Concurrent Metformin and Second-Generation Antipsychotics: The Need to Add Vitamin B₁₂

See reply by Daggolu and Chen and article by Daggolu and Chen

To the Editor: We read with interest the article by Daggolu and Chen¹ discussing improved adherence to, and potentially effectiveness of, second-generation antipsychotics coprescribed with metformin. Their findings extend the results of previous clinical trials and meta-analyses demonstrating the effectiveness of metformin to mitigate antipsychotic-induced weight gain.² However, Daggolu and Chen¹ do not mention an important safety consideration: the association between metformin and vitamin B₁₂ deficiency. Metformin impairs B₁₂ absorption, partly through calcium-dependent mechanisms, with overt deficiency emerging after months to years as hepatic stores decline.^3,4 To our knowledge, the prevalence of B₁₂ deficiency in patients coprescribed antipsychotics, and metformin has not been studied, but it has been reported in 6%–50% of patients with diabetes receiving long-term treatment with metformin.⁴

B₁₂ deficiency can cause an irreversible peripheral neuropathy relatively quickly,³ and it also contributes to cognitive changes and other neuropsychiatric symptoms, including mood or psychotic symptoms.^3,5 Published guidance on how to manage the risk of B₁₂ deficiency in patients taking metformin is inconsistent. An expert consensus guideline on mitigating antipsychotic-induced weight gain recommended that B₁₂ levels be checked annually in patients prescribed metformin (or every 6 months in those with additional specified risk factors for B₁₂ deficiency—for example, a vegan diet or a prescription of a proton pump inhibitor⁶). Another expert opinion endorses a more cost-effective approach consisting of B₁₂ testing when metformin is started, with selective follow-up testing based on individualized risk.⁴ However, B₁₂ testing alone fails to detect about one-third of individuals with B₁₂ deficiency.^3,7 Furthermore, it is expensive and unavailable in many low-and middle-income countries (LMICs).

In this context, we agree with an expert consensus on diagnosing and managing B₁₂ deficiency published by Obeid et al in 2024,⁷ which cautions against routine B₁₂ monitoring in at-risk individuals, noting that testing incurs unnecessary costs compared with B₁₂ supplementation. Given the risk of early neuropathy, this consensus recommends prophylactic vitamin B₁₂ supplementation, suggesting the use of either 1,000 µg intramuscularly every 1–3 months or 1,000–1,500 µg orally daily.⁷ This oral dosage should be enough given that individuals with B₁₂ malabsorption still absorb B₁₂ through passive diffusion that allows the absorption of 1% of an oral dose.^4,8 The use of oral supplementation is supported by a recent meta-analysis that found no significant difference in effectiveness among oral, sublingual, and intramuscular administration routes for vitamin B₁₂ deficiency.⁸ While an oral dosage of 1,000–1,500 µg with a 1% absorption more than exceeds the recommended daily allowance for healthy adults of 2.4 µg per day,³ it is safe since B₁₂ is a water-soluble vitamin excreted in the urine when present in excess.^4,7

In conclusion, clinicians who decide to coprescribe antipsychotics and metformin based on the study of Daggolu and Chen¹ need to consider the associated risk of B₁₂ deficiency and its neuropsychiatric sequelae. The expert consensus of Obeid et al⁷ offers them a practical approach that mitigates this risk: prophylactic oral supplementation. This approach is particularly attractive in LMICs where access to B₁₂ testing is limited.

Article Information

Published Online: March 18, 2026. https://doi.org/10.4088/JCP.25lr16260
© 2026 Physicians Postgraduate Press, Inc.
J Clin Psychiatry 2026;87(2):25lr16260
To Cite: Mulsant LS, Husain MO, Mulsant BH. Concurrent metformin and second-generation antipsychotics: the need to add vitamin B₁₂. J Clin Psychiatry. 2026;87(2):25lr16260.
Author Affiliations: Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada (L.S. Mulsant, M.O. Husain, B.H. Mulsant); Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada (L.S. Mulsant, M.O. Husain, B.H. Mulsant); Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada (M.O. Husain, B.H. Mulsant); The Royal Hospital, Ottawa, Ontario, Canada (B.H. Mulsant).
Corresponding Author: Louise S. Mulsant, 1025 Queen St. West, Toronto, Ontario M6J 1H1, Canada ([email protected]).
Relevant Financial Relationships: Ms Mulsant receives funding from the Canadian Institutes of Health Research (CIHR), Ottawa, Ontario. Dr Husain receives funding from CIHR, Ottawa, Ontario; the Physicians Services Incorporated Foundation, Ontario; the Alternative Funding Plan for the Academic Health Sciences Centres of Ontario Innovation Fund, Ontario; and receives salary support from the Centre for Addiction and Mental Health (CAMH), Toronto, Ontario; and the Academic Scholar Award from the Department of Psychiatry, University of Toronto, Toronto, Ontario. Dr Mulsant holds and receives support from the Labatt Family Chair in Biology of Depression in Late-Life Adults at the University of Toronto. He also receives compensation from the Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; CAMH, Toronto, Ontario; and The Royal, Ottawa, Ontario, Canada (where he serves as an ex-officio Board member).
Funding/Support: None.
ORCID: Louise S. Mulsant: https://orcid.org/0000-0001-7460-0963; Muhammad O. Husain: https://orcid.org/0000-0002-8575-3364; Benoit H. Mulsant: https://orcid.org/0000-0002-0303-6450