Using Complementary and Alternative Medicines for Depression
Maurizio Fava, MD
Department of Psychiatry, Harvard Medical School and Massachusetts General Hospital, Boston
According to the NCCAM,1 complementary refers to medication used in conjunction with conventional medicine, whereas alternative refers to treatments used instead of conventional medicine.
Overview of CAM Treatments
Patients with psychiatric disorders are increasingly using CAM therapies. For example, approximately 50% of patients with MDD have used at least 1 CAM in the past year,2,3 and most respondents do not disclose this use to their psychiatrists.4 Therefore, clinicians must inquire about and be able to discuss the use of CAMs with patients to offer up-to-date advice about the risks and benefits of these types of therapies. Although evidence on CAMs in MDD is limited, this activity reviews the following selected CAM treatments: omega-3 fatty acids, folate, SAM-e, and St John’s wort.
Omega-3 Fatty Acids
Omega-3 fatty acids are essential fatty acids; they are not manufactured by the body and must be taken in as part of the diet, with the primary source being fish. According to the AHA, omega-3 fatty acids have several cardiovascular benefits, including a decreased risk for arrhythmias and thrombosis, decreased triglycerides, decreased atherosclerosis, improved endothelial function, possible lowered blood pressure, and reduced inflammatory responses.5 These cardiovascular benefits are relevant in psychiatry because many patients also have comorbid medical conditions, possibly due to modifiable lifestyle choices or to metabolic effects of psychotropic medications.
Additionally, evidence suggests that omega-3 fatty acids may help to prevent and ameliorate mood disorders, particularly depressive disorders. For example, cross-national analyses have suggested that higher per capita fish and seafood consumption is associated with lower prevalence rates of MDD,6–8 postpartum depression,9 and bipolar disorder.10 Further, trials11–13 of antidepressants plus adjunctive therapy with omega-3s versus placebo have shown significant improvements on depression rating scale scores with active treatment (AV 1).
Overall, the data support using omega-3 fatty acids as adjunctive treatment for MDD, but appropriate dosage levels and effective omega-3 components or ratios of components need to be established. Fish consumption is an efficient way to increase omega-3 fatty acid intake, but concerns about the mercury levels in seafood may dissuade some people from eating fish. If mercury is a concern, people, especially children and pregnant women, should avoid tilefish, swordfish, shark, and king mackerel.5 Fish oil capsules are also an option to increase omega-3 fatty acid intake, but food supplements are not regulated with the same vigilance as pharmaceuticals, so assessing safety and quality can be problematic.
Folate is a naturally occurring B vitamin found in leafy vegetables, legumes, and fruits; synthetic folate is found in breads and cereals. Folate is necessary for the brain to synthesize the neurotransmitters norepinephrine, serotonin, and dopamine, all of which are involved in depression. A deficiency in folate has been associated with the presence of depression14 and with poor cognitive function15 (which is common in patients with MDD) and may hinder patients’ response to antidepressants14 and contribute to depressive relapse.16 Therefore, folate supplementation may help to reduce initial and residual depressive symptoms.
Antidepressant monotherapy tends to produce relatively low remission rates, and residual symptoms are common.17 Three commercially available folate formulations, folic acid, 5-MTHF (also known as methylfolate and L-methylfolate), and folinic acid, can be used in conjunction with antidepressants to possibly provide beneficial effects for depressive symptoms. Several studies have shown that the adjunctive use of folic acid, 5-MHTF, or folinic acid has enhanced antidepressant response rates (P < .05),18 improved clinical outcomes (P < .01),19 and significantly reduced BDI (P < .02)20 and HDRS scores (P < .01).21 Studies22,23 of 5-MTHF monotherapy have also found significant reductions in HDRS scores (AV 2), as well as comparable response rates to antidepressant monotherapy.24,25
Although the available studies have limitations and, historically, concerns have been raised about the role of folate in increasing cancer risk, masking B12 deficiency, and worsening depressive symptoms, folate is generally well tolerated, and 5-MTHF may be less likely to incur some of these risks.26 Folate monotherapy may benefit certain depressed populations, and augmentation with folate may enhance antidepressant efficacy from treatment initiation or may convert partial and nonresponders into responders or even into remitters. Ultimately, many patients with depression may safely benefit from folate supplementation, whether or not they have abnormal folate levels, although more information is needed about using folate in depression.
