St. John's Wort and Major Depression: a critique of the JAMA trial

The April 18, 2001 issue of the Journal of the American Medical Association (JAMA) published a clinical trial that concluded St. John's wort was "not effective for treatment of major depression" even though results were typical for antidepressant drugs trials using placebos.

The trial, performed in 11 U.S. medical centers, was randomized, double-blind, and placebo-controlled. Two hundred participants diagnosed with major depression took either 300 mg. of a standardized St. John's wort extract three times daily, total of 900 mg, for four weeks or took identically matched placebo. The exact content of standardized constituents was not specified. The SJWE dose was increased to 1,200 mg. daily if there was insufficient improvement by week four. The trial duration was eight weeks.

The main outcome was assessed by the rate of change on a Hamilton Rating Scale for Depression (HAM-D), a questionnaire that rates the severity of depression in patients who are already diagnosed as depressed. The higher the score, the greater the depression. Most people with clinical depression score 14 or more on the HAM-D. Participants in this trial had a minimum score of 20 and a median score of 22 on the HAM-D. Five other rating scales were used as secondary measures. Patients with suicidal tendencies were excluded from the trial, as were those responding strongly to an initial placebo screening.

The authors split the patients improving in the trial into a response subgroup (HAM-D score <= 12 and >= 7) and remission subgroup (HAM-D score <= 7). Of the patients completing the trial, the total in the combined response and remission subgroups was 53.2% in the SJW group and 31.0% in placebo group. Each subgroup individually exhibited a strong trend showing St John's wort to be more effective than placebo, but the results did not reach statistical significance (p=.07 for each subgroup). With another method of analysis using the total number of trial participants, rather than only those who completed the trial (usually a stricter standard of analysis), 14.3% of the patients taking St John's wort experienced a remission of their depression, while only 4.9% of those taking placebo did so. These results reached statistical significance (p=.02). These authors do not report whether the combined results of the response and the remission subgroups reached statistical significance, but the results are typical of drug and placebo responses in antidepressant trials (Mulrow), and trials typically measure the combined groups to demonstrate drug effectiveness.

Adverse effects were experienced in 10% of participants (abdominal discomfort, insomnia in both groups). Headaches were reported more frequently in the SJW group (40% SJW vs 26% placebo). (Shelton)

The authors discredited previous SJW studies claiming systematic biases in evaluation or reporting; nonstandard diagnostic practices, failing to use standardized symptom rating instruments (i.e., HAM-D), short study duration, low depression severity (< 18 on the HAM-D) inexperienced investigators, and other shortcomings. In the cases discussed below, the criticisms appear to be without merit.

At least eight previous St John's wort trials have found the herbal extract therapeutically equivalent to various pharmaceutical antidepressants for mild or moderate symptoms, and with fewer side effects.

St. John's wort vs tricyclic antidepressants

Hypericum extract was found equally as effective as imipramine (a tricyclic antidepressant) at reducing moderate depression in a randomized, double-blind, placebo-controlled trial in 18 centers with 263 participants. All participants were diagnosed with moderate depression. Trial participants had a minimum score of 18 on the HAM-D. For eight weeks, 100 patients took 350 mg. hypericum extract three times daily (total of 1050 mg. daily); 100 patients took 100 mg. imipramine split in three daily doses; 46 patients took placebo three times daily. Hypericum was as effective at reducing the HAM-D score as imipramine; comparable results were seen on two other depression rating scales and quality of life was improved for both groups. For physical symptoms, hypericum was superior to placebo and imipramine. 22% of patients taking hypericum experienced side effects (7 with dry mouth, 8 nausea, 4 constipation, 3 headache, 4 palpitations, 1 dizziness), while 46% of the imipramine group reported side effects (42 with dry mouth, 12 nausea, 7 constipation, 6 headache, 6 palpitations, 7 dizziness). The authors state "...hypericum extract may thus be considered an alternative first choice treatment in most cases of mild to moderate depression without psychotic symptoms." (Philipp)

Another trial performed randomized, double-blind, in 40 German outpatient clinics in parallel fashion confirmed SJW efficacy compared to imipramine. 324 participants diagnosed with mild to moderate depression participated. All patients had a score greater than 18 on the HAM-D. 167 participants took 75 mg. imipramine twice daily; 157 participants took 250 mg. hypericum extract twice daily (total of 500 mg.) for six weeks. The HAM-D and other standard rating scales were significantly improved in both groups. The Hamilton anxiety subscale was improved in the hypericum group relative to imipramine. Authors state that hypericum may be better than imipramine in relieving anxiety associated with depression. In the imipramine group, 41 participants reported dry mouth; sweating dizziness, nausea, asthenia, and headache were also reported; 13 participants in the hypericum group reported dry mouth. The author's state "This hypericum perforatum extract is therapeutically equivalent to imipramine in treating mild to moderate depression, but patients tolerate hypericum better." (Woelk)

