An expert review of clinical challenges in primary care and psychiatry
This supplement is supported by Pamlab.
Dr. Farah is chief of Psychiatry at High Point Regional Health Systems, High Point NC, and is clinical faculty at Wake Forest University, Winston-Salem NC.
Disclosures: Dr. Farah serves as consultant to and receives honoraria from Pamlab.
Major depressive disorder (MDD) is a debilitating and often recurrent illness. An initial antidepressant trial is effective at achieving remission for ~30% of patients when prescribed as monotherapy, with the majority of patients returning as partial or non-responders. Switching antidepressants or adding augmentation agents are standard therapeutic options used to achieve and maintain remission. Suboptimal serum and red blood cell folate levels have been associated with a poorer response to antidepressant therapy, a greater severity of symptoms, later onset of clinical improvement, and overall treatment resistance. This Expert Review Supplement reviews the evidence for L-methylfolate as an augmentation agent in depression and discusses its clinical use elaborated by three clinical presentations.
Major depressive disorder (MDD) is a debilitating illness affecting 7% to 12% of men and 20% to 25% of women.1,2 It is usually a recurrent illness, with up to 30% of patients experiencing a depressive episode lasting over 2 years.3 Depression may also increase the morbidity and mortality of numerous medical conditions, such as cardiac disease, myocardial infarction, chronic pain, diabetes, cerebrovascular events, and respiratory illnesses.4-11 The goal of antidepressant therapy is to achieve full remission and functional recovery, and continuing treatment beyond the acute phase is usually necessary to maintain remission. In contrast with full remission, individuals who experience residual symptoms, however mild, have a higher chance of experiencing one or more additional episodes.
An initial antidepressant trial is effective at achieving remission for ~30% of patients when prescribed as monotherapy, with the majority of patients returning as either partial or non-responders.12 Switching antidepressants or adding augmentation agents are standard therapeutic options used to achieve and maintain remission. Adequate levels of central nervous system (CNS) folate are likely essential for a patient to fully recover from a depressive episode. Suboptimal serum and red blood cell (RBC) folate levels have been associated with a poorer response to antidepressant therapy, a greater severity of symptoms, later onset of clinical improvement, and overall treatment resistance.13-20 Lower systemic levels of folate can result from poor dietary intake, diabetes, various gastrointestinal disorders, hypothyroidism, renal failure, nicotine dependence, alcoholism, and a particular genetic polymorphism prevalent in 50% of the United States population,21,22 and up to 70% of depressed patients.23-26 Folate may also be depleted by numerous medications including oral contraceptives, metformin, as well as first generation anticonvulsants and lamotrigine, which are commonly used in psychiatry.
This article reviews the evidence for L-methylfolate as an augmentation agent in depression and discusses its clinical use elaborated by three clinical presentations. L-methylfolate offers a safe and tolerable alternative to traditional agents, particularly for patients at risk for lower systemic folate levels.
The Need for Improved Treatment Strategies
Depression has been traditionally considered one of the most “treatable” of all illnesses, with authors commonly citing study response rates of 50% to 70%. However, “response” as measured and defined by clinical trials has traditionally meant a reduction in score (usually 50%) on a Hamilton Rating Scale for Depression (HAM-D) or a Montgomery-Åsberg Depression Rating Scale (MADRS). A reduction in score may reflect symptomatic improvement but not full remission. In a long-term study following MDD patients, 76% of subjects who did not attain full remission (HAM-D>7) had relapsed by month 15, while a HAM-D of ≤7 was associated with a far lower likelihood of relapse (25%), by month 15.27 Thus, if recovery is only partial, patients remain at high risk for a relapse, possibly as severe as their initial episode.
Upon follow-up, patients generally fall into three categories: full remission, some response but not full remission (thus “partially responding” to antidepressants), and non-responders (Slide 1). Recent attention to the reality of low remission rates in studies and clinical practice, as well as drop-out rates, highlight the fact that a significant number of patients fail to benefit from advances in depression treatment. It is well documented that many patients discontinue antidepressant therapy due to side effects, the most common being sexual dysfunction and weight gain. Further, a perceived lack of efficacy may often lead to antidepressant discontinuation [unpublished data]. Long-term investigations of MDD patients (>10 years) indicate that depressive symptoms will often persist beyond the initial treatment phase, up to 60% of the time during long-term follow-up. The resultant disability is pervasive and chronic, and even a few depressive symptoms, though below the diagnostic threshold for MDD or even dysthymia, are associated with a significant increase in psychosocial disability compared to months in which the same patients are asymptomatic.28,29
Achieving and maintaining remission, rather than a reduction in symptom severity, should be the goal of therapy. Clinicians are faced daily with the question of what steps to take in order to achieve a full response for patients on antidepressant therapy. When no response is reported after an adequate time (generally accepted to be at least 4 weeks), and side effects are minimal, increasing the dose is a common strategy. However, if no response is reported but side effects are significant, switching agents would be preferred over dose escalation because most side effects are dose-dependent. For partial and non-responders, augmentation of antidepressants may have several advantages over dose escalation or switching.
