Depression and Complementary Health Approaches:
What the Science Says

Natural Products

Omega-3 Fatty Acids

Some evidence suggests that omega-3 fatty acid supplementation may provide a small effect in adjunctive therapy in patients with a diagnosis of major depressive disorder (MDD) and on depressive patients without a diagnosis of MDD. Most trials have been adjunctive studies. Although the data are promising, controlled trials of omega-3 fatty acids as a monotherapy are inconclusive compared to standard antidepressant medicines, and it remains unclear that a mechanism is present to suggest that a pharmacological or biological antidepressant effect exists.

The Evidence Base

• The evidence base on efficacy of omega-3 fatty acids for depression consists of many randomized controlled trials, as well as several systematic reviews and meta-analyses. Most randomized controlled trials of omega-3 fatty acids for MDD have been adjunctive studies, and it is important to note that evidence is limited due to variations in formulations and dosages of omega-3s, small sample size, mixed studies of augmentation and monotherapy, and durations of trials.

Efficacy

• The 2010 American Psychiatric Association Task Force on Complementary and Alternative Medicine report found that adjunctive eicosapentaenoic acid (EPA) or the combination of EPA and docosahexaenoic acid (DHA) appear most useful, with less evidence for DHA alone. The report concluded that “the established general health benefits of omega-3 fatty acids, epidemiologic evidence, at most modest efficacy data, and low safety risks make omega-3 fatty acids a reasonable augmentation strategy in MDD.”
• A 2013 review of clinical evidence of omega-3 fatty acids in psychiatry concluded that based on their safety profile and their potential efficacy, particularly in mood disorders, omega-3s deserve further study. The authors suggest that omega-3 fatty acids appear to be a well-tolerated adjunctive therapy for adults with depression, since most clinical trials have used omega-3 fatty acids as adjunctive agents.
• A 2008 Cochrane review of one study involving 75 participants investigating the efficacy of ethyl-EPA as an adjunctive treatment for participants with bipolar disorder found some positive benefits for depressive symptoms but not for mania.
• The most recent and rigorous double-blind, randomized controlled trial comparing EPA and DHA as monotherapy for MDD in 1,954 participants found that neither EPA-enriched nor DHA-enriched fatty acid supplementation was superior to placebo.

Safety

• Omega-3 fatty acid supplements are generally safe and well-tolerated. When side effects do occur, they typically consist of minor gastrointestinal symptoms and fishy aftertaste.
• There is some concern that omega-3 supplements may extend bleeding time. The risk appears to be minimal, and should never be used in patients who take drugs that affect platelet function. It is important to discuss any potential herb-drug interactions with patients if they are considering using omega-3 fatty acids.
• It is uncertain whether people with fish or shellfish allergies can safely consume fish oil supplements and should not be used in such patients.

St. John’s Wort (Hypericum perforatum)

There is some evidence that suggests St. John’s wort (Hypericum perforatum) may have an effect on mild to moderate major depressive disorder (MDD) for a limited number of patients, similar to standard antidepressants, but the evidence is far from definitive. Although some studies have demonstrated a slight efficacy over placebo, others contradict these findings.

The significant herb-drug interactions of St. John’s wort (Hypericum perforatum) are important safety considerations and may outweigh any benefit of its use.

The Evidence Base

• The evidence base on efficacy of Hypericum perforatum for depression consists of many randomized controlled trials and several systematic reviews and meta-analyses. Many of the studies in which findings were favorable were conducted in German-speaking countries.

