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.
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
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. To obtain credits, you should score 70% or better. Termination date: March 31, 2008. The estimated time to complete this activity is 3 hours.
CNS Spectr. 2006;11(3)212-222
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: firstname.lastname@example.org.
Somatic symptoms are common in primary care and clinicians often prescribe antidepressants as adjunctive therapy. There are many possible reasons why this may work, including treating comorbid depression or anxiety, inhibition of ascending pain pathways, inhibition of prefrontal cortical areas that are responsible for “attention” to noxious stimuli, and the direct effects of the medications on the syndrome. There are good theoretical reasons why antidepressants with balanced norepinephrine and serotonin effects may be more effective than those that act predominantly on one pathway, though head-to-head comparisons are lacking. For the 11 painful syndromes review in this article, cognitive-behavioral therapy is most consistently demonstrated to be effective, with various antidepressants having more or less randomized controlled data supporting or refuting effectiveness. This article reviews the randomized controlled trial data for the use of antidepressant and cognitive-behavior therapy for 11 somatic syndromes: irritable bowel syndrome, chronic back pain, headache, fibromyalgia, chronic fatigue syndrome, tinnitus, 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.
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 conditions that can influence symptom severity and functional impairment. Psychiatric comorbidity, particularly depression, anxiety, and posttraumatic 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-depressants 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 activity with noxious stimulation, areas of the brain responsible for increased attention to the stimuli.4,5 This raises the possibility that a common biological 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 projections 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 and NE may exert analgesic effects via inhibitory descending pain pathways7-11 and may be involved in the suppression of somatic symptoms 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 implicated in somatic symptoms. For example tricyclic 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 numerous physical symptoms,16,17 the underlying mechanism for effectiveness is unknown.17 The active component of treatment may be psychological, 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 comorbid conditions. However, emerging data suggests that CBT may also directly modify some of the same brain functions as antidepressants. For example, one study18 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-analysis, 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. 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 recommends diagnosis on the basis of “abdominal discomfort 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 medical evaluation. Predictors of presenting include stress, neuroticism, history of abuse, and poor social support or coping skills24 and most individuals 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 disorder, 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 that TCAs 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 symptoms,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 cognitive-behavioral therapy (CBT) in IBS, using both individual and group therapy models and two systematic reviews. While neither review provided pooled estimates of the magnitude of effect, both suggest that CBT may be effective.32,33 Trials with 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 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 antidepressants 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 antidepressants with placebo run-in,52 one active comparator design.53 and one trial including patients with either neck or back pain.54 The seven placebo-controlled trials included 440 subjects, while all 10 trials 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 moderately effective in reducing back pain. Three of the five studies of these agents, including the two highest quality studies, demonstrated significant benefits in decreasing pain.47,49,50 The drugs studied included nortriptyline 25–100 mg/day, maprotiline 50–150 mg/day, and amitriptyline 50–150 mg/day. A fourth using imipramine 150 mg QD showed decreased pain of borderline 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 significant 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, covering a broad spectrum of medications for which antidepressants were only one category would be appropriate. While they did not pool their data, they found that in five of the seven studies, antidepressants were more effective than placebo in reducing pain and depression.
