Homocysteine (HCY) metabolism is necessary for the ultimate production of neurotransmitters. According to the HCY theory, patients are genetically prone to depression because they produce suboptimal levels of coenzymes necessary for HCY metabolism and monoamine synthesis.
Patients are simply ill-equipped on the molecular level to respond to acute or chronic stress. These same methylation defects may also contribute to chronic depression and posttraumatic stress disorder, influencing DNA expression in response to trauma. The homocysteine theory not only helps explain the etiology of many psychiatric disorders, but may also guide treatment.
The coenzymes necessary for HCY reduction are fully metabolized B vitamins and, in most cases, our patients lack the ability to adequately metabolize ingested vitamins to their active, coenzyme forms. Although they are necessary for numerous other reactions in the central nervous system (CNS), the reduced vitamins B6, B9, and B12 are critical for HCY degradation, optimal DNA methylation, and monoamine synthesis. The common B9 polymorphisms, or methyltetrahydrofolate reductase (MTHFR) variants, are also associated with inadequate BH4 synthesis, a necessary cofactor for the synthesis of serotonin, dopamine, epinephrine, norepinephrine, and melatonin.
Although polymorphisms of MTHFR are commonly associated with depression and numerous neurologic and psychiatric conditions, as well as birth defects and developmental issues, more often than not, there are multiple polymorphisms coexisting within the same genome. Indeed, it is now more accurate to accept that MTHFR is not a sole etiology, but a marker for the presence of a cluster of polymorphisms that are contributory to impaired methylation.
Further, there is often synergy that accentuates impaired methylation when polymorphisms coexist. As mental health professionals address the HCY basis of illness, clinical success will be most consistent if we account for all possible polymorphisms, and not just single markers.
Available antidepressants only block the transport of monoamines that are in short supply, theoretically maximizing their utility. Some newer agents and augmenters also act as serotonin agonists or antagonists at various postsynaptic receptors, yet the root cause of the depression remains the inability to synthesize adequate amounts of monoamines at baseline or in response to stress. Using newer reduced vitamin-based preparations will circumvent the genetic vulnerabilities that result in lower monoamine production, and offers the opportunity to address the underlying cause of depression.
The first and most enduring attempt to effect the HCY cycle as a way of treating depression was the use of s-adenosyl-methionine (SAM), commonly marketed as “SAMe.” Because the core issue of inadequate monoamine synthesis is impaired methylation, and the HCY cycle leads to SAM production as the methyl donor for monoamines, (HCY → methionine + adenosyl group of ATP → SAM) it seems a logical step to simply supply the CNS with excess SAM.
SAM has been popular in Europe for decades and is marketed in the US as a nutritional supplement. The exact amount of SAM and the route of administration seem to contribute to efficacy, and the use as monotherapy or adjunctive therapy have both been explored in various trials. As monotherapy, one meta-analysis found it equally effective as treatment with a tricyclic antidepressant, whereas another concluded SAM was worth an approximate 4- to 5-point reduction in a rating scale.
With respect to the HCY cycle, simply oversupplying the pathway with SAM can be problematic. A complex feed-back system regulates the HCY cycle: low SAM concentrations direct HCY toward the creation of SAM and methylation, yet in the presence of high SAM concentrations, the transsulphuration pathway is favored, converting more HCY (irreversibly) to cystathionine. Also, SAM’s methyl donation results in S-adenosyl-L-homocysteine (SAH), which will be converted back to more homocysteine. Also, an abundance of SAH will compete with binding sites for SAM, and may further impair methylation. Because the goals of depression treatment are HCY reduction and adequate methylation of monoamines, it is clear that SAM, when oversupplied rather than naturally produced, may offer some symptomatic relief, but may indeed exacerbate the underlying causes of depression and neurotoxicity.
Depression has long been associated with folate deficiency, as well as a lack of response to antidepressants, in more severe cases, and frequent relapses.
Various forms of folate have been used, including folic acid, folinic acid (leucovorin), and l-methylfolate. Doses and treatment populations have varied widely, so it is difficult for researchers to draw firm conclusions, and even more difficult for providers to know how to proceed clinically. Yet, the recent emphasis on l-methylfolate has specifically accounted for the fact that, in the methylation cycle, this form, the most reduced form of folate, is the coenzyme necessary (along with reduced B12) for the conversion of HCY to methionine.
