How to Minimize Lamotrigine’s Adverse Effects

Table. Dermatologic Drug Eruption Scale

BRIEF COMMUNICATION

Lamotrigine’s favorable tolerability is a welcome advance for patients with bipolar disorder, particularly in the areas that matter most to patients: weight gain, fatigue, sex, and cognition.¹ Unlike other mood stabilizers, lamotrigine lacks long-term medical risks. Rather, the danger it poses is at the start of treatment, when its mood-lifting effects can easily be waylaid by the eruption of a rash.

Preventing rashes on lamotrigine

There are two ways to prevent serious rashes on lamotrigine: titrate slowly and stop the medicine if there is any significant skin eruption within the first 2 months of treatment. With those precautions, the risk of Stevens Johnson Syndrome drops from 1% to 0.1-0.01%.² Unfortunately, the rate of benign rashes remains high (10%), and these false-alarms can interrupt the therapy just when the patient is starting to recover.

To minimize false-alarms, avoid starting lamotrigine within 2 weeks of an inflammatory illness (eg, a viral syndrome), vaccination, or rash and advise patients to avoid common sources of inflammation (eg, sunburn, poisonous plants, and contact with new animals, foods, soaps, and cosmetics) while titrating the medicine.³

For adults, the standard titration schedule is:

• Weeks 1-2: 25 mg/d; Weeks 3-4: 50 mg/d; Week 5: 100 mg/d. Target dose: 150-250 mg/d.⁴

Slower titration is recommended for children under age 16:

• Weeks 1-2: 0.3 mg/kg/d; Weeks 3-4: 0.6 mg/kg/d; Weeks 5 and onward: increase the daily dose by 0.6 mg/kg every 1 to 2 weeks. (Note: always round down to the nearest whole tablet).* Adolescents have the same target dose as adults, but it is lower for children under 12 (around 150 mg/d).^4-6

*Footnote: This schedule is based on lamotrigine’s FDA-approval in children with epilepsy. Lamotrigine is not FDA-approved for children with bipolar disorder.

There are two adjustments for pharmacokinetic interactions:

• Patients on valproate: Reduce the dose by 50% at each stage of the titration. Target dose is 50% lower.

• Patients on carbamazepine (or phenobarbital, phenytoin, primidone): Double the dose at each stage of the titration. Target dose is two-fold higher.⁴

These titrations safeguard against a potentially lethal reaction, so there is never a good reason to deviate from them. The drug should be restarted with the same schedules if a patient misses more than 5 consecutive days of the medicine.

Management of lamotrigine rash

When patients call with a rash, assess for systemic signs, check temperature, consider drawing labs, and ask them to photograph the rash. The Dermatologic Drug Eruption Scale (Table) lists the signs of a potentially serious rash.² Patients with severe reactions should be referred to an ED or urgent care center (where they are usually treated with a prednisone taper).

Rechallenge is a reasonable option for many patients who discontinued lamotrigine after a rash. Among the 85 published cases of lamotrigine rechallenge, none developed Stevens Johnson syndrome; however, 10% to 15% developed a second rash.^2,7 That risk is lessened by retitrating very slowly and waiting at least 4 weeks before reintroducing lamotrigine. Start at 5 mg/d and increase the daily dose by 5 mg every 2 weeks until 25 mg/d is reached. Then proceed with the standard titration.² A dermatologist should be consulted if the initial rash was serious (eg, ≥ 3 on the Dermatologic Drug Eruption Scale [Table]).

Sometimes lamotrigine is the only treatment a patient responds to but they cannot remain on it because of the rash. Other glutamatergic agents may be helpful in those cases. Amantadine, riluzole, ketamine, pioglitazone, magnesium, D-cycloserine, and dextromethorphan all have pilot data in mood disorders.⁸

Cognitive side effects: A two-edged sword

Lamotrigine is less likely to impair cognition than other mood stabilizers, and it may even confer cognitive benefits. It has improved verbal fluency, working memory, attention, and concentration in studies of bipolar disorder and healthy subjects.⁹ On the other hand, adverse cognitive effects are possible with lamotrigine. This usually manifests as word-finding difficulty and improves with dose reduction.

