Rapid Responses to:
|
|
Rapid Responses: Rapid Responses published:
-
![[Read Rapid Response]](/icons/misc/sectionDOWN.gif)
Seroxat 'v' St. John's Wort: an unfair contest?
- Tim Watkins (11 February 2005)
-
St John's Wort Consumer
- Jane CR Robertson (20 February 2005)
-
Re: Seroxat 'v' St. John's Wort: an unfair contest?
- Stevie M Gamble (24 February 2005)
-
Re: Re: Seroxat 'v' St. John's Wort: an unfair contest?
- Tim Watkins (25 February 2005)
-
On the necessity of placebo controls in clinical trials of hypericum extract
- Brandon A. Gaudiano (25 February 2005)
-
Re: Re: Re: Seroxat 'v' St. John's Wort: an unfair contest?
- Stevie M Gamble (26 February 2005)
-
I may have missed something
- Nicholas D. Moore (4 March 2005)
-
St John's wort is a herbal SSRI?
- AK Al-Sheikhli (4 March 2005)
-
Re: St John's wort is a herbal SSRI?
- Phil Lucas (4 March 2005)
-
"Remission" not defined; safety not addressed
- Richard Braithwaite (4 March 2005)
-
The Run-In Period is methodologically flawed
- Yogi Sehgal (5 March 2005)
-
Re: I may have missed something
- Stevie M Gamble (5 March 2005)
-
What is 'moderate to severe depression'?
- Billy Boland (5 March 2005)
-
European Pharmaceutical Industry v. St. John's Wort.
- Paul G Champion (5 March 2005)
-
For a herbal medicine to be effective, it must act as a drug
- Samantha Line (5 March 2005)
-
Re: "Remission" not defined; safety not addressed
- David A Forbes (5 March 2005)
-
Re: The Run-In Period is methodologically flawed
- David Forbes (5 March 2005)
-
Re: On the necessity of placebo controls in clinical trials of hypericum extract
- David Forbes (5 March 2005)
-
Acute treatment of depression with Hypericum versus paroxetine reconsidered
- Henricus G Ruhe, Mascha C. ten Doesschate, Aart H. Schene (7 March 2005)
-
St. John’s Wort - Issues of Clinical Importance.
- Dr. Murali Krishna, Dr. veera macheneni (9 March 2005)
-
Statistical analysis of adverse events
- Adam Jacobs (10 March 2005)
-
Fishy five a day or Wort a day?
- Srinivasan Ravi (10 March 2005)
-
Standards of WS 5570 are unacceptable
- Arun S Nanivadekar (10 March 2005)
-
The depressing state of psychiatric research
- Howard Mann (11 March 2005)
-
Side-effects of Hypericum extract
- Keay G Smith (21 March 2005)
-
Controller and controlled
- Daniel Sher (6 April 2005)
-
Re: Standards of WS 5570 are unacceptable
- K. M. Phillips (7 May 2005)
|
|
|||
|
Tim Watkins, Director, Depression Alliance Cymru 11 Plas Melin, Westbourne Road, Whitchurch, Cardiff CF14 2BT
Send response to journal:
|
Several Studies have shown that St. John's Wort is at least as effective as TCAs and SSRIs in the treatment of depression. This research adds to our knowledge only in suggesting that St. John's Wort may be as effective in the treatment of severe depression. However, one detects a hidden agenda in this paper. The paper is as much about suggesting that St. John's Wort is more user friendly than other antidepressants. This being so, we should question why the researchers chose to test St. John's Wort against Paroxetine (Seroxat). Of all the SSRIs, Seroxat has the worst reputation, with survivors groups around the world, accusations of a link with suicide, law suits, and enough adverse event reports to cause regulators around the world to alter their safety advice. Whether or not these allegations are true, the researchers behind this paper must have known that the Seroxat users in the trial would report a high number of adverse events, and that, consequently, St. John's Wort would appear considerably better tolerated by comparison. The fact remains that St. John's Wort can have unpleasant side effects, and can be fatal if combined with some blood pressure drugs. What we do not have from this paper, or, as yet, from any other research is data for safety and efficacy from full-scale medical trials of the kind we would insist upon for any prescription medicine. It is perhaps not surprising to find that the research was funded by by Dr William Schwabe Pharmaceuticals, a major global supplier of so- called "herbal remedies" which can be legally sold as food addatives with no requirement to provide patient safety information or warnings about interactions with other medicines. Competing interests: None declared |
|||
|
|
|||
|
Jane CR Robertson, Ceramist JamFactory, Adelaide, South Australia
Send response to journal:
|
I was heartened by your article. I am someone (aged 54) who has had (probably all my life) a depressive state of mind however I dealt with it thinking I needed to correct my own negative thinking and spent about 20 years with various forms of counselling learning many useful modes of cognative therapy. I was only when I started to take St John's Wort (990mcg per tablet) one tablet daily (I found that more than one tablet a day dulled allertness), that I am leading a mentally healthy life without the agonised thinking I spent so long trying to sort out. I have been taking one tablet daily in the morning for the last 3 years. If I cease to take it for more than 6 weeks I start to have faulty thinking again. I have never sought medical treatment as I was not really bad enough and I was afraid that I would be treated as ill as my mother was a diagnosed schizoprenic and I certainly have not had whose problems. There must be many people out there with similar mild yet debilitating thinking. At any rate I just thought I would respond as my life has been changed and I am very grateful for the availability of the product over the counter. Thank you for reading my words, Jane Robertson Competing interests: None declared |
|||
|
|
|||
|
Stevie M Gamble, retired HMIT EC2Y 8BL
Send response to journal:
|
