Can lithium, quetiapine, and lamotrigine (Lamictal) cause a high premature ventricular contraction (PVC) burden?

Can Lithium, Quetiapine, or Lamotrigine Cause High PVC Burden?

Yes, all three medications can cause or increase PVC burden, with quetiapine having the most direct documented association, lamotrigine showing emerging evidence of ventricular arrhythmias including PVCs, and lithium primarily causing bradycardia and conduction abnormalities but also capable of causing ventricular arrhythmias.

Quetiapine and PVC Burden

Quetiapine has the strongest direct evidence for causing frequent PVCs. A case report documented a 17-year-old patient who developed frequent monomorphic PVCs (0.6% burden) during quetiapine treatment, which dramatically increased to 7.1% upon rechallenge and decreased to 1.1% after withdrawal 1. This dose-response relationship provides compelling evidence of causality.

• Quetiapine belongs to the atypical antipsychotic class, which carries dose-dependent risk of sudden cardiac death with adjusted incidence-rate ratios from 1.59 to 2.86 2
• The mechanism likely involves QT prolongation, though the specific case report demonstrated PVCs as the primary manifestation 1

Lamotrigine and Ventricular Arrhythmias

Lamotrigine shows emerging evidence of increasing ventricular arrhythmia risk, including PVCs, particularly in patients with bipolar disorder. A large observational cohort study found lamotrigine significantly increased ventricular tachycardia risk in bipolar disorder patients (adjusted HR 1.326,95% CI 1.122-1.568, p<0.01) 3.

• The FDA added a warning in 2020 regarding lamotrigine's potential to cause cardiac rhythm and conduction abnormalities based on in vitro data showing Class IB antiarrhythmic effects at therapeutic concentrations 4
• A retrospective Veterans Affairs study found 7.3% of patients on lamotrigine had EKG abnormalities potentially related to the medication, though no deaths were directly attributed to cardiac causes 4
• The risk appears higher in patients with structural heart disease and when combined with other sodium channel blocking agents 3, 4
• Guidelines note that anticonvulsants including lamotrigine have "generally not been associated with severe arrhythmia," but this reflects older data predating recent mechanistic discoveries 2

Lithium and Cardiac Arrhythmias

Lithium can cause ventricular arrhythmias, though bradycardia and conduction abnormalities are more common manifestations. Lithium's cardiac effects include T-wave changes, AV block, and less commonly ventricular arrhythmias 2.

• A 2025 case report documented an 80-year-old woman with chronic lithium toxicity presenting with severe sinus bradycardia requiring temporary pacemaker placement, with complete resolution after lithium discontinuation 5
• Historical literature review confirms lithium can cause ventricular arrhythmias, particularly in toxic doses, though sinus node dysfunction is more typical 6
• Reports regarding QT prolongation effects are divergent, but bradycardia, T-wave changes, and AV block are well-established 2
• Lithium has a narrow therapeutic range, making toxicity more likely without routine monitoring 5

Clinical Management Algorithm

Immediate Assessment

• Obtain 12-lead ECG to assess QTc interval, conduction abnormalities, and document PVC morphology 2
• Perform 24-hour Holter monitoring to quantify PVC burden (percentage of total beats) 7, 1
• Check serum lithium level if applicable, as toxicity amplifies cardiac risk 5
• Obtain transthoracic echocardiography to assess for structural heart disease and left ventricular function 7, 8

Risk Stratification Based on PVC Burden

High-risk features requiring aggressive intervention:

• PVC burden >15% of total beats (risk threshold for PVC-induced cardiomyopathy) 7, 8
• QTc >500 ms (associated with 2-3 fold higher risk of torsades de pointes) 2
• Declining left ventricular ejection fraction on serial echocardiography 7
• Structural heart disease present 3, 4

Moderate-risk features:

• PVC burden 10-15% (minimum threshold associated with cardiomyopathy development) 7, 8
• Multifocal PVCs 2
• Symptomatic palpitations, dyspnea, or chest pain 7

Treatment Decision Tree

If PVC burden >15% or declining LV function:

1. Discontinue or reduce the offending medication immediately 2, 1
2. Consider alternative psychiatric medication without cardiac effects 2
3. Initiate beta-blocker therapy (metoprolol or atenolol) as first-line treatment 7, 8
4. Refer for catheter ablation if PVC burden remains >15% despite medication adjustment, as 82% of patients normalize LV function within 6 months post-ablation 7, 8

If PVC burden 10-15%:

1. Reduce dose of offending medication or switch to alternative agent 1
2. Initiate beta-blocker therapy 7, 8
3. Repeat Holter monitoring in 2-4 weeks to assess response 7
4. Perform serial echocardiography every 3-6 months to monitor for cardiomyopathy development 7, 8

If PVC burden <10% and asymptomatic:

1. Consider dose reduction or medication switch based on psychiatric indication 1
2. Reassurance and avoidance of aggravating factors (caffeine, alcohol, stimulants) 7
3. Repeat monitoring if symptoms develop 7

Critical Pitfalls to Avoid

Never use Class IC antiarrhythmic agents (flecainide, propafenone) to treat PVCs in patients taking these psychiatric medications, as they increase mortality risk, particularly if structural heart disease or reduced LVEF is present 2, 7. The CAST trial demonstrated increased mortality with these agents despite PVC suppression 2.

Do not continue quetiapine if PVC burden increases significantly upon rechallenge, as the case report demonstrated a clear dose-response relationship with PVC burden increasing from 0.6% to 7.1% 1.

Avoid combining lamotrigine with other sodium channel blocking agents, as this increases the risk of cardiac complications 4. Nearly half of patients in the Veterans Affairs study were on concomitant sodium channel blockers, potentially amplifying risk 4.

Monitor lithium levels routinely (every 3-6 months at minimum), as the narrow therapeutic window makes toxicity common, and cardiac manifestations may be the presenting feature 5.

Do not delay echocardiography in patients with PVC burden >10%, even if asymptomatic, as left ventricular dysfunction may develop silently and is reversible if caught early 7, 8.

Special Considerations

For patients requiring continuation of these medications for psychiatric stability, close cardiac monitoring is essential: baseline ECG, 24-hour Holter monitoring every 3-6 months, and echocardiography every 6-12 months if PVC burden is 5-15% 7, 4.

In acute coronary syndrome settings, beta-blockers should be administered early to prevent ventricular arrhythmias, and prophylactic antiarrhythmic drugs are not indicated and may be harmful 7.

The combination of structural heart disease with any of these medications substantially increases risk, with lamotrigine showing "notable increased effect" on ventricular tachycardia incidence in this population 3.