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Medically unexplained symptoms (MUS), which are highly prevalent in all fields of medicine, are considered difficult to treat. The primary objective of this systematic review and meta-analysis was to assess the efficacy of self-help for adults with MUS.Four electronic databases were searched for relevant studies. Randomized controlled trials comparing self-help to usual care or waiting list in adults with MUS were selected. Studies were critically appraised using the Cochrane “risk of bias assessment tool.” Standardized mean differences (Hedges g) were pooled using a random-effects model. Outcomes were symptom severity and quality of life (QoL) directly posttreatment and at follow-up.Of 582 studies identified, 18 studies met all inclusion criteria. Studies were heterogeneous with regard to patient populations, intervention characteristics, and outcome measures. Compared with usual care or waiting list, self-help was associated with lower symptom severity (17 studies, n = 1894, g = 0.58, 95% confidence interval = 0.32–0.84, p < .001) and higher QoL (16 studies, n = 1504, g = 0.66, 95% confidence interval = 0.34–0.99, p < .001) directly posttreatment. Similar effect sizes were found at follow-up. A high risk of bias was established in most of the included studies. However, sensitivity analyses suggested that this did not significantly influence study results. Funnel plot asymmetry indicated potential publication bias.Self-help is associated with a significant reduction in symptom severity and improvement of QoL. The methodological quality of included studies was suboptimal, and further research is needed to confirm the findings of this meta-analysis.