Innovations in Symptom Management
Medical Symptoms without Identified Pathology: Relationship to
Psychiatric Disorders, Childhood and Adult Trauma,
and Personality Traits
Wayne Katon, MD; Mark Sullivan, MD, PhD; and Ed Walker, MD
Community studies have shown that stressful life events, psycho-
logical distress, and depressive and anxiety disorders are associ-
ated with 1) a range of medical symptoms without identified
pathology, 2) increased health care utilization, and 3) increased
costs. In both primary care and medical specialty samples, patients
who have syndromes with ill-defined pathologic mechanisms
(such as the irritable bowel syndrome and fibromyalgia) have been
shown to have significantly higher rates of anxiety and depressive
disorders than do patients with comparable, well-defined medical
diseases and similar symptoms. Other studies show that after
adjustment for severity of medical illness, patients with depression
or anxiety and comorbid medical disease have significantly more
I n the past two decades, carefully designed studies ex-
amining the biopsychosocial causes of common phys-
ical symptoms have shown that most health care visits
are made because of common symptoms for which no
identified pathology is found (1). In this paper, we sum-
marize the relationship between common medical symp-
toms without identified pathology and a range of psy-
chosocial variables, such as stressful life events,
psychological distress, psychiatric disorders, and predis-
posing emotional vulnerabilities. We also review the as-
sociation between psychiatric illness and specific clusters
of physical symptoms (such as the chronic fatigue syn-
drome) that are considered syndromes with ill-defined
pathologic mechanisms.
Medical symptoms without identified pathology are
defined as physical symptoms appearing in patients who
do not have proportional tissue abnormalities. In most
studies reviewed here, a symptom was considered to
have no identified pathology when a patient visited a
medical physician and was told that 1) no structural
changes could be found to explain the symptom or 2)
the symptom was secondary to stress or psychiatric ill-
ness. Our medical language to describe these symptoms
is imperfect; advances in research suggest that many
medical symptoms without identified pathology may ac-
tually be caused by problems in psychophysiologic or
brain–body pathways, such as abnormalities in smooth-
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medical symptoms without identified pathology than do patients
with a similar medical disease alone. Both childhood maltreatment
and psychological trauma in adulthood have been associated with
increased vulnerability to psychiatric illness and more medical
symptoms. The substantial functional impairment, distress, and
costs associated with medical symptoms without identified pa-
thology suggest that research studies promoting a better under-
standing of the biopsychosocial cause of these symptoms may
yield pragmatic, cost-effective approaches to treatment in medical
settings.
Ann Intern Med. 2001;134:917-925. www.annals.org
For author affiliations and current author addresses, see end of text.
muscle tone in the gastrointestinal tract during stress in
patients with the irritable bowel syndrome (2). Recent
research also suggests that links between perturbations
in brain physiology and physical symptoms are bidirec-
tional. Changes in brain physiology secondary to stress-
ful life events cause functional abnormalities in the body
(such as abnormalities in smooth-muscle tone in the
gut), and these functional abnormalities in the body are
also associated with changes in brain physiology (3).
The identification of medical symptoms and syn-
dromes without identified pathology may be broken
down into a four-part process (4, 5). First, a person has
a symptom (presumably, a neurophysiologic event brings
it to awareness). Second, the person uses his or her
knowledge, experience, and beliefs about the symptom
and its cause to assign the symptom a level of medical
importance. Most symptoms do not lead to medical vis-
its because patients assign them a relatively low level of
medical importance. Third, the person with the symp-
tom seeks care. Whether a person will seek care can be
predicted by that person’s beliefs about the symptom’s
significance and by his or her attitude toward the med-
ical system. The fourth and final step is the interaction
of the patient’s beliefs and expectations with those of the
physician. This step may be associated with decreased
worry about the symptom’s medical implications when
the patient–physician interaction goes well, or it may
© 2001 American College of Physicians–American Society of Internal Medicine 917
 Innovations in Symptom Management
lead to frustration and doctor-shopping when the inter-
action is problematic. The litigious nature of western
society may also lead the physician to order tests because
of anxiety about missing a medical problem. This may
inadvertently reinforce the patient’s worry over having a
medical illness.
SPECTRUM OF SEVERITY
The fourth edition of Diagnostic and Statistical
Manual of Mental Disorders (DSM-IV) has developed
dichotomous classifications of patients with unexplained
symptoms, such as somatization disorder, conversion
disorder, hypochondriasis, and pain disorder. In general,
these dichotomous diagnoses apply to only a small per-
centage of primary care patients and do not point to
specific treatment regimens. Most primary care patients
who have medical symptoms without identifiable pa-
thology have associated stressful life events or anxiety
and depressive diagnoses (or both) and do not have the
severity or the chronicity needed to qualify for diagnosis
with the somatoform disorders mentioned above (6 – 8).
Several research groups have shown that there is not
a sharp dichotomy between patients with multiple so-
matic symptoms (such as those with the somatization
disorder) and patients with medical symptoms without
identified pathology but actually a spectrum of severity
of somatization (9). As the number of medical symp-
toms without identified pathology increases, the number
of psychological distress symptoms, the number of anx-
iety and depressive diagnoses, and the degree of func-
tional impairment increase linearly (9 –13). Thus, in-
creasing numbers of medically unexplained symptoms
have been found to be proxy measures of the degree of
psychological distress and functional impairment
(9 –11). Longitudinal studies that have examined predic-
tors of chronicity in patients who have medical symp-
toms without identified pathology have found the base-
line number of physical symptoms to be the best
predictor of persistent impairment (14).
EPIDEMIOLOGY
Physical symptoms are common among community
respondents and are responsible for approximately 50%
of all physician visits (1). Epidemiologic surveys of com-
munity respondents have found high rates of such
symptoms as headache (15), fatigue (16), and abdomi-
nal pain (17). One health care diary study (18) reported
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Medical Symptoms without Identified Pathology
that participants had a new physical symptom every 5 to
7 days, and more than 90% of these symptoms were not
brought to a physician’s attention. Another study found
that 85% to 95% of community respondents had at
least one symptom every 2 to 4 days (19). People in the
United States have been found to restrict activities be-
cause of symptoms an average of 9.7 days per year and
to visit physicians an average of 2.7 times per year (20).
Researchers have sought to understand factors pre-
dicting medical visits for common physical symptoms,
such as headache or fatigue. Studies of community par-
ticipants with migraine headaches (15), fatigue (16), and
common gastrointestinal symptoms (17) have shown
that compared with persons who do not seek health
care, persons who do seek health care have significantly
more stressful life events (21, 22), have psychological
distress, and are significantly more likely to meet the
criteria for a DSM-IV anxiety or depressive disorder.
Epidemiologic studies have found that 25% to 35%
of primary care patients meet the criteria for a DSM
psychiatric disorder, most often an anxiety or depressive
disorder (8, 23). Researchers have shown that approxi-
mately half of patients with a DSM anxiety or depressive
disorder do not receive an accurate diagnosis by primary
care physicians (7, 8, 23). This may be because 50% to
80% of patients with a DSM anxiety or depressive dis-
order initially present with physical symptoms (7, 8).
Compared with patients with psychiatric illness who
present with psychological symptoms, significantly more
patients with psychiatric illness who present with phys-
ical symptoms do not receive an accurate diagnosis by a
primary care physician (7, 8).
Patients with common anxiety and depressive disor-
ders have significantly more medical symptoms without
identified pathology than do patients without psychiat-
ric illness (24, 25). In the Epidemiologic Catchment
Area study (25), 50% of community respondents with
five or more medically unexplained symptoms over a
6-month period met the criteria for a DSM-III psychi-
atric disorder; only 5% of respondents without these
symptoms met the criteria. Spitzer and colleagues, in the
Primary Care Evaluation of Mental Disorders (PRIME-
MD) 1000 study (26), showed that as the number of
medical symptoms increased, so did the percentage of
patients who met the criteria for a DSM-III-R anxiety or
depressive disorder (10). This was true both for symp-
toms that the primary care physician rated as “not ex-
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 Medical Symptoms without Identified Pathology Innovations in Symptom Management

