnosis by physical Childhood Trauma USA Exposure to childhood trauma was
2006) 60 controls CDC Symp- Scale examination and labora- Questionnaire Population-based associated with a 3 to 8-fold risk of
tom inven- Diagnostic Interview tory screening study developing CFS
tory Schedule for DSM- Cross-sectional Exposure to childhood trauma was
Multidimen- IV study design associated with CFS severity
sional Self-Rating Depres- Higher levels of PTSD could be found in
Fatigue sion Scale CFS patients compared to controls
Inventory State-Trait Anxiety
Short-form Inventory
Health
Survey 36

(Kato, 447 CFS CDC 1994 Psychiatric asssess- Diagnosis based on self- Single question on daily Sweden Stress levels prior to manifestation of CFS
Sullivan, ment based on self- report and information stress Swedish Twin predicted the risk for developing CFS
Evengard, & report and informa- of national registers and Registry
Pedersen, tion of national medical records
Prospective study
2006) registers and medical
design
records

(Heim et al., 113 CFS CDC 1994 Davidson PTSD Diagnosis by physical Childhood Trauma USA Exposure to childhood trauma was
2009) 124 controls CDC Symp- Scale examination and labora- Questionnaire Population-based associated with a 6-fold risk of developing
tom Inven- Self-Rating Depres- tory screening study CFS
tory sion Scale Cross-sectional Exposure to childhood trauma was
Multidimen- State-Trait Anxiety study design associated with CFS severity
sional Inventory Higher levels of PTSD could be found in
Fatigue Structured Clinical CFS patients compared to controls
Inventory Interview for DSM-
Short-form IV
Health
Survey 36

(Nater et al., 113 CFS CDC 1994 Structured Clinical Diagnosis by physical Comorbidity (PTSD) USA About 15% of CFS patients had current
2009) 264 unwell CDC Symp- Interview for DSM- examination and labora- Population-based PTSD compared to 11% in unwell sub-
subjects tom Inven- IV tory screening study jects
(fatigued or tory Cross-sectional
not fulfilling Multidimen- study design
CFS criteria) sional
Fatigue
Inventory
Short-form
Health
Survey 36
Abbreviations: CFS=chronic fatigue syndrome, CDC=Centers for Disease Control and Prevention, DSM-IV=Diagnostic and Statistical Manual for Mental Disorders – Fourth Edition,
PTSD=post-traumatic stress disorder.
Stress and FSS Current Psychiatry Reviews, 2011, Vol. 7, No. 2 157

2.2. Irritable Bowel Syndrome parasympathetic activity [180]. A recent study reported on
increased chromogranin A (which is thought to reflect sym-
2.2.1. Definition
pathetic activity) levels in IBS patients compared to controls
Irritable bowel syndrome (IBS) is a functional disorder of [181]. These findings are complemented by a study which
the gastrointestinal tract characterized by abdominal pain or showed increased norepinephrine levels in constipation-
discomfort occurring at least 3 days per month during the predominant IBS patients during sleep, while diarrhea-
previous 3 months along with at least two out of three of the predominant IBS patients displayed attenuated norepineph-
following: 1) improved with defecation; 2) onset associated rine levels [165].
with a change in frequency of stool, 3) onset associated with
2.2.5. Findings on Immune System and IBS
a change in form (appearance) of stool (Rome III criteria)
[14, 15]. Alterations in inflammatory processes might reasonably
be associated with IBS. Only very few studies have exam-
2.2.2. Findings on Psychological Stress and IBS
ined the role of cytokines as inflammatory markers, with one
As with CFS, stress is prevalent in IBS (see Table 2). study finding significantly increased baseline IL-6, IL-1b,
Numerous studies show an increased occurrence of negative and TNF-alpha concentrations in IBS, and higher stimulated
life events and/or a decreased occurrence of positive life IL-6 levels [182]. Another study measured IL-6, IL-8, and
events in IBS patients compared to a comparison group [6, IL-8, observing increased IL-6 and IL-8 levels in IBS [166].
136-143], although not all studies show these differences This is a particularly interesting finding in the light of the
[144-146]. With regard to stress experienced at an early above mentioned increased HPA axis activity in the same
point in development, several studies have uniformly shown study, considering the fact that IL-6 is a potent stimulator of
that both sexual and physical abuse during childhood is the endocrine stress axis. Other studies have also shown in-
strongly associated with IBS [4, 147-150]. However, a few creased T-cell [183, 184] and B-cell [185] activation. It is of
studies did not find an association between childhood mal- particular interest in this light that immune dysregulation in
treatment and IBS [151, 152]. Quite in contrast to studies in IBS may be reversible using an anti-inflammatory agent
CFS, however, research has also focused on the impact of [186].
acute stressors in patients with IBS. Altered psychological
2.2.6. Summary
stress reactivity in IBS has been found in various studies
[153-157]. Summarizing, the most evident result from the above
mentioned studies is the high prevalence of stress experi-
2.2.3. Findings on HPA axis and IBS
ences and increased psychological reactivity to stressors in
Only a small number of studies have investigated HPA patients with IBS. HPA axis alterations are less clear-cut,
parameters in IBS, and they yielded inconclusive results. owing most likely to the heterogeneous methodological ap-
One study, e.g. found no significant differences in urinary proaches taken in order to test neuroendocrine changes.
cortisol between IBS patients and non-IBS patients and Studies of the ANS point to a sympathetic overactivity, con-
healthy controls with the exception of afternoon samples, firming the important linkage between brain and gut that
when IBS patients showed significantly higher levels [158]. might explain some of the symptoms [187]. Further, in-
Another study found no significant differences between creased inflammatory activation has been reported in IBS.
functional gastrointestinal patients and controls in basal Considering the close relationship between HPA axis, ANS,
plasma cortisol levels [159]. Both attenuated [160, 161] and and immune system it seems to be evident that these altera-
increased [162, 163] salivary cortisol levels were found in tions are at least in part responsible for IBS symptoms.
IBS patients. Importantly, attenuated cortisol levels were
2.3. Fibromyalgia Syndrome
found to be associated with pain, and high cortisol levels
were correlated with depressive symptoms in IBS patients 2.3.1. Definition
[164]. A recent study reported on increased cortisol in con-
According to the American College of Rheumatology
stipation-predominant IBS patients during sleep, while diar-
fibromyalgia syndrome (FMS) is identified in presence of a
rhea-predominant IBS patients displayed attenuated cortisol
levels [165]. Further studies have examined HPA axis history of chronic widespread pain present for at least three
months, defined as bilateral, upper and lower body (i.e.
changes due to stimulation of the system, finding increased
spine), and excessive tenderness upon application of pressure
[163, 166], decreased [161] or no [154-156, 167, 168] alte-
at 11 of 18 specific tender point sites sites [188].
red cortisol responses. These discrepant findings might in
part be explained by the broad variety of stressors that were 2.3.2. Findings on Psychological Stress and FMS
used in these studies.
Psychological stress is a prevalent observation in patients
2.2.4. Findings on ANS and IBS with FMS (see Table 3). Several studies examining child-
hood adversities found increased rates of both physical and
Studies assessing autonomic function in IBS generally
sexual abuse in patients with FMS [189-192]. Conversely,
point to decreased vagal (parasympathetic) outflow or in-
other studies found no higher rates of childhood adversity
creased sympathetic activity [169-176], although other stud-
[193, 194]. In adulthood, higher frequency of daily hassles
ies found no differences between patients with IBS and
and critical life events were found in FMS when compared to
comparison subjects [177-179]. Most of these studies as-
sessed ANS alterations using heart rate variability (HRV), non-FMS groups [195-197]. Of particular interest is the find-
ing
which provides excellent indices for both sympathetic and
158 Current Psychiatry Reviews, 2011, Vol. 7, No. 2 Nater et al.

Table 2. Psychological Stress in IBS

Subjects IBS Psychiatric Assess- Medical Assessment Stress Assessment Setting Findings
Assessment ment

(Mendeloff, 102 IB 227 Recurrent ab- No details reported Diagnosis by physical Life-stress score USA Patients with IBS were more often
Monk, inflamma- dominal pain, examination and labora- Referral from exposed to critical life events com-
Siegel, & tory bowel changes in bowel tory screening secondary care pared to the other groups
Lilienfeld, disease 735 habit, and changes
Cross-sectional
1970) controls in stool form
study design

(Drossman 72 IBS Illness Behavior Minnesota Multipha- Diagnosis by physical Life Experiences USA IBS patients had lower positive stress-
et al., 1988) patients Questionnaire sic Personality examination and labora- Survey Referral from ful life event scores than IBS non-

82 IBS non- McGill Pain Inventory tory screening primary care and patients and controls

patients Questionnaire Profile of Mood student health Patients had lower scores of negative

84 controls Criteria according States services life events compared to the other

to Drossman et al. Cross-sectional groups which was due to lower inten-

study design sity ratings

Questions on
symptoms

(Whitehead 39 IBS Gastrointestinal No details reported Diagnosis by physical Life Event Scales USA The IBS group reported significantly
, Crowell, 108 func- symptom ques- examination and medi- Recruitment at 2 more stress than controls
Robinson, tional bowel tionnaire cal history parenthood clinics The IBS group showed greater reactiv-
Heller, & disease Manning criteria ity to stress than controls with regard
Prospective study
Schuster, to bowel symptoms and stress scores
232 controls Questions on design
1992) were related to health care visits and
healthcare utiliza-
tion disability days

(Schwarz et 121 IBS Criteria according Beck Depression Diagnosis by physical Social Readjustment USA No differences between groups were
al., 1993) 46 inflam- to Schuster and Inventory examination and medi- Rating Scale Recruitment via found in a measure of critical life

matory Whitehead (modi- Minnesota Multipha- cal records advertisement events

bowel fied) sic Personality Life events score did not correlate with
and referral from
disease Symptom diary Inventory primary care gastrointestinal symptoms

45 controls Psychosomatic Cross-sectional

Symptom Checklist study design
State-Trait Anxiety
Inventory

(Walker, 28 IBS No details re- Diagnostic Interview Diagnosis by physical Structured interview on USA Patients with irritable bowel syndrome
Katon, 19 inflam- ported Schedule for DSM- examination sexual trauma Referral from had a significantly higher rate of
Roy-Byrne, matory III primary and secon- severe adult sexual trauma and any
Jemelka, & bowel dary care lifetime sexual victimization
Russo, disease The severely traumatized subjects
Cross-sectional
1993) reported more medically unexplained
study design
symptoms and psychiatric distress

(Talley, 130 IBS Bowel Disease Brief Symptom Diagnosis based on Questionnaire on abuse USA Fourty-three percent of IBS subjects
Fett, 789 controls Questionnaire Inventory (modified) medical records based on a National Mayo-Clinic and reported a history of sexual abuse
Zinsmeister (modified) Population Survey of Rochester Epidemi- Emotional and verbal abuse were also
, & Melton, Manning criteria Canada ology Project more common in these subjects
1994) Questions on emotional records The odds of visiting a physician were
and verbal abuse Cross-sectional higher in IBS subjects reporting abuse
study design

(Levy, 26 IBS Bowel Disease Mental health history Diagnosis by physician Daily Health Diary USA Groups with IBS showed higher levels
Cain, patients Questionnaire of daily stress
Life Events Survey Recruitment via
Jarrett, &
23 IBS non- Daily Health advertisement Daily stress was moderately correlated
Heitkemper patients Diary with daily symptoms in IBS groups
Cross-sectional
, 1997)
26 controls Rome I study design Groups did not differ with regard to
LES score
Stress and FSS Current Psychiatry Reviews, 2011, Vol. 7, No. 2 159

Table 2. Contd….

