EUROPEAN NEUROLOGICAL JOURNAL REVIEW ARTICLE

Morbid Anxiety as a Risk Factor in Patients with Somatic

Diseases: A Review of Recent Findings
Christer Allgulander, MD
Affiliation: Karolinska Institutet Department of Clinical Neuroscience, Section of Psychiatry, Karolinska University Hospital – Huddinge, Sweden

A B S T R A C T

This review focuses on anxiety in patients with somatic diseases, based on studies published from 2007 through January 2010. It covers
neurological, cardiovascular, respiratory, and endocrine diseases as well as HIV/AIDS, trauma, skin conditions, and other somatic diseases.
Anxiety may be an acute and adequate reaction to receiving a diagnosis of a disabling or life-threatening disease. It may also be precipitated
by stroke, injury, or the distress of having to manage diabetes or AIDS. Several studies show that anxious patients inflate self-perceived health
problems and are more sensitive to physical symptoms in a manner disproportionate to objective disease validators. Therefore, intervention
should be reserved for those patients most likely to benefit from reduced anxiety, improved management of the somatic condition, and
improved functioning.
This issue is particularly important for the elderly, who represent a growing global challenge. Late-onset anxiety may be caused by
loneliness and bereavement, and can be compounded by immobilization and somatic disease. Controlled treatment studies of anxiolytics as
well as their potential benefits in the overall management of anxious patients with somatic disease are generally lacking. Research to
determine the benefits and costs of such treatments in primary and tertiary care is currently underway.

Keywords: anxiety disorders, stroke, diabetes, COPD, pain, IBS, SLE

Correspondence: Christer Allgulander, M.D., Associate Professor, Senior Lecturer, Karolinska Institutet, Department of Clinical
Neuroscience, Section of Psychiatry, M56 Karolinska University Hospital – Huddinge, SE 141 86 Huddinge, Sweden. Tel: +46858585797;
e-mail: Christer.Allgulander@ki.se

INTRODUCTION are part of the epigenetic and neurodevelopmental fields,

‘‘The affection, as far as my own experience enables me to
form an opinion, more frequently occurs in individuals who
have been exposed to the influence of powerfully depressing
causes, either mental or physical, but when it is excited by
severe cold or acute rheumatism, such predisposing causes
may not be met with in so marked a degree… Prolonged
mental anxiety likewise powerfully predisposes to the disease,
especially if, as is often the case, it is combined with night
watching. I have known many instances where rheumatoid
arthritis has followed in daughters in the nursing of parents
during a long illness.’’ Garrod, 1876 [1]
BACKGROUND
Clinicians in many fields of medicine concur that the
observation by Garrod still holds true. Many hypotheses have
since been put forth to explain the bidirectional relationship
between anxiety, depression, stress, and somatic disease.
Franz Alexander (1891–1964) conceptualized psychosomatic
diseases based on seven direct causal models (e.g., that the
suppression of aggressive impulses caused arterial hyperten-
sion, that fear of death caused hyperthyroidism, and that
irritable hostility led to ulcerative colitis). Another Hungarian-
born physician, Hans Selye (1907–1982), began his famous
work on stress-caused disease in 1926. Today, such theories
tying together early-life stress and subsequent psychiatric and
somatic morbidity.
From a population perspective, associations between
medical conditions and mental disorders (including anxiety
disorders) are the rule. In a 2007 Australian national survey,
10% of male and 15% of female survey participants in good
somatic health reported an anxiety disorder; these numbers
contrasted, respectively, with the 12% and 28% observed
among participants with medical illness [2]. The highest rates
of anxiety disorders, 31% in men and 21% in women, were
found in participants with stroke.
One of the first multidisciplinary conferences on anxiety and
depression in general medicine occurred in 1999 [3]. It
brought together oncologists, cardiologists, and psychia-
trists, and highlighted the high disability rates found in the
WHO Global Burden of Disease Survey in 1990 and Medical
Outcomes Study in 1989.
Peter Roy-Byrne et al [4] reported from a multidisciplinary
conference in 2006 and provided a comprehensive list of 197
references to relevant studies through 2007. They reviewed
studies in irritable bowel syndrome, asthma, cardiovascular
disease, cancer, and chronic pain, and concluded that anxiety
is associated with an increased prevalence of these conditions
comparable to that of depression. None of the reviewed

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European Neurological Journal
studies addressed the potential benefits of anxiolytic treat-
ments for the outcome of these somatic conditions, and none
of the controlled studies sought to reduce the anxiety
component. Byrne and co-workers recommended more
research in this field and proposed the implementation of
collaborative, stepped-care treatment programs (demonstra-
tion projects), including cognitive behavioral therapy (CBT),
pharmacotherapy, and means of improving treatment adher-
ence via telephone and the internet (especially for high
utilizers of primary care). It was highlighted that stigma
regarding mental illness in primary care patients needed to be
addressed, and awareness among primary care providers of
the impact of anxiety on patients with chronic medical
conditions needed to be increased. This approach is part of
the emerging effort in comparative effectiveness research that
aims to tailor and evaluate treatments based on the needs of
individual patients in everyday care.
