How does metformin work and what is the appropriate dosing for antipsychotic‑induced weight gain in a patient with severe mental illness who has gained >3% of baseline body weight after starting a second‑generation antipsychotic (SGA)?

Metformin for Antipsychotic-Induced Weight Gain

Mechanism of Action and Clinical Efficacy

Metformin should be initiated at 500 mg once daily and titrated to 1 gram twice daily to attenuate antipsychotic-induced weight gain through reduction of insulin resistance and appetite suppression. 1, 2

Metformin works primarily by:

• Reducing insulin resistance, which is a key driver of antipsychotic-induced metabolic dysfunction 3, 4
• Decreasing hepatic glucose production and improving peripheral glucose uptake 3
• Modulating appetite through effects on hypothalamic pathways, though the exact mechanisms remain incompletely understood 5

The evidence demonstrates that metformin produces a mean weight loss of 3.27 kg (95% CI -4.66 to -1.89 kg) compared to placebo, with 25-50% of patients achieving clinically meaningful weight loss of ≥5-7% of baseline weight 3, 6. Doses greater than 1500 mg daily are associated with the greatest weight loss 6.

Dosing Protocol

Start metformin 500 mg once daily, then increase by 500 mg increments every 2 weeks up to the target dose of 1 gram twice daily (2000 mg/day total), based on tolerability. 1, 2

• Use modified-release preparations when available to minimize gastrointestinal side effects, which are the most common reason for discontinuation 1, 6
• The titration schedule matches standard diabetes treatment protocols and optimizes adherence 1

When to Initiate Metformin

The most recent international guidelines recommend two distinct approaches:

For high-risk antipsychotics (olanzapine and clozapine): Initiate metformin concomitantly at the start of antipsychotic treatment to prevent weight gain before it occurs 1, 6. This proactive approach is explicitly recommended because these agents have such high metabolic liability that waiting for weight gain is inappropriate 1.

For other second-generation antipsychotics: Initiate metformin after ≥3% weight gain from baseline despite lifestyle interventions 1, 6. However, meta-analytic evidence suggests metformin is more effective when started after weight gain has already occurred rather than prophylactically for non-clozapine/olanzapine agents 5.

This represents an important nuance: clozapine and olanzapine warrant immediate metformin co-prescription, while other antipsychotics should trigger metformin after documented weight gain 1, 5.

Pre-Treatment Assessment

Before initiating metformin, obtain:

• Renal function (creatinine, eGFR) - metformin is contraindicated in renal failure 1, 2
• Liver function tests 1, 2
• Baseline vitamin B12 level - metformin requires annual B12 monitoring as it can cause deficiency 1, 2
• Baseline metabolic parameters: fasting glucose, HbA1c, lipid panel 1, 2
• BMI and waist circumference to quantify baseline weight status 1, 2

Monitoring Schedule

Recheck fasting glucose at 4 weeks after metformin initiation 1, 6. If fasting samples are impractical, random glucose is acceptable for initial screening, with fasting glucose obtained if abnormal 1.

Monitor weight, BMI, waist circumference, and blood pressure weekly for 6 weeks after starting metformin or adjusting antipsychotic dose 1, 2, 6.

Repeat complete metabolic assessment at 3 months, then annually: HbA1c, lipids, liver function, renal function, and vitamin B12 1, 2, 6.

Clinical Effectiveness Data

The evidence base is robust:

• Meta-analysis of 12 studies (n=743) demonstrated significant reductions in weight (-3.27 kg), BMI (-1.13 kg/m²), and insulin resistance index (-1.49) compared to placebo 3
• A 12-week RCT (n=72) in first-episode schizophrenia showed significantly more patients in the metformin group lost ≥7% of baseline weight compared to placebo 4
• A 24-week pilot study (n=17) in first-episode psychosis confirmed weight control benefits, though effects did not persist after metformin discontinuation 7

Critical Caveats

Metformin's weight loss effects are modest - approximately 3 kg on average - and do not fully reverse antipsychotic-induced weight gain 5. This underscores the importance of selecting antipsychotics with lower metabolic liability when clinically appropriate (aripiprazole, lurasidone, ziprasidone) rather than relying solely on metformin to counteract high-risk agents 6, 8.

Metformin appears more effective when initiated after weight gain has occurred (except for clozapine/olanzapine where prophylaxis is recommended), based on subgroup analyses showing non-significant effects when started concomitantly with other antipsychotics 5.

Gastrointestinal side effects (nausea, diarrhea) are common but typically transient and can be minimized by slow titration and modified-release formulations 1, 6, 7. Importantly, meta-analysis found nausea rates were not significantly higher than placebo 5.

Weight regain occurs after metformin discontinuation, suggesting ongoing treatment is necessary to maintain benefits 7.

Integration with Lifestyle Interventions

Metformin should be combined with dietary counseling and physical activity promotion, though pharmacological intervention takes priority given the high metabolic liability of many antipsychotics 2, 6. The Lancet Psychiatry Commission emphasizes intervening based on risk rather than waiting for visible metabolic dysfunction 1.