Subjects IBS Psychiatric Assess- Medical Assessment Stress Assessment Setting Findings
Assessment ment

(Romans, 31 IBS No details re- Dissociative Experi- Diagnosis based on self- Interview on childhood New Zealand The women who were sexually abused
Belaise, ported ences Scale report sexual abuse as a child did not differ from controls
Community-based
Martin, regarding IBS diagnosis
Present State Exami- Questions on physical sample
Morris, &
nation abuse Cross-sectional Women that were physically abused
Raffi, 2002) during childhood did not report a
Questions on abuse study design
diagnosis of IBS more often compared
during adulthood
to controls

Abuse during adulthood was not

associated with IBS

(Dickhaus 15 IBS Bowel Symptom Hospital Anxiety and Diagnosis by physical Exposure to a psycho- USA IBS patients reported higher levels of
et al., 2003) Questionnaire Depression Scale examination logical stressor (di- stress during the stress condition than
14 controls Recruitment via
chotomous listening) controls
Rome II advertisement
Exposure to a visceral Visceral stress was perceived as more
Visual analogue Cross-sectional
stressor (rectal disten- unpleasant during the stress condition
scale on symptoms study design
sion)

Stress Symptom Rating

scales

Visual analogue scale

on intensity and un-
pleasantness

(Pace et al., 85 IBS Rome I Symptom Checklist Diagnosis at recruitment Social Readjustment Italy The severity of recent stressful life
2003) 80 inflam- Short-form Health 90R site Rating Scale Referral from experiences was perceived to be higher

matory Survey 36 tertiary care by IBS than by patients with inflam-

bowel matory bowel diseases

Cross-sectional
disease study design

(Salmon, 64 IBS Manning criteria Dissociative Experi- Diagnosis at recruitment Parental Bonding UK Participants with IBS reported having
Skaife, & ences Scale site Instrument experienced less parental care
61 patients Referral from
Rhodes,
with bowel Hopkins Symptom Questions from the secondary care IBS patients recalled more childhood
2003) symptoms Checklist Medical History Ques- sexual and physical abuse as well as
Cross-sectional
explained by tionnaire more sexual and psychological abuse
Hospital Anxiety and study design
physical during adulthood
Depression Scale
disease

(Locke, 69 IBS Bowel Disease Symptom Checklist Diagnosis by physical Life Experiences USA Both groups with functional disorders
Weaver, 47 nonulcer Questionnaire 90R examination and medi- Survey Mayo-Clinic and reported more negative and total life
Melton, & cal records events compared to controls
dyspepsia Manning criteria List of Threatening Rochester Epidemi-
Talley,
119 controls Events ology Project Threatening life events were independ-
2004)
records ently associated with IBS

Cross-sectional
study design

(Posserud 18 IBS Rome II Hospital Anxiety and Diagnosis at recruitment Exposure to a Sweden Patients reported higher levels of stress
et al., 2004) Depression Scale site psychological stressor during exposure to stressors
22 controls Referral from
(Stroop test and mental
State-Trait Anxiety tertiary care Patients reported lower levels of
arithmetic test)
Inventory Cross-sectional arousal before and after stress
Exposure to a visceral
study design Subjects with IBS experienced higher
stressor (rectal disten-
levels of discomfort and pain during
sion)
distension during the stress condition
Visual analogue scale
on arousal, stress,
discomfort, and pain
160 Current Psychiatry Reviews, 2011, Vol. 7, No. 2 Nater et al.

Table 2. Contd….

Subjects IBS Psychiatric Assess- Medical Assessment Stress Assessment Setting Findings
Assessment ment

(Parry, 16 IBS Rome II Hospital Anxiety and Diagnosis based on self- Life Events Survey UK Participants who developed IBS after
Barton, & Depression Scale report gastroenteritis had an average of 6 life
Community-based
Welfare, sample events compared to 3 in those who
2005) were free of symptoms at follow-up
Prospective study
design

(Ross, 2005) 29 IBS No standardized Dissociative Experi- Diagnosis by physician Dissociative Disorders USA Subjects with IBS reported higher rates
diagnostic criteria ences Scale Interview Schedule of childhood sexual abuse
33 inflam- Recruitment via
matory Symptom Checklist advertisement and
bowel 90 referral from
disease secondary care

43 other Cross-sectional
gastrointes- study design
tinal disor-
ders

(Bach, 12 IBS Complaints Anxiety Disorders Diagnosis by physical Exposure to a psycho- Germany Significant group differences were
Erdmann, Checklist Interview Schedule examination and labora- logical stressor (public found regarding stress reactivity with
12 controls Referral from
Schmidtmann tory screening speaking anticipation) patients reporting higher levels of
Gastrointestinal Beck Depression secondary care
,& Inventory stress
Quality of Life Exposure to a visceral
Cross-sectional
Monnikes, Index
State-Trait Anxiety stressor (rectal disten- study design No change in rectal sensitivity in
2006)
Rome II Inventory sion) response to stress could be found

Multidimensional
bodily symptom and
mood checklist

Visual analogue scale

on intensity and un-
pleasantness

(Elsenbruch 17 IBS Questionnaire on Symptom Checklist Diagnosis by physical Exposure to a Germany IBS patients demonstrated significantly
et al., 2006) 12 controls acute gastrointes- 90R examination psychological stressor greater state anxiety before and after
Referral from
tinal symptoms (public speaking task) stress
secondary care
Rome II State-Trait Anxiety Stress did not increase gastrointestinal
Cross-sectional
Inventory symptoms in patients
study design

(Guilarte 20 IBS Rome II Beck Depression Diagnosis by physical Social Readjustment Spain IBS patients showed higher levels of
et al., 2007) Inventory examination, medical Rating Scale (modified) psychological stress
14 controls Referral from
history, and laboratory tertiary care
screening
Cross-sectional
study design

(Blanchard 200 IBS Gastrointestinal Structured Clinical Diagnosis by physical Daily Stress Inventory USA Stress had an impact on most gastroin-
et al., 2008) symptom diary Interview for DSM- examination, medical testinal symptoms and vice versa
Hassles Scale Referral from
IV history, and laboratory
Rome II tertiary care No differences in the retrospective
Life Experiences
screening
Survey measures on stress were found between
Prospective study
design groups

(Husain 117 IBS Brief Disability No details reported Diagnosis based on self- Paykel’s list of events Pakistan Diagnosis of IBS was positively
et al., 2008) 763 controls Questionnaire report associated with stressful life events
Community-based
Modular Ques- sample
tionnaire
Cross-sectional
Rome II study design

Self-reported IBS
Questionnaire

Table 2. Contd….
Stress and FSS Current Psychiatry Reviews, 2011, Vol. 7, No. 2 161

Subjects IBS Psychiatric Assess- Medical Assessment Stress Assessment Setting Findings
Assessment ment

(Nicholl 86 IBS Illness Attitude General Health Diagnosis based on self- Questions on threaten- UK Being in the highest tertile of the list of
et al., 2008) Scales Questionnaire report ing life events Registers of 3 threatening events predicted diagnosis
of IBS after 6 months
Rome II (modi- Hospital Anxiety and general practices
fied) Depression Scale
Prospective study
Somatic Symp- design
toms Checklist

(Videlock 44 IBS Bowel Symptom Hospital Anxiety and Diagnosis by physical Trauma History Ques- USA No differences between groups were
et al., 2009) 39 controls Questionnaire Depression Scale examination tionnaire Recruitment via found regarding prevalence of abuse

Quality of life Structured Clinical advertisement and

measure Interview for DSM- referral from tertiary
IV care
Rome II
Cross-sectional
study design

(Endo et al., Study 1: Modular Ques- No details reported Diagnosis based on self- Questions on traumatic Japan IBS subjects had more traumatic
2011) 251 IBS tionnaire report experiences and life Students sample experiences and perceived their lives
stress as more stressful compared to controls
362 controls Rome II Cross-sectional
Self-reported IBS study design
Questionnaire
Study 2:
Short-form Health
111 IBS
Survey 36
172 controls
Abbreviations: DSM-IV=Diagnostic and Statistical Manual for Mental Disorders – Fourth Edition, IBS=irritable bowel syndrome.

that both negative life events and increased self-reported 2.3.6. Summary
perceived stress (as measured by the Perceived Stress Scale)
Taken together, FMS seems to be associated with in-
were associated with FMS symptoms [198].
creased frequency of both childhood and adulthood stress
2.3.3. Findings on HPA Axis and FMS experiences. Study results tend to show HPA axis hypofunc-
tion, but results are inconclusive. In comparison, most stud-
Examination of the HPA axis in FMS has borne only a
ies investigating the ANS in FMS patients show increased
few studies as yet, with disparate findings being reported
sympathetic tone, which might explain, at least in part, some
[199, 200]. Some studies found increased basal cortisol [201-
of the FMS typical symptoms, such as pain and fatigue
203], whereas others found no differences in cortisol at all
[219]. Immune findings point to an increased activation of
[204-208]. A recent study found increased negative feedback the immune system, which in concert with alterations in
sensitivity to dexamethasone, similar to CFS (see above)
other stress systems might be associated with typical FMS
[209]. Similar findings were obtained from challenge stud-
symptoms such as widespread pain, fatigue, and cognitive
ies, with most studies showing attenuated cortisol responses
disturbances [233].
[210-214] or no differences [202, 206, 215, 216].
2.3.4. Findings on ANS and FMS 3. CONCLUSION
The ANS has been studied extensively in FMS [200, 217, Research on CFS, IBS, and FMS almost uniformly points
218]. Studies assessing heart rate variability have predomi- to increased prevalence of subjective stress experience. Find-
nantly found sympathetic hyperactivity [219-225], whereas ings of alterations in HPA axis, ANS, and immune function
studies using tests of dysautonomia, such as the tilt table test, in FSS indicate that stress and dysfunction of biological
found decreased sympathetic activity [224, 226]. A recent stress response systems seem to play an important role in
review came to the conclusion that FMS was a “sympatheti- FSS. However, no study so far has examined whether expo-
cally maintained pain syndrome”, thus highlighting the sure to a stressor might interact with other vulnerability fac-
pathophysiological role of ANS alterations [217]. tors. It is conceivable that ongoing or acute stressors might
elicit physiological changes in the predisposed body, ulti-
2.3.5. Findings on Immune System and FMS mately leading to the manifestation of FSS [234]. However,
Immune system alterations seem to be particularly inter- this is a notion that needs to be closely examined in future
esting in the light of the aforementioned HPA axis and ANS studies. As the similar findings regarding stress in CFS, IBS,
abnormalities. Studies examining circulating or stimulated and FMS indicate, it might be suggested that FSS might have
cytokines found both increased [22, 227-230] or decreased a common underlying pathophysiology that would result,
[231] concentrations or no abnormalities [232]. through some as far unexplained factors, in variants of the
162 Current Psychiatry Reviews, 2011, Vol. 7, No. 2 Nater et al.

