Literature review about the " Psychological and emotional symptoms in patients suffering from Chronc Fatigue Syndrome "

1. Literature review
Psychiatry department
MF 4th year
Group 30
Tural Abdullayev

2. Introduction
Recurring complaints of psychological or emotional changes and fatigue are very common among the
general population. In particular, studies have shown a strong association between CFS and depressive,
anxiety, somatoform and personality related disorders Patients who present with a combination of these
symptoms may perceive malfunction of sleep as the prime cause of tiredness and other impairments in
daily life. Because of this attribution, dissatisfaction with daytime functioning may be an incentive to seek
medical help for a presumed disturbance of sleep.
Fatigue is a common denominator referring to various aspects of impaired physical, mental, emotional
and neurocognitive functioning. Lack of energy, weakness, attention deficits, memory problems and
irritability are typically associated with the construct of fatigue. It is a frequent manifestation of a variety of
medical, neurological and psychiatric diseases. It may also appear as a side effect of pharmacological
treatment.
The aim of the present review is to:
1. Give an overview of definitions, diagnostic criteria, clinical presentation of CFS;
2. Explore current insights into anxiety
3. Assess the relations between anxiety and CFS.
4. Explore current insights into restorative and nonrestorative aspects of sleep
5. Assess the relations between sleep and CFS
6. The neuropsychiatric and neuropsychological features of chronic fatigue syndrome
7. Explore current insights into depressive disorders
8. Somatoform disorder in CFS
9. Cognitive disorders in CFS
Chronic fatigue syndrome
Chronic fatigue syndrome (CFS) also known as systemic exertion intolerance disease (SEID), has
received considerable attention but remains a complicated and controversial disease. Much of this is due
to the lack of objective findings. Nonetheless, patients with CFS/SEID have real symptoms and are not
malingerers. The prevalence of this syndrome is unclear in part due to difficulties in proving the diagnosis.
In one study of 1000 consecutive patients in a primary care clinic, for example, 8.5 percent had
debilitating fatigue of at least six months’ duration without apparent cause; however, only 15 percent of
these patients satisfied the clinical definition for CFS/SEID.
DEFINITION — There are multiple case definitions for chronic fatigue syndrome (CFS), also known as
systemic exertion intolerance disease (SEID), and these have changed over time. In 1988, the US
Centers for Disease Control and Prevention (CDC) published a "working case definition," with further
revision in 1994. In 2015, the Institute of Medicine (IOM) redefined the diagnostic criteria for CFS/SEID
and suggested the name change to systemic exertion intolerance disease. The IOM diagnostic criteria
focus on the most specific features of the disease. As with previous definitions, symptoms should be
present for at least six months and have moderate, substantial, or severe intensity at least one-half of the
time. Other criteria include: postexertional malaise, sleep problems, cognitive impairment, and orthostatic-
related symptoms.
These clinical case definitions are standard epidemiologic tools that are employed when there is no
diagnostic test for a specific disorder. They are "intentionally restrictive, to maximize the chances that
research studies will detect significant associations if such associations truly exist". Though a clinical case
definition is a well-established instrument, its strict application may not always be appropriate in the
evaluation of a specific patient.

3. 2015 IOM diagnostic criteria for CFS/SEID
Diagnosis requires that the patient have the following three
symptoms
At least one of the two following manifestations is also required
1. A substantial reduction or impairment in the ability to
engage in pre-illness lev els of occupational, educational,
social, or personal activ ities that persists f or more than six
months and is accompanied by f atigue, which is of ten
prof ound, is of new or def inite onset (not lif elong), is not the
result of ongoing excessiv e exertion, and is not substantially
allev iated by rest
1 Cognitiv e impairment
2 Post-exertional malaise 2 Orthostatic intolerance
3 Unref reshing sleep
CLINICAL PRESENTATION — Chronic fatigue syndrome (CFS), also known as systemic exertion
intolerance disease (SEID), is not a homogeneous disorder, but there are certain clinical features which
are common and important to recognize:
1. Relatively sudden onset of fatigue, often associated with a typical infection such as an upper
respiratory infection or true mononucleosis.
2. The patient has overwhelming fatigue and a number of additional symptoms, especially altered
sleep and cognition.
3. Excessive physical activity characteristically exacerbates the symptoms.
4. The pre-CFS/SEID medical history of the patient is not one of multiple somatic problems such as
chronic backache or chronic headache. Affected patients are typically highly functioning
individuals who are "struck down" with this disease. There is often, however, a history of
psychiatric disorders in the past
Numerous other subjective features of CFS/SEID fluctuate with time but do not appear to progress.
Once the inciting illness (if any) is resolved, the physical examination typically is normal.
1. Although patients commonly feel febrile, few ever demonstrate elevated temperatures (greater
than 37.4ºC).
2. Joints ache, but there is no erythema, effusion, or limitation of motion.
3. Although the muscles are easily fatigued, strength is normal, as are biopsies and
electromyograms.
4. Mild cervical and/or axillary lymphadenitis is occasionally noted, and painful lymph nodes
(lymphadenia) are a frequent complaint, but not true lymphadenopathy. Biopsied lymph nodes
show only reactive hyperplasia. The cervical lymph nodes are involved most commonly, but the
axillary lymph nodes may also be affected.
Symptoms in patients with chronic fatigue syndrome (CFS), also known as systemic exertion
intolerance disease (SEID)
Symptom % of patients
Easy f atigability 100
Dif f iculty concentrating 90
Headache 90
Sore throat 85
Tender ly mph nodes 80
Muscle aches 80
Joint aches 75
Fev erishness 75
Dif f iculty sleeping 70

4. Psy chiatric problems 65
Allergies 55
Abdominal cramps 40
Weight loss 20
Rash 10
Rapid pulse 10
Weight gain 5
Chest pain 5
Night sweats 5
Many patients with CFS/SEID are partially or totally disabled by its manifestations. Their outward, healthy
appearance belies the internal sense of ill health. It is common for relatives and colleagues to accuse
them of malingering. A vicious cycle of frustration, anger, and depression commonly ensues.
Anxietyand depression in chronic fatigue
syndrome/myalgic encephalomyelitis (CFS/ME):
Examining the incidence of health anxietyin CFS/ME.
Anxiety Disorders
Etiology
The causes of anxiety disorders are not fully known, but both psychiatric and general medical factors are
involved. Many people develop anxiety disorders without any identifiable antecedent triggers. Anxiety can
be a response to environmental stressors, such as the ending of a significant relationship or exposure to
a life-threatening disaster. Some general medical disorders can directly cause anxiety; they include the
following:
1. Hyperthyroidism
2. Pheochromocytoma
3. Hyperadrenocorticism
4. Heart failure
5. Arrhythmias
6. Asthma
7. COPD
Other causes include use of drugs; effects of corticosteroids, cocaine, amphetamines, and even caffeine
can mimic anxiety disorders. Withdrawal from alcohol, sedatives, and some illicit drugs can also cause
anxiety.
1. Generalized anxiety disorder
Generalized anxiety disorder (GAD) is characterized by excessive anxiety and worry that is present more
days than not for ≥ 6 mo about a number of activities or events. The cause is unknown, although it
commonly coexists in people who have alcohol abuse, major depression, or panic disorder. Diagnosis is
based on history and physical examination. Treatment is psychotherapy, drug therapy, or both.
Diagnosis
Diagnosis is clinical based on criteria in the Diagnostic and Statistical Manual of Mental Disorders, Fifth
Edition (DSM-5). Patients have excessive anxiety and worries about a number of activities or events.
Patients have difficulty controlling the worries, which occur more days than not for ≥ 6 mo. The worries
must also be associated with ≥ 3 of the following:
1. Restlessness or a keyed-up or on-edge feeling
2. Easily fatigability
3. Difficulty concentrating
4. Irritability
5. Muscle tension
6. Disturbed sleep

