Review
Can effects of antidepressants in patients with mild depression be considered as clinically significant?

https://doi.org/10.1016/j.jad.2011.05.015Get rights and content

Abstract

Background

How to define clinical significance of antidepressants has become a matter of far-reaching clinical and regulatory consequences. A mean difference of at least 3 points on the Hamilton Depression Rating Scale (HAMD-17) between active treatment and placebo has been proposed as cut-off score for clinical significance in antidepressant trials.

Objective

We aimed to present arguments that this, and other commonly used related approaches to establish clinical significance are likely to be misleading and risky depriving patients with mild depression of efficient treatments.

Methods

These problems are exemplified with the data from a randomized placebo-controlled five-arm clinical trial with primary care patients with milder depressive syndromes (MIND-study).

Results and conclusions

Designs for studying clinical significance have to be distinguished from those assessing efficacy. Moreover, evaluation of the clinical significance of psychotherapy as a possible alternative to antidepressants faces the problem of how to define a valid control group where blinding of neither therapists nor patients is possible.

Introduction

Mild depression is highly prevalent in non-psychiatric populations, especially primary care (28.5%) (Vuorilehto et al., 2005). However, there are considerable uncertainties and contradictions in guideline recommendations for these patients. For example, “watchful waiting” or “active monitoring” is considered a reasonable option according to past NICE guidelines (Middleton et al., 2005, NICE, 2004) or the national guidelines for care of unipolar depressive disorders in Germany (DGPPN et al., 2009) whereas active treatment with antidepressants is recommended by the APA(2000b) (see also Bauer et al., 2007). Revised NICE guidelines (NICE, 2009) still recommend “active monitoring” and offer new specifics (page 111):

“For people who, in the judgement of the practitioner, may recover with no formal intervention, or people with mild depression who do not want an intervention, or people with subthreshold depressive symptoms who request an intervention:

  • •

    discuss the presenting problem(s) and any concerns that the person may have about them;

  • •

    provide information about the nature and course of depression;

  • •

    arrange a further assessment, normally within 2 weeks;

  • •

    make contact if the person does not attend follow-up appointments.”

In the case of patients with mild depression who seek intervention, the NICE guidelines advise physicians to use antidepressants or CBT only if low-intensity treatments (like guided self-help based on CBT, computerized CBT, and group exercise as well as sleep hygiene education) have been tried and found not effective (NICE, 2009). If patients with mild depression have a history of episodes with more severe intensity, antidepressants can be prescribed as first-line treatment (see also Davidson, 2010).

The importance of this topic stems from the large number of patients suffering from mild depression and the health economic consequences of treatment recommendations and regulations in this area (Cuijpers et al., 2007). For the development of guidelines and for decision makers in health care systems who have to allocate limited resources, a central question is whether the effects obtainable with antidepressants can be considered large enough to be clinically significant. The discussion is enriched by concerns that mild depressive mood swings as part of daily and sometimes bitter life are “psychiatrisized“, possibly in line with the interest and intention of the pharmaceutical industry or other interest groups such as the psychotherapists or psychiatrists to “create” new customers by lowering the disease threshold.

The aim of this article is

  • 1.

    to explain why the term “mild depression” is misleading;

  • 2.

    to draw attention to the fact that the present procedure to measure clinical significance can prove grossly misleading and

  • 3.

    to compare psychotherapy as an alternative to antidepressant pharmacotherapy concerning the evidence of clinically significant effects.

Section snippets

The term “mild depression” is misleading

“Mild depression” is a problematic term for several reasons. One is that there is no consensus how to measure it. Mild depression can be defined by the presence of a certain number of diagnostic criteria. This approach is used in psychiatric classification systems like ICD-10 (WHO, 1992) or DSM-IV-TR (APA, 2000a). Another approach is to define mild depression by a certain range of sum rating scores using rating scales such as the Hamilton Depression Rating Scale (HAMD) (Hamilton, 1960). There

Do antidepressants have ‘clinically significant’ effects?

It becomes important to examine whether antidepressant treatment effects in mild depression are not only statistically significant, but large enough to be also clinically significant. Whereas the statistical significance of treatment effects is not questioned, the clinical significance has been challenged by recent meta-analyses (Fournier et al., 2010, Kirsch et al., 2008) which suggest that the amount of benefit of antidepressants in comparison with placebo escalates with intensity of

Clinical significance of effects of psychotherapy as a possible alternative to antidepressants

Regarding treatment of mild depression, some guidelines prefer psychotherapy (e.g., the German guidelines for the treatment of depressive disorders (DGPPN et al., 2009)). Also in the recent reviews about clinical significance of antidepressants in mild depression, skeptical opinions about antidepressants are often combined with support for psychotherapy as a better alternative (e.g., Kirsch et al., 2008). This happens in spite of the fact that for psychotherapy the evidence base for efficacy is

What to do?

If the drug–placebo difference in depression ratings cannot be used to judge the clinical relevance of antidepressant effects in daily practice, what might be a better alternative? The risk to discard helpful treatment has to be minimized. Thus, for assessing clinical significance it is recommended

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    to use per protocol analyses;

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    to install strict compliance control;

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    to include mainly patients without pre-treatment;

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    to consider other factors such as patients' preferences (Mergl et al., 2011), age,

Conclusion

The paper focused on factors possibly leading to an underestimation of the clinical significance of antidepressant treatment in daily practice when measured with the presently used approach (placebo–verum difference in HAMD-17). It did not address factors which might introduce a bias in the opposite direction, leading to an overestimation of the clinical significance of treatment effects in daily practice. Among these are problems with blinding in RCTs (Porter et al., 2003, Ventegodt et al.,

Role of funding source

There was no study sponsor involved in writing of this review article.

Conflict of interest

The authors have no relevant financial relationships to disclose.

Acknowledgments

We would like to thank all investigators and patients who participated in the MIND study.

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