ReviewTo combine or not to combine? A literature review of antidepressant combination therapy
Introduction
Depression which has not responded adequately using conventional approaches to treatment is a constant challenge to clinicians, and is a significant source of suffering, death and economic loss (Judd et al., 1997, Nierenberg et al., 1999). It is estimated that depression is not fully eradicated to the point of recovery in 2 out of 3 cases (Fava and Davidson, 1996, Paykel et al., 1995). Vos et al. (2004) using a Monte Carlo simulation model found that in a 5-year period following an episode of depressive illness treated with episodic treatments, treatment administered for each episode rather than maintained over the 5-year study period, the mean number of subsequent episodes was 2.4 and the mean proportion of time spent in major depression was 20.8%. In such circumstances, the burden of ongoing and untreated illness needs to be weighed against potential benefits and risks of treatments. In the face of such pervasive illness it is useful to assess recent reports on combination antidepressant treatment strategies in patients who have not responded to traditional therapies.
When a depressed patient fails to respond or only does so partially to an adequate trial of antidepressant monotherapy, a variety of strategies have been proposed as regards what to do next. Unfortunately, the majority of these recommendations are unsupported by evidence. Reasons for this include that a history of treatment-resistant depression (TRD) is an exclusion criterion for most antidepressant clinical trials. Consequently the reported therapeutic interventions in this group are primarily naturalistic studies, though a small number of studies with other experimental designs have been produced.
In this paper the evidence demonstrating the efficacy and utility of combinations of antidepressants for the treatment of TRD is reviewed.
Section snippets
Method
A systematic literature search of published literature, up to and including January 2005, was conducted using PubMED with the key terms; antidepressant, polypharmacy, combination, depression, resistant, refractory, treatment resistant, trials, randomised, controlled, placebo and the names of individual antidepressants. Terms were combined variously to identify papers that specifically addressed the use of combinations of antidepressants for the treatment of depression. Reference sections of
Results
The use of combination antidepressant therapies has received relatively little attention in the medical literature and only 70 pertinent references were identified. Furthermore the clinical importance of the topic is not reflected by the level of evidence furnished by these studies. In total only eight randomised trials of combination therapies were identified (Carpenter et al., 2002, Davidson et al., 1978, Fava et al., 1994, Ferreri et al., 2001, Licht and Qvitzau, 2002, Maes et al., 1999,
Discussion
When faced with a patient with potential TRD the clinician's first task is to investigate the root causes of their non-response. The diagnosis needs to be confirmed, including checking for the presence of a comorbid medical condition. The possibility of a personality disorder and/or a bipolar spectrum disorder needs to be considered and excluded. Patient compliance needs to be verified and context issues such as an adverse domestic or social situation need to be explored (Grote and Frank, 2003
Conclusion
Despite the urgent need for well-designed, large-scale, placebo-controlled trials investigating the efficacy of antidepressant combination therapies, there is an increasing body of empirical evidence to suggest that these therapies should have an important role in the treatment of TRD. Data suggests that combining antidepressants with different mechanisms of action is a worthwhile strategy with some observed success with combinations of bupropion plus an SSRI, reboxetine plus an SSRI,
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