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,

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

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European Neurological Journal

studies addressed the potential benefits of anxiolytic treat- injury. It also summarizes current recommendations for the
ments for the outcome of these somatic conditions, and none treatment of morbid anxiety in patients with medical illness.
of the controlled studies sought to reduce the anxiety
component. Byrne and co-workers recommended more CURRENT CONCEPTUALIZATIONS OF ANXIETY
research in this field and proposed the implementation of IN DISEASE
collaborative, stepped-care treatment programs (demonstra-
Recently, the frontiers of anxiety research were reviewed by a
tion projects), including cognitive behavioral therapy (CBT),
European science advisory panel [8]. Anxiety is currently seen
pharmacotherapy, and means of improving treatment adher-
as a developmental disorder, i.e., the result of gene-environ-
ence via telephone and the internet (especially for high
ment interactions that can induce structural and functional
utilizers of primary care). It was highlighted that stigma
changes in the amygdala-prefrontal circuitry [9, 10]. Such
regarding mental illness in primary care patients needed to be
gene-brain cognitive pathways may involve brain-derived
addressed, and awareness among primary care providers of
neurotrophic factor [11]. Anxiety disorders are genetically
the impact of anxiety on patients with chronic medical
complex, and may phenotypically result from the expression of
conditions needed to be increased. This approach is part of
gene-gene or gene-environment interactions [12]. Candidate
the emerging effort in comparative effectiveness research that
gene findings have not been specific or replicable. Genome-
aims to tailor and evaluate treatments based on the needs of wide scanning of tens of thousands of probands and controls
individual patients in everyday care. are clearly necessary to advance the field.
Katon et al [5] conducted a systematic literature review of 31 Early life stressors begin in the uterus. Women who
quality studies through 2006 examining the associations of reported severe anxiety were at risk for having shorter
anxiety and depression with diabetes, pulmonary disease, gestations and delivering smaller babies, who in turn were
cardiac disease, and arthritis. Most studies were cross- at risk for mental disorders including anxiety disorders [13,
sectional. Two randomized treatment studies in depressed 14]. Behavioral inhibition during early childhood can
diabetes patients and depressed pain patients found that both contribute to anxiety disorders [15]. In one study, childhood
depressive and medical symptoms improved. Patients with mental health problems predicted obesity, eczema, asthma,
these comorbid conditions reported higher rates of all types and epilepsy in early adulthood [16]. Another study showed
of medical symptoms, even after controlling for the severity of that children exposed to adversity had an increased risk for
the somatic disease. It was reasoned that anxiety and both depression and metabolic risk markers for age-related
depression cause poor adherence to lifestyle improvements disease [17]. In the 1958 British Birth Cohort, childhood
and increase the rate of medical complications, resulting in anxiety disorders increased the risk of midlife anxiety and
greater functional impairment, higher costs of care, and affective disorders [18]. Thus, current theories on morbid
polypharmacy. Based on these findings, Katon et al called for anxiety fit a multifactorial epigenetic model that integrates
large intervention studies to determine the potential benefits early stressors, inherited and acquired vulnerabilities, and
of identifying and treating depressed and anxious patients risks of developing interrelated or coincidental somatic
with medical illness. diseases. Proper elucidation of such a model requires very
Larry Culpepper [6] reviewed the potential physiological large prospective cohort studies.