Katon et al [5] conducted a systematic literature review of 31
quality studies through 2006 examining the associations of
anxiety and depression with diabetes, pulmonary disease,
cardiac disease, and arthritis. Most studies were cross-
sectional. Two randomized treatment studies in depressed
diabetes patients and depressed pain patients found that both
depressive and medical symptoms improved. Patients with
these comorbid conditions reported higher rates of all types
of medical symptoms, even after controlling for the severity of
the somatic disease. It was reasoned that anxiety and
depression cause poor adherence to lifestyle improvements
and increase the rate of medical complications, resulting in
greater functional impairment, higher costs of care, and
polypharmacy. Based on these findings, Katon et al called for
large intervention studies to determine the potential benefits
of identifying and treating depressed and anxious patients
with medical illness.
Larry Culpepper [6] reviewed the potential physiological
links between generalized anxiety and medical conditions as
well as the neuroendocrine consequences of untreated
anxiety, and called for anxiolytic treatment in these patients.
In October 2008, the World Federation of Societies of
Biological Psychiatry issued an updated guide for treating
anxiety disorders and obsessive-compulsive disorders [7].
This guideline concluded that there were no controlled
studies showing a robust benefit of anxiolytic treatments on
vital variables of the somatic condition (e.g., percentage of
glycated hemoglobin, cardiac events, seizure rate, or
improved forced expiratory volume).
This paper sets out to review recent studies, building on the
reviews reported above. It includes studies of patients in primary
care with medical illness as well as patients in tertiary somatic
care (e.g., neurology, cardiology, endocrinology, respiratory
medicine, and infectious diseases). In addition to the disease
categories previously reviewed, it captures data on anxiety in
epilepsy, migraine, traumatic brain injury, brain tumor, pain,
stuttering, dementia, Parkinson’s disease, multiple sclerosis,
restless legs, allergies, psoriasis, premenstrual dysphoria, HIV/
AIDS, Systemic Lupus Erythematosus (SLE), and traumatic
ENJ 2010; 2:(1). June 2010
injury. It also summarizes current recommendations for the
treatment of morbid anxiety in patients with medical illness.
CURRENT CONCEPTUALIZATIONS OF ANXIETY
IN DISEASE
Recently, the frontiers of anxiety research were reviewed by a
European science advisory panel [8]. Anxiety is currently seen
as a developmental disorder, i.e., the result of gene-environ-
ment interactions that can induce structural and functional
changes in the amygdala-prefrontal circuitry [9, 10]. Such
gene-brain cognitive pathways may involve brain-derived
neurotrophic factor [11]. Anxiety disorders are genetically
complex, and may phenotypically result from the expression of
gene-gene or gene-environment interactions [12]. Candidate
gene findings have not been specific or replicable. Genome-
wide scanning of tens of thousands of probands and controls
are clearly necessary to advance the field.
Early life stressors begin in the uterus. Women who
reported severe anxiety were at risk for having shorter
gestations and delivering smaller babies, who in turn were
at risk for mental disorders including anxiety disorders [13,
14]. Behavioral inhibition during early childhood can
contribute to anxiety disorders [15]. In one study, childhood
mental health problems predicted obesity, eczema, asthma,
and epilepsy in early adulthood [16]. Another study showed
that children exposed to adversity had an increased risk for
both depression and metabolic risk markers for age-related
disease [17]. In the 1958 British Birth Cohort, childhood
anxiety disorders increased the risk of midlife anxiety and
affective disorders [18]. Thus, current theories on morbid
anxiety fit a multifactorial epigenetic model that integrates
early stressors, inherited and acquired vulnerabilities, and
risks of developing interrelated or coincidental somatic
diseases. Proper elucidation of such a model requires very
large prospective cohort studies.
