Comparison of St John's wort and imipramine for treating depression: randomised controlled trial
BMJ 2000; 321 doi: https://doi.org/10.1136/bmj.321.7260.536 (Published 02 September 2000) Cite this as: BMJ 2000;321:536All rapid responses
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The extract used in the investigation is a hypericum extract
standardised on 0.2% hypericin. Attention has now focused on hyperforin as the
active constituent of the extracts. Is the content of hyperforin in
extract ZE 117 and other extracts used in clinical
investigations known?
Competing interests: No competing interests
The Article by Woelk has found its way into the public domain very
quickly and I am finding that several of my patients are asking to be
treated with St John's Wort over the last few weeks.
In Austalia, Hypericum perfoatum extract is availabe as perforatum
(hypericum) equiv. dry herb 2000 mg, standardised to contain hypericin not
less than 666 mcg. The dose recommended is one tablet ie 2000mg three
times per day.
Does this mean that Australians are very depressed and need massive
doses or is there some formulae we require to convert our hypericum to
your dosage requirements? Or has there been an error?
Competing interests: No competing interests
Is there any knowledge of the longterm effects of SJW. The treatment
for a depressive illness takes more than six weeks? It is good practise
here to treat with a adequate dose of an antidepressant for about nine
months and in the case of recurrent depressions we recommend to treat for
many years. Is there a table of all the molecules that are in the used
Extract of SJW and is the composition of all these substances the same in
all the extracts from different places and different times of the harvest?
Do we know anything of bloodlevels of these substances?
Piet Bakx
Competing interests: No competing interests
Editor - The randomised controlled trial (RCT) of St. John's Wort
(hypericum perforatum) by Woelk et al1 corrects many of the shortcomings
of the many previous trials of hypericum. However, it is disappointing for
two main reasons: firstly it is a short trial lasting only six weeks and
secondly it compares hypericum with imipramine, an antidepressant more
commonly associated with adverse reactions than many other
antidepressants2.
Being a short trial, it considers only the acute phase treatment and
neglects the essential continuation phase. Discontinuation of
antidepressant therapy during the latter phase is common and may lead to
relapse in up to 50% of cases3. The evidence of fewer drop-outs in the
hypericum treatment group might not have been sustained had the trial
continued given that the side-effects of imipramine start to wear off
after a few weeks4. Stopping the trial at six weeks might have unfairly
disadvantaged the imipramine treatment group.
Secondly, it would have been more convincing to have compared hypericum
with an antidepressant with a better side-effect profile rather than
respecting a rather outdated tradition that upholds imipramine as a
reference compound for efficacy. The evidence from meta-analyses suggest
that those treated with selective serotonin reuptake inhibitors in RCTs
have lower discontinuation rates than those treated with older tricyclic
antidepressants.2,5
Andrew Sandor
lecturer
Department of Psychiatry and Behavioural Sciences, Royal Free and
University College Medical School, London N19 5NF.
1. Woelk H for the Remotiv/ Imipramine study group. Comparison of St.
John's wort and imipramine for treating depression: randomised controlled
trial BMJ 2000; 321: 536-539 (2 September).
2. Hotopf M., Hardy R and Lewis G. Discontinuation rates of SSRIs and
tricyclic antidepressants: a meta-analysis and investigation of
heterogeneity. British Journal of Psychiatry 1997; 170, 120-127.
3. Paykel E., Priest R., Recognition and management of depression in
general practice: consensus statement. BMJ 1992; 305: 1198-1202.
4. Shrivastava, R. K., Cohn C., Crowder J, Davidson J, Dunner D,
Feighner, Kiev A, Patrick R. Long-term safety and clinical acceptability
of venlafaxine and imipramine in outpatients with major depression.
Journal of Clinical Psychopharmacology1994; 14 (5) 322-9.
5. Anderson I.M. &Tomenson B. M. Treatment discontinuation with
selective serotonin reuptake inhibitors compared with tricylic
antidepressants: a meta-analysis BMJ 1995; 310: 1433-38.
Competing interests: No competing interests
Laudably, Woelk and colleagues1 have undertaken to confront the
criticism of design and methodology of some studies evaluating the
efficacy of hypericum by attempting to conduct a trial that meets current
methodological standards. Unfortunately, their report appears to be
suffering from methodological shortcomings as well:
1. Owing to the absence of a placebo control group, the magnitude and
relevance of the ‘treatment effect’ cannot be assessed and therefore the
trial’s assay sensitivity2 cannot be demonstrated. While Woelk and
colleagues report 43% of patients in the hypericum group and 40% in the
imipramine group whose HAMD scores were reduced by at least 50% versus
baseline, Linde et al.3 found rates of ‘50%-responders’ of up to 54% in
the placebo groups of the trials included in their review. Therefore the
‘treatment effect’ in this trial could alternatively be explained by a
‘placebo effect’, since there is no proof that the trial was appropriate
to discriminate between pharmacologically active and inactive treatments.