SAM-e is a naturally occurring molecule present in all living human cells that is synthesized as part of a multistep pathway (the one-carbon cycle) involving folic acid and vitamin B12. As with folate, SAM-e plays a key role in the synthesis of the neurotransmitters norepinephrine, serotonin, and dopamine. Low serum and CSF SAM-e levels have been reported in patients with MDD.27,28 Although SAM-e has been prescribed in Europe as an antidepressant since the late 1970s, it became available in the US about a decade ago as a dietary supplement with suggested, but not established, treatment applications for MDD, osteoarthritis, fibromyalgia, and liver disease.
Several studies of intravenous and intramuscular monotherapy for depression have shown SAM-e to be either superior29 or comparable30–32 to TCAs and more effective than placebo.30,32 However, parenteral administration may limit the clinical usefulness of this formulation. Monotherapy with oral SAM-e was found to be as effective as TCAs31 and either superior30,33 or comparable34 to placebo. For adjunctive administration, intramuscular SAM-e may accelerate symptom improvement in major depression (AV 3),35 and oral SAM-e may enhance partial treatment response.36
SAM-e is generally well tolerated, and Delle Chiaie et al31 found that considerably fewer patients reported side effects with SAM-e than a TCA. Some adverse events of SAM-e may be gastrointestinal symptoms, headache, anxiety, fatigue, insomnia, tachycardia, and restlessness.30,36 Overall, evidence supports the use of intravenous, intramuscular, and oral SAM-e in the treatment of depression, with adjunctive therapy being possibly the most advantageous use. However, additional studies are needed to support its clinical relevance.
St John’s Wort
St John’s wort (Hypericum perforatum) has constituents that create certain antidepressant-like chemical actions, including inhibition of monoamine oxidase uptake, serotonin uptake, dopamine/norepinephrine uptake, and sodium channel efflux. However, the doses of St John’s wort needed to produce these antidepressant effects are up to 40 times the standard human dose. Since the late 1980s and early 1990s, St John’s wort has been used in Europe for depression and in the US as a dietary supplement.
Studies of St John’s wort have produced mixed results. In mild-to-moderate depression, St John’s wort extracts were superior to placebo; yet, because of methodological issues, St John’s wort could not be determined to be as effective as antidepressants.37 In major depression, no significant differences were found on depression rating scales or in response/remission rates with St John’s wort as monotherapy versus placebo,38 fluoxetine,39 or sertraline40 (AV 4).41 Interestingly, a meta-analysis42 not only noted that St John’s wort was not more effective than antidepressants but also found that the majority of studies that were positive toward the nutraceutical were from German-speaking countries.
St John’s wort may also have side effects, including headache, abdominal discomfort, anorgasma, frequent urination, and swelling. Additionally, concerns have been raised about possible interactions of St John’s wort extracts with other medications,43 so it cannot be considered a benign treatment. In general, current evidence does not support the efficacy of St John’s wort in major depression, and the evidence in mild/minor depression is insufficient to draw conclusions.
Clinicians and patients should be aware that natural treatments are not always safe, and CAMs may have side effects or drug interactions. Patients should also be informed about all of the treatment options available and understand that CAM therapies do not necessarily replace standard medications, especially for major depression, which is a chronic and debilitating disorder. That said, CAM treatments such as omega-3 fatty acids, folate, and SAM-e may be beneficial for patients with mental disorders, including those with depression; however, St John’s wort does not appear to be effective in treating depression. For an in-depth analysis of each of the CAM therapies discussed, please see the supplement, "The Use of Complementary and Alternative Medicine to Achieve Remission in Major Depressive Disorder."
For Clinical Use
- Educate patients about all types of available treatments for MDD and ensure that they understand that CAM treatments are not necessarily safe
- Use omega-3 fatty acids, folate, and SAM-e when appropriate for patients with depression, typically as augmentation of antidepressant therapy
- Avoid using St John’s wort for patients with depression
fluoxetine (Prozac and others), imipramine (Tofranil and others), sertraline (Zoloft and others)
5-MTHF = 5-methyltetrahydrofolate, AHA = American Heart Association, BDI = Beck Depression Inventory, CAM = complementary and alternative medicine, CSF = cerebrospinal fluid, DHA = docosahexaenoic acid, EPA = eicosapentaenoic acid, HDRS = Hamilton Depression Rating Scale, MDD = major depressive disorder, NCCAM = National Center for Complementary and Alternative Medicine, SAM-e = S-adenosyl-L-methionine, TCA = tricyclic antidepressant
Take the online posttest.
