St John’s wort for major depression (Review) Linde, Berner & Kriston (2008/9)

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: No Caption Found Funnel 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

SJW vs placebo (by precision)

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

SJW vs placebo (by country)

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

SJW vs drug - older/SSRI

SJW vs drug by country

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 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

Hypericin and hyperforin