plained by medical pathology” and for symptoms that Table 1. Medical Specialties and Problem Patients
the physician labeled as “probably due to a medical ill-
Specialty
ness.” Two other large primary care studies (9, 11) also
Cardiology
found a relationship between more medical symptoms Dentistry
without identified pathology and a higher likelihood of Ear, nose, and throat medicine
Endocrinology
a DSM-IV anxiety or depressive disorder. Gastroenterology
This relationship between the number of medical Internal medicine
Neurology
symptoms and psychiatric disorders holds true for pa- Obstetrics and gynecology
tients with subsyndromal psychiatric disorders. Mental Occupational medicine
health researchers (27, 28) have shown that as the num- Orthopedics
Pulmonology
ber of self-rated psychological symptoms increases, so Rehabilitation
does the number of self-rated physical symptoms, with a Rheumatology
Urology
correlation of about 0.5 between psychological scales of
distress and self-rated physical symptom checklists.
Common Presenting Conditions
Atypical chest pain, palpitations
Temporal mandibular joint syndrome
Tinnitus
Hypoglycemia
Irritable bowel syndrome
Chronic fatigue syndrome
Dizziness, headache
Pelvic pain, premenstrual syndrome
Multiple chemical sensitivity
Low back pain, neck pain
Hyperventilation, dyspnea
Closed head injury
Fibromyalgia
Interstitial cystitis

