Rapid Responses to:
|
|
Rapid Responses: Rapid Responses published:
-
![[Read Rapid Response]](/icons/misc/sectionDOWN.gif)
What is a valid measure of antidepressant efficacy in primary care?
- Andrew Thornett (10 December 1999)
-
comments on the controlled trial of hypericum in depressive illness
- Alan M W Porter (13 December 1999)
-
Naturalistic studies are needed
- Mike Walton (13 December 1999)
-
Use of placebo in depression trial unethical
- Andrew Vickers (5 January 2000)
-
The herbalist will see you now
- David B Menkes (6 January 2000)
-
Much work still needed on St. John's Wort
- Tim Gorski (16 January 2000)
-
St. John Wort
- M E J Wise (11 August 2000)
-
Drug interaction of tea containing St. John´s wort with ciclosporin
- Dominik M Alscher (14 June 2001)
|
|
|||
|
Andrew Thornett, Clinical Research Fellow Department of Psychiatry, University of Southampton
Send response to journal:
|
The study comparing Hypericum extract and imipramine or placebo by Phillipp et al. In this week's BMJ appears to demonstrate that Hypericum is as effective at treating moderate depression as impramine1. This impression is strengthened by the design of the study, which is double- blind, randomised and placebo-controlled, using a widely used medication as a comparator, and using globally-accepted depression scales including the Hamilton depression score. However, Linde and Berner2 in the accompanying commentary question the efficacy of Hypericum because of its use in relatively large doses and its comparison with low doses of standard antidepressants. They feel that these, together with the effect of unblinding on outcome, should be taken into account in the analysis of the results. The basis of this criticism is the lack of universal consensus on how antidepressant effects should be measured in primary care. Difficulty arises because lower doses are often used to treat patients who may be less depressed than those seen in secondary care, and the treatments themselves may be more important as an adjunct to the doctor-patient interaction than as a therapeutic intervention alone. Patients, too, may prefer to use treatment options that they see as more natural, including Hypericum, and doctors are beginning to accept the importance of supporting patients' choices3. Linde and Berne do not consider that most general practitioners use 20mg of fluoxetine when treating depressed individuals, and few are prepared to increase the dose beyond this level. This reluctance is less likely to be present with a treatment which is seen as part of alternative medicine and less likely to produce side-effects. Further, in practice both patients and doctors know which medication has been prescribed, and the pragmatic nature of Philipp et al.'s trial reflects this, making the results more applicable to the situation in which the medication will be used. These difficulties in interpreting results of trials in general practice populations will only be solved when a primary care based system of measuring efficacy is developed that is relevant to this population and the treatment it receives. Reference List 1. Philipp MKRHK-O. Hypericum extract versus imipramine or placebo in patients with modrate depression: randomised multicentre study of treatment for eight weeks. BMJ 1999;319:1534-8. 2. Linde K,.Berner M. Commentary: Has Hypericum found its place in antidepressant treatment? BMJ 1999;319:1539. 3. Zollman C,.Vickers A. ABC of complementary medicine: Complementary medicine and the doctor. BMJ 1999;319:1538-61. |
|||
|
|
|||
|
Alan M W Porter, retired general practitioner n/a
Send response to journal:
|
Trials of antidepressant drugs from general practice are to be welcomed for depression is very much a primary care disorder. I wish to comment on the placebo and imipramine controlled trial of Hypericum reported by Philipp and his colleagues. I have four misgivings about the reported study. The first relates to the relatively crude method used to check compliance with drug intake. First, were the tablets counted in front of the patients so that they may have gained insights and perhaps disposed of surplus tablets before the next visit? More subtle methods exist to check compliance (Porter 1969). Second, why were only 46 patients (17%) randomised to the placebo group out of a total of 263? It should have been about a third and the discrepancy remains unexplained. Third, how can they claim that for imipramine they found a strong tendency for it being more effective than placebo after six weeks of treatment, when the comparison was not significant at the 0.05 level? Fourth, did the authors seek the permission of an ethical committee before retaining an attempted suicide in a blinded study? It is sad to learn that tricyclics are still widely prescribed in Germany. These drugs are toxic and no more effective than a placebo for the sort of depression which is so common in primary care (Porter 1970). I believe that Linde and Berner, in their commentary, are wrong to regard tricyclics as the 'gold standard'. Usually the doctor needs only to prescribe himself and an inexpensive placebo and await the almost inevitable remission, which usually occurs within three weeks. Alan MW
