Why we need research: a short history of evidence-based psychiatry John Geddes Oxford Clinical Trials Unit for Mental Illness Conflict of Interest • Funding from: – MRC, ESRC, NIHR – SMRI • Trial drug supplies – GSK – Sanofi-Aventis Pre-evidence-based medicine 1. 2. 3. 4. Ackner and Oldham NIMH MRC Prien et al Long-term treatment: beyond lithium? Lithium Falling use of lithium in USA • Between 1992-5 and 1996-9* – Lithium fell from 51% to 30% – Valproate rose from 11% to 27% Trend has continued Limited evidence for valproate Increasing evidence for lithium *Blanco et al Am J Psych 2002 1005-1010 Pre-evidence-based medicine 1. 2. 3. 4. Ackner and Oldham NIMH MRC Prien et al Aims • To determine if combination therapy with lithium plus divalproex is superior to monotherapy with either agent • To compare lithium and divalproex monotherapy • To establish proof of concept of large, simple randomised trials in psychiatry BALANCE Active run– in Up to 8 weeks lithium + divalproex lithium or divalproex or lithium + divalproex Randomized Phase 2 years Time to first intervention for mood episode Drug doses • Lithium – 0.4 to 1.0 mmol • Divalproex – target 1250mg, dose established during run-in Sites • 4 countries (UK, US, France, Italy) • 90% UK • 41 sites Characteristics of participants • 459 patients with Bipolar Disorder, type 1entered run-in • 129 withdrew before randomisation – 30% couldn’t tolerate drugs – 30% withdrew consent for various reasons • • • • • 330 patients randomised – 110 in each group Equal men and women Mean age 43 years Median 2 hospital admissions (range 0-30) 75% previous long-term drug therapy P ro p o rtio n w ith e ve n t .2 .4 .6 .8 Primary Outcome – New Treatment/Hospital Admission Li+Va vs Va HR 0.59 p=0.002 Li+Va vs Li HR 0.82 p=0.27 Li vs Va HR 0.71 p=0.05 C o m b in a tio n L ith iu m 0 V a lp ro a te 0 3 6 9 12 15 18 21 24 27 30 33 M o n th s to first e ve n t A t risk (e ve nts ): C o m b in a tio n 1 1 0 (1 4 ) 9 6 (1 7 ) 7 7 (1 0 ) 6 7 (7 ) 5 9 (4 ) 5 3 (2 ) 4 7 (4 ) 3 6 (1 ) 2 0 (0 ) 2 (0 ) 1 (0 ) 0 L ithiu m 1 1 0 (2 3 ) 8 6 (1 5 ) 7 0 (1 0 ) 5 9 (8 ) 5 0 (5 ) 4 3 (2 ) 3 9 (2 ) 3 0 (0 ) 1 2 (0 ) 1 (0 ) 1 (0 ) 0 V a lp roa te 1 1 0 (3 4 ) 7 4 (1 8 ) 5 6 (7 ) 4 8 (3 ) 4 2 (6 ) 3 6 (3 ) 2 9 (5 ) 1 7 (0 ) 6 (0 ) 1 (0 ) 0 (0 ) 0 Subgroup analyses No substantial differences between: • • • • • Men and women Different age groups Most recent episode Illness stage/severity Site Sensitivity analyses Results unaffected when: • Events occurring in first 3 months postrandomisation excluded • Events occurring when no longer on allocated treatment excluded • Adjustment by minimisation factors P ro p o