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The SSRI–SSRI combination has only been tried in two open-label studies ( Reference Dodd, Horgan and MalhiDodd 2005). They differ to some extent in their receptor profile and exhibit significantly different pharmacokinetics. Selective serotonin reuptake inhibitors (SSRIs) are widely used antidepressants.

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A full reference list is available from the authors on request. Only key references are cited in this article. Where available, we have reported the populations studied with particular combinations. Defining treatment resistance is a difficult issue, with many definitions available in the literature, and is beyond the scope of this article. We examine the combinations by class of antidepressant (detailed reviews of individual studies can be found elsewhere, e.g.: Reference Dodd, Horgan and MalhiDodd 2005 Reference Rojo, Ros and AgüeraRojo 2005) and we review the nature and extent of the side-effect burden and potential risks of these combinations. Bupropion has been excluded as it is not licensed as an antidepressant in the UK.

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The search was conducted using keywords ‘antidepressants’, ‘combination’, ‘depression’, ‘refractory’ and the names of individual antidepressant drugs, to identify randomised controlled trials (RCTs), open-label trials, case series and case reports on efficacy and toxicity from combining antidepressants currently available in the UK. This article is based on searching the literature indexed in MEDLINE and published in English since 1950. Despite the risks of an increased burden of side-effects or drug–drug interactions with antidepressant combinations, such combinations are common in clinical practice. It reported on antidepressant combinations, but did not show any single combination to be superior. The STAR*D (Sequenced Treatment Alternatives to Relieve Depression) study has been a welcome addition and provides evidence for a variety of options for up to four failed treatment trials ( Reference McGrath, Stewart and FavaMcGrath 2006). This is reflected in the limited number of options that the National Institute for Health and Clinical Excellence (NICE) recommends for consideration in the treatment of these patients. There is very little evidence, however, to guide practice in treatment-refractory patients. If that is unsuccessful, further strategies include the use of higher doses, switching to another antidepressant of the same or different class, augmenting the antidepressant with either psychotherapy or a medication which is not an antidepressant (such as lithium or antipsychotics), or combining with another recognised antidepressant. Optimising antidepressant use by attempting to ensure that patients take an adequate dose for an adequate length of time with measures to improve concordance is the first strategy recommended for managing incomplete response. Responses to subsequent courses are also limited. At least a third of patients make an inadequate response to their first antidepressant monotherapy. Despite an increase in the number of available and effective antidepressants, many patients with depression respond poorly to drug treatment.

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