Although the absence of a placebo control group is an issue in most
‘active control’ trials, a proof of assay sensitivity appears to be
particularly essential in depression, due to the very large extent and
variability of the ‘placebo effect’.
2. The non-inferiority margin used in the trial is highly debatable.
The authors claim that a difference in improvement <=3.5 points between
hypericum and imipramine on the 17-item Hamilton depression scale (HAMD)
is clinically irrelevant. However, taking into account that an effect size
of 3 points is accepted as clinically relevant to distinguish between an
active drug and placebo4, this non-inferiority margin appears to be much
too large. It was in fact larger than the significant differences between
hypericum and placebo in several of the trials reviewed by Linde et al.3
and would thus permit to accept non-inferiority even if hypericum were no
more efficacious than placebo2.
3. The actual standard deviation of the primary variable turned out
to be only about half of the value assumed during sample size calculation.
This strongly indicates that there exist essential differences between
this study and earlier trials, causing doubts in its internal validity.
4. Although the trial was designed to show the non-inferiority of
hypericum extract in comparison to imipramine by a one-sided non-
inferiority test, the authors report the result of a (non-significant) two
-sided superiority test for the primary variable.
1 Woelk H, The Remotiv/Imipramine Study Group. Comparison of St.
John´s wort and impramine for treating depression: randomised controlled
trial. BMJ 2000; 321:536-539.
2 International Conference on Harmonization. Note for guidance on
choice of control group in clinical trials. Draft consensus guideline
London: European Agency for the Evaluation of Medical Products, 1999
3 Linde K, Ramirez G, Mulrow CD, Pauls A, Weidenhammer W, Melchart D.
St. John´s wort for depression - an overview and meta-analysis of
randomised clinical trials. BMJ 1996; 313:253-258
4 Montgomery SA. Clinically relevant effect sizes in depression. Eur
Neuropsychopharmacol 1994; 4:283-284.
Competing interests: No competing interests
Can anything be said about the elimination-time for active
ingredients of ZE 117?
Is it similar to elimination-times for fluoxetine/norfluoxetine?
Competing interests: No competing interests
I read with interest the work done by Woelk et al. comparing an
extract of St. John's Wort with imipramine. I am concerned with the
possibility of differences between the various extract products that are
available. The extract that was used in this trial (ZE 117) is different
from the extracts used in previous studies (1,2). As far as I can tell,
St. John's Wort extracts have not been compared with each other to rule
out the possibility of differences between products. As the literature
showing St. John's Wort's efficacy against standard antidepressants
continues to mount, the next logical question should be which of the
currently available products shall serve as the standard product.
1. Harrer G, Hubner W.-A., Podzuweit H.: Effectiveness and tolerance
of the hypericum extract LI 160 compared to maprotiline: a multicentre
double-blind study. J Geriatr Psychiatry Neurol 1994(Suppl. 1)S24-S28
2. Philipp M, Kohnen R, Hiller KO: Hypericum extract versus
imipramine or placebo in patients with moderate depression: randomised
multicentre study of treatment for eight weeks. Br Med J 1999;3319:1534-9
Competing interests: No competing interests
Editor- It is well recognised that there is increasing use of over-
the-counter vitamins, health products and herbal remedies by the general
public. In this $4b a year industry, the sales of St. John’s Wort has
recorded the fastest growth1. This may be encouraged by the recent
publicatin of medical research suggesting its efficacy as equivalent to
and safety better than imipramine2. The implications of the possible
interactions of such products with NHS-prescribed medication has been
recently highlighted2 . In this survey of eighty two HIV positive
individuals, 27% of them were using non NHS-prescribed medication. This
should prompt clinicians and pharmacists to take detailed histories about
all therapies that patients are using before issuing either prescribed
drugs or non NHS-prescribed preparations.
St John’s Wort (Hypericum perforatum) is commonly used as an over-the
-counter herbal remedy for mild depression and treatment of wounds. In
February 2000 the Committee on Safety of Medicines issued a warning to
doctors and pharmacists about the interactions between St John’s Wort
preparations and some prescription-only medications3. St John’s Wort
induces various drug-metabolising enzymes, including the cytochrome P450
system. Consequent reduction in plasma levels of drugs also utilising this
system for their metabolism has been documented 4. The HIV protease
inhibitors, HIV non-nucleoside reverse transcriptase inhibitors and oral
contraceptives may therefore all possibly interact with St John’s Wort3.