Porter
Porter AMW. Drug defaulting in a general practice. BMJ 1969;1:218- 22. Porter AMW. Depression in general practice. A demographic study and a controlled trial of impramine. BMJ 1970;1:773-78. |
|||
|
|
|||
|
Mike Walton, General Practitioner Harvey Group Practice, St Albans,
Send response to journal:
|
Philipp et al address an important question in attempting to test the effectiveness of hypericum extract in treating mild to moderate depression in a primary care setting. Here in the UK, General Practitioners see and treat the majority of depressive illness. Narritive experience of patients often illustrates that they have already tried - or intend to try St John's Wort or other products for their depression. As a working GP, trying to practice Evidence Based Mental Health care, it is challenging to be able to answer the patient who asks ones advice about 'will St John's Wort work better than fluoxetine (or citalopram or whatever) doctor?' Like many of my GP colleagues - I welcome such research. However, I have concern over the ultimate applicability of research findings to the natural world of primary care. The authors themselves comment "Since hypericum products may vary considerably in composition ... the results cannot be generalised to other extracts" and also "the tested daily dosage of 1050 mg extract, which is equivalent to 6 g of the crude herb, is higher than that recommended". Given that patients who choose to treat their depression with hypericum products frequently buy the product directly over the counter, there is currently little control over or knowledge about the real-life doses taken by those who try this remedy. We need to see what is the actual effective dose to be able to counsel our patients accordingly. Furthermore, one hopes to see more responsibility from the manufacturers and marketers who promote these various products. Far too often the money spent on promoting a health product freely available over the counter is inversely proportional to the evidence of its efficacy. Let us hope to continue to see more quality research on the effectiveness of hypericum to enable us to give a clear message to our patients (No competing interests) |
|||
|
|
|||
|
Andrew Vickers, Assistant Attending Research Methodologist Integrative Medicine Service, Memorial Sloan-Kettering Cancer Center
Send response to journal:
|
Though the reported trial is a valuable addition to the literature on St John's Wort, I believe it to be unethical. The Declaration of Helsinki is quite explicit that patients in a clinical trial should be given the best proven medical care. In the St John's Wort trial, some patients with depression were denied effective treatment with anti-depressant medication as a result of being allocated to placebo. According to the authors, one of these patients attempted to commit suicide. Ethical committees should not approve such trials and patient should not consent to take part in them. |
|||
|
|
|||
|
David B Menkes, Liaison Psychiatrist Dunedin Hospital, New Zealand
Send response to journal:
|
Psychiatrist and GP ambivalence about herbal remedies will persist, despite the well designed trial of Philipp et al (11 December 1999) which shows hypericum (St John's wort) extract comparably effective to imipramine in the treatment of depression. Complementary and conventional treatments in psychiatry do clash, particularly in the English-speaking world, not least because of practitioner attitudes and prejudice [1]. Nonetheless, a strong case can be made that we do need to be familiar with such treatments simply because increasing numbers of our patients are attracted to them and may seek our advice. Significant illnesses such as major depression are best treated by a competent doctor, irrespective of whether the treatment is conventional. Hypericum extracts have Cochrane-proven efficacy in mild to moderate depression [2], and despite received wisdom of a 'weak' antidepressant effect, may also be effective in severe depression if titration above the usual dose is allowed. Unquestionably the main advantage of hypericum extracts is their tolerability: side-effects are even milder