Table 3. Psychological Stress in FMS

Subjects FMS Psychiatric Assess- Medical Assessment Stress Assessment Setting Findings
Assessment ment

(Ahles, Yunus, 45 FMS Criteria Minnesota Multipha- Diagnosis by physical Social Readjustment USA FMS patients scored higher than the
Riley, Bradley, according to sic Personality examination and labora- Rating Scale rheumatoid arthritis and control group
30 rheuma- Referral from
& Masi, 1984) toid Yunus Inventory tory screening tertiary care on the life events scale

arthritis Cross-sectional
32 controls study design

(Boisset-Pioro, 83 FMS No details No details reported Diagnosis at recruitment Questionnaire on abuse Canada Overall sexual and physical abuse was
Esdaile, & 161 reported site based on a National Referral from greater in FMS patients compared to
Fitzcharles, Population Survey of control patients
rheumatol- secondary care
1995) Canada (modified)
ogy Cross-sectional
patients
study design

(Taylor, Trotter, 40 FMS ACR 1990 No details reported Diagnosis at recruitment Questionnaire on abuse USA Prevalence and type of abuse were not
& Csuka, 1995) site based on a National significantly different between groups
42 controls Question on Referral from
impairment Population Survey of secondary care Sexually abused FMS subjects reported
Canada (modified)
Question on Cross-sectional significantly more symptoms than did

pain levels study design non-sexually abused FMS women

(Walker et al., 36 FMS ACR 1990 Dissociative Experi- Diagnosis at recruitment Child Maltreatment USA FMS patients had higher prevalence
1997) ences Scale site Interview rates of lifetime victimization as well as
33 rheuma- Short-form Referral from
childhood trauma
toid Health Survey Childhood Trauma secondary care
arthritis 36 Questionnaire Trauma severity was correlated with
Cross-sectional
study design symptom count, functional impairment,
and psychiatric distress in FMS sub-
jects

(Anderberg, 40 FMS ACR 1990 No details reported Diagnosis by physician Life Event Inventory Sweden Patients experienced significantly more
Marteinsdottir, 38 controls Referral from negative life events during childhood,
Theorell, & von adolescence, and in the past year
secondary care
Knorring, 2000)
Cross-sectional Sixty-five percent of FMS patients
reported at least one negative life event
study design
before illness onset

Life events were experienced as more

negative compared to controls

(Van 110 CFS ACR 1990 Beck Depression Diagnosis at recruitment Everyday Problem Belgium CFS and FMS patients showed higher
Houdenhove Inventory site Checklist frequencies of daily hassles, especially
67 FMS Visual ana- Referral from
et al., 2002) logue scale on State-Trait Anxiety tertiary care dissatisfaction with oneself, insecurity
26 multiple
and a lack of social recognition
sclerosis pain Inventory Cross-sectional
study design
26 rheuma-
toid
arthritis

(Imbierowicz & 38 FMS ACR 1990 No details reported Diagnosis at recruitment Relationship with Germany Patients with FMS reported the highest
Egle, 2003) site parents on a visual scores of childhood adversities
71 somato- Referral from
form pain analogue scale secondary care
disorder Structured Interview for
Cross-sectional
44 controls Pain Patients study design

(Ciccone, 52 FMS ACR 1990 Beck Depression Diagnosis by physi- Sexual and Physical USA Except for rape, sexual and physi-
Elliott, 53 con- Pain Inten- Inventory cal examination Abuse Questionnaire Community- cal abuse were equally prevalent
Chandler, trols sity Survey PTSD Checklist based sample between groups
Nayak, & Subjects with FMS were more
Questions Structured Clinical Cross-sectional
Raphael, likely to obtain a diagnosis of
on illness Interview for study design
2005) PTSD
behavior DSM-IV
Sickness
Impact
Profile
Stress and FSS Current Psychiatry Reviews, 2011, Vol. 7, No. 2 163

Table 3. Contd….

Subjects FMS Psychiatric As- Medical Assess- Stress Assessment Setting Findings
Assessment sessment ment

(Murray, 201 FMS Fibromyal- No details reported Diagnosis based on Life Experiences USA Negative life events and per-
Murray, & gia Impact self-report Survey Recruitment via ceived stress together accounted
Daniels, 2007) Question- Perceived Stress internet for 30% of variance in symptom
naire Scale severity scores
Cross-sectional
study design

(Pae et al., 112 FMS ACR 1990 Beck Anxiety Diagnosis based on Sexual and Physical USA The rate of childhood physical
2009) Fibromyal- Inventory self-report Abuse Questionnaire Referrals and and/or sexual abuse was 52.7%
gia Impact Beck Depression recruitment via Symptom severity, impairment,
Question- Inventory advertisement and psychiatric distress were not
naire Cross-sectional associated with abuse history
Sheehan study design
Disability
Scale
Short-form
Health
Survey 36
Visual
analogue
scale on
pain
Abbreviations: ACR=American College of Rheumatology, CFS=chronic fatigue syndrome, DSM-IV=Diagnostic and Statistical Manual for Mental Disorders – Fourth Edition,
FMS=fibromyalgia syndrome, PTSD=post-traumatic stress disorder

same biopsychosocial process. Similar to other syndromes, HPA axis, ANS, and immune system function within the
in which stress has been discussed as a potential risk factor, same study. In addition, recent advances in the study of mo-
it is plausible that FSS are different expressions of a spec- lecular mechanisms of the stress response (e.g. gene expres-
trum of disorders with stress-related alterations as a common sion or brain activation patterns) should be implemented in
pathophysiological pathway. these studies in order to better understand the effects of al-
tered HPA axis, ANS, and immune markers on a molecular
One of the major findings among studies in CFS, IBS or
level. This approach might be used to discern differential
FMS is the phenomenon of attenuated levels of cortisol, i.e.
stress reactivity patterns that might help explaining differ-
hypocortisolism. Hypocortisolism is a phenomenon that has
ences and commonalities between individual FSS, and ulti-
been found in numerous conditions that are known to be as-
mately lead to improved diagnostic tools and treatment op-
sociated with stress [235-237]. However, it is evident that tions in these disabling illnesses.
differential consequences of hypocortisolism are observed in
FSS: in CFS hypocortisolism leads to immune activation, REFERENCES
which in turn leads to fatigue, whereas in IBS hypocorti- [1] Kroenke K, Mangelsdorff AD. Common symptoms in ambulatory
solism leads to pain and altered bowel movements, and in care: incidence, evaluation, therapy, and outcome. Am J Med 1989;
FMS hypocortisolism, in concert with immune-brain interac- 86: 262-6.
tion [238] leads to pain. In all syndromes, hyperactivity of [2] Stewart WF, Shechter A, Liberman J. Physician consultation for
the ANS might sustain hypocortisolemic states and immune headache pain and history of panic: results from a population-based
study. Am J Med 1992; 92: 35S-40S.
alterations. [3] Rief W, Hessel A, Braehler E. Somatization symptoms and
hypochondriacal features in the general population. Psychosom
We have summarized findings for three selected FSS, i.e. Med 2001; 63: 595-602.
CFS, IBS, FMS. These FSS are most common and have been [4] Walker EA, Katon WJ, Roy-Byrne PP, Jemelka RP, Russo J.
studied extensively. However, despite virtually decades of Histories of sexual victimization in patients with irritable bowel
research, no conclusive pathophysiological explanation has syndrome or inflammatory bowel disease. Am J Psychiatry 1993;
been found for the occurrence of any of these syndromes. 150: 1502-6.
[5] Skapinakis P, Lewis G, Mavreas V. Unexplained fatigue
While research has shown results describing increased stress syndromes in a multinational primary care sample: specificity of
prevalence and marked alterations in endocrine, autonomic, definition and prevalence and distinctiveness from depression and
and immune systems, findings are discrepant and no final generalized anxiety. Am J Psychiatry 2003; 160: 785-7.
conclusion can be drawn at this point. This might in part be [6] Drossman DA, McKee DC, Sandler RS, Mitchell CM, Cramer EM,
Lowman BC, Burger AL. Psychosocial factors in the irritable
due to the fact that only very few studies have examined bowel syndrome. A multivariate study of patients and nonpatients
more than one FSS in one single study, and that most studies with irritable bowel syndrome. Gastroenterology 1988; 95: 701-8.
focused on measurements of single systems or single pa- [7] Hiller W, Rief W, Brahler E. Somatization in the population: from
rameters. Future research should take a multidimensional mild bodily misperceptions to disabling symptoms. Soc Psychiatry
approach by concomitantly measuring psychological stress, Psychiatr Epidemiol 2006; 41: 704-12.
164 Current Psychiatry Reviews, 2011, Vol. 7, No. 2 Nater et al.