Salerno and colleagues42 pooled data from nine of the 10 trials, including all seven trials summarized by Staiger and colleagues43 and Schnitzer and colleagues.44 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 effective 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 represent moderate and large effect sizes, respectively.29 Also, adverse events are more common with antidepressants than with placebo. Despite this, there is stronger placebo-controlled trial evidence45 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 important 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 improvements 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 primary care but they reported greater improvements. Finally, pain self-management programs and exercise have also proven beneficial.60,61
Up to a third of populations worldwide experiencing a migraine or tension headache at some time in their life and >50% seeking medical attention.62 In the United States, 87% of those with headaches report disability, with 25% experiencing 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 productivity 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, tension, and cluster headaches.64 Treatment of headaches 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 common 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 individuals with no history of headaches have a more than three-fold risk of developing migraine.67 Most studies on the effectiveness of antidepressants 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 tension 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 to treat 3.2 patients (95% CI: 2.5-4.3) with an antidepressant for one patient to experience at least a 50% improvement in their headaches. On average, patients treated with TCAs had about a one standard deviation of reduction in headache burden, 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 effective than placebo for subjects with migraine headaches and not as effective as TCAs for tension 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 effectiveness include β-blockers73 (except pindolol), valproate, calcium channel blockers (not dihydropyridines), and gabapentin.74 Recent RCTs have suggested that ACE inhibitors75 or angiotensin 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 is a syndrome of chronic musculoskeletal 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 patterns.86-89 Neurohormonal abnormalities, physical or emotional trauma, psychological stress, and infectious causes have also been postulated, although no single etiologic factor has been identified.82 Thus, there may be several mechanisms by which antidepressants improve fibromyalgia symptoms, such as pain control, mood stabilization, and improved sleep. Disturbed sleep is particularly 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 diagnosed 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-adenosylmethionine and three studied SSRIs (fluoxetine 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 amitryptyline was 7.5 (95% CI: 1.8-29.7). In this analysis, 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, comparing 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 standard 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 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 effectiveness 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 relative 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 questionnaire score associated with duloxetine.100 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 producing modest outcomes across multiple domains, including pain, fatigue, physical functioning, and mood.82 The greatest effects occur with it is combined with an exercise program.101 One review of 13 trials of mind-body therapy and fibromyalgia found it had a moderate effect, superior to placebo, 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 improving 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 magnitude of benefit also appeared clinically significant. Patients treated with antidepressants were more than four times as likely to improve. Study patients experienced a range of improvement 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 trigger 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 primary 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 combination of environmental factors and individual vulnerability initiate a series of social, psychological, and biological processes that eventually 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 avoidance and decreased activity, leading to deconditioning), and lack of social support.
Compared with chronic fatigue not meeting criteria for CFS, CFS is associated with more severe symptoms, more disability, more unemployment (as high as 50%), worse functioning, more associated symptoms, more psychological 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
The prognosis for CFS is variable and typically has a fluctuating chronic course. The prognosis without rehabilitative therapy is for gradual improvement in up to 50%, but with few returning to premorbid functioning. Prospective studies 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, sedating 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 symptoms: 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 treatment 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 controlled 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 improvement 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
There are several other common symptom syndromes, for which there are no meta-analyses 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 effectiveness, two RCTs in tinnitis, and only one each studying antidepressant efficacy in chronic facial pain, noncardiac chest pain, interstitial cystitis and chronic pelvic pain.
There have been two RCTs of a TCA for chronic tinnitus. The better quality study121 involving 107 patients showed improvement in disability and tinnitus loudness with nortriptyline, and additionally no interaction between drug treatment and depression, indicating an independent effect.121 A small study of trimipramine in 26 patients showed no benefit.122 There have been numerous studies of CBT treatment of tinnitus,123,124 and a recent review of 18 of these125 found CBT to be particularly useful in reducing patient annoyance with chronic tinnitus.
An RCT involving 165 women found paroxetine superior to placebo in reducing hot flashes but not in improving mood, sleep, or sexual interest.126 Two RCT’s have explored the effectiveness of venlafaxine. One in 80 women reported improved mood but mixed results regarding hot flashes.127 A second trial among 191 survivors 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 optimum 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.
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
There are a number of mechanisms by which antidepressants may exert a beneficial effect on symptom syndromes. They may improve comorbid 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 psychosocial treatments.16,17 Also, a meta-analysis of observational studies has also shown that functional somatic syndromes can only be partially explained by depression and anxiety.133
Finally, many studies of somatic syndromes have used subtherapeutic doses of antidepressants for relatively short duration, making it less likely that the benefit is entirely due to antidepressant properties of these drugs.
For many symptom syndromes, including headaches, fibromyalgia, IBS, there is good randomized controlled trial evidence of benefit from antidepressant therapy (Table 1). For others, such as back pain and CFS, the evidence of improvement with antidepressant therapy is weak. For other symptom syndromes, the clinical trial evidence to either support or refute effectiveness is still evolving as trials are being conducted. Unfortunately, for none of these symptom syndromes has treatment with antidepressants proven a panacea. Rather, they are typically an adjunct therapy providing symptom reduction rather than eradication and commonly used as part of a symptom treatment regimen rather than monotherapy. Likewise, there is evidence that CBT can be beneficial in some somatic syndromes. While antidepressants and CBT have not been compared head-to-head, the effect of CBT nearly always exceed those seen with antidepressants, and for many symptom syndromes, the evidence comes from numerous, well-conducted 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 antidepressants. In addition, CBT may exert an increasing effectiveness over time, as the individual begins to more efficiently apply CBT principles to the management of their symptom syndrome. CNS
1. Whitehead WE, Palsson O, Jones KR. Systematic review of the comorbidity of irritable bowel syndrome with other disorders: what are the causes and implications? Gastroenterology. 2002;122:1140-1156
2. Lake AE 3rd, Rains JC, Penzien DB, Lipchik GL. Headache and psychiatric comorbidity: historical context, clinical implications, and research relevance. Headache. 2005;45:493-506.