HEALTH CARE UTILIZATION
Patients with depressive and anxiety disorders are
often high utilizers of medical services, perhaps because
they have an increased number of physical symptoms. In
the Epidemiologic Catchment Area Study of five United
States cities (29), community respondents with one or
more with psychiatric disorders were significantly more
likely than respondents without psychiatric disorders to
be high utilizers of medical services. A study in a large
health maintenance organization (HMO) (30) found
that patients with depression who were treated with
antidepressants incurred about twice the health care
costs of age- and sex-matched patients without depres-
sion, even after adjustment for comorbid chronic med-
ical illness. These differences in medical costs were
found in every component measured, including primary
care, medical specialty, and mental health visits; in-
patient medical days; laboratory costs; emergency de-
partment costs; and radiography (30). Elderly patients
in an HMO who had positive results on screening tests
for depression were found to incur 30% to 50% more
overall costs than did nondepressed elderly persons after
adjustment for comorbidity (31). A retrospective
case–control study (32) showed that patients with a spe-
cific type of anxiety—panic disorder— had increased
medical costs in every year over a 10-year period com-
pared with age- and sex-matched controls.
This association between psychiatric disorders and
health care utilization is also evident if patients are iden-
tified by utilization patterns. High utilizers of medical
services have been shown to have high levels of psycho-
logical distress, anxiety, and depressive disorders (33,
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34). One study (33) reported that half of HMO patients
in the top 10% of utilization of ambulatory care were
significantly distressed on measures of anxiety, depres-
sion, and somatization; 80% of these patients met the
criteria for a lifetime DSM-III-R anxiety or depressive
disorder. These distressed high utilizers had a mean of
approximately eight physical symptoms without identi-
fied pathology, and more than two thirds had at least
one chronic medical illness.
MEDICAL SYNDROMES WITH ILL-DEFINED PATHOLOGY
In addition to evaluating patients who have single
medical symptoms without identified pathology, pri-
mary care and medical specialty physicians often evalu-
ate patients who have a cluster of symptoms for which
no medical explanation is found. As Table 1 shows,
these medical syndromes with no clearly defined causal
mechanisms are responsible for high percentages of visits
to specialists (35).
Our research group has completed a series of case–
control studies in which patients who have one of these
medical syndromes with ill-defined causal pathology
were compared with patients who were evaluated by the
same specialist and received a single clear medical diag-
nosis. For instance, we compared patients with the irri-
table bowel syndrome to those with inflammatory bowel
disease (36), and we compared patients with fibromyal-
gia to those with rheumatoid arthritis (37). In each
study, extensive medical testing had clearly divided the
patients into these diagnostic subgroups. Table 2 de-
scribes the similarity of findings in these studies. Patients
who have these syndromes without clear pathophysio-
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 Innovations in Symptom Management Medical Symptoms without Identified Pathology