[8] Nimnuan C, Hotopf M, Wessely S. Medically unexplained [33] Piche T, Huet PM, Gelsi E, Barjoan EM, Cherick F, Caroli-Bosc
symptoms: an epidemiological study in seven specialities. J FX, Hebuterne X, Tran A. Fatigue in irritable bowel syndrome:
Psychosom Res 2001; 51: 361-7. characterization and putative role of leptin. Eur J Gastroenterol
[9] Katon W, Sullivan M, Walker E. Medical symptoms without Hepatol 2007; 19: 237-43.
identified pathology: relationship to psychiatric disorders, [34] Whitehead WE, Palsson O, Jones KR. Systematic review of the
childhood and adult trauma, and personality traits. Ann Intern Med comorbidity of irritable bowel syndrome with other disorders: what
2001; 134: 917-25. are the causes and implications? Gastroenterology 2002; 122:
[10] Barsky AJ, Borus JF. Functional somatic syndromes. Ann Intern 1140-56.
Med 1999; 130: 910-21. [35] Aaron LA, Burke MM, Buchwald D. Overlapping conditions
[11] Henningsen P, Zipfel S, Herzog W. Management of functional among patients with chronic fatigue syndrome, fibromyalgia, and
somatic syndromes. Lancet 2007; 369: 946-55. temporomandibular disorder. Arch Intern Med 2000; 160: 221-7.
[12] Reeves WC, Wagner D, Nisenbaum R, Jones JF, Gurbaxani B, [36] Robbins JM, Kirmayer LJ, Hemami S. Latent variable models of
Solomon L, Papanicolaou DA, Unger ER, Vernon SD, Heim C. functional somatic distress. J Nerv Ment Dis 1997; 185: 606-15.
Chronic fatigue syndrome - a clinically empirical approach to its [37] Taylor RT, Jason LA, Schoeny ME. Evaluating latent variable
definition and study. BMC Med 2005; 3: 19. models of functional somatic distress in a community-based
[13] Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff sample. Journal of Mental Health 2001; 10: 335-49
A. The chronic fatigue syndrome: a comprehensive approach to its [38] Wyller VB. The chronic fatigue syndrome--an update. Acta
definition and study. International Chronic Fatigue Syndrome neurologica Scandinavica. Supplementum 2007; 187: 7-14.
Study Group. Ann Intern Med 1994; 121: 953-9. [39] Moss-Morris R, Spence M. To "lump" or to "split" the functional
[14] Drossman DA, Dumitrascu DL. Rome III: New standard for somatic syndromes: can infectious and emotional risk factors
functional gastrointestinal disorders. J Gastrointestin Liver Dis differentiate between the onset of chronic fatigue syndrome and
2006; 15: 237-41. irritable bowel syndrome? Psychosom Med 2006; 68: 463-9.
[15] Drossman DA. The functional gastrointestinal disorders and the [40] Clauw DJ. Fibromyalgia: an overview. The American journal of
Rome III process. Gastroenterology 2006; 130: 1377-90. medicine 2009; 122: S3-S13.
[16] Wolfe F. Fibromyalgia. Rheum Dis Clin North Am 1990; 16: 681- [41] Jensen KB, Petzke F, Carville S, Fransson P, Marcus H, Williams
98. SC, Choy E, Mainguy Y, Gracely R, Ingvar M, Kosek E. Anxiety
[17] Ehlert U, Heim C, Hellhammer DH. Chronic pelvic pain as a and depressive symptoms in fibromyalgia are related to poor
somatoform disorder. Psychother Psychosom 1999; 68: 87-94. perception of health but not to pain sensitivity or cerebral
[18] Abraham I, Killackey-Jones B. Lack of evidence-based research for processing of pain. Arthritis and rheumatism 2010; 62: 3488-95.
idiopathic low back pain: the importance of a specific diagnosis. [42] Ohman L, Simren M. New insights into the pathogenesis and
Arch Intern Med 2002; 162: 1442-4; discussion 7. pathophysiology of irritable bowel syndrome. Digestive and liver
[19] Bigal ME, Lipton RB. Tension-type headache: classification and disease : official journal of the Italian Society of Gastroenterology
diagnosis. Curr Pain Headache Rep 2005; 9: 423-9. and the Italian Association for the Study of the Liver 2007; 39:
[20] Gouda JJ, Brown JA. Atypical facial pain and other pain 201-15.
syndromes. Differential diagnosis and treatment. Neurosurg Clin N [43] Yazar A, Atis S, Konca K, Pata C, Akbay E, Calikoglu M, Hafta A.
Am 1997; 8: 87-100. Respiratory symptoms and pulmonary functional changes in
[21] Fang J, Bjorkman D. A critical approach to noncardiac chest pain: patients with irritable bowel syndrome. The American journal of
pathophysiology, diagnosis, and treatment. Am J Gastroenterol gastroenterology 2001; 96: 1511-6.
2001; 96: 958-68. [44] Sharpe M, Carson A. "Unexplained" somatic symptoms, functional
[22] Bazzichi L, Rossi A, Massimetti G, Giannaccini G, Giuliano T, De syndromes, and somatization: do we need a paradigm shift? Ann
Feo F, Ciapparelli A, Dell'Osso L, Bombardieri S. Cytokine Intern Med 2001; 134: 926-30.
patterns in fibromyalgia and their correlation with clinical [45] Nater UM, Gaab J, Rief W, Ehlert U. Recent trends in behavioral
manifestations. Clin Exp Rheumatol 2007; 25: 225-30. medicine. Curr Opin Psychiatry 2006; 19: 180-3.
[23] Burge PS. Sick building syndrome. Occup Environ Med 2004; 61: [46] McEwen BS. The neurobiology of stress: from serendipity to
185-90. clinical relevance. Brain Res 2000; 886: 172-89.
[24] Szabo RM, King KJ. Repetitive stress injury: diagnosis or self- [47] McEwen BS. Stress, adaptation, and disease. Allostasis and
fulfilling prophecy? J Bone Joint Surg Am 2000; 82: 1314-22. allostatic load. Ann N Y Acad Sci 1998; 840: 33-44.
[25] Eck JC, Hodges SD, Humphreys SC. Whiplash: a review of a [48] Affairs SSfE. The costs of stress in Switzerland. Position Paper
commonly misunderstood injury. Am J Med 2001; 110: 651-6. 2000.
[26] Feder HM, Jr., Johnson BJ, O'Connell S, Shapiro ED, Steere AC, [49] Lazarus RS, Folkman S. Stress, appraisal, and coping. New York:
Wormser GP, Agger WA, Artsob H, Auwaerter P, Dumler JS, Springer Publishing Company, 1984.
Bakken JS, Bockenstedt LK, Green J, Dattwyler RJ, Munoz J, [50] Herman JP, Figueiredo H, Mueller NK, Ulrich-Lai Y, Ostrander
Nadelman RB, Schwartz I, Draper T, McSweegan E, Halperin JJ, MM, Choi DC, Cullinan WE. Central mechanisms of stress
Klempner MS, Krause PJ, Mead P, Morshed M, Porwancher R, integration: hierarchical circuitry controlling hypothalamo-
Radolf JD, Smith RP, Jr., Sood S, Weinstein A, Wong SJ, Zemel L. pituitary-adrenocortical responsiveness. Front Neuroendocrinol
A critical appraisal of "chronic Lyme disease". N Engl J Med 2007; 2003; 24: 151-80.
357: 1422-30. [51] Gaab J, Rohleder N, Nater UM, Ehlert U. Psychological
[27] Wessely S. Ten years on: what do we know about the Gulf War determinants of the cortisol stress response: the role of anticipatory
syndrome? King's College Gulf War Research Unit. Clin Med cognitive appraisal. Psychoneuroendocrinology 2005; 30: 599-610.
2001; 1: 28-37. [52] Stratakis CA, Chrousos GP. Neuroendocrinology and
[28] Biondi M, Picardi A. Temporomandibular joint pain-dysfunction pathophysiology of the stress system. Ann N Y Acad Sci 1995;
syndrome and bruxism: etiopathogenesis and treatment from a 771: 1-18.
psychosomatic integrative viewpoint. Psychother Psychosom 1993; [53] Campeau S, Day HE, Helmreich DL, Kollack-Walker S, Watson
59: 84-98. SJ. Principles of psychoneuroendocrinology. Psychiatr Clin North
[29] Wessely S, Nimnuan C, Sharpe M. Functional somatic syndromes: Am 1998; 21: 259-76.
one or many? Lancet 1999; 354: 936-9. [54] Huether G. The central adaptation syndrome: psychosocial stress as
[30] Yunus MB, Masi AT, Aldag JC. A controlled study of primary a trigger for adaptive modifications of brain structure and brain
fibromyalgia syndrome: clinical features and association with other function. Prog Neurobiol 1996; 48: 569-612.
functional syndromes. J Rheumatol Suppl 1989; 19: 62-71. [55] Pacak K, Palkovits M. Stressor specificity of central
[31] Wysenbeek AJ, Shapira Y, Leibovici L. Primary fibromyalgia and neuroendocrine responses: implications for stress-related disorders.
the chronic fatigue syndrome. Rheumatol Int 1991; 10: 227-9. Endocr Rev 2001; 22: 502-48.
[32] Norregaard J, Bulow PM, Prescott E, Jacobsen S, Danneskiold- [56] Ehlert U, Straub R. Physiological and emotional response to
Samsoe B. A four-year follow-up study in fibromyalgia. psychological stressors in psychiatric and psychosomatic disorders.
Relationship to chronic fatigue syndrome. Scand J Rheumatol Ann N Y Acad Sci 1998; 851: 477-86.
1993; 22: 35-8.
Stress and FSS Current Psychiatry Reviews, 2011, Vol. 7, No. 2 165

