lamotrigine

General Information

Lamotrigine (Lamictal) is a phenyltriazine anticonvulsant repurposed as a weight-neutral mood stabilizer that prevents bipolar depressive relapse without appreciable metabolic or cognitive burden.

The FDA approved lamotrigine in 2003 for maintenance treatment of bipolar I disorder; because it provides little protection against acute mania, clinicians usually combine it with lithium, valproate, or an atypical antipsychotic for sustained hypomanic prophylaxis.

Contemporary CANMAT/ISBD and NICE guidelines endorse lamotrigine as a first-line option for depressive polarity maintenance when slow titration is acceptable and metabolic neutrality, pregnancy planning, or antidepressant sensitivity are priorities; coordinate longitudinal plans using the bipolar disorder hub.

The compare tool and the lamotrigine evidence feed support side-by-side review of titration speed, metabolic effects, and antimanic coverage when updating maintenance strategies or augmentation.

Relied on for bipolar depression prevention, postpartum transitions, and patients prioritizing weight neutrality; typically paired with broader antimanic coverage because lamotrigine has minimal impact on mania.

Mechanism of Action

Refer to the Glossary entry on Neurotransmitters for background on receptor systems involved in serious mental illness.

Stabilizes presynaptic membranes by inhibiting voltage-sensitive sodium channels and dampening pathologic glutamate release.

Secondarily modulates calcium currents and monoaminergic tone, supporting antidepressant effects without dopaminergic blockade.

• Voltage-gated sodium channel modulator with downstream glutamate dampening.
• Minimal direct activity at dopamine, adrenergic, or histamine receptors.

Metabolism and Pharmacokinetics

• Oral bioavailability approaches 98%; immediate-release tablets reach peak plasma levels in 1–3 hours, extended-release in 4–6 hours.
• Primarily metabolized by hepatic UGT1A4 (UGT2B7 minor) with negligible CYP involvement.
• Mean elimination half-life is ~25 hours, prolonged to 48–60 hours with valproate and shortened to ~13–15 hours by enzyme inducers; clearance rises substantially during pregnancy and falls postpartum.
• Approximately 94% of a dose is renally excreted as glucuronide conjugates; dose titration is approached cautiously in severe renal or hepatic impairment.

Dosing and Administration

• Standard regimen (no valproate or strong inducers): 25 mg once daily for weeks 1–2, 50 mg once daily weeks 3–4, 100 mg once daily week 5, then 200 mg/day from week 6 onward with optional increases to 300–400 mg based on response.
• With valproate: 25 mg every other day weeks 1–2, 25 mg once daily weeks 3–4, 50 mg once daily week 5, then 100 mg/day (maximum 200 mg/day) from week 6.
• With enzyme inducers (carbamazepine, phenytoin, phenobarbital, primidone, rifampin) and without valproate: 50 mg once daily weeks 1–2, 100 mg/day in two divided doses weeks 3–4, 200 mg/day week 5, 300 mg/day week 6, and 400 mg/day thereafter as tolerated.
• Extended-release tablets follow the same total daily targets but are taken once daily; tablets are not crushed, chewed, or split.
• If therapy is interrupted for more than five consecutive days, titration is typically restarted from the beginning. Rash with mucosal involvement or systemic features is generally treated as an indication for permanent discontinuation.

Adverse Effects

Interactions

• Valproate inhibits lamotrigine glucuronidation and roughly doubles serum concentrations—titration and maintenance doses are typically halved, and toxicity monitoring is increased.
• Potent enzyme inducers (carbamazepine, phenytoin, phenobarbital, primidone, rifampin) increase clearance—an accelerated titration schedule is often used, and higher maintenance doses may be needed.
• Estrogen-containing contraceptives or hormone therapy can increase clearance by 40–60%; dose adjustments are often needed when estrogen is started or stopped.
• Atazanavir/ritonavir and lopinavir/ritonavir reduce lamotrigine exposure—clinical response is monitored and dose increases may be considered.
• Prior serious rash with aromatic antiepileptics (e.g., carbamazepine, oxcarbazepine) heightens rash risk; counseling often emphasizes rash recognition and risk–benefit tradeoffs.

Other Useful Information

• Titration packs or digital reminders are commonly used to support adherence throughout the six-week escalation.
• Education commonly covers rash, fever, swollen glands, or flu-like symptoms, with urgent evaluation for concerning presentations.
• Therapeutic drug monitoring is not routine but can guide dosing in pregnancy, postpartum, or when strong inducers/inhibitors are introduced or withdrawn.
• If therapy is interrupted for more than five consecutive days, titration is typically restarted from the beginning to reduce serious rash risk.
• Contraceptive plans and pregnancy intentions are often reviewed; doses may need adjustment and mood symptoms are followed as clearance changes during pregnancy and after delivery.
• The compare tool can help weigh lamotrigine against lithium and quetiapine when balancing metabolic neutrality against acute antimanic protection.

References

1. Lamotrigine tablets — Prescribing Information — DailyMed (2024)
2. The CANMAT and ISBD Guidelines for the Management of Patients With Bipolar Disorder: 2021 Update — Bipolar Disorders (2021)Guidelinebipolarclinical
3. Bipolar disorder: assessment and management (NICE guideline CG185) — National Institute for Health and Care Excellence (2020)
4. Lamotrigine Augmentation IN Treatment Resistant Bipolar Depression: A Step BD Randomized Trial — American Journal of Psychiatry (2006)
5. Lamotrigine in mood disorders: a systematic review — Annals of Clinical Psychiatry (2018)
6. FDA safety communication: lamotrigine and hemophagocytic lymphohistiocytosis
7. AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology — Pharmacopsychiatry (2018)