St John's wort for depression the history of a Cochrane review from (1993) 1996 to 2008 Klaus Linde, MD Zentrum für Naturheilkundliche Forschung II. Med. Klinik und Poliklinik, Klinikum rechts der Isar

St John's wort for depression

the history of a Cochrane review

from (1993) 1996 to 2008

Klaus Linde, MD

4 versions… BMJ 1996 Linde K, Ramirez G, Mulrow C, Pauls A, Weidenhammer W, Melchart D Cochrane Library 1998 Linde K, Mulrow C Cochrane Library/Br J Psychiatry 2005 Linde K, Berner M, Egger M, Mulrow C Cochrane Library 2008 (submitted) Linde K, Kriston L, Berner M

BMJ 1996 Linde K, Ramirez G, Mulrow C, Pauls A, Weidenhammer W, Melchart D

Cochrane Library 1998 Linde K, Mulrow C

Cochrane Library/Br J Psychiatry 2005 Linde K, Berner M, Egger M, Mulrow C

Cochrane Library 2008 (submitted) Linde K, Kriston L, Berner M

4 versions and their conclusions BMJ 1996 “There is evidence that extracts of hypericum are more effective than placebo for the treatment of mild to moderately severe depressive disorders. Further studies comparing extracts with standard antidepressants … are needed“ Cochrane Library 1998 Cochrane Library/Br J Psychiatry 2005 Cochrane Library 2008 (submitted)

BMJ 1996 “There is evidence that extracts of hypericum are more effective than placebo for the treatment of mild to moderately severe depressive disorders. Further studies comparing extracts with standard antidepressants … are needed“

Cochrane Library 1998

Cochrane Library/Br J Psychiatry 2005

Cochrane Library 2008 (submitted)

4 versions and their conclusions BMJ 1996 “There is evidence that extracts of hypericum are more effective than placebo for the treatment of mild to moderately severe deressive disorders. Furthes studies comparing extracts with standard antidepressants … are needed“ Cochrane Library 1998 “There is evidence that extracts of hypericum are more effective than placebo for the short-term treatment of mild to moderately severe depressive disorders. The current evidence is insufficient to establish whether hypericum is as effective as other antidepressants“ Cochrane Library/Br J Psychiatry 2005 Cochrane Library 2008 (submitted)

BMJ 1996 “There is evidence that extracts of hypericum are more effective than placebo for the treatment of mild to moderately severe deressive disorders. Furthes studies comparing extracts with standard antidepressants … are needed“

Cochrane Library 1998 “There is evidence that extracts of hypericum are more effective than placebo for the short-term treatment of mild to moderately severe depressive disorders. The current evidence is insufficient to establish whether hypericum is as effective as other antidepressants“

Cochrane Library/Br J Psychiatry 2005

Cochrane Library 2008 (submitted)

4 versions and their conclusions BMJ 1996 “There is evidence that extracts of hypericum are more effective than placebo for the treatment of mild to moderately severe deressive disorders. Furthes studies comparing extracts with standard antidepressants … are needed“ Cochrane Library 1998 “There is evidence that extracts of hypericum are more effective than placebo for the short-term treatment of mild to moderately severe deressive disorders. The current evidence is insufficient to establish whether hypericum is as effective as other antidepressants“ Cochrane Library/Br J Psychiatry 2005 “Current evidence regarding hypericum extracts is inconsistent and confusing. In … major depression recent placebo-controlled trials suggest that h. has minimal beneficial effects while other trials suggest that h. and standard antidepressants have similar benefical effects“ Cochrane Library 2008 (submitted)

BMJ 1996 “There is evidence that extracts of hypericum are more effective than placebo for the treatment of mild to moderately severe deressive disorders. Furthes studies comparing extracts with standard antidepressants … are needed“

Cochrane Library 1998 “There is evidence that extracts of hypericum are more effective than placebo for the short-term treatment of mild to moderately severe deressive disorders. The current evidence is insufficient to establish whether hypericum is as effective as other antidepressants“

Cochrane Library/Br J Psychiatry 2005 “Current evidence regarding hypericum extracts is inconsistent and confusing. In … major depression recent placebo-controlled trials suggest that h. has minimal beneficial effects while other trials suggest that h. and standard antidepressants have similar benefical effects“

Cochrane Library 2008 (submitted)

4 versions and their conclusions BMJ 1996 “There is evidence that extracts of hypericum are more effective than placebo for the treatment of mild to moderately severe deressive disorders. Furthes studies comparing extracts with standard antidepressants … are needed“ Cochrane Library 1998 “There is evidence that extracts of hypericum are more effective than placebo for the short-term treatment of mild to moderately severe deressive disorders. The current evidence is insufficient to establish whether hypericum is as effective as other antidepressants“ Cochrane Library/Br J Psychiatry 2005 “Current evidence regarding hypericum extracts is inconsistent and confusing. In … major depression recent placebo-controlled trials suggest that h. has minimal beneficial effects while other trials suggest that h. and standard antidepressants have similar benefical effects“ Cochrane Library 2008 (submitted) “The available evidence suggests that the hypericum extracts tested in the included trials a) are superior to placebo in patients with major depression; b) are similarly effective as standard antidepressants; c) and have less side effects than standard antidepressants“

BMJ 1996 “There is evidence that extracts of hypericum are more effective than placebo for the treatment of mild to moderately severe deressive disorders. Furthes studies comparing extracts with standard antidepressants … are needed“