3. Patten SB, Beck CA, Kassam A, Williams JV, Barbui C, Metz LM. Long-term medical conditions and major depression: strength of association for specific conditions in the general population. Can J Psychiatry. 2005;50:195-202.
4. Bonaz B, Baciu M, Papillon E, et al. Central processing of rectal pain in patients with irritable bowel syndrome: an fMRI study. Am J Gastroenterol. 2002;97:654-656.
5. Drossman DA, Toner BB, Whitehead WE, et al. Cognitive-behavioral therapy versus education and desipramine versus placebo for moderate to severe functional bowel disorders. Gastroenterology. 2003;125:19-31.
6. Jackson JL. Somatic and vegetative symptoms in depression. Depression, Mind and Body. 2004;1:42-49.
7. Damatarca C. Pain and depression: bridging the body and mind. Depression, Mind and Body. 2003;1:7-13.
8. Jones SL. Descending noradrenergic influences on pain. Prog Brain Res. 1991;88:391-394.
9. Richardson BP. Serotonin and nocioception. Ann N Y Acad Sci. 1990;600:511-519.
10. Stahl SM. The psychopharmacology of painful physical symptoms in depression. J Clin Psychiatry. 2002;63:382-383.
11. Willis WD, Westlund KN. Neuroanatomy of the pain system and the pathways that modulate pain. J Clin Neurophysiol. 1997;14:2-31.
12. Naliboff BD, Munakata J, Fullerton S, et al. Evidence for two distinct perceptual alterations in irritable bowel syndrome. Gut. 1997;41:505-512.
13. Petzke F, Harris RE, Williams DA, Clauw DJ, Gracely RH. Differences in unpleasantness induced by experimental pressure pain between patients with fibromyalgia and healthy controls. Eur J Pain. 2005;9:325-335.
14. Montoya P, Pauli P, Batra A, Wiedemann G. Altered processing of pain-related information in patients with fibromyalgia. Eur J Pain. 2005;9:293-303.
15. Gorard DA, Libby GW, Farthing MJ. Influence of antidepressants on whole gut and orocaecal transit times in health and irritable bowel syndrome. Aliment Pharmacol Ther. 1994;8:159-166.
16. Kroenke K, Swindle R. Cognitive-behavioral therapy for somatization and symptom syndromes: a critical review of controlled clinical trials. Psychother Psychosom. 2000;69:205-215.
17. Allen LA, Escobar JI, Lehrer PM, Gara MA, Woolfolk RL. Psychosocial treatments for multiple unexplained physical symptoms: a review of the literature. Psychosom Med. 2002;64:939-950.
18. Lackner JM, Lou Coad M, Mertz HR, et al. Cognitive therapy for irritable bowel syndrome is associated with reduced limbic activity, GI symptoms, and anxiety. Behav Res Ther. 2005 Jul 20; [Epub ahead of print].
19. Brandt LJ, Bjorkman D, Fennerty MB, Locke GR, Olden K, Peterson W et al. Systematic review on the management of irritable bowel syndrome in North America. Am J Gastroenterol. 2002;97(11 suppl):S7-S26.
20. Thompson WG, Heaton KW, Smyth GT, Smyth C. Irritable bowel syndrome: the view from general practice. Eur J Gastroenterol Hepatol. 1997;9:689-692.
21. Gladman LM, Gorard DA. General practitioner and hospital specialist attitudes to functional gastrointestinal disorders. Aliment Pharmacol Ther. 2003;17:651-654.
22. American College of Gastroenterology Functional Gastrointestinal Disorders Task Froce. Evidence-based position statement on the management of irritable bowel syndrome in North America. Am J Gastroenterol. 2002;97(11 Suppl):S1-S5.
23. Guilera M, Balboa A, Mearin F. Bowel habit subtypes and temporal patterns in irritable bowel syndrome: systematic review. Am J Gastroenterol. 2005;100:1174-1184.
24. Koloski NA, Talley NJ, Boyce PM. Predictors of health care seeking for irritable bowel syndrome and nonulcer dyspepsia: a critical review of the literature on symptom and psychosocial factors. Am J Gastroenterol. 2001;96:1340-1349.