Efficacy

• The 2010 American Psychiatric Association Task Force on Complementary and Alternative Medicine report states that St. John’s wort (Hypericum perforatum) may eventually become a reasonable treatment for mild to moderate major depressive disorder (MDD) for a limited number of individuals, although not all recent studies for the treatment of MDD demonstrated efficacy over placebo. The report also indicates any potential efficacy is only a greater consensus and support from studies in mild to moderate MDD.
• A 2015 systematic review and network meta-analysis of 66 studies involving 15,161 patients examined whether antidepressants and other agents, including St. John’s wort (Hypericum perforatum), may be more effective than placebo in the primary care setting. The reviewers found that St. John’s wort (Hypericum perforatum), as well as some other agents, showed some positive results, but because the current evidence is limited, conclusions about their place in clinical practice cannot be drawn.
• In a 2011 randomized controlled trial examining the treatment of minor depression with St. John’s wort (Hypericum perforatum) or citalopram over the course of 12 weeks, neither St. John’s wort nor citalopram showed any benefit over placebo.
• A 2012 study examined longer-term efficacy of St. John’s wort (Hypericum perforatum) versus sertraline and placebo in patients with major depressive disorder and found that St. John’s wort, sertraline, and placebo produced similar treatment effects over the course of 26 weeks.
• A 2008 Cochrane review of 29 studies involving 5,489 patients with depression concluded that the formulations of St. John’s wort (Hypericum perforatum) extract tested in these trials were better than placebo in patients with major depression and were similarly effective as standard antidepressants.

Safety

• Drug interactions with St. John’s wort (Hypericum perforatum) limit use and are important safety considerations.
• Combining St. John’s wort (Hypericum perforatum) and certain antidepressants can lead to serotonin syndrome, with dangerouse symptoms ranging from tremor and diarrhea to very dangerous confusion, muscle stiffness, drop in body temperature, and even death.
• Other side effects of St. John’s wort (Hypericum perforatum) are usually minor and uncommon and may include upset stomach and sensitivity to sunlight. Also, St. John’s wort may worsen feelings of anxiety in some people.
• A rare, but possible side effect of taking St. John’s wort (Hypericum perforatum) is psychosis. Those with certain mental health disorders, such as bipolar disorder, are at risk of experiencing this rare side effect. Therefore, it is important to discuss this potential side effect with patients who are considering using St. John’s wort and encourage discontinuation of the herb if they experience a worsening of symptoms.
• Taking St. John’s wort (Hypericum perforatum) increases the activity of cytochrome P450 3A4 (CYP3A4) enzyme and reduces plasma concentrations and can weaken many prescription medicines, such as:
  • Antidepressants
  • Oral contraceptives
  • Cyclosporine
  • Digoxin
  • Some HIV drugs including indinavir
  • Some chemotherapeutic agents including irinotecan
  • Warfarin and other anticoagulants

S-Adenosyl-L-Methionine (SAMe)

Current scientific evidence does not support the use of SAMe for the treatment of depression.

The Evidence Base

• The evidence base on efficacy of SAMe for the treatment of depression consists of many randomized controlled trials; however, most of these trials were not rigorous because of their short duration, small sample size, and extensive methodological flaws. Early human studies utilized parenteral administration of SAMe, but more recent studies have used oral administration of stable SAMe preparations.

Efficacy

• The 2010 American Psychiatric Association Task Force on Complementary and Alternative Medicine report suggest the need for more rigorous studies “to determine the efficacy of SAMe and its comparative efficacy to standard antidepressants.”
• Preliminary results from a 2014 randomized controlled trial in a subsample of 144 participants with major depressive disorder (MDD) who received SAMe, escitalopram, or placebo for 12 weeks provided some evidence for the use of SAMe in the treatment of MDD. However, in the parent study, SAMe failed to demonstrate any advantage over placebo for MDD.
• A 2002 Agency for Healthcare Research and Quality meta-analysis of SAMe for depression found no statistically significant difference in outcomes compared to conventional antidepressants. Compared to placebo, treatment with SAMe was associated with clinically significant improvements equivalent to a partial response to treatment.

Safety

• A 2009 review of evidence for SAMe for the treatment of MDD concluded that there is insufficient evidence examining whether the oral preparations of SAMe can be safe or efficacious when used as adjunctive treatment for patients with MDD who are unresponsive to antidepressants.
• Information on the long-term safety of SAMe is limited and inconclusive. However, in one study of alcohol-related liver disease in which participants took SAMe for 2 years, no serious side effects were reported.
• SAMe may decrease the effects of levodopa. It is also possible that SAMe might interact with drugs and dietary supplements that increase levels of serotonin, including some antidepressants, L-tryptophan, and St. John’s wort, but the evidence for such interactions is very limited.
• SAMe promotes the growth of Pneumocystis, a fungus that can cause pneumonia in people with suppressed immune systems. It is possible that taking SAMe might increase the likelihood or severity of Pneumocystis infection in people who are HIV positive and should never be used in these patients.
• Side effects of SAMe appear to be uncommon, and when they do occur they are usually problems such as nausea or digestive upsets.