Commentary

Tricyclic antidepressants are believed to cause long-term changes in the way nerve endings function. They produce a mild sedative-like effect by counteracting acetylcholine, blocking stimulant chemicals-serotonin and norepinephrine in and out of nerve endings. It takes two-four weeks for their effects to come into play. Many patients stop taking tricyclics due to adverse effects. Shelton's criticized Phillip's trial for use of a low dose of imipramine. The trial used 100 mg imipramine (standard dose starts at 50-100 mg. and doesn't usually exceed 150 mg). Philips et al states in his published trial, in regard to the imipramine dose "The participating doctors would not have accepted higher doses for the treatment of moderate depression owing to the expectation of frequent and severe side effects with consequences for compliance (increased drop out rates from the study) in this patient population" Woelk's trial was criticized by Shelton et al for low depression severity, but a HAM-D baseline score of 18 was required to participate in the trial. This was only 2 points on the scale lower than that in Shelton et al.

St. John's wort vs SSRIs

Hypericum compared to the selective serotonin reuptake inhibitor (SSRI) fluoxetine (prozac) revealed equal effectiveness. This trial was randomized, double-blind in parallel groups. 240 people, diagnosed with mild to moderate depression, having a baseline HAM-D score of 16-24, participated in the study. 126 participants took one 250 mg. tablet twice daily (total 500 mg), and 114 participants took 20 mg. prozac, once daily, for six weeks. The HAM-D and other standard scales were used to assess results, in addition to laboratory tests. The authors state "Analysis of the main efficacy variable rejected the hypothesis of hypericum being inferior to fluoxetine. Thus the two treatments were confirmed to be 'equivalent' with regard to overall antidepressant affect." Six hypericum patients reported GI disturbances; the prozac group reported 9 with agitation, 7 GI disturbances, 5 retching, 4 dizziness, 3 tiredness, 3 anxiety/nervousness, 3 erectile dysfunction. (Schrader)

Commentary

The new class of antidepressants--SSRIs (prozac, zoloft, paxil, luvox, etc.), are believed to exert a pronounced affect on 5-HT serotonin (serotonin is believed to affect depression, mood). SSRI's are not proven to exert a significant advantage over tricyclics in regard to depression (Mulrow). SSRIs are believed effective in about 50% of people, compared to a typical placebo response of 32% (Mulrow). Standard dose for zoloft starts at 25-50 mg. daily and usually doesn't exceed 200 mg. daily. Standard dose for prozac starts at 20-60 mg. and usually doesn't exceed 80 mg. daily.
Schrader's trial was criticized by Shelton for low depression severity. A HAM-D baseline score of 16-24 participated in the trial (indicating mild to moderate depression), and the average was only 2 points lower than than in Shelton et al.

A press release from the American Herbal Products Association (AHPA) has criticized JAMA for printing an incomplete financial disclosure statement of Pfizer-information accompanying the study states that Pfizer, the pharmaceutical company that funded the study, is a manufacturer of both antidepressants and St Johnswort. According to the AHPA release, when the study was conducted Pfizer did not manufacture St. John's wort. Pfizer recently acquired Warner-Lambert, which had a St. John's wort product line, but Pfizer discontinued the product after the acquisition.
References

Mulrow C, Williams J, Trivedi M, Chiquette E, et al. Treatment of Depression: New Pharmacotherapies. Evidence Report/Technology Assessment Number 7-Agency for Health Care Policy and Research. http://www.ahcpr.gov

Philipp M, Kohnen R, Hiller K. Hypericum extract versus imipramine or placebo in patients with moderate depression: randomized multicentre study of treatment for eight weeks. British Medical Journal 319:1534-1539, 1999

Schrader E, et al. Equivalence of St John's wort extract (Ze 117) and fluoxetine: a randomized, controlled study in mild-moderate depression. International Clinical Psychopharmacology 15:61-68, 2000

Shelton C, Keller M, Glenberg A, Dunner D, Hirschfeld R, Thase M, Russell J, et al: Effectiveness of St John's Wort in Major Depression: A Randomized Controlled Trial. JAMA 285(15):1978-1986, 2001