5. Also, the anxiety and worry cannot be accounted for by substance use or another medical disorder (eg,
hyperthyroidism).
Anxiety and Depression in Chronic Fatigue Syndrome
Study has been made which aimed to determine the incidence of anxiety and depression in a sample of
CFS/ME patients over a 3-month period. The research was a cross-sectional questionnaire-based study,
using a consecutive sample of patients who were assessed in a CFS/ME service.
Data were collected from 45 CFS/ME patients over the sampling period.
− 31 patients (68.9%) scored above the normal range but within the subclinical range of health anxiety
− 19 patients (42.2%) scored within the clinically significant health anxiety range.
Anxiety and depression were common, with prevalence rates of 42.2% and 33.3% respectively, which is
comparable to data found in a recent large-scale trial.
CONCLUSION
Anxiety and depression were common in a sample of chronic fatigue syndrome/myalgic
encephalomyelitis (CFS/ME) patients, with a high proportion meeting criteria for severe health anxiety.
Clinicians should consider screening for health anxiety due to the possible clinical implications for
treatment; mutual maintenance may negatively influence treatment success in a complex condition such
as CFS/ME.
Health anxiety has been found to be common across other chronic medical conditions but has been
shown to be effectively treated with appropriately tailored interventions.
Sleep in the chronic fatigue syndrome
The restorative function of sleep
Because unrefreshing or nonrestorative sleep (NRS) is a hallmark of CFS, insights into the restorative
function of sleep are mandatory.
Sleep is a universal phenomenon in living creatures. While sleep is conceived essential for normal life, its
functions are as yet incompletely understood. Regarding non-rapid eye movement (NREM) sleep, most
theories suggest a role in energy conservation and nervous system recuperation, whereas rapid eye
movement (REM) sleep is thought to be implicated in localized recuperative processes and emotional
regulation.
That sleep is for rest and restoration of body and mind is above all an intuitive notion. The feeling of
recuperation after a good night of sleep is so fundamental that a restorative function is attributed to sleep
from mere subjective experience. Presumably, it is a time of quiescence when the body seems to be able
to generally reverse the wear and tear accumulated during wakefulness. Conversely, when night-time
sleep is curtailed or interrupted, people may experience a lack of replenishment that expectedly would
have occurred if their sleep had been normal.
Shortage of sleep, however, unveils a lack of restoration. All kinds of sleep deprivation, whether acute
complete sleep loss, chronic partial sleep restriction, or sleep fragmentation, result in increased daytime
sleepiness, various aspects of mental fatigue and in demonstrable neurocognitive impairment. Therefore,
the emergence of psychophysiological ‘nonrestoration’ after loss of sleep could be accepted as a proof by
contradiction that sleep has a role to replenish the body and mind for daily functioning. In addition, sleep
curtailment increases sleep propensity31 and subsequent sleep is characterized by a rebound of slow
wave activity, which could tentatively signify an intensified recovery process in the brain.
Nonrestorative sleep
The clinical phenomenon of interest is a subjective experience of unrefreshing sleep. Typically, patients
report awakening unrestored or unrefreshed after a preceding night with sufficient sleep duration. From
the 1970s on, unrefreshing sleep was observed as a frequent complaint in unexplained chronic pain and
fatigue. Borrowing from the theory that sleep serves a restorative purpose, the construct of NRS was

6. introduced as a possible lead to the etiologies of CFS and fibromyalgia syndrome (FMS). NRS was first
mentioned as a symptom of insomnia in the Diagnostic and statistical manual - third edition- revised
(DSM-III-R) of the American Psychiatric Association in 1987, and subsequently embraced by other coding
systems, including the International classification of sleep disorders - second edition (ICSD-2)37 and
research diagnostic criteria (RDC).
In a recent review, it was pointed out that the construct of NRS is highly complex, and suffers from
conceptual inconsistencies. NRS currently lacks a uniform working definition, known causal agents, and
empirically validated assessment and treatment strategies. While different descriptions of NRS have been
used in the past, the following definition is currently proposed: ‘a feeling of being unrefreshed upon
awakening that occurs at least three times a week for at least one month. To conceptualize NRS as a
distinct condition, that is not a symptom of another disorder, two additional criteria are appended, i.e.,
normal sleep duration, and the absence of an organic sleep disorder. This construct remains a theoretical
model and requires further empirical validation. Finally, current evaluation of NRS is based on a
dichotomous approach (i.e., present or not), whereas its severity may vary among patients. No self-report
questionnaires are currently available to assess different degrees of NRS.
As a consequence of variant definitions, methods and target populations, disparate figures on the
prevalence of NRS have been reported in the general population, varying from 1.4% to 35%.
Interestingly, NRS is not invariably associated with subjective daytime dysfunction. In the general
population, only one fifth of individuals with NRS reported fatigue or irritable mood.
As waking up unrefreshed is a frequent manifestation of insomnia or organic sleep disorders, it has long
been debated whether NRS may exist in the absence of known sleep or health problems. To clarify this
matter, Roth and colleagues investigated a cohort of subjects selected on a self-report of awakening
unrestored or unrefreshed at least three times weekly over a period of three months. Impaired daytime
functioning was an obligatory inclusion criterion. Individuals with evidence of any medical, neurological, or
psychiatric condition were excluded. Polysomnography (PSG) was used to rule out organic sleep
disorders. Out of 226 patients, 115 (50.9%) had NRS with normal sleep duration, and had no difficulties
with initiating sleep (DIS) or maintaining sleep (DMS). In these NRS-only patients, PSG showed no
relevant differences regarding sleep architecture or indices of sleep disturbance in comparison with
healthy controls. Whilst this is the first study to show that NRS may exist outside the context of classical
insomnia, organic sleep disorders, and comorbid diseases, no inferences could be drawn on any
underlying pathophysiological mechanism. PSG did not provide a ‘diagnostic marker’ for NRS and the
pathophysiological construct of ‘nonrefreshing sleep’ could not be validated. Furthermore, as the trial was
limited to subjects with significant daytime dysfunction, the correlation between NRS and impaired
daytime function could not be addressed.
The absence of any objective indicators that corroborate the subjective report of ‘feeling unrefreshed
upon awakening’ is a salient weakness of the NRS construct.
Sleep complaints and assessment of sleep in chronic fatigue and CFS
In all available case definition guidelines of CFS, sleep problems are described as a minor criterion. The
terms used vary substantially from (aspecific) sleep disturbance, to unrefreshing or nonrestorative sleep,
to various aspects of sleep quality, sleep duration and elements of insomnia and/or hypersomnia.
Evidently, the lack of uniformity in working definition mirrors the gap in our understanding of the
pathophysiological role of sleep in CFS. Sleep disturbance is reported by the vast majority of individuals
who receive a final diagnosis of CFS. This complaint persists over a time course of several years after
diagnosis.
A complaint of NRS is present in 87–95% of CFS cases identified in community surveys . Subjects with
CFS have a very high co-occurrence of NRS and daytime dysfunction. In a study by Unger et al., the
adjusted odds ratio for NRS in CFS in comparison with non-fatigued controls was estimated to be 28.1
(95% confidence interval = 7.4–107.0). Insomnia patients with NRS have more frequent daytime
sequelae than those without NRS. Sarsour et al. found that NRS vs. no NRS insomnia groups had a
different prevalence of decreased daytime physical function (73% vs. 33%), cognitive function (51% vs.
20%) and emotional function (53% vs. 22%). In the study by Ohayon, all measures of impaired daytime
functioning were at least twice as frequent in NRS subjects compared to those without NRS. These
studies indicate a potential relationship between NRS and the various aspects of daytime fatigue, but the
fundamentals of this connection remain to be further explored. Clearly, CFS and insomnia share features
with respect to NRS and daytime dysfunctioning, and could actually be manifestations of one and the
same underlying disorder. For semantic reasons, different diagnostic labels are being used in current
clinical practice.
PSG is the standard clinical tool to objectively assess sleep complaints and to establish their
neurophysiological correlates. Sleep recording has been performed in subjects with CFS with two
purposes:

7. 1. To elucidate as yet undisclosed mechanisms that would explain the impaired restorative function
of sleep
2. To identify PSD that would exclude the diagnosis of CFS. Obviously, treatable PSD must be
excluded if investigation is aimed at finding the very nature of unrefreshing sleep. On the other
hand, if PSD are believed to account for the CFS symptoms, their treatment should remediate the
complaint of fatigue. If not, PSD are not exclusionary, but unrelated or – at the most – comorbid
conditions. In the subsequent paragraphs, these two aspects will be expounded separately.
Structural and dynamic aspects of sleep in chronic fatigue and CFS
PSG has been performed in CFS patients using different outcomes, including classical sleep architecture,
spectral analysis, sleep stage dynamics and the study of cyclic alternating patterns (CAP) in the sleep
electro-encephalography (EEG).
Regarding sleep architecture, i.e., the structural and temporal features of sleep with respect to
wakefulness and the different sleep stages, data are available from a twin study and from a survey in the
general population.
Investigators from the University of Washington have conducted a monozygotic co-twin control study of
22 pairs discordant for the phenotype of CFS. In this sample, they explored subjective and objective
measures of insomnia, as well as objective measures of sleep. Compared with their healthy co-twins, the
subjects with CFS had more subjective complaints of insomnia and poor sleep. However, no relevant
differences were found between CFS and healthy co-twins in the objective polysomnographic measures.
Only percent NREM stage 3 and percent stage REM sleep were slightly increased in the individuals with
CFS, as compared with their healthy controls (NREM stage 3: 10.7% vs 8.6%; REM: 27.7% vs.
24.4%, P ≤ 0.05). There was no convincing evidence to support a major role for abnormalities in sleep
architecture in CFS. Although the subtle differences in the PSG outcomes did not sufficiently account for
the prominence of sleep complaints in the CFS group, there was an indication that individuals with CFS
may suffer from an element of sleep-state misperception.
PSG has been performed in a subset of cases and non-fatigued controls from a population based survey,
i.e., the Wichita CFS surveillance study. Approximately 18% of persons with CFS and 7% of
asymptomatic controls were diagnosed with severe PSD and were excluded from further analysis. The
final assessment of PSG data comprised 35 individuals with CFS and 40 controls. Despite the fact that
sleep problems were significantly more often reported by people with CFS as compared with healthy
subjects, common characteristics of sleep architecture did essentially not differ between these groups.
Thus, the hypnogram does not seem to discriminate individuals with CFS from healthy controls. Whilst
methodological issues including limited montage and only single night recordings may have an influence
on these results, the methods used are identical for individuals with CFS and healthy controls. Therefore,
the lack of difference between the two groups may not be due to technical limitations in the first place, but
rather to limitations inherent to the very method of assessing sleep architecture. Defining sleep stages by
conventional scoring methods is a crude and arbitrary approach to the physiological process of sleep, and
subtle anomalies may go unnoticed.
Early reports have drawn attention to the appearance of prominent alpha activity in NREM sleep, also
known as ‘alpha–delta sleep’. This EEG abnormality has been conceptualized as an intrusion of
wakefulness into sleep, that could be a neurophysiological correlate of NRS. Alpha–delta sleep has been
observed in heterogeneous groups of patients presenting with chronic daytime dysfunctioning, especially
in FMS. Meanwhile, it has become evident that alpha–delta sleep is not an essential feature of NRS, nor
a consistent marker of FMS or CFS. Moreover, alpha–delta sleep may be observed in subjects with other
disorders or who do not complain about fatigue.
Measurement techniques that analyze sleep EEG on a continuous basis may be more suitable to detect
delicate neurophysiological intricacies of sleep. Power spectrum analysis of the EEG has been utilized in
different groups of subjects with CFS and has failed to corroborate intrusion of alpha activity in NREM
sleep as a clinically relevant issue. Armitage et al. reassessed 13 pairs of female twins out of the original
22 pairs from the Washington CFS twin registry. PSG was repeated and power spectral analysis using
fast Fourier transformation (FFT) was applied on the EEG recordings. No significant differences in
spectral power in any frequency band were found between co-twins with or without CFS. Phasic alpha
activity, coupled with delta was noted in five subjects with CFS but was also present in four out of five
healthy co-twins, indicating that this finding rather reflects genetic influences on the sleep EEG. PSG
recordings from the individuals that were included in the Wichita CFS surveillance study were reassessed
using FFT. The spectral power of each frequency domain for each sleep state was compared between
persons with CFS and matched controls. Surprisingly, alpha power was reduced during NREM stages 2
and 3, and REM sleep in the CFS group. In a clinical population, Guilleminault et al. compared 14
consecutive patients with chronic fatigue to 14 controls. Using FFT, they also found decrements in the
power of the alpha bands in the patient group.67 In conclusion, power spectrum analysis of the EEG does

8. not seem to provide strong evidence for abnormal alpha intrusion in NREM sleep in subjects with chronic
fatigue. Analysis of other spectral bands (theta, delta, beta) shows inconsistent results. For instance,
delta power has been reported increased, decreased, or to be similar in CFS groups as compared with
normal controls.
Increased CAP rates in NREM are presumed to be an index of sleep instability. Guilleminault et al. also
looked at CAP rates in their sample of clinical CFS patients versus controls, to find significantly higher
values in subjects with chronic fatigue as compared with controls (50.9 ± 32.0 vs. 27.0 ± 26.2, P = 0.04).
They speculated that this mechanism may be associated with a complaint of unrefreshing sleep. An
investigation of sleep stage dynamics showed different profiles regarding probabilities of transitions from
waking to sleep and between different sleep stages, when comparing CFS and FMS patients with
controls. In addition, the rates of these transitions were also significantly increased in subjects with CFS
and FMS. Evidently, these results are preliminary, as the new paradigms on which they are based must
be reassessed by independent research groups. If these findings can be replicated, their relevance in
respect of hypothetical models of sleep dysfunction should be determined.
In conclusion, an undisclosed disturbance of the neurobiological sleep process may still be a plausible
explanation for NRS and daytime dysfunction in CFS. However, no robust pathophysiological correlate
has been identified as yet to demonstrate that a deficit in sleep function is accountable for these
symptoms. The concept of nonrestorative sleep is contentious as it carries the attribution that the problem
lies intrinsically within sleep. By the same token, sleep may be normal. It is conceivable that chronic
fatigue may persist throughout the entire 24-h period, and is already noticed by the individual after the
period of nocturnal sleep. The timing of the first experience of fatigue, i.e., upon awakening in the
morning, may falsely raise the individual's perception that something is wrong with sleep. Until a specific
neurophysiological impairment is demonstrated, the claim that NRS is part of the domain of CFS – or
insomnia – will remain speculative.
Primary sleep disorders in chronic fatigue and CFS
PSD, including primary insomnia, obstructive sleep apnea (OSA), periodic limb movement disorder and
narcolepsy, are not infrequently diagnosed in patients who otherwise meet the Fukuda et al. criteria for
chronic fatigue or CFS. Taking an appropriate sleep history and performing PSG are key to detecting
these disorders. Due to different criteria, diagnostic methods, as well as different target populations, the
prevalence rates of PSD vary substantially among studies. The Wichita CFS surveillance study revealed
the presence of severe PSD in 18% of subjects with CFS in the general population. In clinical settings,
the prevalences of PSD vary between 46 and 81%.
Two issues stand out in the clinical differentiation between PSD and CFS.
1. First, the constructs of primary insomnia and CFS overlap considerably. Psychophysiological
insomnia, more than any other sleep disorder, is associated with high scores on daytime fatigue.
As discussed earlier, NRS is a hallmark in the contemporary nosological definitions of both
insomnia and CFS. Patients with CFS tend to increase the duration of staying in bed, leading to
decreased sleep efficiency. They also may suffer from DIS, DMS or both. All these findings are
also characteristic of insomnia. Therefore, the concepts of insomnia and CFS should be further
clarified with respect to mutual differences and similarities.
2. Second, organic sleep disorders, especially sleep apnea and narcolepsy, are regarded conditions
that exclude CFS. This concept has recently been challenged. In a comparative study, Libman
et al. found no significant differences between CFS patients with and without associated OSA
regarding subjective sleep variables, CFS symptoms, indexes of anxiety and depression, and
MOS SF-36 quality of life parameters. Neither was there a difference in fatigue scores between
subgroups who were and who were not compliant for treatment with nasal continuous positive
airway pressure (CPAP). From these findings, the authors concluded that OSA should not be an
exclusion criterion for CFS. On the other hand, there is preliminary evidence to indicate that
treatment of PSD may reduce scores of daytime fatigue. In moderate to severe OSA, a recent
placebo-controlled trial with nasal CPAP demonstrated a significant reduction in fatigue and
increase in vigor (P values <0.05) in a group of 29 subjects treated with active CPAP, but not in a
group of 30 subjects receiving placebo treatment. The beneficial effect of CPAP treatment was
most pronounced in patients with high levels of fatigue at onset. In contrast, EDS was reduced
only in a subset of patients who were excessively sleepy at onset. Clearly, more studies are
needed to brace these results, especially in patients whose presenting complaint is severe
chronic fatigue. It is not yet clear whether primary severe fatigue is sufficiently responsive to
adequate treatment of comorbid sleep disorders.

9. CONCLUSION
Overall, according to 2015 IOM diagnostic criteria for CFS/SEID, sleeping disorder is present in 70% of
patients with CFS. According to research has been done, concept of NRS implies that fatigue is the
consequence of dysfunctional sleep, whilst evidence for such cause–effect relationship has not yet been
provided. Preferably, this complaint should be referred to as ‘waking up unrefreshed’. Moreover, a
uniform working definition should be validated, based on an empirical approach involving experts,
clinicians and patients. Patients who report NRS are not necessarily functionally impaired during the
daytime. Patients in whom CFS is suspected should be routinely screened for the presence of PSD.
Assessment is based on appropriate questionnaires and semi-structured history. PSG should be carried
out in individuals with high pre-test probability for PSD. CFS can be excluded, not by the mere presence
of PSD, but by satisfactory symptomatic relief obtained by causal treatment.
The neuropsychiatric and neuropsychological features of
chronic fatigue syndrome
A number of neuropsychiatric complaints have been linked to CFS and relate primarily to disorders of
mood, affect and behaviour.. Between 60 and 70 percent of CFS patients are thought to suffer from a
psychiatric disorder, especially depressive illness. Numerous studies have demonstrated significant co-
morbidity between CFS and depression and estimate that 15 to 40 percent of CFS patients suffer from
major depression. The vast majority of the neuropsychiatric literature however is devoted to depression,
as it is one of the most significant clinical problems facing CFS patients.
Depressive disorders
Depressive disorders are characterized by sadness severe enough or persistent enough to interfere with
function and often by decreased interest or pleasure in activities. Exact cause is unknown but probably
involves heredity, changes in neurotransmitter levels, altered neuroendocrine function, and psychosocial
factors. Diagnosis is based on history. Treatment usually consists of drugs, psychotherapy, or both and
sometimes electroconvulsive therapy.
Etiology
Exact cause of depressive disorders is unknown, but genetic and environmental factors contribute.
Heredity accounts for about half of the etiology (less so in late-onset depression). Thus, depression is
more common among 1st-degree relatives of depressed patients, and concordance between identical
twins is high. Also, genetic factors probably influence the development of depressive responses to
adverse events.
Other theories focus on changes in neurotransmitter levels, including abnormal regulation of cholinergic,
catecholaminergic (noradrenergic or dopaminergic), and serotonergic (5-hydroxytryptamine)
neurotransmission. Neuroendocrine dysregulation may be a factor, with particular emphasis on 3 axes:
hypothalamic-pituitary-adrenal, hypothalamic-pituitary-thyroid, and growth hormone.
Psychosocial factors also seem to be involved. Major life stresses, especially separations and losses,
commonly precede episodes of major depression; however, such events do not usually cause lasting,
severe depression except in people predisposed to a mood disorder.
People who have had an episode of major depression are at higher risk of subsequent episodes. People
who are less resilient and/or who have anxious tendencies may be more likely to develop a depressive
disorder. Such people often do not develop the social skills to adjust to life pressures. Depression may
also develop in people with other mental disorders.
Women are at higher risk, but no theory explains why. Possible factors include the following:
1. Greater exposure to or heightened response to daily stresses
2. Higher levels of monoamine oxidase (the enzyme that degrades neurotransmitters considered
important for mood)
3. Higher rates of thyroid dysfunction