- National Center for Complementary and Alternative Medicine, National Institutes of Health, US Department of Health and Human Services. What is CAM? Bethesda, MD: National Center for Complementary and Alternative Medicine; 2007. NCCAM publication D347. http://nccam.nih.gov/health/whatiscam/overview.htm. Accessed December 2, 2009.
- Wu P, Fuller C, Liu X, et al. Use of complementary and alternative medicine among women with depression: results of a national survey. Psychiatr Serv. 2007;58(3):349–356.
- Hsu MC, Moyle W, Creedy D, et al. Use of antidepressants and complementary and alternative medicine among outpatients with depression in Taiwan. Arch Psychiatr Nurs. 2009;23(1):75–85.
- Elkins G, Rajab MH, Marcus J. Complementary and alternative medicine use by psychiatric inpatients. Psychol Rep. 2005;96(1):163–166.
- Kris-Etherton PM, Harris WS, Appel LJ for the AHA Nutrition Committee. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease [published correction appears in Arterioscler Thromb Vasc Biol. 2003;23(2):e31]. Arterioscler Thromb Vasc Biol. 2003;23(2):e20–e30.
- Hibbeln JR. Fish consumption and major depression. Lancet. 1998;351(9110):1213.
- Golding J, Steer C, Emmett P, et al. High levels of depressive symptoms in pregnancy with low omega-3 fatty acid intake from fish. Epidemiology. 2009;20(4):598–603.
- Tanskanen A, Hibbeln JR, Tuomilehto J, et al. Fish consumption and depressive symptoms in the general population in Finland. Psychiatr Serv. 2001;52(4):529–531.
- Hibbeln JR. Seafood consumption, the DHA content of mothers' milk and prevalence rates of postpartum depression: a cross-national, ecological analysis. J Affective Disord. 2002;69(1–3):15–29.
- Noaghiul S, Hibbeln JR. Cross-national comparisons of seafood consumption and rates of bipolar disorders. Am J Psychiatry. 2003;160(12):2222–2227.
- Peet M, Horrobin DF. A dose-ranging study of the effects of ethyl-eicosapentaenoate in patients with ongoing depression despite apparently adequate treatment with standard drugs. Arch Gen Psychiatry. 2002;59(10):913–919.
- Nemets B, Stahl Z, Belmaker RH. Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder. Am J Psychiatry. 2002;159(3):477–479.
- Su KP, Huang SY, Chiu CC, et al. Omega-3 fatty acids in major depressive disorder: a preliminary double-blind, placebo-controlled trial [published correction appears in Eur Neuropsychopharmacol. 2004;14(2):173]. Eur Neuropsychopharmacol. 2003;13(4):267–271.
- Alpert JE, Fava M. Nutrition and depression: the role of folate. Nutr Rev. 1997;55(5):145–149.
- Ramos MI, Allen LH, Mungas DM, et al. Low folate status is associated with impaired cognitive function and dementia in the Sacramento Area Latino Study on Aging. Am J Clin Nutr. 2005;82(6):1346–1352.
- Papakostas GI, Petersen T, Mischoulon D, et al. Serum folate, vitamin B12, and homocysteine in major depressive disorder, part 2: predictors of relapse during the continuation phase of pharmacotherapy. J Clin Psychiatry. 2004;65(8):1096–1098.
- Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006;163(1):28–40.
- Coppen A, Bailey J. Enhancement of the antidepressant action of fluoxetine by folic acid: a randomized, placebo controlled trial. J Affect Disord. 2000;60(2):121–130.
- Godfrey PSA, Toone BK, Carney MWP, et al. Enhancement of recovery from psychiatric illness by methylfolate. Lancet. 1990;336(8712):392–395.
- Coppen A, Chaudhry SSC. Folic acid enhances lithium prophylaxis. J Affect Disord. 1986;10(1):9–13.
