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Efficacy of selective serotonin reuptake inhibitors and adverse events: Meta-regression and mediation analysis of placebo-controlled trials

  • Michael Barth (a1), Levente Kriston (a2), Swaantje Klostermann (a3), Corrado Barbui (a4), Andrea Cipriani (a5) and Klaus Linde (a6)...
Abstract
Background

It has been suggested that the efficacy of antidepressants has been overestimated in clinical trials owing to unblinding of drug treatments by adverse events.

Aims

To investigate the association between adverse events and the efficacy of selective serotonin reuptake inhibitors (SSRIs).

Method

The literature was searched to identify randomised, double-blind, placebo-controlled trials of SSRIs in the treatment of major depression. Efficacy outcomes were response to treatment and change in depressive symptoms. Reporting of adverse events was used as an indicator of tolerability. Random effects meta-analyses were used to calculate pooled estimates. Meta-regression analyses were performed to investigate the association between adverse events and efficacy. Potential mediation was investigated with the Baron & Kenny approach.

Results

A total of 68 trials (n = 17 646) were included in the analyses. In meta-analysis SSRIs were superior to placebo in terms of efficacy (odds ratio, OR = 1.62, 95% CI 1.51–1.72). More patients allocated to SSRIs reported adverse events than did patients receiving placebo (OR = 1.73, 95% CI 1.58–1.89). Meta-regression analyses did not find an association between adverse events and efficacy (P = 0.439). There was no indication of adverse events mediating the effect of SSRI treatment.

Conclusions

Our results do not support, but also do not unequivocally disprove, the hypothesis that adverse events lead to an overestimation of the effect of SSRIs over placebo.

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Copyright
Corresponding author
Michael Barth, Institute for General Practice, Klinikum Rechts der Isar, Technische Universität München, Orleansstr. 47, 81667 München, Germany. Email: michael.barth@tum.de
Footnotes
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Declaration of interest

None.

Footnotes
References
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Efficacy of selective serotonin reuptake inhibitors and adverse events: Meta-regression and mediation analysis of placebo-controlled trials

  • Michael Barth (a1), Levente Kriston (a2), Swaantje Klostermann (a3), Corrado Barbui (a4), Andrea Cipriani (a5) and Klaus Linde (a6)...
Submit a response

eLetters

Unblinding in SSRI trials due to side effects is an important source of bias

Peter C Gøtzsche, Professor, Nordic Cochrane Centre
02 February 2016

Michael Barth and colleagues did not find a relation between adverse events and efficacy in their meta-regression of 68 placebo-controlled SSRI trials (1). I agree with them that their results should be interpreted cautiously and considered only preliminary evidence due to the methodological problems with the trials they analysed. Furthermore, it has been shown that breaking the blinding in SSRI trials is common due to their adverse effects (2). If this leads to overestimation of the effect, it might affect the trials similarly, which could explain their negative findings. I therefore believe their method is not well suited to study their hypothesis.

A much better method is to look at trials that have both a blinded and a non-blinded observer, which researchers at my centre have done (3). In their systematic review, they found 21 such trials, for a variety of diseases, and the treatment effect was overestimated by 36% on average (measured as odds ratio) when the non-blinded observer assessed the effect compared to the blinded observer. If we assume that the blinding is broken for all patients in the antidepressant trials, and adjust for the bias the loss of blinding causes, we will find that antidepressants have no effect (odds ratio 1.02) (2). The blinding needs not be broken for all patients, however, before the effect of antidepressants is gone. All that is required for the effect to disappear is that 5% of the patients are misclassified in terms of whether they became better or not (2).

An effective way to eliminate the bias related to unblinding due to drug side effects is to use placebos that also cause side effects. Barth and colleagues did not mention an important Cochrane review by psychiatrist Joanna Moncrieff and colleagues of nine trials (751 patients) with tricyclic antidepres¬sants, where the placebo contained atropine to mimic the side effects of the active drug (4). This review did not find any meaningful effect; the effect corresponded to only 1.3 points on the Hamilton scale (2), and the smallest effect that can be perceived on this scale is 5-6 points (5).

It is also noteworthy that when patients are asked of their opinion in the placebo-controlled trials, they say that antidepressants don’t work, whereas their psychiatrists in the same trials say that they work (2). It is for reasons such as these that some of us have come to the conclusion that antidepressants likely don’t have a true effect on depression (2).

Conflicts of interest: none.

References

1. Barth M, Kriston L, Klostermann S, Barbui C, Cipriani A, Linde K. Efficacy of selective serotonin reuptake inhibitors and adverse events: meta-regression and mediation analysis of placebo-controlled trials. Br J Psychiatry 2016; 208: 114–9.

2. Gøtzsche PC. Deadly psychiatry and organised denial. Copenhagen: People’s Press; 2015.

3. Hróbjartsson A, Thomsen AS, Emanuelsson F, Tendal B, Hilden J, Boutron I, et al. Observer bias in randomised clinical trials with binary outcomes: systematic review of trials with both blinded and non-blinded outcome assessors. BMJ 2012; 344: e1119.

4. Moncrieff J, Wessely S, Hardy R. Active placebos versus antidepressants for depression. Cochrane Database Syst Rev 2004; 1: CD003012.

5. Leucht S, Fennema H, Engel R, Kaspers-Janssen M, Lepping P, Szegedi A. What does the HAMD mean? J Affect Disord 2013; 148: 243-8.

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Conflict of interest: None Declared

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