10. 4. Endocrine changes that occur with menstruation and at menopause
Major Depressive Disorder
Patients may appear miserable, with tearful eyes, furrowed brows, down-turned corners of the mouth,
slumped posture, poor eye contact, lack of facial expression, little body movement, and speech changes
(eg, soft voice, lack of prosody, use of monosyllabic words). Appearance may be confused with Parkinson
disease. In some patients, depressed mood is so deep that tears dry up; they report that they are unable
to experience usual emotions and feel that the world has become colorless and lifeless.
Nutrition may be severely impaired, requiring immediate intervention, and some depressed patients
neglect personal hygiene or even their children, other loved ones, or pets.
For diagnosis, ≥ 5 of the following must have been present nearly every day during the same 2-wk period,
and one of them must be depressed mood or loss of interest or pleasure:
Depressed mood most of the day
Markedly diminished interest or pleasure in all or almost all activities for most of the day
Significant (> 5%) weight gain or loss or decreased or increased appetite
Insomnia (often sleep-maintenance insomnia) or hypersomnia
Psychomotor agitation or retardation observed by others (not self-reported)
Fatigue or loss of energy
Feelings of worthlessness or excessive or inappropriate guilt
Diminished ability to think or concentrate or indecisiveness
Recurrentthoughts of death or suicide,a suicide attempt, or a specific plan for committing suicide
Depressive Illness and CFS
CFS shares a number of significant overlapping symptoms with depressive illness. Symptoms such as
profound fatigue, sleep disturbance, poor concentration and memory difficulties are prominent features of
both CFS and depression. The precise relationship between CFS and depression remains unexplained
and is an area of intense debate and controversy. The debate focuses on three key areas:
1. High rates of depressive illness are present in CFS because CFS is a form of atypical
depression.
2. High rates of depressive illness are present in CFS because of the disability imposed by the CFS
disease process.
3. High rates of depressive illness are present in CFS because CFS and depression share an
aetiological pathway.
Despite the on-going debate regarding the aetiology, it is clear that CFS is a disabling condition that is
associated with high rates of depression.
The prevalence of depressive illness in CFS varies widely with estimates ranging from between 21 to 27
percent. More recent studies endorse these early findings with one population study noting that 22
percent of CFS patients suffer from current co-morbid depressive illness and have an overall lifetime
prevalence of 65 percent. Similarly, Taylor et al. in a large community study found that nearly one in three
patients with CFS experience clinically significant depression.
Major Depressive Disorder (MDD) and CFS
The symptoms of MDD and CFS overlap significantly and as such it is not surprising that that the CFS
literature indicates that MDD is the single most frequently occurring psychiatric disorder associated with
CFS. Although high rates of MDD are linked with CFS, as many as 30 to 50 percent of CFS patients do
not experience psychiatric symptoms. Thus, it is important to note that while MDD is a prominent feature
of CFS, it affects some and not all CFS patients.

11. The research literature also indicates that CFS is different from MDD in a number of important symptom
presentations. Johnson et al. discriminated CFS patients from those with MDD using the Beck
Depression Inventory (BDI). The study revealed that the CFS participants had BDI scores that related
principally to physical complaints and the somatic symptoms of fatigue, while participants with MDD
identified with symptoms of disturbed mood and self-reproach. Furthermore, Powell et al. found significant
differences between patients with CFS and patients with MDD. The CFS patients expressed fewer
problems with self-esteem, guilt and suicidal ideation than the MDD group. The CFS patients were also
inclined to attribute their symptoms to physical causes whereas the MDD patients experienced inward
attribution. More recently, Hawk et al. found that measuring the severity of post-exertional malaise,
unrefreshing sleep, impaired concentration, shortness of breath and self-reproach could effectively
discriminate between patients suffering from CFS and MDD.
The findings from these studies collectively indicate that while MDD and CFS share many similar
symptoms (profound fatigue, pain, sleep disturbance and poor concentration) they are distinct illnesses
and highlight that the types of symptoms expressed by CFS patients are qualitatively different. A good
illustration of this point was demonstrated by Silver et al. who indicated that CFS patients could be
distinguished from depressive patients by measuring their response to physical exertion. The study
highlighted that the CFS patients experienced an increase in fatigue post exertion, which was in contrast
to the depressed patients who experienced an increase in positive mood. Furthermore, Axe in a
surveillance study of MDD and CFS concluded that the classic CFS symptoms of post-exertional malaise,
painful lymph nodes and sore throat are not normally observed in MDD and point tentatively to a different
underlying aetiology.
The Biological Basis of Symptom Overlap Between CFS and MDD
The link between CFS and MDD might be explained through shared oxidative and nitrosative stress
(IO&NS) pathways. The IO&NS pathways refer to a complex succession of biochemical reactions that
result in damaging free radical and nitric oxide effects at a cellular level. In one study of CFS and MDD,
IO&NS was found to be responsible for damaging DNA, proteins and fatty acids and was significantly
correlated to patient complaints of fatigue, muscle pain and flu-like malaise. The activation of IO&NS
pathways is known to give rise to fatigue and somatic symptoms and can be activated by infections,
psychosocial stress and immune disorders. Thus, these studies indicate that CFS and MDD may share
clinical manifestations of a shared IO&NS pathway.
Maes et al. assert that CFS and MDD can be distinguished from each other by focusing on research
evidence emerging from other biological systems. For example, MDD is classically associated with
increased hypothalamus-pituitary-adrenal (HPA) axis activity and raised cortisol levels. Raised cortisol is
known to cause problems with verbal memory, visuo-spatial memory and executive functioning in MDD.
By contrast, HPA studies in CFS have found reduced rather than increased cortisol levels.
Hypocortisolism has been consistently demonstrated in CFS and is supported by recent population-based
neuroendocrine investigations. Unlike MDD, the impaired HPA axis functioning is thought to be
responsible for the symptoms of fatigue, post-exertional malaise and headaches in CFS patients.
During psychological or physical stress there should be a shift from the production of androgens to
glucocorticoids in order to maintain homeostasis. However, Scott et al. in a preliminary study of
dehydroepiandrosterone (DHEA) in CFS found that the anticipated metabolic shift from DHEA to cortisol
did not occur in CFS patients. The study also highlighted that CFS patients exhibited lower levels of
DHEA and significantly lower levels of dehydroepiandrosterone-sulphate (DHEA-S) compared to patients
with MDD and healthy controls.
In addition to differences in HPA axis activity between CFS and MDD, recent research has also
highlighted important immunological differences. The antiviral 2-5A/RNase L pathway is one of the
primary mechanisms by which interferons inhibit viral and bacterial infections. Cells exposed to
interferons within the system instigate the expression of genes that result in an antiviral state. In recent
years, a number of studies have indicated that various components of the 2-5A /RNase L pathway are
both upregulated and deregulated in CFS patients compared to controls. Suhadolnik et al., in a study
examining the immune abnormalities and status of the RNase L pathway in patients with CFS compared
to patients with MDD and healthy controls, found that the CFS patients exhibited distinct RNase L
abnormalities that were not present in the MDD patients or healthy controls. Similarly, De Meirleir et al.,
found that the RNase L abnormalities were specific for CFS and extracts of peripheral blood mononuclear

