CME 3 Review Article

Antidepressants and
Cognitive-Behavioral Therapy
for Symptom Syndromes
By Jeffrey L. Jackson, MD, MPH, Patrick G. O’Malley, MD, MPH, and Kurt Kroenke, MD

ABSTRACT
Somatic symptoms are common in pri-
mary care and clinicians often prescribe
antidepressants as adjunctive therapy.
There are many possible reasons why
this may work, including treating comor-
bid depression or anxiety, inhibition of
ascending pain pathways, inhibition of
prefrontal cortical areas that are responsi-
ble for “attention” to noxious stimuli, and
the direct effects of the medications on the
syndrome. There are good theoretical rea-
sons why antidepressants with balanced
norepinephrine and serotonin effects may
be more effective than those that act pre-
dominantly on one pathway, though head-
to-head comparisons are lacking. For the
11 painful syndromes review in this arti-
cle, cognitive-behavioral therapy is most
consistently demonstrated to be effec-
tive, with various antidepressants having
more or less randomized controlled data
Needs Assessment
There are several common symptom syndromes for which clinicians often prescribe
antidepressants. This article will review the biological mechanisms that may underlie
this treatment’s potential effectiveness and review the randomized controlled data
on the use of antidepressant and cognitive-behavioral therapy for 11 common pain
syndromes
Learning Objectives
At the end of this activity, the participant should be able to:
• Recognize the prevalence and impact of common symptom syndromes.
• Understand the mechanisms by which antidepressant therapy may be effective in
somatic symptom syndromes.
• Become aware of the current state of randomized controlled trial data on the
effectiveness of antidepressant therapy in common symptom syndromes.
Target Audience: Neurologists and psychiatrists
Accreditation Statement
Mount Sinai School of Medicine is accredited by the Accreditation Council for
Continuing Medical Education to provide Continuing Medical Education for physicians.
Mount Sinai School of Medicine designates this educational activity for a maximum of
3.0 Category 1 credit(s) toward the AMA Physician’s Recognition Award. Each physician
should claim only those credits that he/she actually spent in the educational activity.
It is the policy of Mount Sinai School of Medicine to ensure fair balance, independence,
objectivity and scientific rigor in all its sponsored activities. All faculty participating
in sponsored activities are expected to disclose to the audience any real or apparent
discussion of unlabeled or investigational use of any commercial product or device not
yet approved in the United States.
This activity has been peer-reviewed and approved by Eric Hollander, MD, professor of
psychiatry, Mount Sinai School of Medicine. Review Date: January 24, 2006.
To Receive Credit for This Activity: Read this article, and the two
CME-designated accompanying articles, reflect on the information presented, and
then complete the CME quiz found on pages 233 and 234. To obtain credits, you
should score 70% or better. Termination date: March 31, 2008. The estimated time
to complete this activity is 3 hours.

Dr. Jackson is associate professor of medicine in the Department of Medicine at the Uniformed Services University of the Health Sciences
in Bethesda, Maryland. Dr O’Malley is chief of General Internal Medicine Services in the Department of Medicine at Walter Reed Army
Medical Center in Washington, DC. Dr. Kroenke is Professor of Medicine in the Division of General Internal Medicine and Geriatrics at
Indiana University and research scientist at the Regenstrief Institute, both in Indianapolis.
Disclosure: Views expressed in this article are those of the author(s) and do not reflect the official policy of the United States Department
of Army, US Department of Defense, or the US Government. Drs. Jackson and O’Malley do not have an affiliation with or financial
interest in any organization that might pose a conflict of interest. Dr. Kroenke has received honoraria/research grants from Eli Lilly, Pfizer,
and Wyeth, is on the advisory board of Eli Lilly, and is an independent contractor for Pfizer and Wyeth.
This article was submitted on October 12, 2005, and accepted on January 30, 2006.
Please direct all correspondence to: Jeffrey L. Jackson, MD, MPH, Uniformed Services University of the Health Sciences, Medicine-EDP,
4301 Jones Bridge Road, Bethesda, MD 20814; Tel: 202-782-5603, Fax: 202-782-7363; E-mail: jejackson@usuhs.mil.
CNS Spectr 11:3 © MBL Communications Inc. 212 March 2006
 Review Article
supporting or refuting effectiveness. This article
reviews the randomized controlled trial data for
the use of antidepressant and cognitive-behav-
ior therapy for 11 somatic syndromes: irritable
bowel syndrome, chronic back pain, headache,
fibromyalgia, chronic fatigue syndrome, tinni-
tus, menopausal symptoms, chronic facial pain,
noncardiac chest pain, interstitial cystitis, and
chronic pelvic pain. For some syndromes, the
data for or against treatment effectiveness is
relatively robust, for many, however, the data,
one way or the other is scanty.