Tim Watkins, Director, Depression Alliance Cymru, in his Rapid Response of 11/2/2005 states that: ‘Seroxat has the worst reputation, with survivors groups around the world, accusations of a link with suicide, law suits, and enough adverse event reports to cause regulators around the world to alter their safety advice. Whether or not these allegations are true, the researchers behind this paper must have known that the Seroxat users in the trial would report a high number of adverse events.’ This was a randomised controlled double blind non-inferiority trial; the participants did not know what they were taking. It is irrational, therefore, to suggest that in such a trial the Seroxat users would report a high number of adverse effects if the allegations surrounding Seroxat were untrue. It could only happen if the allegations were well founded. Tim Watkins also makes the entirely reasonable point that the research in question was funded by the manufacturers of the hypericum extract used. For the benefit of those who lack the time to read the paper in full themselves, I should note that this was fully disclosed. I am surprised, however, that Tim Watkins failed to disclose any of the links between the Depression Alliance and the pharmaceutical industry. For example, the booklet ‘Depression and Antidepressants’ published by the Depression Alliance, was funded by Organon Ltd, a manufacturer of antidepressants. It may not be entirely coincidental that the tone of the commentary on side effects is cheerily up-beat: see http://www.depressionalliance.org/publications/DA_Anti-Dep.pdf In another example the Depression Alliance is currently soliciting volunteers for a research program funded by GlaxoSmithKline. The entry on the website concludes with the statement that: ‘All volunteers will be generously reimbursed for their time and travel expenses.’ http://www.depressionalliance.org/docs/what_we_offer/research.html It does not appear to have occurred to GSK, the relevant researcher at the University of Cambridge or the Depression Alliance itself, that there may be a problem with this… Stevie M Gamble Competing interests: None declared |
|||
|
|
|||
|
Tim Watkins, Director, Depression Alliance Cymru 11 Plas Melin, Westbourne Road, Whitchurch, Cardiff CF14 2BT
Send response to journal:
|
I cannot speak for Depression Alliance, as Depression Alliance Cymru is separately funded. Although I sometimes wish that Depression Alliance Cymru had the huge sums from the pharmaceutical companies that we are sometimes attacked for, the sad fact is that donations from this source account for less than 2% of our income over the last 4 years. Indeed, in the same period, we received three times as much from collections at the funerals of supporters whose depression finally got the better of them. Sadly, of course, very little research (and very little charitable activity) gets done these days without some corporate interest. That which does is that which meets the government's agenda. None of this, of course, detracts from the criticism I made of this research: St John's Wort is not an alternative to antidepressants, it is an antidepressant! Not only that, it is a potentially dangerous antidepressant! The point here is not a defence of GSK or Seroxat (I am sure one of their PR people is paid more than our organisation runs on every year!). Rather, it is to point out that a researcher wishing to contrast St John's Wort with an SSRI would have been better advised to opt for one not surrounded by controversy around its side effects - The recent NICE guidance on the treatment of depression suggests cipramil for patients who cannot tolerate Prozac, so it would seem there is some recognition that some SSRIs are better tolerated than others. As it stands, despite the internal validity of the St John's Wort trial, all we are really able to say is that St John's wort is beter tolerated than an SSRI that many patient groups want banned! Not really a recommendation. What we need, and what this research takes us no nearer toward is full medical trials for the efficacy and safety of St Johns Wort. But why should a multinational like Schwabe Pharmaceuticals engage in such (expensive) trials, when they can get away with selling the product as a "food addative"? And why is it that many critics of corporate pharmaceutical companies have a blind spot when it comes to those who market so-called "natural" products? Competing interests: None declared |
|||
|
|
|||
|
Brandon A. Gaudiano, postdoctoral research fellow Psychosocial Research, Butler Hospital, 345 Blackstone Blvd., Providence, RI 02906
Send response to journal:
|
Based on results from their double-blind, randomized trial, Szegedi and colleagues(1) conclude that hypericum extract is at least as efficacious as paroxetine for treating moderate to severe depression. However, the absence of a placebo control group in the study precludes them from being able to draw such a definitive conclusion. Comparisons of effect sizes between studies are often unreliable and represent improper substitutes for the use of appropriate controls within a trial. Unfortunately, the Szegedi et al. trial is plagued by problems similar to those apparent in other investigations of St John’s wort. In fact, the study design replicated the same methodological error made in a previous trial comparing hypericum and imiprimine(2). The problems with the Szegedi et al. trial are typical of those found in many other antidepressant trials, in that insufficient attention was given to confounds such as non-specific treatment effects and experimenter biases(3). Apparently, little has been learned from a previous large randomized trial comparing hypercium, sertraline, and placebo conducted by the Hypericum Depression Trial Study Group(4). Patients in all conditions improved significantly, with no superiority for hypericum or sertraline over placebo on Hamilton depression ratings. If a placebo control group had not been included in this trial, the authors note that they would have erroneously concluded that hypericum was an effective treatment for depression. Szegedi et al. argue that a placebo control would have been unethical to use because patients had severe depression, but nevertheless make overstated conclusions about their trial’s results. To compound problems, Szegedi et al. failed to report formal inter-rater reliability ratings for their assessments or to assess the adequacy of their blinding procedures. Without such data, it is difficult to determine whether experimenter bias in fact was responsible for the slight advantages detected for hypericum in the study. 