rtio n h o sp italis e d .0 5 .1 .1 5 .2 .2 5 Time to Hospital Admission T im e to 1 0 % h o s p ita lis e d (m o n th s ) (9 5 % C I) C om bina tion : 11 .3 (4 .0 to -) L ith iu m : 7 .7 (3 .2 to 1 0 .0 ) 0 V a lp ro a te : 4 .7 (1 .6 to 10 .8 ) 0 3 6 9 A t risk (e ve nts ): 12 15 18 21 M o n th s to first h o sp ita lis a tio n 24 27 30 33 C o m b in a tio n 1 1 0 (2 ) 1 0 8 (7 ) 9 9 (1 ) 9 8 (3 ) 9 3 (0 ) 8 9 (0 ) 8 1 (1 ) 6 9 (2 ) 2 9 (0 ) 2 (0 ) 1 (0 ) 0 L ithiu m 1 1 0 (4 ) 1 0 5 (3 ) 1 0 1 (6 ) 9 2 (4 ) 8 7 (3 ) 8 1 (2 ) 7 1 (0 ) 6 1 (0 ) 2 1 (0 ) 2 (0 ) 1 (0 ) 0 V a lp roa te 1 1 0 (8 ) 1 0 0 (4 ) 9 6 (0 ) 9 5 (6 ) 8 5 (4 ) 7 8 (0 ) 7 0 (3 ) 5 7 (0 ) 2 2 (0 ) 3 (0 ) 1 (0 ) 0 P ro p o rtio n w ith a d d e d m e d ic a tio n .2 .4 .6 .8 Time From Randomization to First Use of Additional Medication C o m b in a tio n L ith iu m 0 V a lp ro a te 0 3 6 9 12 15 18 21 24 M o n th s to first a d d e d m e d ic a tio n 27 30 33 A t risk (e ve n ts ): C o m b in a tio n 1 1 0 (1 4 ) 9 6 (1 6 ) 7 8 (1 0 ) 6 8 (7 ) 6 0 (4 ) 5 3 (2 ) 4 7 (4 ) 3 6 (1 ) 20 (0 ) 2 (0 ) 1 (0 ) 0 L ith iu m 1 1 0 (2 2 ) 8 7 (1 5 ) 7 1 (1 0 ) 5 9 (8 ) 5 0 (5 ) 4 3 (2 ) 3 9 (2 ) 3 0 (0 ) 12 (0 ) 1 (0 ) 1 (0 ) 0 V a lp ro a te 1 1 0 (3 3 ) 7 5 (1 8 ) 5 7 (7 ) 4 9 (3 ) 4 3 (6 ) 3 7 (3 ) 3 0 (5 ) 1 8 (0 ) 6 (0 ) 1 (0 ) 0 (0 ) 0 P ro p o rtio n w ith e p is o d e o f m a n ia .1 .2 .3 .4 .5 Time From Randomization to First Treatment for Mania C o m b in a tio n L ith iu m 0 V a lp ro a te 0 3 6 9 12 15 18 21 M o n th s to first m a n ic e p is o d e 24 27 30 33 A t risk (e ve n ts ): C o m b in a tio n 1 1 0 (2 ) 1 0 8 (1 1 ) L ith iu m 1 1 0 (1 3 ) 96 V a lp ro a te 1 1 0 (1 8 ) 90 9 5 (4 ) 9 1 (5 ) 84 (4 ) 7 6 (1 ) 6 8 (1 ) 5 9 (2 ) 2 5 (0 ) 2 (0 ) 1 (0 ) 0 (6 ) 8 9 (8 ) 7 9 (7 ) 71 (3 ) 6 6 (2 ) 5 9 (1 ) 4 9 (0 ) 1 9 (0 ) 1 (0 ) 1 (0 ) 0 (1 1 ) 7 9 (5 ) 7 3 (2 ) 68 (7 ) 5 9 (2 ) 5 1 (4 ) 3 7 (0 ) 1 5 (0 ) 3 (0 ) 1 (0 ) 0 P ro p o rtio n w ith e p iso d e o f d e p re ssio n 0 .1 .2 .3 .4 .5 Time From Randomization to First Treatment for Depression T im e to 2 5 % d e p re sse d (m o n th s ) (9 5 % C I) C om bina tion : 9 .6 (5 .8 to 17 .1 ) L ith iu m : 12 .0 (6 .0 to 19.9 ) V a lp ro a te : 5 .2 (3 .1 to 10 .1 ) 0 3 6 9 12 15 18 21 24 M o n th s to first e p is o d e d e p re ss io n 27 30 33 A t risk (e ve nts ): C o m b in a tio n 1 1 0 (1 1 ) 9 9 (9 ) 8 8 (7 ) 8 1 (4 ) 7 6 (3 ) 7 0 (2 ) 6 2 (2 ) 5 1 (1 ) 2 4 (0 ) 2 (0 ) 1 (0 ) 0 L ithiu m 1 1 0 (8 ) 1 0 1(1 0 ) 8 9 (3 ) 8 3 (6 ) 7 5 (3 ) 6 8 (2 ) 5 9 (3 ) 4 9 (0 ) 1 8 (0 ) 2 (0 ) 1 (0 ) 0 V a lp roa te 1 1 0 (1 7 ) 9 1 (1 3 ) 7 8 (4 ) 7 3 (5 ) 6 5 (5 ) 5 9 (3 ) 4 9 (2 ) 3 9 (1 ) 1 4 (0 ) 2 (0 ) 0 (0 ) 0 P ro p o rtio n n o t o n tria l rx .1 .2 .3 .4 .5 Time From Randomization to Stopping Allocated Treatment C o m b in a tio n L ith iu m 0 V a lp ro a te 0 3 6 9 12 15 18 21 M o n th s to sto p p in g tria l rx 24 27 30 33 A t risk (e ve nts ): C o m b in a tio n 1 1 0 (1 0 ) 1 0 0 (8 ) 9 2 (8 ) 8 4 (6 ) 7 7 (4 ) 7 2 (4 ) 6 2 (4 ) 5 3 (3 ) 2 3 (0 ) 1 (0 ) 1 (0 ) 0 L ithiu m 1 1 0 (1 4 ) 9 6 (1 2 ) 8 4 (5 ) 7 9 (3 ) 7 6 (4 ) 7 0 (6 ) 6 1 (3 ) 5 0 (2 ) 2 0 (0 ) 2 (0 ) 1 (0 ) 0 V a lp roa te 1 0 9 (1 6 ) 9 3 (7 ) 8 6 (3 ) 8 2 (2 ) 7 8 (9 ) 6 7 (2 ) 5 9 (4 ) 4 8 (1 ) 1 8 (0 ) 2 (0 ) 1 (0 ) 0 Secondary outcomes No differences on: • • • • Quality of life Deliberate self harm/parasuicide/suicide Global functioning Adverse events including deaths Conclusions • For people with bipolar disorder for whom long-term therapy is clinically indicated, combination therapy with lithium plus divalproex is more likely to prevent relapse than monotherapy • The relative advantage is most robust compared to divalproex monotherapy – risk reduced by about 40% • This relative benefit appears to be irrespective of patient or illness characteristics and is maintained for up to two years • Efficient, cost-effective trial designs are possible in psychiatry and can yield clinically useful results Numbers Needed to Treat – Combination vs. valproate 7 – Combination vs. lithium 20 – Lithium vs. valproate 10 Clinical Scenarios • 56 year old female, 10 episodes, currently on lithium COMBINATION • 75 year old male, 5 episodes, on valproate COMBINATION • 36 year old male, 5 episodes, currently on valproate COMBINATION • 21 year old male, no previous long-term therapy, 2 episodes COMBINATION • 21 year old female, no previous long-term therapy 2 episodes LITHIUM Methodology • Open design – potential for – Ascertainment bias – Performance bias • Active run-in: – Effects on generalisability • Drug dosing – Optimize vs clinically typical Acknowledgements • Thanks to all participants in the study and the clinical and administrative staff in all four countries who assisted with the trial. • • • • • • Writing Committee: Prof John R Geddes (Chief Investigator)*; Prof Guy M. Goodwin, Dr Jennifer Rendell (Trial Manager), Prof Jean-Michel Azorin (Chief Investigator, France), Dr Andrea Cipriani (Chief Investigator, Verona, Italy) Dr Michael J Ostacher (Chief Investigator, Massachusetts, USA), Prof Richard Morriss, Nicola Alder (Statistician), Ed Juszczak (Statistician) Trial Steering Committee: Prof Shon Lewis (Chair), Prof John R Geddes (Chief Investigator); Prof Guy Goodwin, Professor Richard Morriss, Dr Jennifer Rendell (Trial Manager) Trial Management