links between generalized anxiety and medical conditions as
well as the neuroendocrine consequences of untreated NEUROLOGICAL DISEASES
anxiety, and called for anxiolytic treatment in these patients. The relationship between anxiety disorders and epilepsy is
In October 2008, the World Federation of Societies of complex. Anxiety may cause serious impairment in patients
Biological Psychiatry issued an updated guide for treating with epilepsy. The mechanism might be linked, in part, to the
anxiety disorders and obsessive-compulsive disorders [7]. GABA-A receptor, and thus modifiable by anxiolytic/anti-
This guideline concluded that there were no controlled seizure medications such as pregabalin [19]. Anxiety may be
studies showing a robust benefit of anxiolytic treatments on ictal (simple focal seizures of temporal lobe origin), postictal
vital variables of the somatic condition (e.g., percentage of (not due to epileptic discharges), or interictal (limbic
glycated hemoglobin, cardiac events, seizure rate, or epilepsies, perhaps due to kindling). Interictal anxiety is
improved forced expiratory volume). associated with the possibility of brain damage, repeated
seizures, and memory impairment. Roughly 20–30% of
This paper sets out to review recent studies, building on the patients develop seizure phobia. Among primary care patients
reviews reported above. It includes studies of patients in primary with epilepsy, 11% had an anxiety disorder; in candidates for
care with medical illness as well as patients in tertiary somatic epilepsy surgery, this value was 10–30%. In one study of 217
care (e.g., neurology, cardiology, endocrinology, respiratory candidates for chronic epilepsy surgery, psychiatric comor-
medicine, and infectious diseases). In addition to the disease bidity was carefully investigated [20]. Four men and two
categories previously reviewed, it captures data on anxiety in women, mostly with right focus localization, had a general-
epilepsy, migraine, traumatic brain injury, brain tumor, pain, ized anxiety disorder with a mean duration of 14 years.
stuttering, dementia, Parkinson’s disease, multiple sclerosis, Another study of patients with temporal lobe epilepsy (partial
restless legs, allergies, psoriasis, premenstrual dysphoria, HIV/ epilepsy) found no increase in psychiatric symptoms as
AIDS, Systemic Lupus Erythematosus (SLE), and traumatic compared to patients with other forms of epilepsy [21].

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 Morbid anxiety as a risk factor in patients with somatic diseases

Anxiety was present in many children and adolescents with Duloxetine significantly reduced pain scores in 9 to 10-week
epilepsy, with similar rates in boys and girls [22]. In addition treatment trials, and the effect was sustained for up to 26 weeks.
to providing optimization of seizure control, general In a U.S. primary care sample of 500 patients with chronic
counseling, and support, CBT may be of benefit and even pain, comorbid anxiety and depression increased the severity
reduce seizure frequency by improving the patient’s lifestyle. of the reported pain and disability, and impaired patient
Children may also benefit from education intended to quality of life [29]. More psychosocial stress was reported by
enhance communication skills and decision-making. patients with comorbid depression [30]. In a study of 96 war
Pregabalin is recommended due to its combined antiepileptic veterans (predominantly males) with heart failure, 37%
and anxiolytic effects, as well as its lack of relevant reported moderate-to-severe pain; pain was more frequent
pharmacokinetic interactions. SSRIs are reportedly useful, than dyspnea [31]. Anxiety was investigated with two
but controlled trials are absent. Buspirone is also to be questions regarding worry, and anxiousness was correlated
considered for epileptic patients with anxiety. to pain severity. Twenty of the probands were diagnosed with
Migraine affects 12% of the adult U.S. population and is an anxiety disorder. Many had concurrent diabetes and
comorbid with major depression, panic disorder, and bipolar pulmonary disease.
disorder. Among 112 consecutive patients in tertiary referral
Temporomandibular pain is estimated to affect 12% of
centers in Italy and Germany interviewed using the M.I.N.I.
adults in the United States, usually in the age group ranging
Plus 5.0 neuropsychiatric inventory, 29% had a current anxiety
from 20–40 years. Bruxism is the associated involuntary
disorder, 13% had lifetime GAD, and 8% had a lifetime panic
excessive grinding or clenching of teeth that may occur
disorder [23].
during the waking or sleeping state. A review of the role of
Traumatic brain injury (TBI) occurs in 1.5–2 million psychosocial factors in bruxism revealed no association
individuals each year in the United States. A systematic between anxiety and sleep bruxism [32]. A German study of
review of pooled studies reported GAD in 25% of TBI 223 patients with temporomandibular pain found no
patients, panic disorder in 4%, PTSD in 17%, and OCD in 9% association with self-reported anxiety [33].