Table 2. Major Depressive Disorder in Patients with Medically Unexplained Symptoms and in Controls with Clearly
Explained Symptoms*

Symptom (Reference) Major Current Major Lifetime Mean Lifetime Medically Unexplained
Depression Depression Depressive Episodes Symptoms

% n
Irritable bowel syndrome (36) 21 61 2.5 12
Inflammatory bowel disease 6 17 4

Fibromyalgia (37) 14 86 5 15
Rheumatoid arthritis 6 31 5

Chest pain without CAD (38) 35 64 5 6

Chest pain with CAD 3 16 3

Fatigue (39) 15 77 2 12
Rheumatoid arthritis 3 42 4

Pelvic pain (40) 34 66 5 8

No pain 10 16 2

Idiopathic dizziness (41) 12 42 2 8

Peripheral ear disease on electronystagrogram 5 18 – 2

* CAD ⫽ coronary artery disease on arteriography.

logic mechanisms were significantly more likely to have
met criteria for current and lifetime major depressive
episodes than were those with defined medical diseases
(36 – 40). Compared with medical controls, they also
had significantly more medical symptoms without
identified pathology in other organ systems (36 – 41). As
Figure 1 shows, patients with the irritable bowel syn-
drome (36), fibromyalgia (37), unexplained chest pain
(38), and labile hypertension plus negative results on
pheochromocytoma work-ups (42) were more likely
to meet the criteria for panic disorder than were the
medical controls with inflammatory bowel disease, rheu-
matoid arthritis, coronary artery disease on angiography,
and hypertension plus cholesterol screening, respectively.
Given the above-mentioned evidence showing that
increasing numbers of physical symptoms are associated
with more psychological symptoms and anxiety and de-
pressive disorders, it is not surprising that patients who
meet the criteria for two or more medical syndromes
with no clearly defined pathology have even higher de-
grees of psychopathology and functional impairment
than do those with only one syndrome (43). Walker and
coworkers (43) showed that women who met the criteria
for chronic pelvic pain and the irritable bowel syndrome
had a higher degree of psychological distress and disabil-
ity than did those with chronic pelvic pain alone.
Confirmatory evidence of high rates of psychiatric
920 1 May 2001 Annals of Internal Medicine Volume 134 • Number 9 (Part 2)
disorders in patients who had medical syndromes with
no clearly defined pathology has also been found in pri-
mary care. Rates of psychiatric disorder were signifi-
cantly higher in primary care patients with a symptom
(for example, fatigue) and syndrome (for example, irri-
table bowel syndrome) with no identified pathology
than in those who had a medical illness that explained
their symptoms (44).
ANXIETY AND DEPRESSIVE DISORDERS
Physicians have often said that patients with similar
tissue pathology vary considerably in their perception of
symptoms and their degree of functional impairment.
Some patients minimize physiologic events due to
chronic illness; others amplify them. Comorbid psychi-
atric illness and stressful life events are often associated
with amplification. In studies of patients with well-
defined chronic medical disease (head injury [45], in-
flammatory bowel disease [46], hepatitis C [47], and
chronic tinnitus with hearing impairment [48]), our re-
search group has found that patients with comorbid
anxiety or depressive disorders have significantly more
medical symptoms without identified pathology and sig-
nificantly more functional impairment than do those
with chronic medical illness alone, after adjustment for
severity of physical disease (Figure 2). Patients with
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 Medical Symptoms without Identified Pathology Innovations in Symptom Management