- Alpert JE, Mischoulon D, Rubenstein GE, et al. Folinic acid (leucovorin) as an adjunctive treatment for SSRI-refractory depression. Ann Clin Psychiatry. 2002;14(1):33–38.
- Guaraldi GP, Fava M, Mazzi F, et al. An open trial of methyltetrahydrofolate in elderly depressed patients. Ann Clin Psychiatry. 1993;5(2):101–105.
- Di Palma C, Urani R, Agricola R, et al. Is methylfolate effective in relieving major depression in chronic alcoholics? A hypothesis of treatment. Curr Ther Res. 1994;55(5):559–567.
- Crellin R, Bottiglieri T, Reynolds EH. Folates and psychiatric disorders: clinical potential. Drugs. 1993;45(5):623–636.
- Passeri M, Cucinotta D, Abate G, et al. Oral 5'-methyltetrahydrofolic acid in senile organic mental disorders with depression: results of a double-blind multicenter study. Aging (Milano). 1993;5(1):63–71.
- Mischoulon D, Fava M, Stahl SM. In reply to: Frankenburg FR. Folate supplementation: is it safe and effective? J Clin Psychiatry. 2009;70(5):767–769.
- Bottiglieri T, Chary TK, Laundy M, et al. Transmethylation in depression. Ala J Med Sci. 1988;25(3):296–301.
- Bottiglieri T, Godfrey P, Flynn T, et al. Cerebrospinal fluid S-adenosylmethionine in depression and dementia: effects of treatment with parenteral and oral S-adenosylmethionine. J Neurol Neurosurg Psychiatry. 1990;53(12):1096–1098.
- Bell KM, Pion L, Bunney WE Jr, et al. S-adenosylmethionine treatment of depression: a controlled clinical trial. Am J Psychiatry. 1988;145(9):1110–1114.
- Hardy M, Coulter I, Morton SC, et al. S-adenosyl-L-methionine for treatment of depression, osteoarthritis, and liver disease. Evidence Report/Technology Assessment Number 64. AHRQ Publication No. 02-E034. Prepared by Southern California Evidence-based Practice Center under Contract No. 290-97-0001. Rockville, MD: Agency for Healthcare Research and Quality: 2002. http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=hstat1a.section.2161. Accessed November 9, 2009.
- Delle Chiaie R, Pancheri P, Scapicchio P. Efficacy and tolerability of oral and intramuscular S-adenosyl-L-methionine 1,4-butanedisulfonate (SAMe) in the treatment of major depression: comparison with imipramine in 2 multicenter studies. Am J Clin Nutr. 2002;76(5):1172S-1176S.
- Janicak PG, Linpinski J, Davis JM, et al. S-adenosylmethionine in depression. A literature review and preliminary report. Ala J Med Sci. 1988;25(3):306–313.
- Kagan BL, Sultzer DL, Rosenlicht N, et al. Oral S-adenosylmethionine in depression: a randomized, double-blind, placebo-controlled trial. Am J Psychiatry. 1990;147(5):591–595.
- Fava M, Rosenbaum JF, Birnbaum R, et al. The thyrotropin response to thyrotropin-releasing hormone as a predictor of response to treatment in depressed outpatients. Acta Psychiatr Scand. 1992;86(1):42–45.
- Berlanga C, Ortega-Soto HA, Ontiveros M, et al. Efficacy of S-adenosyl-L-methionine in speeding the onset of action of imipramine. Psychiatry Res. 1992;44(3):257–262.
- 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.
- Linde K, Ramirez G, Mulrow CD, et al. St John's wort for depression: an overview and meta-analysis of randomised clinical trials.BMJ. 1996;313(7052):253–258.
- 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.
- Fava M, Alpert J, Nierenberg AA, et al. A double-blind, randomized trial of St John's wort, fluoxetine, and placebo in major depressive disorder. J Clin Psychopharmacol. 2005;25(5):441–447.
- 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.
- Shelton RC. St. John's wort (Hypericum perforatum) in major depression. J Clin Psychiatry. 2009;70(suppl 5):23–27.
- Linde K, Berner MM, Kriston L. St John's wort for major depression. Cochrane Database Syst Rev. 2008;4:CD000448.
- Di YM, Li CG, Xue CC, et al. Clinical drugs that interact with St. John's wort and implication in drug development. Curr Pharm Des. 2008;14(17):1723–1742.