than those of the SSRIs, with notably less sexual dysfunction. Interestingly, hypericum extracts appear to act like SSRIs in terms of possible interaction with MAOIs, and (like most antidepressants) may provoke mania in patients with a bipolar tendency. As with any active treatment, it is important that appropriate cautions are given -- in this case with regard to ingestion during pregnancy or in combination with MAOIs. Some of the justifiable skepticism about hypericum arises from the myriad of different preparations available, and Philipp et al rightly emphasize that their findings cannot be generalized to other extracts. Standardization is attempted by the more reputable suppliers, generally with respect to hypericin and pseudohypericin content ('total hypericins'). Hypericins are weak inhibitors of MAO-A, but now appear to be less important to antidepressant action than other constituents of the herb, notably hyperforin [3]. Consistent with the clinical profile of hypericum extracts, hyperforin enhances the synaptic availability of serotonin, as well as dopamine and noradrenaline [3,4]. It is not widely appreciated that hypericins and hyperforin also differ in their relative concentrations across the growth cycle of the herb, the latter being far more abundant toward the end of flowering [5]. The unfortunate conclusion is that current standardization (with respect to hypericins) may correlate poorly with clinical potency (more likely due to hyperforin). This may explain the 'modest' or 'weak' results seen with some extracts, and indicates both the importance of further research and the urgent need for better standardization. It is to the credit of Steiner Arzneimittel (suppliers of the extract used by Philipp et al.) that hyperforin as well as hypericin content is specified. The efficacy, tolerability and popular appeal of hypericum pose a real challenge to conventional medicine. It seems inescapable that, like it or not, doctors require an up-to-date, working knowledge of effective herbal treatments -- otherwise we will be eschewed by patients we could benefit. Conflict of interest: none 1. Walter G, Rey J. The relevance of herbal treatments for psychiatric practice. Australian and New Zealand Journal of Psychiatry 1999;33:482-9. 2. Hotopf M. Review: St. John's wort is more effective than placebo for treating depressive disorders. Evidence-Based Medicine 1999;May/June:82. 3. Chatterjee SS, Bhattacharya SK, Wonnemann M, Singer A, Muller WE. Hyperforin as a possible antidepressant component of hypericum extracts. Life Sciences 1998;63:499-510. 4. Kaehler ST, Sinner C, Chatterjee SS, Philippu A. Hyperforin enhances the extracellular concentrations of catecholamines, serotonin and glutamate in the rat locus coeruleus. Neuroscience Letters 1999;262:199- 202. 5. Martonfi P, Repcak M. Secondary metabolites during flower ontogenesis of Hypericum Perforatum. Zahradnictvi 1994;21:37-44. |
|||
|
|
|||
|
Tim Gorski, Associate Clinical Professor North Texas Health Science Center private practice, Arlington, TX
Send response to journal:
|
The report by Philipp et. al. [BMJ 1999; 319: 1534-1539] offers additional helpful confirmation that St. John's Wort offers potential benefits in the treatment of depression. But what is now needed is not more clinical studies on raw extracts. Rather, what is now needed is to isolate and characterize the active substance(s) and to determine their likely pharmacological site and mechanism of action, their pharmacokinetics, and their metabolic fate. This is no more and no less than what has been done in the case of numerous other useful medications of plant derivation, from opium to salicylates. It is also the only way to evaluate the potency, stability, duration of action, toxicity, and potential for drug interactions of the active substance(s), whatever it or they are. If the past is any guide, it is also the only way to further and deepen our understanding of human health and disease and to show the way to better therapeutic agents. Sincerely, Tim Gorski MD (Associate Editor, The Scientific Review of Alternative Medicine) |
|||
|
|
|||
|
M E J Wise
Send response to journal:
|
