Transcript a short history of evidence-based psychiatry

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