Inositol

Current scientific evidence does not support the use of inositol for the treatment of depression.

The Evidence Base

• The current evidence for efficacy of inositol for depression consists of inadequate, small, randomized controlled trials and a single meta-analysis, as well as inclusion in a few systematic reviews along with other nutrient-based therapies for depressive disorders.

Efficacy

• A 2014 meta-analysis of seven randomized controlled trials (two bipolar studies, one bipolar and major depressive disorder (MDD) study, two MDD studies, and two premenstrual dysphoric disorder (PMDD) studies) involving 242 participants found no significant treatment effect of inositol for depressed patients. However, inositol showed a trend of efficacy of depressive symptoms over placebo in patients with PMDD.
• A 2004 Cochrane review of four double-blind, randomized controlled trials involving a total of 141 participants found no clear evidence of a therapeutic benefit.

Safety

• There is a paucity of data on the safety and side effects of inositol. A 2014 meta-analysis of inositol for depression and anxiety disorders found that inositol marginally caused gastrointestinal upset compared with placebo. A 2011 European review on the safety of inositol had similar findings in that inositol induced gastrointestinal side effects such as nausea, flatus, and diarrhea.

Mind and Body Practices

Acupuncture

Current scientific evidence does not support the use of acupuncture for the treatment of depression.

The Evidence Base

• The evidence base on efficacy of acupuncture for depression consists of several randomized controlled trials, systematic reviews, and meta-analyses. Findings from systematic reviews and meta-analyses have been at best inconsistent regarding efficacy, and there are only a few trials comparing manual acupuncture to control conditions. Evidence is limited due to different types of acupuncture studied, duration and frequency of sessions, and methodological flaws, including small sample sizes, and inconsistent randomization and blinding.

Efficacy

• A 2010 Cochrane review of 30 studies involving 2,812 participants found insufficient evidence to support the use of acupuncture for people with depression. There was a high risk of bias in most of the trials included in the review, limiting any conclusions based on scientific rigor.
• The 2010 American Psychiatric Association Task Force on Complementary and Alternative Medicine report found that evidence for the efficacy of acupuncture as a primary treatment of depression is at best inconclusive, and studies to date have been unable to demonstrate efficacy of acupuncture compared to a control for the treatment of MDD.

Safety

• Relatively few complications from using acupuncture have been reported. Still, complications have resulted from the use of nonsterile needles and improper delivery of treatments.
• When not delivered properly, acupuncture can cause serious adverse effects, including skin infections, punctured organs, pneumothoraces, and injury to the central nervous system.

Music therapy

There is some limited evidence that suggests music therapy may provide an improvement in mood.

The Evidence Base

• The evidence base on efficacy of music therapy for depression consists of a few randomized trials and a few systematic reviews.

Efficacy

• Findings from a 2008 Cochrane review of five studies suggest that music therapy is accepted by people with depression and is associated with improvements in mood. However, because evidence is limited by the small number and low methodological quality of studies, its effectiveness remains unclear.

Safety

• There are no adverse effects associated with music therapy.

Relaxation Training

Evidence suggests that relaxation training is better than no treatment in reducing symptoms of self-reported depression, but is not as beneficial as psychological therapies.

The Evidence Base

• The evidence base on efficacy of relaxation training for depression consists of several randomized or quasi-randomized controlled trials and a 2008 Cochrane review.

Efficacy

• A 2008 Cochrane review of 11 studies found that relaxation techniques were more effective at reducing self-rated symptoms of depression than no or minimal treatment, but they were not as effective as a psychological intervention.

Safety

• Relaxation techniques are generally considered safe for healthy people. However, occasionally, people report unpleasant experiences such as increased anxiety, intrusive thoughts, or fear of losing control.
• There have been rare reports that certain relaxation techniques might cause or worsen symptoms in people with epilepsy or certain psychiatric conditions, or with a history of abuse or trauma.

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