Dear Editor - The recent article by Phillip, Kohnen and Hiller (1) on the efficacy of St.John's Wort raises the public profile of all alternative medicines. Journals have highlighted the risk of interactions with conventional medicines (2,3). Medical practitioners may be comforted to know that alternative health practitioners (AP) are now under a more clearly defined duty of care to their patients. Since the case of Shakoor v Situ (4) there has been a change in the case law. In his judgement, Mr. Livesey QC listed several implications of prescribing a "…remedy, be it chemical or herbal, for internal consumption.". These were that AP's were holding themselves as competent to practice within a system of law and medicine, which would review the standard of care given to a patient. Secondly that it was not enough to say that the remedy was traditional and believed not to be harmful; the AP had a duty to ensure that it was not actually or potentially harmful. Thirdly that the AP should take steps to ensure that there had not been any reports in any journal of adverse effects of that remedy which ought to affect its use. Membership of an association that arranged to search the relevant literature and promptly report any material publication would be adequate protection. Thus whilst doctors should still ask patients about all medicines that they take, they should receive better care from their AP. Dr M E J Wise
1. Phillip M, Kohnen R, Hiller K-O. Hypericum extract versus imipramine or placebo in patients with moderate depression; randomised multi-centre study of treatment for eight weeks. BMJ;319: 1534-9. (11 December 1999) 2. Johne A. Interactions of Hypericum perforatumClinical Pharmacology & Therapeutics 1999; 66:338-45. 3. Fugh-Berman A. Herb Drug Interaction. The Lancet 2000; 355: 134- 138. 4. K. O'Hanlon. Standard by which to judge alternative practitioner. Shakoor v Situ. The Independent, 25/5/00 |
|||
|
|
|||
|
Dominik M Alscher, Physician/ Nephrology Robert-Bosch-Hospital, Stuttgart, Germany
Send response to journal:
|
Letter to the editor Drug interaction of tea containing St. John’s wort with ciclosporin Sir- as recently pointed out by Linde and Berner (1) hypericum extracts are widely prescribed antidepressants and their popularity is increasing in many countries. Little information exists regarding the safety of these herbal agents, including potential drug interactions2. In several case reports it has been shown that St. John´s wort (Hypericum perforatum) can induce drug metabolism and thus leads to a reduction in ciclosporin blood concentrations with the risk of acute transplant rejection (3-5). In a kidney transplant patient (57-years-old, 70 kg, serum creatinine 1.1- 1.3 mg/dl) with long-term regular ciclosporin (125-150mg/day) and prednisolon (5mg/day) intake, routinely monitored blood levels of ciclosporin constantly varied within the last 2 years between 100 and 130 µg/l (trough steady state concentrations). At the beginning of this year, his blood levels suddenly fall to values around 70 µg/ml despite elevating the daily dose up to 250mg. Surprised by these low blood concentrations, the patient was thoroughly checked for any suspicious comedication and initially no putative agent could be verified. Later the patient briefly mentioned that he had started to drink regularly a tea mixture (Greek remedy), which turned out to contain St. John’s wort and which effectively controlled his seasonal depressive symptoms. The patient was requested to stop drinking this special tea. Five days later, blood levels of ciclosporin increased from 70 to 170 µg/l (250mg/day) and subsequently dosage was reduced to 175mg/day resulting in trough steady state blood levels around 130 µg/l. This case again illustrates that intake of (local) remedies might result in uncontrolled variations of ciclosporin blood concentrations, which can have important clinical implications for patients needing this immunosuppressant. Consequently, all physicians should be aware that even (special) tea mixtures have the potential to affect the pharmacokinetics and pharmacodynamics of concomitantly given drugs. In addition, therapeutic plasma level monitoring (TDM) will help in identifying drug interactions. D.M. Alscher, U. Klotz* Robert-Bosch-Hospital and *Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology D-70376 Stuttgart, Germany 1.Linde K, Berner M. Commentary: Has hypericum found its place in antidepressant treatment? Br Med J 1999; 319: 1539. 2.Greeson JM, Sanford B, Monti DA. St. John's wort (Hypericum perforatum): a review of the current pharmacological, toxicological, and clinical literature. Psychopharmacology 2001; 153(4): 402-14. 3.Ruschitzka F, Meier PJ, Turina M, Lüscher TF, and Noll G. Acute heart transplant rejection due to Saint John's wort. Lancet 2000; 355: 548-9. 4.Breidenbach T, Hoffmann M W, Becker T, Schlitt H, Klempnauer J. Drug interaction of St John's wort with cyclosporin. Lancet 2000; 355: 1912. 5.Breidenbach T, Kliem V, Burg M, Radermacher J, Hoffmann MW, Klempnauer J. Profound drop of cyclosporin A whole blood trough levels caused by St. John's wort (Hypericum perforatum). Transplantation 2000, 69: 2229-32. |
|||