CNS Spectr. 2006;11(3)212-222
INTRODUCTION
Antidepressant medications have long been
used by clinicians in dealing with common
somatic symptom syndromes and as adjuncts
for managing chronic pain. There are several
reasons antidepressants may be effective. First,
they have effects on psychiatric comorbid condi-
tions that can influence symptom severity and
functional impairment. Psychiatric comorbidity,
particularly depression, anxiety, and posttrau-
matic stress, is common in patients with these
syndromes and even higher in patients who seek
medical attention.1-3
There is biological plausibility why anti-depres-
sants may help, distinct from effects on mood
or anxiety. In many syndromes, such as irritable
bowel syndrome (IBS) and fibromyalgia, patients
demonstrate increased prefrontal cortex activ-
ity with noxious stimulation, areas of the brain
responsible for increased attention to the stimuli.4,5
This raises the possibility that a common biologi-
cal pathway may link both pain and depression.6
Serotonin (5-HT) and norepinephrine (NE),
seem to be involved in the pathophysiology of
depression. Axonal projections of these systems
throughout the brain may be important in many
of the depressive symptoms. Frontal cortex
projections may regulate mood and cognition;
hypothalamic projections may affect appetite,
pleasure, and sex drive; limbic regions affect
emotions and anxiety; and basal ganglia projec-
tions affect psychomotor function. Many of these
areas of the brains appear to have abnormal
activity levels in patients with several of these
symptom syndromes. In addition, both 5-HT
CNS Spectr 11:3 © MBL Communications Inc.
and NE may exert analgesic effects via inhibi-
tory descending pain pathways 7-11 and may be
involved in the suppression of somatic symp-
toms at the level of the spinal cord. This could
help explain why patients with IBS experience
gastric and colonic distention as more painful
than those without the syndrome12 and patients
with fibromyalgia experience pain with noxious
stimuli at lower thresholds than those without
fibromyalgia. 13,14 Finally, antidepressants may
alter certain pathophysiological systems impli-
cated in somatic symptoms. For example tricy-
clic antidepressants (TCAs) slow gastrointestinal
transit, probably by anticholinergic effects, which
can improve diarrhea-predominant IBS.15
While cognitive-behavioral therapy (CBT) has
been evaluated for effectiveness against numer-
ous physical symptoms, 16 , 17 the underlying
mechanism for effectiveness is unknown. 17 The
active component of treatment may be psycho-
logical, including altering patient’s expectation
of improvement and encouragement to resume
healthy functioning. 17 CBT is also effective
against mood and anxiety disorders and may
exert some benefit by its effects on these comor-
bid conditions. However, emerging data sug-
gests that CBT may also directly modify some of
the same brain functions as antidepressants. For
example, one study 18 recently found that CBT
reduced activity in prefrontal cortical regions,
areas of the brain responsible for the increased
attention to noxious stimuli seen with many of
these somatic syndromes. Future research may
uncover other direct effects on brain function
with CBT.
The purpose of this article is to conduct an
evidence-based review with the question “What
is the efficacy of antidepressants in common
symptom syndromes?” Our strategy was to
search MEDLINE and the Cochrane Database of
Systematic Reviews and Database of Reviews of
Effectiveness, searching for published systematic
reviews of the effects of antidepressants on the
specific symptom syndrome. For those symptom
syndromes that had no published meta-analy-
sis, we searched MEDLINE and the Cochrane
Clinical Trials database for English-language
randomized controlled trials (RCTs). Finally, we
searched these databases for meta-analyses or
RCTs of the effects of CBT, for these symptom
syndromes. The hierarchy for inclusion in this
analysis was meta-analysis first and RCTs only
when no meta-analyses had been published.
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The symptoms reviewed in this article include
IBS, fibromyalgia, headache, back pain, chronic
fatigue syndrome (CFS), tinnitus, menopausal
symptoms, chronic facial pain, noncardiac chest
pain, interstitial cystitis, and chronic pelvic pain.