12. cells were effective at discriminating CFS patients from those with depression, fibromyalgia and healthy
controls.
The studies reviewed above indicate that although CFS is often accompanied by depressive symptoms,
there is evidence to support the contention that CFS is distinct from MDD. The abnormalities
demonstrated in the HPA axis, DHEA and the RNase L pathways are beginning to tentatively unravel part
of the CFS enigma; however further studies are required to examine these abnormalities in more detail.
CFS, Depression and Illness Limitations
No evidence to suggest that CFS patients are particularly hypochondriacal was found. Thus, the study
concluded that psychiatric illness is most probably a consequence of the CFS illness experience rather
than something that brings about the development of the syndrome. Pepper et al. came to a similar
conclusion when they compared CFS patients with those suffering from multiple sclerosis (MS) and
MDD. In this study, CFS patients were found to more closely resemble the MS patients than the MDD
group. The study found that the CFS group experienced considerably fewer axis 1 disorders than the
patients with MDD.
Additionally, Jason et al., assert that CFS patients do not typically exhibit the hallmark depressive
symptoms of anhedonia and worthlessness. Johnson et al. examined the depressive symptom pattern in
patients with clinical depression, CFS and multiple sclerosis using the Beck Depression Inventory (BDI)
and found that the CFS and MS patients experienced significantly fewer symptoms of self-reproach than
depressed patients. In a more recent study, Moss-Morris and Petrie, found that depressed controls could
be distinguished from CFS patients by their low self-esteem, the inclination to make cognitive distortions
across all situations and to attribute their illness to psychological factors. In contrast, the CFS patients
were typified by low ratings of their current health status, a strong illness identity and external
attributions for their illness. They were also more likely than depressed patients to cope with their illness
by limiting stress and activity levels.
Somatoform Disorder in CFS
Somatization disorder is a multisomatoform cluster of symptoms characterized by two or more years of
somatic complaints with no known overt medical cause. A variety of different terms have been used to
label this condition, including ‘psychosomatic syndrome', ‘somatoform disorder’, or ‘functional somatic
symptoms. This multisymptomatic syndrome has a prevalence rate of 0.03–0.3% in the general
population. The DSM-IV criteria for somatization disorder were very restrictive and narrow and may fail to
reflect the healthcare relevance of patients with multisomatoform disorders, a problem still evident in
somatic symptom disorder of DSM-V, although criteria for specific number of symptoms have been
removed. In DSM-V, somatization disorder and undifferentiated somatoform disorder are combined to
form somatic symptom disorder. Somatization is a subthreshold syndrome of somatization
disorder/somatic symptom disorder defined by a cutoff score of 8 or more on the Somatization Index
(SSI) , a structured interview based on the SCID criteria of somatization disorder. In contrast to the
diagnosis somatization disorder, somatization is externally validated, differentiating patients with high vs.
low disabilities.
Diagnostic criteria of somatization (DSM-IV)
A history of unexplained phy sical complaints
Beginning bef ore age 30 y ears
Occurs ov er a period of sev eral y ears
Results in treatment being sought or signif icant impairment in f unctioning
Includes f our potential pain sy mptoms, i.e. Two gastrointestinal sy mptoms, One sexual sy mptom, One pseudoneurological sy mptom
Characteristc sy mptoms of ME/CFS: the London criteria
Muscular f atigue f ollowing minimal exertion with a prolonged recov ery time
Impairment of short-term memory and loss of power of concentration
Usually coupled with other neurological and psy chological disturbances
Emotional lability
Nominal dy sphasia
Disturbed sleep patterns
Disequilibrium or tinnitus
With additional autonomic and immunological sy mptoms
Other sy mptoms of ME/CFS
Gastro-intestinal sy mptoms, reminiscent of irritable bowel sy ndrome hy peralgesia

13. Phenomenologically, considerable overlap exists between somatization (disorder) and myalgic
encephalomyelitis (ME)/chronic fatigue syndrome (CFS), highlighted in Table, which shows the London
criteria for ME/CFS. This overlap explains why many patients with ME/CFS are often classified as
suffering from somatization (disorder) when assessed with the DSM-IV criteria, which is likely to change
little with somatic symptom disorder of DSM-V. Patients with ME/CFS suffer significantly more from
somatization disorder than fatigued patients and in addition are more likely to attribute their illness to a
physical cause. Martin et al. reported that up to 72% of patients with ME/CFS fulfill the criteria for
somatization syndrome. This overt phenomenological overlap between somatization syndrome and
ME/CFS supports the hypothesis that both syndromes might share underlying processes.
A further confound to the classification of somatization is its common coincidence with depression. In
primary care, depression is the most common comorbid disorder associated with somatization disorder.
This comorbidity is often labeled somatoform, somatic, or masked depression. In a large-scaled study on
primary care patients, 69% of depressed individuals had somatic symptoms. In somatization, increased
numbers of symptoms are significantly associated with greater risk of depression. Somatic symptoms
predominate in about 50% of depressed individuals in primary care settings. Similarly, there is a
phenomenological overlap between irritable bowel syndrome and depression. Some patients with
depression report high scores on somatization symptoms, including fatigue, concentration difficulties,
failing memory, hyperalgesia, muscular tension, irritability, gastrointestinal symptoms, headache, and a
flu-like malaise. The presence of this fatigue–somatic symptom cluster in depression is not only a key
feature of depression but predicts melancholia and chronicity of depression.
Although depression is considered to be a biologically mediated disorder, some clinicians still regard the
comorbid conditions, somatization, and ME/CFS, as functional syndromes without a biological substrate.
Likewise, psychiatric or psychological theories are often used to explain the overlap between
somatization and depression:
1. Depression reduces the pain threshold increasing hyperalgesia, contributing to a negative view of
one's health and somatic hypervigilance, in turn increasing somatization
2. Alexithymia or a focus on somatic symptoms conceals or represses affective symptoms .
3. Feelings of helplessness induced by somatization lead to depression
4. Somatization is an early-entrained pattern of social communication driven by insecure
attachment.
5. Illness investment and abnormal illness behaviour drive somatization and mood symptoms.
Somatization is often seen as an alternative mode for the expression of distress and can manifest as
expectation of harm secondary to medical intervention—the nocebo effect.
Here, we review recent data and argue that the ‘psychosomatic’ symptoms have a biological explanation.
Consequently, we use the term physio-somatic symptoms to underscore the biological nature of these
symptoms.
Inflammatory pathways and physio-somatic symptoms in depression, somatization, and ME/CFS
There is abundant evidence that activation of inflammatory and CMI pathways are observed in a subs et
of patients with depression. CMI activation involves interactions between, for example, T lymphocytes
and monocytes/macrophages, but does not involve the acute phase response or the induction of
complement or antibodies. Once triggered, T-cells are activated to produce cytokines, including interferon
(IFN)γ and interleukin-2 (IL-2), which then activate monocytes/macrophages. IFNγ-activated monocytes
produce neopterin, a consequent indicant of IFNγ activity. Activated monocytes/macrophages produce
cytokines, such as IL-1β, that further stimulate T-cells. In contrast, inflammation comprises cytokine,
immune cell and complement cascades in conjunction with an acute phase response. Proinflammatory
cytokines, such as IL-1β and tumor necrosis factor (TNF)α, are primary mediators of inflammation. These
cytokines activate intracellular signaling pathways, such as nuclear factor κB (NF-κB), which enhance
inflammatory mediators, including cytokines, for example, IL-6 and IL-8, as well as activating T-cells to
produce IFNγ. Proinflammatory cytokines, including IL-1, IL-6, and TNFα, enhance the synthesis of
positive acute-phase proteins in the liver, for example, haptoglobin and C-reactive protein (CRP), the
latter at high concentrations contributing to blood–brain barrier (BBB) permeability. A countering or
compensatory anti-inflammatory reflex system (CIRS) accompanies inflammation, negatively feeding
back on the initiating inflammation, including monocytic production of the IL-1 receptor antagonist (IL-
1RA), which negatively feeds back on the proinflammatory effects of IL-1.
Surrogate markers of CMI activation in clinical depression include, for example, increased serum and
urine neopterin levels; increased production of IFNγ by peripheral blood mononuclear cells; increased
numbers of T-cells bearing activation markers (e.g., CD25+), and associated levels of soluble IL-2
receptor (IL-2R). Inflammation in depression is indicated by increased levels of IL-1, IL-6, and TNFα;
increased levels of positive acute phase proteins, such as haptoglobin and CRP; and increased levels of
complement factors. Three recent meta-analyses examined the results of clinical and community-based

