Antidepressant Therapy for Unexplained Symptoms and Symptom Syndromes

Discussion

Antidepressants proved efficacious in more than two thirds of the studies we reviewed. Patients receiving antidepressants were more than 3 times as likely to experience symptomatic improvement than patients receiving placebo. This benefit was consistent across 6 different symptom syndromes. Although there was considerable variability in the methodologic quality of the studies, the beneficial effect demonstrated was similar in low-, medium-, and high-quality studies.

When quantitative synthesis was possible, the consistency of benefit across symptom syndromes suggests some real effect of antidepressants. However, it is not clear from this data whether such therapy is treating underlying subclinical psychiatric disorders, acting merely as a symptom or pain-threshold modifier, or treating a disorder that has a common neurotransmitter pathology. Studies that assessed for comorbid psychiatric disease were in the minority, and of the few that did, there was little correlation between efficacy and depressive symptoms. The systematic assessment of depression and control for this effect was inadequately done in these studies to determine whether the efficacy demonstrated was independent of a depression response.

Earlier reviews and meta-analyses in this area focused predominantly on well-defined organic disorders and found antidepressants, particularly TCAs, to be efficacious.^7-9 Onghena and colleagues⁷ reviewed 39 studies on the analgesic effect of antidepressants and chronic nonmalignant pain. They found that antidepressants have significant efficacy in reducing pain when compared with placebo, even when controlling for psychogenic etiology (though the frequency and quality of controlling for psychiatric disorders in the individual trials was limited). McQuay and coworkers8 published a systematic review of the literature on antidepressant therapy for neuropathic pain (diabetic neuropathy, postherpetic neuralgia, central pain) and found that antidepressants are effective in alleviating chronic neuropathic pain.

Jung and colleagues⁹ looked specifically at the efficacy of SSRIs in the management of selected chronic pain syndromes (diabetic neuropathy, headaches, fibromyalgia, mixed psychogenic, or organic chronic pain) and showed there was benefit for mixed chronic pain but unclear benefit for headaches, diabetic neuropathy, or fibromyalgia.

In the only review of antidepressants and nonorganic pain disorders Fishbain and coworkers¹¹⁴ did a meta-analysis of 11 studies of antidepressants for patients with specific diagnoses of psychogenic pain and somatoform pain disorder and found that the drugs decreased pain intensity better than placebo, by one standard deviation. This is remarkably consistent with our meta-analysis, and indeed most of the studies included in that analysis were included in our analysis. This corroborates the validity of our review, but also highlights the tremendous variation in the classification of these symptom syndromes.

Methodology Weaknesses of the Studies

There were several weaknesses to the methodology of this literature. First, many of the studies were of relatively short duration (mean = 9 weeks), despite symptom syndromes that were generally of many years duration. Since depressive symptoms tend to require significant time to respond completely, much longer treatment and follow-up periods may be required to confidently assess the relationship between efficacy for physical symptoms and resolution of comorbid depressive symptoms, as well as to assess the optimal duration of treatment. Second, a crossover design was used in one third of the studies. Using crossover designs for assessing antidepressant efficacy is problematic because of the possibility of carryover effects of antidepressants. Third, withdrawal rates were high in these studies, indicating possible limited generalizability of the efficacy of antidepressants for these syndromes because of side effects. Fourth, double-blind trials with drugs that have side effects may not be truly double blinded, and such potential bias might overestimate an effect for antidepressants relative to placebo. Finally, only a minority of placebo-controlled trials used an intention-to-treat analysis, undermining the power of randomization to minimize bias; thus, it is possible there is a significant overestimation of the effect size in a majority of these studies.

Limitations

There are several limitations to our systematic review. First, other sources of unpublished studies (eg, pharmaceutical companies) and non-English language literature not included in this review might alter the cumulative evidence we found. However, after repeating our search method including non-English literature there were only 20 additional references, of which a significant proportion were unlikely to meet our inclusion criteria. There was evidence of publication bias, meaning that it is likely there were unpublished studies that showed no efficacy. This is not surprising given the negative stigma associated with unexplained symptom syndromes in the medical community, making it difficult to publish any data in this area, especially data demonstrating no effect. Thus, our meta-analysis of effect size may be an overestimate of the true effect. However, our sensitivity analysis indicates there would have to be more than 600 negative studies to counteract the summary effect found in this review, so any of the limitations involving possible missing literature would likely have only a small impact on the summary effect size in this meta-analysis.