chronic medical illness tend to have significantly higher
rates of psychiatric disorders, and the tendency of pa-
tients with comorbid medical and psychiatric disorders
to amplify physical symptoms may be diagnostically
confusing to the primary care physician and may lead to
excessive medical testing. For instance, among patients
with type 2 diabetes mellitus, those with comorbid de-
pression have been shown to have 51% higher primary
care costs, 75% higher ambulatory care costs, and 86%
higher total health care costs than do those without co-
morbid depression, even when after careful adjustment
for severity of diabetes and other medical disorders (49).
These increases in costs are probably explained by the
increase in physical symptoms experienced by depressed
or anxious patients. Lustman and colleagues (50)
showed that diabetic patients with comorbid anxiety
and depression had significantly more of the 13 symp-
toms associated with poor control of diabetes (for exam-
ple, polyphagia and polydipsia) than did diabetic pa-
tients without psychiatric illness, but hemoglobin A1c
levels did not correlate with the differences in symptoms.
Sullivan and colleagues (51) reported that in pa-
tients with documented coronary heart disease, anxiety
and depressive symptoms predict symptom severity and
functional impairment occurring up to 5 years later.
This predictive power remains significant after adjust-
ment for severity of coronary disease on angiography
and cardiac procedures administered during follow-up.
Similarly, Walker and associates (46) showed that
patients with inflammatory bowel disease and comorbid
anxiety and depressive disorders have significantly more
gastrointestinal symptoms, nongastrointestinal symptoms,
and functional impairment than do patients with in-
flammatory bowel disease and no psychiatric illness,
after adjustment for the severity of inflammatory bowel
disease (46).
The important lesson to be drawn from studies of
medical–psychiatric comorbidity is that distress and dis-
ease both produce physical symptoms. It is not produc-
tive to dichotomize symptoms as “somatogenic” and
“psychogenic” because physiologic and psychological
processes are involved in all symptom production and
perception. “Rule out” diagnostic strategies that search
for either a medical or a psychiatric cause of a physical
symptom are not supported by epidemiologic findings
of high rates of medical and psychiatric comorbidity.
CHILDHOOD ADVERSITY
Adverse childhood experiences, such as abuse or ne-
glect; unexplained childhood physical symptoms, such
as abdominal pain; and having at least one parent with a
chronic illness are associated with adult vulnerability to
anxiety and depressive disorders and increases in medical
utilization and somatization (52–57). Some experiences

Figure 1. The association of current panic disorder with medical syndromes without identified pathology.

The figure compares 1-month prevalence of panic disorder in patients with medically unexplained symptoms (white bars) and in controls with a
well-defined medical illness (gray bars). *On angiography. CAD ⫽ coronary artery disease; RA ⫽ rheumatoid arthritis; P ⫽ pheochromocytoma.

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 Innovations in Symptom Management Medical Symptoms without Identified Pathology

Figure 2. Association of depression with number of somatic symptoms in patients with chronic medical illness.

White bars represent patients with current depressive or anxiety disorders according to Diagnostic and Statistical Manual of Mental Disorders, fourth
edition, criteria; gray bars represent patients without such disorders. IBD ⫽ inflammatory bowel disease.