14. samples, reporting that IL-1, IL-6, IL-2R, and CRP levels are consistently increased in clinical depression
or self-reported depression. Inflammatory processes may precede and operate as risk factors for the
development of depression.
It was first reported in 1993 that the vegetative symptoms of depression, and not cognitive symptoms,
such as suicidal ideation and feelings of guilt, are associated with inflammatory processes in that illness.
Significant associations were detected between plasma haptoglobin, an inflammatory biomarker, and
symptoms, such as psychomotor retardation, anorexia, weight loss, middle insomnia, and loss of interest.
In depression, increased plasma proinflammatory cytokines, such as TNFα and IL-1, are related to
specific physio-somatic symptoms, such as fatigue, concentration, and memory disturbances, whereas
increased serum neopterin concentrations are related to hyperalgesia, neurocognitive disorders, and a
flu-like malaise.
Immuno-inflammatory pathways also underpin the pathophysiology of ME/CFS, indicated by the
activation of NF-κB, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS). Increased
levels of Th1- and Th2-like as well as proinflammatory cytokines are reported in ME/CFS, including IL-1,
IL-1β, IL-6, IL-12, TNFα, IL-10, IL-4, and IL-5. Increased plasma PMN elastase is another biomarker of
the inflammatory response in ME/CFS. Markers of immune activation are reported, for example, CD8+ T-
cells expressing higher levels of the activation markers CD38+ and HLA-DR+, and increased serum
levels of neopterin. Thus, increased levels of proinflammatory cytokines, neopterin, and PMN elastase
are detected in both depression and ME/CFS. Although these shared immuno-inflammatory pathways
underpin the pathophysiology of clinical depression and ME/CFS, other pathways may discriminate both
disorders. Depression is characterized by a Th1-like response with increased IFNγ production, while
ME/CFS is sometimes accompanied by Th2 and T regulatory (Treg) cell responses, increasing the
production of the anti-inflammatory cytokine IL-10, coupled with reduced Th1 and Th17 immune
responses.
In ME/CFS, physio-somatic symptoms are also significantly associated with immuno-inflammatory
biomarkers, including increased plasma IL-1 and TNFα associated with a flu-like malaise; increased CMI
marker, neopterin, associated with irritability and a flu-like malaise; and increased PMN elastase
associated with lowered daily functioning, reduced exercise capacity as well as a flu-like malaise. When
ME/CFS and depressed patients were pooled, significant correlations were found between TNFα, IL-1,
and neopterin (the explanatory variables) and physio-somatic symptoms, including fatigue, concentration
disturbances, memory disturbances, autonomic symptoms, and a flu-like malaise (the dependent
variables), suggesting significant overlaps in biological underpinnings across diagnoses.
The first publication showing a relationship between somatization and inflammation was published in
2001. Serum IL-1RA was significantly higher in patients with somatization than in normal controls.
Increased IL-1RA levels are also an indirect index of monocytic activation because the IL-1RA is released
together with IL-1, antagonizing the proinflammatory activity of IL-1. Although depression and
somatization are both accompanied by increased IL-1RA, T-lymphocytic markers, such as sCD8, and
endogenous anti-inflammatory substances, including CC16 (uteroglobulin/Clara cell protein), are
significantly different between these disorders. While depression is characterized by increased serum IL-6
and sCD8, both factors are significantly decreased in somatization. While depression is characterized by
reduced serum CC16, there are no significant alterations in serum CC16 in patients with somatization. A
recent study shows that patients with somatization have increased TNFα and neopterin levels, indicating
activation of immuno-inflammatory pathways. All in all, depression is accompanied by monocytic and CMI
activation and by lowered endogenous anti-inflammatory defenses, while somatization is accompanied by
monocytic activation.
Other data also show that immuno-inflammatory pathways are associated with the onset of physio-
somatic symptoms. Significantly increased scores on depression, anxiety, and somatization are found in
patients with hepatitis C virus not receiving antiviral therapy. Bell and others reported significant
correlations between serum neopterin levels and physio-somatic complaints in patients with subjective
chemical intolerance. These results consistently indicate that activation of immune-inflammatory
pathways is accompanied by increased somatization.
The TRYCAT pathway in depression, ME/CFS, and somatization
Abnormalities of serotonergic neurotransmission are associated with depression and many related
disorders and provide the rationale for the use of selective serotonin reuptake inhibitors. The production
of serotonin requires tryptophan. Over 95% of tryptophan in the body is driven down the TRYCAT
pathway, with further increases in TRYCAT production decreasing the availability of tryptophan for
serotonin and melatonin production. The conversion of tryptophan into kynurenine (kyn) is the rate-
limiting step in this pathway. The latter is induced by two enzymes: IDO and tryptophan 2,3-dioxygenase
(TDO). IDO is activated by IFNγ, which is potentiated by IL-1β, TNFα, and IL-18, while cortisol, and
perhaps cyclic adenosine monophosphate (cAMP), induces TDO. IDO is widely expressed, including in
microglia and other immune cells. TDO is mainly hepatic and also evident in astrocytes and neurons. In

15. diverting tryptophan away from serotonin and melatonin synthesis, the first step in the TRYCAT pathway
determines the kyn/tryptophan ratio. An early step in the TRYCAT pathway is the conversion of
kynurenine to kynurenic acid (KYNA), induced by kynurenine 2,3-aminotransferase (KAT). KAT activity
therefore predominantly determines the kyn/KYNA ratio. In TDO-expressing cells, this is the extent of
TRYCAT pathway products. In IDO-expressing cells, however, a number of other TRYCATs can be
produced, including quinolinic acid (QUIN), picolinic acid, and xanthurenic acid. Many of these TRYCATs
have neuroregulatory activity, QUIN and picolinic acid being excitotoxic and excitatory, respectively, at
the glutamate NMDAr, while KYNA is inhibitory at the alpha 7 nicotinic acetylcholine receptor (a7-nAChr).
As such, the activation of the TRYCATs by proinflammatory cytokines alters neuronal activity contributing
to depression and somatization, not simply via decreased serotonin but by the induction of significant
neuronal modulators. The pattern of expression of specific TRYCATs will determine the consequences of
IDO and TDO induction.
The relationship between depression and altered TRYCATs was established in 1993, with decreased
tryptophan being a consistent finding in depression. Decreased tryptophan in depression is negatively
related to indices of immuno-inflammatory pathways, such as increased IL-6, IL-8, IL-1RA, plasma
haptoglobin, and neopterin, and positively related to decreased plasma transferrin, zinc, and albumin.
These findings suggest that immuno-inflammatory responses in depression, characterized by increased
IFNγ and proinflammatory cytokines, have activated IDO and, subsequently, lowered plasma tryptophan.
Interestingly, during immune activation, IDO is stimulated, while hepatic TDO may be suppressed.
Whether this is paralleled in astrocyte and neuronal TDO awaits investigation. The availability of plasma
tryptophan to the brain is significantly and inversely correlated with indicants of hypothalmic –pituitary–
adrenal axis (HPA) function, such as postdexamethasone cortisol values, but not with increased baseline
activity of the axis. This suggests that glucocorticoid hypersecretion in clinical depression is probably not
the main cause of reduced availability of plasma tryptophan through TDO induction, although HPA axis
hyperactivity cannot be excluded. TDO is important to brain serotonin levels, as indicated by the 20-fold
increase in brain serotonin occurring in TDO KO rodents. These results suggest that lowered plasma
tryptophan in clinical depression is probably a marker of activated immuno-inflammatory pathways. The
excitatory and neurotoxic TRYCATs, kyn and QUIN, are elevated in depression, whereas the generally
neuroprotective KYNA is decreased. An increase in microglia QUIN in regions of the CNS associated with
emotional further processing is evident in depressed suicide victims.
The activation of the TRYCAT pathway also plays a role in the onset of somatization. Plasma tryptophan
is significantly lower in patients with somatization, even in the absence of depression. In this study, Maes
and colleagues compared depression, somatization, depression + somatization, and controls, finding that
plasma tryptophan was lowest in individuals with somatization. Importantly, the Kyn/KYNA and
Kyn/tryptophan ratios were significantly increased in somatization as compared with depression and
control subjects, with plasma KYNA levels being significantly lower in patients with somatization. KYNA in
depressed patients was significantly higher than patients with somatization, but significantly lower than
controls. Plasma tryptophan and KYNA levels negatively correlated with the severity of somatization. Both
ratios and plasma kyn positively associated with somatization severity. Also kyn and KYNA are
significantly correlated in individuals with depression, and depression + somatization, and in normal
controls, but not in those with somatization, suggestive of altered KAT regulation in somatization.
There are only a few studies on the TRYCAT pathway in ME/CFS. Enhanced tryptophan degradation was
significantly related to neopterin in patients with Epstein–Barr virus infection, but not in controls. Patients
with more severe symptoms of fatigue showed increased tryptophan degradation. Vassalo and others
reported lowered plasma tryptophan levels in patients with ME/CFS. However, another study that
measured the ratio of tryptophan to competing amino acids found no significant differences in the
availability of plasma tryptophan in patients with ME/CFS. Competing amino acids utilize the same
cerebral uptake mechanism as tryptophan. This study found that plasma tryptophan was 17% higher in
patients with ME/CFS than in the controls. Georgiades and others also found that the levels of free
tryptophan were higher, whereas the competing amino acid levels were lower in patients with ME/CFS in
particular during exhaustion.
On the other hand, Kirmayer and Robbins indicate that the term somatisation encompasses a broad
range of patient experiences and perceptions. These include situations in which
1. Patients describe symptoms that are entirely physical despite the presence of emotional distress
2. Patients who are convinced they have a disease in the absence of evidence
3. Patients who persistently present to clinicians complaining of medically unexplained somatic
symptoms.