1 Szegedi A, Kohnen, R, Dienel A, Kieser. Acute treatment of moderate to sever depression with hypericum extract WS 5570 (St John’s wort): randomised controlled double blind non-inferiority trial versus paroxetine. BMJ;doi:10.1136/bmj.38356.655266.82 (published 11 February 2005). 2 Vorbach EU, Hubner WD, Arnoldt KH. Effectiveness and tolerance of the hypericum extract LI 160 in comparison with imipramine: randomized double-blind study with 135 outpatients. J Geriatric Psychiatry Neurol 1994;7(suppl 1):S19-23. 3 Gaudiano BA, Herbert JD. Methodological issues in clinical trials of antidepressant medications: perspectives from psychotherapy outcome research. Psychother Psychosom 2005;74:17-25. 4 Hypericum Depression Trial Study Group. Effect of Hypericum perforatum (St John’s Wort) in major depressive disorder: a randomized controlled trial. JAMA 2002;287:1807-1817. Competing interests: None declared |
|||
|
|
|||
|
Stevie M Gamble, retired HMIT EC2Y 8BL
Send response to journal:
|
Tim Watkins, Director, Depression Alliance Cymru, asserts in his Rapid Response of 25th February that: ‘St John's Wort is not an alternative to antidepressants, it is an antidepressant!’ I entirely agree. I am puzzled, therefore, as to why the Depression Alliance Booklet ‘Depression and Antidepressants’ http://www.depressionalliance.org/publications/DA_Anti-Dep.pdf doesn’t. Perhaps he could enlighten us? The booklet specifically refers to the English, Scottish and Welsh branches of the Depression Alliance, so he cannot claim ignorance of the matter. He goes on to say ‘Not only that, it is a potentially dangerous antidepressant!’ Again, I entirely agree. As Szegedi et al note in their paper ‘As in any effective antidepressant, potential interactions with other drugs deserve clinical attention.’ He also states that: ‘What we need, and what this research takes us no nearer toward is full medical trials for the efficacy and safety of St Johns Wort.’ It would appear that Szegedi et al agree with that also: ‘The convincing results for hypericum extract WS 5570 observed in this trial deserve independent confirmation by other research.‘ Incidentally, Tim Watkins continues to misrepresent himself as possessing no competing interests. Whilst I do appreciate that, given my professional background, I may pick up on this rather more than most, I suspect that he has simply failed to read Richard Smith’s editorial: http://bmj.bmjjournals.com/cgi/content/full/317/7154/291 which is signposted in your guidance notes. This is regrettable, not least because the free exchange of informed views is hindered whenever someone decides that the rules cannot possibly apply to them… Stevie M Gamble Competing interests: None declared |
|||
|
|
|||
|
Nicholas D. Moore, Professor of clinical pharmacology Université Victor Segalen, 33076 Bordeaux
Send response to journal:
|
Strangely enough, I have always thought that the therapeutic activity of medicines was subtended by a chemical action of some sort or another. This is certainly true of all plant-derived drugs I know of. In the case of St John's wort, there seems to be some kind of strange scientific limbo that contrasts this "natural" ingredient with the "chemicals" used to treat depression, eg tricyclics, or SSRI. There has to be an active ingredient in St John's wort, that needs to be characterized chemically and pharmacologically. For all I know, it may be a tricyclic SSRI, or some other dangerous chemical. What a horrible thought - Chemicals in plants!!? Shades of Withering! Shouldn't foxglove extract be sold OTC? and aren't willow-bark decoctions safer than aspirin? (as I was once asked - since they're natural) Nicholas Moore, clinical pharmacologist Competing interests: I have been working with a large number of pharmaceutical companies over the years, including some that manufacture antidepressants, mostly chemical… And the BMJ has rejected some of my work on plant extracts, on the basis, among many other failings, that I didn't know what was in them. |
|||
|
|
|||
|
AK Al-Sheikhli, Psychiatrist St.Michael's Hospital,Warwick,UK
Send response to journal:
|
EDITOR-It was interesting to read the paper of Szegedi etal{BMJ 2005,330;503},Acute treatment of moderate to severe depression...,. There was some evidence that St John's Wort is a herbal SSRI?, Yours sincerely, AK.Al-Sheikhli Competing interests: None declared |
|||
|
|
|||
|
Phil Lucas, medical herbalist and medical student Sheffield
Send response to journal:
|
Hypericum is unlikely to be an SSRI. Work so far suggests that that any action is non-specific, and not due to interaction with transporters. Further work suggests that its action may be due to vesicle depletion. Some papers that may be of interest are Roz N, Rehavi M 2004. Hyperforin depletes synaptic vesicles content and induces compartmental redistribution of nerve ending monoamines.Life Sci. 75(23):2841-50. Mennini T, Gobbi M. 2004. The antidepressant mechanism of Hypericum perforatum.Life Sci. 75(9):1021-7. There are many more. It must be said however that this work is mainly in vitro and in rat species. "Hypericum is potentially dangerous" So are a vast amount of drugs. It is how it is used that is important, i.e. by qualified practitioners who understand potential problems Competing interests: Medical herbalist |
|||
|
|
|||
|
Richard Braithwaite, Staff Grade Adult Psychiatry West Wight Community Mental Health Team, Newport, Isle of Wight, PO30 1JW
Send response to journal:
|
