Psychiatric Annals

CME 

Homocysteine and Neuropsychiatric Disease

Angela Pana, MD

Abstract

Elevated homocysteine (HCY) is a risk factor for a variety of vascular and neuropsychiatric pathologies. Although long recognized as a contributor to disease, and as an amino acid that is destructive to cell integrity and DNA, agents that were developed specifically to lower homocysteine were not available until very recently. Those agents are mainly composed of B vitamins in their metabolized forms, as they function as coenzymes in the pathway of homocysteine degradation. It is no surprise that hyperhomocysteinemia is most often the result of low B6, B9, or B12 levels; however, blood levels may not always reflect levels in the central nervous system (CNS), where HCY metabolism is most critical. HCY levels may also be normal in the periphery but not reflect CNS levels, where vascular, neuronal, and DNA damage is occurring. This article discusses the basics of HCY, its proposed mechanisms of toxicity, and the clinical consequences of hyperhomocysteinemia. [Psychiatr Ann. 2015;45(9):463–468.]

Abstract

Elevated homocysteine (HCY) is a risk factor for a variety of vascular and neuropsychiatric pathologies. Although long recognized as a contributor to disease, and as an amino acid that is destructive to cell integrity and DNA, agents that were developed specifically to lower homocysteine were not available until very recently. Those agents are mainly composed of B vitamins in their metabolized forms, as they function as coenzymes in the pathway of homocysteine degradation. It is no surprise that hyperhomocysteinemia is most often the result of low B6, B9, or B12 levels; however, blood levels may not always reflect levels in the central nervous system (CNS), where HCY metabolism is most critical. HCY levels may also be normal in the periphery but not reflect CNS levels, where vascular, neuronal, and DNA damage is occurring. This article discusses the basics of HCY, its proposed mechanisms of toxicity, and the clinical consequences of hyperhomocysteinemia. [Psychiatr Ann. 2015;45(9):463–468.]

Homocysteine (HCY) is a sulphur-containing amino acid most similar in structure to methionine and cysteine (Figure 1). There are no specific base-triplets for homocysteine; therefore, it is not present in naturally occurring proteins, and thus cannot be obtained from the diet. Dietary methionine is converted to homocysteine in the methylation cycle, or cysteine through transsulphuration (Figure 2).

Molecular structure of homocysteine.

Figure 1.

Molecular structure of homocysteine.

The metabolism of homocysteine. ATP, adenosine triphosphate; CH3, methyl radical; HCY, homocysteine; MTHF, methyltetrahydrofolate; Pi, inorganic phosphate; PPi, inorganic pyrophosphate; SAM, S-adenosyl methionine; THF, tetrahydrofolate.

Figure 2.

The metabolism of homocysteine. ATP, adenosine triphosphate; CH3, methyl radical; HCY, homocysteine; MTHF, methyltetrahydrofolate; Pi, inorganic phosphate; PPi, inorganic pyrophosphate; SAM, S-adenosyl methionine; THF, tetrahydrofolate.

HCY in the periphery has been linked to numerous conditions, with the most studied being cardiovascular disease. Elevated HCY levels across the blood-brain barrier have not only been associated with vascular injury, but also with depressive disorders, heightened risk of stroke, and various forms of dementia, Parkinson’s disease, multiple sclerosis, bipolar disorder, schizophrenia, and, in particular, prominent negative symptoms of schizophrenia (which mimic depression).1–3

Hyperhomocysteinemia is defined as a serum level of homocysteine >15 mcmol/L. It was first described in 1932, and by 1962, it was identified in high quantities in the urine of some children with IQs below 60.4 Further evidence of elevated HCY levels in various syndromes involving mental deficits and vascular pathology left no doubt that HCY was neurotoxic, as well as toxic to vasculature.5 What these syndromes all had in common were defective enzymes necessary for HCY metabolism, such as methionine synthase or cystathionine beta-synthase, and/or defective enzymes necessary to convert B vitamins into the coenzymes also necessary for HCY metabolism, such as methyltetrahydrofolate reductase (MTHFR).

Less severe manifestations of these genetic variants also have consequences, as demonstrated by epidemiologic studies. Even moderate elevations in HCY are associated with pregnancy complications and neural tube defects, cognitive decline in aging, vascular disease both in the central nervous system (CNS) and periphery, and an increased mortality rate overall.5

Only about 1% of the HCY filtered by the glomeruli is normally found in urine; thus, the body relies on internal metabolism to eliminate the toxic burden of HCY centrally and peripherally. Also, metabolizing HCY in the CNS is critical for the production of the antioxidant glutathione and the methylation of DNA, RNA, phospholipids, and monoamines. Thus, the methylation cycle, or the “HCY cycle” serves multiple roles across the blood-brain barrier.