[57] Sternberg EM. Neural regulation of innate immunity: a coordinated [78] Cleare AJ. The HPA axis and the genesis of chronic fatigue
nonspecific host response to pathogens. Nat Rev Immunol 2006; 6: syndrome. Trends Endocrinol Metab 2004; 15: 55-9.
318-28. [79] Cleare AJ. The neuroendocrinology of chronic fatigue syndrome.
[58] Clauw DJ, Chrousos GP. Chronic pain and fatigue syndromes: Endocr Rev 2003; 24: 236-52.
overlapping clinical and neuroendocrine features and potential [80] Van Den Eede F, Moorkens G, Van Houdenhove B, Cosyns P,
pathogenic mechanisms. Neuroimmunomodulation 1997; 4: 134- Claes SJ. Hypothalamic-pituitary-adrenal axis function in chronic
53. fatigue syndrome. Neuropsychobiology 2007; 55: 112-20.
[59] Charmandari E, Kino T, Souvatzoglou E, Chrousos GP. Pediatric [81] Demitrack MA, Dale JK, Straus SE, Laue L, Listwak SJ, Kruesi
stress: hormonal mediators and human development. Hormone MJ, Chrousos GP, Gold PW. Evidence for impaired activation of
Research 2003; 59: 161-79. the hypothalamic-pituitary-adrenal axis in patients with chronic
[60] de Kloet ER. Hormones, brain and stress. Endocr Regul 2003; 37: fatigue syndrome. J. Clin. Endocrinol. Metab. 1991; 73: 1224-34.
51-68. [82] Roberts AD, Wessely S, Chalder T, Papadopoulos A, Cleare AJ.
[61] Vollmer-Conna U, Lloyd A, Hickie I, Wakefield D. Chronic Salivary cortisol response to awakening in chronic fatigue
fatigue syndrome: an immunological perspective. Aust N Z J syndrome. Br J Psychiatry 2004; 184: 136-41.
Psychiatry 1998; 32: 523-7. [83] Strickland P, Morriss R, Wearden A, Deakin B. A comparison of
[62] Chrousos GP. The hypothalamic-pituitary-adrenal axis and salivary cortisol in chronic fatigue syndrome, community
immune-mediated inflammation. N Engl J Med 1995; 332: 1351- depression and healthy controls. J Affect Disord 1998; 47: 191-4.
62. [84] Nater UM, Maloney E, Boneva RS, Gurbaxani BM, Lin JM, Jones
[63] Nater UM, Heim C, Reeves WC. The role of stress in chronic JF, Reeves WC, Heim C. Attenuated morning salivary cortisol
fatigue syndrome. International Journal of Medical and Biological concentrations in a population-based study of persons with chronic
Frontiers in press. fatigue syndrome and well controls. J. Clin. Endocrinol. Metab.
[64] Lutgendorf SK, Antoni MH, Ironson G, Fletcher MA, Penedo F, 2008; 93: 703-9.
Baum A, Schneiderman N, Klimas N. Physical symptoms of [85] Jerjes WK, Cleare AJ, Wessely S, Wood PJ, Taylor NF. Diurnal
chronic fatigue syndrome are exacerbated by the stress of patterns of salivary cortisol and cortisone output in chronic fatigue
Hurricane Andrew. Psychosom. Med. 1995; 57: 310-23. syndrome. J Affect Disord 2005; 87: 299-304.
[65] Reyes M, Dobbins JG, Mawle AC, Steele L, Gary HE, Jr., Malani [86] Steptoe A, Cropley M, Griffith J, Kirschbaum C. Job strain and
H, Schmid S, Fukuda K, Stewart J, Nisenbaum R, Reeves WC. anger expression predict early morning elevations in salivary
Risk factors for CFS: a case control study. Journal of Chronic cortisol. Psychosom. Med. 2000; 62: 286-92.
Fatigue Syndrome 1996; 2: 17-33. [87] Schlotz W, Hellhammer J, Schulz P, Stone AA. Perceived work
[66] Hatcher S, House A. Life events, difficulties and dilemmas in the overload and chronic worrying predict weekend-weekday
onset of chronic fatigue syndrome: a case-control study. Psychol differences in the cortisol awakening response. Psychosom. Med.
Med 2003; 33: 1185-92. 2004; 66: 207-14.
[67] Salit IE. Precipitating factors for the chronic fatigue syndrome. J [88] Pruessner JC, Hellhammer DH, Kirschbaum C. Burnout, perceived
Psychiatr Res 1997; 31: 59-65. stress, and cortisol responses to awakening. Psychosom. Med.
[68] Sundbom E, Henningsson M, Holm U, Soderbergh S, Evengard B. 1999; 61: 197-204.
Possible influence of defenses and negative life events on patients [89] Jerjes WK, Cleare AJ, Wessely S, Wood PJ, Taylor NF. Diurnal
with chronic fatigue syndrome: a pilot study. Psychol Rep 2002; patterns of salivary cortisol and cortisone output in chronic fatigue
91: 963-78. syndrome. J Affect Disord 2005.
[69] Theorell T, Blomkvist V, Lindh G, Evengard B. Critical life events, [90] Nater UM, Youngblood LS, Jones JF, Unger ER, Miller AH,
infections, and symptoms during the year preceding chronic fatigue Reeves WC, Heim C. Alterations in diurnal salivary cortisol
syndrome (CFS): an examination of CFS patients and subjects with rhythm in a population-based sample
a nonspecific life crisis. Psychosom. Med. 1999; 61: 304-10. of cases with chronic fatigue syndrome. Psychosom Med 2008; 70: 298–
[70] Masuda A, Nozoe SI, Matsuyama T, Tanaka H. Psychobehavioral 305.
and immunological characteristics of adult people with chronic [91] Young AH, Sharpe M, Clements A, Dowling B, Hawton KE,
fatigue and patients with chronic fatigue syndrome. Psychosom. Cowen PJ. Basal activity of the hypothalamic-pituitary-adrenal axis
Med. 1994; 56: 512-8. in patients with the chronic fatigue syndrome (neurasthenia). Biol
[71] Nater UM, Lin JM, Maloney EM, Jones JF, Tian H, Boneva RS, Psychiatry 1998; 43: 236-7.
Raison CL, Reeves WC, Heim C. Psychiatric comorbidity in [92] Gaab J, Huster D, Peisen R, Engert V, Schad T, Schurmeyer TH,
persons with chronic fatigue syndrome identified from the Georgia Ehlert U. Low-dose dexamethasone suppression test in chronic
population. Psychosom. Med. 2009; 71: 557-65. fatigue syndrome and health. Psychosom. Med. 2002; 64: 311-8.
[72] Heim C, Wagner D, Maloney E, Papanicolaou DA, Solomon L, [93] Jerjes WK, Taylor NF, Wood PJ, Cleare AJ. Enhanced feedback
Jones JF, Unger ER, Reeves WC. Early adverse experience and sensitivity to prednisolone in chronic fatigue syndrome.
risk for chronic fatigue syndrome: results from a population-based Psychoneuroendocrinology 2007; 32: 192-8.
study. Arch Gen Psychiatry 2006; 63: 1258-66. [94] Segal TY, Hindmarsh PC, Viner RM. Disturbed adrenal function in
[73] Kato K, Sullivan PF, Evengard B, Pedersen NL. Premorbid adolescents with chronic fatigue syndrome. J Pediatr Endocrinol
predictors of chronic fatigue. Arch Gen Psychiatry 2006; 63: 1267- Metab 2005; 18: 295-301.
72. [95] Papadopoulos A, Ebrecht M, Roberts AD, Poon L, Rohleder N,
[74] Heim C, Nater UM, Maloney E, Boneva R, Jones JF, Reeves WC. Cleare AJ. Glucocorticoid receptor mediated negative feedback in
Childhood trauma and risk for chronic fatigue syndrome: chronic fatigue syndrome using the low dose (0.5 mg)
association with neuroendocrine dysfunction. Arch Gen Psychiatry dexamethasone suppression test. J Affect Disord 2009; 112: 289-
2009; 66: 72-80. 94.
[75] MacDonald KL, Osterholm MT, LeDell KH, White KE, Schenck [96] Scott LV, Medbak S, Dinan TG. The low dose ACTH test in
CH, Chao CC, Persing DH, Johnson RC, Barker JM, Peterson PK. chronic fatigue syndrome and in health. Clin Endocrinol (Oxf)
A case-control study to assess possible triggers and cofactors in 1998; 48: 733-7.
chronic fatigue syndrome. Am J Med 1996; 100: 548-54. [97] Hudson M, Cleare AJ. The 1microg short Synacthen test in chronic
[76] Fiedler N, Lange G, Tiersky L, DeLuca J, Policastro T, Kelly- fatigue syndrome. Clin Endocrinol (Oxf) 1999; 51: 625-30.
McNeil K, McWilliams R, Korn L, Natelson B. Stressors, [98] Gaab J, Huster D, Peisen R, Engert V, Heitz V, Schad T,
personality traits, and coping of Gulf War veterans with chronic Schurmeyer T, Ehlert U. Assessment of cortisol response with low-
fatigue. J Psychosom Res 2000; 48: 525-35. dose and high-dose ACTH in patients with chronic fatigue
[77] Gaab J, Huster D, Peisen R, Engert V, Heitz V, Schad T, syndrome and healthy comparison subjects. Psychosomatics 2003;
Schurmeyer TH, Ehlert U. Hypothalamic-pituitary-adrenal axis 44: 113-9.
reactivity in chronic fatigue syndrome and health under [99] Roberts AD, Papadopoulos AS, Wessely S, Chalder T, Cleare AJ.
psychological, physiological, and pharmacological stimulation. Salivary cortisol output before and after cognitive behavioural
Psychosom. Med. 2002; 64: 951-62. therapy for chronic fatigue syndrome. J Affect Disord 2009; 115:
280-6.
166 Current Psychiatry Reviews, 2011, Vol. 7, No. 2 Nater et al.

