Lamotrigine adverse effects

Lamotrigine is not approved for the acute treatment of depression, and the dose must be started low and slowly titrated up to decrease adverse effects if used for maintenance therapy of bipolar I disorder. A drug interaction and a severe dermatologic rash may occur when lamotrigine is combined with valproate (i.e., lamotrigine doses must be halved from standard dosing titration). 

Use standard therapeutic serum concentration ranges if clinically indicated if partial response or breakthrough episode, adjust dose to achieve higher serum concentrations without causing intolerable adverse effects valproate is preferred over lithium for mixed episodes and rapid cycling lithium and/or lamotrigine is preferred over valproate for bipolar depression. 

Severe skin rashes appear to be the major concern with lamotrigine use. The incidence of rash is greater in children than in adults. Other adverse effects are similar to those of drugs with the same mechanism of action, such as cerebellovestibular changes leading to dizziness, diplopia, ataxia, and blurred vision. Disseminated intravascular coagulation has been reported. 

Nervous system effects were among the most frequent adverse effects reported in patients receiving lamotrigine as adjunctive therapy in controlled clinical trials (Matsuo et ah, 1993). The frequency of dizziness and ataxia and the rate of discontinuance of lamotrigine because of these adverse effects were dose related in clinical trials in a dose-response study, dizziness occurred in 31% and 27% of patients receiving lamotrigine at 500 mg/day, and 300 mg/day (Rambeck et ah, 1996). 

At least three drugs are effective against absence seizures. Two are nonsedating and therefore preferred ethosuximide and valproate. Clonazepam is also highly effective but has disadvantages of dose-related adverse effects and development of tolerance. Lamotrigine and topiramate may also be useful. 

The adverse effects of lithium in elderly patients include cognitive status worsening, tremor, and hypothyroidism. The authors suggested that divalproex is also useful in elderly patients with mania and that concentrations of divalproex in the elderly are similar to those useful for the treatment of mania in younger patients. They noted that carbamazepine should be considered a second-line treatment for mania in the elderly. A partial response would warrant the addition of an atypical antipsychotic drug. For bipolar depression, they recommended lithium in combination with an antidepressant, such as an SSRI. They also noted that lamotrigine may be useful for bipolar depression. Electroconvulsive therapy (ECT) may also be useful, but there have been no comparisons of ECT and pharmacotherapy in elderly patients with bipolar depression. 

A 26-year-old woman with bipolar I disorder took lithium and valproate, and sometimes additional risperidone and lamotrigine. Both risperidone and lamo-trigine produced dermatological adverse effects. Her serum lithium concentration was 0.82 mmol/1. Topiramate 75 mg/day was added. A week later, she continued to show a mixed state with mostly manic features and a raised lithium concentration of 1.24 mmol/1. The lithium concentration continued to increase over the next 4 days to 1.97 mmol/1 even though the lithium dosage was reduced from 900 to 750 mg/day. Lithium was withdrawn and the lithium concentration fell. Lithium was then restarted at half the admission dose to achieve a blood concentration of 0.67 mmol/1. Subsequent increases in the dose of topiramate resulted in further increases in the lithium concentration. 

The cost-effectiveness of four antiepileptic drugs used to treat newly diagnosed adult epilepsy has been studied by cost minimization analysis in 12 European countries (6). The analysis took account of each drug s adverse effects and tolerability profiles. Lamotrigine incurred higher costs than carbamazepine, phenytoin, and valproate, whose costs were similar. 

Pharmacodynamic interactions also occur. In particular, the adverse effects of any drug can be increased by other drugs with similar properties. One example is the reciprocal potentiation of the neurotoxic effects of carbamazepine and lamotrigine in patients taking a combination of these drugs (180). Some drugs (for example ciclosporin, clozapine) have a proconvulsant effect and can reduce the efficacy of antiepileptic drugs. 

The possibility of renal dysfunction as a rare adverse effect should be considered. The patient had a history of allergic reactions to lithium, carbamazepine, clozapine, haloperidol, and lamotrigine. 

In an open study, there were adverse events (details not given) in two of 30 patients with serum lamotrigine concentrations between 16 and 39 pmol/1, and in 5 of 11 patients with serum concentrations between 39 and 86 pmol/1 (3). This is one of the few studies to have provided preliminary evidence for a relation between serum lamotrigine concentrations and the risk of adverse effects. 

Lamotrigine has been stndied in 32 children with epilepsy refractory for at least 1 year to other antiepileptic drugs (7). Adverse effects were uncommon, and there were no skin rashes. 

The most common adverse effects of lamotrigine include dizziness, weakness, headache, diplopia, ataxia, blurred vision, and somnolence (SEDA-18, 65) (SEDA-20, 63) (19). These effects resemble those seen with carbamaze-pine and can result from an adverse pharmacodynamic interaction. Tolerability is better when lamotrigine is given as monotherapy or with drugs other than carbama-zepine however, tremor develops in some patients taking valproate in combinations (SEDA-18, 66). During monotherapy, serum lamotrigine concentrations associated with intolerable adverse effects (mostly headache, dizziness, and ataxia) were 0.4-18.5 qg/ml and overlapped widely with those tolerated in other patients (20). 

Choreoathetosis is a rare adverse effect of some anticonvulsants, but has especially been associated with phenytoin. In a retrospective survey, three of 39 adults and one of 38 children developed choreoathetosis acutely when lamotrigine was added to phenytoin or vice versa (78). The effect was reversible by withdrawing one of the drugs. It was calculated that the risk of choreoathetosis is increased more than 50-fold when these drugs are combined, possibly owing to a pharmacodynamic interaction. 

Faught E, Morris G, Jacobson M, French J, Harden C, Montouris G, Rosenfeld W. Adding lamotrigine to valproate incidence of rash and other adverse effects. Postmarketing Antiepileptic Drug Survey (PADS) Group. Epilepsia 1999 40(8) 1135-40. 

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