I welcome this study into use of hypericum in severely depressed patients, as it may represent an important advance in our treatment of depression in secondary care. However, Szegedi et al state (1): "At the end of the acute treatment phase 86/122 patients (71%) in the hypericum group and 73/122 (60%) in the paroxetine group responded to treatment (P = 0.08; 2 test), and 61/122 (50%) and 43/122 patients (35%) showed remission (P = 0.02)." They define "response" earlier in their paper, thus "Those who responded to treatment (that is, their total score on the 17 item Hamilton depression scale decreased by 50%) were invited to participate in a four month double blind maintenance phase (reported elsewhere)." although this important definition is regretfully left out of the abridged printed version of the paper published today. Furthermore, "remission" is not defined by the researchers at all. This is odd, given that their results relating to "remission" suggest a statistically significant superiority of their drug over paroxetine (see above). This leaves unanswered questions about the efficacy of the drug. On a further note, the authors discuss "safety and tolerability" of the drug. The tolerability of the drug has been well addressed by this study; its safety has not - it is impossible to study the safety of a drug by conducting a trial involving administration of the drug to 122 individuals. Even a sudden death rate of 1% may conceivably not be picked up by a such a trial! References 1 A Szegedi, R Kohnen, A Dienel, and M Kieser Acute treatment of moderate to severe depression with hypericum extract WS 5570 (St John's wort): randomised controlled double blind non-inferiority trial versus paroxetine, BMJ 2005; 330: 503. Competing interests: None declared |
|||
|
|
|||
|
Yogi Sehgal, MD CCFP Sioux Lookout, Ontario, Canada, P8T1A8
Send response to journal:
|
Run-in periods can be useful tools, but in this case, only testing St John's wort in the run-in period skews the results. It is unclear from the paper how many people withdrew during the run-in period because they did not like the St John's wort (there were some that revoked consent and one adverse event, but it's unclear if any just felt worse and didn't want to take it any more). Therefore, it makes sense that hypericum will look as good if not better than paroxetine because this paper is looking at the question "In people who tolerate and do fine for a week on St John's wort, do they do as well as people started on paroxetine without a run-in evaluation period?". This essentially negates the results. In addition, one of the exclusion criteria is non-responders to an equivalent dose of 150mg of amitryptilline. (Did this include SSRI's?). Knowing that SSRI's and TCA's are similar in efficacy, basically we are comparing responders to St John's Wort to non-responders to TCA's/SSRI's, and even so, they worked out almost the same! I would love to see this trial repeated with better methodology. Competing interests: None declared |
|||
|
|
|||
|
Stevie M Gamble, retired HMIT EC2Y 8BL
Send response to journal:
|
Nicholas D. Moore, in his rapid response of 4th March on the paper by A Szegedi et al, states: ‘In the case of St John's wort, there seems to be some kind of strange scientific limbo that contrasts this "natural" ingredient with the "chemicals" used to treat depression, eg tricyclics, or SSRI.’ The use of inverted commas suggests that he is quoting from the paper, which contains no such terms, and no such suggestions. This is at best misleading, and at worst disingenuous. He goes on to say that ‘…the BMJ has rejected some of my work on plant extracts, on the basis, among many other failings, that I didn't know what was in them.’ I note that where the BMJ leads the Food and Drug Administration follows, having ordered the seizure of GlaxoSmithKline's Paxil CR tablets today on the grounds that the tablets: ‘could split apart and patients could receive a portion of the tablets that lacks any active ingredient, or alternatively a portion that contains active ingredient and does not have the intended controlled- release effect.’ http://www.fda.gov/bbs/topics/news/2005/NEW01162.html Stevie M Gamble Competing interests: None declared |
|||
|
|
|||
|
Billy Boland, Clinical Teaching Fellow Dept. of Mental Health, St. George's Hospital Medical School, Cranmer Terrace, London, SW17 0RE
Send response to journal:
|
The authors have chosen to define moderate to severe depression as 22 or greater on the 17 item Hamilton depression scale. It is of note that it is unclear from their paper as to why this value has been used, or whether it in fact correlates to 'Gold Standard' ICD 10 or DSM IV derived definitions of moderate or severe depression. It should be assumed therefore that the diagnosis has been made on a clinical basis only, increasing the potential of observer bias. The same argument could be made for identifying those who were excluded. This weakness could have been avoided. Use of a structured or semi- structured interview such as the CIDI (Composite International Diagnostic Interview) or SCAN (Schedules for Clinical Assessment in Neuropsychiatry) could be used to obtain relevant data. The subsequent use of an appropriate software package could produce a diagnostic classification with more robust validity and reliability. This may have required more time and expense for the research team, but could have had a significant impact on the quality of the results. Competing interests: None declared |
|||
|
|
|||
|
Paul G Champion, n/a Southall UB2 4UP
Send response to journal:
|
If this study means that SJW is about to eat deeply into some of the profits of the Pharmaceutical Industry, should not the Medicines and Healthcare Products Regulatory Agency take steps to have it banned -- as it did with Kava Kava? Competing interests: None declared |
|||
|
|
|||
|
Samantha Line, Research student in psychopharmacology The University of Oxford, OX1 3BN
Send response to journal:
|
Nicholas Moore makes an important point -