IRRITABLE BOWEL SYNDROME
IBS is common, affecting up to 15% of North
Americans, with a 2:1 female predominance. 19
While formal criteria for the diagnosis of IBS
exist, most clinicians are unaware of them20,21 and
the American College of Gastroenterology recom-
mends diagnosis on the basis of “abdominal dis-
comfort associated with altered bowel habits”.22
IBS is heterogeneous. Patients can present
with predominantly constipation, diarrhea, or
alternating bowel habits and may change over
time, from one type to another.23 While IBS is
common, <50% of patients present for medi-
cal evaluation. Predictors of presenting include
stress, neuroticism, history of abuse, and poor
social support or coping skills24 and most indi-
viduals presenting with IBS have other comorbid
conditions.1 Up to 94% have depression, anxiety
or somatoform disorders and over half also have
fibromyalgia, CFS, temporomandibular joint dis-
order, or chronic pelvic pain.1
There have been 11 trials of TCAs on IBS and
several published meta-analyses25-28 Of the five
meta-analyses, four found evidence thatTCAs were
effective for global IBS symptom improvement,
with pooled odds ratios for 50% improvement
ranging from 2.6–4.2. Only one meta-analysis29
also included an estimate of the magnitude of
pain relief, with an effect size of 0.9, a large effect.
Unfortunately, the studies with antidepressants
have numerous methodological problems that
limit confidence in these results. Consequently,
most experts recommend that antidepressents be
considered for patients with daily, persistent pain.
There are two studies on the effects of selective
serotonin reuptake inhibitors (SSRIs) on IBS, one
found that paroxetine improved well-being more
than placebo with no effect on IBS specific symp-
toms,30 another that fluoxetine had nonsignificant
improvements in global symptoms with no effect
on the perception of noxious rectal stimuli.31
There have been at least 14 trials32,33 of cogni-
tive-behavioral therapy (CBT) in IBS, using both
individual and group therapy models and two sys-
tematic reviews. While neither review provided
pooled estimates of the magnitude of effect, both
suggest that CBT may be effective.32,33 Trials with
CNS Spectr 11:3 © MBL Communications Inc.
head-to-head comparisons suggest that CBT is
effective as anti-spasmodic medications,34,35 “usual
medical care,”36-38 or desipramine.5
BACK PAIN
Back pain is among the most frequent reasons
for outpatient visits39 and accounts for 10% to 15%
of missed workdays.40 Although most patients
with back pain improve substantially within 1–3
months, 15% continue to report severe pain 1 year
after an acute episode.41 There have been 3 recent
systematic reviews evaluating the efficacy of anti-
depressants for chronic low back pain.42-44 A total
of 10 randomized clinical trials were reviewed,
including seven placebo-controlled trials, 45-51
one pre-post design comparing two antidepres-
sants with placebo run-in,52 one active compara-
tor design.53 and one trial including patients with
either neck or back pain.54 The seven placebo-con-
trolled trials included 440 subjects, while all 10 tri-
als encompassed 544 subjects. Only two trials49,50
specifically excluded patients with depression.
Staiger and colleagues43 focused on the seven
placebo-controlled trials. There were a total of
eight active drug-placebo comparisons, since
one trial included two antidepressants arms.
Antidepressants that inhibit NE reuptake (TCAs
and tetracyclics) were found to be mildly to mod-
erately effective in reducing back pain. Three of
the five studies of these agents, including the
two highest quality studies, demonstrated sig-
nificant benefits in decreasing pain. 47,49,50 The
drugs studied included nortriptyline 25–100 mg/
day, maprotiline 50–150 mg/day, and amitripty-
line 50–150 mg/day. A fourth using imipramine
150 mg QD showed decreased pain of border-
line significance46 A single negative TCA study of
imipramine 75 mg QD was performed on patients
admitted to a military hospital for the treatment of
low back pain.45 The impact of TCAs on functional
status was unclear. Among the four studies that
included a functional measure, one found sig-
nificant improvement,46 one found improvements
of borderline significance, 49 and two found no
significant improvement.45,47 In the three studies
of antidepressants that do not inhibit NE reuptake
(two with paroxetine in doses averaging 25 mg
QD and one with trazodone in doses averaging
200 mg QD),48,50,51 no analgesic benefit was seen.
