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As Assies & Pouwer appropriately point out, there has been growing evidence for an underlying metabolic link between the key components of one-carbon metabolism and PUFAs both in depression and dementia. 1 However, we do not fully agree with their recommendation for measuring these factors in combination. Our reasons are as follows. One of the main potential mood stabilising effects of PUFAs in depression is thought to be their dampening action against abnormal intracellular signal transduction by (a) inhibiting G-protein-mediated and phospholipase-C-mediated hydrolysis of crucial membrane phospholipids; 2 (b) modulating the influx of calcium ions; 3 and (c) reducing the activity of protein kinase C. 4 In addition, PUFA actions are closely related to inflammatory and immune pathways, which are also potentially important in the pathogenesis of depression. 5 Compared with these more established findings, the evidence for relationships between one-carbon metabolism and PUFAs in depression is relatively scant. For these reasons, we cannot recommend measuring PUFAs in the context of one-carbon metabolism at the present time, particularly for clinical purposes. However, we do feel that Assises & Pouwer's suggestions should encourage future animal and clinical studies on these interesting research issues.

1 Das, UN. Folic acid and polyunsaturated fatty acids improve cognitive function and prevent depression, dementia, and Alzheimer's disease – but how and why? Prostaglandins Leukot Essent Fatty Acids 2008; 78: 11–9.
2 Sperling, RI, Benincaso, AI, Knoell, CT, Larkin, JK, Austen, KF, Robinson, DR. Dietary omega-3 polyunsaturated fatty acids inhibit phosphoinositide formation and chemotaxis in neutrophils. J Clin Invest 1993; 91: 651–60.
3 Honen, BN, Saint, DA, Laver, DR. Suppression of calcium sparks in rat ventricular myocytes and direct inhibition of sheep cardiac RyR channels by EPA, DHA and oleic acid. J Membr Biol 2003; 196: 95103.
4 Seung Kim, HF, Weeber, EJ, Sweatt, JD, Stoll, AL, Marangell, LB. Inhibitory effects of omega-3 fatty acids on protein kinase C activity in vitro . Mol Psychiatry 2001; 6: 246–8.
5 Maes, M, Smith, RS. Fatty acids, cytokines, and major depression. Biol Psychiatry 1998; 43: 313–4.