Evidence-Based Reviews

CAM for your depressed patient: 6 recommended options

Current Psychiatry. 2009 October;8(10):39-47

References

1. Kessler RC, Soukup J, Davis RB, et al. The use of complementary and alternative therapies to treat anxiety and depression in the United States. Am J Psychiatry. 2001;158(2):289-294.

2. Phillips B, Ball C, Sackett D, et al. Oxford University Centre for Evidence Based Medicine levels of evidence and grades of recommendation (March 2009). Available at: http://www.cebm.net/index.aspx?o=1025#levels. Accessed August 19, 2009.

3. Pilkington K, Kirkwood G, Rampes H, et al. Yoga for depression: the research evidence. J Affect Disord. 2005;89(1-3):13-24.

4. Blumenthal JA, Babyak MA, Doraiswamy PM, et al. Exercise and pharmacotherapy in the treatment of major depressive disorder. Psychosom Med. 2007;69(7):587-596.

5. Dunn AL, Trivedi MH, Kampert JB, et al. Exercise treatment for depression: efficacy and dose response. Am J Prev Med. 2005;28(1):1-8.

6. Legrand F, Heuze JP. Antidepressant effects associated with different exercise conditions in participants with depression: a pilot study. J Sport Exercise Psychol. 2007;29(3):348-364.

7. Gregory RJ, Schwer Canning S, Lee TW, et al. Cognitive bibliotherapy for depression: a meta-analysis. Professional Psychology: Research and Practice. 2004;35(3):275-280.

8. Floyd M, Scogin F, McKendree-Smith NL, et al. Cognitive therapy for depression: a comparison of individual psychotherapy and bibliotherapy for depressed older adults. Behav Modif. 2004;28(2):297-318.

9. Burns DD. Feeling good: the new mood therapy. New York, NY: HarperCollins; 1980.

10. Linde K, Berner MM, Kriston L. St John’s Wort for major depression. [update of Cochrane Database Syst Rev. 2005;(2):CD000448; PMID: 15846605]. Cochrane Database Syst Rev. 2008(4):000448.

11. Rahimi R, Nikfar S, Abdollahi M. Efficacy and tolerability of Hypericum perforatum in major depressive disorder in comparison with selective serotonin reuptake inhibitors: a meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33(1):118-127.

12. Kasper S, Gastpar M, Müller WE, et al. Efficacy of St. John’s wort extract WS 5570 in acute treatment of mild depression: a reanalysis of data from controlled clinical trials. Eur Arch Psychiatry Clin Neurosci. 2008;258(1):59-63.

13. Shelton RC, Keller MB, Gelenberg A, et al. Effectiveness of St John’s wort in major depression: a randomized controlled trial. JAMA. 2001;285(15):1978-1986.

14. Hypericum Depression Trial Study Group. Effect of Hypericum perforatum (St. John’s wort) in major depressive disorder: a randomized controlled trial. JAMA. 2002;287(14):1807-1814.

15. Mischoulon D, Fava M. Role of S-adenosyl-L-methionine in the treatment of depression: a review of the evidence. Am J Clin Nutr. 2002;76(suppl):1158S-1161S.

16. Hardy ML, Coulter I, Morton SC, et al. S-adenosyl-L-methionine for treatment of depression, osteoarthritis, and liver disease [comment in ACP J Club. 2003;139(1):20]. Evid Rep Technol Assess (Summ). 2003;Aug(64):1-3.

17. Shippy RA, Mendez D, Jones K, et al. S-adenosylmethionine (SAM-e) for the treatment of depression in people living with HIV/AIDS. BMC Psychiatry. 2004;4:38.-

18. Alpert JE, Papakostas G, Mischoulon D, et al. S-adenosyl-L-methionine (SAMe) as an adjunct for resistant major depressive disorder: an open trial following partial or nonresponse to selective serotonin reuptake inhibitors or venlafaxine. J Clin Psychopharmacol. 2004;24(6):661-664.

19. Lin PY, Su KP. A meta-analytic review of double-blind, placebo-controlled trials of antidepressant efficacy of omega-3 fatty acids. J Clin Psychiatry. 2007;68(7):1056-1061.

20. Freeman MP, Hibbeln JR, Wisner KL, et al. Omega-3 fatty acids: evidence basis for treatment and future research in psychiatry [published correction appears in J Clin Psychiatry. 2007;68(2):338]. J Clin Psychiatry. 2006;67(12):1954-1967.

21. Ross BM, Seguin J, Sieswerda LE. Omega-3 fatty acids as treatments for mental illness: which disorder and which fatty acid? Lipids Health Dis. 2007;6:21.-

22. Appleton KM, Hayward RC, Gunnell D, et al. Effects of n-3 long-chain polyunsaturated fatty acids on depressed mood: systematic review of published trials [comment in Am J Clin Nutr. 2007;85(6):1665-1666; author reply 1666]. Am J Clin Nutr. 2006;84(6):1308-1316.

23. da Silva TM, Munhoz RP, Alvarez C, et al. Depression in Parkinson’s disease: a double-blind, randomized, placebo-controlled pilot study of omega-3 fatty-acid supplementation. J Affect Disord. 2008;111(2-3):351-359.

24. Su KP, Huang SY, Chiu TH, et al. Omega-3 fatty acids for major depressive disorder during pregnancy: results from a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2008;69(4):644-651.

25. Grenyer BF, Crowe T, Meyer B, et al. Fish oil supplementation in the treatment of major depression: a randomised double-blind placebo-controlled trial. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31(7):1393-1396.

