Hypericum extract versus imipramine or placebo in patients with moderate depression: randomised multicentre study of treatment for eight weeksCommentary: Has hypericum found its place in antidepressant treatment?
BMJ 1999; 319 doi: https://doi.org/10.1136/bmj.319.7224.1534 (Published 11 December 1999) Cite this as: BMJ 1999;319:1534All rapid responses
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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
Specialist Registrar in Adult Psychiatry
Paterson Centre for Mental Health,
South Wharf Rd,
London W2 1NY
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
Competing interests: No competing interests
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)
Competing interests: No competing interests
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.
Competing interests: No competing interests
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.
Competing interests: No competing interests
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)
Competing interests: No competing interests
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
Redcrest,
Heath Rise,
Camberley,
Surrey
GU15 2ER
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.
Competing interests: No competing interests
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.
Competing interests: No competing interests
Drug interaction of tea containing St. John´s wort with ciclosporin
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.
Competing interests: No competing interests