NEUROLOGICAL DISEASES
The relationship between anxiety disorders and epilepsy is
complex. Anxiety may cause serious impairment in patients
with epilepsy. The mechanism might be linked, in part, to the
GABA-A receptor, and thus modifiable by anxiolytic/anti-
seizure medications such as pregabalin [19]. Anxiety may be
ictal (simple focal seizures of temporal lobe origin), postictal
(not due to epileptic discharges), or interictal (limbic
epilepsies, perhaps due to kindling). Interictal anxiety is
associated with the possibility of brain damage, repeated
seizures, and memory impairment. Roughly 20–30% of
patients develop seizure phobia. Among primary care patients
with epilepsy, 11% had an anxiety disorder; in candidates for
epilepsy surgery, this value was 10–30%. In one study of 217
candidates for chronic epilepsy surgery, psychiatric comor-
bidity was carefully investigated [20]. Four men and two
women, mostly with right focus localization, had a general-
ized anxiety disorder with a mean duration of 14 years.
Another study of patients with temporal lobe epilepsy (partial
epilepsy) found no increase in psychiatric symptoms as
compared to patients with other forms of epilepsy [21].
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Anxiety was present in many children and adolescents with
epilepsy, with similar rates in boys and girls [22]. In addition
to providing optimization of seizure control, general
counseling, and support, CBT may be of benefit and even
reduce seizure frequency by improving the patient’s lifestyle.
Children may also benefit from education intended to
enhance communication skills and decision-making.
Pregabalin is recommended due to its combined antiepileptic
and anxiolytic effects, as well as its lack of relevant
pharmacokinetic interactions. SSRIs are reportedly useful,
but controlled trials are absent. Buspirone is also to be
considered for epileptic patients with anxiety.
Migraine affects 12% of the adult U.S. population and is
comorbid with major depression, panic disorder, and bipolar
disorder. Among 112 consecutive patients in tertiary referral
centers in Italy and Germany interviewed using the M.I.N.I.
Plus 5.0 neuropsychiatric inventory, 29% had a current anxiety
disorder, 13% had lifetime GAD, and 8% had a lifetime panic
disorder [23].
Traumatic brain injury (TBI) occurs in 1.5–2 million
individuals each year in the United States. A systematic
review of pooled studies reported GAD in 25% of TBI
patients, panic disorder in 4%, PTSD in 17%, and OCD in 9%
[24]. It is speculated that these high rates are due to disrupted
brain anxiety circuits as well as problems in restoring
function after TBI.
Primary brain tumors are diagnosed in 41,000 patients per
year in the United States, and 18,000 of these tumors are
malignant. The Brief Patient Health Questionnaire, including
seven items for generalized anxiety disorder, was used to
ascertain anxiety and depression in a sample of 363 new adult
patients referred to an oncology clinic with brain tumors [25].
Five percent had a prior psychiatric diagnosis. GAD
symptoms were found in 48% of the patients, and
psychoactive medications were used by a third of them.
Current depression was found in 41% of the patients, one-
fourth of whom were taking psychoactive medications.
Pain is an intriguing, multifaceted phenomenon. Pain
accounts for 20% of all outpatient visits in the U.S. Primary
care physicians face a large group of patients requiring frequent
visits for chronic pain that overlaps with fatigue, depression,
anxiety, and somatoform disorders, and members of this group
are often elderly, female, or less educated [26]. The DSM-IV
nosology fails to capture these diagnostic overlaps. Psychiatric
studies have only recently explored the association between pain
and anxiety. Beesdo et al [27] studied GAD symptoms in relation
to pain symptoms reported in a German community sample of
4,181 adults interviewed in 1998. The pain was more strongly
associated with GAD (OR 1.0 for pain symptoms and OR 16.0
for DSM-IV pain disorder) than with other anxiety disorders; this
finding extended to subthreshold GAD. The association
remained after controlling for comorbid conditions. Pain
disorders were found in 38% of GAD cases and preceded the
onset of GAD in the majority of cases. The same group also
reported a post hoc analysis of the pain-relieving effect of
duloxetine in patients with GAD [28]. Self-rated pain was
assessed in three double-blind studies with 1,727 patients.
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Morbid anxiety as a risk factor in patients with somatic diseases
Duloxetine significantly reduced pain scores in 9 to 10-week
treatment trials, and the effect was sustained for up to 26 weeks.
In a U.S. primary care sample of 500 patients with chronic
pain, comorbid anxiety and depression increased the severity
of the reported pain and disability, and impaired patient
quality of life [29]. More psychosocial stress was reported by
patients with comorbid depression [30]. In a study of 96 war
veterans (predominantly males) with heart failure, 37%
reported moderate-to-severe pain; pain was more frequent
than dyspnea [31]. Anxiety was investigated with two
questions regarding worry, and anxiousness was correlated
to pain severity. Twenty of the probands were diagnosed with
an anxiety disorder. Many had concurrent diabetes and
pulmonary disease.