25. Clouse RE. Antidepressants for irritable bowel syndrome. Gut. 2003;52:598-599.
26. Lesbros-Pantoflickova D, Michetti P, Fried M, Beglinger C, Blum AL. Meta-analysis: The treatment of irritable bowel syndrome. Aliment Pharmacol Ther. 2004;20:1253-69.
27. Jailwala J, Imperiale TF, Kroenke K. Pharmacologic treatment of the irritable bowel syndrome: a systematic review of randomized, controlled trials. Ann Intern Med. 2000;133:136-147.
28. Jackson JL, O’Malley PG, Tomkins G, Balden E, Santoro J, Kroenke K. Treatment of functional gastrointestinal disorders with antidepressant medications: a meta-analysis. Am J Med. 2000;108:65-72.
29. Kazis LE, Anderson JJ, Meenan RF. Effect sizes for interpreting changes in health status. Med Care. 1989;27(3 suppl):S178-S189.
30. Tabas G, Beaves M, Wang J, Friday P, Mardini H, Arnold G. Paroxetine to treat irritable bowel syndrome not responding to high-fiber diet: a double-blind, placebo-controlled trial. Am J Gastroenterol. 2004;99:914-920.
31. Kuiken SD, Tytgat GN, Boeckxstaens GE. The selective serotonin reuptake inhibitor fluoxetine does not change rectal sensitivity and symptoms in patients with irritable bowel syndrome: a double blind, randomized, placebo-controlled study. Clin Gastroenterol Hepatol. 2003;1:219-228
32. Toner BB, Segal ZV, Emmot S, et al. Cognitive-behavioral group therapy for patients with irritable bowel syndrom. Int J Group Psychother. 1998;48:215-243.
33. Hutton J. Cognitive behaviour therapy for irritable bowel syndrome. Eur J Gastroenterol Hepatol. 2005;17:11-14
34. Kennedy T, Jones R, Darnley S, Seed P, Wessely S, Chalder T. Cognitive behaviour therapy in addition to antispasmodic treatment for irritable bowel syndrome in primary care: randomised controlled trial. BMJ. 2005;331:435.
35. Shaw G, Srivastava ED, Sadlier M, Swann P, James JY, Rhodes J. Stress management for irritable bowel syndrome: a controlled trial. Digestion. 1991;50:36-42.
36. Bennett P, Wilkinson S. A comparison of psychological and medical treatment of the irritable bowel syndrome. Br J Clin Psychol. 1985;24(pt 3):215-216.
37. Heymann-Monnikes I, Arnold R, Florin I, Herda C, Melfsen S, Monnikes H. The combination of medical treatment plus multicomponent behavioral therapy is superior to medical treatment alone in the therapy of irritable bowel syndrome. Am J Gastroenterol. 2000;95:981-994.
38. Boyce PM, Talley NJ, Balaam B, Koloski NA, Truman G. A randomized controlled trial of cognitive behavior therapy, relaxation training, and routine clinical care for the irritable bowel syndrome. Am J Gastroenterol. 2003;98:2209-2218.
39. Hart LG, Deyo RA, Cherkin DC. Hart LG, Deyo RA, Cherkin DC. Physician office visits for low back pain. Frequency, clinical evaluation, and treatment patterns from a U.S. national survey. Spine. 1995;20:11-19.
40. Maniadakis N, Gray A. The economic burden of back pain in the UK. Pain 2000;84:95-103.
41. Von Korff M, Saunders K. The course of back pain in primary care. Spine. 1996;21:2833-2837.
42. Salerno SM, Browning R, Jackson JL. The effect of antidepressant treatment on chronic back pain: a meta-analysis. Arch Intern Med. 2002;162;19-24.
43. Staiger TO, Gaster B, Sullivan MD, Deyo RA. Systematic review of antidepressants in the treatment of chronic low back pain. Spine. 2003;28:2540-2545.
44. Schnitzer TJ, Ferraro A, Hunsche E, Kong SX. A comprehensive review of clinical trials on the efficacy and safety of drugs for the treatment of low back pain. J Pain Symptom Manage. 2004;28:72-95.
45. Jenkins DG, Ebbutt AF, Evans CD. Tofranil in the treatment of low back pain. J Int Med Res. 1976;4(2 Suppl):28-40.
46. Alcoff J, Jones E, Rust P, et al. Controlled trial of imipramine for chronic low back pain. J Fam Pract. 1982;14:841-846.
47. Pheasant H, Bursk A, Goldfarb J, et al. Amitriptyline and chronic low-back pain. A randomized doubleblind crossover study. Spine. 1983;8:552-557.