in adulthood, such as physical assault, domestic vio-
lence, trauma (58, 59), and natural disasters (60, 61),
have also been linked to increased psychological distress
and reporting of physical symptoms.
A large epidemiologic study of more than 1200
women in an HMO showed that as the number of re-
ported adverse childhood experiences (emotional ne-
glect, physical neglect, emotional abuse, physical abuse,
and sexual abuse) increased, so did the number of med-
ical symptoms without identified pathology and medical
costs (54, 55). Severity of childhood adversity was also
significantly associated with maladaptive high-risk behav-
iors, such as smoking, drinking, obesity, teenage preg-
nancy, more sexual partners, and lack of use of safe-sex
techniques (54, 55). The fact that these high-risk behav-
iors are likely to lead to chronic medical diseases may
explain why high utilizers of primary care often have a
complex combination of multiple medical symptoms,
psychiatric disorders, and chronic medical diseases (55).
922 1 May 2001 Annals of Internal Medicine Volume 134 • Number 9 (Part 2)
A substantial body of literature now links childhood
maltreatment and adult assault to persistent syndromes,
such as the irritable bowel syndrome (36), chronic pelvic
pain (40), and fibromyalgia (62). Moreover, in studies
of patients with the irritable bowel syndrome, chronic
pelvic pain, and fibromyalgia, the best predictor of those
who had and had not experienced childhood abuse was
the number of physical symptoms without identified pa-
thology that the patient had had (36, 40, 62).
SPECIFIC PERSONALITY TRAITS
For most patients, distress is a temporary state, but
some patients face enduring or lifelong distress. This
enduring distress has been linked with specific personal-
ity traits. Increasing numbers of physical symptoms have
been linked to high levels of neuroticism or harm avoid-
ance as well as to high negative affectivity (13, 27, 28,
63). Patients who score high on these overlapping per-
sonality measures describe more negative emotions (such
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 Medical Symptoms without Identified Pathology
as anger, depression, and anxiety) (13, 27, 28, 63), re-
port more negative life events over time (64), and are
more likely to develop an axis I psychiatric disorder (for
example, major depression) when faced with an adverse
life event (65, 66). Higher levels of neuroticism and
harm avoidance also correlate with axis II personality
disorders in which poor ability to cope with stress is the
norm (67). Patients with personality disorders often
have a sense of powerlessness in dealing with life prob-
lems, and physical symptoms may be expressing their
distress and perceived powerlessness. In some environ-
ments, physical symptoms can be the only available
source of leverage and power. Pain may be the only way
to increase support from family members or to attain
financial stability (through disability payments).
IMPLICATIONS OF RESEARCH
One implication of the large body of emerging lit-
erature reviewed above is that primary care physicians
and specialists should screen for anxiety and depressive
disorders in patients who present with multiple physical
symptoms and in patients with chronic medical disor-
ders who seem to have excess symptoms and disabilities.
Patients who present with physical symptoms and have
comorbid anxiety and depressive disorders are more
likely to have unmet expectations after the physician
visit, to be considered difficult, and to report persistent
stress over a 3-month period (15, 24). A single measure
that has been shown to be an effective screening test for
the likelihood of psychiatric disorders is the identifica-
tion of 6 or more physical symptoms on the 15-item
somatic symptom checklist of the PRIME-MD (26).
The importance of accurate diagnosis is evident in two
recent critical reviews showing that patients who have
persistent medical symptoms without identifiable pa-
thology can respond to antidepressant medication (94
controlled trials) (68) as well as cognitive– behavioral
therapy (31 controlled trials) (69).
CONCLUSIONS
Medical symptoms such as headache and fatigue are
associated with approximately 50% of visits to primary
care physicians. Most of the time, no clear medical ex-
planation of the symptom is found. Stressful life events,
anxiety and depressive disorders, childhood and adult
trauma, and specific personality traits have all been
found to be associated with multiple physical symptoms
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Innovations in Symptom Management
among primary care and medical specialty patients.
Given the high prevalence and high medical costs of
these symptoms, we have a pressing need for research on
pragmatic primary care interventions to improve recog-
nition of biopsychosocial causes of medical symptoms
and syndromes with no clearly identified pathology and
cost-effective management approaches.
From University of Washington Medical School, Seattle, Washington.
Grant Support: By grant MH-01643 from the National Institute of
Mental Health (Dr. Katon).
Requests for Single Reprints: Wayne Katon, MD, Department of
Psychiatry and Behavioral Sciences, University of Washington Medical
School, Box 356560, 1959 NE Pacific Street, Seattle, WA 98195-6560;
e-mail, wkaton@u.washington.edu.
Current Author Addresses: Drs. Katon, Sullivan, and Walker: Depart-
ment of Psychiatry and Behavioral Sciences, University of Washington
Medical School, Box 356560, 1959 NE Pacific Street, Seattle, WA
98195-6560.
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