Temporomandibular pain is estimated to affect 12% of
adults in the United States, usually in the age group ranging
from 20–40 years. Bruxism is the associated involuntary
excessive grinding or clenching of teeth that may occur
during the waking or sleeping state. A review of the role of
psychosocial factors in bruxism revealed no association
between anxiety and sleep bruxism [32]. A German study of
223 patients with temporomandibular pain found no
association with self-reported anxiety [33].
Stuttering is estimated to affect 1% of the population, with a
male:female ratio of 4:1. Its cause is unknown. In a matched
case-control study of 92 adults seeking speech therapy for
stuttering, the odds of having an anxiety disorder were
increased seven-fold [34]. There was a 34-fold increased odds
of having a social anxiety disorder. Among the probands, 22%
had social anxiety, 9% had GAD, and 3.3% had OCD. These
anxiety disorders may negatively impact social skills, be
aggravated by bullying and stigma, and reduce or obviate the
benefits of speech therapy.
Dementia and cognitive impairment not dementia (CIND)
were studied as outcomes in a prospective study over a 17-year
period in 1,160 men, 585 of whom scored high on an anxiety
trait scale at baseline [35]. Anxiety was found to be associated
with cognitive impairment for participants in the upper 30th
percentile of the anxiety score. The age-adjusted odds ratio of
dementia or CIND among those men with anxiety and no
cognitive decline at baseline was 4.0. For dementia alone, the
age-adjusted odds ratio for men with baseline anxiety traits
was 5.0. Vascular and non-vascular dementia cases had
similar odds ratios.
A prospective case-control study of 196 subjects who
developed Parkinson’s disease was conducted at the historical
medical record register of the Mayo Clinic [36]. There was a
statistically significant association to a DSM-IV diagnosis of
anxiety disorder at 5, 10, and 20 years before the onset of
motor symptoms. The odds ratio of anxiety preceding motor
symptoms was 3.1 in women and 1.8 in men. Similar findings
were shown for 90 cases and matched controls in Pisa, Italy;
thirty percent of the cases had a panic disorder [37].
The north part of Norway is a high-risk area for multiple
sclerosis (MS), and a study of 172 MS patients compared to
56,000 controls found high rates of anxiety among the
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European Neurological Journal
patients [38]. Among the male subjects, 31% of the patients
compared to 12% of the matched controls reported anxiety on
the Hospital Anxiety Depression Scale. In women, the rates
were 30% and 17%, respectively, and these rates were
reportedly similar to findings in a Canadian study.
Restless legs syndrome (RLS) was already recognized to
cause anxiety in the late 1800s. Rates of anxiety disorders were
compared between 130 RLS patients and 2,265 community
residents using a psychiatric diagnostic interview [39]. The
odds ratios for RLS subjects having a panic disorder, GAD, or
major depression in the last year were 4.7, 3.5, and 2.6,
respectively.
CARDIOVASCULAR DISEASES
Anxiety is a well-known risk factor in cardiovascular
disease. Taiwan has a national database on practically all
residents (21.7 million) that includes ICD-9 diagnoses,
prescriptions, age, and gender. A study of 913,570 cases of
anxiety disorder treated with psychoactive medications during
a 4-year period compared the prevalence of ischemic heart disease
and hypertensive disorders to that among residents without
treatment with psychoactive medications [40]. The relative
risk of having treatment for ischemic heart disease and
hypertension increased 10- and 5-fold, respectively, in treated
anxiety subjects younger than 20 years in age. The risks
decreased substantially with age, as cardiovascular disease
became more common in the matched population.
Another Taiwanese study examined whether panic disorder
first diagnosed in 2004 increased the risk of a first myocardial
infarction during a 12-month period [41]. The 9,641 probands
were compared to 28,923 matched healthy controls. Probands
were more likely at baseline to have hypertension, hyperlipi-
demia, and coronary heart disease, and less likely to have
diabetes and renal disease. A subsequent first myocardial
infarction occurred in 5% of the probands and 3% of the
controls. The hazard ratio for infarction, after controlling for
other risk factors, was 1.8 among the probands. Additional
baseline risks were concurrent hypertension and coronary
heart disease after controlling for age and other social and
medical risk factors.
A household interview survey of 4,351 South Africans
evaluated DSM-IV anxiety disorders in relation to self-reported
hypertension [42]. Having hypertension was associated to
having an anxiety disorder with a 1.6 odds ratio in a
multivariate model. Subjects with a history of multiple traumas
had odds ratio of 3.8 for having an anxiety disorder. GAD and
panic disorder were the diagnoses most strongly associated
with hypertension, with odds ratios of 3.6 and 3.2, respectively.