[24]. It is speculated that these high rates are due to disrupted
Stuttering is estimated to affect 1% of the population, with a
brain anxiety circuits as well as problems in restoring
male:female ratio of 4:1. Its cause is unknown. In a matched
function after TBI.
case-control study of 92 adults seeking speech therapy for
Primary brain tumors are diagnosed in 41,000 patients per stuttering, the odds of having an anxiety disorder were
year in the United States, and 18,000 of these tumors are increased seven-fold [34]. There was a 34-fold increased odds
malignant. The Brief Patient Health Questionnaire, including of having a social anxiety disorder. Among the probands, 22%
seven items for generalized anxiety disorder, was used to had social anxiety, 9% had GAD, and 3.3% had OCD. These
ascertain anxiety and depression in a sample of 363 new adult anxiety disorders may negatively impact social skills, be
patients referred to an oncology clinic with brain tumors [25]. aggravated by bullying and stigma, and reduce or obviate the
Five percent had a prior psychiatric diagnosis. GAD benefits of speech therapy.
symptoms were found in 48% of the patients, and
Dementia and cognitive impairment not dementia (CIND)
psychoactive medications were used by a third of them.
were studied as outcomes in a prospective study over a 17-year
Current depression was found in 41% of the patients, one-
period in 1,160 men, 585 of whom scored high on an anxiety
fourth of whom were taking psychoactive medications.
trait scale at baseline [35]. Anxiety was found to be associated
Pain is an intriguing, multifaceted phenomenon. Pain with cognitive impairment for participants in the upper 30th
accounts for 20% of all outpatient visits in the U.S. Primary percentile of the anxiety score. The age-adjusted odds ratio of
care physicians face a large group of patients requiring frequent dementia or CIND among those men with anxiety and no
visits for chronic pain that overlaps with fatigue, depression, cognitive decline at baseline was 4.0. For dementia alone, the
anxiety, and somatoform disorders, and members of this group age-adjusted odds ratio for men with baseline anxiety traits
are often elderly, female, or less educated [26]. The DSM-IV was 5.0. Vascular and non-vascular dementia cases had
nosology fails to capture these diagnostic overlaps. Psychiatric similar odds ratios.
studies have only recently explored the association between pain
and anxiety. Beesdo et al [27] studied GAD symptoms in relation A prospective case-control study of 196 subjects who
to pain symptoms reported in a German community sample of developed Parkinson’s disease was conducted at the historical
4,181 adults interviewed in 1998. The pain was more strongly medical record register of the Mayo Clinic [36]. There was a
associated with GAD (OR 1.0 for pain symptoms and OR 16.0 statistically significant association to a DSM-IV diagnosis of
for DSM-IV pain disorder) than with other anxiety disorders; this anxiety disorder at 5, 10, and 20 years before the onset of
finding extended to subthreshold GAD. The association motor symptoms. The odds ratio of anxiety preceding motor
remained after controlling for comorbid conditions. Pain symptoms was 3.1 in women and 1.8 in men. Similar findings
disorders were found in 38% of GAD cases and preceded the were shown for 90 cases and matched controls in Pisa, Italy;
onset of GAD in the majority of cases. The same group also thirty percent of the cases had a panic disorder [37].
reported a post hoc analysis of the pain-relieving effect of The north part of Norway is a high-risk area for multiple
duloxetine in patients with GAD [28]. Self-rated pain was sclerosis (MS), and a study of 172 MS patients compared to
assessed in three double-blind studies with 1,727 patients. 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 years, at which point 236 had died. Of these, 10% had a GAD
compared to 12% of the matched controls reported anxiety on diagnosis and 7% a major depressive episode. These factors
the Hospital Anxiety Depression Scale. In women, the rates were associated with an elevated risk of 1.7- and 1.6-fold,
were 30% and 17%, respectively, and these rates were respectively, for all causes of mortality after adjustment for
reportedly similar to findings in a Canadian study. age and covariate risk factors. Comorbid PTSD, depression,
Restless legs syndrome (RLS) was already recognized to and GAD conferred an increased risk of cardiovascular death.
cause anxiety in the late 1800s. Rates of anxiety disorders were Patients in Montreal who had been diagnosed with stable
compared between 130 RLS patients and 2,265 community coronary artery disease by catheterization underwent a
residents using a psychiatric diagnostic interview [39]. The structured diagnostic interview and received symptom ratings.
