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Review: antidepressants are effective for clinical improvement in unexplained physical symptoms and syndromes
  1. Jonathan Price, MA, MSc, BMBCh
  1. University of Oxford Oxford, UK

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 QUESTION: In adults who have medically unexplained physical symptoms (MUPS), do antidepressants improve outcomes?

    Data sources

    Studies were identified by searching Medline (1966–98), PsycLIT (1974–98), EMBASE/Excerpta Medica (1974–98), the Cochrane Library, the Federal Research in Progress database, and bibliographies of relevant articles.

    Study selection

    2 reviewers independently selected studies that were randomised controlled trials (RCTs) (including crossover trials), involved adults with MUPS, compared antidepressants with placebo or a non-antidepressant intervention, reported measurable outcomes, and were published in English.

    Data extraction

    Data extracted included symptoms, setting, treatment (regimens and follow up), patient characteristics, assessment of comorbid psychiatric disease, adverse effects, outcomes, statistical analysis of reported results, and quality of study methods (Jadad scale).

    Main results

    94 RCTs on 6 symptom syndromes met the selection criteria. 6595 patients (76% women) were studied for a median of 9 weeks. The dropout rate was >20% in 40% of the RCTs. A meta-analysis combined results for improvement: global assessment (patient or physician), summary symptom index scores, or pain severity scale scores (table). 4 patients (95% CI 3 to 7) would need to be treated to improve 1 additional patient's condition. A meta-analysis of the results for continuous outcomes reported a pooled standardised mean difference of 0.87 (CI 0.59 to 1.14).

    Antidepressants v placebo for unexplained symptoms or syndromes*


    In patients with medically unexplained physical symptoms or syndromes, antidepressants are effective for improving outcomes, including symptoms and disability.


    Patients with MUPS are common in primary and secondary care. Increasing evidence exists that such psychological therapies as cognitive behavior therapy (CBT) are effective in the treatment of these symptoms.1, 2 Unfortunately, suitably trained therapists are scarce, and psychological treatment is unacceptable to some patients. Thus, effective pharmacological treatments have a potentially substantial role in the treatment of patients with MUPS.

    The review by O'Malley et al supports the use of antidepressants for treating MUPS. The number needed to treat of 4 for short term improvement is clinically significant and is similar to that obtained with CBT.1, 2 People with a wide range of MUPS seem to benefit from antidepressants, even though not all are depressed. An important caveat is that most evidence applies to patients in secondary care who have chronic symptoms.

    Clinicians therefore have 2 evidence-based types of treatment for MUPS: psychological (CBT) and pharmacological (antidepressants). If CBT is available, the choice between it and antidepressants is difficult. Patient choice should therefore be encouraged because compliance with and enthusiasm for the chosen treatment may profoundly influence outcome. People with MUPS who reject psychological treatment, however, may also reject the use of antidepressants for “physical” problems. The term “antidepressants” is unhelpful in this situation and is increasingly inappropriate as evidence for other indications accumulates.

    Several other decisions face clinicians. Firstly, which antidepressant should be used? No convincing evidence exists for 1 group. Secondly, what dose should be given? Little evidence is available, although, as therapeutic action seems independent of antidepressive action, low doses may be effective. Finally, how long should the patient receive the medication? Antidepressants are effective for people with MUPS over periods of weeks. It is unclear, however, whether treatment can be withdrawn and what the optimal duration of treatment is. Several key knowledge gaps must therefore be addressed by more primary research. Until then, clinicians should consider prescribing antidepressants that are safe and well tolerated, with dose and duration determined empirically.



    • Source of funding: In part, the MacArthur Foundation Initiative on Depression in Primary Care.

    • For correspondence: Dr P G O'Malley, Department of Medicine, Walter Reed Army Medical Center, 6900 Georgia Avenue, Washington, DC 20307-5001, USA. Fax +1 202 782 7363.

    • Abstract and commentary also appear in Evidence-Based Mental Health.