These three classes of medication are regularly prescribed to patients
attending Genitourinary Medicine Clinics in the United Kingdom. There is
no literature on the use of such products by HIV positive individuals or
by women using oral contraceptives. Many products claim to improve the
immune system, and HIV positive individuals making choices about their
future therapies may be tempted to use them. We set out to determine the
use of non NHS-prescribed medication in a small population of HIV positive
individuals, at the same time issuing a health warning to them about
possible interactions of various medications with St John’s Wort.
Three Genitourinary Medicine clinics (Oxford, High Wycombe and
Swindon) contacted the HIV positive individuals registered with the
clinics to ascertain what, if any, non NHS-prescribed medications they
were consuming. The results of the survey are shown in the table.
The reduction in the plasma levels of certain classes of anti-
retroviral agents in the presence of St John’s Wort could have serious
implications for treatment failure and the development of viral
resistance. In the patient group surveyed there was no patient identified
on St John’s Wort. However, fortunately, in one case its initiation was
avoided.
Importantly, 27% of patients surveyed used non NHS-prescribed therapies.
These were mainly various multivitamin and iron preparations but also
included ‘anti-oxidants’, cod liver oil, ginseng and garlic. It is not
clear what proportion of patients nationally use such preparations, or how
many on non NHS-medication are taking the medicines listed in the
Committee on Safety of Medicines warning. Products sold as ‘alternative
therapies’ and ‘natural health’ remedies do not have the same licensing
requirements as NHS-prescription medications. They are therefore not
always required to carry health warnings. Health-care professionals need
to raise this issue more frequently with patients.
Table: Results of Patient Survey No (%) Patients contacted 82 Replies 56 (82) On anti-retroviral therapy 30 (54) On anti-retroviral therapy utilising cytochrome P450 pathway 13 (23) Using non-NHS medication/ remedies 15 (27) On anti-retroviral therapy and using non-NHS medication/ remedies 12 (21) Using St John’s Wort 0 Unsure if products contained St John’s Wort 2 Considering commencing St John’s Wort prior to warning 1
Lynn A Riddell
Specialist Registrar
Genitourinary Medicine, Radcliffe Infirmary,
Oxford 0X2 6HE
Guy Rooney
consultant GUM
Oxford and Swindon
Graz Luzzi
consultant GUM Oxford and High Wycombe
References
1. Ernst E. Herbal medicines: where is the evidence? BMJ 2000; 321:
395-6
2. Woelk H. Comparison of St John’s wort and imipramine for treating
depression: randomised controlled trial. BMJ 2000; 321: 536-539
3. Reminder: St. John’s Wort (Hypericum perforatum) interactions. Current
Problems in Pharmacovigilance. Committee on Safety of Medicines May 2000;
26: 6-7
4. Piscitelli SC, Burstein AH, Magnuson WG. Indinavir concentrations and
St. John’s Wort. Lancet 2000; 355; 547-8
Competing interests: Table: Results of Patient Survey No (%)Patients contacted 82 Replies 56 (82) On anti-retroviral therapy 30 (54)On anti-retroviral therapyutilising cytochromeP450 pathway 13 (23)Using non-NHS medication/remedies 15 (27)On anti-retroviral therapyand using non-NHS medication/remedies 12 (21)Using St John’s Wort 0Unsure if products containedSt John’s Wort 2Considering commencing St John’sWort prior to warning 1
Dear Editor - St John's Wort (Hypericum perforatum) extracts have a
long history of use in folk medicine and are presently an attractive
alternative for people who do not wish to take powerful synthetic
antidepressants. There have been several head to head studies comparing
Hypericum with the antidepressants maprotiline, imipramine and
amitriptyline, although no statistical difference in treatment outcome has
been reported singly or combined in these trials. Criticism has been
raised that the antidepressant dose in these studies was inappropriately
low. Woelk and the Imipramine Study Group1 recently attempted to address
this issue but unfortunately do little to clarify the present situation.
Their conclusion that St John's Wort is equivalent to therapeutic doses of
Imipramine at 6 weeks is incorrect as Imipramine was only given for 5
weeks due to its dose titration. As the daily dose of hypericum extract
has varied considerably in previous trials and has not been a criterion
used to judge efficacy, it also should have been titrated to make the
results comparable. Conclusions can therefore only be drawn upon a
comparison of 6 weeks Hypericum to 5 weeks Imipramine.
