Is metformin recommended for patients on second‑generation (atypical) antipsychotics who have metabolic side effects or are at high risk for weight gain, impaired glucose tolerance, pre‑diabetes, or type‑2 diabetes?

Metformin with Second-Generation Antipsychotics

Yes, metformin is recommended as adjunctive therapy when starting antipsychotics with poor cardiometabolic profiles (olanzapine and clozapine), and should be strongly considered for patients who develop metabolic side effects on any second-generation antipsychotic. 1

When to Initiate Metformin

Prophylactic Use (Preferred Approach)

• Start metformin at antipsychotic initiation when prescribing olanzapine or clozapine, as these carry the highest metabolic risk 1
• This prophylactic approach is most effective when implemented early, particularly in young adults newly exposed to antipsychotic drugs 2, 3
• The evidence strongly supports early intervention rather than waiting for metabolic complications to develop 4

Reactive Use (After Metabolic Changes Occur)

• Initiate metformin if weight gain occurs despite lifestyle interventions after starting any second-generation antipsychotic 5
• Consider metformin for patients showing rapid weight gain patterns and/or glucose dysregulation when switching antipsychotics is not feasible 4
• Use metformin for treatment of prediabetes in patients on atypical antipsychotics 6

Dosing Protocol

Follow the standard diabetes treatment regimen: 1

• Start at 500 mg once daily
• Increase by 500 mg increments every 2 weeks
• Target dose: 1 g twice daily (dependent on tolerability)
• Use modified-release preparation when available to minimize gastrointestinal side effects 1

Mandatory Pre-Treatment Assessment

Before initiating metformin, check: 1

• Renal function (avoid if renal failure present; safe with eGFR ≥30 mL/min/1.73 m²) 1
• Baseline liver function tests
• HbA1c
• Vitamin B12 level 1

Ongoing Monitoring Requirements

Annual monitoring must include: 1

• Liver function tests
• HbA1c
• Renal function
• Vitamin B12 (metformin causes B12 deficiency and can worsen neuropathy) 1

Screening Requirements for All Patients on Antipsychotics

Screen for prediabetes and diabetes: 1

• At 4 months after antipsychotic initiation
• Annually thereafter
• More frequently if on high-risk agents (olanzapine, clozapine) 7, 8

Comprehensive baseline assessment before starting any antipsychotic: 1

• BMI and waist circumference
• Blood pressure
• HbA1c and glucose (fasting preferred; random acceptable for initial screening)
• Lipid panel
• Prolactin
• Liver function tests
• Urea and electrolytes
• Full blood count
• Electrocardiogram

Follow-up schedule: 1

• Fasting glucose at 4 weeks post-initiation
• BMI, waist circumference, and blood pressure weekly for 6 weeks
• Repeat all baseline measures at 3 months
• Annual reassessment thereafter

Alternative Strategies to Consider First

Before defaulting to metformin, evaluate: 7, 8

• Switching to lower metabolic-risk antipsychotics: aripiprazole, ziprasidone, brexpiprazole, cariprazine, or lurasidone (these have minimal glucose metabolism effects) 7, 6
• Avoid or use extreme caution with olanzapine, clozapine, quetiapine, and risperidone in diabetic patients 7
• If positive symptoms are well-controlled, consider gradual dose reduction within therapeutic range 1

Additional Pharmacologic Options

For patients requiring more intensive metabolic management: 1

• GLP-1 receptor agonists (e.g., liraglutide 3.0 mg daily) can be considered as add-on therapy, with demonstrated cardiovascular safety 1, 6
• SGLT-2 inhibitors may provide cardio-renal benefits, though RCT data in this specific population is lacking 6

Critical Pitfalls to Avoid

• Do not delay treatment: Intensification should not be postponed when metabolic parameters worsen 1
• Do not rely solely on lifestyle interventions: While important, lifestyle changes alone have shown disappointing outcomes in this population 6
• Do not ignore vitamin B12: Metformin consistently causes B12 deficiency, requiring periodic monitoring 1
• Do not prescribe metformin with eGFR <30 mL/min/1.73 m²: This increases lactic acidosis risk 1
• Minimize other weight-promoting medications: Review and reduce anticholinergic burden and other medications associated with weight gain (tricyclic antidepressants, gabapentin, pregabalin, glucocorticoids) 1

Coordination of Care

Psychiatric prescribers bear primary responsibility for: 9

• Initiating cardiometabolic monitoring
• Managing initial metabolic complications
• Implementing lifestyle counseling (diet, physical activity, tobacco cessation)
• Considering antipsychotic switching or adjunctive metformin

Refer to primary care or endocrinology when: 9

• Persistent dyslipidemia despite antipsychotic optimization
• Multiple cardiovascular risk factors requiring comprehensive assessment
• Patient requires medications outside psychiatric prescriber's comfort zone
• Diabetes management becomes complex

A shared care model with coordinated management between psychiatric and medical providers improves outcomes for patients with serious mental illness 9, 1