"In the case of St John's wort, there seems to be some kind of strange scientific limbo that contrasts this "natural" ingredient with the "chemicals" used to treat depression, eg tricyclics, or SSRI. There has to be an active ingredient in St John's wort, that needs to be characterized chemically and pharmacologically" If a drug (herbal or "chemical") has an effect, it must have a pharmacological action. Although the mechanism of action of St John's wort isn't fully characterised (it may or may not be an SSRI), it certainly acts through effects on the serotonin system, and the strong likelihood is that the active compound binds to one or more transporter, receptor or enzyme, in the same way that prescribed antidepressants do. I’ve never understood the widespread belief that if a drug comes from a plant the it must be better for you than drugs which have been specifically developed to treat an illness. In actuality, St John's wort is a very "dirty" drug (i.e. it has many other effects as well as the intended one, which is likely to be caused by the variety of chemical compounds it contains and the fact that these are likely to each have their effects on the body). This is especially evident with the marked increase in activity of liver enzymes it causes, and the resultant reduction in the effect of oral contraceptives, anticonvulsants, cardiovascular treatments and antivirals among others. I often wonder about how many epileptic seizures and unwanted pregnancies have resulted from people thinking that because St John's wort is a "natural" drug, it has no adverse effects. In short, for a herbal medicine such as St John's wort to be effective, it must have an active compound with a pharmacological effect. However, alternative therapies derived from plant extracts tend to contain many chemical compounds, and as a result have complex - and often messy - pharmacology. Thus, because they haven't been designed for a specific purpose, herbal medicines can be prone to many adverse effects, and are not the innocuous and harmless therapies that they are often perceived to be. Competing interests: I research the pharmacology of depression, including the neurochemical changes involved in the disorder and the effects of antidepressant drugs |
|||
|
|
|||
|
David A Forbes, Pharmacist Nanaimo Regional General Hospital, Nanaimo, BC, Canada
Send response to journal:
|
Remission is defined in the statistical methods, sample size section. "For the Hamilton total score, we defined response as a decrease in total score of 50% from baseline and remission as a score 10 points at week six." Competing interests: None declared |
|||
|
|
|||
|
David Forbes, Pharmacist Nanaimo, BC, Canada
Send response to journal:
|
I believe the run-in period used placebo - not active St. John's Wort. In fact, the paper describes the use of both a St. John's Wort placebo and a paroxetine placebo during the 3-7 day run-in. I assume the purpose of the run-in was to exclude early responders that may not, in fact, have a moderate to severe depression. It would also exclude those who would be unlikely to be compliant early in the trial, causing an unnecessary sample size slippage. The exclusion criterion re: amitriptyline seems to be an effort to exclude those suffering from a refractory depression that may be unlikely to respond to either therapy. Results, therefore, not applicable to refractory depression. I don't quite see how this selects St. John's Wort responders. Competing interests: None declared |
|||
|
|
|||
|
David Forbes, Pharmacist Nanaimo, BC, Canada
Send response to journal:
|
It seems that the necessity of a placebo controlled trial for the treatment of a condition that has proven effective therapies is controversial. It does seem unethical to treat moderate to severe depression with a placebo. Our real question is not whether St. John's Wort is better than placebo. Our question is whether it is as good or better than currently effective therapies. A well designed trial with an active control should be valid for comparing treatment effects. This one sided non-inferiority trial addresses the real question without wasting time and money on a placebo arm or subjecting depressed patients to placebo when there are ample effective therapies available. The previous trial mentioned involving St. John's Wort, sertraline and placebo is problematic. I do note that the extracts used in the two trials differ. The previous trial used an extract containing only hypericin. This trial uses an extract containing hypericin and hyperforin. There is some evidence that hyperforin is the active compound and that hypericin has little antidepressant effect. e.g. The antidepressant mechanism of Hypericum perforatum. Life Sci. 2004 Jul 16;75(9):1021-7. Review Perhaps this could explain the lack of effect in the previous trial. As for sertraline, it seems the dosing may have been a little conservative with plenty of room for increased dosages, possibly contributing to a lack of effect. Competing interests: None declared |
|||
|
|
|||
|
Henricus G Ruhe, MD, Psychiatrist Program for Mood Disorders, Dept of Psychiatry AMC/De Meren, Tafelbergweg 25, 1105 BC, Amsterdam, Mascha C. ten Doesschate, Aart H. Schene
Send response to journal:
|
To the editor Dear Sir, The randomized controlled trial by Szegedi et al. (1) probably promises more than can be expected from Hypericum The authors demonstrate non-inferiority of Hypericum compared to paroxetine, with a significant larger decrease in Hamilton (HDRS) score at study endpoint for Hypericum (difference of 3 points (0.8-5.2)), a nonsignificant increased response rate (NNT= 10 (4.4-infinity)) and a significant remisson rate (NNT= 7 (3.7-40.3)). We think the design of the study may have contributed to the findings. First problem is the absence of a placebo-arm. As found in earlier Hypericum trials and summarized in a recent meta-analysis of Linde et al. (2) the superiority of Hypericum against placebo is equivocal, especially in more precise trials restricted to patients with major depressive disorder (pooled RR 1.15 (1.02-1.29). The high inclusion criterion of a Hamilton Depression Rating Scale (HDRS) >=22 in the trial by Szegedi is reassuring, however a closer inspection of these criteria and table 1 provides doubt as patients with a relatively short duration of current episodes (>=2 weeks) were included, and the median duration of their depressive episodes indeed was 4.7 months. Due to the natural course of major depressive disorder, 63% of patients recover in 6 months (3) in an unselected population. This and previous