After controlling for other risk factors, a United States
household interview survey of 43,093 adults found that
cardiovascular disease was associated with odds ratios of 1.5,
1.5, and 1.3 for having GAD, panic disorder, or a specific
phobia, respectively [43].
In 1986, 4,256 Vietnam veterans selected from army records
of 4.9 million people were medically examined in
Albuquerque [44]. Causes of death were monitored for 15
ENJ 2010; 2:(1). June 2010
years, at which point 236 had died. Of these, 10% had a GAD
diagnosis and 7% a major depressive episode. These factors
were associated with an elevated risk of 1.7- and 1.6-fold,
respectively, for all causes of mortality after adjustment for
age and covariate risk factors. Comorbid PTSD, depression,
and GAD conferred an increased risk of cardiovascular death.
Patients in Montreal who had been diagnosed with stable
coronary artery disease by catheterization underwent a
structured diagnostic interview and received symptom ratings.
They were monitored with regard to cardiac events for 2 years
[45]. Of the 804 patients, 115 had a cardiac event. After
controlling for medical and social baseline characteristics, a
GAD diagnosis conferred an odds ratio of 2.6 for a cardiac
event; a major depressive episode conferred an odds ratio of
2.5. Treatment with antidepressants or benzodiazepines was
not related to the risk of cardiac events. The authors
recommended treatment for depression and anxiety with
SSRIs in patients with coronary artery disease.
Middle-aged, healthy women in the general population of the
Netherlands completed a three-item anxiety scale and were
monitored for all-cause mortality over a 10-year period, during
which 114 died [46]. Among the 5,073 probands, self-reported
anxiety was associated with a hazard ratio of 1.8 for all-cause
mortality; for cardiovascular causes, the hazard ratio was 2.8.
Eight studies of anxiety in chronic heart failure were
reviewed by Yohannes et al [47]. Current clinical anxiety was
found in 18% of outpatients. Studies showed a substantial
overlap between heart failure, chronic obstructive pulmonary
disease, and depression. Anxiety was related to comorbid
diabetes and angina in heart failure patients. Cardiac
rehabilitation (exercise, relaxation, stress management, and
education) was shown to be anxiolytic in an uncontrolled
intervention study, although it had no measurable benefit in a
different study. In a randomized study, exercise and diet
combined with CBT were more effective in reducing anxiety
than digoxin or placebo.
Implantable cardioverter fibrillators (ICDs), indicated in
patients with life-threatening arrhythmias, were the subject of
a Dutch prospective study of 284 patients over a 12-month
period [48]. The prevalence of chronic anxiety in 96 patients
with no risk factors was 34%. In the 120 probands with
diabetes, cardiac resynchronization therapy, or Type D
personality, chronic anxiety was reported in 64%. ICD-
induced shocks were not related to persistent anxiety.
RESPIRATORY DISEASE
A review of 22 studies of anxiety and 30 studies of
depression in the setting of chronic obstructive pulmonary
disease (COPD; air flow limitation that is not fully reversible)
was compiled by Yohannes et al [47]. Clinical anxiety, often
secondary to depression, was found in up to 55% of patients
with COPD. Functional impairment was more strongly
associated to depression and anxiety than to reduced
respiratory function. Anxiety was reportedly associated with
worry, nausea, tachycardia, sweating, and dyspnea as well as
with increased rates of COPD exacerbations, emergency care
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visits, and hospitalizations. Chronic hypoxia may be one of
the mechanisms involved. Less than one-fourth of the anxious
or depressed COPD patients received antidepressant or
anxiolytic treatment. In fact, 72% of patients refused
antidepressant treatment, perhaps because of the large
number of other medications they were taking. Indeed, the
treatment data are not convincing, as one placebo-controlled
study employing nortriptyline for 3 months and another
employing buspirone for 2 weeks improved anxiety and
depressive symptoms without affecting respiratory function
[49, 50]. On the other hand, exercise may be beneficial, as
shown in controlled intervention trials. According to a
controlled trial, COPD education and CBT may also reduce
depressive and anxious symptoms. Collaborative care pro-
grams assigning a personal nurse manager to patients with
heart failure and/or COPD are endorsed by the World Health
Organization.
A postal questionnaire survey was conducted among 110
COPD patients in the British general population, and anxiety
measures were correlated with spirometric and demographic
data from general practice records [51]. Fifty percent of the
patients were current or past smokers. One-third of the
participants scored for anxiety on the Hospital Anxiety
Depression Scale. Health-related impairment and severity of
COPD symptoms were correlated to anxiety levels.
