Review
Antidepressant combination for major depression in incomplete responders—a systematic review

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Abstract

Background

Antidepressant combination has been suggested as a strategy to increase treatment efficacy. The objective of this study was to perform a systematic review and meta-analysis of studies that assessed the effect of antidepressant combination for major depression in patients with incomplete response to an initial antidepressant.

Methods

Studies were retrieved from PubMed (1966–February, 2012), Cochrane Library (–February, 2012), Embase (1980–February, 2012), PsycINFO (1980–February, 2012), Lilacs (1982–February, 2012), clinical trials registry, thesis database (www.capes.gov.br), and secondary references. Included studies had an open label phase in which an initial antidepressant was used for the treatment of major depression and a double blind phase for the incomplete responders that compared monotherapy with the first antidepressant versus the association of a second antidepressant to the first one.

Results

Out of the 4,884 studies retrieved, only five satisfied the inclusion criteria. The total number of patients included was 483. Only two small trials reported benefits of adding a second antidepressant to the initial antidepressant. Dropouts due to side effects were not reported in three studies. Meta-analysis was not performed due to the small number of studies, the inconsistency in the direction of effect and the possible instability of effect size. Only limited kinds of combination, involving mianserin, mirtazapine and desipramine were studied. Some properties of the first two drugs such as the anxiolytic, sedative, and orexigenic effects, can mimic depression improvement.

Limitations

Publication bias cannot be ruled out. Only one study included a monotherapy arm with the antidepressant used for augmentation of the first antidepressant.

Conclusions

The practice of using a combination of antidepressants for major depression in incomplete responders is not warranted by the literature.

Introduction

Antidepressants are a mainstay of the treatment of major depression. However the overall treatment outcome of depressed patients is usually far from optimal. Regardless of the initial choice of antidepressant, 30–50% of patients with a major depressive episode will not respond satisfactorily to adequate standard treatment (Bauer et al., 2007). Remission rates vary from 42% to 46% (Casacalenda and Perry, 2002, Smith and Dempster, 2002) and about 30% of patients may not reach remission after multiple treatment trials (Rush et al., 2006). A review of four meta-analyses of efficacy trials submitted to the US Food and Drug Administration (FDA) suggests that antidepressants are only marginally efficacious compared with placebo and documents a profound publication bias that inflates their apparent efficacy (Pigott et al., 2010).

Antidepressant combination has been suggested as a strategy to increase treatment efficacy. There are two kinds of studies that evaluate antidepressant combination. One uses the combination from the beginning of treatment. We have published a systematic review and meta-analysis of this approach (Rocha et al., 2012). Another strategy is to add a second antidepressant to the treatment regimen of patients with persistent major depression despite adequate antidepressant monotherapy. However there are sparse data to support this strategy since the few trials that investigated this strategy have methodological flaws and involve small samples (Dodd and Horgan, 2005, El-Mallakh and Kaur, 2010, Rush, 2010, Thase, 2011). The larger studies about antidepressant combination in incomplete responders were conducted as part of the STAR⁎D trial but the lack of placebo control in these studies, among other drawbacks, prevents definite conclusions about the results. The objective of the present study was to perform a systematic review and meta-analysis of the combination of antidepressants versus a single antidepressant for the treatment of major depressive disorder with incomplete remission.

Section snippets

Material and methods

This systematic review was conducted at Instituto de Previdência dos Servidores do Estado de Minas Gerais, Faculdade da Saúde e Ecologia Humana, Faculdade de Medicina da Universidade Federal de Minas Gerais, and Faculdade de Ciências Médicas de Minas Gerais.

Studies were retrieved from the following sources: PubMed (1966 to February, 2012), Cochrane Library (until February, 2012), Excerpta Medica Database (Embase) (1980 to February, 2012), PsycINFO (1980 to February, 2012) and Literatura

Description of studies with potential for inclusion

Out of the 4,884 studies retrieved through the search strategy, 809 were excluded because they were duplicated records and 4,063 were excluded because they failed to meet the inclusion criteria (non-randomized controlled trials, narrative reviews, case reports, retrospective studies and studies not dealing with the clinical condition or intervention of interest). Twelve full-text studies were assessed for eligibility. Out of the 12 full-text studies, 7 were excluded due to several reasons. Four

Discussion

The results of this systematic review showed a paucity of studies evaluating antidepressant combination for depressed patients with incomplete response. There were only five studies with methodological differences and some methodological drawbacks involving a total of 565 patients (483, considering only the arms of interest). Only two small trials reported benefits with antidepressant combination (Ferreri and Lavergne, 2001, Carpenter and Yasmin, 2002). In both studies, the combination arm was

Role of funding source

The authors didn't receive support or grant of any funding body.

Conflict of interest

Fábio Lopes Rocha—Principal investigator in clinical trials (Current: AstraZeneca, Eli Lilly, Roche, and Servier; Past: Janssen Cilag, Pfizer)

Cíntia Fuzikawa—none

Rachel Riera—none

Melissa Guarieiro Ramos—none

Cláudia Hara—Sub-investigator in clinical trials (Current: AstraZeneca, Eli Lilly, Roche, and Servier; Past: Janssen Cilag, Pfizer)

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