St John's for depression, worts and all

Your patients are using it, but does it work?

Depressive disorders are serious illnesses that cause enormous personal suffering and a high economic burden. The World Health Organization projects that major depression will be the second leading cause of disability worldwide by the year 2020. Most depressed patients are treated in primary care and the most common treatment is antidepressant medication. Despite rapid growth in antidepressant prescribing, outcomes are often poor and patients are increasingly using complementary and alternative medicine such as St John's wort (SJW). In 2002, 12% of US adults reported using SJW within the past 12 months.1 Should we encourage our patients to try St John's wort for depression?

Szegedi et al conducted a methodologically sophisticated study to determine whether SJW was about as good as and no worse than paroxetine in patients with moderate to severe major depression. The study produced surprising results.

Szegedi et al conducted a methodologically sophisticated study (p 160) designed to determine whether SJW was about as good as and no worse than paroxetine in patients with moderate to severe major depression. An active control, non-inferiority trial is appropriate when there are established effective therapies and the new treatment is potentially as effective and less expensive or safer. The comparators in this trial meet the standard. Selective serotonin reuptake inhibitors (SSRIs) such as paroxetine are more efficacious than placebo for acute treatment; continued treatment after remission protects against relapse.2 The efficacy of SJW for major depression, particularly more severe depression, remains in doubt. Depending on brand and dose, SJW costs $9 to $26 per month at a local pharmacy, and prior studies suggest that fewer patients discontinue treatment due to adverse effects than with SSRIs.3

The study produced surprising results. Patients randomized to SJW showed greater symptom reduction than patients taking immediate release paroxetine. At 6 weeks, 71% of SJW patients compared to 60% of paroxetine patients showed a 50% or greater reduction in depressive symptoms. Compared to paroxetine, significantly fewer patients taking SJW reported adverse effects. The investigators addressed weaknesses in prior studies through careful diagnosis of moderate to severe major depression and aggressive medication titration; treatment adherence was unusually high. Patients with symptoms for greater than one year were appropriately excluded, because chronic major depression responds better to the combination of psychotherapy and antidepressant medication than either alone.4

How should we integrate these results with prior evidence? Linde et al recently completed a meta-analysis of randomized double-blind trials of SJW and concluded that the “current evidence… is inconsistent and confusing.”3 They analyzed 6 trials comparing SJW to an SSRI in patients with major depression. Meta-analysis showed no difference in response rates; the rate ratio (ratio of SJW responders to SSRI responders) was 0.98 (95% CI 0.85 to 1.12). If the current trial were added to this analysis, the rate ratio would not change significantly. Linde analyzed an additional 12 studies comparing SJW to placebo. SJW was more efficacious than placebo, but the larger, more precise trials showed only a small benefit: rate ratio 1.15 (1.02 to 1.29).

In contrast, trials not restricted to major depression showed marked benefits for SJW. For context, a previous meta-analysis of SSRIs compared to placebo showed substantial benefit for major depression: rate ratio 1.6 (1.4 to 1.7).2 Thus, clinicians are faced with the problem of acting on evidence for SJW showing marked benefits for milder depression, minimal benefits for major depression, and similar benefits compared to standard antidepressants.

Considering other effects, such as drug-drug interactions and treatment availability, can aid decision making. SJW induces the cytochrome system, especially the 3A enzymes and the multidrug resistance transporter P-glycoprotein. More than 40% of prescription drugs are metabolized via the cytochrome 3A system.5 As a result, SJW can cause decreased levels of cyclosporine, indinavir, fexofenadine, simvastatin, omeprazole, warfarin, digoxin, oral contraceptives, and theophylline, among others. SJW can also interact with concomitantly used SSRIs to cause serotonin syndrome.

Another concern is drug quality. In the United States, SJW is classified as a dietary supplement, and there is considerable variation in amounts of active compounds found in preparations labeled as SJW.6 Hyperforin, a likely primary active constituent of SJW, acts as a serotonin uptake inhibitor7 and has been shown to vary 100-fold between brands8; some products vary significantly between batches.9 Consistency problems are not confined to American products. As measured by hyperforin content, German products were found to be highly potent, but only in products sold in pharmacies and not in less regulated formulations available in supermarkets.7

Given the inconsistent evidence about efficacy in major depression and the questionable quality of OTC products, SJW should not be a first or second choice for US patients with moderate to severe major depression. For patients with minor depression, where the evidence for SJW is more robust and standard antidepressants have not been proved efficacious, the lower cost and lower side effect profile make SJW a reasonable option for patients who are able to locate quality preparations.

Accurate diagnosis and careful follow-up may be at least as important as which drug is chosen. Over a dozen controlled trials have demonstrated that careful symptom assessment using an instrument such as the PHQ-9,10 patient education, early follow-up, and active medication management will double the number of responders compared to usual care. Better treatments are needed for depression, but we also have the evidence to do better with the treatments on hand.

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