This is the third in a series of blog posts on last Wednesday's SIGN draft guideline seminar on "Non-pharmacological management of mild to moderate depression."  The first session of the day was on "Lifestyle and Alternative/Complementary Therapies 1".  Yesterday's blog discussed the first presenter, Ian Ross's talk on the value of exercise in depression.  The second presentation was by Cliff Sharp, a psychiatrist from NHS borders.  He reviewed St John's Wort & Dietary Supplements.  He talked about the possible value of folate in treating depression when used to supplement conventional antidepressants.  He concluded that current evidence was insufficient to determine whether folate boosts response for those on antidepressants only if their initial folate levels are low, or whether it boosts response for anyone taking antidepressants.  See an earlier blog post I wrote about folate supplementation for more details - and for a caution about the possible dangers of taking long term high doses of this supplement.  Cliff also talked about polyunsaturated fatty acids (PUFAs) and fish oil concluding that " ... although there is some evidence to support modest benefit of PUFAs as a supplement to antidepressant treatment, larger trials are needed."  Again I have discussed this in a previous blog post as well as in a written article (Hawkins 2006).  Brief mention was also made of Ginkgo Biloba, Inositol, and SAMe.  Only SAMe looked somewhat hopeful, but more research is needed here.  It might have been worth also briefly mentioning chromium.  Studies backing it as a depression treatment are weak, but are at least out there (McLeod, Gaynes et al. 1999; McLeod and Golden 2000; Davidson, Abraham et al. 2003; Docherty, Sack et al. 2005).   

Cliff was able to make more of a meal of St John's Wort, which has much the most extensive supporting evidence of all herbs and supplements used to treat depression.  The SIGN draft guideline gives it a grade A recommendation "Extract of hypericum (St John's Wort) is recommended as a treatment option for patients with mild to moderate depression."  This is quite a major new departure for a national guideline recommendation on St John's Wort.  The 2004 NICE depression guideline (for England & Wales) states on page 210 "Although there is evidence that St John's wort may be of benefit in mild or moderate depression, healthcare professionals should not prescribe or advise its use by patients because of uncertainty about appropriate doses, variation in the nature of preparations and potential serious interactions with other drugs (including oral contraceptives, anticoagulants and anticonvulsants)."  At least NICE acknowledged this recommendation as only level "C" - just supported by "level IV" evidence - the lowest evidence grade cited by the guideline (p.43).  NICE level IV evidence is based on "... expert committee reports or opinions and/or clinical experiences of respected authorities."  I think SIGN - in contrast to NICE - is probably right to recommend St John's Wort.  I do however think this recommendation brings responsibilities.  NICE's comments about problems with dose, preparation variation, and potential herb-drug interactions are largely correct.

Doctors often know less about St John's Wort than they know about standard antidepressants (McGarry, Pirotta et al. 2007).  Pharmacists and health food store employees can also be worryingly ignorant (Sarino, Dang et al. 2007).  For example, it has been estimated that approximately 75% of people suffering from major depressive disorder also have at least one other comorbid psychiatric condition (Kessler, Berglund et al. 2003).  Common comorbid diagnoses include anxiety disorders and substance use disorders.  In this situation it can be helpful to know that current research suggests that St John's Wort is probably ineffective in treating social anxiety disorder (Kobak, Taylor et al. 2005a) and obsessive compulsive disorder (Kobak, Taylor et al. 2005b), while in contrast commonly encountered mixed anxiety and depression may be a better candidate for St John's Wort treatment (Davidson and Connor 2001; Friede, Henneicke von Zepelin et al. 2001). 

As far as dose is concerned, the SIGN draft guideline notes that "Although most of the clinical trials have been carried out using 300mg preparations of Hypericum extract taken three times daily, doses range from 600mg to 1800mg daily".  Although there are case reports of doses of 1800mg in total per day apparently being more effective than lower doses in certain situations (Davidson and Connor 2001), in general it seems that (as least for depression) manufacturer recommended doses of well-researched products are likely to be as effective as higher doses (Kasper, Anghelescu et al. 2006).  The problem lies in the phrase "well-researched".  Most St John's Wort products on sale have not been researched for their effectiveness.  This may well produce difficulties because St John's Wort acts via several different psychoactive components, including hypericin, hyperforin and flavonoids (Butterweck, Christoffel et al. 2003).  Although different manufacturers typically state the amount of hypericin in their preparations, even this limited information about only one psychoactive component is often inaccurate with frequent mismatch between label and actual content (de los Reyes and Koda 2002).  Another paper (Wurglics, Westerhoff et al. 2001) reported on analysis of products from eight different manufacturers stated "Concentrations were compared among different batches of the same product and among products from different manufacturers. Results: The products contained widely differing amounts of hypericin and hyperforin, even after correcting for differences in the amount of extract per dose. Some products demonstrated consistent concentrations of hyperforin and hypericin from batch to batch, others exhibited pronounced interbatch variability. Conclusion: The St. John's wort preparations studied exhibited large differences in hypericin and hyperforin content and are not interchangeable for the treatment of mild-to-moderate depression. Pharmacists should take this variability into account when counseling patients on the use of St. John's wort products."  The way I grasped this nettle in my own 2006 paper (Hawkins 2006) was to say "The sensible and very informed Knuppel and Linde review (Knuppel and Linde 2004) ... suggests that ideally one should use products that have been tested in clinical trials - the most widely researched is the Kira brand produced by Jarsin and quite easily available in the UK.  They go on to suggest that one should avoid products that do not give important content information such as the amount of total extract, the extraction fluid, and the raw material to extract ratio.  One economic option would be for an individual to start with the relatively expensive Kira brand and, if there is an adequate response, then later see whether a reputable but cheaper alternative product is as effective." Now, writing in 2008, I would also recommend the well researached Schwabe product WS5570 with its hyperforin-guaranteed content.  Unfortunately WS5570 is hard to get hold of in the UK - although this situation may well change over the next year or two (Middleton 2008).  I do think SIGN should seriously consider this issue of preparation variability and give clear advice about current best practice to both health professionals and the general public.

