Natural Products Used to Treat Depressed Mood as Monotherapies and Adjuvants to Antidepressants: A Review of the Evidence

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Educational Objectives

After reading this article, you will be familiar with:

• Complementary and alternative medicine (CAM) modalities available for the treatment of depressed mood
• Indications for use of CAM
• Effectiveness and safety issues associated with the different CAM modalities

Who will benefit from reading this article?
Psychiatrists, geriatric psychiatrists, psychologists, primary care physicians, nurse practitioners, and other health care professionals. To determine whether this article meets the continuing education requirements of your specialty, please contact your state licensing and certification boards.

Every year one-third of the adults in the United States use 1 or more complementary and alternative medicine (CAM) modalities to treat a medical or psychiatric problem.¹ It is estimated that 1 in 10 adults see CAM practitioners, and he or she does so primarily for a mental health problem.² A large population survey found that receiving a diagnosis of a mood disorder is a strong predictor of CAM use.³ Another survey found that persons with major depressive disorder were significantly more likely to use CAM therapies than nondepressed persons.⁴ Almost two-thirds of psychiatrically hospitalized patients use at least 1 CAM modality before being hospitalized, and the majority self-treat depressed mood while failing to disclose CAM use to their psychiatrist or primary physician.⁵

Most persons who use CAM modalities to self-treat a mental health problem take prescription antidepressants concurrently. Combined use can result in serious supplement-drug interactions.³ Because of the high prevalence of CAM use among patients with mental illness, and especially among persons with major depressive disorder, it is important to examine the efficacy and safety evidence of CAM modalities used as either monotherapies or in combination with conventional pharmacological agents to treat depressed mood.

Select natural products used to treat depressed mood have been examined in well-designed, placebo-controlled, double-blind studies and in systematic reviews. Natural products used as stand-alone treatments of depressed mood include St John’s wort (Hypericum perforatum); S-adenosyl-L-methionine (SAMe); 5-hydroxytryptophan (5-HTP); folic acid; omega-3 essential fatty acids; and to a lesser extent, acetyl-L-carnitine (ALC) and dihydroepiandrosterone (DHEA). Some of these naturally occurring substances have also been evaluated in controlled trials for their potential role as adjuvants to conventional antidepressants. Two publications review the research evidence for natural products used to treat depressed mood.^6,7

This article is offered as a concise summary of research and clinical treatment issues pertaining to select natural products for which there is significant evidence. The Table presents natural products commonly used to treat depressed mood as both monotherapies and adjuvants in combination with antidepressants.

Vitamins

Depressed mood is commonly seen in patients with folate deficiency, and refractory depressed mood is often associated with low serum levels of folate and vitamin B12.^8,9 Low serum folate levels are associated with increased risk of relapse in patients who have successfully responded to fluoxetine or other antidepressants.¹⁰ Folate is an essential cofactor in the synthesis of SAMe, which has established antidepressant efficacy.

In a small randomized placebo-controlled trial, depressed patients treated with a combination of folic acid (0.5 mg) plus fluoxetine experienced significantly greater improvements in mood than the fluoxetine-only group.¹¹ Significantly, only women experienced a differential beneficial response to folate augmentation. The researchers theorized that this gender difference may be caused by a relatively higher male requirement for folate to efficiently convert homocysteine back to SAMe.

It has been suggested that the optimal form of folate for depressed mood is folinic acid because it more readily crosses the blood-brain barrier.¹² This is consistent with cases of patients with treatment-refractory depression who responded to antidepressants when folinic acid was added to their regimen.¹³

The authors of a systematic review of placebo-controlled studies of folate in depressed mood (N = 247) commented that folate may have a potential role as an adjuvant to pharmacological treatments of depressed mood.¹⁴ Sarris and colleagues6 have remarked that failure to take into account vitamins B12 (cobalamin) and B6 (pyridoxine) status may confound studies of folate or SAMe in patients with depressed mood in that remethylation of homocysteine to SAMe requires B12, and synthesis of all monoamine neurotransmitters requires B6.

Depressed patients with relatively higher serum vitamin B12 levels have shown a more robust response with antidepressants than matched patients with lower B12 levels.¹⁵ On this basis, B12 supplementation (800 µg/d) has been suggested as adjuvant therapy for depressed patients with B12 deficiency.¹⁶ Case reports suggest that some depressed patients experience consistent improvements in mood and energy with 50 mg/d of thiamine.¹⁷

A daily dose of 400 to 800 IU of vitamin D noticeably improved mood in patients with seasonal affective disorder after 5 days.¹⁸