St. John's Wort for Major Depressive Disorder

Abstract

RAND researchers conducted a systematic review that synthesized evidence from randomized controlled trials of St. John's wort (SJW)—used adjunctively or as monotherapy—to provide estimates of its efficacy and safety in treating adults with major depressive disorder.

Outcomes of interest included changes in depressive symptomatology, quality of life, and adverse effects. Efficacy meta-analyses used the Hartung-Knapp-Sidik-Jonkman method for random-effects models. Quality of evidence was assessed using the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach.

In total, 35 studies met inclusion criteria. There is moderate evidence, due to unexplained heterogeneity between studies, that depression improvement based on the number of treatment responders and depression scale scores favors SJW over placebo, and results are comparable to antidepressants. The existing evidence is based on studies testing SJW as monotherapy; there is a lack of evidence for SJW given as adjunct therapy to standard antidepressant therapy. We found no systematic difference between SJW extracts, but head-to-head trials are missing; LI 160 (0.3% hypericin, 1–4% hyperforin) was the extract with the greatest number of studies. Only two trials assessed quality of life. SJW adverse events reported in included trials were comparable to placebo, and were fewer compared with antidepressant medication; however, adverse event assessments were limited, and thus we have limited confidence in this conclusion.

Introduction

Worldwide, depressive disorders are one of the largest sources of disease burden. Depression is commonly treated with prescription medications. However, these can cause side effects, and many patients turn to alternative treatments, such as St. John's wort (SJW). Previous systematic reviews have shown the efficacy of SJW in mild to moderate depression, but additional studies have been completed since that time. This systematic review aims to synthesize evidence from trials of SJW to provide estimates of its effectiveness in treating major depressive disorder (MDD) (PROSPERO record CRD42015016406).

This review was guided by the following key questions (KQs):

• KQ 1: What are the efficacy and safety of St. John's wort (SJW), as an adjunctive or monotherapy, for depressive symptoms and quality of life in adults with MDD compared with placebo or active comparator?

  • ▪KQ 1a: Is SJW more effective as monotherapy than as an adjunctive therapy?
  • ▪KQ 1b: Is there a difference in efficacy, depending on the amount and type of extract of SJW used?
  • ▪KQ 1c: Is there a difference in efficacy, depending on the type of MDD (i.e., mild, moderate, or severe)?
  • ▪KQ 1d: Are adverse events associated with SJW comparable to standard antidepressant treatment?
  • ▪KQ 1e: Is the efficacy of SJW comparable to standard antidepressant treatment?

Methods

To answer our key questions, we conducted a systematic search of electronic databases (PubMed, CINAHL, PsycINFO, CENTRAL, Embase, AMED, MANTIS, Web of Science, and ICTRP) without language restriction to November 2014, as well as bibliographies of existing systematic reviews and included studies, to identify reports of randomized controlled trials (RCTs) testing the efficacy and safety of SJW—used adjunctively or as monotherapy—to treat adults with MDD.

Two independent reviewers screened the identified literature using predetermined eligibility criteria, abstracted prespecified study-level information, and assessed the quality of included studies. Outcomes of interest included changes in depressive symptomatology, quality of life, and adverse effects.

Meta-analyses for efficacy outcomes and the number of patients with adverse events were conducted using the Hartung-Knapp-Sidik-Jonkman method for random-effects models to estimate the relative risk (RR) and standardized mean differences (SMDs), together with the 95-percent confidence interval (CI). For specific adverse events, many of which are very rare, we used exact conditional methods to estimate odd ratios (ORs). The quality of evidence was assessed using the Grades of Recommendation, Assessment, Development, and Evaluation (or GRADE) approach.

Results

In total, 35 studies met inclusion criteria. All studies reported on the efficacy of SJW, and 34 addressed safety. Risk of bias in included studies varied: Ten studies obtained a “good” quality rating, 14 studies were rated “fair,” and 11 were rated “poor” quality.

Key Question 1

We found moderate evidence (due to unexplained heterogeneity between studies) that, compared with placebo, SJW is associated with improvement in depression symptoms. SJW groups reported significantly more treatment responders, usually defined by study authors as a 50-percent reduction in Hamilton Rating Scale for Depression scores (RR 0.65; CI 0.51, 0.84; I2 79%; 18 RCTs; n=2,922), and participants receiving SJW had significantly lower depression scale scores (SMD 0.49; CI 0.23, 0.74; 16 RCTs; I2 89%, n=2,888) than participants receiving a placebo. Sensitivity analyses showed very similar results when excluding poor quality studies. There is low quality evidence of no statistically significant differences in the number of patients in remission (RR 0.60; CI 0.22 to 1.66; 10 RCTs; I2 94%).