Several studies have examined the use of l-methylfolate in depression as monotherapy and as adjunctive therapy. The most recent studies have standardized the dosing to 15 mg/day. A retrospective analysis study of the use of l-methylfolate at the initiation of serotonin reuptake inhibitor (SRI)/serotonin-norepinephrine reuptake inhibitor (SNRI) found that patients receiving this combination at the outset (
= 95) experienced symptomatic improvement more rapidly than selective serotonin reuptake inhibitor (SSRI)/SNRI monotherapy patients (
Two recent trials examined the augmentation therapy of l-methylfolate in partial or nonresponders to SSRIs. The first trial indicated that the 7.5-mg dose was ineffective, whereas the second trial, using 15 mg as an augmenter, demonstrated significantly greater efficacy compared with continued SSRI therapy plus placebo on all outcome measures (response rate, degree of change in depression symptom scores, and symptom severity). As with previous studies, l-methylfolate was generally well tolerated, with rates of adverse events no different from those seen with placebo.
The American Psychiatric Association guidelines
for the treatment of major depressive disorder (MDD) elaborate that folate “can be recommended as a reasonable augmentation strategy for major depressive disorder,” citing its attractive risk-benefit profile, and further, that it may prevent birth defects in the case of pregnancy. The guidelines also state that “data are inadequate to suggest efficacy as a monotherapy.”
Limitations with current l-methylfolate preparations include bioavailability, as the available products are l-methylfolate calcium, a less bioavailable form than l-methylfolate magnesium. Folate absorption in the small intestine is also dependent on iron, so preparations without iron will be even less bioavailable. Because the vast majority of folate across the blood-brain barrier is used for DNA and RNA transcription, it is also critical to replenish the folate pool in the CNS to have the maximal impact on methylation. Simply supplying l-methylfolate in the presence of a depleted folate pool would be minimally ineffective; therefore, it is best to supply other forms of folate (dihydrofolate and folinic acid) as well.
Folate preparations have been marketed on the claim that only the l-methyl form will cross the blood brain barrier, yet this is not true.
The CNS relies on folate in all forms of reduction for various reactions and can transport any form into the CNS. Although no case reports of mania have surfaced, in the author’s experience, the most common side effect observed outside of trials is irritability. Although beneficial for some, the success of l-methylfolate may rely on the patient’s having only an MTHFR polymorphism and no other enzymatic variants, which is the minority of our patients.
A New Approach: Maximizing Methylation
Recently a capsule containing a combination of reduced B vitamins and micronutrients, including all coenzymes needed for HCY metabolism and adequate methylation, has been made available (a capsule containing fully metabolized B6, B12, and three forms of B9 [folate] and all micronutrients essential in HCY metabolism). It is regulated by the US Food and Drug Administration (FDA), and described as “indicated for the distinct nutritional requirements of individuals who have suboptimal folate levels in the cerebrospinal fluid, plasma, and/or red blood cells, and require a maintenance level. Folate is effective in the treatment of hyperhomocysteinemia and/or megaloblastic anemia, as well as in anemias of nutritional origin, pregnancy, infancy, childhood, or other related folate-malabsorption complications of an inborn or environmental origin.”
The brand is further described as “a rescue or adjunctive folate-therapy to provide a protective effect in reducing the risk of secondary endpoints and/or disease-states of a hyperhomocysteinemia and/or methylation metabolic imbalance as may be found with depressed patients.”
Although primarily used for depression, it is also prescribed as a prenatal vitamin for those at high-risk for neural tube defects. The FDA’s labeling has permitted use for a wide array of conditions, including risks of future pathology—ie, any condition in which folate deficiency in the CNS is presumed and subsequent HCY elevations would be expected to result in clinical pathology would qualify. Thus, neuroprotection is also a common and legitimate use for this HCY-reducing agent, for both CNS and peripheral diseases.
A recent trial of 330 people with depression randomized 170 of them to receive the reduced B vitamin capsule as monotherapy, and 160 of them to receive placebo.
In this double-blinded study, all patients tested positive for one of the MTHFR polymorphisms associated with depression. The vitamin group displayed on average a 12-point reduction in the Montgomery–Asberg Depression Rating Scale (MADRS) by week 8, and 42% achieved full remission (MADRS <8). HCY levels dropped in the treatment group by 33% on average, whereas placebo patients had a small elevation of HCY at the end of the study, consistent with the stress of an ongoing, untreated depressive disorder.
