Evidence-Based Reviews

Nontraditional therapies for treatment-resistant depression: Part 2

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Options include OTC agents, anti-inflammatory/immune system therapies, and devices.



When patients with major depressive disorder (MDD) do not achieve optimal outcomes after FDA-approved first-line treatments and standard adjunctive strategies, clinicians look for additional approaches to alleviate their patients’ symptoms. Recent research suggests that several “nontraditional” treatments used primarily as adjuncts to standard antidepressants have promise for treatment-resistant depression.

In Part 1 of this article (Current Psychiatry, September 2021), we examined off-label medications. In Part 2, we will review other nontraditional approaches to treatment-resistant depression, including herbal/nutraceutical agents, anti-inflammatory/immune system therapies, device-based treatments, and other alternative approaches. Importantly, some treatments also demonstrate adverse effects (Table1-32). With a careful consideration of the risk/benefit balance, this article reviews some of the better-studied nontraditional treatment options for patients with treatment-resistant depression.

Risk levels and adverse effects of adjunctive therapies for treatment-resistant depression

Herbal/nutraceutical agents

This category encompasses a variety of commonly available “natural” options patients often ask about and at times self-prescribe. Examples evaluated in clinical trials include:

  • vitamin D
  • essential fatty acids (omega-3, omega-6)
  • S-adenosyl-L-methionine (SAMe)
  • hypericum perforatum (St. John’s Wort)
  • probiotics.

Vitamin D deficiency has been linked to depression, possibly by lowering serotonin, norepinephrine, and dopamine concentrations.1-3

A meta-analysis of 3 prospective, observational studies (N = 8,815) found an elevated risk of affective disorders in patients with low vitamin D levels.4 In addition, a systematic review and meta-analysis supported a potential role for vitamin D supplementation for patients with treatment-resistant depresssion.5

Toxicity can occur at levels >100 ng/mL, and resulting adverse effects may include weakness, fatigue, sleepiness, headache, loss of appetite, dry mouth, metallic taste, nausea, and vomiting. This vitamin can be considered as an adjunct to standard antidepressants, particularly in patients with treatment-resistant depression who have low vitamin D levels, but regular monitoring is necessary to avoid toxicity.

Essential fatty acids. Protein receptors embedded in lipid membranes and their binding affinities are influenced by omega-3 and omega-6 polyunsaturated fatty acids. Thus, essential fatty acids may benefit depression by maintaining membrane integrity and fluidity, as well as via their anti-inflammatory activity.

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