If you are experiencing selective serotonin reuptake inhibitor resistance (SSRI resistance), you are far from alone. Some feel no effect from an SSRI whatsoever and others feel an initial effect that wanes quickly. Nearly two in three patients with depression do not achieve remission with SSRI treatment alone [1,2].

Living with a mood disorder difficult in its own right. People with depressive disorders are more likely to incur high medical bills, have difficulty maintaining employment, and experience suicidal thoughts and inclinations [1]. All of these effects are amplified in patients that are treatment-resistant, or specifically experiencing SSRI resistance. 

Luckily, for many treatment-resistant patients, filling a nutritional gap may aid in lifting a depressed mood. 

Folate and Mood

A link between low folate status and depression has been repeatedly documented since the 1960s [3]. Low folate levels correlate with a low mood and there is a clear biochemical pathway that explains this effect. Enzymes convert dietary folate into its active form, L-methylfolate, which regulates the production of the neurotransmitters serotonin, dopamine, and norepinephrine [3].

More specifically, L-methylfolate provides a methyl group for the formation of tetrahydrobiopterin (BH4). BH4 acts as a cofactor for the activation of rate-limiting enzymes, tryptophan hydroxylase and tyrosine hydroxylase. These enzymes are necessary for the production of serotonin, dopamine, and norepinephrine [3]. Therefore, L-methylfolate status indirectly controls the abundance of neurotransmitters in the body. 

Folate Supports SSRI Therapy

Traditional therapies such as SSRIs and SNRIs (serotonin-norepinephrine reuptake inhibitors) block reuptake of neurotransmitters, so that existing neurotransmitters can remain signaling for longer. If the brain is not making enough neurotransmitters however, a treatment like this may be ineffective. It may present as SSRI resistance. Dissimilarly, L-methylfolate can actually promote the production of more neurotransmitters by providing substrate to the process. 

Often, doctors recommend L-methylfolate as a complement to an SSRI or SNRI therapy. L-Methylfolate provides nutrient building blocks for appropriate levels of neurotransmitters, which an SSRI medication can then manipulate. L-methylfolate alone may fill a nutritional inadequacy that could be contributing to the presentation of a depressed mood. 

Traditionally, a folic acid (synthetic folate) supplement may have been suggested to fill a patients need for folate. New evidence, however, has arisen revealing a problem with this recommendation. Folic acid must be converted to L-methylfolate before it can cross the blood brain barrier or participate in the neurotransmitter production pathway. We now know that approximately half of the general population and up to 70% of patients diagnosed with depression have a genetic polymorphism that inhibits the conversion of folic acid to L-methylfolate [1].

A single nucleotide polymorphism (SNP) in the methylenetetrahydrofolate reductase (MTHFR) gene is responsible for this processing deficiency. Those who inherit one normal copy of the gene and one copy with a SNP (heterozygous) can only process folate at 65% of the normal rate and are more likely to experience depression than those with normal gene expression [2]. Those with two abnormal copies of the gene (homozygous) process folate at only 30% of the normal rate and are the most likely to experience a more severe depression than those who are either heterozygous or express normal MTHFR production [2].

Therefore, dietary folic acid may not be appropriate to rescue some individuals from downstream effects of folate deficiency, especially those experiencing a depressed mood who test positive for an MTHFR SNP. 

Try MethylPro L-Methylfolate

Fortunately, L-methylfolate is now available as a supplement. Taking L-methylfolate in place of folic acid bypasses the necessity for MTHFR enzyme. Regardless of one’s genetic makeup, supplementary L-methylfolate can work effectively in the body upon absorption and readily crosses the blood brain barrier [2]. As a B vitamin, L-methylfolate is water soluble and not stored in the body. This means, if one is folate deficient, they must take a supplement regularly/daily to maintain nutritional balance. It also means L-methylfolate is generally well-tolerated and unlikely to cause adverse reactions [3]. 

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  1. LeBano, Lauren. “L-Methylfolate: A Promising Therapy for Treatment-Resistant Depression?” Psychiatry and Behavioral Health Learning Network. May 08, 2013 https://www.psychcongress.com/article/l-methylfolate-promising-therapy-treatment-resistant-depression
  2. Kose, Samet, and Kemal Sayar. “L-methylfolate in patients with treatment resistant depression: fulfilling the goals of personalized psychopharmacological therapy.” (2018): 359-362.
  3. Papakostas, George I., et al. “L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials.” American Journal of Psychiatry 169.12 (2012): 1267-1274.