This study helps to confirm the HCY theory, and although results need to be replicated, in this large sample of patients with MTHFR polymorphisms, reduced B vitamin therapy that circumvents all potential enzymatic defects was indeed curative for 42%.
Key Principles: Metabolized Vitamin B and Micronutrients for HCY Reduction and Treatment
Patients may ask why they can’t simply take B vitamins as sold in over-the-counter (OTC) preparations. Indeed, unmetabolized vitamins have been used in various studies, not only for depression, but in a variety of other neuropsychiatric conditions and even in trials for neuroprotection. Yet, the issue for the majority of our patients is not vitamin intake, but genetic polymorphisms leading to suboptimal metabolism of these vitamins to their coenzyme forms that is responsible for elevated HCY and suboptimal monoamine synthesis. When prescribed the B vitamins in their fully metabolized forms, patients may ask if they should continue with OTC multivitamins while taking the prescription vitamins; the answer in most cases will be that the OTC version is no longer necessary.
Normal Versus High Vitamin Ranges
When taking newer prescription vitamin agents, patients may indeed have higher than normal ranges of B6, folate, and/or B12, causing further confusion as to their necessity for treatment. Yet, we know that blood/serum levels may not reflect CNS levels, and certainly not reflect the status of intracellular, metabolized, coenzyme forms.
We also know from the classic studies of B1(thiamine) for Wernicke’s treatment that simply restoring B1 levels to the “normal” range will not have therapeutic value, as only higher than normal peripheral values were associated with adequate CNS amounts that result in clinical improvement.
Thus, “high” vitamin levels are necessary for clinical response in many conditions, including MDD.
Should We Check Polymorphisms and HCY Levels?
Office-based tests of various genetic markers are now available and usually include MTHFR genotyping as a standard measure. HCY levels are also easily checked. However, the mere presence of depression or other neuropsychiatric pathology argues for some polymorphisms associated with methylation and elevated HCY in the CNS. Although HCY levels may be low or normal in the periphery, they may still be elevated in the CNS.
Despite the fact that low levels of B6, folate, and B12 have been repeatedly associated with depression, B vitamins are usually normal in our patients. These routine laboratory levels will not reflect the adequacy of vitamin metabolism, which is most often the etiology, not vitamin intake. Finally, many patients may still benefit from therapies that maximize methylation even in the presence of normal HCY levels and adequate B vitamin intake and metabolism. Because these therapies are generally recognized as safe, and often some clinical improvement may begin to appear within 2 weeks, it is unnecessary in most cases to check HCY and polymorphism status before proceeding with therapy.
Addressing Nonvitamin Polymorphism
Our discussion has focused on coenzymes, ie, reduced B vitamins for therapeutic purposes, as most depressed individuals have polymorphisms associated with B vitamin metabolism. Yet, HCY reduction and monoamine methylation may be inadequate due to enzymes directly involved in the methylation cycle, not solely from enzyme polymorphisms responsible for coenzyme synthesis. Variants in all key enzymes are possible, such as methionine synthase, methionine-adenosine transferase, and cystathionine beta-synthase. Clinicians may assume that no available therapy can correct the impaired methylation that results from these defective enzymes when present, and this has been speculated to account for a percentage of “treatment-resistant depression” cases. However, recent evidence has indicated that high doses of the corresponding coenzymes can indeed restore adequate enzymatic functioning.
According to a recent report, the deficits caused by less functional enzymes are likely to be “remedied or ameliorated” by the administration of high doses of their corresponding vitamin coenzymes.
In summary, the administration of coenzymes in a more than adequate supply may indeed compensate for less functional enzymes, and restore optimal HCY metabolism, methylation, and monoamine synthesis.
The Future of Antidepressant Treatment
For decades, we have been treating depression primarily by blocking the reuptake of monoamines, which are in short supply. Clinicians now have the opportunity to prescribe natural, safe agents that provide neurons with the coenzymes necessary to synthesize adequate amounts of monoamines. Some patients have lacked these coenzymes for a lifetime. Based on the currently available data, we do not expect weight gain, sexual side effects, or an increase in suicidal thinking when using reduced B vitamins for MDD.
Providing the CNS with cofactors and coenzymes necessary to synthesize monoamines, as well as to overcome other, less studied, but still clinically relevant polymorphisms associated with impaired neurotransmitter synthesis, in this author’s view, addresses the root cause of depression. In the near future, reduced B vitamins could be standard monotherapy, and standard SRI/SNRI medications could be used as augmenters to this new vitamin-therapy approach for MDD.
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