Sarris J, Fava M, Schweitzer I, Mischoulon D. St John's wort (Hypericum perforatum) versus sertraline and placebo in major depressive disorder: continuation data from a 26-week RCT. Pharmacopsychiatry. May 16, 2012; [epub ahead of print]. doi: 10.1055/s-0032-1306348.

St. John's wort (SJW; Hypericum perforatum) is used to treat mild-to-moderate depression. Its effects are erroneously reported to include serotonin, noradrenaline, and dopamine re-uptake inhibition. Other effects may result from gamma-aminobutyric acid (GABA) and L-glutamate pathway modulation; and interaction with the neuroendocrine system. SJW has been shown in meta-analyses to be equally effective to synthetic antidepressants in treating mild-to-moderate major depressive disorder (MDD).

There are many short-term studies, but there is a paucity of long-term continuation studies. In 2002, the National Institute of Mental Health (NIMH) funded the Hypericum Depression Trial Study Group (HDTSG) randomized, controlled trial, which compared the efficacy of SJW, sertraline, and placebo after 8 weeks of acute treatment and 26 weeks of continuous treatment in patients with moderately severe MDD.¹ The study found neither SJW nor sertraline were significantly different from placebo after 8 weeks of acute treatment. The authors state, "While this study can be considered as 'failed' due to the high placebo-response and no separation between treatments at week 8, it is still of interest to explore the continuation data to determine the long-term effects of SJW (sertraline and placebo) in this sample." Hence, the purpose of this short report was to present the HDTSG study's continuation data from responders who remained in treatment from weeks 8-26.

The multicenter study was a randomized, double-blind, 3-arm study comparing SJW (LI 160; Lichtwer Pharma; Berlin, Germany; 900-1500 mg/day), sertraline (Zoloft^®; Pfizer; New York, New York; 50-100 mg/day), or a matching placebo in patients diagnosed with MDD. The subjects' pooled mean baseline Hamilton Rating Scale for Depression (HAM-D) score was 22.8 ± 2.7, indicating moderately severe depression. The SJW was standardized to 0.12-0.28% hypericin. At baseline, patients (n = 124; mean age = 42-46 years) were randomly assigned to receive either SJW (900 mg/day), sertraline (50 mg/day), or placebo and were titrated according to response (to a maximum of 1500 mg/day of SJW, 100 mg/day of sertraline, or placebo). Medications were taken 3x/day. Patients who fully or partially responded during the 8-week acute phase (HAM-D reduction ≥ 50%) were eligible for entry into the continuation phase, with data collection occurring at weeks 10, 14, 18, 22, and 26. Outcomes included the 17-item HAM-D, Beck depression inventory (BDI), global assessment of functioning (GAF), clinical global impression scales for severity (CGI-S) and improvement (CGI-I).

At week 26, there was no significant difference between treatment groups for HAM-D scores, BDI scores, relapse rates, and remission rates. Results were similar for all secondary outcomes; there was no significant difference between groups for CGI-S, CGI-I, or GAF scores. In regard to tolerability, the SJW-treated group had a significant increase in frequent urination, anorgasmia (inability to have orgasm), and swelling, while the sertraline-treated group had a significant increase in rates of diarrhea, nausea, sweating, and anorgasmia compared to placebo.

The authors state that the results of this study are in line with those of the acute study; all 3 groups had similar improvements in depression scores, remission rates, and relapse rates. They assert that both SJW and sertraline were effective, but the placebo response was very strong so that the improvements were not evident. This robust placebo effect is very common in short-term studies evaluating pharmaceutical treatments of MDD. But the apparent sustained effect of placebo over 6 months' time is considered by the authors as an anomaly, and why it may have occurred is of interest.

The adverse side effects of SJW warrant comment (especially swelling and anorgasmia); they have not been reported in any previous MDD trial. SJW is anti-inflammatory. Anorgasmia is a common side effect of pharmaceutical antidepressants and, hence, was probably included in the standard queries regarding adverse effects. Over 25 clinical trials have found SJW effective in treating mild-to-moderate depression. The fact that sertraline was equally ineffective should be correspondingly emphasized.


—Heather S. Oliff, PhD

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