[100] Roberts AD, Charler ML, Papadopoulos A, Wessely S, Chalder T, [121] De Becker P, Dendale P, De Meirleir K, Campine I, Vandenborne
Cleare AJ. Does hypocortisolism predict a poor response to K, Hagers Y. Autonomic testing in patients with chronic fatigue
cognitive behavioural therapy in chronic fatigue syndrome? syndrome. Am J Med 1998; 105: 22S-6S.
Psychol Med 2009: 1-8. [122] Pagani M, Lucini D, Mela GS, Langewitz W, Malliani A.
[101] Komaroff AL, Buchwald D. Symptoms and signs of chronic Sympathetic overactivity in subjects complaining of unexplained
fatigue syndrome. Rev Infect Dis 1991; 13 Suppl 1: S8-11. fatigue. Clin Sci (Lond) 1994; 87: 655-61.
[102] Tanaka H, Matsushima R, Tamai H, Kajimoto Y. Impaired postural [123] Montague TJ, Marrie TJ, Klassen GA, Bewick DJ, Horacek BM.
cerebral hemodynamics in young patients with chronic fatigue with Cardiac function at rest and with exercise in the chronic fatigue
and without orthostatic intolerance. J Pediatr 2002; 140: 412-7. syndrome. Chest 1989; 95: 779-84.
[103] De Lorenzo F, Hargreaves J, Kakkar VV. Possible relationship [124] Soetekouw PM, Lenders JW, Bleijenberg G, Thien T, van der Meer
between chronic fatigue and postural tachycardia syndromes. Clin JW. Autonomic function in patients with chronic fatigue syndrome.
Auton Res 1996; 6: 263-4. Clin. Auton. Res. 1999; 9: 334-40.
[104] Yataco A, Talo H, Rowe P, Kass DA, Berger RD, Calkins H. [125] Nater UM, Miller AH, Jones JF, Reeves WC. Altered endocrine
Comparison of heart rate variability in patients with chronic fatigue and autonomic activity under basal and stimulated conditions in
syndrome and controls. Clin Auton Res 1997; 7: 293-7. chronic fatigue syndrome. Panminerva Medica in press.
[105] Stewart J, Weldon A, Arlievsky N, Li K, Munoz J. Neurally [126] Patarca R. Cytokines and chronic fatigue syndrome. Ann N Y Acad
mediated hypotension and autonomic dysfunction measured by Sci 2001; 933: 185-200.
heart rate variability during head-up tilt testing in children with [127] Patarca-Montero R, Antoni M, Fletcher MA, Klimas NG. Cytokine
chronic fatigue syndrome. Clin. Auton. Res. 1998; 8: 221-30. and other immunologic markers in chronic fatigue syndrome and
[106] Stewart JM, Gewitz MH, Weldon A, Munoz J. Patterns of their relation to neuropsychological factors. Appl Neuropsychol
orthostatic intolerance: the orthostatic tachycardia syndrome and 2001; 8: 51-64.
adolescent chronic fatigue. J Pediatr 1999; 135: 218-25. [128] Kruesi MJ, Dale J, Straus SE. Psychiatric diagnoses in patients who
[107] Schondorf R, Benoit J, Wein T, Phaneuf D. Orthostatic intolerance have chronic fatigue syndrome. J Clin Psychiatry 1989; 50: 53-6.
in the chronic fatigue syndrome. J Auton Nerv Syst 1999; 75: 192- [129] Borish L, Schmaling K, DiClementi JD, Streib J, Negri J, Jones JF.
201. Chronic fatigue syndrome: identification of distinct subgroups on
[108] Duprez DA, De Buyzere ML, Drieghe B, Vanhaverbeke F, Taes Y, the basis of allergy and psychologic variables. J Allergy Clin
Michielsen W, Clement DL. Long- and short-term blood pressure Immunol 1998; 102: 222-30.
and RR-interval variability and psychosomatic distress in chronic [130] Cannon JG, Angel JB, Abad LW, Vannier E, Mileno MD, Fagioli
fatigue syndrome. Clin Sci (Lond) 1998; 94: 57-63. L, Wolff SM, Komaroff AL. Interleukin-1 beta, interleukin-1
[109] LaManca JJ, Peckerman A, Walker J, Kesil W, Cook S, Taylor A, receptor antagonist, and soluble interleukin-1 receptor type II
Natelson BH. Cardiovascular response during head-up tilt in secretion in chronic fatigue syndrome. J Clin Immunol 1997; 17:
chronic fatigue syndrome. Clin. Physiol. 1999; 19: 111-20. 253-61.
[110] Poole J, Herrell R, Ashton S, Goldberg J, Buchwald D. Results of [131] Whiteside TL, Friberg D. Natural killer cells and natural killer cell
isoproterenol tilt table testing in monozygotic twins discordant for activity in chronic fatigue syndrome. Am J Med 1998; 105: 27S-
chronic fatigue syndrome. Arch Intern Med 2000; 160: 3461-8. 34S.
[111] Jones JF, Nicholson A, Nisenbaum R, Papanicolaou DA, Solomon [132] Mawle AC, Nisenbaum R, Dobbins JG, Gary HE, Jr., Stewart JA,
L, Boneva R, Heim C, Reeves WC. Orthostatic instability in a Reyes M, Steele L, Schmid DS, Reeves WC. Immune responses
population-based study of chronic fatigue syndrome. Am J Med associated with chronic fatigue syndrome: a case-control study. J
2005; 118: 1415. Infect Dis 1997; 175: 136-41.
[112] Freeman R, Komaroff AL. Does the chronic fatigue syndrome [133] von Mikecz A, Konstantinov K, Buchwald DS, Gerace L, Tan EM.
involve the autonomic nervous system? Am J Med 1997; 102: 357- High frequency of autoantibodies to insoluble cellular antigens in
64. patients with chronic fatigue syndrome. Arthritis Rheum 1997; 40:
[113] van de Luit L, van der Meulen J, Cleophas TJ, Zwinderman AH. 295-305.
Amplified amplitudes of circadian rhythms and nighttime [134] Skowera A, Cleare A, Blair D, Bevis L, Wessely SC, Peakman M.
hypotension in patients with chronic fatigue syndrome: High levels of type 2 cytokine-producing cells in chronic fatigue
improvement by inopamil but not by melatonin. Angiology 1998; syndrome. Clin Exp Immunol 2004; 135: 294-302.
49: 903-8. [135] Steinau M, Unger ER, Vernon SD, Jones JF, Rajeevan MS.
[114] Karas B, Grubb BP, Boehm K, Kip K. The postural orthostatic Differential-display PCR of peripheral blood for biomarker
tachycardia syndrome: a potentially treatable cause of chronic discovery in chronic fatigue syndrome. J Mol Med 2004; 82: 750-5.
fatigue, exercise intolerance, and cognitive impairment in [136] Mendeloff AI, Monk M, Siegel CI, Lilienfeld A. Illness experience
adolescents. Pacing Clin Electrophysiol 2000; 23: 344-51. and life stresses in patients with irritable colon and with ulcerative
[115] Streeten DH, Thomas D, Bell DS. The roles of orthostatic colitis. An epidemiologic study of ulcerative colitis and regional
hypotension, orthostatic tachycardia, and subnormal erythrocyte enteritis in Baltimore, 1960-1964. N Engl J Med 1970; 282: 14-7.
volume in the pathogenesis of the chronic fatigue syndrome. Am J [137] Whitehead WE, Crowell MD, Robinson JC, Heller BR, Schuster
Med Sci 2000; 320: 1-8. MM. Effects of stressful life events on bowel symptoms: subjects
[116] Naschitz JE, Rozenbaum M, Rosner I, Sabo E, Priselac RM, with irritable bowel syndrome compared with subjects without
Shaviv N, Ahdoot A, Ahdoot M, Gaitini L, Eldar S, Yeshurun D. bowel dysfunction. Gut 1992; 33: 825-30.
Cardiovascular response to upright tilt in fibromyalgia differs from [138] Pace F, Molteni P, Bollani S, Sarzi-Puttini P, Stockbrugger R,
that in chronic fatigue syndrome. J Rheumatol 2001; 28: 1356-60. Bianchi Porro G, Drossman DA. Inflammatory bowel disease
[117] Winkler AS, Blair D, Marsden JT, Peters TJ, Wessely S, Cleare AJ. versus irritable bowel syndrome: a hospital-based, case-control
Autonomic function and serum erythropoietin levels in chronic study of disease impact on quality of life. Scand J Gastroenterol
fatigue syndrome. J Psychosom Res 2004; 56: 179-83. 2003; 38: 1031-8.
[118] Sisto SA, Tapp W, Drastal S, Bergen M, DeMasi I, Cordero D, [139] Locke GR, 3rd, Weaver AL, Melton LJ, 3rd, Talley NJ.
Natelson B. Vagal tone is reduced during paced breathing in Psychosocial factors are linked to functional gastrointestinal
patients with the chronic fatigue syndrome. Clin Auton Res 1995; disorders: a population based nested case-control study. Am J
5: 139-43. Gastroenterol 2004; 99: 350-7.
[119] Cordero DL, Sisto SA, Tapp WN, LaManca JJ, Pareja JG, Natelson [140] Parry SD, Barton JR, Welfare MR. Factors associated with the
BH. Decreased vagal power during treadmill walking in patients development of post-infectious functional gastrointestinal diseases:
with chronic fatigue syndrome. Clin. Auton. Res. 1996; 6: 329-33. does smoking play a role? Eur J Gastroenterol Hepatol 2005; 17:
[120] Stewart JM. Autonomic nervous system dysfunction in adolescents 1071-5.
with postural orthostatic tachycardia syndrome and chronic fatigue [141] Nicholl BI, Halder SL, Macfarlane GJ, Thompson DG, O'Brien S,
syndrome is characterized by attenuated vagal baroreflex and Musleh M, McBeth J. Psychosocial risk markers for new onset
potentiated sympathetic vasomotion. Pediatr Res 2000; 48: 218-26. irritable bowel syndrome--results of a large prospective population-
based study. Pain 2008; 137: 147-55.
Stress and FSS Current Psychiatry Reviews, 2011, Vol. 7, No. 2 167