The Toxic Mechanisms of Homocysteine

The most commonly suggested mechanisms of HCY toxicity are oxidative injury, direct vascular damage, impaired methylation, and impaired DNA synthesis as well as impaired DNA repair. Another proposed mechanism involves a heightening of inflammatory responses, which is likely, at the very least, a contributory mechanism of cell injury when other mechanisms are at work.6–10 What most of these mechanisms highlight is the overlap between vascular and neuropsychiatric pathology; the most obvious examples being stroke and vascular dementia.

Although still an evolving theory, elevated HCY appears to result in a form of oxidative stress. The interaction between HCY and nitric oxide (NO) is complex, but NO is a free radical, and neurons are particularly sensitive to free radical attack. Several studies have demonstrated that HCY will stimulate NO synthesis.11–13 High concentrations of NO are indeed neurotoxic and a major contributor to neurodegeneration.

When HCY is oxidized, homocysteine sulphinic acid and homocysteic acid are formed. These acids display very potent excitotoxic effects at the N-methyl-D-aspartate (NMDA) receptors. The NMDA glutamate receptors play a critical role in “synaptic plasticity” (ie, learning and memory). Activation of the NMDA receptor results in a calcium influx, followed by the release of cellular proteases and eventually cell death. This excitotoxic mechanism has been implicated in a variety of neurodegenerative disorders, as well as schizophrenia.

HCY itself is also known to directly damage endothelial cells while increasing platelet activity and procoagulant effects, further accelerating the atherosclerotic process. HCY’s interactions with inflammatory markers are also quite complicated, but its concentrations will impact the production of prostaglandin derivatives.

Causes of Elevated Homocysteine

Elevation in HCY to levels commonly associated with neuropsychiatric pathology may result from numerous causes, and most of the time multiple factors are at work in the same patient. Genetic, epigenetic, environmental, and lifestyle contributors are all key, as are certain medications.

The most common causes of elevated HCY are smoking, excessive alcohol consumption, lack of exercise, obesity, medications, and psychosocial stress. Male smokers can expect a 0.5% rise in HCY levels for every cigarette smoked per day, whereas female smokers experience a 1% rise.14 Although modest alcohol consumption is associated with a decrease in HCY levels, chronic high consumption will result in an elevation (the usual mechanism being vitamin depletion).15 By the time cirrhosis is diagnosed, methionine metabolism is altered, due to reduced activity of methionine adenosine transferase in the liver. People with alcoholism can expect plasma HCY levels about twice that of matched controls.

Exercise is expected to help distribute HCY more evenly throughout the body, and thus help facilitate its metabolism. Psychosocial stress has long been associated with HCY elevations, and in men, a tendency to suppress anger has been associated with a rise in HCY levels.16 Poor vitamin intake is also a common cause, yet even health-conscious people may be unaware that microwave cooking will destroy approximately 40% of the B12 content of food, and that conventional cooking will inactivate up to 50% of dietary folate.17 In people who practice a vegan diet, B12 levels are also low in at least 78%, resulting in hyperhomocysteinemia,18 and in infants who receive a strict vegetarian diet, HCY levels will be double that of controls.19

Many medications can raise levels of HCY, such as lipid-lowering agents, certain first-generation anticonvulsants, lamotrigine, methotrexate, isoniazide, L-dopa, lithium, nitrous oxide anesthesia, theophylline, and oral contraceptives.20 The first-generation anticonvulsants that impair HCY metabolism are the stronger enzyme inducers, such as phenobarbital and carbamazepine. Lamotrigine inhibits the enzyme dihydrofolate reductase, which is the mechanism of action of methotrexate, and both deplete reduced folate levels. In fact, the use of lamotrigine without concomitant supplementation with reduced folate may worsen a patient’s depression.

Patients treated with L-dopa have demonstrated elevated HCY levels, particularly with prolonged therapy. L-dopa is metabolized by catechol-O-methyltransferase (COMT), with magnesium as a cofactor, and S-adenosyl methionine (SAM) as the methyl donor. Yet, exogenous L-dopa increases methylation 4 to 5 times more than dopamine, thus increasing turnover of SAM. This high turnover rate of SAM results in the creation of excess S-adenosyl-L-homocysteine (SAH), which is finally converted to HCY.

Many illnesses are associated with levels of HCY that are classified as neurotoxic. They include thyroid disease, renal failure, chronic inflammatory conditions, malignancies, diabetes, and numerous gastrointestinal disorders such as Crohn’s disease, ulcerative colitis, atrophic gastritis, and any disorders associated with poor vitamin absorption.

Genetic predisposition has long been correlated with abnormal HCY levels. The first step in HCY metabolism is its conversion to methionine, using methyl-B12 and also l-methylfolate (or fully metabolized folate) as coenzymes. Therefore, any mutation, or even variants of the enzymes necessary to reduce B12 and folate, can result in a shortage of these coenzymes and cause impaired HCY metabolism.