Group: Prof John R Geddes (Chief Investigator)*; Prof Guy Goodwin, Dr Jennifer Rendell (Trial Manager), Jane Hainsworth, Emma Van der Gucht, Christine Healey, Will Stevens, Brigid Carter, Heather Young, Ed Juszczak Clinical Trial Service Unit: Dr Christina Davies, Prof Richard Peto Data Monitoring and Ethics Committee: Prof Thomas RE Barnes (Chair); Dr Vivienne Curtis; Dr Tony Johnson Trial Pharmacy: Michael Marven Avon and Wiltshire Mental Health Partnership NHS Trust (9) Dr Ourania Anagnosti Dr Bill Bruce-Jones Dr Jonathan Evans Dr Geoffrey Woodin Belfast City Hospital Trust (2) Dr Chris Kelly Berkshire Healthcare NHS Foundation Trust (28) Dr David Briess Dr Alfonso Ceccherini-Nelli Dr Elizabeth Clifford, Dr Robert Croos Dr Jane Da Rosa Davis Dr Lalitha De Silva Dr Savitha Eranti Dr Rafi Mahmoud Dr Anil Maurya Dr Peter Partovi-Tabar Dr Yousuf Rahimi Dr Jacqueline Tuson Birmingham and Solihull Mental Health NHS Foundation Trust (1) Dr Jayne Greening Causeway Health and Social Services Trust (1) Dr Timothy Leeman Cambridgeshire and Peterborough NHS Foundation Trust (2) Dr Neil Hunt Professor Peter Jones Dr Rajini Ramana Cheshire and Wirral Partnership NHS Foundation Trust (10) Dr Roger Chitty Dr Carl Littlejohns Dr Anil Suri Cornwall Partnership NHS Trust (1) Dr Richard Laugharne Coventry and Warwickshire Partnership NHS Trust (11) Dr Colin Campbell Dr Jasdey Singh Grewal Dr Ashok Kumar Dr Dieter Schultewolter Devon Partnership NHS Trust (16) Dr Andrew E Blewett Dr Subhash Gupta Dr Bharat Saluja Down Lisburn Health and Social Services Trust (1) Dr Mark Macauley Dr Deidre Shields Dudley Primary Care Trust (4) Dr Mohammad Iqbal Dr Panayiotis Zikis Glasgow (9) Dr Jacqui Anderson Dr Alison McRae Dr Mark Taylor Greater Manchester West Mental Health NHS Foundation Trust (5) Dr David O’Driscoll Dr Natalie Robbins Hampshire Partnership NHS Trust (4) Dr David Baldwin Dr Nick Best Dr Nicola Herod Dr Richard Polson Dr Charles Shawcross Hertfordshire Partnership NHS Foundation Trust (4) Dr Jeremy Chase Isle Of Wight NHS PCT (1) Dr Umama Khan Lancashire Care NHS Foundation Trust (11) Dr Graham Ash Dr Imran Chaudhry Dr Venu Duddu Dr Paul Reed Dr Stephan Van Wyk Dr Adarsh Vohra Dr Zukiswa Zingela Leeds Partnerships NHS Foundation Trust (1) Dr Tariq Mahmood Leicestershire Partnership NHS Trust (7) Dr Mohammed Arif Dr Janet Bruce Dr Gary Drybala Dr Enda Hayden Dr Harsh P Jhingan Dr Mangesh Marudkar Lincolnshire Partnership NHS Foundation Trust (2) Dr Richard Hillier Mersey Care NHS Trust (6) Dr Heidi Diedricks Dr Mohammad A Faizal Dr James McCarthy Prof. Richard Morriss NHS Lothian (5) Dr Lucy Carrick Dr Elizabeth Hare Dr Diana