As for side effects and potential interactions, SIGN states "In general, extracts of hypericum have a lower side effect profile and are better tolerated than synthetic antidepressants."  SIGN goes on to list important herb-drug interactions.  Doctors, pharmacists, other relevant health professionals and members of the general public considering taking St John's Wort will need to be aware of these interactions.  I would make three points about this much talked about subject.  Firstly it is worth noting that the list of potentially problematic interactions with other drugs listed in the current British National Formulary is much more extensive for conventional antidepressants (e.g. SSRIs or Tricyclics) than it is for St John's Wort.  Secondly, and more idiosyncratically, it is worth mentioning the potential risk of taking St John's Wort - which is photosensitising - when being potentially over exposed to light (excessive sunbathing or use of bright light therapy for seasonal affective disorder).  Thirdly I am interested and questioning of the often cited warning not to take St John's Wort if also taking oral contraceptives.  This is a significant limitation.  Probably the most likely group to consider taking St John's Wort are women of child bearing age (Linden, Wurzendorf et al. 2008) many of whom may already be taking oral contraceptives.  Is it really so disastrous to take these two substances simultaneously?  The two trials that I can find relevant to this issue (Pfrunder, Schiesser et al. 2003; Murphy, Kern et al. 2005) show some reduction in the level of circulating hormones.  The Pfrunder et al study commented that "During concomitant administration of low-dose oral contraceptive and St John's wort, there was no significant change in follicle maturation, serum oestradiol or progesterone concentrations when compared with oral contraceptive treatment alone. However, significantly more subjects reported intracyclic bleeding during cycles A (13/17 (77%), P < 0.015) and cycle B (15/17 (88%), P < 0.001) than with oral contraceptives alone."  In the Murphy et al study, the authors found that "Treatment with St. John's Wort was associated with a significant 13-15% reduction in the dose exposure from the contraceptive."  In both trials the women were taking low dose oral contraceptives, so in the Murphy et al trial the women took Loestrin 20 (with 1mg of norethisterone acetate & 20 micrograms of ethinylestradiol).  If there was the reported 13-15% reduction in dose exposure from the contraceptive, surely simply moving to the 50% stronger standard preparation Loestrin 30 (with 1.5mg norethisterone acetate & 30 micrograms of ethinylestradiol) would have more than solved the problem.  Again, this is an issue SIGN could very usefully clarify.  Stating St John's Wort shouldn't be taken with oral contraceptives is a major limitation for an antidepressive agent.  Simply saying it shouldn't be taken with low dose oral contraceptives seems much less limiting.  Possibly if one is taking St John's Wort with standard dose contraceptives and one experiences increased intracyclic bleeding then one should consider stopping the St John's Wort.  Advice on this by SIGN would be very worthwhile.

The major 2004 NICE guideline on depression treatment concluded St John's Wort shouldn't be recommended by health professionals because of " ... uncertainty about appropriate doses, variation in the nature of preparations and potential serious interactions with other drugs."  I think SIGN are correct to reverse this advice and support the potential value of using St John's Wort for mild to moderate depression.  In doing this, I believe SIGN should address NICE's concerns and give best possible information on negotiating these difficulties - especially with preparation variation and concern over interaction with oral contraceptives. 

Butterweck, V., V. Christoffel, et al. (2003). "Step by step removal of hyperforin and hypericin: activity profile of different Hypericum preparations in behavioral models." Life Sci 73(5): 627-39.  [PubMed] 
CG23 Depression: Full guideline (amended). (2004)  http://www.nice.org.uk/Guidance/CG23 accessed 15 September 2008.
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