16. What is common among these three categories of somatisation behaviour is the assumption that
medically unexplained patient complaints are consequent to underlying emotional distress. In addition to
these three forms of somatisation, there is also a formal psychiatric diagnosis of somatisation disorder as
described by DSM-III. The diagnosis of somatisation disorder is made in the presence of several years of
medically unexplained symptoms, with onset before the age of 30, together with 13 of 35 functional
symptoms.
Studies of psychiatric illness in CFS have found very high rates of somatisation disorders. Johnson et al.
in an investigation into the prevalence of somatisation disorder in CFS found that patients demonstrated a
higher rate of somatisation disorder type symptoms than patients with multiple sclerosis or healthy
controls. However, the study also indicated that very few of the CFS patients met the exact DSM-III-R
criteria for somatisation disorder. The Johnson et al. study further revealed that by changing the
attribution of somatisation symptoms from psychiatric to physical (i.e. CFS symptoms were not coded as
psychiatric) radically influenced the number of CFS patients diagnosed with somatisation disorder.
Demitrack arrived at similar conclusions, finding that when symptoms attributable to CFS were excluded,
6 of 30 patients demonstrated a lifetime history of major depression. However, when using criteria that
included all symptoms, 12 of 30 patients reported a lifetime history of major depressive illness. Thus, the
Johnson et al. and Demitrack studies demonstrate that the diagnosis of somatisation in CFS depends
upon patient reports of physical symptoms and the assumption by the researcher that there is no physical
cause for the symptoms.
Finally, Katon and Walker assert that if CFS patients were presenting physical symptoms as a method of
masking their psychological distress, then there should be an inverse association between the number of
depression and anxiety symptoms and the number of reported somatic symptoms. This, however, has not
been the case, with CFS patients detailing somatic, depressive and anxiety-related symptoms
simultaneously.
Personality Disorder in CFS
Research evidence indicates that personality disorder is present in as many as 39 % of CFS patients,
predominantly obsessive-compulsive disorder . Similar rates of personality disorder were reported in a
more recent study by Cicone et al. In a study by Johnson et al., 37 % of subjects with CFS met the criteria
for at least one personality disorder (typically histrionic or borderline personality disorder). These studies
indicate that there are higher rates of personality disorder amongst CFS patients than in non-clinical
populations, which are estimated to range between nine and six percent in the general population .
However, these high rates of personality disorder in CFS are similar to those found in patients with other
chronic medical conditions. Furthermore, some of the measures used increase the likelihood of achieving
a diagnosis of personality disorder in chronically ill patients. Co-morbid depression accounted for most
personality pathology in one study.
Chronic fatigue syndrome and personality: A case-
control studyusing the alternative five factor model
Neuroticism is the personality dimension most frequently associated with chronic fatigue
syndrome (CFS). Most studies have also shown that CFS patients are less extraverted than non-CFS
patients, but results have been inconsistent, possibly because the facets of the extraversion dimension
have not been separately analyzed.
This study has the following aims:
1. To assess the personality profile of adults with CFS using the Alternative Five-Factor Model
(AFFM), which considers Activity and Sociability as two separate factors of Extraversion
2. To test the discriminant validity of a measure of the AFFM, the Zuckerman–Kuhlman Personality
Questionnaire, in differentiating CFS subjects from normal-range matched controls.
The CFS sample consisted of 132 consecutive patients referred for persistent fatigue or pain to the
Department of Medicine of a university hospital. These were compared with 132 matched normal
population controls. Significantly lower levels of Activity and significantly higher levels of Neuroticism-

17. Anxiety best discriminated CFS patients from controls. The results are consistent with existing data on t he
relationship between Neuroticism and CFS, and clarify the relationship between Extraversion and CFS by
providing new data on the relationship of Activity to CFS.
The CFS sample consisted of 132 consecutive patients, 125 (94.7%) women and 7 men (age: M=47.69
years, S.D.=8.98, range=22–72) referred to the Department of Internal Medicine, Hospital Universitari Vall
d‫׳‬Hebron, Barcelona. CFS diagnosis was established according to the Centers for Disease Control (CDC)
criteria ( Fukuda et al., 1994). Inclusion criteria were as follows: age greater than 18, meeting CDC
diagnostic criteria for CFS, completing a clinical assessment, and providing informed consent to
participate. Exclusion criteria were the presence of a psychotic, major depressive or manic
episode, substance use disorders (except for nicotine), or a diagnosis of an eating disorder.
The CFS sample was matched subject-to-subject with a normal-range sample which acted as a control
group. This comparison sample comprised 132 subjects, 125 women and 7 men (age: M=47.69 years,
S.D.=8.98). This control group was extracted from a general population sample consisting of 570 males
and 599 females ranging in age from 18 to 93 years. This sample was part of a previous study aimed at
obtaining the Spanish norms of the ZKPQ and matched the census projections of the Statistical Institute
in the distribution of age and sex groups ( Gomà-i-Freixanet et al., 2003). A similar selection of controls
was used in other studies ( Gomà-i-Freixanet et al., 2008a; Valero et al 2012).
The Fatigue Impact Scale (FIS; Fisk et al., 1994) was used to assess the impact of fatigue on patients’
live.
The severity of symptoms of depression and anxiety was assessed by the Hospital Anxiety-Depression
Scale (HAD; Zigmond and Snaith, 1983) aimed at the evaluation of these symptoms in patients with a
physical illness.
Personality was assessed with the Zuckerman–Kuhlman Personality Questionnaire
Methods
1. Use of case-control design, randomly selecting one control for each case, matched by age and
gender
2. Control subjects answered the personality questionnaire anonymously and only demographic
data such as age, gender and educational level were recorded.
3. all patients completed an extensive clinical history and underwent a medical examination at the
Department of Internal Medicine by physicians with experience in CFS
4. Participants with a probable CFS diagnosis were given a comprehensive assessment carried out
in three sessions by a psychiatrist and a clinical psychologist who recorded sociodemographic
and clinical data, interviewed the patient, conducted a psychopathological examination with
the Structured Clinical Interview for DSM-IV (SCID-I; First et al., 1997), and administered
questionnaires (FIS, HAD and ZKPQ).
Results
1. Matched case-control study, the two samples did not differ in age or in the distribution of gender
2. There was no significant statistical difference between CFS patients and community subjects in
level of education
3. The variables Age at early symptoms and Age at CFS diagnosis were not significantly correlated
with any of the personality scales
4. symptoms of depression assessed by the HAD, correlations were calculated with values
respectively.
The Neuropsychological Features of CFS
CFS patients frequently report a variety of neuropsychological symptoms indicative of marked cognitive
decline. As estimated, 50 to 80 % of CFS patients complain of significant cognitive difficulties and
impose considerable occupational and social morbidity on sufferers. To date, neuropsychological studies
in CFS have endeavoured to unravel and understand the precise nature of cognitive complaints in CFS.

18. As such, objective evidence of cognitive disturbance has been demonstrated with deficits in attention,
memory and reaction time being the most problematic for CFS patients.
Attention
Caseras et al. in a Functional Magnetic Resonance Imaging Study of working memory found significant
differences in brain activation between CFS patients and control subjects, particularly as the demands
on the working memory were increased. The study concluded that CFS patients did not engage
working memory in the same way as healthy controls. The results indicated that the CFS patients had
to employ additional strategies to offset their underlying cognitive problems in order to attain similar
results to the control subjects. Furthermore, CFS patients displayed consistent problems with working
memory in studies that required patients to concentrate over prolonged periods of time
Memory
The memory problems associated with CFS have divided scientific opinion. Some studies have found
evidence of memory difficulties in CFS, while others have not . The majority of neuropsychological studies
of memory in CFS used verbal and visual memory tests. In particular, tests that assessed memory for
word lists are used. In terms of verbal memory, several studies demonstrate moderate to large deficits in
neuropsychological tests of word list learning (e.g. Auditory Verbal Learning Test and other word list
learning tasks). These studies concluded that immediate recall, delayed recall and recognition were
impaired in CFS subjects.
DeLuca et al., in a comprehensive study into the nature of memory impairment in CFS, found that CFS
patients had significant difficulty in the acquisition of verbal information. The CFS participants required
considerably more attempts to learn a word list than did healthy controls. The study concluded that the
memory difficulties experienced by CFS patients relate to compromises in their ability to recall verbal
information. DeLuca et al. suggest that these memory problems may be consequent to poor initial
learning. The discrepancies in information-processing speed and working memory identified in this study
may add to CFS patient difficulties with initial learning. More recently, Duffy et al. in an EEG spectral
coherence analysis of patients with CFS, MDD and healthy controls found that CFS patients exhibit
abnormal brain physiology that is not present in MDD or healthy controls. The study implicates bilateral
temporal lobe involvement in CFS pathophysiology and is consistent with the wide-ranging memory
problems reported by CFS patients.
Reaction Time
The most frequently observed cognitive difficultly found in CFS relates to impairments in patient
information-processing speed and efficiency. Numerous studies demonstrate that CFS patients perform
less well on tasks that require rapid manipulation of information and on complex and time-limited tasks
than controls. More recently, Majer et al., in a population-based study of neuropsychological performance,
found that compared with controls CFS patients exhibited significant decreases in motor speed, as
demonstrated by slower response times on the movement component of both the simple and choice
reaction time tasks.
Furthermore, Lutgendorf et al. concluded that while having controlled for depression CFS patients who
experienced higher levels of cognitive difficulties also exhibited more immune abnormalities. This, they
argue, is evidence to suggest that the occurrence of cognitive difficulties in CFS can be explained
independently of those that typically occur with depression. Finally, Michiels and Cluydts in a review of
neuropsychological functioning in CFS argue that the cognitive dysfunction found in patients with CFS is
unlikely to be accounted for by depression and anxiety. Daly et al. came to a similar conclusion while
comparing the neuropsychological function in patients with CFS, multiple sclerosis, and depression,
asserting that the cognitive deficits found in CFS cannot be ascribed exclusively to the presence of
depressive symptoms.
The findings from these studies indicate that CFS patients exhibit moderate to significant impairments in
reaction times. These studies assert that that the information-processing difficulties found in CFS patients
contribute to impairments noted in reaction time tasks. Moreover, fine motor speed was not impaired in
persons with CFS, making it unlikely that motor functioning is predominately responsible for slower
reaction times.