Schnitzer and colleagues’s44 systematic review
evaluated treatment of chronic back pain, cover-
ing a broad spectrum of medications for which
antidepressants were only one category would
214 March 2006
 Review Article
be appropriate. While they did not pool their
data, they found that in five of the seven studies,
antidepressants were more effective than pla-
cebo in reducing pain and depression.
Salerno and colleagues 42 pooled data from
nine of the 10 trials, including all seven trials
summarized by Staiger and colleagues43 and
Schnitzer and colleagues. 4 4 The duration of
chronic back pain averaged >10 years. Patients
treated with antidepressants were more likely
to improve in pain severity (ES=0.41) but not in
activities of daily living. Patients treated with
antidepressants experienced more adverse
events (22% vs 14%; P=.01).
In summary, antidepressants are more effec-
tive than placebo in reducing pain severity but
not functional status in patients with chronic
back pain. However, the effect size (0.41) on pain
reduction is modest, given that 0.5 and 1.0 rep-
resent moderate and large effect sizes, respec-
tively.29 Also, adverse events are more common
with antidepressants than with placebo. Despite
this, there is stronger placebo-controlled trial evi-
dence45 for antidepressants (seven trials) than for
nonsteroidal antiinflammatory drugs (four trials),
opioid analgesics (two trials), or muscle relaxants
(one trial) in the treatment of chronic back pain.
Though head-to-head trials are few, it appears
that inhibition of the NE pathway may be impor-
tant in antidepressant analgesia. This is consistent
with previous reviews55-58 showing the relevant
importance of NE inhibition in pain reduction.
There have been no adequate studies on the use
of antidepressants for acute back pain. Given this
lack of evidence and the fact that acute back pain
usually resolves in 1–3 months,42 antidepressants
should not be used routinely for acute back pain.
In contrast to pharmacologic treatments, there
is substantial evidence for the effectiveness of
CBT and behavior therapy for back pain. 59 Out
of 16 studies59 of CBT in patients with back pain,
seven were in primary care (891 patients) and
nine in secondary care (625 patients). Patients
from both settings reported sustained improve-
ments in pain, disability, and depression.
Similarly for behavior therapy, eight out of nine
primary care studies on 659 patients and five
out of six secondary care studies on 398 patients
reported improvements in symptoms. There was
some evidence from both settings that these
improvements were sustained at 1-year follow-
up. The initial health status of secondary care
patients was poorer than that of patients in pri-
CNS Spectr 11:3 © MBL Communications Inc.
mary care but they reported greater improve-
ments. Finally, pain self-management programs
and exercise have also proven beneficial.60,61
HEADACHE
Up to a third of populations worldwide expe-
riencing a migraine or tension headache at some
time in their life and >50% seeking medical atten-
tion. 62 In the United States, 87% of those with
headaches report disability, with 25% experienc-
ing at least four disabling episodes per month.
Ten years ago, it was estimated that migraine
headaches alone cost the US $1 billion annually
in direct medical cost, with $13 billion lost produc-
tivity annually.63 The total cost to society is close
to that of diabetes and exceeds that of asthma. In
the ensuing decade there has been an explosion
of costly new treatments for headaches, so it is
likely that these figures are a gross underestimate
of today’s costs for headache management. The
vast majority of headaches seen in primary care
can be divided into three types: migraine, ten-
sion, and cluster headaches.64 Treatment of head-
aches can be either abortive, designed to manage
the acute headache, or prophylactic, designed to
reduce the frequency, severity and duration of
headaches. Antidepressants have no role in the
management of cluster headaches and are used
as prophylactic rather than abortive management
of migraine and tension headaches.
Depression is at least three fold more com-
mon among patients suffering from headaches
than the general population,65 though it is unclear
which came first. 66 There is evidence that the
relationship may be bi-directional. Subjects with
headaches have a more than three-fold risk of
developing depression, while depressed individ-
uals with no history of headaches have a more
than three-fold risk of developing migraine. 67
Most studies on the effectiveness of antidepres-
sants in the prophylaxis of headaches either
exclude patients with comorbid depression or
adjust for the severity of depression.68
TCAs were first shown to be effective in the
prophylaxis against migraine headaches in 196469
and have subsequently become a standard drug
for prophylaxis against both migraine and ten-
sion headaches. In a meta-analysis of 38 RCTs,68
TCAs were twice as likely to experience at least a
50% improvement in symptoms compared with
those treated with placebo (RR: 2.0; 95% CI: 1.6-
2.4). The absolute risk difference was 31% (95%
CI: 23-40), suggesting that clinicians would need
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to treat 3.2 patients (95% CI: 2.5-4.3) with an anti-
depressant for one patient to experience at least
a 50% improvement in their headaches. On aver-
age, patients treated with TCAs had about a one
standard deviation of reduction in headache bur-
den, reflected by patients requiring on average,
21 fewer analgesic doses over the average 6-
week study period than placebo-treated patients.