Cochrane Library 1998 “There is evidence that extracts of hypericum are more effective than placebo for the short-term treatment of mild to moderately severe deressive disorders. The current evidence is insufficient to establish whether hypericum is as effective as other antidepressants“

Cochrane Library/Br J Psychiatry 2005 “Current evidence regarding hypericum extracts is inconsistent and confusing. In … major depression recent placebo-controlled trials suggest that h. has minimal beneficial effects while other trials suggest that h. and standard antidepressants have similar benefical effects“

Cochrane Library 2008 (submitted) “The available evidence suggests that the hypericum extracts tested in the included trials a) are superior to placebo in patients with major depression; b) are similarly effective as standard antidepressants; c) and have less side effects than standard antidepressants“

How the story begun 1992 Desire to produce something where a positive results seemed likely: hypericum a good option Contact with C Mulrow (and Gil Ramirez) 1996 BMJ version published/CCDAN registered 1998 First Cochrane version

1992 Desire to produce something where a positive results seemed likely: hypericum a good option

Contact with C Mulrow (and Gil Ramirez)

1996 BMJ version published/CCDAN registered

1998 First Cochrane version

How the story begun 1992 Desire to produce something where a positive results seemed likely: hypericum a good option Contact with C Mulrow (and Gil Ramirez) 1996 BMJ version published/CCDAN registered 1998 First Cochrane version and now there is no more chance to get out!

1992 Desire to produce something where a positive results seemed likely: hypericum a good option

Contact with C Mulrow (and Gil Ramirez)

1996 BMJ version published/CCDAN registered

1998 First Cochrane version

and now there is no more chance to get out!

One thing that remained (almost) – the questions In patients with depression (major depression) Hypericum extracts better than placebo? Hypericum extract similarly effective as standard antidepressants? Hypericum extract associated with less side effects compared to standard antidepressants?

In patients with depression (major depression)

Hypericum extracts better than placebo?

Hypericum extract similarly effective as standard antidepressants?

Hypericum extract associated with less side effects compared to standard antidepressants?

The inclusion criteria BMJ 1996/Cochrane Library 1998 Patients depressive disorder Design randomised clinical trials Interventions hypericum extracts (also in comb. with other herbs) Controls placebo, antidepressant Outcomes any clinical Cochrane Library/Br J Psychiatry 2005 Patients (adults with) depressive disorders Design double-blind , randomised trials Interventions hypericum extracts ( no combinations ) Controls placebo, standard antidepressant ( no diazepam etc.) Outcome any clinical but at least 4 weeks observation Cochrane Library 2008 (submitted) Patients major depression Design double-blind, randomised Interventions hypericum extracts (no combinations) Controls placebo standard antidepressants adequately dosed Outcomes any clinical but at least 4 weeks observation

BMJ 1996/Cochrane Library 1998 Patients depressive disorder Design randomised clinical trials Interventions hypericum extracts (also in comb. with other herbs) Controls placebo, antidepressant Outcomes any clinical

Cochrane Library/Br J Psychiatry 2005 Patients (adults with) depressive disorders Design double-blind , randomised trials Interventions hypericum extracts ( no combinations ) Controls placebo, standard antidepressant ( no diazepam etc.) Outcome any clinical but at least 4 weeks observation

Cochrane Library 2008 (submitted) Patients major depression Design double-blind, randomised Interventions hypericum extracts (no combinations) Controls placebo standard antidepressants adequately dosed Outcomes any clinical but at least 4 weeks observation

Trial flow 1996: included 23 trials

Trial flow 1996: included 23 trials + 4 new 1998: included 27 trials

Trial flow 1996: included 23 trials + 4 new 1998: included 27 trials - 7 old + 17 new 2005: included 37 trials

Trial flow 1996: included 23 trials + 4 new 1998: included 27 trials - 7 old + 17 new 2005: included 37 trials - 16 old + 7 new 2008 included: 28 (29) trials

Trial flow 1996: included 23 trials + 4 new 1998: included 27 trials - 7 old + 17 new 2005: included 37 trials - 15+1 old + 7 new 2008 included: 28 (29) trials 1 trial included in 1996 still included in 2008 version

Copyright ©1996 BMJ Publishing Group Ltd. Linde, K. et al. BMJ 1996;313:253-258 Fig 2--Treatment responders and rate ratios in randomised controlled trials of hypericum extracts

2005 placebo

2005 placebo

2005 standard

Discussion The total funding from 1993 to 2008 was 0 € (0 US$) Updates were huge work! Things became more difficult when -- more and better trials became available -- we had a closer look to the data -- review methods became more sophisticated What should we conclude about hypericum extracts? -- only a placebo and the results all biased? -- the first line therapy for patients with mild to moderate d.? If review methods become better will it all be resolved? Where did I change I became more skeptic about RCTs and systematic reviews Happy birthday German Cochrane Centre!!!!

The total funding from 1993 to 2008 was 0 € (0 US$)

Updates were huge work!

Things became more difficult when -- more and better trials became available -- we had a closer look to the data -- review methods became more sophisticated

What should we conclude about hypericum extracts? -- only a placebo and the results all biased? -- the first line therapy for patients with mild to moderate d.?

If review methods become better will it all be resolved?

Where did I change

I became more skeptic about RCTs and systematic reviews

Happy birthday German Cochrane Centre!!!!