48. Goodkin K, GullionCM, Agras WS. A randomized, double-blind, placebo-controlled trial of trazodone hydrochloride in chronic low back pain syndrome. J Clin Psychopharmacol. 1990;10:269-278.
49. Atkinson JH, Slater MA, Williams RA, et al. A placebo-controlled randomized clinical trial of nortriptyline for chronic low back pain. Pain. 1998;76:287-296.
50. Atkinson JH, Slater MA, Wahlgren DR, et al. Effects of noradrenergic and serotonergic antidepressants on chronic low back pain intensity. Pain. 1999;83:137-145.
51. Dickens C, Jayson M, Sutton C, Creed F. The relationship between pain and depression in a trial using paroxetine in sufferers of chronic low back pain. Psychosomatics. 2000;41:490-499.
52. Ward N, Bokan JA, Phillips M, Benedetti C, Butler S, Spengler D. Antidepressants in concomitant chronic back pain and depression: doxepin and desipramine compared. J Clin Psychiatry. 1984;45(3 pt 2):54-59.
53. Schreiber S, Vinokur S, Shavelzon V, Pick CG, Zahavi E, Shir Y. A randomized trial of fluoxetine versus amitriptyline in musculo-skeletal pain. Isr J Psychiatry Relat Sci. 2001;38:88-94.
54. Hameroff SR, Weiss J, Lerman JC, et al. Doxepin’s effects on chronic pain and depression. J Clin Psychiatry. 1984;45(3 pt 2):47-52.
55. O’Malley PG, Jackson JL, Tomkins G, Santoro J, Balden E, Kroenke K. Antidepressant therapy for unexplained symptoms and symptom syndromes: a critical review. J Fam Pract. 1999;48;980-993.
56. Jung AC, Staiger T, Sullivan M. The efficacy of selective serotonin reuptake inhibitors for the management of chronic pain. J Gen Intern Med. 1997;12:384-389.
57. Onghena P, Van Houdenhove B. Antidepressant-induced analgesia in chronic non-malignant pain: a meta-analysis of 39 placebo-controlled studies. Pain. 1992;49:205-219.
58. Grothe DR, Scheckner B, Albano D. Treatment of pain syndromes with venlafaxine. Pharmacotherapy. 2004;24:621-629.
59. Raine R, Haines A, Sensky T, Hutchings A, Larkin K, Black N. Systematic review of mental health interventions for patients with common somatic symptoms: can research evidence from secondary care be extrapolated to primary care? BMJ. 2002;325:1082.
60. van Tulder MW, Koes BW, Bouter LM. Conservative treatment of acute and chronic nonspecific low back pain. A systematic review of randomized controlled trials of the most common interventions. Spine. 1997;22:2128-2156.
61. Lorig KR, Holman H. Self-management education: history, definition, outcomes, and mechanisms. Ann Behav Med. 2003;26:1-7.
62. Rasmussen BK, Olesen J. Epidemiology of headache in a general population: a prevalence study. Curr Opin Neurol. 1994;7:264-227.
63. Hu XH, Markson LE, Lipton RB, Stewart WF, Berger ML. Burden of migraine in the United States: disability and economic costs. Arch Intern Med. 1999;159:813-818.
64. Taylor FR. Diagnosis and classification of headache. Prim Care. 2004;31:243-259.
65. Lake AE 3rd, Rains JC, Penzien DB, Lipchik GL. Headache and psychiatric comorbidity: historical context, clinical implications, and research relevance. Headache. 2005;45:493-506.
66. Gesztelyi G, Bereczki D. Disability is the major determinant of the severity of depressive symptoms in primary headaches but not in low back pain. Cephalalgia. 2005;25:598-604.
67. Torelli P, D‘Amico D. An updated review of migraine and co-morbid psychiatric disorders. Neurol Sci. 2004;25(suppl 3):S234-S235.
68. Tomkins GE, Jackson JL, O’Malley PG, Balden E, Santoro JE. Treatment of chronic headache with antidepressants: a meta-analysis. Am J Med. 2001;111:54-63.
69. Lance JW, Curran DA. Treatment of chronic tension headache. Lancet. 1964;1:1236-1239.
70. Moja PL, Cusi C, Sterzi RR, Canepari C. Selective Serotonin Re-uptake Inhibitors for Preventing Migraine and Tension-Type Heaches. Cochrane Database Syst Rev. 2005:CD002919.
