Metformin Mental Health and Mood Impact

What does the label say about vitamin B12?

In metformin clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B12 was observed in approximately 7% of patients, and the label says to measure hematologic parameters annually and vitamin B12 at 2 to 3 year intervals [1].

Longer-term figures come from the Diabetes Prevention Program Outcomes Study. Low B12 (203 pg/mL or less) was more common with metformin at 5 years, 4.3% vs 2.3%, but not significantly different at 13 years, 7.4% vs 5.4%; the odds of deficiency rose 13% for each year of metformin use (OR 1.13, 95% CI 1.06 to 1.20) [2].

Does low vitamin B12 affect mood?

The best data are observational. In the Women's Health and Aging Study, 700 physically disabled, nondemented women aged 65 and older had B12, methylmalonic acid and homocysteine measured. Metabolically significant B12 deficiency was present in 14.9% of the 478 non-depressed women, 17.0% of the 100 with mild depression and 27.0% of the 122 with severe depression; after adjustment, deficient women were 2.05 times as likely to be severely depressed [3]. This study did not involve metformin.

The label describes the B12 decrease as possibly associated with anemia and as appearing to be rapidly reversible with vitamin B12 supplementation or discontinuation of metformin [1].

What about memory and thinking?

In the Singapore Longitudinal Aging Study, 365 people aged 55 and older with diabetes were followed for 4 years; 204 used metformin and 161 did not. Metformin use was associated with lower odds of cognitive impairment (Mini-Mental State Exam 23 or below), OR 0.49 (95% CI 0.25 to 0.95) [4]. That is one observational cohort and cannot show that metformin protects memory.

Which side effects could be mistaken for a change in mood?

In the label's US trial of immediate-release metformin up to 2,550 mg/day (141 patients vs 145 on placebo), diarrhea occurred in 53% vs 12%, nausea or vomiting 26% vs 8%, flatulence 12% vs 6%, asthenia 9% vs 6% and headache 6% vs 5%; diarrhea led to discontinuation in 6% [1]. Asthenia means weakness or lack of energy and is a listed reaction, not a mood diagnosis.

The boxed warning describes metformin-associated lactic acidosis as often beginning subtly, with malaise, muscle aches, breathing difficulty, sleepiness and abdominal pain; the label says to stop metformin and treat in hospital if it is suspected [1].

Metformin for people taking antipsychotics

A meta-analysis of 21 placebo-controlled trials with 1,547 participants (778 on metformin, 769 on placebo) found metformin better than placebo on body weight, BMI, fasting glucose, fasting insulin, triglycerides and total cholesterol [5]. These findings address weight, glucose, insulin and lipids; they do not show that metformin changes mood [5].