Morrison Norfolk and Waveney Mental Health NHS Foundation Trust (3) Dr Iain Macmillan Dr Larry Ayuba Northamptonshire Healthcare NHS Trust (12) Dr Mamdouh El-Adl Dr Chandrashekar Rao Dr Bryan Timmins Dr Nadim Almosmosh Northumberland, Tyne and Wear NHS Trust (5) Professor Nicol Ferrier Dr Alison Conway Dr Tim Oakley Dr Nicholas Tower Professor Allan Young Nottinghamshire Healthcare NHS Trust (9) Dr Sara Barrett Dr Jasvinder Sing Lidder Dr Mark McCartney Dr Hugh Middleton Dr Frank Ononye Dr Ramesh D Solanki Oxford and Buckinghamshire NHS Foundation Trust (103) Dr Mary-Jane Attenburrow Dr Rob Bale Dr Sandeep Bansal Dr Zubin Bhagwagar Dr Ali Carre Dr Julia Cartright Dr Julie Chalmers Dr Apa Chisuse Dr Phil Davison Dr David Elwell Dr David Geaney Prof John Geddes Prof. Guy Goodwin Dr Simon Hampson Prof. Paul Harrison Dr Emma Henderson Dr Sophie Johnson Dr Christopher Massey Dr Alan Ogilvie Dr Denis O'Leary Dr Catherine Oppenheimer Dr Michael Orr Dr Digby Quested Dr Peter Sargent Dr Philip Wilkinson Oxfordshire Learning Disability NHS Trust (1) Dr Tafazul Hussain South London and Maudsley NHS Foundation Trust (3) Prof Sophia Frangou Dr Harm Gijsman Dr Elizabeth Parker Prof. Mary Phillips South Staffordshire and Shropshire Healthcare NHS Foundation Trust (5) Dr Ignasi Agell Dr Rubina Anjum Suffolk Mental Health Partnership NHS Trust (1) Dr Albert Michael West London Mental Health NHS Trust (8) Dr Graham Behr Prof. Peter Tyrer Worcestershire Mental Health Partnership NHS Trust (8) Dr Steve Franklin Dr John King Dr Janet White CEQUEL....... • Comparing lamotrigine plus quetiapine with quetiapine monotherapy • MRC funded • Currently recruiting • Join us! With SPaRCLe data – All Relapse With SPaRCLe data – Manic Relapse With SPaRCLe data – Depressive Relapse Lithium: prevention of suicide Cipriani, A, Pretty H, Hawton K, and Geddes JR. Am.J.Psychiatry 162 (10):1805-1819, 2005. P ro p o rtio n w ith e ve n t .2 .4 .6 .8 Primary Outcome – New Treatment/Hospital Admission Li+Va vs Va HR 0.59 p=0.002 Li+Va vs Li HR 0.82 p=0.27 Li vs Va HR 0.71 p=0.05 C o m b in a tio n L ith iu m 0 V a lp ro a te 0 3 6 9 12 15 18 21 24 27 30 33 M o n th s to first e ve n t A t risk (e ve nts ): C o m b in a tio n 1 1 0 (1 4 ) 9 6 (1 7 ) 7 7 (1 0 ) 6 7 (7 ) 5 9 (4 ) 5 3 (2 ) 4 7 (4 ) 3 6 (1 ) 2 0 (0 ) 2 (0 ) 1 (0 ) 0 L ithiu m 1 1 0 (2 3 ) 8 6 (1 5 ) 7 0 (1 0 ) 5 9 (8 ) 5 0 (5 ) 4 3 (2 ) 3 9 (2 ) 3 0 (0 ) 1 2 (0 ) 1 (0 ) 1 (0 ) 0 V a lp roa te 1 1 0 (3 4 ) 7 4 (1 8 ) 5 6 (7 ) 4 8 (3 ) 4 2 (6 ) 3 6 (3 ) 2 9 (5 ) 1 7 (0 ) 6 (0 ) 1 (0 ) 0 (0 ) 0 ECT Atypical antipsychotics Conclusion • Scepticism is appropriate • We need replication • Multiples of trials