, Volume 63, Issue 19, pp 2029-2050
Date: 17 Sep 2012

Lamotrigine

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Summary

Abstract

Lamotrigine (Lamictal®), a phenyltriazine derivative, is a well established anticonvulsant agent that has shown efficacy in the prevention of mood episodes in adult patients with bipolar I disorder. The mechanism of action of the drug in patients with bipolar disorder may be related to the inhibition of sodium and calcium channels in presynaptic neurons and subsequent stabilisation of the neuronal membrane.

Lamotrigine monotherapy significantly delayed time to intervention with additional pharmacotherapy or electroconvulsive therapy for any new mood episode (mania, hypomania, depression and mixed episodes), compared with placebo, in two large, randomised, double-blind trials of 18 months’ duration. Additionally, lamotrigine was significantly superior to placebo at prolonging time to intervention for depression. These effects of lamotrigine were demonstrated in both recently manic/hypomanic and recently depressed patients. Lamotrigine showed efficacy in delaying manic/hypomanic episodes in pooled data only, although lithium was superior to lamotrigine on this measure.

Two of four double-blind, short-term studies have shown lamotrigine to be more effective than placebo in the treatment of patients with treatment-refractory bipolar disorder or those with bipolar depression. Lamotrigine has not demonstrated efficacy in the treatment of acute mania.

Lamotrigine was generally well tolerated in maintenance studies with the most common adverse events being headache, nausea, infection and insomnia. Incidences of diarrhoea and tremor were significantly lower in lamotrigine-than in lithium-treated patients. The incidence of serious rash with lamotrigine treatment was 0.1% in all studies of bipolar disorder and included one case of mild Stevens-Johnson syndrome. Lamotrigine did not appear to cause bodyweight gain.

The dosage of lamotrigine is titrated over a 6-week period to 200 mg/day to minimise the incidence of serious rash. Adjustments to the initial and target dosages are required if coadministered with valproate semisodium or carbamazepine.

Conclusion: Lamotrigine has been shown to be an effective maintenance therapy for patients with bipolar I disorder, significantly delaying time to intervention for any mood episode. Additionally, lamotrigine significantly delayed time to intervention for a depressive episode and showed limited efficacy in delaying time to intervention for a manic/hypomanic episode, compared with placebo. Although not approved for the short-term treatment of mood episodes, lamotrigine has shown efficacy in the acute treatment of patients with bipolar depression but has not demonstrated efficacy in the treatment of acute mania. Lamotrigine is generally well tolerated, does not appear to cause bodyweight gain and, unlike lithium, generally does not require monitoring of serum levels.

Pharmacodynamic Properties

Lamotrigine is a phenyltriazine derivative. The mechanism of action of the drug in the treatment of patients with bipolar disorder is not fully understood, but may be related to the inhibition of sodium and calcium channels in presynaptic neurons and subsequent stabilisation of the neuronal membrane. In addition, lamotrigine has demonstrated neuroprotective effects in animal models. Lamotrigine lacks appreciable in vitro affinity for dopaminergic, adrenergic, muscarinic, opioid and adenosine receptors at clinically relevant concentrations, but binds weakly to serotonin 5HT3 receptors. It also down-regulates cortical 5HT1A receptor-mediated adenyl cyclase responses in an animal model.

Normal synaptic conduction is unaffected by lamotrigine, which suppresses abnormal (sustained repetitive) firing of sodium-dependent action potentials in animal models.

Early studies in patients with epilepsy who received lamotrigine indicated a propensity for improved mood, which led to controlled clinical trials in patients with bipolar disorder. Lamotrigine has minimal effects on psychomotor, cognitive and memory function and appears not to be associated with sedative effects or bodyweight gain.

Pharmacokinetic Properties

Oral lamotrigine is readily bioavailable (98%), and undergoes minimal first-pass metabolism. Absorption of lamotrigine is unaffected by food. Linear pharmacokinetics show peak lamotrigine concentrations occurring 1–3 hours after a dose. Mean protein binding is 55–68% and the drug is widely distributed to all organs and tissues, including brain tissue. It also crosses the placenta and is found in the fetus and in breast milk. Lamotrigine is extensively metabolised in the liver, predominantly via N-glucuronidation (the rate-limiting step in elimination of the drug). Clearance is 1.6–2.6 L/h and the mean plasma elimination half-life is 25–35 hours.

Drug Interactions

Lamotrigine pharmacokinetics appear not to be significantly altered by many commonly used psychotropic agents, nor does lamotrigine alter the pharmacokinetics of lithium. However, enzyme-inhibiting drugs (e.g. valproate semi-sodium) increase lamotrigine plasma concentrations and enzyme-inducing drugs (e.g. carbamazepine) decrease lamotrigine concentrations. Lamotrigine appears not to have clinically significant reciprocal effects on the pharmacokinetics of these drugs.

Therapeutic Efficacy

Lamotrigine has been shown to be an effective maintenance treatment in patients with bipolar I disorder who have had a recent depressive or manic/hypomanic episode. Data from two placebo-controlled, double-blind, 18-month comparative studies showed that lamotrigine (100–400 mg/day) or lithium (dose titrated to a serum level of 0.8–1.1 mEq/L) each significantly delayed the time to intervention with additional pharmacotherapy or electroconvulsive therapy for an emerging mood episode compared with placebo (p < 0.05 for lamotrigine vs placebo and for lithium vs placebo in both studies). In addition, both studies showed that lamotrigine, but not lithium, was significantly superior to placebo at prolonging time to intervention for a depressive mood episode. Similarly lithium, but not lamotrigine, was significantly better than placebo at delaying time to intervention for an emerging manic/hypomanic episode. However, in pooled data lamotrigine also significantly delayed time to intervention for a manic/hypomanic episode, although lithium was superior to lamotrigine on this measure.

