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In their recent article, Bottiglieriet al describe increased homocysteine concomitant with decreased folate concentrations in a subgroup of patients with depression.1 In addition, some relation between reduced folate availability and disturbed monoamine metabolism was found. The close relation between increased homocysteine and reduced folate concentrations, which was described previously in other clinical conditions such as cardiovascular and cerebrovascular diseases is usually ascribed to a reduced dietary intake of folate, and dietary supplementation with folate is capable of reducing hyperhomocysteinaemia.
The coincidence described of disturbed homocysteine and monoamine metabolism may shed some additional light to the possible mechanism underlying this metabolic abnormality. Both metabolic pathways depend on the presence of reduced pteridine species: (1) the biosynthesis of methionine requires supply of methyl groups from methyl-5,6,7,8-tetrahydrofolic acid, deficiency of which results in hyperhomocysteinaemia; (2) biosynthesis of serotonin, dopamine, and noradrenaline (norepinephrine) depends on the presence of 5,6,7,8-tetrahydrobiopterin, deficiency of which thus results in monoamine deficiency. Both tetrahydropteridines are recycled by dihydropteridine reductases2; both compounds have strong reducing capacities and are thus rapidly oxidised by oxidising chemicals. Interestingly, recent studies show that depression is associated with activation of the immune system,3 and it is even speculated that an infectious agent might be involved. Immune system activation is accompanied by an increased production of reactive species by cytotoxic cells such as activated monocytes and macrophages to achieve antimicrobial and cytocidal activities. Activated human monocytes/macrophages also release increased amounts of neopterin—another pteridine derivative—which is a sensitive index for the mediation of cell mediated immune reactions in patients.4 Recent data also point to a new functional aspect of neopterin—namely, to enhance oxidative processes.4 Increased concentrations of neopterin have been described in patients with depression.3 Therefore the question arises whether oxidative stress rather than insufficient dietary intake of folate is the basis of 5,6,7,8-tetrahydrofolate and also 5,6,7,8-tetrahydrobiopterin deficiency. Interestingly, in patients with Alzheimer's dementia a similar relation has already been demonstrated: hyperhomocysteinaemia was associated with reduced folate concentrations, but also an increased degree of immune activation could be detected in the same patients.5 There is good reason to think that the scenario might be similar in patients with depression, and enhanced oxidative stress due to chronic immune system activation is a major cause of the loss of reductants such as 5,6,7,8-tetrahydrofolic acid and 5,6,7,8-tetrahydrobiopterin.
Reynolds and Botiglieri reply:
We thank Widner et al for suggesting an explanation of our findings of impaired folate and monoamine metabolism in some patients with depression.
The relation between homocysteine and folate is well established, which is why we included it in our study. We agree that simply dietary deficiency is an inadequate explanation for folate deficiency in many patients with depression as several studies have failed to confirm this.1-1 We have recently reported a fall in CSF folate with aging1-2 and this may be a factor contributing to the high incidence of folate deficiency in psychogeriatric patients, including depression and dementia.1-1 We have also reported a fall in CSF tetrahydrobiopterin (BH4) in depression which is correlated with folate deficiency, as reflected in a fall in red cell folate, and with impaired monoamine metabolism—that is, a fall in CSF monamine metabolites.1-3
The mechanisms of these relations between impaired folate and monoamine metabolism remain uncertain but the suggestion that oxidative stress plays a part is speculative. We are unaware of any clinical or experimental evidence that oxidative stress leads to folate deficiency. It has been suggested that folates play a part in maintaining BH4 synthesis.1-3 1-4 The relation of folate and BH4 to aging requires clarification. It is also relevant that S-adenosyl-methionine, the major methyl donor in the brain which derives its methyl group from methyl folate can, like folates, increase the turnover of monoamines in the brain.1-5 This and other evidence suggest that methylation mechanisms are involved in these relations and in mood and cognitive function.1-6