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Allowing for non-adherence to treatment in a randomized controlled trial of two antidepressants (citalopram versus reboxetine): an example from the GENPOD trial

  • N. J. Wiles (a1), K. Fischer (a2), P. Cowen (a3), D. Nutt (a4), T. J. Peters (a5), G. Lewis (a6) and I. R. White (a7)...

Abstract

Background

Meta-analyses suggest that reboxetine may be less effective than other antidepressants. Such comparisons may be biased by lower adherence to reboxetine and subsequent handling of missing outcome data. This study illustrates how to adjust for differential non-adherence and hence derive an unbiased estimate of the efficacy of reboxetine compared with citalopram in primary care patients with depression.

Method

A structural mean modelling (SMM) approach was used to generate adherence-adjusted estimates of the efficacy of reboxetine compared with citalopram using GENetic and clinical Predictors Of treatment response in Depression (GENPOD) trial data. Intention-to-treat (ITT) analyses were performed to compare estimates of effectiveness with results from previous meta-analyses.

Results

At 6 weeks, 92% of those randomized to citalopram were still taking their medication, compared with 72% of those randomized to reboxetine. In ITT analysis, there was only weak evidence that those on reboxetine had a slightly worse outcome than those on citalopram [adjusted difference in mean Beck Depression Inventory (BDI) scores: 1.19, 95% confidence interval (CI) –0.52 to 2.90, p = 0.17]. There was no evidence of a difference in efficacy when differential non-adherence was accounted for using the SMM approach for mean BDI (–0.29, 95% CI –3.04 to 2.46, p = 0.84) or the other mental health outcomes.

Conclusions

There was no evidence of a difference in the efficacy of reboxetine and citalopram when these drugs are taken and tolerated by depressed patients. The SMM approach can be implemented in standard statistical software to adjust for differential non-adherence and generate unbiased estimates of treatment efficacy for comparisons of two (or more) active interventions.

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Copyright

The online version of this article is published within an Open Access environment subject to the conditions of the Creative Commons Attribution licence http://creativecommons.org/licenses/by/3.0/

Corresponding author

* Address for correspondence: N. J. Wiles, Ph.D., Centre for Academic Mental Health, School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Clifton, Bristol BS8 2BN, UK. (Email: nicola.wiles@bristol.ac.uk)

