Day # 57: Lamotrigine

Welcome back to our current theme of bipolar disorder. We are continuing our conversation on the medications classified as "mood stabilizers" and today we will discuss lamotrigine.

Today's content level: Beginner; Intermediate

INTRODUCTION AND MECHANISM OF ACTION

•Lamotrigine = Lamictal

•Lamotrigine is a mood stabilizer used in bipolar disorder and an anti-epileptic drug (AED) used for seizures.

Mechanism of action includes:

• Blocks voltage-dependent sodium channels.

• Inhibits release of glutamate and aspartate.

• Also has some inhibition of serotonin reuptake and increases serotonin concentrations.

• Delayed onset of action (weeks) due to required slow up-titration.

•Does not inhibit or induce hepatic metabolism of other drugs but its metabolism may be induced or inhibited by other medications (see dosing section below).

INDICATIONS

FDA approved indications:

• Bipolar disorder: Specifically approved for maintenance treatment, but also used off-label for bipolar depression and adjunctive treatment for mania. Particularly effective in prolonging time to relapse of bipolar depression. Effective in preventing mania, but inferior to valproic acid. Limited use in acute mania due to slow up-titration schedule.

• Epilepsy: Approved to treat partial seizures and generalized seizures of Lennox-Gastaut syndrome.

Other off-label indications:

• Major depressive disorder (adjunctive): Lamotrigine augmentation is reasonably well researched and possibly the best tolerated augmentation strategy. Appropriate dosing is unclear and obviously a requires slow titration due to risk of SJS.

• Borderline personality disorder: Some data suggest lamotrigine may be effective in alleviating mood symptoms, impulsivity, and even substance use in these patients. 1

• Schizophrenia (adjunctive): May be useful as an adjunct to atypical antipsychotics in schizophrenia.

• Neuropathic pain / chronic pain: Evidence for possible utility for patients with neuropathic pain such as diabetic peripheral neuropathy, HIV-associated neuropathy, and other pain conditions including migraine.

SIDE EFFECTS

•Overall lamotrigine is typically well-tolerated. Among the treatment options for bipolar disorder it may actually be the best tolerated mood stabilizer as there are relatively minimal side effects, less weight gain, and less sedation.

Common side effects include:

• GI upset: during early treatment. Nausea, dyspepsia, abdominal pain, constipation.

• Some patients report sedation or insomnia: some studies show that taking at night leads to disruption of stage 3 sleep.

• Benign rash: benign maculopapular rash can occur in around 10% of patient within the first four months of treatment. If the rash is considered benign (non-tender, non-mucosal, spotty & non-confluent, no systemic features, normal labs) then the patient can be re-challenged with a slower titration. Reduce dose or stop dose increase -> provide additional psychoeducation about serous rash -> Antihistamine +/- topical corticosteroid for itching -> if rash improves/disappears in 10-14 days may re-challenge with slow dose titration.

• Headache

• Tremor

• Ataxia/Dizziness

Serious side effects include:

• Rare serious rash = Stevens Johnson Syndrome (SJS) or Toxic Epidermal Necrolysis (TEN). Severe skin and systemic reaction that exists on a spectrum (TEN more severe than SJS). Syndrome includes fever + flu-like symptoms -> painful blistering/peeling rash -> mucous membranes (such as the mouth) are often involved -> potential complications include dehydration, sepsis, pneumonia, multiple organ failure, and death. This is urgent and treatment occurs in an ICU setting or burn unit. This potential side effect should obviously be taken very seriously, however it is very rare. The risk is about 0.08% (0.8 in 1,000 patients) and even lower with careful dose titration. 2

• Aseptic meningitis: rare. 3

• Bone marrow suppression: rare, including thrombocytopenia and leukopenia. 4

• Possible increased suicidal ideation.

• Overdose -> confusion, ataxia, coma, arrhythmias, SJS/TEN, and in some cases death.

DOSING

•Dosing for lamotrigine requires our particular attention. Slow up-titrations are required due to much lower risk of developing Steven-Johnson's Syndrome.

•Start at 25 mg/day for two weeks -> 50 mg/day for two weeks -> 100 mg/day by week four. Max dosing for bipolar disorder is 200 mg/day

Notable exceptions to dosing schedule

• Co-administered with Carbamazepine (or other enzyme inducing AEDs): above typical dosing schedule is doubled.

• Co-administered with Valproate: dosing schedule is cut in half. 25mg/every other day for two weeks -> 25 mg/day for two weeks -> 50mg/day by week four. Max dosing for bipolar disorder is 100 mg/day when also taking valproate.

•If patient stops taking lamotrigine for 5 days or more it may be necessary to restart the drug with the initial dose titration, as rashes have been reported on re-exposure.

CONCLUSION

Great job today. Tomorrow we will discuss carbamazepine/oxcarbamazepine.

Resources for today's post include the Maudsley Prescribers Guide, Stahl's Essentials for Psychopharmacology, and Pocket Psychiatry.