Respiratory disease was diagnosed at 1 year of age in a
cohort of 399 children; the children were assessed again
between the ages of 30 and 39 years for anxiety and
depression [52]. The adjusted odds ratios of GAD diagnosis
in adulthood if diagnosed with a respiratory disease at ages 1
and 7 were 1.9 and 0.8, respectively.
ENDOCRINE DISEASES
Diabetes patients are at risk of anxiety and depression,
which may impair glycemic control [53]. Several controlled
studies have shown that antidepressant and anxiolytic
treatment may improve diabetes status [54–57]. However,
the relationship between major depression, diabetes distress,
and improvement in glycated hemoglobin (A1C) is complex. A
study of 506 patients with Type 2 diabetes found a concurrent
and longitudinal association between diabetes distress and
A1C but no association with major depression or depressive
symptoms [58]. In a study in Ireland, 1,456 patients with
Types 1 and 2 diabetes self-rated their anxiety and depressive
symptoms on the Hospital Anxiety Depression Scale [53].
One-third of the patients had high anxiety scores, and one-
fourth of them had high depression scores. Both categories
were associated with diabetes complications, smoking, and
alcohol consumption. These associations were particularly
prevalent in young patients and occurred regardless of the
primary or secondary care setting.
In a 5-year prospective study of 4,623 primary care patients
with Type 2 diabetes, major depression was associated with
microvascular and macrovascular complications [59].
A telephone survey of 201,575 residents in the United States
included questions about diagnoses of diabetes and anxiety
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Morbid anxiety as a risk factor in patients with somatic diseases
disorders [60]. The rate of anxiety disorders in diabetic
individuals was estimated as 16%, compared to a rate of 11%
in non-diabetic individuals. In American Indians/Alaska
natives and people of Hispanic ethnicity, a lifetime anxiety
disorder was reported by 40% and 20% of individuals with
diabetes, respectively.
Premenstrual dysphoric disorder (PMDD) affects 5% of
fertile women in the United States and Europe [61]. Two of
the chief symptoms are depressed mood/dysphoria and
anxiety/tension that consistently impair social functioning
during the 6 days prior to menses. Women with PMDD are
more likely than other women to have a history of psychiatric
disorders, particularly mood and anxiety disorders. They are
more prone to react with panic attacks upon lactate challenge.
Exacerbations of obsessive-compulsive disorder are seen
during the premenstrual phase. Intermittent or continuous
treatment with serotonin reuptake inhibitors has been shown
to be effective in reducing depression and anxiety/tension in
several studies. Long-acting gonadotrophin-releasing hor-
mone agonists have also proven effective, whereas oral
contraceptives are ineffective.
OTHER SOMATIC DISEASES
Depression, adjustment disorder, and posttraumatic stress
disorder are commonly seen in patients with HIV/AIDS. HIV-
associated dementia is an encephalitis associated with
cognitive decline, behavioral abnormalities, and progressive
spastic paraparesis with sensory ataxia [62]. The initial
symptoms may include mania, irritability, confusion, and
impaired judgment. Untreated cases have a survival of 6–9
months. HAART treatment rapidly reduces the symptoms, but
cognitive decline can still be seen. Currently, treatment with
SSRI/SNRIs is recommended to ameliorate symptoms of
anxiety and depression. Because of their adjunct pain-
reducing effects, pregabalin, venlafaxine, and duloxetine
may be preferred.
Mood, anxiety, and substance use disorders are associated
with a more rapid CD4 cell count decline, progression to AIDS,
and death [63]. Among a total of 1,125 patients in an HIV
academic center in North Carolina, 148 probands 30–50 years
old underwent a psychiatric diagnostic interview. Twenty
percent were diagnosed with an anxiety disorder (6% PTSD,
5% panic disorder, and 10% other anxiety disorders).
In Cape Town, South Africa, 429 HIV-infected adults
underwent screening for depression and anxiety disorders
with the K-10, a self-report instrument; the results obtained
with this instrument were validated with the MINI neurop-
sychiatric interview [64]. A current diagnosis of GAD was
made in 18%, PTSD in 22%, agoraphobia in 18%, panic
disorder in 15%, and social phobia in 12% of the adults. The
K-10 instrument was also found to be a useful proxy measure
in Afrikaans- and Xhosa-speaking subgroups.
The risk of developing a psychiatric disorder following a
traumatic injury was assessed in a prospective cohort of 1,084
patients admitted to major trauma hospitals in Australia [65].