71. Rains JC, Penzien DB, McCrory DC, Gray RN. Behavioral Headache Treatment: History, Review of the Empirical Literature, and Methodological Critique. Headache. 2005;45(suppl 2):S92-S109.
72. Linde, K. Rossnagel, K. Propranolol for migraine prophylaxis. Cochrane Database Syst Rev. 2004;(4):CD003225.
73. Melchart D, Streng A, Hoppe A, et al. Acupuncture in patients with tension-type headache: randomised controlled trial. BMJ. 2005;331:376-382.
74. Silberstein SD. Practice parameter: evidence-based guidelines for migraine headache (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2000;55:754-762.
75. Schrader H, Stovner LJ, Helde G, Sand T, Bovim G. Prophylactic treatment of migraine with angiotensin converting enzyme inhibitor (lisinopril): randomised, placebo controlled, crossover study. BMJ. 2001;322:19-22.
76. Tronvik E, Stovner LJ, Helde G, Sand T, Bovim G. Prophylactic treatment of migraine with an angiotensin II receptor blocker: a randomized controlled trial. JAMA. 2003;289:65-69.
77. Ernst E. Manual therapies for pain control: chiropractic and massage. Clin J Pain. 2004;20:8-12.
78. Yunus MD, Kalayan-Raman UP, Masi AT, Aldag AT. Electron microscopic studies of muscle biopsy in primary fibromyalgia syndrome: a controlled and blinded study. J Rheumatol. 1989;16:97-10
79. Simms RW, Roy SH, Hrovat M, et al. Lack of association between fibromyalgia syndrome and abnormalities and muscle energy metabolism. Arthritis Rheum. 1994;37:794-800.
80. Pillemer SR, Bradley LA, Crofford LJ, Moldofsky H, Chrousos GP. The neuroscience and endocrinology of fibromyalgia. Arthritis Rheum. 1997;40:1928-1939
81. Wolfe F. Fibromyalgia: the clinical syndrome. Rheum Dis Clin North Am. 1989;15:1-17
82. Goldenberg DL, Burckhardt C, Crofford L. Management of fibromyalgia syndrome.JAMA. 2004;292:2388-2395.
83. Arroyo JF, Cohen ML. Abnormal responses to electrocutaneous stimulation in fibromyalgia. J Rheumatol. 1993;20:1925-1931.
84. Kosek E, Ekholm J, Hansson P. Modulation of pressure pain thresholds during and following isometric contraction in patients with fibromyalgia and in healthy controls. Pain. 1996;64:415-423.
85. Kosek E, Ekholm J, Hansson P. Increased pressure pain sensibility in fibromyalgia patients is located deep in the skin but not restricted to muscle tissue. Pain. 1995;63:335-339.
86. Drewes AM, Gade K, Nielsen KD, Bjerregard K, Taagholt SJ, Svendsen L. Clustering of sleep electroencephalographic patterns in patients with the fibromyalgia syndrome. Br J Rheumatol. 1995;34:1151-1156.
87. May KP, West SG, Baker MR, Everett DW. Sleep apnea in male patients with the fibromyalgia syndrome. Am J Med. 1993;94:505-508.
88. Yunus MB, Aldag JC. Restless leg syndrome and leg cramps in fibromyalgia syndrome: a controlled study. BMJ. 1996;312:1339.
89. MacFarlane JG, Shahal B, Mously C, Moldofsky H. Periodic K-alpha sleep EEG activity and periodic limb movements during sleep: comparisons of clinical features and sleep parameters. Sleep. 1996;19:200-204.
90. Hudson JL, Goldenberg DL, Pope HG Jr, Keck PE Jr, Schlesinger L. Comorbidity of fibromyalgia with medical and psychiatric disorders. Am J Med. 1992;92:363-367.
91. Triadafilopoulos G, Simms RW, Goldenberg DL. Bowel dysfunction in fibromyalgia syndrome. Dig Dis Sci. 1991;36:59-64.
92. Ahles TA, Khan SA, Yunus MB, Spiegell DA, Masi AT. Psychiatric status of patients with primary fibromyalgia, patients with rheumatoid arthritis and subjects without pain: a blind comparison of DSM-III diagnoses. Am J Psychiatry. 1991;148:1721-1726.
93. O’Malley PG, Balden E, Tomkins G, Santoro J, Kroenke K, Jackson JL. Treatment of fibromyalgia with antidepressants: a meta-analysis. J Gen Intern Med. 2000;15:659-666.