19. CONCLUSIONS
1. Anxiety and depression were common in a sample of chronic fatigue syndrome/myalgic
encephalomyelitis (CFS/ME) patients, with a high proportion meeting criteria for severe health
anxiety.
2. Health anxiety has been found to be common across other chronic medical conditions but has
been shown to be effectively treated with appropriately tailored interventions.
3. Overall, according to 2015 IOM diagnostic criteria for CFS/SEID, sleeping disorder is present in
70% of patients with CFS. According to research has been done, concept of NRS implies that
fatigue is the consequence of dysfunctional sleep, whilst evidence for such cause–effect
relationship has not yet been provided Patients in whom CFS is suspected should be routinely
screened for the presence of PSD. Assessment is based on appropriate questionnaires and
semi-structured history. PSG should be carried out in individuals with high pre-test probability for
PSD. CFS can be excluded, not by the mere presence of PSD, but by satisfactory symptomatic
relief obtained by causal treatment.
4. Construct of NRS was introduced as a possible lead to the etiologies of CFS and fibromyalgia
syndrome (FMS). In the general population, only one fifth of individuals with NRS reported fatigue
or irritable mood. Sleep problems are described as a minor criterion, and sleep disturbance is
reported by the vast majority of individuals who receive a final diagnosis of CFS. In case study
carried by Sarsour et al. , Unger et al., it has been proposed that CFS and insomnia share
features with respect to NRS and daytime dysfunctioning, and could actually be manifestations of
one and the same underlying disorder.
5. In case study carried out by Ohayon, there can be seen a potential relationship between NRS
and the various aspects of daytime fatigue.
6. Investigators from the University of Washington have conducted a monozygotic co-twin control
study of 22 pairs discordant for the phenotype of CFS. According to twin study, in comparison to
healthy co-twins there was presence of insomnia in co-twins having CFS
7. Survey in the general population (Wichita CFS surveillance study) has been done in order to
evaluate sleep architecture of patients with CFS. PSG has been performed in a subset of cases
and non-fatigued controls from a population based survey. Despite that the primary sleep
disorder is a common complaint of CFS patients, there was no significant difference between the
PSG of healthy and CFS patients.
8. According to EEG analysis, alpha–delta sleep has been observed in heterogeneous groups of
patients presenting with chronic daytime dysfunctioning, especially in FMS. Meanwhile, it has
become evident that alpha–delta sleep is not an essential feature of NRS, nor a consistent
marker of FMS or CFS
9. Power spectrum analysis of the EEG has been utilized in different groups of subjects with CFS,
Fourier transformation (FFT) was applied on the EEG recordings. No significant differences in
spectral power in any frequency band were found between co-twins with or without CFS
10. Studies endorse these early findings with one population study noting that 22 percent of CFS
patients suffer from current co-morbid depressive illness and have an overall lifetime prevalence
of 65 percent. Similarly, Taylor et al. in a large community study found that nearly one in three
patients with CFS experience clinically significant depression.
11. Symptoms of MDD and CFS overlap significantly and MDD is the single most frequently
occurring psychiatric disorder associated with CFS. Half of CFS patients are present with MDD
and it is important to note that while MDD is a prominent feature of CFS, it affects some and not
all CFS patients. Study revealed that the CFS participants had Beck Depression Inventory (BDI)
scores that related principally to physical complaints and the somatic symptoms of fatigue, while
participants with MDD identified with symptoms of disturbed mood and self-reproach. According
to study done by Powell et al. and Hawk et al. MDD and CFS share many similar but they are

20. distinct illnesses, and highlight that the types of symptoms expressed by CFS patients are
qualitatively different.
12. Study done by Silver at al., the CFS patients experienced an increase in fatigue post exertion,
which was in contrast to the depressed patients who experienced an increase in positive mood
13. According to Axe in a surveillance study of MDD and CFS concluded that the classic CFS
symptoms of post-exertional malaise, painful lymph nodes and sore throat are not normally
observed in MDD and point tentatively to a different underlying aetiology.
14. Maes et al. assert that CFS and MDD can be distinguished from each other by focusing on
research evidence emerging from other biological systems
− MDD is classically associated with increased hypothalamus-pituitary-adrenal (HPA) axis activity
and raised cortisol levels
− In CFS HPA is reduced and hypocortisolism has been consistently demonstrated in CFS
Scott et al. in a preliminary study of dehydroepiandrosterone (DHEA) in CFS found that the
anticipated metabolic shift from DHEA to cortisol did not occur in CFS patients. The study also
highlighted that CFS patients exhibited lower levels of DHEA and significantly lower levels of
dehydroepiandrosterone-sulphate (DHEA-S) compared to patients with MDD and healthy controls.
Abnormalities demonstrated in the HPA axis, DHEA and the RNase L pathways are beginning to
tentatively unravel part of the CFS enigma; however further studies are required to examine these
abnormalities in more detail.
15. Martin et al. reported that up to 72% of patients with ME/CFS fulfill the criteria for somatization
syndrome. In a large-scaled study on primary care patients, 69% of depressed individuals had
somatic symptoms.
16. The physio-somatic symptoms of depression, ME/CFS, and somatization are associated with
specific biomarkers of inflammation and CMI activation, which are correlated with, and causally
linked to, changes in the tryptophan catabolite (TRYCAT) pathway. Biological underpinnings,
such as immune-inflammatory pathways, may explain, at least in part, the occurrence of physio-
somatic symptoms in depression, somatization, or myalgic encephalomyelitis/chronic fatigue
syndrome and thus the clinical overlap among these disorders.
17. According to study carried by Cicone et al., personality disorder is present in as many as 39 % of
CFS patients, predominantly obsessive-compulsive disorder. In a study by Johnson et al., 37 %
of subjects with CFS met the criteria for at least one personality disorder/
High rates of personality disorder in CFS are similar to those found in patients with other chronic
medical conditions
18. Caseras et al. in a Functional Magnetic Resonance Imaging Study of working memory found
significant differences in brain activation between CFS patients and control subjects,
particularly as the demands on the working memory were increased. The study concluded that
CFS patients did not engage working memory in the same way as healthy controls.
19. DeLuca et al., in a comprehensive study into the nature of memory impairment in CFS, found that
CFS patients had significant difficulty in the acquisition of verbal information. The study
concluded that the memory difficulties experienced by CFS patients relate to compromises in
their ability to recall verbal information. The study implicates bilateral temporal lobe involvement
in CFS pathophysiology and is consistent with the wide-ranging memory problems reported by
CFS patients.
20. According to study carried by Daly et al., Michiels and Cluydts ,CFS patients exhibit moderate to
significant impairments in reaction times.

21. REFERENCES
1. https://www.ncbi.nlm.nih.gov/pubmed/?term=Anxiety+and+depression+in+chronic+fatigu
e+syndrome%2Fmyalgic+encephalomyelitis+(CFS%2FME)%3A+Examining+the+incide
nce+of+health+anxiety+in+CFS%2FME
2. http://onlinelibrary.wiley.com/doi/10.1111/papt.12118/abstract;jsessionid=0F3F63B1E2B
1EEE8DB24D75F2F79A68B.f02t01
3. http://www.sciencedirect.com/science/article/pii/S1087079212000731
4. https://link.springer.com/article/10.1007%2Fs11920-013-0353-8
5. https://www.ncbi.nlm.nih.gov/pubmed/23952563
6. http://onlinelibrary.wiley.com/doi/10.1111/acps.12182/full
7. https://www.ncbi.nlm.nih.gov/pubmed/24630915
8. http://www.sciencedirect.com/science/article/pii/S0165178114001693
9. https://www.ncbi.nlm.nih.gov/pubmed/23527651
10. https://www.ncbi.nlm.nih.gov/pubmed/22571806
11. https://www.ncbi.nlm.nih.gov/pubmed/23440559
12. http://www.msdmanuals.com/professional/psychiatric-disorders