Only two studies assessed quality of life and compared effects of SJW with placebo or with standard antidepressant medication.

Most (34 of 35) of the included studies addressed the safety of SJW, but rigor of assessment varied greatly. In the included RCTs, there was moderate evidence that SJW is not more likely to cause adverse events than placebo, overall (OR 0.83; CI 0.62, 1.13; 13 RCTs). However, specific adverse events, such as neurologic/nervous system and organ system (e.g., eye, ear, liver, renal, reproductive) adverse events, were more likely in those taking SJW. Furthermore, the adverse events assessments were limited and inadequate for rare adverse events.

Key Question 1a

We found only one study examining the use of SJW used adjunctive to standard antidepressant treatment (medication or psychotherapy). Therefore, the review is unable to assess whether SJW is more effective as monotherapy than as an adjunctive therapy. The existing evidence for SJW is based on monotherapy research.

Key Question 1b

We found only one study that compared two different standardized extracts and three studies that compared different dosages, none of which found statistically significant differences. Several studies did not specify the extract of SJW used. Of those that did, the most common extract was LI 160 (0.3% hypericin, 1–4% hyperforin). A comparison across studies did not indicate systematic differences in outcomes depending on the extract used (outcome responders p=0.347; depression scale scores p=0.127; remission p=0.371).

Key Question 1c

Analyses did not suggest that the effectiveness or safety of SJW varies by depression severity, but the existing research is primarily based on combined mild and moderate depression patient samples and there is a lack of research studies in severe depression.

The review did not find sufficient evidence to estimate the treatment effect of SJW compared with placebo for mild depression alone or severe depression alone. Three studies provided results for patients with moderate depression compared with placebo and found statistically significant effects in the number of responders and continuous depression outcome in the individual studies, but confidence intervals in the pooled analyses did not suggest a statistically significant difference compared with placebo. The treatment effects in the largest subgroup (combined mild and moderate depression) were similar to the main analysis that included all studies, and a meta-regression did not show statistically significant effects of an association between the depression severity and the size of the treatment effect of SJW compared with placebo (outcome responders p=0.798; depression scale scores p=0.365; remission p=0.159).

Key Question 1d

In the included monotherapy RCTs comparing SJW with standard antidepressant medications, there was moderate evidence that those patients taking antidepressants experienced more adverse events overall (OR 0.67; CI 0.56, 0.81; 11 RCTs). Compared with such antidepressants as selective serotonin reuptake inhibitors (SSRIs), there was low quality evidence showing that SJW is associated with fewer specific adverse events, including gastrointestinal (OR 0.43; CI 0.34, 0.55; 15 RCTs) and neurologic (OR 0.29; CI 0.24 to 0.36; 15 RCTs) adverse events. We identified only one study reporting a comparison with psychotherapy. The rigor of adverse event assessments and reporting varied greatly, comparative analyses were potentially limited due to the lack of statistical power to show differences in individual rare events, and RCTs addressed only a limited range of potential adverse events.

Key Question 1e

We found no systematic differences in treatment responders (RR 0.99; CI 0.88, 1.11; 17 RCTs, I2 53%; moderate evidence), depression scale scores (SMD 0.03; CI 0.15, 0.21; 14 RCTs; I2 74%; moderate evidence), or patients in remission (RR 0.86; CI 0.61, 1.20; 7 RCTs; I2 29%; low evidence) comparing SJW and antidepressant medications used to treat adults with mild or moderate depression. The effects for the outcome responders and depression scale scores remained stable when limiting analysis to RCTs reporting a power calculation and with sufficient statistical power to identify an effect. However, the quality of these identified studies was limited. Studies reporting on remission were also limited in study quality, and the statistical power to detect differences between interventions was unclear. Only one study compared SJW and psychotherapy. There is a lack of data on quality of life. The included studies showed the efficacy of SJW as comparable to antidepressant medication, with SJW being neither inferior nor superior for the treatment of mild or moderate depression.

Conclusions

The review showed SJW given as monotherapy for mild and moderate depression is superior to placebo in improving symptoms and not significantly different from antidepressant medication; however, there was evidence of substantial heterogeneity between studies. SJW adverse events reported in included RCTs were comparable to placebo groups, and there were fewer compared with antidepressant medication; however, adverse event assessments were limited and inadequate for rare events, and thus we have limited confidence in this conclusion.