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In patients with treatment-resistant depression, consider addition of L-methylfolate, which is the reduced metabolite of folate (B9). L-methylfolate promotes the synthesis of key monoamine neurotransmitters, such as serotonin, dopamine, and norepinephrine. Increased inflammation leads to increased oxidative stress and inhibits this synthesis. This also causes rapid depletion of available neurotransmitters.

L-methylfolate provides “salvage pathways” in order to prevent this and readily crosses the blood brain barrier. Increased inflammation and oxidative stress is more likely in patients with obesity and/or diabetes, and research has shown that treatment response has been highest when adding L-methylfolate to the regimen of patients with obesity and elevated inflammatory biomarkers.

The highest treatment response has been in patients with BMI >30. It has shown to be a safe, low risk intervention with very few adverse events, and those who responded well were likely to maintain this response. Doses of 7.5mg per day were equivalent to placebo, however response was seen at 15mg per day. Recommend continued dosing for an extended period of time to fully evaluate response, as some who did not respond after 8 weeks, did eventually see benefit. Currently, there is a prescription formulation, Deplin, which may be covered by insurance, however this can also be obtained OTC.

The short summary is that if you have a patient with treatment-resistant depression or who is only partially responding to medication treatment, especially patients with diabetes and/or BMI >30, there is evidence to support 15mg/day of L-methylfolate as a low-risk adjunct that may provide modest benefit.

Lindsey Hiatt, PA-C
Physician Assistant
Saint Sophie’s Psychiatric Center

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