odds ratios for RLS subjects having a panic disorder, GAD, or They were monitored with regard to cardiac events for 2 years
major depression in the last year were 4.7, 3.5, and 2.6, [45]. Of the 804 patients, 115 had a cardiac event. After
respectively. controlling for medical and social baseline characteristics, a
GAD diagnosis conferred an odds ratio of 2.6 for a cardiac
CARDIOVASCULAR DISEASES event; a major depressive episode conferred an odds ratio of
Anxiety is a well-known risk factor in cardiovascular 2.5. Treatment with antidepressants or benzodiazepines was
disease. Taiwan has a national database on practically all not related to the risk of cardiac events. The authors
residents (21.7 million) that includes ICD-9 diagnoses, recommended treatment for depression and anxiety with
prescriptions, age, and gender. A study of 913,570 cases of SSRIs in patients with coronary artery disease.
anxiety disorder treated with psychoactive medications during Middle-aged, healthy women in the general population of the
a 4-year period compared the prevalence of ischemic heart disease Netherlands completed a three-item anxiety scale and were
and hypertensive disorders to that among residents without monitored for all-cause mortality over a 10-year period, during
treatment with psychoactive medications [40]. The relative which 114 died [46]. Among the 5,073 probands, self-reported
risk of having treatment for ischemic heart disease and anxiety was associated with a hazard ratio of 1.8 for all-cause
hypertension increased 10- and 5-fold, respectively, in treated mortality; for cardiovascular causes, the hazard ratio was 2.8.
anxiety subjects younger than 20 years in age. The risks Eight studies of anxiety in chronic heart failure were
decreased substantially with age, as cardiovascular disease
reviewed by Yohannes et al [47]. Current clinical anxiety was
became more common in the matched population.
found in 18% of outpatients. Studies showed a substantial
Another Taiwanese study examined whether panic disorder overlap between heart failure, chronic obstructive pulmonary
first diagnosed in 2004 increased the risk of a first myocardial disease, and depression. Anxiety was related to comorbid
infarction during a 12-month period [41]. The 9,641 probands diabetes and angina in heart failure patients. Cardiac
were compared to 28,923 matched healthy controls. Probands rehabilitation (exercise, relaxation, stress management, and
were more likely at baseline to have hypertension, hyperlipi- education) was shown to be anxiolytic in an uncontrolled
demia, and coronary heart disease, and less likely to have intervention study, although it had no measurable benefit in a
diabetes and renal disease. A subsequent first myocardial different study. In a randomized study, exercise and diet
infarction occurred in 5% of the probands and 3% of the combined with CBT were more effective in reducing anxiety
controls. The hazard ratio for infarction, after controlling for than digoxin or placebo.
other risk factors, was 1.8 among the probands. Additional
Implantable cardioverter fibrillators (ICDs), indicated in
baseline risks were concurrent hypertension and coronary
patients with life-threatening arrhythmias, were the subject of
heart disease after controlling for age and other social and
a Dutch prospective study of 284 patients over a 12-month
medical risk factors.
period [48]. The prevalence of chronic anxiety in 96 patients
A household interview survey of 4,351 South Africans with no risk factors was 34%. In the 120 probands with
evaluated DSM-IV anxiety disorders in relation to self-reported diabetes, cardiac resynchronization therapy, or Type D
hypertension [42]. Having hypertension was associated to personality, chronic anxiety was reported in 64%. ICD-
having an anxiety disorder with a 1.6 odds ratio in a induced shocks were not related to persistent anxiety.
multivariate model. Subjects with a history of multiple traumas
had odds ratio of 3.8 for having an anxiety disorder. GAD and RESPIRATORY DISEASE
panic disorder were the diagnoses most strongly associated
with hypertension, with odds ratios of 3.6 and 3.2, respectively. A review of 22 studies of anxiety and 30 studies of
depression in the setting of chronic obstructive pulmonary
After controlling for other risk factors, a United States disease (COPD; air flow limitation that is not fully reversible)
household interview survey of 43,093 adults found that was compiled by Yohannes et al [47]. Clinical anxiety, often
cardiovascular disease was associated with odds ratios of 1.5, secondary to depression, was found in up to 55% of patients
1.5, and 1.3 for having GAD, panic disorder, or a specific with COPD. Functional impairment was more strongly
phobia, respectively [43]. associated to depression and anxiety than to reduced
In 1986, 4,256 Vietnam veterans selected from army records respiratory function. Anxiety was reportedly associated with
of 4.9 million people were medically examined in worry, nausea, tachycardia, sweating, and dyspnea as well as
Albuquerque [44]. Causes of death were monitored for 15 with increased rates of COPD exacerbations, emergency care

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 Morbid anxiety as a risk factor in patients with somatic diseases

visits, and hospitalizations. Chronic hypoxia may be one of disorders [60]. The rate of anxiety disorders in diabetic
the mechanisms involved. Less than one-fourth of the anxious individuals was estimated as 16%, compared to a rate of 11%
or depressed COPD patients received antidepressant or in non-diabetic individuals. In American Indians/Alaska
anxiolytic treatment. In fact, 72% of patients refused natives and people of Hispanic ethnicity, a lifetime anxiety
antidepressant treatment, perhaps because of the large disorder was reported by 40% and 20% of individuals with
number of other medications they were taking. Indeed, the diabetes, respectively.