References

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Baxter, H, Winder, R, Chalder, M, Wright, C, Sherlock, S, Haase, AM, Wiles, NJ, Montgomery, AA, Taylor, AH, Fox, KR, Lawlor, DA, Peters, TJ, Sharp, D, Campbell, J, Lewis, G (2010). Physical activity as a treatment for depression: the TREAD randomized controlled trial protocol. Trials 11, 105.
Beck, A, Steer, RA, Brown, GK (1996). Manual for the Beck Depression Inventory –Second Edition. The Psychological Corporation: San Antonio, TX.
Cipriani, A, Furukawa, TA, Salanti, G, Geddes, JR, Higgins, JPT, Churchill, R, Watanabe, N, Nakagawa, A, Omori, IM, McGuire, H, Tansella, M, Barbui, C (2009). Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet 373, 746758.
Dunn, G, Maracy, M, Dowrick, C, Ayuso-Mateos, JL, Dalgard, OS, Page, H, Lehtinen, V, Casey, P, Wilkinson, C, Vázquez-Barquero, JL, Wilkinson, G; ODIN group (2003). Estimating psychological treatment effects from a randomised controlled trial with both non-compliance and loss to follow-up. British Journal of Psychiatry 183, 323331.
Eyding, D, Leigemann, M, Grouven, U, Harter, M, Kromp, M, Kaiser, T, Kerekes, MF, Gerken, M, Wieseler, B (2010). Reboxetine for acute treatment of major depression: systematic review and meta-analysis of published and unpublished placebo and selective serotonin reuptake inhibitor controlled trials. British Medical Journal 341, c4737.
Fischer, K, Goetghebeur, E, Vrijens, B, White, IR (2011). A structural mean model to allow for noncompliance in a randomized trial comparing 2 active treatments. Biostatistics 12, 247257.
Fleming, TR (2008). Current issues in non-inferiority trials. Statistics in Medicine 27, 317332.
Freemantle, N, Anderson, IM, Young, P (2000). Predictive value of pharmacological activity for the relative efficacy of antidepressant drugs. British Journal of Psychiatry 177, 292302.
Gordon, D, Levitas, R, Pantazis, C, Payne, S, Townsend, P, Adelman, L, Ashworth, K, Middleton, S, Bradshaw, J, Williams, J (2000). Poverty and Social Exclusion Survey of Britain Questionnaire. Joseph Rowntree Foundation: York.
Hill, SA, Taylor, MJ, Harmer, CJ, Cowen, PJ (2003). Acute reboxetine administration increases plasma and salivary cortisol. Journal of Psychopharmacology 17, 273275.
HSCIC (2012). Prescription Cost Analysis – England, 2011. Health and Social Care Information Centre: London.
Jenkinson, C, Layte, R (1997). Development and testing of the UK SF-12 (short form health survey). Journal of Health Services Research and Policy 2, 1418.
John, OP, Donahue, EM, Kentle, RL (1991). The ‘Big Five’ Inventory – versions 4a and 54. Institute of Personality and Social Research, University of California, Berkeley: Berkeley, CA.
Jones, B, Jarvis, P, Lewis, J, Ebbutt, A (1996). Trials to assess equivalence: the importance of rigorous methods. British Medical Journal 313, 3639.
Last, JM (1995). A Dictionary of Epidemiology. Oxford University Press: Oxford.
Lewis, G (1994). Assessing psychiatric disorder with a human interviewer or a computer. Journal of Epidemiology and Community Health 48, 207210.
Lewis, G, Mulligan, J, Wiles, N, Cowen, PJ, Craddock, N, Ikeda, M, Grozeva, D, Mason, V, Nutt, DJ, Sharp, D, Tallon, D, Thomas, L, O'Donovan, M, Peters, TJ (2011). The 5HT transporter polymorphism and response to antidepresants: a randomized controlled trial. British Journal of Psychiatry 198, 464471.
Lewis, G, Pelosi, AJ, Araya, R, Dunn, G (1992). Measuring psychiatric disorder in the community: a standardized assessment for use by lay interviewers. Psychological Medicine 22, 465486.
Meyer, JH, Wilson, AA, Ginovart, N, Goulding, V, Hussey, D, Hood, K, Houle, S (2001). Occupancy of serotonin transporters by paroxetine and citalopram during treatment of depression: a [11C]DASB PET imaging study. American Journal of Psychiatry 158, 18431849.
Papakostas, GI, Nelson, JC, Kasper, S, Moller, H-J (2008). A meta-analysis of clinical trials comparing reboxetine, a norepinephrine reuptake inhibitor, with selective serotonin reuptake inhibitors for the treatment of major depressive disorder. European Neuropsychopharmacology 18, 122127.
Piccinelli, M, Tessari, E, Bortolomasi, M, Piasere, O, Semenzin, M, Garzotto, N, Tansella, M (1997). Efficacy of the alcohol use disorders identification test as a screening tool for hazardous alcohol intake and related disorders in primary care: a validity study. British Medical Journal 314, 420424.
Robins, JM (1994). Correcting for non-compliance in randomized trials using structural nested mean models. Communications in Statistics – Theory and Methods 23, 23792412.
Robins, JM, Tsiatis, AA (1991). Correcting for non-compliance in randomized trials using rank preserving structural failure time models. Communications in Statistics – Theory and Methods 20, 26092631.
Szabadi, E, Bradshaw, CM, Boston, PF, Langley, RW (1998). The human pharmacology of reboxetine. Human Psychopharmacology 13, S3S12.
Thomas, L, Mulligan, J, Mason, V, Tallon, D, Wiles, N, Cowen, PJ, Nutt, DJ, O'Donovan, M, Sharp, D, Peters, T, Lewis, G (2008). Genetic and clinical predictors of treatment response in depression: the GENPOD randomized trial protocol. Trials 9, 29.
Vansteelandt, S, Goetghebeur, E (2003). Causal inference with generalized structural mean models. Journal of the Royal Statistical Society: Series B (Statistical Methodology) 65, 817835.
White, IR, Kalaitzaki, R, Thompson, SG (2011). Allowing for missing outcome data and incomplete uptake of randomized interventions, with application to an internet-based alcohol trial. Statistics in Medicine 30, 31923207.
Wiles, NJ, Mulligan, J, Peters, TJ, Cowen, PJ, Mason, V, Nutt, DJ, Sharp, D, Tallon, D, Thomas, L, O'Donovan, M, Lewis, G (2012). Severity of depression and response to antidepressants: the GENPOD randomised controlled trial. British Journal of Psychiatry 200, 130136.
Zigmond, AS, Snaith, RP (1983). The hospital anxiety and depression scale. Acta Psychiatrica Scandinavica 67, 361370.

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