St. John's wort for depression - the history of a Cochrane review from 1996 to 2008

Slide 1: 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

Slide 2: 4 versions… 1. BMJ 1996 Linde K, Ramirez G, Mulrow C, Pauls A, Weidenhammer W, Melchart D 2. Cochrane Library 1998 Linde K, Mulrow C 3. Cochrane Library/Br J Psychiatry 2005 Linde K, Berner M, Egger M, Mulrow C 4. Cochrane Library 2008 (submitted) Linde K, Kriston L, Berner M

Slide 3: 4 versions and their conclusions 1. 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“ 2. Cochrane Library 1998 3. Cochrane Library/Br J Psychiatry 2005 4. Cochrane Library 2008 (submitted)

Slide 4: 4 versions and their conclusions 1. 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“ 2. 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“ 3. Cochrane Library/Br J Psychiatry 2005 4. Cochrane Library 2008 (submitted)

Slide 5: 4 versions and their conclusions 1. 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“ 2. 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“ 3. 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“ 4. Cochrane Library 2008 (submitted)

Slide 6: 4 versions and their conclusions 1. 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“ 2. 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“ 3. 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“ 4. 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“

Slide 7: How the story begun 1992 Desire to produce something where a positive results seemed likely: hypericum a good option 3 Contact with C Mulrow (and Gil Ramirez) 1996 BMJ version published/CCDAN registered 1998 First Cochrane version

Slide 8: How the story begun 1992 Desire to produce something where a positive results seemed likely: hypericum a good option 3 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!

Slide 9: 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?

Slide 10: The inclusion criteria 1. 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 2. 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 3. 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

Slide 11: Trial flow 1996: included 23 trials

Slide 12: Trial flow 1996: included 23 trials + 4 new 1998: included 27 trials

Slide 13: Trial flow 1996: included 23 trials + 4 new 1998: included 27 trials - 7 old + 17 new 2005: included 37 trials

Slide 14: 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

Slide 15: 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

Slide 17: Study Hypericum Placebo RR (fixed) RR (fixed) or sub-category n/N n/N 95% CI 95% CI 01 Restricted to major depression - smaller (less precise) trials Lehrl 1993 4/25 2/25 2.00 [0.40, 9.95] Hänsgen 1996 35/53 12/54 2.97 [1.74, 5.07] Schrader 1998 45/80 12/79 3.70 [2.12, 6.46] Kalb 2001 23/37 15/35 1.45 [0.92, 2.29] Laakmann 1998 24/49 16/49 1.50 [0.92, 2.46] Shelton 2001 26/98 19/102 1.42 [0.84, 2.40] Subtotal (95% CI) 342 344 2.06 [1.65, 2.59] Total events: 157 (Hypericum), 76 (Placebo) Test for heterogeneity: Chi² = 11.86, df = 5 (P = 0.04), I² = 57.9% Test for overall effect: Z = 6.29 (P < 0.00001) 02 Restricted to major depression - larger (more precise) trials Witte 1995 34/48 25/49 1.39 [1.00, 1.93] Philipp 1999 67/106 22/47 1.35 [0.96, 1.89] Volz 2000 46/70 34/70 1.35 [1.01, 1.82] HDTSG 2002 46/113 56/116 0.84 [0.63, 1.13] Montgomery 2000 55/123 57/124 0.97 [0.74, 1.28] Lecrubier 2002 98/186 80/189 1.24 [1.00, 1.54] Subtotal (95% CI) 646 595 1.15 [1.02, 1.29] Total events: 346 (Hypericum), 274 (Placebo) Test for heterogeneity: Chi² = 9.62, df = 5 (P = 0.09), I² = 48.0% Test for overall effect: Z = 2.36 (P = 0.02) 03 Not restricted to major depression - smaller (less precise) trials Osterheider 1992 0/23 0/24 Not estimable Halama 1991 10/25 0/25 21.00 [1.30, 340.02] Hoffmann 1979 19/30 3/30 6.33 [2.09, 19.17] Quandt 1993 29/44 3/44 9.67 [3.18, 29.41] Schlich 1987 15/25 3/24 4.80 [1.59, 14.50] Schmidt 1989 10/20 4/20 2.50 [0.94, 6.66] Subtotal (95% CI) 167 167 6.13 [3.63, 10.38] Total events: 83 (Hypericum), 13 (Placebo) Test for heterogeneity: Chi² = 4.81, df = 4 (P = 0.31), I² = 16.8% Test for overall effect: Z = 6.76 (P < 0.00001) 04 Not restricted to major depression - larger (more precise) trials Schmidt 1993 20/32 6/33 3.44 [1.59, 7.44] Hübner 1993 14/20 9/20 1.56 [0.89, 2.73] Reh 1992 20/25 11/25 1.82 [1.12, 2.95] Sommer 1994 28/50 13/55 2.37 [1.39, 4.04] Winkel 2000 34/60 17/59 1.97 [1.24, 3.11] König 1993 29/55 31/57 0.97 [0.69, 1.37] Subtotal (95% CI) 242 249 1.71 [1.40, 2.09] Total events: 145 (Hypericum), 87 (Placebo) Test for heterogeneity: Chi² = 15.48, df = 5 (P = 0.008), I² = 67.7% Test for overall effect: Z = 5.31 (P < 0.00001) Total (95% CI) 1397 1355 1.55 [1.42, 1.70] Total events: 731 (Hypericum), 450 (Placebo) Test for heterogeneity: Chi² = 89.42, df = 22 (P < 0.00001), I² = 75.4% Test for overall effect: Z = 9.64 (P < 0.00001) 2005 0.1 0.2 0.5 favours placebo 1 2 5 10 favours hypericum placebo