treatment data are not convincing, as one placebo-controlled Premenstrual dysphoric disorder (PMDD) affects 5% of
study employing nortriptyline for 3 months and another fertile women in the United States and Europe [61]. Two of
employing buspirone for 2 weeks improved anxiety and the chief symptoms are depressed mood/dysphoria and
depressive symptoms without affecting respiratory function anxiety/tension that consistently impair social functioning
[49, 50]. On the other hand, exercise may be beneficial, as during the 6 days prior to menses. Women with PMDD are
shown in controlled intervention trials. According to a more likely than other women to have a history of psychiatric
controlled trial, COPD education and CBT may also reduce disorders, particularly mood and anxiety disorders. They are
depressive and anxious symptoms. Collaborative care pro- more prone to react with panic attacks upon lactate challenge.
grams assigning a personal nurse manager to patients with Exacerbations of obsessive-compulsive disorder are seen
heart failure and/or COPD are endorsed by the World Health during the premenstrual phase. Intermittent or continuous
Organization. treatment with serotonin reuptake inhibitors has been shown
A postal questionnaire survey was conducted among 110 to be effective in reducing depression and anxiety/tension in
COPD patients in the British general population, and anxiety several studies. Long-acting gonadotrophin-releasing hor-
measures were correlated with spirometric and demographic mone agonists have also proven effective, whereas oral
data from general practice records [51]. Fifty percent of the contraceptives are ineffective.
patients were current or past smokers. One-third of the
participants scored for anxiety on the Hospital Anxiety OTHER SOMATIC DISEASES
Depression Scale. Health-related impairment and severity of
Depression, adjustment disorder, and posttraumatic stress
COPD symptoms were correlated to anxiety levels.
disorder are commonly seen in patients with HIV/AIDS. HIV-
Respiratory disease was diagnosed at 1 year of age in a associated dementia is an encephalitis associated with
cohort of 399 children; the children were assessed again cognitive decline, behavioral abnormalities, and progressive
between the ages of 30 and 39 years for anxiety and spastic paraparesis with sensory ataxia [62]. The initial
depression [52]. The adjusted odds ratios of GAD diagnosis symptoms may include mania, irritability, confusion, and
in adulthood if diagnosed with a respiratory disease at ages 1 impaired judgment. Untreated cases have a survival of 6–9
and 7 were 1.9 and 0.8, respectively. months. HAART treatment rapidly reduces the symptoms, but
cognitive decline can still be seen. Currently, treatment with
ENDOCRINE DISEASES SSRI/SNRIs is recommended to ameliorate symptoms of
Diabetes patients are at risk of anxiety and depression, anxiety and depression. Because of their adjunct pain-
which may impair glycemic control [53]. Several controlled reducing effects, pregabalin, venlafaxine, and duloxetine
studies have shown that antidepressant and anxiolytic may be preferred.
treatment may improve diabetes status [54–57]. However, Mood, anxiety, and substance use disorders are associated
the relationship between major depression, diabetes distress, with a more rapid CD4 cell count decline, progression to AIDS,
and improvement in glycated hemoglobin (A1C) is complex. A and death [63]. Among a total of 1,125 patients in an HIV
study of 506 patients with Type 2 diabetes found a concurrent academic center in North Carolina, 148 probands 30–50 years
and longitudinal association between diabetes distress and old underwent a psychiatric diagnostic interview. Twenty
A1C but no association with major depression or depressive percent were diagnosed with an anxiety disorder (6% PTSD,
symptoms [58]. In a study in Ireland, 1,456 patients with 5% panic disorder, and 10% other anxiety disorders).
