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Depression Everyday term but specific diagnostic
criteria for “major” or “clinical” depression – DSM IV of APA
Drug treatments raise serotonin (5HT) and/or noradrenalin levels in CNS Monoamine oxidase (MAO) inhibitors Tricyclic antidepressants Selective serotonin re-uptake inhibitors
(SSRIs) High placebo effect – implications?
St John’s wort – Hypericum perforatum Flowering plant used for food(?), herbal
medicine and food supplement Traditionally used as “mood enhancing” &
to treat clinical depression Hypericin said in 1980s to be MAO
inhibitor – often used to “standardise” Hyperforin now thought to be key
component – non selective re-uptake inhibitor in CNS?
Studies in UK, Germany, & USA – supplements often low in active substances (much less than claimed)
Systematic reviews and meta-analyses Technique for identifying and combining
inconclusive trials into 1 large trial of greater statistical power
Finding trials – electronic search engine but may go further - why?
Publication bias (also get multi-publication) Positive trials more likely to be published Detection - simple method is funnel plot
Copyright ©2000 BMJ Publishing Group Ltd.
Sutton, A J et al. BMJ 2000;320:1574-1577
No Caption FoundFunnel plots (hypothetical data)
Publication bias (real example)
Effect of sponsorship? Turner et al (2008)
74 antidepressant trials registered with FDA
38 positive outcome – 37 published 36 negative/? – 14 published but 11
made to seem positive
Inclusion criteria - typical Type of subjects Placebo controlled? Ethical? –
alternative? Dose and duration of trial Specified outcome measures “Quality” – e.g. Jadad score (0→5)
Double blinding (0→2) Random allocation (0→2) Dropouts recorded & explained (0→1)
Inclusion criteria – Linde et al Double blind randomised trials Adult subjects meeting DSM-IV criteria
for major depression SJW versus placebo or SJW vs synthetic
antidepressant (4 weeks minimum and adequate dose of “recognised” antidepressant drug)
Outcome assessed clinically using depression scales or symptoms
Main safety assessment – dropouts (side-effects)
Searching
Several electronic databases searched
Bibliographies of articles checked Direct contact manufacturers,
experts and authors 18 eligible placebo trials & 17 vs
synthetic drug (total 5500 patients)
Outcome measure(s) Responder rate ratios (RR) = %
responders in SJW group/% in placebo group (or synthetic drug group) and 95% CI (i.e. RR<1, SJW better)
Data presented as a series of “Forest plots”
Funnel plots – not significantly asymmetric
Comments Less precise trials give bigger
overall effect: Less RR 1.87 (1.22→2.87) More RR 1.28 (1.10→1.49) Total RR 1.48 (1.23→1.77)
Significant heterogeneity in both groups but greater in less precise
A typical finding from a meta-analysis
Comments
Much larger effect in trials from German speaking countries: RR 1.78 (1.42→2.25) German RR 1.07 (0.88→1.31) R.O.W. (non sig)
German trials significant heterogeneity, less and non sig. in ROW
Comments
No significant differences in any 4 splits or overall
No significant heterogeneity Studies from German speaking
countries still significantly favour hypericum
Authors’ conclusions (Germans) 5 “German” studies pre 2000 all other
2000+ Could not rule out “some smaller
studies from German speaking countries flawed and reported overoptimistic results”
Geoff’s comment – outcome measures seem to be insensitive and to show poor discrimination