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Leveraging CAM to Treat Depression and Anxiety

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Leveraging CAM to Treat Depression and Anxiety Amanda E. Olagunju, DO; Leveraging CAM to treat Heidi Gaddey, MD Department of Family Medicine, Langley Hospital, depression and anxiety Langley Air Force Base, VA (Dr. Olagunju); Department of Family Medicine, David Grant Conventional medications and psychotherapy are still Medical Center, Travis Air Force Base, CA (Dr. Gaddey) first-line treatments, but certain complementary and amanda.olagunju@gmail. alternative strategies have value as adjunctive measures. com The authors reported no potential conflict of interest relevant to this article. The views expressed in this article lmost 8% of Americans ages ≥ 12 years have depression are those of the authors and do not PRACTICE necessarily reflect the official policy and 19.1% of Americans ages ≥ 18 years have experienced or position of the US government or any other agency, organization, RECOMMENDATIONS 1,2 an anxiety disorder in the past year. Furthermore, sui- employer, or company. ❯ Consider standardized A cide, which can result from depression and anxiety, is the 10th preparations of St. John’s leading cause of death in the United States, claiming about 40,000 wort for the treatment of 3 mild to moderate depression to 49,000 lives per year since 2012, with increasing yearly rates. in certain patients. A While multiple conventional medication and therapy treatments are available, patients remain interested in complementary and ❯ Encourage patients with alternative medicine (CAM) options. According to the National depression or anxiety to engage in exercise and Center for Complementary and Integrative Health, more than 30% 4 meditation to help with of American adults use CAM treatments. symptom management. A This article provides an overview of the evidence for com- monly used CAM treatments for unipolar depression and anxiety ❯ Consider methylfolate in adults. It is designed to serve as a useful resource when patients and S-adenosyl methionine as adjunctive treatments to are interested in looking beyond conventional medications. improve depression. B Strength of recommendation (SOR) St. John’s wort: A Good-quality patient-oriented evidence ‘Yes’ for depression; ‘no’ for anxiety B Inconsistent or limited-quality Hypericum perforatum, more commonly known as St. John’s patient-oriented evidence wort, is a widely used antidepressant, especially in Europe C Consensus, usual practice, opinion, disease-oriented where it is prescribed, rather than offered over the counter as it evidence, case series is here. Its mechanism of action is not completely understood because its various constituents have different neuropharma- cologic activities.5,6 A 2008 Cochrane review evaluated 29 randomized, dou- ble-blind studies (N = 5489) that compared St. John’s wort with placebo or standard antidepressants in the treatment of de- pression.7 St. John’s wort was found to be superior to placebo and comparable to standard antidepressants. More recently, a 2017 meta-analysis of 27 studies (N = 3808) had similar find- ings.8 In patients with mild-to-moderate depression, St. John’s wart produced rates of remission that were comparable to those produced by selective serotonin reuptake inhibitors (SSRIs) but with a lower discontinuation rate. CONTINUED MDEDGE.COM/FAMILYMEDICINE VOL 69, NO 5 | JUNE 2020 | THE JOURNAL OF FAMILY PRACTICE 221 ❚ Mood disorders other than depres- tive observational study evaluated the cere- sion. Studies do not support a role for St. John’s bral spinal fluid of 33 patients with refractory wort in the treatment of anxiety disorders. depression. The authors found metabolic ab- There are no trials that assess the efficacy of normalities in the cerebrospinal fluid of most St. John’s wort for the reduction of symptoms of those patients, the most common of which of general anxiety disorder as a primary out- was folate deficiency in 12 patients despite come of treatment. Some small clinical trials normal serum folate levels.15 have investigated the efficacy of St. John’s wort Additionally, current understanding in obsessive-compulsive disorder and social of the role of the Methylenetetrahydrofo- anxiety disorder. In those studies, St. John’s late reductase (MTHFR) gene and the folate wort performed no better than placebo.9,10 cycle in depression supports a potential role ❚ A few words of caution. Preparations of methylfolate in depression treatment.16 of St. John’s wort in the United States are not The MTHFR gene encodes for an enzyme standardized, so St. John’s wort should be called MTHFR. The MTHFR enzyme converts used in America with caution. Furthermore, 5,10-MTHF to 5-MTHF, which then crosses long-term use of St. John’s wort for depres- the blood–brain barrier and donates a methyl IMAGE: WILL & DENI MCINTYRE/ SCIENCE SOURCE sion is questionable given that most studies group for the conversion of homocysteine have evaluated only up to 12 weeks of use.8 to methionine. Methionine is a precursor to If used, studies indicate that the St. John’s monoamine