[142] Husain N, Chaudhry IB, Jafri F, Niaz SK, Tomenson B, Creed F. A irritable bowel syndrome (IBS). J Endocrinol Invest 2001; 24: 173-
population-based study of irritable bowel syndrome in a non- 7.
Western population. Neurogastroenterol Motil 2008; 20: 1022-9. [163] Chang L, Sundaresh S, Elliott J, Anton PA, Baldi P, Licudine A,
[143] Guilarte M, Santos J, de Torres I, Alonso C, Vicario M, Ramos L, Mayer M, Vuong T, Hirano M, Naliboff BD, Ameen VZ, Mayer
Martinez C, Casellas F, Saperas E, Malagelada JR. Diarrhoea- EA. Dysregulation of the hypothalamic-pituitary-adrenal (HPA)
predominant IBS patients show mast cell activation and hyperplasia axis in irritable bowel syndrome. Neurogastroenterol Motil 2008.
in the jejunum. Gut 2007; 56: 203-9. [164] Ehlert U, Nater UM, Böhmelt AH. Salivary cortisol levels in
[144] Schwarz SP, Blanchard EB, Berreman CF, Scharff L, Taylor AE, subgroups of patients with functional gastrointestinal disorders
Greene BR, Suls JM, Malamood HS. Psychological aspects of correspond to measures of depressive mood and pain perception.
irritable bowel syndrome: comparisons with inflammatory bowel Journal of Psychosomatic Research 2005.
disease and nonpatient controls. Behav Res Ther 1993; 31: 297- [165] Burr RL, Jarrett ME, Cain KC, Jun SE, Heitkemper MM.
304. Catecholamine and cortisol levels during sleep in women with
[145] Levy RL, Cain KC, Jarrett M, Heitkemper MM. The relationship irritable bowel syndrome. Neurogastroenterol Motil 2009.
between daily life stress and gastrointestinal symptoms in women [166] Dinan TG, Quigley EM, Ahmed SM, Scully P, O'Brien S,
with irritable bowel syndrome. J Behav Med 1997; 20: 177-93. O'Mahony L, O'Mahony S, Shanahan F, Keeling PW.
[146] Blanchard EB, Lackner JM, Jaccard J, Rowell D, Carosella AM, Hypothalamic-pituitary-gut axis dysregulation in irritable bowel
Powell C, Sanders K, Krasner S, Kuhn E. The role of stress in syndrome: plasma cytokines as a potential biomarker?
symptom exacerbation among IBS patients. J Psychosom Res Gastroenterology 2006; 130: 304-11.
2008; 64: 119-28. [167] Fukudo S, Nomura T, Hongo M. Impact of corticotropin-releasing
[147] Ross CA. Childhood sexual abuse and psychosomatic symptoms in hormone on gastrointestinal motility and adrenocorticotropic
irritable bowel syndrome. J Child Sex Abus 2005; 14: 27-38. hormone in normal controls and patients with irritable bowel
[148] Salmon P, Skaife K, Rhodes J. Abuse, dissociation, and syndrome. Gut 1998; 42: 845-9.
somatization in irritable bowel syndrome: towards an explanatory [168] Elsenbruch S, Holtmann G, Oezcan D, Lysson A, Janssen O,
model. J Behav Med 2003; 26: 1-18. Goebel MU, Schedlowski M. Are there alterations of
[149] Talley NJ, Fett SL, Zinsmeister AR, Melton LJ, 3rd. neuroendocrine and cellular immune responses to nutrients in
Gastrointestinal tract symptoms and self-reported abuse: a women with irritable bowel syndrome? Am J Gastroenterol 2004;
population-based study. Gastroenterology 1994; 107: 1040-9. 99: 703-10.
[150] Endo Y, Shoji T, Fukudo S, Machida T, Noda S, Hongo M. The [169] Adeyemi EO, Desai KD, Towsey M, Ghista D. Characterization of
features of adolescent irritable bowel syndrome in Japan. J autonomic dysfunction in patients with irritable bowel syndrome by
Gastroenterol Hepatol 2011; 26 Suppl 3: 106-9. means of heart rate variability studies. Am J Gastroenterol 1999;
[151] Romans S, Belaise C, Martin J, Morris E, Raffi A. Childhood abuse 94: 816-23.
and later medical disorders in women. An epidemiological study. [170] Heitkemper M, Burr RL, Jarrett M, Hertig V, Lustyk MK, Bond
Psychother Psychosom 2002; 71: 141-50. EF. Evidence for autonomic nervous system imbalance in women
[152] Videlock EJ, Adeyemo M, Licudine A, Hirano M, Ohning G, with irritable bowel syndrome. Dig Dis Sci 1998; 43: 2093-8.
Mayer M, Mayer EA, Chang L. Childhood trauma is associated [171] Karling P, Nyhlin H, Wiklund U, Sjoberg M, Olofsson BO, Bjerle
with hypothalamic-pituitary-adrenal axis responsiveness in irritable P. Spectral analysis of heart rate variability in patients with irritable
bowel syndrome. Gastroenterology 2009; 137: 1954-62. bowel syndrome. Scand J Gastroenterol 1998; 33: 572-6.
[153] Bach DR, Erdmann G, Schmidtmann M, Monnikes H. Emotional [172] Waring WS, Chui M, Japp A, Nicol EF, Ford MJ. Autonomic
stress reactivity in irritable bowel syndrome. Eur J Gastroenterol cardiovascular responses are impaired in women with irritable
Hepatol 2006; 18: 629-36. bowel syndrome. J Clin Gastroenterol 2004; 38: 658-63.
[154] Dickhaus B, Mayer EA, Firooz N, Stains J, Conde F, Olivas TI, [173] Lee CT, Chuang TY, Lu CL, Chen CY, Chang FY, Lee SD.
Fass R, Chang L, Mayer M, Naliboff BD. Irritable bowel syndrome Abnormal vagal cholinergic function and psychological behaviors
patients show enhanced modulation of visceral perception by in irritable bowel syndrome patients: a hospital-based Oriental
auditory stress. Am J Gastroenterol 2003; 98: 135-43. study. Dig Dis Sci 1998; 43: 1794-9.
[155] Posserud I, Agerforz P, Ekman R, Bjornsson ES, Abrahamsson H, [174] Orr WC, Elsenbruch S, Harnish MJ. Autonomic regulation of
Simren M. Altered visceral perceptual and neuroendocrine cardiac function during sleep in patients with irritable bowel
response in patients with irritable bowel syndrome during mental syndrome. Am J Gastroenterol 2000; 95: 2865-71.
stress. Gut 2004; 53: 1102-8. [175] Tillisch K, Mayer EA, Labus JS, Stains J, Chang L, Naliboff BD.
[156] Elsenbruch S, Lucas A, Holtmann G, Haag S, Gerken G, Sex specific alterations in autonomic function among patients with
Riemenschneider N, Langhorst J, Kavelaars A, Heijnen CJ, irritable bowel syndrome. Gut 2005; 54: 1396-401.
Schedlowski M. Public speaking stress-induced neuroendocrine [176] Cain KC, Jarrett ME, Burr RL, Hertig VL, Heitkemper MM. Heart
responses and circulating immune cell redistribution in irritable rate variability is related to pain severity and predominant bowel
bowel syndrome. Am J Gastroenterol 2006; 101: 2300-7. pattern in women with irritable bowel syndrome.
[157] Suarez KA, Schwizer W, Fried M, Ehlert U. Altered Neurogastroenterol Motil 2007; 19: 110-8.
psychobiological stress responsiveness to psychosocial stress in [177] Lustyk MK, Jarrett ME, Bennett JC, Heitkemper MM. Does a
women with irritable bowel syndrome. submitted. physically active lifestyle improve symptoms in women with
[158] Heitkemper M, Jarrett M, Cain K, Shaver J, Bond E, Woods NF, irritable bowel syndrome? Gastroenterol Nurs 2001; 24: 129-37.
Walker E. Increased urine catecholamines and cortisol in women [178] Robert JJ, Orr WC, Elsenbruch S. Modulation of sleep quality and
with irritable bowel syndrome. Am J Gastroenterol 1996; 91: 906- autonomic functioning by symptoms of depression in women with
13. irritable bowel syndrome. Dig Dis Sci 2004; 49: 1250-8.
[159] Mishra KK, Pandey HP. A study on physiological changes in [179] Elsenbruch S, Lovallo WR, Orr WC. Psychological and
certain psychosomatic disorders with reference to cortisol, blood physiological responses to postprandial mental stress in women
glucose and lipid profile. Indian J Physiol Pharmacol 1996; 40: with the irritable bowel syndrome. Psychosom. Med. 2001; 63:
151-4. 805-13.
[160] Alfven G, de la Torre B, Uvnas-Moberg K. Depressed [180] Berntson GG, Bigger JT, Jr., Eckberg DL, Grossman P, Kaufmann
concentrations of oxytocin and cortisol in children with recurrent PG, Malik M, Nagaraja HN, Porges SW, Saul JP, Stone PH, van
abdominal pain of non-organic origin. Acta Paediatr 1994; 83: der Molen MW. Heart rate variability: origins, methods, and
1076-80. interpretive caveats. Psychophysiology 1997; 34: 623-48.
[161] Bohmelt AH, Nater UM, Franke S, Hellhammer DH, Ehlert U. [181] Hamaguchi T, Fukudo S, Kanazawa M, Tomiie T, Shimizu K,
Basal and stimulated hypothalamic-pituitary-adrenal axis activity in Oyama M, Sakurai K. Changes in salivary physiological stress
patients with functional gastrointestinal disorders and healthy markers induced by muscle stretching in patients with irritable
controls. Psychosom Med 2005; 67: 288-94. bowel syndrome. Biopsychosoc Med 2008; 2: 20.
[162] Patacchioli FR, Angelucci L, Dellerba G, Monnazzi P, Leri O. [182] Liebregts T, Adam B, Bredack C, Roth A, Heinzel S, Lester S,
Actual stress, psychopathology and salivary cortisol levels in the Downie-Doyle S, Smith E, Drew P, Talley NJ, Holtmann G.
168 Current Psychiatry Reviews, 2011, Vol. 7, No. 2 Nater et al.