Augmentation of Antidepressants
Practitioners currently have many effective options for depressed patients including several Food and Drug Administration approved antidepressants and several effective psychotherapies, the most common being cognitive-behavioral. Because no one treatment is universally effective, and many depressed patients do not experience a satisfactory clinical benefit from the initial treatment they receive, a series of therapies or a combination may be required. Augmentation/combination has been generally defined as the addition of one or more agents to existing antidepressant therapy to enhance recovery and speed response. Traditional agents have included lithium, thyroid hormone (T3), buspirone, bupropion, stimulants, pindolol, and in recent years, atypical antipsychotics, and modafinil. Currently, aripiprozole is the only drug FDA-approved for adjuvant therapy in depression.
The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial was a longitudinal, multi-center, 5-year study of common strategies for treating depression. To date, it is the United States’ largest National Institute of Mental Health funded study including over 4,000 patients. This four level trial compared traditional augmentation strategies with switching agents (Slide 2).30-34 Unlike most depression studies, in STAR*D the outcome measure was full remission.
In Level 1, the initial monotherapy phase, citalopram (mean dose of 41.8 mg) was effective at achieving remission for only ~30% of subjects. This finding has been accepted as an accurate reflection of clinical experience with any initial monotherapy. The remaining 70% were randomized to either receive bupropion or buspirone augmentation, or switched to one of three antidepressants as monotherapy—bupropion, venlafaxine, or sertraline. Augmentation resulted in a 30% response, while switching antidepressants resulted in ~20% of patients achieving remission. Level 3 included those non-remitters from Level 2 who were then randomized to either T3 or lithium augmentation, resulting in remission rates of 25% and 16% respectively. A Level 3 switch to nortriptyline (NTP) or mirtazapine (MTZ) was in general less successful than Level 3 augmentation, with 20% of NTP patients and 12% of MTZ patients remitting. Level 4 treatment options (monoamine oxidase inhibitors [MAOIs] or venlafaxine–mirtazapine-combination therapy) were provided to patients who had not responded satisfactorily to previous levels of the treatment protocol, and very few experienced full remission (14% and 7% respectively).12,35
An overall analysis of STAR*D results indicates that the chances of achieving and maintaining remission in patients with difficult-to-treat depression diminishes with every additional strategy needed. Those who fully remit early in the course of treatment have a better chance of remaining well than those who experience only symptomatic improvement. STAR*D does not tell us which treatment works better as a first or second adjunct, simply that the greatest chance of recovery appears to lie with the first two sequential treatments.
While there are advantages to switching antidepressants in some cases, augmentation has several advantages over switching antidepressants as well. It eliminates the need to taper some medications that pose a risk of withdrawal, and augmentation may allow the patient to build on the partial response already achieved rather than risk losing that response, which can occur when switching the primary agent to a newer choice. Further, some augmentation agents can often ameliorate the side effects of primary agents (such as sexual side effects) or have other benefits (eg, lower anxiety or help with insomnia). Clinicians must also be aware that potential benefits of augmentation may be countered by issues arising from polypharmacy, such as higher costs to patients and a greater potential for side effects and possible drug interactions.
