To fail or not to fail : clinical trials in depression
Sante, G.W.E.
Citation
Sante, G. W. E. (2008, September 10). To fail or not to fail : clinical trials in depression.
Retrieved from https://hdl.handle.net/1887/13091
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License: Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden
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TO FAIL OR NOT TO FAIL - CLINICAL TRIALS IN DEPRESSION
Proefschrift
ter verkrijging van
de graad van Doctor aan de Universiteit Leiden,
op gezag van Rector Magnificus prof.mr. P.F. van der Heijden, volgens besluit van het College voor Promoties
te verdedigen op woensdag 10 september 2008 klokke 13.45 uur
door
Gijs Willem Eduard Santen geboren te Groningen
in 1980
Promotiecommissie:
Promotor: Prof. dr. M. Danhof Co-promotor: Dr. O.E. Della Pasqua
Referent: Prof. dr. S.A. Montgomery, Imperial College, London, UK Overige leden: Prof. dr. A. de Boer, Universiteit van Utrecht
Prof. dr. A.F. Cohen Prof. dr. J. van der Greef Prof. dr. A.P. IJzerman Prof. dr. E.R. de Kloet Prof. dr. F.G. Zitman
"Although a man shall never be able to hit Stars by shooting at them,
yet he shall come much nearer to them, than another that throws at Apples."
Nehemiah Grew (1641-1712)
Aan mijn ouders Aan Nina
The research presented in this thesis was made possible by a Worlwide Development Fellowship for Post-graduate Training in Clinical Pharmacology and Discovery Medicine from GlaxoSmithKline and was performed at the Division of Pharmacology of the Leiden- Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands.
The printing of this thesis was financially supported by:
GlaxoSmithKline
J.E. Jurriaanse Stichting
Leiden-Amsterdam Center for Drug Research
Photo cover by Bo Gort (www.bogort.com) Typeset in LATEX
Printed by Optima Grafische Communicatie, Rotterdam, The Netherlands ISBN 978-90-8559-377-5
©2008 Gijs Santen
No part of this thesis may be reproduced or transmitted in any form or by any means without written permission of the author.
CONTENTS
SECTION I GENERAL INTRODUCTION 7
Chapter 1 Clinical trials in depression: Challenges and opportunities 9
Chapter 2 Scope and outline of the investigations 37
SECTION II CLINICAL ENDPOINTS 43
Chapter 3 Sensitivity of the individual items of the Hamilton depression rat- ing scale to response and its consequences for the assessment of
efficacy 45
Chapter 4 Comparative analysis of the sensitivity of the individual items of the Montgomery Asberg depression rating scale to response and
its consequences for the assessment of efficacy 61 Chapter 5 The missing link between clinical endpoint and pharmacological
receptor systems in depression 77
SECTION III DATA ANALYSIS 95
Chapter 6 Evaluation of treatment response in depression studies using a
Bayesian parametric cure rate model 97
Chapter 7 Heterogeneity in patient response in depression:
The relevance of functional data analysis 111
Chapter 8 Relevance of a new hierarchical model for the analysis of longitu-
dinal data with dropout in depression trials 127
SECTION IV CLINICAL TRIAL SIMULATION 145
Chapter 9 From trial and error to trial simulation: An appraisal of current
beliefs in clinical research practice in depression 147 Chapter 10 Information-based adaptive designs for the assessment of efficacy
of antidepressant drugs: A Bayesian framework for interim anal-
ysis accounting for enrolment rate 171
SECTION V CONCLUSIONS AND PERSPECTIVES 189 Chapter 11 To fail or not to fail - clinical trials in depression:
Summary, discussion and perspectives 191
Chapter 12 Nederlandse samenvatting (Synopsis in Dutch) 209
List of abbreviations 217
Nawoord 219
Curriculum Vitae 221
List of publications 223