Adverse effects

Lamotrigine’s adverse effect profile is similar to placebo in all categories except sleep disruption.¹ This often presents as vivid dreams and can be minimized by dosing in the morning and using behavioral methods to deepen sleep. Other adverse effects usually improve with dose reduction. Difficulties in swallowing the tablets can be managed by switching to the orally disintegrating form or dosing with the smaller 25 mg size.

Lamotrigine can increase the risk of sunburn, particularly when taken with other photosensitizing medications (eg, antipsychotics, tricyclics, and –cycline antibiotics). Recommended precautions include a broad-spectrum sunscreen with a SPF of at least 30.

Rarely, patients report worsened mood with lamotrigine, although controlled studies have not linked this reaction to the medication. In these cases, I often retry lamotrigine 6-12 months later. The dysphoric reaction rarely recurs and the medicine usually proves beneficial.

The bottom line

23andMe once asked their members with bipolar disorder to rank the treatments they found most helpful.¹⁰ Surprisingly, only one medicine made it into the top 10. Not surprisingly, it was lamotrigine. The medicine’s unique benefits, which were explored in last month’s column, only partly explain that sentiment. Recovery in bipolar disorder often comes with a cost of intolerable adverse effects, and few patients are willing to make that exchange for very long. Non-adherence hovers around 50% in bipolar disorder, and lamotrigine can often tip those scales in a more favorable direction.

Disclosures:

Dr. Aiken is the Director of the Mood Treatment Center and an Instructor in Clinical Psychiatry at the Wake Forest University School of Medicine. He does not accept honoraria from pharmaceutical companies but receives honoraria from W.W. Norton & Co. for Bipolar, Not So Much, which he coauthored with Jim Phelps, MD. He does not accept honoraria from pharmaceutical companies.

References:

1. Reid JG, Gitlin MJ, Altshuler LL. Lamotrigine in psychiatric disorders.J Clin Psychiatry. 2013;74:675-684.

2. Aiken CB, Orr C. Rechallenge with lamotrigine after a rash: a prospective case series and review of the literature.Psychiatry (Edgmont). 2010;7:27-32.

3. Ketter TA, Wang PW, Chandler RA, et al. Dermatology precautions and slower titration yield low incidence of lamotrigine treatment-emergent rash.J Clin Psychiatry. 2005;66:642-645.

4. GlaxoSmithKline. Lamictal prescribing information. Accessed February 1, 2018.

5. Findling RL, Chang K, Robb A, et al. Adjunctive maintenance lamotrigine for pediatric bipolar I disorder: a placebo-controlled, randomized withdrawal study. J Am Acad Child Adolesc Psychiatry. 2015;54:1020-1031.

6. Biederman J, Joshi G, Mick E, et al. A prospective open-label trial of lamotrigine monotherapy in children and adolescents with bipolar disorder. CNS Neurosci Ther. 2010;16:91-102.

7. Serrani Azcurra DJ. Lamotrigine rechallenge after a skin rash. A combined study of open cases and a meta-analysis.Rev Psiquiatr Salud Ment. 2013;6:144-149.

8. Deutschenbaur L, Beck J, Kiyhankhadiv A, et al. Role of calcium, glutamate and NMDA in major depression and therapeutic application.Prog Neuropsychopharmacol Biol Psychiatry. 2016;64:325-333.

9. Dias VV, Balanzá-Martinez V, Soeiro-de-Souza MG, et al. Pharmacological approaches in bipolar disorders and the impact on cognition: a critical overview.Acta Psychiatr Scand. 2012;126:315-331.

10. CureTogether. 60 bipolar disorder treatments compared, Accessed February 1, 2018.