Association of Low Folate with Depression
Since the early 1960s, reports have shown a correlation between low folate levels and MDD. Since these initial findings, community studies have strengthened the association between low folate and depressive illnesses.36 Whether measuring serum, plasma, or RBC folate, patients diagnosed with MDD have been shown to have significantly lower folate levels when compared to non-depressed controls. RBC folate levels will generally reflect CNS folate levels,37 and have been demonstrated to be low in as many as 56% of depressed patients.19,38 Folate deficiency has also been linked to courses of depressions that are more severe, longer in duration, and treatment resistant.20,39-47 Suboptimal folate may also predict non-responders and partial responders, as patients with low RBC folate are 6 times more likely not to respond to antidepressant therapy and are less likely to achieve and maintain remission.15,48 The connection between folate and MDD is believed to be L-methylfolate, a necessary cofactor in the synthesis of monoamine neurotransmitters. Thus, a deficiency may result in inadequate CNS synthesis of serotonin, norepinephrine, and dopamine.49
Folate and L-methylfolate
Folate is a water soluble B vitamin (B9), considered one of the 13 essential vitamins. The primary function of folate is the transfer of methyl and formyl groups, thus, it is essential for cell growth and reproduction, the breakdown and utilization of proteins, the formation of nucleic acids, red blood cell maturation, and a variety of CNS reactions. Dihydrofolate is the dietary form found in orange juice, spinach, asparagus, beans, liver, yeast, whole grain cereals, and eggs. Folic acid is the synthetic form of folate in over-the-counter vitamins and used to fortify the food supply (to help prevent neural tube defects, the FDA mandated folic acid fortification of flour in 1998). Folic acid is also the predominant form used in prescription strength prenatal vitamins. Both folic acid and dihydrofolate are not biologically active forms of folate, but are essentially pro-drugs, and must undergo enzymatic transformation to L-methylfolate in order to be used by cells, and unlike other forms of folate, L-methylfolate readily crosses the blood-brain barrier for use in the CNS.
Almost 85% of dietary folate and nearly all supplemental folic acid is absorbed into the venous system in the proximal small intestine. The enzymatic conversion begins in the intestinal wall—it is a three step process for dihydrofolate, and a four step process for folic acid (Slide 3). Folic acid is converted to dihydrofolate (DHF) by dihydrofolate reductase enzyme (DHFR), and DHF is then converted to tetrahydrofolate (THF). The conversion of THF to 5,10-methyleneTHF follows. Finally, the conversion of 5,10-methyleneTHF to L-methylfolate is achieved by the methyltetrahydrofolate reductase enzyme (MTHFR). This last step completes the four step transformation process by which the bioactive cofactor, L-methylfolate, is made available to the brain to be used in the synthesis of monoamine neurotransmitters associated with mood regulation (serotonin, norepinephrine, and dopamine).50
For many, dietary folate will result in adequate delivery of L-methylfolate to the brain, however, inhibition of any of the above enzymes, or having defective, less functional forms of enzymes could result in inadequate CNS L-methylfolate levels. There are over 40 identified mutations of the MTHFR gene that codes for the enzyme responsible for the last step in the conversion of folate to L-methylfolate,51 but the three main genotypes are of particular interest. The most common genotype is the C/C which codes for a normally functioning enzyme. The C/T and T/T polymorphisms are less functional forms that result in suboptimal amounts of L-methylfolate. This variant is known as C677T polymorphism.
C677T polymorphism is characterized by a mutation at position 677 of the MTHFR gene resulting in a single amino acid substitution, rendering the MTHFR enzyme thermolabile, thus significantly reducing its activity (Slide 4).52 Numerous studies indicate an association between the C677T polymorphism and depression.52-60 In one study, 70% of depressed individuals were positive for either the heterozygous or homozygous from of the C677T polymorphism (14% T/T, 56% C/T). The C/T, or heterozygous polymorphism reduces the MTHFR activity by 35%, while for the homozygous, T/T form, enzyme activity is decreased by more than 70%. Thus depressed patients may be at significant risk for inadequate levels of CNS L-methylfolate, and thus, lower synthesis of serotonin, norepinephrine, and dopamine.26,52-58
The Evidence for L-methylfolate in Depression
There are five trials that examine folate therapy in depressive disorders. In a study59 with patients who had low or borderline low RBC folate, depressed patients on tricyclic antidepressants or MAOIs were augmented with methylfolate 15 mg (L-methylfolate 7.5 mg) experienced significantly greater clinical improvement and social improvement at 3 months (P<.02) and 6 months (P<.01) compared to patients treated with antidepressants alone. The methylfolate-augmented patients continued to improve for 6 months compared to patients augmented with placebo, and none experienced relapse. In a separate double-blind, controlled trial60 comparing methylfolate 50 mg/day to trazodone 100 mg/day, depressed patients experienced a significant decrease in HAM-D scores at 4 and 8 weeks in both groups, with response rates in the methylfolate group at 45%, and in the trazodone group (not statistically significant) at 29%.
An open label trial61 of methylfolate as monotherapy in elderly depressed subjects demonstrated an 81% response rate (>50% reduction in HAM-D) by 6 weeks of therapy. A second monotherapy study examined a depressed population of 36 chronic alcoholics. After a week of placebo wash-out, subjects received 4 weeks of 90 mg methylfolate therapy. This dosing (30 mg TID) significantly improved depressive symptoms based on the HAM-D scale with the majority reporting improved mood and less fatigue (P<.01).62 Alpert and colleagues63 conducted an open label trial augmenting selective serotonin reuptake inhibitor (SSRIs) with folinic acid in patients who had failed at least 4 weeks of SSRI therapy. The response to folinic acid was not robust (P<.01, n=22), but it was well tolerated overall.