Forty percent of the probands had a mild traumatic brain
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European Neurological Journal
injury (TBI). The MINI 5.5 neuropsychiatric interview was
administered one week after discharge as well as 3 months
and 12 months after the injury. At the 12-month follow-up,
23% of the probands had developed a new psychiatric
disorder, most commonly depression (9%), GAD (9%),
PTSD (6%), and agoraphobia (6%). These rates were five
times higher than those in the Australian mental health
survey, and the rates did not decrease between the 3- and 12-
month follow-up interviews. Of the new cases, 38% were
involved in litigation and 33% received mental health
treatment.
Tinnitus (Latin: ringing) is a symptom known in medicine
since the time of the ancient Greeks. It can be intermittent or
continuous, in one ear or both, and is often accompanied by
hearing loss. It can cause or be caused by anxiety and distress. A
particularly high association to PTSD was found among 300 war
veterans at a tinnitus clinic; one in three had PTSD, with tinnitus
that was perhaps triggered by sounds associated with traumatic
memories [66]. A thorough psychiatric examination was
conducted in 224 patients referred for audiology assessment
in Sweden; 144 of these patients were judged to be at a high risk
for developing chronic and disabling tinnitus [67]. Almost half
of all patients had one or several anxiety disorders. Compared to
tinnitus patients without a psychiatric disorder, the effect sizes
of having a current anxiety disorder and multiple anxiety
disorders were 0.59 and 0.63, respectively. These patients also
scored high on ratings of anxiety symptoms.
Many studies have suggested that allergies and anxiety are
linked. A recent prospective cohort study of 1,037 children
found correlations between self-reported allergies and anxiety
disorders or self-reports of anxious traits at age 21 but no
correlation with skin prick tests for allergies [68]. It was
concluded that the self-report methodology might be
influenced by negative affectivity that inflates self-perceived
health problems. Anxious individuals misinterpret, misre-
port, or are more sensitive to physical symptoms; such a bias
would affect most association studies in the absence of
objective validators.
Irritable bowel syndrome (IBS) affects 10–15% of the
population, incurring substantial healthcare costs. Studies
have found an association between IBS and fibromyalgia,
chronic pain, depression, anxiety disorders, headaches,
palpitations, back pain, fatigue, and low back pain [69]. To
elucidate these associations, 357 subjects with IBS at an
anxiety clinic in Hamilton, Ontario, underwent the Structured
Clinical Interview for the DSM-IV as well as symptom ratings.
Only 17% of the probands, mostly those with GAD (26%),
panic disorder (22%), and major depressive disorder (25%),
met the strict criteria for IBS. It was concluded that
physiological symptoms of worry and anxiety may be
responsible for these increased rates, particularly among
patients with GAD (who reported more severe IBS symp-
toms). Therefore, anxiolytic therapies may also reduce the
symptoms of IBS, as has been noted in previous studies. The
proneness of anxious subjects to experience and report
somatic symptoms more severely was also noted in a study of
self-reported quality of life in patients with ulcerative colitis
ENJ 2010; 2:(1). June 2010
and Crohn’s disease [70]. Personality was an important
moderator for treatment outcomes. Internet-based CBT was
employed for 54 IBS patients, randomly assigned to
immediate treatment or a waiting list [71]. Patients who
completed treatment reported a significant decline in IBS
symptoms and improved quality of life at the end of treatment
and at a 3-month follow-up, an effect possibly mediated by
reduced catastrophizing.
Studies of the association between skin diseases, anxiety,
depression, and other psychological variables have been
conducted mostly on patients in specialist care. A study in
Newcastle, Australia included 108 patients with acne,
psoriasis, and atopic dermatitis in both primary and specialist
care [72]. Questionnaires were also obtained from 96 general
practice patients. Psychoactive medications were used by 15
and 14 patients in the two groups, respectively. Poor health
was self-assessed by 3 and 1 patients in these groups,
respectively. There were univariate associations with the score
on the General Health Questionnaire (GHQ-12), self-rated
self-consciousness, and neuroticism that did not persist in a
multivariate regression analysis. Additionally, there were no
such differences between patients in primary care and
specialist care. It was suggested that prospective popula-
tion-based studies that control for confounding factors
should be conducted.