The most studied of these is the MTHFR enzyme, of which there are over 40 possible variants. MTHFR status is the single most important determinant of plasma HCY levels. The two most common variants, TT and CT, have repeatedly been shown to be major risk factors for developing depression.21 This enzyme facilitates the last enzymatic step in the conversion to fully reduced folate, and having one of the C677T polymorphisms, and/or one of the A1298C polymorphisms (another MTHFR polymorphism associated with diminished activity) will lead to inadequate monoamine production. When the C→T and A→C polymorphisms coexist, there is marked synergy further impairing MTHFR function (Figure 3).

The role of reduced B vitamin as coenzymes in homocysteine metabolism. DHF, dihydrofolate; DHFR, dihydrofolate reductase; DMG, dimethylglycine; dTMP, deoxythymidine monophosphate; dUMP, deoxyuridine monophosphate; MTHFR, methyltetrahydrofolate receptor; SAH, S-adenosyl-L-homocysteine hydrolase; SAM, S-adenosyl methionine; SHMT, sodium hexametaphosphate; THF, tetrahydrofolate; TS, thymidylate synthetase; UMFA, unmetabolized folic acid.

Figure 3.

The role of reduced B vitamin as coenzymes in homocysteine metabolism. DHF, dihydrofolate; DHFR, dihydrofolate reductase; DMG, dimethylglycine; dTMP, deoxythymidine monophosphate; dUMP, deoxyuridine monophosphate; MTHFR, methyltetrahydrofolate receptor; SAH, S-adenosyl-L-homocysteine hydrolase; SAM, S-adenosyl methionine; SHMT, sodium hexametaphosphate; THF, tetrahydrofolate; TS, thymidylate synthetase; UMFA, unmetabolized folic acid.

Other common polymorphisms do not involve the enzymes in vitamin metabolism, but rather those used in the HCY cycle itself, such as the cystathionine beta-synthase gene, for which over 90 mutations have been identified. Polymorphisms are also associated with methionine synthase and methionine adenosine transferase. A few of these mutations actually increase enzyme activity and would be expected to help lower HCY levels (which can be observed occasionally in patients when checking HCY levels). What is becoming clear is that a polymorphism for vitamin metabolism often may coexist with those for HCY cycle enzymes, which can also result in a synergistic effect, further elevating the level of HCY.

Homocysteine Metabolism

Figure 2 shows the metabolism of HCY. Some references will label it “the methylation cycle,” or “the carbon-1 cycle.” There are two major pathways through which HCY is metabolized: (1) roughly 50% is remethylated to convert it back to methionine using reduced folate (l-methylfolate) and reduced B12 (methylcobalamin) as coenzymes for methionine synthase, and (2) approximately 50% is converted to cysteine (some of which is converted to glutathione) by way of transsulphuration, using pyridoxal-5-phosphate (reduced B6).

There is a confusing tendency in the literature to discuss HCY metabolism in the CNS and the periphery as if they are synonymous. Neurons lack the ability for transsulphuration, and the CNS relies on glial cells for this pathway and antioxidant production. Glial cells have limited B12 and are unable to effectively proceed to methionine. Other than glial cells, transsulphuration is active in liver, kidney, pancreas, and small intestine cells.

A few tissues, mainly liver and kidney cells, express the zinc-containing enzyme betaine homocysteine methyltransferase, which allows an alternative pathway for the remethylation of HCY to methionine. The majority of all other tissues, particularly in the CNS, are entirely dependent upon methionine synthase.

The CNS is dependent upon adequate supplies of reduced B12 and folate for this first step in HCY metabolism. In the absence of adequate B12, methionine can still be converted back to HCY with the aid of reduced folate alone.

Methionine then accepts the adenosine group from adenosine triphosphate, via methionine adenosine transferase, to form SAM. SAM is the main methyl group donor in the body, and the only methyl donor in the CNS; thus, methylation of neurotransmitters is achieved via SAM. Once the methyl donation occurs, SAH remains. SAH can be hydrolyzed to HCY in a reversible reaction, and this is the preferred flow of the reaction; therefore, elevated HCY will also elevate SAH. This is expected to be problematic because SAH competes with SAM for binding sites, and this is another mechanism whereby excess HCY can impair methylation.

Again, the transsulphuration pathway is more active glial cells, and in the periphery (eg, the liver, kidney, small intestine, and pancreas). HCY is converted to cysteine using reduced B6, and further to glutathione, the principle antioxidant in the CNS. Depressive disorders in the CNS are experienced on the molecular level as a form of oxidative stress.

