I was surprised that in the January 2019 issue of the British Journal of Psychiatry that was wholly devoted to treatment-resistant mood disorders there is no mention of neurometabolic investigation or treatment. Malhi et al, rightly emphasise our lack of understanding of pathophysiology and the future importance of identifying subtypes of depressive disorders.^{Reference Malhi, Das, Mannie and Irwin1} Even in the article on augmentation therapies by Strawbridge et al only pharmacological and psychological treatments were considered.^{Reference Strawbridge, Carter, Marwood, Bandelow, Tsapekos and Nikolova2}

During the 1990s my colleagues and I identified a subgroup of patients with major depression with evidence of disturbed one-carbon metabolism reflected in low serum, red cell and cerebrospinal fluid (CSF) folate, raised plasma homocysteine and low CSF S-adenosylmethionine, the methyl donor in numerous vital methylation reactions in the nervous system. These findings were associated with a disturbance in monoamine metabolism i.e. low CSF 5-hydroxyindoleacetic acid, homovanillic acid and tetrahydrobiopterin through well understood mechanisms.^{Reference Bottiglieri, Laundy, Crellin, Toone, Carney and Reynolds3} We also described significant enhancement of recovery from major depression in a placebo controlled trial of methylfolate 15 mg daily as adjunctive vitamin therapy over 3–6 months.^{Reference Godfrey, Toone, Carney, Flynn, Bottiglieri, Laundy and Reynolds4}

In a further placebo controlled trial of 15 mg methylfolate for 60 days in 75 patients with selective serotonin reuptake inhibitor-resistant depression. Papakostas et al confirmed a significant beneficial response to this adjunctive treatment.^{Reference Papakostas, Shelton, Zajecka, Etemad, Rickels and Clain5} Papakostas et al did not describe the folate status of their patients, but a pilot study of methylfolate as monotherapy for depression suggests that any benefit is linked to improvement in folate status as measured by red cell folate.^{Reference Reynolds, Crellin, Bottiglieri, Laundy, Toone and Carney6} In a recent review and meta-analyses of adjunctive nutraceuticals for depression, Sarris et al concluded that current evidence supports adjunctive use of methylfolate, S-adenosylmethionine, omega-3 and vitamin D.^{Reference Sarris, Murphy, Mischoulon, Papakostas, Fava and Berk7}

More recently Pan et al described a case–control neurometabolic investigation of 33 adolescent or young adults with treatment-refractory depression,^{Reference Pan, Martin, Zimmer, Segreti, Kassiff and McKain8} i.e. unresponsive to three maximum-dose and adequate duration antidepressant medication. Twelve of the patients had low CSF folate levels with normal serum folate, but red cell folate was not measured. One patient had a low CSF tetrahydrobiopterin and five patients had abnormalities of acylcarnitine profile. In an open trial of folinic acid (in addition to continuing antidepressant medication) for 6 weeks in those patients with low CSF folate all were reported to show improvement, some dramatic.

I think Malhi et al are right that a new approach is needed to treatment-resistant depression.^{Reference Malhi, Das, Mannie and Irwin1} Academic departments of psychiatry should invest more in the neurometabolic evaluation of major depression, including in relation to responders and non-responders, and perhaps less in the continuing search for new more powerful drugs of uncertain mechanisms and undesirable side-effects. One-carbon metabolism is a potentially fertile area for such research, not least because the folate cycle is intimately linked to the synthesis of purines as well as providing the methyl groups ultimately donated by S-adenosylmethionine in the methylation, among others, of DNA and RNA and thus in the genetic and epigenetic mechanisms of interest to Fabbri et al.^{Reference Fabbri, Kasper, Kautzky, Bartova, Dold and Zohar9}

In the meanwhile no patient's depression need be designated treatment resistant without at least a trial of adjunctive treatment with, for example, 15 mg methylfolate for 3–6 months in conjunction with pre- and post-treatment measurements of folate and vitamin B12 status. Folic acid is an unnatural synthetic form of folate and the evidence indicates that methylfolate is a more appropriate treatment as the active and transport form of the vitamin that enters the nervous system slowly through a highly efficient blood–brain barrier mechanism.^{Reference Reynolds, Biller and Ferro10}