Vitamin B12

Methylation and neurotransmitter synthesis. Vitamin B12 (as methylcobalamin) is a key cofactor in one-carbon/methylation chemistry that converts homocysteine → methionine → S-adenosylmethionine (SAMe). SAMe is the universal methyl donor needed to make and regulate monoamine neurotransmitters (serotonin, dopamine, norepinephrine) and for membrane and DNA methylation in the brain — processes implicated in mood regulation. Low B12 → impaired methylation, higher homocysteine, and altered neurotransmitter metabolism — which can contribute to depressive symptoms. Cambridge University Press & Assessment

Association with depressive symptoms. Observational and cohort studies show low B12 (or elevated homocysteine) is associated with higher rates of depressive symptoms, especially in older adults. That supports the biological plausibility that correcting deficiency could improve mood in people whose depression is linked to deficiency. Cambridge University Press & Assessment

Two different clinical roles:

1. Correcting deficiency-related neuropsychiatric symptoms. If depression is caused or worsened by true B12 deficiency, replacement often helps improve mood and other neuropsychiatric signs. NICE
2. Augmentation in non-deficient patients. Trials of B12 (often combined with folate/B6) as an adjunct to antidepressants in patients without overt deficiency have given mixed results — some trials/meta-analyses show little short-term benefit, while others suggest possible benefit in specific subgroups or long-term use. So the evidence is inconclusive for using B12 as a standalone antidepressant in non-deficient people. ScienceDirect

A. Test before treating

• Measure serum B12 (and consider active B12 / methylmalonic acid and homocysteine if the diagnosis is unclear). If levels are low (or clinical features strongly suggest deficiency), treat the deficiency first rather than empirically supplementing for depression. NICE and UK NHS guidance recommend assessing and managing B12 deficiency in adults. NICE

B. If deficiency is confirmed — typical regimens used in guidelines (regimens used in NHS/UK practice and many local guidelines):

• Intramuscular (IM) hydroxocobalamin (preferred for many non-dietary deficiencies): common loading and maintenance examples used in UK practice: 1,000 µg IM on alternate days for 1–2 weeks (or 3×/week for 2 weeks), then 1,000 µg IM weekly for several weeks, then maintenance 1,000 µg every 8–12 weeks (exact schedules vary by guideline and clinical context). nhs.uk
• Oral high-dose cyanocobalamin or methylcobalamin: high doses (e.g. 1,000–2,000 µg oral daily initially, then weekly maintenance) can be effective because a proportion is absorbed passively even without intrinsic factor. Some trials/guidelines use 1 mg (1,000 µg) daily for weeks, then reduce to weekly/monthly dosing; 2,000 µg daily has been shown effective for raising levels. Oral is often used when IM is not possible. AAFP

C. If patient is NOT deficient but you’re considering B-vitamin augmentation

• Most clinical trials used combination supplements (folate, B12 ± B6) as augmentation with antidepressants rather than B12 alone. Evidence is mixed; augmentation is not standard first-line for everyone. If considered, do so under clinician supervision, and measure baseline levels and monitor response. SpringerLink

D. Formulations and choice

• Hydroxocobalamin (IM) is commonly used in the UK (retained longer). Cyanocobalamin is widely available orally and inexpensive. Methylcobalamin is a biologically active form sometimes used in neuropathy/neuropsychiatric contexts. Guidelines note IM hydroxocobalamin for many non-dietary causes; oral high-dose cyanocobalamin is an acceptable alternative if IM not possible and patient can comply. Choice depends on cause of deficiency, availability, and local guidance. South East London ICS

E. Monitoring

• Recheck blood counts, B12 level and, if needed, methylmalonic acid/homocysteine and clinical symptoms after a few months. If oral therapy fails to correct deficiency or symptoms persist, switch to IM therapy. NICE and NHS local guidance outline monitoring schedules. NICE

• Systematic reviews / meta-analyses (mixed results):
• A systematic review and meta-analysis concluded folate + vitamin B12 treatment does not decrease severity of depressive symptoms over short periods overall, though may help in certain populations long-term; available trials were few and heterogeneous. ScienceDirect
• A broader review/meta-analysis of B12 (alone or in B-complex) found uncertain benefit for depressive symptoms in people without overt deficiency; many trials differ in dose, patient population, and whether folate/B6 were co-administered. MDPI
• Randomized clinical trials:
• Several RCTs have looked at B12 (often with folate & B6) as an adjunct to antidepressants; one larger trial in older adults (n≈153) examined B-vitamin augmentation and found mixed/no clear benefit except in some subgroups. Reviews summarising these RCTs note limited, inconsistent evidence. SpringerLink
• Observational/cohort studies:
• Prospective cohort data show low B12 is associated with incident depressive symptoms in older community-dwelling adults over several years — supporting association but not necessarily causation. Cambridge University Press & Assessment
• Mechanistic literature & narrative reviews:
• Multiple biochemical and neurochemical reviews explain how B12/folate/homocysteine pathways affect methylation and neurotransmitter systems relevant to depression. These provide biological plausibility for benefit when deficiency is present. ScienceDirect

Summary: evidence is solid that treating true B12 deficiency can improve neuropsychiatric symptoms (including depression) in many cases. However, evidence that B12 supplementation improves depression in people without deficiency (as a primary antidepressant) is weak and mixed — some trials/meta-analyses show little short-term benefit; others show possible benefit in selected subgroups or as long-term adjunct. ScienceDirect