Clinical Consequences of Inadequate Homocysteine Metabolism

Numerous studies have confirmed the fact that depressive disorders are associated with elevated HCY and lower-than-optimal B12 and/or folate levels.5 It has long been understood that a functional lack of monoamines results in depression, but it is now clear that the various genetic polymorphisms that result in inadequate HCY metabolism will result also in inadequate monoamine production, and thus, a functional depletion of serotonin, norepinephrine, and dopamine.22 The clinical syndrome that results is not rooted in the reuptake of neurotransmitters, but in the production of neurotransmitters at baseline and/or during times of stress.

The damage that HCY exerts on the vasculature is at least partly related to impaired methylation: HCY appears to decrease carboxyl methylation in vascular endothelial cells. This damage, and the resultant inflammatory response with the oxidative injury from HCY, in addition to HCY’s procoagulant effects and increased platelet activity, all explain why hyperhomocyteinemia (defined as HCY >15 mcmol/L) is seen in less than 5% of the population but in at least 50% of stroke patients.23 A recent study24 also found that stroke patients with higher levels of HCY were at greatest risk for early (ie, within 7 days) neurologic deterioration after their event.

The two most common forms of dementia are Alzheimer’s disease (AD) and vascular dementia (VD). HCY is certainly toxic to vasculature, but a recent study25 of VD patients indicated that HCY is particularly damaging to smaller vessels, as HCY levels were high when compared with controls, and even when compared to patients with larger strokes or cerebral macroangiopathy. The same study noted that lower B12 and B6 levels were common in VD patients, and, not surprisingly, HCY levels were inversely correlated with levels of folate and B6.25 HCY is also a risk factor for AD, and it remains unclear whether HCY’s contribution to AD pathology is through vascular toxicity, a separate mechanism, or, more likely, a combination of mechanisms.

A known risk factor for schizophrenia is maternal folate deficiency and the related high HCY level during pregnancy.26 The risk of developing schizophrenia is also increased in people with one of the MTHFR polymorphisms.27 A study from 2002 noted that young men with schizophrenia had on average a 5.7-mcmol increase in HCY when compared with healthy controls.28 In a placebo-controlled crossover trial, a 3-month HCY-lowering strategy of B6, folate, and B12 demonstrated improvement in both positive and negative symptoms of schizophrenia.29

Areas of ongoing investigation in which the toxic and genetic stress of HCY are noted to play a role in pathogenesis include bipolar disorder, migraines, multiple sclerosis, HIV-associated dementia and encephalopathy, autism, hereditary and diabetic neuropathies, and various birth defects.

Lowering HCY should be a priority not only in the neonatal/prenatal phase of life, but a lifelong goal. The agents available that reduce HCY, particularly in the CNS, are natural and generally recognized as safe. The benefits far outweigh the risks. It is time we addressed hyperhomocysteinemia in all phases of the life cycle for therapeutic and neuroprotective purposes.

Checking Homocysteine and Vitamin Levels

There are several issues facing clinicians when deciding whether to check HCY and/or vitamin levels. Firstly, serum/plasma vitamin levels do not mirror intracellular status. As discussed previously, metabolism of vitamins may be impaired although normal intake may be reflected by blood levels. It is typical for a patient with an MTHFR polymorphism to have a normal folate level yet a functional deficiency in the CNS. For clinical purposes, it is wiser to check for MTHFR polymorphisms than for standard vitamin levels.

When checking HCY levels, it is important to get a fasting sample and to be mindful that after a protein-rich meal, HCY will start to rise in about 3 hours and may reach a maximum increase of 20% by 8 hours.30 Blood cells continually form HCY and export it into plasma. Careless sample handling will increase the levels artificially, as will prolonged idle time for the sample, which will result in a 10% rise in HCY per hour at room temperature. Samples drawn from patients who are supine for at least 30 minutes are also much lower than ambulatory ones.

Most importantly, the presence of depression and other neuropsychiatric disease argues strongly for HCY elevation, and treatment strategies that target HCY metabolism may be effective even in the presence of normal blood HCY levels.

Conclusion

HCY is no longer simply a risk factor for illness; its toxicity is accepted as partial or sole etiology for many conditions. Agents that are designed for optimal HCY metabolism are accepted as a legitimate antidepressant therapies, and clinicians who are focused on preventive care, whether neonatal, neurologic, or psychiatric, must be well aware of the HCY-lowering strategies that may benefit patients.

References

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Authors

Angela Pana, MD, is a first-year Resident, Department of Neurology, Louisiana State University Health.

Address correspondence to Angela Pana, MD, Department of Neurology, LSU Health Sciences Center, 1501 Kings Highway, Shreveport LA 71103; email: angela_pana@yahoo.com.

Disclosure: The author has no relevant financial relationships to disclose.

10.3928/00485713-20150901-05

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