This meta-analysis also found no difference in
the effectiveness of TCAs between patients with
migraine or tension headaches (migraine RR: 2.1,
95% CI: 1.6-2.6; tension RR: 1.8, 95% CI: 1.3-2.6).
Early studies68 suggested that SSRIs may also
be effective, but a subsequent meta-analysis of
13 RCTs70 found that SSRIs were no more effec-
tive than placebo for subjects with migraine
headaches and not as effective as TCAs for ten-
sion headaches.
Behavioral treatments, including relaxation
therapy, biofeedback, and CBT, have been shown
to yield a 35% to 55% improvement in migraine
and tension headaches, with effects persisting
out to 7 years, the longest reported follow-up.71
Acupuncture may be useful for treatment of
headaches, though more data is needed.72 Other
therapies with evidence for prophylactic effec-
tiveness include β-blockers73 (except pindolol),
valproate, calcium channel blockers (not dihy-
dropyridines), and gabapentin. 74 Recent RCTs
have suggested that ACE inhibitors75 or angio-
tensin receptor blockers76 may also be effective,
though larger trials are needed before their use
can be recommended. Chiropractic and massage
therapy appear to be ineffective.77
FIBROMYALGIA
Fibromyalgia is a syndrome of chronic mus-
culoskeletal pain that is commonly diagnosed,
poorly understood, and difficult to treat. 78-80
Fibromyalgia accounts for 15% of outpatient
rheumatology visits and 5% of general medicine
visits.81 It is more common in females and the
incidence increases with age.82 Typical symptoms
include chronic musculoskeletal pain and stiffness,
tenderness over specific trigger points, fatigue,
and disrupted sleep. There is some evidence that
patients with fibromyalgia have a heightened
pain response,83-85 as well as abnormal sleep pat-
terns.86-89 Neurohormonal abnormalities, physi-
cal or emotional trauma, psychological stress,
and infectious causes have also been postulated,
although no single etiologic factor has been iden-
tified.82 Thus, there may be several mechanisms
CNS Spectr 11:3 © MBL Communications Inc.
by which antidepressants improve fibromyalgia
symptoms, such as pain control, mood stabiliza-
tion, and improved sleep. Disturbed sleep is par-
ticularly interesting, as it may be both a causative
factor and a symptom of disease. If abnormal
sleep precedes the development of fibromyalgia,
the effect of antidepressants may be primarily
associated with improved sleep.
The role of psychological factors in the
pathogenesis of fibromyalgia is controversial.
Depressive symptoms are often present, but it has
been difficult to determine if depressive disorders
are a primary cause of fibromyalgia, or a reaction
to the debilitating symptoms of this disease. It
has been reported90,91 that >50% of patients diag-
nosed with fibromyalgia have a lifetime history of
depression, though active depression is present
in only one third. On the other hand, Ahes and
colleagues92 have shown that the prevalence of
depression is no higher in fibromyalgia than in
rheumatoid arthritis or normal controls.
