5. Complementary and alternative treatments

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a. St. John's wort

Despite a large number of trials examining St. John's wort (usually in the form of Hypericum perforatum extract), there is no consensus on its efficacy in major depressive disorder. A 2005 Cochrane meta-analysis (1093) provided a summary of treatment studies utilizing St. John's wort for the treatment of major depressive disorder. The published studies demonstrate heterogeneity in methods used and great inconsistency in study outcomes. A number of double-blind studies have demonstrated its superiority over placebo, although some have not (370, 371). In addition, St. John's wort may have better tolerability than TCAs and SSRIs, and several randomized studies have shown noninferiority relative to approved antidepressant medications, although the distinctive taste of St. John's wort extract may have caused some unblinding during the studies.

Among the larger and most rigorous recently published placebo-controlled trials, the studies by Shelton et al. (371) (N=200) and Davidson et al. (370) (N=340) did not demonstrate a difference between St. John's wort and placebo on primary outcome measures, but Lecrubier et al. (1094) found a significant difference between St. John's wort and placebo in mild to moderate depression (N=375). In addition, a recent review of 14 short-term, double-blind trials conducted in outpatients with mild to moderate symptoms of major depressive disorder demonstrated that St. John's wort in doses of 300 mg/day and 1,800 mg/day had efficacy superior to placebo and was generally comparable to low-dose TCA treatment (e.g., 30–150 mg/day of amitriptyline) (105). Side effects were observed in a lower proportion of individuals taking St. John's wort than among those taking a TCA (25% vs. 40%) (105).


b. S-adenosyl methionine

A number of studies have found SAMe to be efficacious in oral doses that range from 800 mg/day to 1,600 mg/day. In a double-blind trial, 15 inpatients with major depressive disorder received oral SAMe or placebo for 21 days (1095). Six of nine patients receiving SAMe demonstrated response as defined by a reduction of 50% or more in HAM-D scores, and depression ratings compared with placebo were significantly lower in the SAMe group than in the placebo group at days 14 and 21. Side effects were mild and transient. In a meta-analysis of studies comparing effects of SAMe with those of TCAs, SAMe was found to have better tolerability and greater efficacy in the treatment of depression, although the doses of TCAs were subtherapeutic in some studies (381). Data from two multicenter studies also demonstrated that parenteral and oral formulations of SAMe were comparable in efficacy to the TCA imipramine (1096), although side effects were significantly more frequent in the imipramine-treated group. In one of the larger controlled trials, which included 293 participants, Pancheri et al. (382) found SAMe (administered intramuscularly at a dose of 400 mg/day) and imipramine (administered by mouth at a dose of 150 mg/day) to be similarly efficacious in a 4-week trial. Other studies have focused on specific subgroups of patients, such as HIV-positive patients and postmenopausal women (1097, 1098).


c. Omega-3 fatty acids

Two large meta-analyses found benefits of omega-3 fatty acids overall in mood disorder trials (384, 385) but also highlighted the heterogeneity of study designs and results. The one monotherapy study of DHA for major depressive disorder in adults did not demonstrate benefit of DHA over placebo (1099), although small trials in major depressive disorder in children and in pregnant women did demonstrate a benefit of monotherapy with omega-3 fatty acids (EPA and DHA) (1100, 1101).


d. Folate

In a study by Coppen and Bailey (389) that included 127 subjects, 94% of women who received fluoxetine and 500 mcg/day of folate responded to treatment, compared with 61% of those who received fluoxetine and placebo (p <0.005). Patients who received folate were also less likely to report side effects (p <0.05).


e. Light therapy

In a meta-analysis, Golden et al. (395) found clinically significant benefit of bright light therapy in seasonal major depressive disorder (eight studies), with a large effect size (0.84), and in nonseasonal major depressive disorder in three studies with a medium effect size (0.53). However, the authors, who were participants of an APA work group on the topic of light therapy, determined that many of the studies of light therapy for mood disorders had methodological flaws, including small sample sizes, with only 13% of the studies they assessed meeting the inclusion criteria for their meta-analysis. Bright light therapy in nonseasonal major depressive disorder was not found to be significantly more efficacious than placebo in trials when used adjunctively in addition to antidepressants. As determined by the APA work group, an adequate placebo condition requires a maximum dose of 300 lux (versus at least 3,000 lux-hours for an active treatment condition for bright light treatment). Randomized, placebo-controlled studies have ranged from 7–42 days in treatment duration, with provision of between 2,500–10,000 lux illuminance of white light, with delivery time between 0.5–6 hours/day. Some published studies were found to have bright light exposure at levels too high to constitute a scientifically valid control condition, and the difficulty in creating a reasonable control condition for bright light therapy may have contributed to the limited evidence base to date. Control groups have included lower doses of white light, red light, active light avoidance, negative air ionizer, and no treatment. Despite heterogeneity of designs and results, evidence supports the efficacy of bright light as a monotherapy for acute major depressive disorder. Individualization of a regimen may be required in terms of lux, length of exposure, and time of day of delivery. In addition, patients should be monitored for emergence of mania during treatment (1102).


f. Acupuncture

Assessment of the evidence base for acupuncture is complicated by the fact that many reports are in Asian languages and therefore often overlooked by English language literature searches. Results from studies in acupuncture are difficult to interpret, because the description of the methods is often limited and there is variability in diagnosis and in interventions (403). Wang et al. (407) published a recent meta-analysis of eight trials of acupuncture and depression chosen from more than 200 studies on the basis of having a randomized design, specific diagnostic criteria for depression, and specific acupuncture interventions (manual, electro-acupuncture, or laser). The depression criteria included DSM, International Classification of Diseases, and Chinese Classification of Mental Disorders criteria. The meta-analysis did not demonstrate a benefit of acupuncture over control conditions on either response rates or remission but was based on a small number of trials with variable methodological quality. Consequently, additional systematic study is required to assess the role of acupuncture for major depressive disorder.

There have been few randomized, double-blind, placebo-controlled studies to inform the use of acupuncture for depression. In one published study, Allen et al. (405) compared 38 women, ages 18–45 years, who were assigned to three different groups: an acupuncture regimen specifically chosen to address their depression, sham acupuncture, or a waiting-list control condition. The active acupuncture group experienced a significantly greater remission rate. However, Allen et al. (406) failed to replicate these results in a larger randomized trial, in which 151 patients with major depressive disorder received acupuncture specific for depression, sham acupuncture, or a waiting-list condition. After 8 weeks, there was no evidence of benefit for the acupuncture intervention specific for depression, compared with sham acupuncture or the waiting-list condition. Response rates were 22% for the depression-specific acupuncture treatment and 39% for the sham acupuncture treatment.

In another randomized study, Luo et al. (404) compared effects of electro-acupuncture combined with placebo medication to the effects of amitriptyline in 241 inpatients. Electro-acupuncture appeared equivalent to amitriptyline at a dose of 150–175 mg/day in treating depression, with greater improvement for symptoms of anxiety, cognitive problems, and somatization; it also resulted in a lower side effect burden than amitriptyline. However, no group received the placebo medication alone, and no sham treatment was used to elucidate nonspecific benefits of acupuncture treatment.


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