findings (4;5) should have urged the authors to include a placebo-arm, despite their ethical concerns. Second problem with a potentially negative bias against paroxetine is the decision to double the dose of paroxetine 2 weeks after the start of treatment. Although often applied this is an irrational strategy (6), and this might increase drop-out due to side-effects (7). Maybe for Hypericum a high dose is warranted, but for paroxetine this may have biased the results as (more disadvantageous) last observations of those dropped-out are carried forward in the analyses. Maybe this effect fully explains the significant difference in remission rates between Hypericum and paroxetine. Unfortunately the authors did not state the number of drop- outs to overcome this major concern. Finally the importance of this trial should be reconsidered with the recent meta-analysis by Linde et al. (2) in mind. If the results of this trial are added to their meta-analysis (fig. 5), the RR slightly changes from 0.98 (0.85-1.12) to 1.03 (0.92-1.15). All together we think Hypericum extracts should first be tested against the same standards that are requested for conventional drugs before their registration by the FDA and the EMAE. Further fixed dose studies against placebo are warranted, and in future head-to-head comparisons a placebo-arm is obligatory. References 1. Szegedi A, Kohnen R, Dienel A, Kieser M. Acute treatment of moderate to severe depression with hypericum extract WS 5570 (St John's wort): randomised controlled double blind non-inferiority trial versus paroxetine. BMJ 2005;330:503-507. 2. Linde K, Berner M, Egger M, Mulrow C. St John's wort for depression: meta-analysis of randomised controlled trials. Br J Psychiatry 2005; 186:99-107. 3. Spijker J, de Graaf R, Bijl RV, Beekman AT, Ormel J, Nolen WA. Duration of major depressive episodes in the general population: results from The Netherlands Mental Health Survey and Incidence Study (NEMESIS). Br J Psychiatry 2002; 181:208-213. 4. Hypericum Depression Trial Study Group. Effect of Hypericum perforatum (St John's wort) in major depressive disorder: a randomized controlled trial. JAMA 2002; 287:1807-1814. 5. Storosum JG, van Zwieten BJ, van den BW, Gersons BP, Broekmans AW. Suicide risk in placebo-controlled studies of major depression. Am J Psychiatry 2001; 158:1271-1275. 6. Benkert O, Szegedi A, Wetzel H, Staab HJ, Meister W, Philipp M. Dose escalation vs. continued doses of paroxetine and maprotiline: a prospective study in depressed out-patients with inadequate treatment response. Acta Psychiatr Scand 1997; 95:288-296. 7. Dunner DL, Dunbar GC. Optimal dose regimen for paroxetine. J Clin Psychiatry 1992; 53 Suppl:21-26. Competing interests: None declared |
|||
|
|
|||
|
Dr. Murali Krishna, Specialist Registrar, Old age Psychiatry. Mossley Hill Hospital, Park Avenue, Liverpool L18, Dr. veera macheneni
Send response to journal:
|
Dear Editor, I read with interest Szegedi et al and several on line rapid responses to the article which have followed since. I would like to highlight certain issues of clinical importance in relation to St. John’s Wort. First of all, it is not licensed in the UK for treatment of depression. However St. John’s Wort is widely used as self-medication. In addition, St. John’s Wort presents potentially serious drug interactions. It can induce metabolism of Anti convulsants, Anti HIV drugs, Cyclosporin, Oral contraceptives, Theophylline, Digoxin and Warfarin, reducing their efficacy and therefore should not be taken in combination with any of these (CSM warning 2000). Due to minor serotonin, nor adrenaline and dopamine reuptake inhibitory activity St. John’s Wort potentiates existing MAOI (Mono amine oxidase inhibitor), SSRI (selective serotonin re uptake inhibitor) and Tricyclic Antidepressant therapy and therefore, concurrent use of St. John’s Wort is best avoided, particularly at higher doses. Serotonin syndrome and other serious adverse effects including toxicity have been reported with St. John’s Wort. St.John’s Wort may exacerbate bipolar disorder by inducing mania. Safety of St. John’s Wort in children, pregnancy and in the elderly is not well established. Antidepressant effect of St. John’s Wort in severe depression is still disputed. Clinicians should be fully aware of these issues whilst treating patients taking St. John’s Wort. Refernces: 1. Psychotropic Drug Directory (2003 –04), Stephen Bazire 313-315. 2. Drug Information Handbook 2000, Fuller 958. 3. Szegedi et al. Acute treatment of moderate to severe depression with St. John’s Wort. BMJ Mar 2005. Competing interests: None declared |
|||
|
|
|||
|
Adam Jacobs, Director Dianthus Medical Limited, London SW19 3TZ
Send response to journal:
|
I would like to congratulate Szegedi et al on an excellent article, which I found a pleasure to read. The consistency of their results across different outcome measures and analysis populations makes it hard to disagree with their main conclusion that 6 weeks of treatment with St John's wort is at least as effective as paroxetine. I look forward with interest to reading the report of their follow-up study and learning whether that efficacy is maintained in the long-term. However, I do have one minor criticism of the statistical methods used for the adverse event data. The confidence interval for the incidence rate ratio appears to have been calculated based on the assumption that adverse events were statistically independent, but since a single patient can have more than one adverse event, that assumption is unwarranted. A correct calculation of the confidence interval around the incidence rate ratio would take account of the non-independence of adverse events within patients, and would doubtless produce a wider confidence interval than the one they report. My guess is that it would still show a significant difference between the treatments, but it would be interesting if Szegedi et al could re-calculate the confidence interval taking account of the clustering by patient and report it as a rapid response. ajacobs@dianthus.co.uk Competing interests: My company has provided consultancy services to GlaxoSmithKline, although not on any projects relating to paroxetine. |