Systemic lupus erythematosus (SLE) is a chronic, relapsing
autoimmune disorder that involves multiple organ systems
and occurs mostly in women. In a study in the Lupus Genetic
Project in California, 326 white women with SLE were
interviewed over the telephone to determine their lifetime
rates of DSM-IV psychiatric disorders and were sent a
questionnaire in the mail [73]. Data on somatic aspects were
retrieved from medical records. The age-adjusted lifetime
prevalence of major depressive disorders was 42%, dysthymic
disorders 3%, social phobia 14%, specific phobias 22%, panic
disorders 15%, OCD 9%, and GAD 4%. The majority of
patients experienced their first onset of a psychiatric disorder
prior to receiving an SLE diagnosis. However, in 40–50% of
patients with depression or anxiety, the onset occurred after
receiving a SLE diagnosis. It was stated that SLE disease
activity may cause or aggravate anxiety and depressive
symptoms through shared pathophysiological mechanisms
(e.g., proinflammatory cytokines or CNS antibodies), or
through interference with daily activities.
DISCUSSION
The studies reviewed vary in quality, scope, representative-
ness, and generalizability; thus, clear-cut conclusions cannot
be made. Anxiety appears to be common in many somatic
conditions treated in primary and tertiary care settings.
Anxiety may be an adequate acute emotion in a previously
healthy individual (e.g., when it occurs as part of a crisis
reaction in a patient receiving a diagnosis of HIV, diabetes, or
brain tumor). It can arise following a stroke that disrupts
neuronal networks and induces adequate fear of loss of
function and relapse. It can precipitate or aggravate dyspnea
in respiratory disease, or be caused by hypoxia. It can be
36 www.slm-neurology.com

primary, chronic, and related to increased endogenous activity
in the amygdala (e.g., in GAD). It can be secondary to a major
depressive episode that, in turn, may be due to a genetic
vulnerability, adverse life circumstances, or both. It can be
pain-related. It can occur as a consequence of the stigma of
having a disabling somatic condition such as AIDS, dementia,
stuttering, seizures, asthma, or psoriasis.
The complexity of anxiety in somatic conditions becomes
apparent when reviewing the above studies. One specialty that
addresses these issues is psychosomatic medicine (formerly
consultation-liaison psychiatry) [74]. Primary care serves as
the other arena of attention; primary care practitioners need
to address anxiety and depression issues in a third of their
patients.
Several studies have shown that anxious patients misinter-
pret, overstate, and are more sensitive to physical symptoms
in a manner disproportionate to the objective severity of their
concurrent somatic disorders. Some intervention studies have
shown benefits in terms of symptom reduction and improved
function. This raises the following important questions. 1)
Should the clinician disregard such subjective perceptions and
focus on treating the somatic condition per se? Many
physicians probably follow this course due to limitations of
time, fee system, and professional interest. 2) Should
physicians take anxiety seriously and provide anxiolytic
treatment to improve the cognition of patients, thereby
improving both their lifestyle and adherence to somatic
treatment regimens? 3) Can the added effort and cost be
justified and show value in effectiveness studies?
Based on the encouraging results of programs for depressed
patients in primary care, collaborative care programs are
currently being tested for anxiety disorders. The determinants
of effectiveness for depression care across 37 randomized
studies of 12,355 patients included medication compliance,
professional competence, and supervision by a case manager
[75,76]. Such programs have also been evaluated for chronic
pain patients [77–79]. Evaluation of the effectiveness of
stepped care for primary care patients with depression and
anxiety is underway in the Netherlands [80]. The CALM
(Coordinated Anxiety Learning and Management) study is a
collaborative care program in 17 clinics in the United States
funded by the NIMH. It screens patients for anxiety disorders
based on the MINI neuropsychiatric interview and minimum
symptom severity. Algorithms are given for medications and
computer-assisted CBT [81,82]. Algorithms for the most
common anxiety disorder, GAD, are provided by Davidson et
al [83] and Pollack [84].
These issues are particularly important for the elderly. In
societies with a comprehensive and equitable health care
system, people generally stay healthy until roughly the age of
85, live independently, and enjoy life. Even beyond 85,
neurodegenerative diseases affect a minority of individuals.
However, the demographic shift in the Western world will
have a profound impact on medicine, including the treatment
of anxiety disorders in the elderly. Our current knowledge
base regarding late-life anxiety disorders is limited [85–87].
Although some anxiety disorders characterized in adulthood
www.slm-neurology.com
Morbid anxiety as a risk factor in patients with somatic diseases
tend to decrease in late life, late-onset anxiety can be caused
or aggravated by social isolation, bereavement, immobiliza-
tion, stroke, pain, adverse drug effects, trauma, malnutrition,
neurodegenerative processes, and inflammatory and immune
processes. Therefore, there is a direct need for translational
research and care effectiveness studies in the elderly.
Disclosures: The development of this article was made possible by
an educational grant by Pfizer. The content, direction and conclusions
in the article are entirely those of Christer Allgulander. Dr. Allgulander
is on the advisory and speaker boards of Pfizer and Eli Lilly.
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