A meta-analysis synthesized the evidence on
the efficacy of antidepressants in the management
of fibromyalgia.93 In this synthesis, the majority
of arms (10 of 15) studied TCAs. Three TCAs were
studied: amitriptyline in eight, clomipramine in
one, and maprotiline in one. Two trials used S-ade-
nosylmethionine and three studied SSRIs (fluox-
etine in trials, citalopram in one trial). The resulting
odds ratio for improvement with therapy was 4.2
(95% CI: 2.6-6.8). In these trials, all drugs included
found benefit compared to placebo, with odds
ratios ranging from 2.5–12.3 The summary odds
ratio for 50% improvement in headaches with ami-
tryptyline was 7.5 (95% CI: 1.8-29.7). In this analy-
sis, the other antidepressants included only one
to two trials each. The study by Goldenberg and
colleagues94 is the only one that compared two
antidepressants, fluoxetine and amitriptyline, com-
paring both with placebo and with the combination
of fluoxetine and amitriptyline. In this small (n=19),
short (6 week) crossover trial, both fluoxetine and
amitriptyline were equally better than placebo and
the combination was better than either alone.94
Continuous outcomes were extractable from
10 of the trials. The number of trigger points
improved 0.17 standard deviation units (95% CI:
–0.07-0.42); fatigue scores improved 0.39 stan-
dard deviation units (95% CI: 0.11-0.66); sleep
scores improved 0.49 standard deviation units
(95% CI: 0.3-0.69); overall well-being scores
improved 0.49 standard deviation units (95%
CI: 0.18-0.80); and pain scores improved 0.52
216 March 2006
 Review Article
standard deviation units (95% CI: 0.21-0.81). Only
five of the 13 studies reported an analysis of a
correlation between treatment effect and change
in depression scores.90-93,95
Only three of the trials assessed the effective-
ness of SSRIs on fibromyalgia.94-98 While there
was no difference in the efficacy of SSRIs and
the other drug classes studied, the small sample
size of studies makes it difficult to assess rela-
tive efficacy. Since this meta-analysis, there has
been another trial that reported on the efficacy
of high-dose fluoxetine.99
In this trial, patients who received fluoxetine
(mean±SD dose of 45 mg/day) experienced a
greater reduction in pain, fatigue, and depressed
mood compared with placebo. This contrasts
with a small previous trial of fluoxetine 20 mg/
day which did not show a benefit,97 suggesting
that larger does may be needed in using SSRIs.
One recent, large placebo-controlled trial of a
new serotonin and norepinephrine reuptake
inhibitor, duloxetine, also published after this
meta-analysis, showed improvement in pain,
stiffness, and overall fibromyalgia impact ques-
tionnaire score associated with duloxetine. 10 0
This efficacy was independent of depressive
symptoms. Well-designed RCTs are needed to
assess the relative efficacy of different classes of
antidepressants in fibromyalgia.
The literature supports the use of cognitive
behavior therapy with fibromyalgia in produc-
ing modest outcomes across multiple domains,
including pain, fatigue, physical functioning, and
mood.82 The greatest effects occur with it is com-
bined with an exercise program.101 One review of
13 trials of mind-body therapy and fibromyalgia
found it had a moderate effect, superior to pla-
cebo, but no data on its effectiveness compared
with other treatment modalities.102
Cyclobenzaprine, a TCA chemically similar to
amytriptyline but used as a “muscle relaxant”
rather than as an antidepressant, was shown
in a meta-analysis of five randomized, placebo-
controlled trials103 to be efficacious in improv-
ing symptoms of fibromyalgia, especially pain
and sleep disturbances. Because this drug is so
similar in chemical structure to amitriptyline, it
is possible this effect is mediated by an effect on
depressive symptoms or other pain modulation,
and not on its muscle relaxant effect.
The probability of benefit based on these
clinical trials is clinically appealing, and the mag-
nitude of benefit also appeared clinically sig-
CNS Spectr 11:3 © MBL Communications Inc.
nificant. Patients treated with antidepressants
were more than four times as likely to improve.
Study patients experienced a range of improve-
ment in various symptoms of fibromyalgia, from
0.2 standard deviation units improvement in
the number of trigger points to >50% standard
deviation improvement in average pain scores.
The symptomatic benefits of antidepressants
seem to be mild for fatigue and number of trig-
ger points and moderate for sleep, overall well-
being, and pain severity.
CHRONIC FATIGUE SYNDROME
Chronic fatigue, defined as disabling fatigue
for >6 months, is a common symptom in pri-
mary care settings, occurring <10% of patients.
Of these, only a small minority (one in seven)
meet criteria for CFS. The core clinical features
of chronic fatigue syndrome are physical and
mental fatigue exacerbated by physical and
mental effort. These are subjective phenomena
and often less evident on objective testing. Up
to 75% of all patients with CFS also meet criteria
for depression and/or anxiety syndromes.104
The precise etiology of CFS remains unknown.
A wide range of etiological factors have been
proposed but none unequivocally established.
One etiologic model is that of a variable combi-
nation of environmental factors and individual
vulnerability initiate a series of social, psycho-
logical, and biological processes that eventu-
ally leads to the development and perpetuating
nature of CFS. Factors that have been positively
associated with CFS include genetics, abuse,
socioeconomic status, education, infection
(Epstein-Barr virus, Q fever, viral meningitis,
hepatitis), stress (particularly where there are
difficult dilemmas), illness beliefs (specifically,
attribution of symptoms to physical causes, and
low self-efficacy), behavioral factors (fear avoid-
ance and decreased activity, leading to decon-
ditioning), and lack of social support.
