Evidence-Based Reviews

Nontraditional therapies for treatment-resistant depression: Part 2

Current Psychiatry. 2021 October;20(10):32-38 | doi: 10.12788/cp.0179

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Although results from controlled trials are mixed, a systematic review and meta-analysis of adjunctive nutraceuticals supported a potential role for essential fatty acids, primarily eicosapentaenoic acid (EPA), by itself or in combination with docosahexaenoic acid (DHA), with total EPA >60%.⁵ A second meta-analysis of 26 studies (N = 2,160) that considered only essential fatty acids concluded that EPA ≥60% at ≤1 g/d could benefit depression.⁶ Furthermore, omega-3 fatty acids may be helpful as an add-on agent for postpartum depression.⁷

Be aware that a diet rich in omega-6 greatly increases oxidized low-density lipoprotein levels in adipose tissue, potentially posing a cardiac risk factor. Clinicians need to be aware that self-prescribed use of essential fatty acids is common, and to ask about and monitor their patients’ use of these agents.

S-adenosyl-L-methionine (SAMe) is an intracellular amino acid and methyl donor. Among other actions, it is involved in the biosynthesis of hormones and neurotransmitters. There is promising but limited preliminary evidence of its efficacy and safety as a monotherapy or for antidepressant augmentation.⁸ For example, when compared with placebo for depressive symptoms in 19 randomized controlled trials (RCTs) (N = 878)⁸:

Five out of 6 earlier controlled studies reported SAMe IV (200 to 400 mg/d) or IM (45 to 50 mg/d) was more effective than placebo
When the above studies were added to 14 subsequent studies for a meta-analysis, 12 of 19 RCTs reported that parenteral or oral SAMe was significantly more effective than placebo for depression (P < .05).

Overall, the safety and tolerability of SAMe are good. Common adverse effects include nausea, mild insomnia, dizziness, irritability, and anxiety. This is another compound widely available without a prescription and at times self-prescribed. It carries an acceptable risk/benefit balance, with decades of experience.

Hypericum perforatum (St. John’s Wort) is widely prescribed for depression in China and Europe, typically in doses ranging from 500 to 900 mg/d. Its mechanism of action in depression may relate to inhibition of serotonin, dopamine, and norepinephrine uptake from the synaptic cleft of these interconnecting neurotransmitter systems.

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