ReviewEfficacy and tolerability of antidepressants for sub-threshold depression and for mild major depressive disorder
Introduction
Establishing the efficacy of antidepressants for milder forms of depression is important because diagnoses such as minor, sub-threshold or mild depression have been found to be as prevalent as more severe forms (Ackermann and Williams, 2002, Oxman and Sengupta, 2002). Such diagnoses are associated with considerable functional impairment (Rapaport et al., 2002, Broadhead et al., 1990) and are linked with increased risk of developing a major depressive disorder (Kessler et al., 1997).
Robust evidence supports treatment of moderate to severe depression with antidepressant drugs (WFSBP Task Force on Unipolar Depressive,Disorders, 2007, NHS National Institute for Clinical Excellence, 2009, Nutt, 2011). It is commonly assumed that there is equally robust evidence for their lack of efficacy at the milder end of the severity spectrum (Nutt, 2011, Baumeister, 2012, Godlee, 2013). Guidelines (WFSBP Task Force on Unipolar Depressive,Disorders, 2007, NHS National Institute for Clinical Excellence, 2009, Nutt, 2011) do not currently recommend the routine use of antidepressants for those with sub-threshold depression (also referred to as Minor Depression – MinD) or mild major depressive disorder (Mild MDD).
Four recent meta-analyses (Kirsch et al., 2008, Fournier et al., 2010, Barbui et al., 2011, Gibbons et al., 2012) have been taken to have settled the question as to whether antidepressants are effective or not for milder presentations. Three of these reviews (Kirsch et al., 2008, Fournier et al., 2010, Barbui et al., 2011) concluded that antidepressants were no better than placebo in treating either mild MDD (Kirsch et al., 2008, Fournier et al., 2010) or sub-threshold depression (Fournier et al., 2010, Barbui et al., 2011) and one in a patient level, industry sponsored, data analysis (Gibbons et al., 2012) found antidepressants to be favourable over placebo (regardless of baseline severity). However, each of these meta-analyses had specific limitations in this regard. Kirsch et al.׳s review was selective (including only industry sponsored trials) with only one small trial involving participants with mild depression. In a patient level meta-analysis, Fournier et al. were only able to include a relatively small proportion of the relevant data (26% of identified studies) due to limited availability. Barbui et al. pooled clinically heterogeneous studies (e.g. adult and older residential care adult populations, treatment with different classes of antidepressants). The study by Gibbons et al. was limited to two antidepressants (fluoxetine and venlafaxine) and, in their patient level data analysis of adult populations, included only studies sponsored by the related drug companies (Wyeth, and Eli Lilly and Co.) despite the existence of other studies in this area (Dunlop et al., 1990, Judd et al., 1998, Fabre and Putman, 1987). Given that none of the reviews highlighted above have focussed on milder forms of depressive disorder, we conducted a review that specifically attempts to fill this gap.
Assessing the efficacy of antidepressants for mild or minor depressive symptoms has been complicated by issues of definition, (Pincus et al., 1999) compounded by discrepancies between the two major diagnostic classification systems (American Psychiatric Association, 1994, World Health Organisation, 2007). For example ICD-10 requires two or three symptoms to be present to meet criteria for mild depression whereas DSM-IV requires five. As such ICD-10 mild depression appears more akin to DSM-IV sub-threshold depression. The emergence of DSM-V does not allay these concerns as the core criterion symptoms for a major depressive disorder remain unaltered (American Psychiatric Association, 2013). The issue is further confused in that sub-threshold depression, mild MDD and moderate or severe depressive disorders are frequently considered to be on a continuum (Judd et al., 1998) (in clinical trials, the severity of depressive symptoms has tended to be measured with the Hamilton Rating Scale for Depression [HRSD] (Hamilton, 1960) or with the Montgomery Åsberg Depression Rating Scale [MÅDRS]) (Montgomery and Asberg, 1979). Confusion exists because there are both categorical and dimensional aspects to the classification of these disorders.
Our study aimed to examine the evidence for the effectiveness of antidepressants in milder forms of depressive disorder and addressed the following questions: (1) are antidepressants more efficacious than placebo/treatment as usual (TAU) in the treatment of sub-threshold depression and; (2) Are antidepressants more efficacious than placebo/TAU in the treatment of mild MDD or depression (however specified) with symptoms which have been assessed to be mild? (3) Are antidepressants tolerable for people with sub-threshold or mild MDD as compared with those receiving placebo/TAU?
Section snippets
Material and methods
The methods of this systematic review and meta-analysis were pre-specified and are registered with Prospero in a written protocol: http://www.crd.york.ac.uk/PROSPERO/. (Reference number: CRD42013004505).
Study selection
Fig. 1 outlines the process of screening and selecting studies for inclusion. Eight studies met criteria for inclusion. In five studies severity status was defined as sub-threshold by diagnostic criteria (Williams et al., 2000, Barrett et al., 2001, Burrows et al., 2002, Judd et al., 2004, Rapaport et al., 2011) and in three studies severity status was defined in terms of symptom severity entry criteria (HRSD<20) (McGrath et al., 1985, Fabre and Putman, 1987, Dunlop et al., 1990). Seventy
Summary of evidence
To the best of our knowledge, our study is the first to systematically review the research literature on the efficacy and tolerability of antidepressants in the treatment of sub-threshold depression and mild MDD, without the limitations found in previous reviews. There is a scarcity of studies with low risk of bias which can address our research questions. None of the studies which assessed efficacy in mild MDD could be pooled due to clinical heterogeneity and insufficient reporting. These
Conclusion
Despite the widespread assumption that antidepressants are ineffective in milder forms of depression, there is insufficient evidence to contest their use. Further well-designed studies are required to allow the definitive assessment of their efficacy and tolerability. Ideally such studies should be conducted in primary care settings – where the majority of individuals with sub-threshold depression and mild MDD are treated. Until sufficient evidence emerges, clinicians should recognise that
Role of funding source
No external funding supported this review.
Conflict of interest
No external funding supported this review. IMC and SAM declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work. ICR declares personal fees from AstraZeneca, Sanofi Aventis and Sunovion and non-financial support from Lundbeck, all outside the submitted work.
Acknowledgements
We would like to thank Dr. Daniel Bennett, Dr. James Currie, Dr. Jennifer Perrin and Dr. Catriona Stickle for helping with screening searches and retrieving papers. We would also like to thank Dr. Marina McLoughlin who helped with the interpretation of a Russian language paper during the screening process.
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