Slide 18: 2005 placebo

Slide 19: Review: St John's Wort for major depression (CocLib250205) Comparison: 04 Hypericum mono-preparations vs. standard antidepressants. A. Dichotomous measures Outcome: 01 Responder (intent to treat) - primary analysis Study hypericum standard RR (fixed) RR (fixed) or sub-category n/N n/N 95% CI 95% CI 01 vs. older antidepressants Bergmann 1993 32/40 28/40 1.14 [0.89, 1.48] Harrer 1993 27/51 28/51 0.96 [0.67, 1.38] Vorbach 1994 42/67 37/68 1.15 [0.87, 1.53] Vorbach 1997 36/107 41/102 0.84 [0.59, 1.20] Wheatley 1997 40/87 42/78 0.85 [0.63, 1.16] Woelk 2000 68/157 67/167 1.08 [0.83, 1.40] Philipp 1999 76/106 70/110 1.13 [0.94, 1.36] Subtotal (95% CI) 615 616 1.03 [0.93, 1.14] Total events: 321 (hypericum), 313 (standard) Test for heterogeneity: Chi² = 5.14, df = 6 (P = 0.53), I² = 0% Test for overall effect: Z = 0.54 (P = 0.59) 02 vs. SSRIs Brenner 2000 7/15 6/15 1.17 [0.51, 2.66] Behnke 2002 16/35 21/35 0.76 [0.49, 1.20] van Gurp 2002 20/45 22/45 0.91 [0.58, 1.42] Schrader 2000 57/125 39/113 1.32 [0.96, 1.82] Harrer 1999 50/77 57/84 0.96 [0.77, 1.19] HDTSG 2002 46/113 55/111 0.82 [0.61, 1.10] Subtotal (95% CI) 410 403 0.97 [0.85, 1.12] Total events: 196 (hypericum), 200 (standard) Test for heterogeneity: Chi² = 6.29, df = 5 (P = 0.28), I² = 20.5% Test for overall effect: Z = 0.36 (P = 0.72) Total (95% CI) 1025 1019 1.01 [0.93, 1.10] Total events: 517 (hypericum), 513 (standard) Test for heterogeneity: Chi² = 12.36, df = 12 (P = 0.42), I² = 2.9% Test for overall effect: Z = 0.18 (P = 0.85) 0.1 0.2 0.5 1 2 5 10 favours standard favours hypericum 2005 standard

Slide 20: 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!!!!

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