Compared with chronic fatigue not meet-
ing criteria for CFS, CFS is associated with
more severe symptoms, more disability, more
unemployment (as high as 50%), worse func-
tioning, more associated symptoms, more psy-
chological distress, higher rates of healthcare
utilization, and twice the rate of depression.105,106
Demographic factors associated with CFS
include female gender (2:1), age (30–50 years),
lower socioeconomic status, less education,
and Western nationality.107
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The prognosis for CFS is variable and typically
has a fluctuating chronic course. The progno-
sis without rehabilitative therapy is for gradual
improvement in up to 50%, but with few return-
ing to premorbid functioning. Prospective stud-
ies in the general population report that ~50%
have partial or complete remission at 2–3 years.
Factors associated with persistence of symptoms
include older age, longer illness duration, sedat-
ing medications, less education, unemployment,
worse mental health, lack of social support, and
somatic attributions.
A systematic review of interventions for CFS
revealed that only two interventions108 were found
to be beneficial in improving but not curing symp-
toms: CBT and graded exercise. The efficacy of
CBT for CFS was substantiated in another recent
literature synthesis as well. 59 There are good
reasons to consider antidepressant drug treat-
ment since many patients have depressive and
anxiety symptoms and syndromes. However, the
evidence that antidepressants lead to an overall
improvement in symptoms is mixed.
There are only four randomized placebo con-
trolled trials of antidepressants for CFS.109-112 Two
trials with fluoxetine110,112 showed no benefit other
than for depressive symptoms, one trial using
phenelzine showed improvement in multiple CFS
symptoms, illness severity, and mood,109 and the
other using moclobemide showed an improve-
ment in the subjective sense of vigor and energy.111
Although stimulants, such as methylphenidate,
are often used to alleviate the symptoms of low
energy and fatigue, there is no randomized trial
evidence demonstrating any efficacy. In sum, there
is only limited evidence addressing the efficacy of
antidepressants for CFS and the data is insufficient
to draw convincing conclusions.
On the other hand, six of the seven RCTs of
the effectiveness of CBT on CFS found benefit,113-
119
an effect lasting for 5 years.120
OTHER SYNDROMES
There are several other common symptom
syndromes, for which there are no meta-analy-
ses of the effects of antidepressants, largely
because there are few RCTs of the efficacy of
antidepressants. For menopausal symptoms,
there are three RCTs of antidepressants effec-
tiveness, two RCTs in tinnitis, and only one
each studying antidepressant efficacy in chronic
facial pain, noncardiac chest pain, interstitial
cystitis and chronic pelvic pain.
CNS Spectr 11:3 © MBL Communications Inc.
Tinnitus
There have been two RCTs of a TCA for
chronic tinnitus. The better quality study121 involv-
ing 107 patients showed improvement in dis-
ability and tinnitus loudness with nortriptyline,
and additionally no interaction between drug
treatment and depression, indicating an inde-
pendent effect.121 A small study of trimipramine
in 26 patients showed no benefit.122 There have
been numerous studies of CBT treatment of tin-
nitus,123,124 and a recent review of 18 of these 125
found CBT to be particularly useful in reducing
patient annoyance with chronic tinnitus.
Menopausal Symptoms
An RCT involving 165 women found parox-
etine superior to placebo in reducing hot flashes
but not in improving mood, sleep, or sexual
interest.126 Two RCT’s have explored the effective-
ness of venlafaxine. One in 80 women reported
improved mood but mixed results regarding
hot flashes.127 A second trial among 191 survi-
vors of breast cancer compared venlafaxine 37.5
mg/day, 75mg/day, and 150 mg/day. They found
that all three doses of venlaxafine decreased hot
flashes, compared with placebo, with the opti-
mum dose, in this 4-week study of 75 mg/day.128
Chronic Facial Pain
An RCT in 95 patients with several types of
atypical facial pain (temporomandibular joint
syndrome; “psychogenic” facial pain)129 found
the TCA dothiepin 150 mg/day to be superior to
placebo in reducing pain and analgesic use.129
Noncardiac Chest Pain
An RCT in 60 patients with normal coronary
arteries130 found imipramine 50 mg/day superior
to clonidine or placebo in reducing the frequency
of chest pain. Eight randomized trials of CBT on
noncardiac chest pain131 were reviewed with the
authors concluding that there was a modest to
moderate benefit for CBT, particularly in the first
3 months after therapy.