Types 1 and 2 diabetes self-rated their anxiety and depressive In Cape Town, South Africa, 429 HIV-infected adults
symptoms on the Hospital Anxiety Depression Scale [53]. underwent screening for depression and anxiety disorders
One-third of the patients had high anxiety scores, and one- with the K-10, a self-report instrument; the results obtained
fourth of them had high depression scores. Both categories with this instrument were validated with the MINI neurop-
were associated with diabetes complications, smoking, and sychiatric interview [64]. A current diagnosis of GAD was
alcohol consumption. These associations were particularly made in 18%, PTSD in 22%, agoraphobia in 18%, panic
prevalent in young patients and occurred regardless of the disorder in 15%, and social phobia in 12% of the adults. The
primary or secondary care setting. K-10 instrument was also found to be a useful proxy measure
In a 5-year prospective study of 4,623 primary care patients in Afrikaans- and Xhosa-speaking subgroups.
with Type 2 diabetes, major depression was associated with The risk of developing a psychiatric disorder following a
microvascular and macrovascular complications [59]. traumatic injury was assessed in a prospective cohort of 1,084
A telephone survey of 201,575 residents in the United States patients admitted to major trauma hospitals in Australia [65].
included questions about diagnoses of diabetes and anxiety Forty percent of the probands had a mild traumatic brain

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injury (TBI). The MINI 5.5 neuropsychiatric interview was and Crohn’s disease [70]. Personality was an important
administered one week after discharge as well as 3 months moderator for treatment outcomes. Internet-based CBT was
and 12 months after the injury. At the 12-month follow-up, employed for 54 IBS patients, randomly assigned to
23% of the probands had developed a new psychiatric immediate treatment or a waiting list [71]. Patients who
disorder, most commonly depression (9%), GAD (9%), completed treatment reported a significant decline in IBS
PTSD (6%), and agoraphobia (6%). These rates were five symptoms and improved quality of life at the end of treatment
times higher than those in the Australian mental health and at a 3-month follow-up, an effect possibly mediated by
survey, and the rates did not decrease between the 3- and 12- reduced catastrophizing.
month follow-up interviews. Of the new cases, 38% were Studies of the association between skin diseases, anxiety,
involved in litigation and 33% received mental health depression, and other psychological variables have been
treatment. conducted mostly on patients in specialist care. A study in
Tinnitus (Latin: ringing) is a symptom known in medicine Newcastle, Australia included 108 patients with acne,
since the time of the ancient Greeks. It can be intermittent or psoriasis, and atopic dermatitis in both primary and specialist
continuous, in one ear or both, and is often accompanied by care [72]. Questionnaires were also obtained from 96 general
hearing loss. It can cause or be caused by anxiety and distress. A practice patients. Psychoactive medications were used by 15
particularly high association to PTSD was found among 300 war and 14 patients in the two groups, respectively. Poor health
veterans at a tinnitus clinic; one in three had PTSD, with tinnitus was self-assessed by 3 and 1 patients in these groups,
that was perhaps triggered by sounds associated with traumatic respectively. There were univariate associations with the score
memories [66]. A thorough psychiatric examination was on the General Health Questionnaire (GHQ-12), self-rated
conducted in 224 patients referred for audiology assessment self-consciousness, and neuroticism that did not persist in a
in Sweden; 144 of these patients were judged to be at a high risk multivariate regression analysis. Additionally, there were no
for developing chronic and disabling tinnitus [67]. Almost half such differences between patients in primary care and
of all patients had one or several anxiety disorders. Compared to specialist care. It was suggested that prospective popula-
tinnitus patients without a psychiatric disorder, the effect sizes tion-based studies that control for confounding factors
of having a current anxiety disorder and multiple anxiety should be conducted.