|||
|
|
|||
|
Srinivasan Ravi, Consultant Surgeon Blackpool FY3 8NR
Send response to journal:
|
Wort a day! Some time ago, the New Scientist carried an article on the benefits of Omega 3 fatty acids in preventing depression. It quoted the example of Japanese who have a very low risk of depression. It was believed that the low risk is due to their high consumption of oily fish. Studies were then done with omega 3 dietary replacement and showed a drop in depression. It makes me wonder if increasing the consumption of oily fish in diet would reduce the risk of depression in society and add a new slogan of 'fishy five a day'. Competing interests: None declared |
|||
|
|
|||
|
Arun S Nanivadekar, Medical Research Consultant C-2 Flushel Apts, 21 Road, Bandra (W), Mumbai 400050, India
Send response to journal:
|
The authors state that the extract of St Jonh's wort, WS 5570, was standardized to contain 3-6% hyperforin and 0.12-0.28% hypericin. This means a variation of 100% for hyperforin and 133% for hypericin. Would we accept a similar variation in the potency of paroxetine tablets, namely, 20-40 mg? I doubt it. The conclusions of the study, therefore, are untenable. Competing interests: None declared |
|||
|
|
|||
|
Howard Mann, Faculty Member University of Utah School of Medicine
Send response to journal:
|
The published Rapid Responses so far to this paper express a variety of concerns about methodologic and ethical aspects of the randomized controlled trial (RCT) reported by Szegedi and colleagues. Respondents have questioned the choice of the comparator intervention (active agent rather than a placebo) ; the use of a placebo run-in period; the dose of the comparator agent (paroxetine) ; the extract of Hypericum used; and potentially wide variations in the amount of active agents (hyperforin and hypericin) in the Hypericum preparation. As is typically the case with debate of this kind, some contentions are pertinent, while others betray substantive misunderstandings of the conduct and interpretation of RCTs. It is unfortunate that Szegedi et al. did not use the
Discussion section of their report to discuss the trial’s results in the
context of what is known about the merits of Hypericum in the treatment of
depression. Fortunately, Ruhe et al. [1] alerted us to the presence of an
up-to-date Systematic Review [2] relevant to this issue. Has the uncertainty
regarding Hypericum’s clinical utility been resolved? What may we learn from
all this? In reading the cited review by Linde et al., one is struck
by the Abstract’s conclusions : Current
evidence regarding Hypericum extracts is inconsistent and confusing. In
patients who meet criteria for major depression, several recent
placebo-controlled trials suggest that Hypericum has minimal beneficial while other trial suggest that
Hypericum and standard antidepressants
have similar beneficial effects. This, in spite of the fact that the
reviewers identified 37 suitable trials for analysis. The
authors identify prevalent methodologic weaknesses such as inadequate sample
sizes, improper dosages of control drugs, and inadequate quality control of
administered herbal extracts. Like
Szegedi et al., they finally express a distressingly familiar refrain : that “…more
trials that compare specific extracts with both placebo and synthetic
antidepressants in clearly defined patient populations with and without major
depression are needed.” Why has all the
research performed to date not resolved the therapeutic research question ? The answer, I believe, derives in large part from
the prevalence of poor quality clinical research performed by the psychiatric
community. In addressing the recent controversy surrounding the merits
of anti-depressants in childhood depression, Peter Kramer, psychiatrist and
author, has written[3] : It may just be that
Prozac is more effective than Paxil in young patients. But it is also possible
that the difference in the research results has less to do with the medication
than with the nature of the studies. It turns out that drug companies are
shockingly inept at testing their own products. When independent
psychiatrists and psychologists look at data submitted to the Food and Drug
Administration—the results of corporations' early studies on their own
antidepressants—the medications look only modestly effective. But these
findings always strike me as suspect, since the same antidepressants have
proven highly useful in treating recalcitrant kinds of depression, such as
depression after strokes and post-partum depression. Why would the medications
fail only in research on the run-of-the-mill mood disorders? There are a number
of answers to this puzzling question, but mostly it comes down to this: The
pharmaceutical companies do shoddy research on the
drugs' efficacy. Because the patents on medication have a limited duration, the
corporations are always in a rush to bring drugs to market. The companies
pressure the subcontractors that perform the studies, demanding that they
gather research subjects fast. The recruiters then stretch diagnostic criteria,
signing up patients who may not have the disease in question. Studies often
include people with a host of shifting complaints, many of which are based less
on acute illness than on personality style. The result is a group with poorly
defined conditions and high placebo response rates—enough static to drown out
whatever effects the medications have on substantial disease. Drug company
studies can have other problems. Sometimes they are conducted before the proper
dosage or length of treatment has been established. Inexact dosing leads to low
rates of response, or to excessive side effects—and a tendency for subjects to
drop out of a study. These and other study design defects tend to make
medications appear less effective than they prove in clinical practice or in
later research. Notably,
other active members of the psychiatric community have voiced similar concerns.