This is critical in
interpreting the findings as it is well documented that response for many
patients can be considerably slower than this period of time particularly
in the elderly. The study population had a mean age in there mid 40s with
a SD of nearly 13 years. Older patients may take longer to respond to
treatment than their adult counterparts, median time to remission being
reported as 12.9 weeks and 7.3 weeks respectively for elderly patients
defined as having early-onset (a first lifetime episode of depression at
59 years of age or earlier) or late-onset illness (age 60 years or later).
Hypericum has been shown to be significantly better than placebo in
treating depression2 and it is therefore perhaps not surprising,
considering the above, that no statistical significant difference was
found between the two treatment groups.
Clinicians repeatedly spend months, often years wasting effort planning
trials of short-duration and ultimately undermining the interpretability
of the results. The conclusions from this work will goes little to
answering the question is Hypericum as effective as a therapeutic dose of
antidepressant. Furthermore, comparing tolerability to a relatively toxic
antidepressant such as Imipramine appears illogical. Results from an
adequate length trial assessing efficacy and tolerability against SSRIs
are what most clinicians are waiting for.
1. Woelk H. Comparison of St John's Wort and Imipramine for treating
depression: randomised controlled trial. BMJ 2000;321:536-9.
2. Linde K, Ramirez G, Mulrow CD et al. St John's Wort for depression
- an overview and Meta-analysis of randomised clinical trials. BMJ
1996;313:253-8.
Dr Mark C Dale
Honorary Senior Lecturer
Consultant in Old Age Psychiatry
Fleetwood Hospital,
Pharos Street,
Fleetwood
FY7 6BE
Competing interests: No competing interests
SEEING THE MOTE IN THE EYE OF THE SAINT JOHN'S WORT SUPPORTER
A recent study by Woelk tried to demonstrate the antidepressant
properties of Saint John's Wort (SJW) 1. Its methodology has been much
criticised 2-4. We put the four major criticisms together to form a short
"methodological quality" checklist and added an item regarding blindness
integrity :
1- Use of remission criteria.
2- Use of a three-arm design.
3- Use of an active placebo.
4- Individual determination of the dosage of the reference compound.
5- Evaluation of blindness integrity.
We recently stated that blindness break was a major defect in
antidepressant trials and that it often jeopardised their validity 5. In
the Woelk study, considering the tolerance profile of imipramine, it was
probably easy for the patients (and evaluators) to guess whether they were
under SJW or imipramine. The expectations of both patients and evaluators
may thus have biased the results.
We checked whether the criticisms made against the Woelk study were
addressed or not in "regular" antidepressant trials. We performed a
Medline search for the year 2000 and identified 19 randomised controlled
trials which evaluated the short term efficacy of "regular"
antidepressants in major depression. We reviewed the 19 studies and rated
them according to the above checklist. Only 2/19 studies addressed three
of the requirements in the above checklist ; 5/19 addressed two of them ;
12/19 addressed one or none. Interestingly, these twelve studies were not
the target of any critical correspondence, as checked in the three issues
that followed publication. In conclusion, many trials which evaluated the
efficacy of regular antidepressants bore the limitations observed in the
Woelk study.
If the criticisms against the Woelk study are correct, then SJW still
needs to prove itself. But this may also hold for some regular
antidepressants. In fact, the general methodological defects of
antidepressant trials (eg : two-arm designs, blindness break) smooth out
the differences in efficacy of antidepressants. It leads to the lumping of
all antidepressants into a single category that may comprise compounds
with different levels of efficacy. But the compounds which have
demonstrated their efficacy in high quality trials (e.g. : three-arm
design) should not be lumped with those which have not. Only better
designs and methods could enable discrimination between efficacious and
unefficacious compounds. But this holds for new or "alternative" compounds
as well as for more "classical" ones.
REFERENCES
1. Woelk H. Comparison of St John's wort and imipramine for treating
depression: randomised controlled trial. BMJ 2000;321(7260):536-9.
2. Alkhenizan A. Comparison of St John's Wort and imipramine. Finding must
be treated with caution. BMJ 2001;322(7284):493; discussion 494.
3. Cornwall PL. Comparison of St John's Wort and imipramine. Remission is
important outcome. BMJ 2001;322(7284):493.
4. Spira JL. Comparison of St John's Wort and imipramine. Study design
casts doubt on value of St John's wort in treating depression. BMJ
2001;322(7284):493.
5. Even C, Siobud-Dorocant E, Dardennes RM. Critical approach to
antidepressant trials. Blindness protection is necessary, feasible and
measurable. Br J Psychiatry 2000;177:47-51.
Competing interests: No competing interests