disorders were 0.59 and 0.63, respectively. These patients also Systemic lupus erythematosus (SLE) is a chronic, relapsing
scored high on ratings of anxiety symptoms. autoimmune disorder that involves multiple organ systems
Many studies have suggested that allergies and anxiety are and occurs mostly in women. In a study in the Lupus Genetic
linked. A recent prospective cohort study of 1,037 children Project in California, 326 white women with SLE were
found correlations between self-reported allergies and anxiety interviewed over the telephone to determine their lifetime
disorders or self-reports of anxious traits at age 21 but no rates of DSM-IV psychiatric disorders and were sent a
correlation with skin prick tests for allergies [68]. It was questionnaire in the mail [73]. Data on somatic aspects were
concluded that the self-report methodology might be retrieved from medical records. The age-adjusted lifetime
influenced by negative affectivity that inflates self-perceived prevalence of major depressive disorders was 42%, dysthymic
health problems. Anxious individuals misinterpret, misre- disorders 3%, social phobia 14%, specific phobias 22%, panic
port, or are more sensitive to physical symptoms; such a bias disorders 15%, OCD 9%, and GAD 4%. The majority of
would affect most association studies in the absence of patients experienced their first onset of a psychiatric disorder
objective validators. prior to receiving an SLE diagnosis. However, in 40–50% of
patients with depression or anxiety, the onset occurred after
Irritable bowel syndrome (IBS) affects 10–15% of the
receiving a SLE diagnosis. It was stated that SLE disease
population, incurring substantial healthcare costs. Studies
activity may cause or aggravate anxiety and depressive
have found an association between IBS and fibromyalgia,
symptoms through shared pathophysiological mechanisms
chronic pain, depression, anxiety disorders, headaches,
(e.g., proinflammatory cytokines or CNS antibodies), or
palpitations, back pain, fatigue, and low back pain [69]. To
through interference with daily activities.
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. DISCUSSION
Only 17% of the probands, mostly those with GAD (26%), The studies reviewed vary in quality, scope, representative-
panic disorder (22%), and major depressive disorder (25%), ness, and generalizability; thus, clear-cut conclusions cannot
met the strict criteria for IBS. It was concluded that be made. Anxiety appears to be common in many somatic
physiological symptoms of worry and anxiety may be conditions treated in primary and tertiary care settings.
responsible for these increased rates, particularly among Anxiety may be an adequate acute emotion in a previously
patients with GAD (who reported more severe IBS symp- healthy individual (e.g., when it occurs as part of a crisis
toms). Therefore, anxiolytic therapies may also reduce the reaction in a patient receiving a diagnosis of HIV, diabetes, or
symptoms of IBS, as has been noted in previous studies. The brain tumor). It can arise following a stroke that disrupts
proneness of anxious subjects to experience and report neuronal networks and induces adequate fear of loss of
somatic symptoms more severely was also noted in a study of function and relapse. It can precipitate or aggravate dyspnea
self-reported quality of life in patients with ulcerative colitis in respiratory disease, or be caused by hypoxia. It can be

ENJ 2010; 2:(1). June 2010 36 www.slm-neurology.com

 Morbid anxiety as a risk factor in patients with somatic diseases

primary, chronic, and related to increased endogenous activity tend to decrease in late life, late-onset anxiety can be caused
in the amygdala (e.g., in GAD). It can be secondary to a major or aggravated by social isolation, bereavement, immobiliza-
depressive episode that, in turn, may be due to a genetic tion, stroke, pain, adverse drug effects, trauma, malnutrition,
vulnerability, adverse life circumstances, or both. It can be neurodegenerative processes, and inflammatory and immune
pain-related. It can occur as a consequence of the stigma of processes. Therefore, there is a direct need for translational
having a disabling somatic condition such as AIDS, dementia, research and care effectiveness studies in the elderly.
stuttering, seizures, asthma, or psoriasis. Disclosures: The development of this article was made possible by
The complexity of anxiety in somatic conditions becomes an educational grant by Pfizer. The content, direction and conclusions
apparent when reviewing the above studies. One specialty that in the article are entirely those of Christer Allgulander. Dr. Allgulander
addresses these issues is psychosomatic medicine (formerly is on the advisory and speaker boards of Pfizer and Eli Lilly.
consultation-liaison psychiatry) [74]. Primary care serves as
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