neurotransmitters. Thus, de- In patients wort extract that should be used is 0.3% hy- creased expression of the MTHFR gene leads with mild- pericin or 5% hyperforin administered in a to decreased methylfolate levels, which, in to-moderate dosage of 300 to 400 mg tid.7,8,11 Physicians turn, potentially leads to insufficient neu- depression, and patients can use www.consumerlabs. rotransmitter synthesis and homocysteine St. John’s wort com to find St. John’s wort brands that have excess. produced rates met specified quality criteria based on inde- MTHFR gene polymorphisms and in- of remission pendent laboratory studies. This Web site can creased homocysteine levels have been that were also be used to investigate the quality of the found to be associated with the occurrence of comparable to brands available for the other supplements depression. One thought is that methylfolate those produced discussed in this article. supplementation compensates for an under- by SSRIs— ❚ Adverse effects. St. John’s wort and an lying MTHFR enzyme deficiency in patients with a lower SSRI can lead to serotonin syndrome, which with depression. Further studies are needed discontinuation is a constellation of symptoms involving to determine if screening depressed pa- rate. mental status changes and autonomic and tients for MTHFR gene polymorphisms is of neuromuscular hyperactivity caused by sero- benefit.16 tonin overactivity.12 Furthermore, treatment A 2012 randomized controlled trial failures with anticoagulants, digoxin, hor- (RCT) (N = 75) compared L-methylfolate monal contraceptives, immunosuppressants, 15 mg/d plus an SSRI with placebo plus an and narcotics due to concomitant use with SSRI in patients with SSRI-resistant major St. John’s wort have been reported.13 depression.17 The trial found that a reduc- The most common adverse reactions to tion of baseline symptoms by ≥ 50% occurred St. John’s wort include gastrointestinal symp- in more patients who received adjunctive toms, dizziness, sedation, photosensitivity, dry L-methylfolate than placebo (32% vs 15%) mouth, urinary frequency, anorgasmia, and and tolerability was comparable. These find- swelling.14 However, multiple studies have sup- ings were again supported in 2016 with a ported St. John’s wort to be equally or better 12-month study showing L-methylfolate to tolerated than conventional antidepressants.7,8 have long-term tolerability comparable to placebo,18 and in 2017 with a randomized tri- al (N = 260) that found escitalopram 10 mg/d Certain forms of folate can be plus L-methylfolate 15 mg/d to be signifi- adjunctive treatment for depression cantly more effective at treating depression ❚ Methylfolate is the form of folate that than escitalopram 10 mg/d alone.19 Thus, crosses the blood–brain barrier. A prospec- methylfolate may be an effective adjunc- 222 THE JOURNAL OF FAMILY PRACTICE | JUNE 2020 | VOL 69, NO 5 CAM FOR DEPRESSION AND ANXIETY tive treatment for depression at a dosage of A 2019 study (N = 30) evaluated the 15 mg/d. impact of vitamin D supplementation on gen- ❚ S-adenosyl methionine (SAMe) is a eralized anxiety disorder in patients with co- metabolite of folate derived from methionine occurring vitamin D deficiency. Half received that facilitates the synthesis of neurotrans- standard-of-care general anxiety disorder mitters including dopamine, norepineph- treatment plus 50,000 IU of vitamin D weekly rine, and serotonin. In Europe, as is the for 3 months, while the other half received case with St. John’s wort, it is a prescription standard of care alone. Significant improve- medication. ments in anxiety scores, increases in serum A randomized trial (N = 73) compared serotonin, and decreases in serum neopterin adjunctive SAMe 800 mg bid with placebo in (an inflammatory marker) were observed in the treatment of patients with unipolar ma- the vitamin D–treated group compared to the jor depression who did not experience im- group that did not receive vitamin D.24 provement with SSRI treatment alone.20 The It is not currently standard of care to investigators found that more patients who check vitamin D levels in all patients pre- received SAMe than who received placebo senting with mood disorders. However, if had improvement in their depression (36.1% screening is indicated for another reason and vs 17.6%), and more patients who received low levels are confirmed, vitamin D replace- SAMe compared to placebo went into de- ment may improve anxiety and/or depressive pression remission (25.8% vs 11.7%). symptoms. Despite this, no evidence exists to S-adenosyl Adverse effects were comparable in both support vitamin D supplementation for de- methionine groups. Thus, SAMe at a dosage of 400 to 1600 pression or anxiety in patients with normal (SAMe) at a mg/d may be effective in the treatment of de- vitamin D levels.24,25 dosage of 400 to pression.20,21 The findings of 1 study (N = 65) 1600 mg/d may suggest that patients could experience fur- be effective in ther improvement in their depression symp- The effects of omega-3 fatty acids the treatment of toms with SAMe at doses of as much as 3200 are largely unclear depression.
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