94. Goldenberg D, Mayskiy M, Mossey C, Ruthazer R, Schmid C. A randomized, double-blind, crossover trial of fluoxetine and amitriptyline in the treatment of fibromyalgia. Arthritis Rheum. 1996;39:1852-1859.
95. Carette S, McCain GA, Bell DA, Fam AG. Evaluation of amitriptyline in primary fibrositis. A double-blind placebo-controlled study. Arthritis Rheum. 1986;29:655-659.
96. Hannonen P, Malminiemi K, Yli-Kerttula U, Isomeri R, Roponen P. A randomized, double-blind, placebo-controlled study of moclobemide and amitriptyline in the treatment of fibromyalgia in females without psychiatric disorder. Br J Rheumatol. 1998;37:1279-1286.
97. Wolfe F, Cathey MA, Hawley DJ. A double-blind placebo controlled trial of fluoxetine in fibromyalgia. Scand J Rheumatol. 1994;23:255-259.
98. Norregaard J, Volkmann H, Danneskiold-Samsoe B. A randomized controlled trial of citalopram in the treatment of fibromyalgia. Pain. 1995;61:445-449.
99. Arnold LM, Hess EV, Hudson JI, Welge JA, Berno SE, Keck PE Jr.A randomized, placebo-controlled, double-blind, flexible-dose study of fluoxetine in the treatment of women with fibromyalgia. Am J Med. 2002;112:191-197.
100. Arnold LM, Lu Y, Crofford LJ, et al. A double-blind, multicenter trial comparing duloxetine with placebo in the treatment of fibromyalgia patients with or without major depressive disorder. Arthritis Rheum. 2004;50:2974-2984.
101. Williams DA. Psychological and behavioural therapies in fibromyalgia and related syndromes. Best Pract Res Clin Rheumatol. 2003;17:649-665.
102. Hadhazy VA, Ezzo J, Creamer P, Berman BM . Mind-body therapies for the treatment of fibromyalgia. A systematic review. J Rheumatol. 2000;27:2911-2918.
103. Tofferi JK, O’Malley PG, Jackson JL. Treatment of fibromyalgia with cyclobenzaprine: A meta-analysis. Arthritis Rheum. 2004;51:9-13.
104. Sharpe M, O’Malley PG. Chronic fatigue and fibromyalgia syndromes. In: Levinson J, ed. Textbook of Consultation-Liaison Psychiatry, 1st ed. Washington, DC: American Psychiatric Press; 2004:108-134
105. Fukuda K, Straus SE, Hickie IB, Sharpe M, Dobbins JG, Komaroff AL. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med. 1994;121:953-959.
106. Sullivan PF, Pedersen NL, Jacks A, Evengard B. Chronic fatigue in a population sample: definitions and heterogeneity. Psychol Med. 2005;35:1337-1348.
107. Darbishire L, Ridsdale L, Seed PT. Distinguishing patients with chronic fatigue from those with chronic fatigue syndrome: a diagnostic study in UK primary care. Br J Gen Pract. 2003;53:441-445.
108. Whiting P, Bagnall AM, Sowden AJ, Cornell JE, Mulrow CD, Ramirez G. Interventions for the treatment and management of chronic fatigue syndrome: a systematic review. JAMA. 2001;286:1360-1368.
109. Natelson BH, Cheu J, Pareja J, Ellis SP, Policastro T, Findley TW. Randomized, bouble blind, controlled placebo-phase in trial of low dose phenelzine in the chronic fatigue syndrome. Psychopharmacology. 1996;124:226-230.
110. Vercoulen JH, Swanink CM, Zitman FG, et al. Randomized double-blind placebo-controlled study of fluoxetine in chronic fatigue syndrome. Lancet. 1996;347:858-861.
111. Hickie IB, Wilson AJ, Wright JM, Bennet BK, Wakefield D, Lloyd AR. A randomized, double-blind placebo-controlled trial of moclobemide in patients with chronic fatigue syndrome. J Clin Psychiatry. 2000;61:643-648.
112. Wearden AJ, Morriss RK, Mullis R, et al. Randomised, double-blind, placebo-controlled treatment trial of fluoxetine and graded exercise for chronic fatigue syndrome. Br J Psychiatry. 1998;172:485-490.
113. Sharpe M, Hawton K, Simkin S, et al. Cognitive behavior therapy for the chronic fatigue syndrome: a randomised controlled trial. BMJ. 19963;12:22-26.