Two examples should suffice. Safer [4] has detailed the myriad ways in which
the validity and informativeness of psychiatric research is undermined by poor
trial methodology and reporting, and conflicting interests. Klein and
colleagues (cited by Kramer) made many similar points in a 2002 article [5],
and even called for the establishment of a putatively independent “Federal Proactive Pharmaceutical
Agency” to remedy this distressing situation. It
is time for national professional psychiatric societies to lay aside any and
all parochial and proprietorial interests, and collaborate with each other and
other independent actors to promote the performance of scientifically valid and
ethical research. Psychiatric investigators need to develop a standard
methodology for conducting psychiatric RCTs that will produce internally valid
results in which patients and their physicians will have confidence. In this,
they would do well to collaborate with members of the CONSORT group, taking notice also
of recently published and upcoming CONSORT guidance for the conduct and
interpretation of non-inferiority trials, the proper elicitation and reporting
of harms in RCTs, and the conduct of trials using herbal interventions. In
formulating such guidance, psychiatric investigators also need to consult with
knowledgeable representatives of the patient and research ethics communities. Patient
representatives (secured, for example, through collaboration with groups such
as the James Lind Alliance)
should clarify which research is most relevant to them; which interventions are
suitable comparators for particular trials; which clinical endpoints are
important to them; which patients should be recruited for a particular trial
(for example, patients in whom “standard” drug
therapy has been tried and has failed may ethically be recruited for a
placebo-controlled trial); how long trials should be run; and should help
define clinically relevant non-inferiority and superiority margins for the
analysis of a trial’s results. Research
ethics committees should not acquiesce to this lamentable state of affairs by
approving trials that do not meet universal requirements for the ethical
conduct of research : social and scientific value; scientific validity; fair
subject selection; a favorable balance of harms and benefits; informed consent;
and respect for potential and enrolled volunteers [6]. Among the ethical
disputes that still need to be addressed are the unethical conduct of
single-blind placebo run-in periods [7], and the circumstances in which a
placebo instead of an active comparator intervention may ethically be used [8].
A collaboration should produce a checklist for
psychiatric RCTs that research ethics committees should uniformly use in the
evaluation of proposed trials. References
1.Ruhe HG, et
al. Acute
treatment of depression with hypericum versus paroxetine reconsidered 2. Linde K, Berner M, Egger M, Mulrow C. St John's
Wort for depression: meta-analysis of randomised controlled trials. Br J
Psychiatry 2005; 186:99-107. 3. Kramer PD. Should
teenagers take drugs ? Slate.
June 4, 2004. 4. Safer DJ.
Design and reporting modifications in industry-sponsored comparative
psychopharmacology trials J Nerv Ment Dis 2002; 190: 583-592 5. Kline DF, et al. Improving
clinical trials Arch Gen Psychiatry 2002; 59: 272-2786. 6. Emanuel EJ, et al. What makes clinical research ethical ? JAMA 2000; 283: 2701-2711 7. Senn S. Are placebo run ins justified
? BMJ 1997; 314: 1191 Competing interests: None declared |
|||
|
|
|||
|
Keay G Smith, Occupational Physician Self-employed RG40 1TQ
Send response to journal:
|
Having taken Hypericum extract myself for a mild depressive illness I feel one of the side-effects should be better known.
After being on 1-2 300mg tablets for a couple of months (and feeling its benefit in terms of the depression) I developed episodes of severe tachycardia. A 24-hour ECG showed runs of atrial fibrillation with ventricular rates of up to 168/min. Full investigation was (fortunately) normal and the episodes ceased completely shortly after I stopped taking the tablets.
I believe that this side-effect has been the subject of several reviews.
Competing interests: None declared |
|||
|
|
|||
|
Daniel Sher, Licensing Executive 20145 Milan
Send response to journal:
|
Sirs:
The reader of a study final report can only assess its internal consistency, but cannot determine whether the original data had been altered, intentionally or by mistake. In the case of clinical trials sponsored by pharmaceutical companies, who most often utilize Contract Research Organizations, all data undergo several controls. Without listing all the obligations, it is worth mentioning that during the course of the study clinical sites are regularly inspected by professional clinical monitors and that during data analysis every single piece of information is double-checked to ensure that it is correctly transcribed from the clinical record, onto the case report form, and into the computer. Potential from bias is particularly strong when a commercial interest is involved. Formal declarations by investigators, monitors and company sponsors might not be worth the paper on which they are written, were it not for the fact that the whole process is reviewed by Regulatory Authorities, who may disqualify investigators and penalize sponsors and monitors. Are clinical trials on herbal remedies subjected to the same scrutiny? Competing interests: None declared |
|||
|
|
|||
|
K. M. Phillips, Research Scientist Virginia Tech, Blacksburg, VA 24060
Send response to journal:
|
I believe that the dose of the hyperforin in the tablets was misunderstood by the author of a previous Rapid Response. It appears from my reading of the article that the content did not vary from 0.3 to 0.6%, but rather there were tablets of two potencies (0.3 and 0.6%) so that if an increase in dose of hypericum were made at two weeks, as described in the protocol, the change would be blinded (i.e. no change in the number and size of tablets). Competing interests: None declared |
|||