Immune activation in patients with irritable bowel syndrome. [203] Gur A, Cevik R, Sarac AJ, Colpan L, Em S. Hypothalamic-
Gastroenterology 2007; 132: 913-20. pituitary-gonadal axis and cortisol in young women with primary
[183] Cremon C, Gargano L, Morselli-Labate AM, Santini D, Cogliandro fibromyalgia: the potential roles of depression, fatigue, and sleep
RF, De Giorgio R, Stanghellini V, Corinaldesi R, Barbara G. disturbance in the occurrence of hypocortisolism. Ann Rheum Dis
Mucosal immune activation in irritable bowel syndrome: gender- 2004; 63: 1504-6.
dependence and association with digestive symptoms. Am J [204] Klerman EB, Goldenberg DL, Brown EN, Maliszewski AM, Adler
Gastroenterol 2009; 104: 392-400. GK. Circadian rhythms of women with fibromyalgia. J Clin
[184] Ohman L, Isaksson S, Lindmark AC, Posserud I, Stotzer PO, Strid Endocrinol Metab 2001; 86: 1034-9.
H, Sjovall H, Simren M. T-cell activation in patients with irritable [205] Korszun A, Sackett-Lundeen L, Papadopoulos E, Brucksch C,
bowel syndrome. Am J Gastroenterol 2009; 104: 1205-12. Masterson L, Engelberg NC, Haus E, Demitrack MA, Crofford L.
[185] Ohman L, Lindmark AC, Isaksson S, Posserud I, Strid H, Sjovall Melatonin levels in women with fibromyalgia and chronic fatigue
H, Simren M. B-cell activation in patients with irritable bowel syndrome. J Rheumatol 1999; 26: 2675-80.
syndrome (IBS). Neurogastroenterol Motil 2009; 21: 644-50, e27. [206] Adler GK, Kinsley BT, Hurwitz S, Mossey CJ, Goldenberg DL.
[186] Corinaldesi R, Stanghellini V, Cremon C, Gargano L, Cogliandro Reduced hypothalamic-pituitary and sympathoadrenal responses to
RF, De Giorgio R, Bartesaghi G, Canovi B, Barbara G. Effect of hypoglycemia in women with fibromyalgia syndrome. Am J Med
mesalazine on mucosal immune biomarkers in irritable bowel 1999; 106: 534-43.
syndrome: a randomized controlled proof-of-concept study. [207] Maes M, Lin A, Bonaccorso S, van Hunsel F, Van Gastel A,
Aliment Pharmacol Ther 2009; 30: 245-52. Delmeire L, Biondi M, Bosmans E, Kenis G, Scharpe S. Increased
[187] Mayer EA, Naliboff BD, Chang L. Basic pathophysiologic 24-hour urinary cortisol excretion in patients with post-traumatic
mechanisms in irritable bowel syndrome. Dig Dis 2001; 19: 212-8. stress disorder and patients with major depression, but not in
[188] Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C, patients with fibromyalgia. Acta Psychiatr Scand 1998; 98: 328-35.
Goldenberg DL, Tugwell P, Campbell SM, Abeles M, Clark P, et [208] McLean LM, Gallop R. Implications of childhood sexual abuse for
al. The American College of Rheumatology 1990 Criteria for the adult borderline personality disorder and complex posttraumatic
Classification of Fibromyalgia. Report of the Multicenter Criteria stress disorder. Am J Psychiatry 2003; 160: 369-71.
Committee. Arthritis and rheumatism 1990; 33: 160-72. [209] Wingenfeld K, Wagner D, Schmidt I, Meinlschmidt G,
[189] Boisset-Pioro MH, Esdaile JM, Fitzcharles MA. Sexual and Hellhammer DH, Heim C. The low-dose dexamethasone
physical abuse in women with fibromyalgia syndrome. Arthritis suppression test in fibromyalgia. J Psychosom Res 2007; 62: 85-91.
Rheum 1995; 38: 235-41. [210] Kirnap M, Colak R, Eser C, Ozsoy O, Tutus A, Kelestimur F. A
[190] Walker EA, Keegan D, Gardner G, Sullivan M, Bernstein D, Katon comparison between low-dose (1 microg), standard-dose (250
WJ. Psychosocial factors in fibromyalgia compared with microg) ACTH stimulation tests and insulin tolerance test in the
rheumatoid arthritis: II. Sexual, physical, and emotional abuse and evaluation of hypothalamo-pituitary-adrenal axis in primary
neglect. Psychosom Med 1997; 59: 572-7. fibromyalgia syndrome. Clin Endocrinol (Oxf) 2001; 55: 455-9.
[191] Imbierowicz K, Egle UT. Childhood adversities in patients with [211] Paiva ES, Deodhar A, Jones KD, Bennett R. Impaired growth
fibromyalgia and somatoform pain disorder. Eur J Pain 2003; 7: hormone secretion in fibromyalgia patients: evidence for
113-9. augmented hypothalamic somatostatin tone. Arthritis Rheum 2002;
[192] Pae CU, Masand PS, Marks DM, Krulewicz S, Han C, Peindl K, 46: 1344-50.
Mannelli P, Patkar AA. History of early abuse as a predictor of [212] Gursel Y, Ergin S, Ulus Y, Erdogan MF, Yalcin P, Evcik D.
treatment response in patients with fibromyalgia: a post-hoc Hormonal responses to exercise stress test in patients with
analysis of a 12-week, randomized, double-blind, placebo- fibromyalgia syndrome. Clin Rheumatol 2001; 20: 401-5.
controlled trial of paroxetine controlled release. World J Biol [213] Calis M, Gokce C, Ates F, Ulker S, Izgi HB, Demir H, Kirnap M,
Psychiatry 2009; 10: 435-41. Sofuoglu S, Durak AC, Tutus A, Kelestimur F. Investigation of the
[193] Taylor ML, Trotter DR, Csuka ME. The prevalence of sexual abuse hypothalamo-pituitary-adrenal axis (HPA) by 1 microg ACTH test
in women with fibromyalgia. Arthritis Rheum 1995; 38: 229-34. and metyrapone test in patients with primary fibromyalgia
[194] Ciccone DS, Elliott DK, Chandler HK, Nayak S, Raphael KG. syndrome. J Endocrinol Invest 2004; 27: 42-6.
Sexual and physical abuse in women with fibromyalgia syndrome: [214] Wingenfeld K, Heim C, Schmidt I, Wagner D, Meinlschmidt G,
a test of the trauma hypothesis. Clin J Pain 2005; 21: 378-86. Hellhammer DH. HPA axis reactivity and lymphocyte
[195] Van Houdenhove B, Neerinckx E, Onghena P, Vingerhoets A, glucocorticoid sensitivity in fibromyalgia syndrome and chronic
Lysens R, Vertommen H. Daily hassles reported by chronic fatigue pelvic pain. Psychosom. Med. 2008; 70: 65-72.
syndrome and fibromyalgia patients in tertiary care: a controlled [215] Riedel W, Schlapp U, Leck S, Netter P, Neeck G. Blunted ACTH
quantitative and qualitative study. Psychother Psychosom 2002; 71: and cortisol responses to systemic injection of corticotropin-
207-13. releasing hormone (CRH) in fibromyalgia: role of somatostatin and
[196] Anderberg UM, Marteinsdottir I, Theorell T, von Knorring L. The CRH-binding protein. Ann N Y Acad Sci 2002; 966: 483-90.
impact of life events in female patients with fibromyalgia and in [216] Giske L, Vollestad NK, Mengshoel AM, Jensen J, Knardahl S, Roe
female healthy controls. Eur Psychiatry 2000; 15: 295-301. C. Attenuated adrenergic responses to exercise in women with
[197] Ahles TA, Yunus MB, Riley SD, Bradley JM, Masi AT. fibromyalgia--a controlled study. Eur J Pain 2008; 12: 351-60.
Psychological factors associated with primary fibromyalgia [217] Martinez-Lavin M. Biology and therapy of fibromyalgia. Stress,
syndrome. Arthritis Rheum 1984; 27: 1101-6. the stress response system, and fibromyalgia. Arthritis Res Ther
[198] Murray TL, Murray CE, Daniels MH. Stress and family 2007; 9: 216.
relationship functioning as indicators of the severity of [218] Petzke F, Clauw DJ. Sympathetic nervous system function in
fibromyalgia symptoms: a regression analysis. Stress and Health fibromyalgia. Curr Rheumatol Rep 2000; 2: 116-23.
2007; 23: 3-8. [219] Martinez-Lavin M, Hermosillo AG, Rosas M, Soto ME. Circadian
[199] Tanriverdi F, Karaca Z, Unluhizarci K, Kelestimur F. The studies of autonomic nervous balance in patients with fibromyalgia:
hypothalamo-pituitary-adrenal axis in chronic fatigue syndrome a heart rate variability analysis. Arthritis Rheum 1998; 41: 1966-
and fibromyalgia syndrome. Stress 2007; 10: 13-25. 71.
[200] Adler GK, Geenen R. Hypothalamic-pituitary-adrenal and [220] Cohen H, Neumann L, Alhosshle A, Kotler M, Abu-Shakra M,
autonomic nervous system functioning in fibromyalgia. Rheum Dis Buskila D. Abnormal sympathovagal balance in men with
Clin North Am 2005; 31: 187-202, xi. fibromyalgia. J Rheumatol 2001; 28: 581-9.
[201] Crofford LJ, Pillemer SR, Kalogeras KT, Cash JM, Michelson D, [221] Cohen H, Neumann L, Shore M, Amir M, Cassuto Y, Buskila D.
Kling MA, Sternberg EM, Gold PW, Chrousos GP, Wilder RL. Autonomic dysfunction in patients with fibromyalgia: application
Hypothalamic-pituitary-adrenal axis perturbations in patients with of power spectral analysis of heart rate variability. Semin Arthritis
fibromyalgia. Arthritis Rheum 1994; 37: 1583-92. Rheum 2000; 29: 217-27.
[202] Lentjes EG, Griep EN, Boersma JW, Romijn FP, de Kloet ER. [222] Raj SR, Brouillard D, Simpson CS, Hopman WM, Abdollah H.
Glucocorticoid receptors, fibromyalgia and low back pain. Dysautonomia among patients with fibromyalgia: a noninvasive
Psychoneuroendocrinology 1997; 22: 603-14. assessment. J Rheumatol 2000; 27: 2660-5.
Stress and FSS Current Psychiatry Reviews, 2011, Vol. 7, No. 2 169

[223] Stein PK, Domitrovich PP, Ambrose K, Lyden A, Fine M, Gracely [231] Uceyler N, Valenza R, Stock M, Schedel R, Sprotte G, Sommer C.
RH, Clauw DJ. Sex effects on heart rate variability in fibromyalgia Reduced levels of antiinflammatory cytokines in patients with
and Gulf War illness. Arthritis Rheum 2004; 51: 700-8. chronic widespread pain. Arthritis Rheum 2006; 54: 2656-64.
[224] Furlan R, Colombo S, Perego F, Atzeni F, Diana A, Barbic F, Porta [232] Amel Kashipaz MR, Swinden D, Todd I, Powell RJ. Normal
A, Pace F, Malliani A, Sarzi-Puttini P. Abnormalities of production of inflammatory cytokines in chronic fatigue and
cardiovascular neural control and reduced orthostatic tolerance in fibromyalgia syndromes determined by intracellular cytokine
patients with primary fibromyalgia. J Rheumatol 2005; 32: 1787- staining in short-term cultured blood mononuclear cells. Clin Exp
93. Immunol 2003; 132: 360-5.
[225] Ulas UH, Unlu E, Hamamcioglu K, Odabasi Z, Cakci A, Vural O. [233] Van Houdenhove B, Egle UT. Fibromyalgia: a stress disorder?
Dysautonomia in fibromyalgia syndrome: sympathetic skin Piecing the biopsychosocial puzzle together. Psychother
responses and RR interval analysis. Rheumatol Int 2006; 26: 383-7. Psychosom 2004; 73: 267-75.
[226] Friederich HC, Schellberg D, Mueller K, Bieber C, Zipfel S, Eich [234] Nater UM, Heim C. Childhood trauma and functional somatic
W. [Stress and autonomic dysregulation in patients with syndromes. In: Worthman CM, Plotsky PM, Schechter DS,
fibromyalgia syndrome]. Schmerz 2005; 19: 185-8, 90-2, 94. Cummings C, editors. Formative experiences: The interaction of
[227] Gur A, Karakoc M, Nas K, Remzi, Cevik, Denli A, Sarac J. caregiving, culture, and developmental psychobiology. Cambridge:
Cytokines and depression in cases with fibromyalgia. J Rheumatol University Press, 2010. p.270-7.
2002; 29: 358-61. [235] Heim C, Nater UM. Hypocortisolism and stress. In: Fink G, editor.
[228] Maes M, Libbrecht I, Van Hunsel F, Lin AH, De Clerck L, Stevens Encyclopedia of stress, vol. 2. Oxford: Academic Press, 2007.
W, Kenis G, de Jongh R, Bosmans E, Neels H. The immune- p.400-7.
inflammatory pathophysiology of fibromyalgia: increased serum [236] Heim C, Ehlert U, Hellhammer DH. The potential role of
soluble gp130, the common signal transducer protein of various hypocortisolism in the pathophysiology of stress-related bodily
neurotrophic cytokines. Psychoneuroendocrinology 1999; 24: 371- disorders. Psychoneuroendocrinology 2000; 25: 1-35.
83. [237] Ehlert U, Gaab J, Heinrichs M. Psychoneuroendocrinological
[229] Wallace DJ, Linker-Israeli M, Hallegua D, Silverman S, Silver D, contributions to the etiology of depression, posttraumatic stress
Weisman MH. Cytokines play an aetiopathogenetic role in disorder, and stress-related bodily disorders: the role of the
fibromyalgia: a hypothesis and pilot study. Rheumatology (Oxford) hypothalamus-pituitary-adrenal axis. Biol Psychol 2001; 57: 141-
2001; 40: 743-9. 52.
[230] Macedo JA, Hesse J, Turner JD, Ammerlaan W, Gierens A, [238] Wieseler-Frank J, Maier SF, Watkins LR. Immune-to-brain
Hellhammer DH, Muller CP. Adhesion molecules and cytokine communication dynamically modulates pain: physiological and
expression in fibromyalgia patients: increased L-selectin on pathological consequences. Brain Behav Immun 2005; 19: 104-11.
monocytes and neutrophils. J Neuroimmunol 2007; 188: 159-66.

Received: February 23, 2011 Revised: June 12, 2011 Accepted: June 20, 2011