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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. Ackner and Oldham NIMH MRC

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Why we need research: a short history of evidence-based psychiatry


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why we need research 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
Conflict of Interest

Funding from:

MRC, ESRC, NIHR

SMRI

Trial drug supplies

GSK

Sanofi-Aventis

pre evidence based medicine
Pre-evidence-based medicine
  • Ackner and Oldham
  • NIMH
  • MRC
  • Prien et al
falling use of lithium in usa
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 medicine10
Pre-evidence-based medicine
  • Ackner and Oldham
  • NIMH
  • MRC
  • Prien et al
slide11
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
slide12

lithium

or

divalproex

or

lithium + divalproex

BALANCE

Active run–in

Up to 8 weeks

lithium + divalproex

Randomized

Phase

2 years

Time to first intervention

for mood episode

drug doses
Drug doses
  • Lithium – 0.4 to 1.0 mmol
  • Divalproex – target 1250mg, dose established during run-in
sites
Sites
  • 4 countries (UK, US, France, Italy)
  • 90% UK
  • 41 sites
characteristics of participants
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
slide16

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

subgroup analyses
Subgroup analyses

No substantial differences between:

  • Men and women
  • Different age groups
  • Most recent episode
  • Illness stage/severity
  • Site
sensitivity analyses
Sensitivity analyses

Results unaffected when:

  • Events occurring in first 3 months post-randomisation excluded
  • Events occurring when no longer on allocated treatment excluded
  • Adjustment by minimisation factors
secondary outcomes
Secondary outcomes

No differences on:

  • Quality of life
  • Deliberate self harm/parasuicide/suicide
  • Global functioning
  • Adverse events including deaths
conclusions
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
Numbers Needed to Treat
  • Combination vs. valproate 7
  • Combination vs. lithium 20
  • Lithium vs. valproate 10
clinical scenarios
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
Methodology
  • Open design – potential for
    • Ascertainment bias
    • Performance bias
  • Active run-in:
    • Effects on generalisability
  • Drug dosing
    • Optimize vs clinically typical
acknowledgements
Acknowledgements
  • Thanks to all participants in the study and the clinical and administrative staff in all four countries who assisted with the trial.
slide32
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
cequel
CEQUEL.......
  • Comparing lamotrigine plus quetiapine with quetiapine monotherapy
  • MRC funded
  • Currently recruiting
  • Join us!
slide41

With SPaRCLe data

– Manic Relapse

lithium prevention of suicide
Lithium: prevention of suicide

Cipriani, A, Pretty H, Hawton K, and Geddes JR.

Am.J.Psychiatry 162 (10):1805-1819, 2005.

slide44

Primary Outcome – New Treatment/HospitalAdmission

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

conclusion
Conclusion
  • Scepticism is appropriate
  • We need replication
  • Multiples of trials