Lamotrigine was shown to be more effective than placebo in the treatment of patients with treatment-refractory bipolar disorder or those with bipolar depression in two of four double-blind short-term studies. Lamotrigine has not demonstrated efficacy in the treatment of acute mania.

Tolerability

Lamotrigine 100–400 mg/day as monotherapy was generally well tolerated in two maintenance trials in patients with bipolar I disorder, with a similar adverse event profile to that of placebo. The most common adverse events were headache (19%), nausea (14%), infection (13%) and insomnia (10%). Significantly fewer lamotrigine recipients, compared with those receiving lithium, reported diarrhoea and tremor. The incidence of adverse events was similar in patients who received lamotrigine dosages of 50 mg/day compared with those who received 200 mg/day.

Maintenance therapy with lamotrigine did not appear to increase bodyweight after 52 weeks’ treatment. Obese patients (body mass index ≥30 kg/m2) receiving lamotrigine lost an average 2.96kg, whereas those who received lithium or placebo gained 3.3 and 1.46kg, respectively.

In a meta-analysis of eight randomised, double-blind, placebo-controlled trials in patients with bipolar disorder, serious adverse events occurred at a similar rate in patients receiving lamotrigine (8%), lithium (8%) and placebo (7%). Induction of mania was the most common serious adverse event and occurred in 3% of patients in each treatment group.

The incidence of suicide per year in the meta-analysis was similar between patients receiving lamotrigine and placebo (0.7% vs 0.6%) while no suicides occurred among lithium recipients. Suicide attempts occurred at a similar rate per year in both lamotrigine (1.8%) and placebo (1.1%) recipients. Sexual problems were reported in <1% of patients receiving lamotrigine.

Three of 2272 (0.1%) patients receiving lamotrigine in all controlled and uncontrolled bipolar disorder studies developed a serious rash, including one case of mild Stevens-Johnson syndrome, which was reported in a patient while receiving adjunctive lamotrigine during an open-label phase. The patient did not require hospitalisation and recovered uneventfully.

Dosage and Administration

Lamotrigine is approved in the US for the maintenance treatment of adults with bipolar I disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania and mixed episodes) in patients treated for acute mood episodes with standard therapy.

The initial recommended monotherapy dosage is 25 mg/day orally which is gradually increased to 200 mg/day over 6 weeks. Dosages over 200 mg/day as monotherapy are not recommended, as no additional efficacy has been demonstrated in clinical trials evaluating dosages up to 400 mg/day. For patients taking valproate semisodium, the initial recommended lamotrigine dosage is 25mg every other day and the target dosage is 100 mg/day from week 6. In recipients of carbamazepine (or other enzyme-inducing drugs), the initial recommended lamotrigine dosage is 50 mg/day, which is gradually increased up to 400 mg/day from week 7. Dosages ≥50 mg/day can be given once-daily or as two divided doses. There are no formal recommendations as to the duration of maintenance therapy in bipolar I disorder. Lamotrigine should be gradually discontinued over a period of at least 2 weeks.

The risk of serious rash, including Stevens-Johnson syndrome, may be increased by coadministration of lamotrigine with valproate semisodium, by exceeding the recommended initial lamotrigine dosage or by exceeding the recommended dosage titration. Lamotrigine should be discontinued at the first sign of any rash, unless the rash is clearly not drug-related.

Reduced maintenance dosages are recommended for patients with hepatic impairment.

Various sections of the manuscript reviewed by: M. Berk, Department of Psychiatry, University of Melbourne, Geelong, Victoria, Australia; C.L. Bowden, Department of Psychiatry, University of Texas Health Science Center, San Antonio, Texas, USA; J.R. Calabrese, Mood Disorders Program, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA; R.T. Joffe, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey, USA; T.A. Ketter, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California, USA; P.B. Mitchell, School of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia.
Data Selection
Sources: Medical literature published in any language since 1980 on lamotrigine, identified using Medline and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.
Search strategy: Medline search terms were ‘lamotrigine’ and (‘bipolar*’ or ‘manic depression’ or ‘mania’ or ‘depressive’ or ‘depression’ or ‘affective’ or ‘manic depressive disorder’). EMBASE search terms were ‘lamotrigine’ and (‘bipolar’ or ‘depression’ or ‘manic depression’ or ‘mania’ or ‘manic depressive disorder’ or ‘affective’). AdisBase search terms were ‘lamotrigine’ and (‘manic depression’ or ‘mania’ or ‘bipolar depression’ or ‘bipolar-disorders’ or ‘depression’ or ‘depressive’ or ‘antidepress*’ or ‘affective’). Searches were last updated 6th August 2003.
Selection: Studies in patients with bipolar disorder who received lamotrigine. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.
Index terms: lamotrigine, bipolar disorder, depression, mania, pharmacodynamics, pharmacokinetics, therapeutic use.