Clinical Presentation # 1
EF is a 62-year-old female with Parkinson’s disease who was taking ropinirole when she presented with significant depressive symptoms. She had failed to respond to citalopram 20 mg/day at 5 weeks, and due to past weight gain and excessive anxiety while taking serotonin reuptake inhibitor and serotonin-norepinephrine reuptake inhibitors she requested no dose escalations. Symptoms included dysphoria, poor concentration, short term memory deficits, fatigue, hypersomnia, and irritability. Mindful of her request to maintain the current SRI dose, L-methylfolate was started at 7.5 mg/day. By week 4 she reported a resolution in most of her symptoms, but still had residual fatigue and felt her concentration was not baseline. L-methylfolate was doubled to 7.5 mg BID, and within 2 weeks she was in remission. L-methylfolate augmentation was well tolerated and EF remains well after 9 months of therapy.
Clinical Presentation #2
JL is a 28-year-old female who presented with severe depression of rapid postpartum onset. Symptoms included crying spells, guilty ruminations, poor memory and concentration, insomnia, fatigue, and intrusive thoughts of harming her infant. She had failed to fully respond to sertraline 150 mg/day for 4 weeks, and L-methylfolate was added, as well as lorazepam PRN. After 3 weeks of combination therapy, she had achieved remission (HAM-D of 5), and reported no further intrusive thoughts. She remains stable and euthymic at 7 months of sertraline 150 mg/day and L-methylfolate 7.5 mg/day therapy. She continues breast feeding while on these agents.
Clinical Presentation # 3
BR is a 54-year-old male who met the Diagnostic and Statistical Manual, Fourth Edition, criteria for MDD, severe without psychosis, and was suffering from fatigue, insomnia, excessive anxiety and ruminations, and suicidal thoughts. He reported stress at work and recently had placed his mother in a nursing home due to rapidly progressing dementia. He was already on escitalopram 10 mg/day without benefit. After 5 weeks, his dose was escalated to 20 mg/day, and clonazepam 1 mg TID PRN was added. He was on this new regimen for three weeks when he presented to our clinic with only modest improvement in symptoms. He reported sedation when he took clonazepam. The dose of his benzodiazepine was cut in half, and L-methylfolate was added at 7.5 mg/day. At day 10 he phoned to report he was nearly baseline, and by day 14 was euthymic. He remains stable at 10 weeks of therapy reporting no additional side effects with L-methylfolate augmentation.
Specific Populations that May Benefit
Depressed patients are known to be at risk for C677T polymorphism, which translates into lower serum levels of L-methylfolate64 and possibly lower CNS folate, and thus lower monoamine levels. Specific ethnic groups are at higher risk for the less functional forms of MTHFR. The T/T genotype is present in as many as 10% of whites, and up to 22% of samples of Hispanic or Mediterranean populations.26,54 Several other groups are also at risk for lower L-methylfolate levels, including substance abusers, smokers, and those with gastrointestinal disorders (Slide 5).
Medications that are known to reduce folate levels include all first-generation anticonvulsants (phenytoin, valproic acid products, carbamazepine, primidone, and phenobarbital) and the second-generation anticonvulsant lamotrigine, which is a specific inhibitor of dihydrofolate reductase (DHFR) (Slide 6). DHFR activity is the first step necessary for the conversion of dietary folate or supplemental folic acid to L-methylfolate. Other second-generation anticonvulsants are not known to be folate depleting (though information is limited, and this cannot be ruled out). This may explain why traditional mood stabilizers have had less success at preventing or treating depression and perhaps why the antidepressant effects of lamotrigine can be lost with continued therapy over a period of weeks to months and dose escalation is not usually helpful. Other medications associated with folate depletion include oral contraceptives, acne medicine, metformin, lithium, dopaminergic medications for Parkinson’s disease and methotrexate, which, like lamotrigine, is a specific inhibitor of DHFR.
