Patrick G. O’Malley, MD, MPH Jeffrey L. Jackson, MD, MPH James Santoro, MD, MPH Glen Tomkins, MD, MPH Erin Balden, MD, MPH Kurt Kroenke, MD Washington, DC; Bethesda, Maryland; El Paso, Texas; and Indianapolis, Indiana Submitted, revised, July 15, 1999. From the Department of Medicine (P.G.O., G.T., E.B.), Walter Reed Army Medical Center, Washington, DC; Uniformed Services University of the Health Sciences (J.L.J), Bethesda; William Beaumont Army Medical Center (J.S.), El Paso; and the Regenstrief Institute for Health Care and Indiana University School of Medicine (K.K.), Indianapolis. The opinions and assertions in this paper are the private views of the authors and should not be interpreted to reflect the views of the Department of the Army or the Department of Defense.Reprint requests should be addressed to Patrick G. O’Malley, MD, MPH, Division of General Internal Medicine, Walter Reed Army Medical Center, 6800 Georgia Avenue, Washington, DC 20307. E-mail: pgomalley@msn.com.
References
OBJECTIVE: To determine the efficacy of antidepressant therapy for unexplained symptoms or symptom syndromes.
SEARCH STRATEGIES: We identified original studies through searching MEDLINE, EMBASE, PsycLIT, the Federal Research in Progress database, and The Cochrane Library. We also searched the bibliographies of primary and review articles for additional studies.
SELECTION CRITERIA: We excluded trials of patients with neuropathic, oncologic, or degenerative joint pain. Independent duplicate review of 392 articles identified 94 relevant reports of randomized trials involving 6595 patients across 6 symptom syndromes. Independent duplicate assessment was made for inclusion and data abstraction. Meta-analysis was performed on extractable placebo-controlled data.
MAIN RESULTS: Of 94 included trials, most studied either tricyclic antidepressants, antiserotonin antidepressants, selective serotonin reuptake inhibitors (SSRIs), or multiple agents for the treatment of the following syndromes: headache (50), fibromyalgia (18), functional gastrointestinal syndromes (13), idiopathic pain (11), tinnitus (2), and chronic fatigue (2). The quality of the studies was fair (mean score = 4.8 on a scale of 0 to 8). A majority of the studies (69%) demonstrated benefit for at least one outcome measure. Symptom improvement typically did not correlate with depression response in the few studies where it was assessed. Meta-analysis of all extractable data showed a substantial benefit from antidepressants: For the dichotomous outcome of improvement, the odds ratio was 3.4 (95% confidence interval [CI], 2.6 - 4.5), and for continuous outcomes, the standardized mean difference was 0.87 (95% CI, 0.59 - 1.14). The absolute percentage difference in improvement between the antidepressant and placebo arms was 32%, yielding a number needed to treat of 3 to improve one person’s symptoms. Meta-regression indicated no differential effect across the classes of antidepressants; however, onbivariate tally tricyclic studies were associated with a greater likelihood of efficacy than SSRI studies (P = .02).
CONCLUSIONS: Antidepressants can be effective for various physical symptoms and symptom syndromes. The relation of outcome to depression and the efficacy of SSRIs needs further study.
Clinical Question Are antidepressants efficacious in the treatment of unexplained symptoms and symptom syndromes?
Chronic physical symptoms that defy etiologic understanding but cause significant morbidity are common in outpatient practice, and diagnostic testing frequently fails to reveal a discrete disease that has a specific therapy. Examples include irritable bowel syndrome, migraine or tension headaches, chronic fatigue syndrome, nonulcerative dyspepsia, fibromyalgia, unexplained dyspnea, tinnitus, and idiopathic pain syndromes. For many of these types of syndromes there is increased psychiatric comorbidity, especially depressive and anxiety disorders.1-3 The vast majority of patients with depression in primary care present with physical, not emotional, complaints.4-6 Although antidepressant therapy has been demonstrated to be efficacious in pain syndromes for which there is a well-established understanding of the pathophysiology,7-9 the evidence for its efficacy for other types of physical symptom syndromes has not been critically reviewed.
Methods
Data Sources
We searched MEDLINE (1966 to December 1998), PsycLIT (1974 to December 1998), and EMBASE (1974 to December 1998) using the following text words and key words (all languages, limited to “human”): antidepressive agents “or” selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, tricyclic, amitriptyline, amoxapine, clomipramine, trimipramine, desipramine, doxepin, imipramine, maprotiline, nortriptyline, protriptyline, trazodone, nefazodone, fluoxetine, fluvoxamine, paroxetine, sertraline, femoxetine, venlafaxine, buproprion, citalopram, mianserin, pizotyline, pizotifen; antidepressive agents “and” headache, colonic diseases-functional, abdominal pain, dyspepsia, chronic fatigue syndrome, fibromyalgia, myofascial pain syndromes, dyspnea, tinnitus, back pain, pelvic pain, and chest pain. The symptom syndromes we included in the search were derived from a panel of general internists. We used The Cochrane Library, searching The Cochrane Controlled Trials Register for randomized trials and The Cochrane Database of Systematic Reviews for systematic reviews.10 We also searched the Federal Research in Progress database to identify unpublished literature. All of the citations identified from the search were pulled and their references reviewed for additional articles missed during the database search. All primary articles and review articles and their references were reviewed independently, in duplicate.
Study Selection
Studies were screened for inclusion using the following criteria: adult study population; the symptom syndrome being evaluated was either idiopathic or the pathophysiology was poorly understood; at least one study group received an antidepressant; there was a placebo or non-antidepressant control arm; the allocation of the intervention was randomized (this included crossover trials); and measurable outcomes were reported. Articles were excluded if any of these criteria were not met. Each article was reviewed independently in duplicate for inclusion assessment. Agreement was substantial among raters (k ranged from .55 - .85 among pairs of raters). Disagreements were arbitrated by discussion and consensus.
Quality Scores
The methodologic quality of each included study was assessed using a quality assessment instrument developed and validated by Jadad and colleagues.11 This instrument uses the following criteria: appropriate randomization and blinding, description of withdrawals, dropouts, statistical analysis, inclusion criteria, exclusion criteria, and the method used to assess adverse effects. The score ranges from 0 (poor) to 8 (excellent). Scores were assessed independently in duplicate by 4 of the investigators (P.G.O., G.T., E.B., J.J). Agreement was substantial (intraclass correlation coefficient >0.70 for all pairs of raters). Disagreements were arbitrated by consensus, and when consensus could not be achieved discordant scores were averaged and rounded to the higher whole number.
