Relationship between placebo response rate and clinical trial outcome in bipolar depression

https://doi.org/10.1016/j.jpsychires.2015.12.016Get rights and content

Highlights

  • We searched for RCTs of monotherapy oral drugs for bipolar depression.

  • We investigated the impact of placebo response rates on the relative risk of response to drug versus placebo.

  • Higher placebo response rates correlate with a lower risk ratio of response to drug versus placebo.

  • Studies with placebo response rates >30% have a worse performance in showing a superiority of the drug versus placebo.

  • Placebo response rates should be maintained below the threshold of 30%.

Abstract

The aim of this work is to investigate the impact of placebo response rates on the relative risk of response to drug versus placebo in randomized, double-blind, placebo-controlled clinical trials of pharmacological therapy in Bipolar Depression (BPD).

Medline/PubMed publication databases were searched for randomized, double-blind, placebo-controlled trials of oral drugs used as monotherapy for the treatment of BPD. The search was limited to articles published between January 1980 and September 2015. Data extracted from 12 manuscripts and one poster with yet unpublished results, representing a total of 17 clinical trials were pooled (n = 6578). Pooled response rates for drug and placebo were 55.1% and 39.2%, corresponding to a risk ratio (RR) for responding to active treatment versus placebo of 1.29 (p < 0.001). Clinical response was defined as a 50% or greater reduction in depression scores, baseline to endpoint. A higher placebo response rate correlated with a significantly lower RR of responding to pharmacotherapy versus placebo (p = 0.002). The pooled drug and placebo response rates for studies with a placebo response rate ≤30% were 50.5% versus 26.6%, while corresponding values from studies with a placebo response rate >30 were 55.0% versus 41.6%.

These results suggest that the relative efficacy of the active drug compared to placebo in clinical trials for BPD is highly heterogeneous across studies with different placebo response rates, with a worse performance in showing a superiority of the drug versus placebo for studies with placebo response rates >30%. It is important to maintain placebo response rates below this critical threshold, since this is one of the most challenging obstacles for new treatment development in BPD.

Introduction

Bipolar disorder, a prevalent debilitating illness, is distinguished by its defining feature of one or more episodes of abnormal mood elevation (i.e. mania or hypomania). However, depressive episodes are very common during the lifetime of patients with bipolar disorder and, in fact, are often associated with the majority of the burden on the patient's suffering, functional impairment, morbidity, and mortality (Judd et al., 2002, Judd et al., 2005, Kupka et al., 2007, Calabrese et al., 2003; Goldberg and Harrow, 2011). There has been a large amount of research that supports the treatment efficacy of pharmacotherapies for mania and hypomania (Grunze et al., 2009, Grunze et al., 2013, Cipriani et al., 2011, Yildiz et al., 2011, Kanba et al., 2014), however there are only a few adequately powered studies of rigorous design that examine the treatment efficacy of pharmacotherapies for bipolar depression (BPD) and that have gone on to be replicated (Vieta et al., 2010, Vieta and Valenti, 2013, Young et al., 2014). In a landmark meta-analysis, for instance, Vieta et al. (2010) found that of eight medications examined in randomized, double-blind trials, only quetiapine, olanzapine, and the combination of olanzapine and fluoxetine had demonstrated superior efficacy in treating BPD compared to placebo. More recently, lurasidone has also demonstrated higher remission rates versus placebo (Loebel et al., 2014a, Loebel et al., 2014b). In comparison, ziprasidone (Sachs et al., 2011), aripirazole (Thase et al., 2008), and lamotrigine monotherapy (Geddes et al., 2009), in many but not all trials, failed to separate sufficiently from placebo for the treatment of BPD.

Although double-blind, randomized, placebo-controlled clinical trials (RCTs) are considered the gold standard for testing the efficacy of proposed treatments for major depression (unipolar and bipolar), statistically significant differences in remission rates between drug and placebo are not always apparent. In major depressive disorder (MDD), for instance, Turner et al. (2008) conducted a meta-analysis of 74 RCTs of 12 FDA-approved drugs and found that approximately 50% of these RCTs failed to show statistically significant differences in efficacy between drug and placebo. Additionally, meta-analyses of placebo-controlled RCTs for MDD demonstrate that a large placebo response rate can mask a clinically significant effect of an antidepressant, thus making such trials uninformative (Iovieno and Papakostas, 2012). In fact, in MDD trials, it has been shown that treatment effect size is inversely proportional to placebo response rates, an important finding with implications both for clinical trials as well as clinical practice (Iovieno and Papakostas, 2012).

Unfortunately, to date, no study has examined in detail the relationship between placebo response rates and overall study outcome for pharmacological therapies in BPD. Therefore, the aim of the present analysis is to investigate the impact of placebo response rates on the relative risk of response to drug versus placebo in randomized, double-blind, placebo-controlled clinical trials of pharmacological therapy in BPD.

Section snippets

Data source and search strategy

Our aim was to identify randomized, double-blind, placebo-controlled trials of oral medications used as monotherapy for the treatment of BPD for inclusion in the analysis. Potentially eligible trials were first identified with a systematic search of several literature databases (PubMed, PsychInfo, EMBASE, and ClinicalTrials.gov) using the search terms “bipolar” and “placebo”. The search was limited to papers published between January 1st, 1980 (since the DSM-III was introduced in 1980 (20)) and

Results

A total of 1658 abstracts were identified in the PubMed search (Fig. 1). Of these, 1633 were excluded for various reasons (other topics, reviews, duplicate reports, non-monotherapy (adjunctive) trials). Abstracts for the remaining 25 manuscripts (describing trials of medications as monotherapy for BPD) were collected and reviewed. No further manuscripts were identified after reviewing the reference list. Of these 25 papers, 5 were excluded for the reasons listed in Fig. 1. Thus, a total of 15

Discussion

This study is the first to examine the relationship between placebo responses rate and the risk ratio of responding to drug versus placebo (drug-placebo “separation”, a direct measure of the success of a clinical study) in randomized, double-blind, placebo-controlled clinical trials of pharmacotherapies as monotherapy for the treatment of patients with BPD. In this analysis, we found that higher placebo response rates correlated with lower RRs of response to drug versus placebo. Specifically,

Contributors

NI and GIP designed the study and managed the literature searches and analyses. NI, GIP, SRP and DJHK wrote the first draft of the manuscript. All authors contributed to and approved the final manuscript.

Conflicts of interest

Dr. Iovieno, Ms. Rosemary S. D. Walker, Ms. Susannah R. Parkin and Mr. Daniel Ju Hyung Kim declare that they have no conflict of interest.

Dr. Papakostas has served as a consultant for Abbott Laboratories, AstraZeneca PLC, Avanir Pharmaceuticals, Brainsway Ltd, Bristol-Myers Squibb Company, Cephalon Inc., Dey Pharma, L.P., Eli Lilly Co., GlaxoSmithKline, Evotec AG, H. Lundbeck A/S, Inflabloc Pharmaceuticals, Jazz Pharmaceuticals, Novartis Pharma AG, Otsuka Pharmaceuticals, PAMLAB LLC, Pfizer

Role of funding source

None.

Acknowledgments

None.

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