Mechanism of Action and Clinical Use of L-methylfolate
There are numerous CNS roles for L-methylfolate, and those affecting neurotransmitter production are believed to be critical to its antidepressant properties. L-methylfolate is thought to exert its action by enhancing synthesis of monoamine neurotransmitters, and has been categorized as a “trimonoamine modulator” because it is necessary for serotonin, dopamine, and norepinephrine synthesis.50
Depression is well known to involve dysregulation of one or more monoamines—serotonin (5-HT), norepinephrine (NE), and dopamine (DA). L-methylfolate acts as an important regulator of a critical cofactor needed for neurotransmitter synthesis. The cofactor is known as tetrahydrobiopterin (BH4). L-methyloflate combines with BH2 utilizing MTHFR to synthesize BH4. The trimonoamine synthetic enzymes that require BH4 as a cofactor are tryptophanhydroxylase, the rate-limiting enzyme for 5-HT synthesis, and tyrosine hydroxylase, the rate-limiting enzyme for DA and NE synthesis (Slide 7).49,50
Another mechanism of antidepressant activity of L-methylfolate is its role in the homocysteine cycle. High CNS homocysteine levels are associated with depression, dementia, and stroke,65 as well as negative symptoms of schizophrenia.66 Homocysteine is transformed to methionine utilizing B12 and L-methylfolate, both necessary cofactors for this transformation. Methionine is then converted to s-adenyl-methionine, which serves as the methyl donor for all three monoamines—serotonin, norepinephrine, and dopamine. Thus, patients with low CNS L-methylfolate are less able to convert homocysteine to methionine, the first necessary step of the homocysteine cycle.65
Unlike antidepressants, which block the re-uptake of neurotransmitters in short supply, L-methylfolate allows necessary methyl donation for adequate formation of trimonoamines. Results are often seen within 2 weeks, sometimes even remission. As is common with other traditional augmentation strategies, some form of early response is encouraging. Drop-out rates due to side effects are consistently similar to placebo.59-62
Safety of L-Methylfolate
The standard dose of L-methylfolate for the augmentation of antidepressants is one 7.5 mg tablet/day. No titration is necessary, and it is not associated with withdrawal symptoms at discontinuation. The maximum amount of L-methylfolate that can be absorbed in one dose is ~15 mg.67 If more than one 7.5 mg tablet/day is needed, it may be prudent to give in divided doses. All reported adverse events occur at placebo rates or lower, and overall it is an extremely well tolerated agent, allowing patients to continue L-methylfolate therapy as long as necessary to maintain remission. There are no known contraindications and no known drug interactions.
L-methylfolate is available by prescription and is regulated by the FDA as a prescription medical food for the specific nutritional requirements of depressed individuals with suboptimal serum, RBC, or CNS folate. It is specifically intended as adjunctive therapy for depressed patients who have only partially responded to antidepressant therapy. However, L-methylfolate may provide benefit to patients with or without serum or RBC folate deficiency, particularly if they are at risk for low neurotransmitter production.
Placement Among Augmentation Agents
Adding an additional therapy to augment an antidepressant effect usually carries the concern of adding additional side effects or potential drug interactions. Although buproprion and buspirone are considered well tolerated, discontinuation due to side effects in the STAR*D trial ranged from 13% to 21%. Response rates to these therapies in STAR*D approximated 30% when added to existing antidepressant therapy, and discontinuation rates were ~15%.12 The recent trend of adding antipsychotics as augmenters is worrisome as it assumes that all newer agents (those launched after clozapine) qualify as “atypical,” and this assumption has recently been challenged in the literature.68 The importance of this debate is underscored by the fact that patients with affective disorders are at higher risk for tardive dyskinesia (TD). Thus, when giving antipsychotic medications to non-psychotic individuals, one must not only consider weight and metabolic concerns, but also risks of extrapyramidal symptoms, akathisia, and TD.
There have been recent concerns about the safety of very high levels of circulating unmetabolized synthetic folic acid.69 In one study, high amounts of unmetabolized folate did lower the effectiveness of natural killer cells in postmenopausal women, yet other forms of folate, such as L-methylfolate have not been associated with such risks. High dose folic acid has been associated with toxic effects in healthy subjects70 and an increase in depressive symptoms in some studies.71
There have been eight folate studies (including all forms of folate) published thus far that evaluate the use of folate in depression,44,45,48,59-62,72 and though various forms have been used, L-methylfolate appears to be the optimal compound for augmentation, as it is the active form utilized by the CNS, and readily crosses the blood-brain barrier. It is a necessary cofactor for the synthesis of monoamine neurotransmitters. Many depressed patients are at risk for low levels of CNS folate due to lifestyle, medications, and genetics, but even those with normal CNS folate may benefit from L-methylfolate augmentation. There are no known drug interactions and no case reports to date of mania induction. L-methylfolate is a well tolerated agent which stands out as one of the safest of available augmentation options.
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