26. Rees AM, Austin MP, Parker GB. Omega-3 fatty acids as a treatment for perinatal depression: randomized double-blind placebo-controlled trial. Aust N Z J Psychiatry. 2008;42(3):199-205.

27. Rogers PJ, Appleton KM, Kessler D, et al. No effect of n-3 long-chain polyunsaturated fatty acid (EPA and DHA) supplementation on depressed mood and cognitive function: a randomised controlled trial. Br J Nutr. 2008;99(2):421-431.

28. Jazayeri S, Tehrani-Doost M, Keshavarz SA, et al. Comparison of therapeutic effects of omega-3 fatty acid eicosapentaenoic acid and fluoxetine, separately and in combination, in major depressive disorder. Aust N Z J Psychiatry. 2008;42(3):192-198.

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Data selected from double-blind RCTs totaling 217 patients with mild depression [Hamilton Depression Rating Scale (HDRS) scores 12 Studies routinely show that treating MDD with St. John’s wort is comparable to using tricyclic or SSRI antidepressants.

Side effects with St. John’s wort generally are no different than with placebo and significantly less than with comparison treatments. Even so, using St. John’s wort instead of SSRIs for MDD remains controversial.

Studies vs SSRIs. Many of the favorable St. John’s wort trials were conducted in Europe, particularly in Germany. Two large RCTs conducted in the United States reported that the St. John’s wort standardized extract LI-160 was not more effective than placebo, but neither could be clearly interpreted as negative for St. John’s wort:

In an 8-week trial, St. John’s wort and placebo groups improved significantly but at unusually low rates. The remission rate with St. John’s wort was small but significantly higher than with placebo.¹³
A study sponsored by the National Institute of Mental Health compared St. John’s wort, 900 to 1,500 mg/d; sertraline, 50 to 100 mg/d; and placebo in 340 adults with MDD. No positive effects were found for St. John’s wort or sertraline.¹⁴

Side effects. St. John’s wort can affect blood levels of circulating medications metabolized by the cytochrome P450 liver enzyme system, including tricyclic antidepressants. Case studies have reported pregnancy from oral contraceptive failure, skin rashes, headache, and mania with St. John’s wort use. Although these reports are disturbing, St. John’s wort’s side effects when compared with SSRIs have been less frequent (40% vs 49%) and milder (clinical trial dropout rate 2% vs 7%).¹¹

Conclusion. Standardized extracts of St. John’s wort—particularly WS5570, 300 mg tid, and ZE117, 250 mg bid—appear to be effective treatments, especially for mild-to-moderate MDD. Because St. John’s wort is available without prescription and can interact with SSRIs or other antidepressants:

care is required for its complementary use
it is important to ask if patients are using St. John’s wort on their own.

St. John’s wort is used as a first-line depression treatment in Europe, but U.S. physicians may be less familiar with its potential interactions with other medications. We recommend that you consider St. John’s wort:

Clinical Point

Consider St. John’s wort for first-line use only when you can adequately gauge its effects on your patient’s other medications

for first-line use only when you can adequately gauge its effects on your patient’s other medications
especially for depressed patients who cannot tolerate SSRIs.

SAMe is a metabolite involved in bio-synthesis of norepinephrine, serotonin, and dopamine.¹⁵ SAMe salts (such as 1,4-butanedisulfonate) are used as an over-the-counter supplement for depression treatment. Dozens of RCTs show SAMe has greater efficacy than placebo and positive effects comparable to those of standard antidepressants. In a meta-analysis of 28 RCTs by the Agency for Healthcare Quality and Research, SAMe produced significantly greater symptom improvement compared with placebo.¹⁶

SAMe has become a popular alternative treatment for depression since its introduction to the United States in the late 1990s, but it has been studied in only 2 U.S. open trials. One showed SAMe to be very effective in reducing depressive symptoms in patients with HIV/AIDS.¹⁷ The other found a 50% response rate and 43% remission rate with adjunctive SAMe, 800 to 1,600 mg/d for 6 weeks, in 30 adults with MDD who failed to respond adequately to SSRIs or the serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine. The most common side effects were gastrointestinal (GI) symptoms and headaches.¹⁸ This open trial led to an ongoing National Institutes of Health-sponsored RCT on the safety and efficacy of SAMe for patients with treatment-resistant depression.

Conclusion. SAMe appears to have a faster onset of antidepressant effect than standard SSRIs or SNRIs and a favorable side-effect profile, which make the lack of rigorous trials in the United States striking. We recommend that you consider SAMe:

Clinical Point

SAMe could be useful as a complementary treatment to speed the onset of antidepressant effects

as an adjunct in patients with incomplete response to standard treatments
as a complementary treatment to speed onset of antidepressant effects.

Polyunsaturated fatty acids (PUFAs), usually from fish oils, have long been popular nutritional supplements because of their beneficial effects on cholesterol and cardiovascular health. Omega-3 and omega-6 fatty acids are the most common PUFAs. The omega-3 PUFAs include eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).

Four meta-analyses independently looked at largely the same dozen RCTs through 2006 and found that 1 to 2 grams daily of omega-3 PUFAs was significantly more effective at reducing depressive symptoms than placebo.^19-22 Other data suggest that omega-3 PUFAs can induce depression remission in depressed Parkinson’s disease patients²³ and depressed pregnant women.²⁴ Since 2006, however, findings have been inconsistent. Several trials have found PUFAs no more effective than placebo.^25-27