Interstitial Cystitis
In an RCT involving 50 women, amitriptyline
proved superior to placebo in reducing pain and
urgency.132
Chronic Pelvic Pain
A small RCT in 25 women found sertraline no
better than placebo.133
218 March 2006
 Review Article

CONCLUSION tional somatic syndromes can only be partially

There are a number of mechanisms by which
antidepressants may exert a beneficial effect on
symptom syndromes. They may improve comor-
bid mental disorders, that commonly occur with
these syndromes. They may also have effects on
the processing of painful stimuli both centrally
and peripherally. In addition, antidepressants
may exert some effects directly on specific organ
systems, for example the anticholinergic effects
that may help in diarrhea-predominant IBS. A
common question is whether responsiveness
to antidepressants implies the improvement is
mediated principally by treatment of depression.
Analyses in clinical trials that have controlled for
the effect of depression have suggested that at
least part of the effect on somatic symptoms is
independent of depression,55 which incidentally
also seems to be the case for CBT and other psy-
chosocial treatments.16,17 Also, a meta-analysis of
observational studies has also shown that func-
explained by depression and anxiety.133
Finally, many studies of somatic syndromes
have used subtherapeutic doses of antidepres-
sants for relatively short duration, making it less
likely that the benefit is entirely due to antide-
pressant properties of these drugs.
For many symptom syndromes, including
headaches, fibromyalgia, IBS, there is good ran-
domized controlled trial evidence of benefit from
antidepressant therapy (Table 1). For others, such
as back pain and CFS, the evidence of improve-
ment with antidepressant therapy is weak. For
other symptom syndromes, the clinical trial evi-
dence to either support or refute effectiveness
is still evolving as trials are being conducted.
Unfortunately, for none of these symptom syn-
dromes has treatment with antidepressants
proven a panacea. Rather, they are typically an
adjunct therapy providing symptom reduction
rather than eradication and commonly used as

TABLE.
Antidepressants and CBT for Somatic Syndromes
Syndrome TCAs SSRIs CBT/Behavior Therapy
IBS Effective for global symptoms Probably not effective As effective as antispasmodics
and pain
Back pain Modestly effective, should not Probably not effective Effective
be used routinely
Headache Effective in prophylaxis against Not effective Effective in prophylaxis against
headaches headache
Fibromyalgia Effect, particularly for pain and Weak effect Effective
sleep
Chronic fatigue syndrome Not effective Not effective Effective
Tinnitus May be effective Not studied Effective against annoyance

Menopausal syndrome Not studied Possibly effective Not studied

(also SNRI study)
Chronic facial pain Single study suggesting effec- Not studied Not studied
tiveness
Noncardiac chest pain Single study suggesting effec- Not studied Effective
tivenes
Interstitial cystitis Single study suggesting effec- Not studied Not studied
tiveness
Chronic pelvic pain Not studied Single study suggest- Not studied
ing not effective
CBT=cognitive-behavioral therapy; TCAs=tricyclic antidepressants; SSRIs=selective serotonin reuptake inhibitors; IBS=irritable bowel syndrome; SNRI=serotonin and
norepinephrine reuptake inhibitor.

Jackson JL, O’Malley PG, Kroenke K. CNS Spectr. Vol 11, No 3. 2006.

CNS Spectr 11:3 © MBL Communications Inc. 219 March 2006

 Review Article
part of a symptom treatment regimen rather
than monotherapy. Likewise, there is evidence
that CBT can be beneficial in some somatic syn-
dromes. While antidepressants and CBT have
not been compared head-to-head, the effect of
CBT nearly always exceed those seen with anti-
depressants, and for many symptom syndromes,
the evidence comes from numerous, well-con-
ducted RCTs. Direct comparisons between CBT
and antidepressants are needed.
CBT may also have other benefits. An obvious
one is that there is no need to be concerned about
possible interactions with other medications, side
effects or other sequella from long-term use of anti-
depressants. In addition, CBT may exert an increas-
ing effectiveness over time, as the individual begins
to more efficiently apply CBT principles to the man-
agement of their symptom syndrome. CNS
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