114. Deale A, Chalder T, Marks I, Wessely S. Cognitive behavior therapy for chronic fatigue syndrome: a randomized controlled trial. Am J Psychiatry. 1997;154:408-414.
115. Lloyd AR, Hickie I, Brockman A, et al. Immunologic and psychologic therapy for patients with chronic fatigue syndrome: a double-blind, placebo-controlled trial. Am J Med. 1993;94:197-203.
116. Friedberg F, Krupp LB. A comparison of cognitive behavior treatment for chronic fatigue syndrome and primary depression. Clin Infect Dis. 1994;18(suppl 1):S105-S110.
117. Stulemeijer M, de Jong LW, Fiselier TJ, Hoogveld SW, Bleijenberg G. Cognitive behaviour therapy for adolescents with chronic fatigue syndrome: randomised controlled trial. BMJ. 2005;330:14.
118. Huibers MJ, Beurskens AJ, Van Schayck CP, et al. Efficacy of cognitive-behavioural therapy by general practitioners for unexplained fatigue among employees: randomised controlled trial. Br J Psychiatry. 2004;184:240-246.
119. Ridsdale L, Darbishire L, Seed PT. Is graded exercise better than cognitive behaviour therapy for fatigue? A UK randomized trial in primary care. Psychol Med. 2004;34:37-49.
120. Deale A, Husain K, Chalder T, Wessely S. Long-term outcome of cognitive behavior therapy versus relaxation therapy for chronic fatigue syndrome: a 5-year follow-up study. Am J Psychiatry. 2001;158:2038-2042.
121. Sullivan M, Katon W, Russo J, Dobie R, Sakai C. A randomized trial of nortriptyline for severe chronic tinnitus. Effects on depression, disability, and tinnitus symptoms. Arch Intern Med. 1993;153:2251-2259.
122. Mihail RC, Crowley JM, Walden BE, Fishburne J, Reinwall JE, Zajtchuk JT. The tricyclic trimipramine in the treatment of subjective tinnitus. Ann Otol Rhinol Laryngol. 1988;97:120-123.
123. Kroner-Herwig B, Frenzel A, Fritsche G, Schilkowsky G, Esser G.The management of chronic tinnitus: comparison of an outpatient cognitive-behavioral group training to minimal-contact interventions. J Psychosom Res. 2003;54:381-389.
124. Zachriat C, Kroner-Herwig B. Treating chronic tinnitus: comparison of cognitive-behavioural and habituation-based treatments. Cogn Behav Ther. 2004;33:187-198.
125. Andersson G, Lyttkens L. A meta-analytic review of psychological treatments for tinnitus. Br J Audiol. 1999;33:201-210.
126. Stearns V, Beebe KL, Iyengar M, Dube E. Paroxetine controlled release in the treatment of menopausal hot flashers: a randomized controlled trial. JAMA. 2003;289:2827-2834.
127. Evans ML, Pritts E, Vittinghoff E, McClish K, Morgan KS, Jaffe RB. Management of postmenopausal hot flashes with venlafaxine hydrochloride: a randomized, controlled trial. Obstet Gynecol. 2005;105:161-166.
128. Loprinzi CL, Kugler JW, Sloan JA, et al. Venlafaxine in management of hot flashes in survivors of breast cancer: a randomised controlled trial. Lancet. 2000;356:2059-2063.
129. Feinmann C, Harris M, Cawley R. Psychogenic facial pain: presentation and treatment. Br Med J (Clin Res Ed). 1984;288:436-438.
130. Cannon RO, Quyyumi AA, Mincemoyer R, et al. Imipramine in patients with chest pain despite normal coronary angiograms. N Engl J Med. 1994;30:1411-1417.
131. Kisely S, Campbell LA, Skerritt P. Psychological interventions for symptomatic management of non-specific chest pain in patients with normal coronary anatomy. Cochrane Database Syst Rev. 2005;CD004101.
132. van Ophoven A, Pokupic S, Heinecke A, Hertle L. A prospective, randomized, placebo controlled, double-blind study of amitriptyline for the treatment of interstitial cystitis. J Urol. 2004;172:533-536.
133. Engel CC Jr, Walker EA, Engel AL, Bullis J, Armstrong A. A randomized, double-blind crossover trial of sertraline in women with chronic pelvic pain. J Psychosom Res. 1998;44:203-207.
134. Henningsen P, Zimmermann T, Sattel H. Medically unexplained physical symptoms, anxiety, and depression: a meta-analytic review. Psychosom Med. 2003;65:528-533.