Deplin (L-Methylfolate) for Depression - How does it work?

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Deplin (L-methylfolate): A Nutritional Supplement for Depression and Schizophrenia

Deplin is a prescription medical food, also known as a nutraceutical, that contains L-methylfolate, a form of folic acid or vitamin B9. Folic acid is a synthetic version of folate, which is naturally found in some foods and in our bodies. Folate is essential for many biological processes, such as DNA synthesis, cell division, and neurotransmitter production. However, some people with depression and schizophrenia may have low levels of folate or impaired ability to convert folic acid into L-methylfolate, the active form that can cross the blood-brain barrier and affect brain function. Deplin is designed to provide these people with the optimal amount of L-methylfolate to enhance their response to antidepressants and antipsychotics.

Deplin was developed by Pamlab LLC, a subsidiary of Nestlé Health Science, and approved by the Food and Drug Administration (FDA) in 2006 as a medical food for the dietary management of low plasma or low red blood cell folate 1. It was initially marketed as Metanx, a product for diabetic peripheral neuropathy, but later rebranded as Deplin for depression and schizophrenia. Deplin is not considered a drug by the FDA, but rather a food that requires a prescription from a healthcare provider.

L-methylfolate is the biologically active form of folate that can enter the brain and participate in neurotransmitter synthesis. Neurotransmitters are chemical messengers that regulate mood, cognition, and behavior. Some of the most important neurotransmitters for depression and schizophrenia are serotonin, dopamine, and norepinephrine. These neurotransmitters are made from amino acids, such as tryptophan and tyrosine, that need to be activated by an enzyme called tetrahydrobiopterin (BH4). BH4 is synthesized from L-methylfolate through a series of reactions. Therefore, low levels of L-methylfolate can impair the production of BH4 and consequently reduce the availability of serotonin, dopamine, and norepinephrine in the brain 2.

Antidepressants and antipsychotics work by increasing the levels of these neurotransmitters in the brain, but they may not be effective if there is not enough L-methylfolate to support their synthesis. Deplin provides L-methylfolate directly to the brain, bypassing the need for conversion from folic acid. By doing so, Deplin may enhance the production of BH4 and neurotransmitters, and thus augment the efficacy of antidepressants and antipsychotics 2.

Several clinical trials have shown that Deplin can improve the outcomes of patients with depression and schizophrenia when used as an adjunct to antidepressants and antipsychotics.

In a randomized, double-blind, placebo-controlled trial involving 148 patients with major depressive disorder who had an inadequate response to selective serotonin reuptake inhibitors (SSRIs), adding Deplin (15 mg/day) for 60 days resulted in significantly greater improvement in depressive symptoms than adding placebo 3. The response rate (defined as at least 50% reduction in Hamilton Depression Rating Scale score) was 32% for Deplin versus 15% for placebo. The remission rate (defined as Hamilton Depression Rating Scale score less than 7) was 19% for Deplin versus 7% for placebo.

In another randomized, double-blind, placebo-controlled trial involving 75 patients with major depressive disorder who had an inadequate response to SSRIs or serotonin-norepinephrine reuptake inhibitors (SNRIs), adding Deplin (7.5 mg/day or 15 mg/day) for 30 days resulted in significantly greater improvement in depressive symptoms than adding placebo 4. The response rate was 38% for Deplin versus 18% for placebo. The remission rate was 23% for Deplin versus 11% for placebo.

In a randomized, double-blind, placebo-controlled trial involving 55 patients with schizophrenia who had residual symptoms despite treatment with antipsychotics, adding Deplin (15 mg/day) for 12 weeks resulted in significantly greater improvement in negative symptoms (such as apathy, social withdrawal, and blunted affect) than adding placebo . The change in Scale for the Assessment of Negative Symptoms score was -8.3 for Deplin versus -1.5 for placebo.

The recommended dose of Deplin for depression is 7.5 mg or 15 mg once daily with or without food. The recommended dose of Deplin for schizophrenia is 15 mg once daily with or without food. Deplin should be used under the supervision of a healthcare provider and in conjunction with antidepressants or antipsychotics as prescribed. Deplin is available as capsules that can be swallowed whole or opened and sprinkled on applesauce.

Deplin is generally well tolerated and has no known drug interactions. However, some people may experience allergic reactions, such as rash, itching, swelling, or difficulty breathing. If this occurs, stop taking Deplin and seek medical attention immediately .

Deplin is contraindicated in people who have a known hypersensitivity to any of the ingredients in Deplin or to folic acid . Deplin is also contraindicated in people who have pernicious anemia, a condition caused by vitamin B12 deficiency, as Deplin may mask the symptoms and delay the diagnosis .

Deplin should be used with caution in people who have a history of seizures, as high doses of folate may lower the seizure threshold . Deplin should also be used with caution in people who have cancer, as high doses of folate may stimulate the growth of existing tumors .

Deplin is not intended for use in children, pregnant women, or nursing mothers, as the safety and efficacy of Deplin in these populations have not been established.

Deplin has several advantages over other treatments for depression and schizophrenia. Some of the benefits of Deplin are:

• It can enhance the response to antidepressants and antipsychotics, especially in patients who have low levels of folate or impaired conversion of folic acid to L-methylfolate 2 3 4.
• It can improve the negative symptoms of schizophrenia, which are often resistant to antipsychotics.
• It has no known drug interactions and does not affect the metabolism or clearance of antidepressants or antipsychotics.
• It has minimal side effects and is generally well tolerated by most patients .
• It is a natural substance that is essential for many biological functions and can also prevent neural tube defects in pregnant women.

Deplin also has some limitations and drawbacks that should be considered before using it. Some of the disadvantages of Deplin are:

• It is not a standalone treatment for depression or schizophrenia and should be used only as an adjunct to antidepressants or antipsychotics as prescribed by a healthcare provider .
• It is not effective for everyone and may not work for patients who have normal levels of folate or adequate conversion of folic acid to L-methylfolate 2.
• It is expensive and may not be covered by insurance plans, as it is classified as a medical food rather than a drug by the FDA .
• It may cause allergic reactions in some people who are sensitive to folic acid or any of the ingredients in Deplin .
• It may interfere with the diagnosis and treatment of pernicious anemia, a condition caused by vitamin B12 deficiency .
• It may lower the seizure threshold in people who have a history of seizures .
• It may stimulate the growth of existing tumors in people who have cancer.

Deplin is a prescription medical food that contains L-methylfolate, a form of folic acid or vitamin B9. Deplin is designed to provide optimal levels of L-methylfolate to patients with depression and schizophrenia who have low levels of folate or impaired conversion of folic acid to L-methylfolate. Deplin can enhance the production of neurotransmitters in the brain and augment the efficacy of antidepressants and antipsychotics. Deplin has been shown to improve depressive symptoms and negative symptoms of schizophrenia in clinical trials. Deplin has no known drug interactions and minimal side effects. However, Deplin is not a standalone treatment and should be used only as an adjunct to antidepressants or antipsychotics as prescribed by a healthcare provider. Deplin is also contraindicated in some conditions, such as pernicious anemia, seizures, and cancer. Deplin is expensive and may not be covered by insurance plans. Deplin is a promising nutritional supplement for depression and schizophrenia, but more research is needed to establish its long-term safety and effectiveness.

By Birk Gundersen, RN, BSN. 

1: Medscape: DEPLIN (L-methylfolate) dosing, indications, interactions, adverse effects, and more 

2: How DEPLIN® Works | DEPLIN® 

3: Papakostas GI et al