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 1 This Spotlight is derived from abstract and summary text of an Adis Drug Evaluation originally published in full in Drugs 2003; 63 (19): 2029-2050. Reviewers of the original full text article are listed in the Acknowledgements section. 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.
Bipolar Disorder Lamotrigine Bipolar Depression Bodyweight Gain Valproate Semisodium
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
This is a preview of subscription content, log in to check access.
The full text article in Drugs 2003; 63 (19): 2029-50 was 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.
Goa KL, Ross SR, Chrisp P, et al. Lamotrigine: a review of its pharmacological properties and clinical efficacy in epilepsy. Drugs 1993; 46(1): 152–76PubMedCrossRefGoogle Scholar
Li X, Ketter TA, Frye MA. Synaptic, intracellular, and neuroprotective mechanisms of anticonvulsants: are they relevant for the treatment and course of bipolar disorders? J Affect Disord 2002 May; 69(1–3): 1–14PubMedCrossRefGoogle Scholar
Fitton A, Goa KL. Lamotrigine: an update of its pharmacology and therapeutic use in epilepsy. Drugs 1995 Oct; 50: 691–713PubMedCrossRefGoogle Scholar
Stefani A, Spadoni F, Siniscalchi A, et al. Lamotrigine inhibits Ca2+ currents in cortical neurons: functional implications. Eur J Pharmacol 1996; 307: 113–6PubMedCrossRefGoogle Scholar
Wang S-J, Huang C-C, Hsu K-S, et al. Inhibition of N-type calcium currents by lamotrigine in rat amygdalar neurones. Neuroreport 1996; 7: 3037–40PubMedCrossRefGoogle Scholar
von Wegerer J, Hesslinger B, Berger M, et al. A calcium antagonistic effect of the new antiepileptic drug lamotrigine. Eur Neuropsychopharmacol 1997 May; 7(2): 77–81CrossRefGoogle Scholar
Siniscalchi A, Zona C, Guatteo E, et al. An electrophysiological analysis of the protective effects of felbamate, lamotrigine, and lidocaine on the functional recovery from in vitro ischemia in rat neocortical slices. Synapse 1998 Dec; 30(4): 371–9PubMedCrossRefGoogle Scholar
Leach MJ, Baxter MG, Critchley MAE, et al. Neurochemical and behavioral aspects of lamotrigine. Epilepsia 1991; 32Suppl 2: S4–8PubMedCrossRefGoogle Scholar
Rataud J, Debarnot F, Mary V, et al. Comparative study of voltage-sensitive sodium channel blockers in focal ischaemia and electric convulsions in rodents. Neurosci Lett 1994; 172: 19–23PubMedCrossRefGoogle Scholar
Shuaib A, Mahmood RH, Wishart T, et al. Neuroprotective effects of lamotrigine in global ischemia in gerbils. A histological, in vivo microdialysis and behavioral study. Brain Res 1995; 702: 199–206Google Scholar
Smith SE, Meldrum BS. Cerebroprotective effect of lamotrigine after focal ischemia in rats. Stroke 1995; 26: 117–22PubMedCrossRefGoogle Scholar
Wiard RP, Dickerson MC, Beek O, et al. Neuroprotective properties of the novel antiepileptic lamotrigine in a gerbil model of global cerebral ischemia. Stroke 1995; 26: 466–72PubMedCrossRefGoogle Scholar
Casanovas A, Ribera J, Hukkanen M, et al. Prevention by lamotrigine, MK-801 and Nw-nitro-L-arginine methyl ester of motoneuron cell death after neonatal axotomy. Neuroscience 1996; 71(2): 313–25PubMedCrossRefGoogle Scholar
Schulz JB, Matthews RT, Henshaw DR, et al. Neuroprotective strategies for treatment of lesions produced by mitochondrial toxins: implications for neurodegenerative diseases. Neuroscience 1996; 71(4): 1043–8PubMedCrossRefGoogle Scholar
Adams J, Collaço-Moraes Y, de Belleroche J, et al. Cyclooxygenase-2 induction in cerebral cortex: an intracellular response to synaptic excitation. J Neurochem 1996; 66: 6–13PubMedCrossRefGoogle Scholar
Xie X, Hagan RM. Cellular and molecular actions of lamotrigine: possible mechanisms of efficacy in bipolar disorder. Neuropsychobiology 1998 Oct; 38(3): 119–30PubMedCrossRefGoogle Scholar
Smith D, Chadwick D, Baker G, et al. Seizure severity and the quality of life. Epilepsia 1993; 34Suppl. 5: S31–5PubMedCrossRefGoogle Scholar
Smith D, Baker G, Davies G, et al. Outcomes of add-on treatment with lamotrigine in partial epilepsy. Epilepsia 1993; 34(2): 312–22PubMedCrossRefGoogle Scholar
Jacoby A, Baker G, Bryant-Comstock L, et al. Lamotrigine add-on therapy is associated with improvement in mood in patients with severe epilepsy [abstract no. I.4]. Epilepsia 1996; 37 Suppl. 5: 202Google Scholar
Cohen AF, Ashby D, Crowley G, et al. Lamotrigine (BW430C), a potential anticonvulsant. Effects on the central nervous system in comparison with phenytoin and diazepam. Br J Clin Pharmacol 1985; 20: 619–29Google Scholar
Ginsberg L, Sachs G, KetterT, et al. Effects of mood stabilizers on body weight in bipolar I disorder [abstract no. NR463 plus poster]. American Psychiatric Association 2003 Annual Meeting — new research abstracts; 2003 May 17–22; San Francisco (CA), 173–4Google Scholar
Yuen WC, Peck AW. Lamotrigine pharmacokinetics: oral and i.v. infusion in man. Proceedings of the British Pharmacological Society; 1988 Apr 6–8. Br J Clin Pharmacol 1988; 26(2): 242PGoogle Scholar
Berry DJ. The disposition of lamotrigine throughout pregnancy [abstract no. 90]. Ther Drug Monit 1999 Aug; 21: 450CrossRefGoogle Scholar
Ohman I, Vitols S, Tomson T. Lamotrigine in pregnancy: pharmacokinetics during delivery, in the neonate, and during lactation. Epilepsia 2000 Jun; 41: 709–3PubMedCrossRefGoogle Scholar
Posner J, Holdich T, Crome P. Comparison of lamotrigine pharmacokinetics in young and elderly healthy volunteers. J Pharm Med 1991; 1: 121–8Google Scholar
Chen C, Veronese L, Yin Y. The effects of lamotrigine on the pharmacokinetics of lithium. Br J Clin Pharmacol 2000 Sep; 50(3): 193–5PubMedCrossRefGoogle Scholar
Anderson GD, Yau MK, Gidal BE, et al. Bidirectional interaction of valproate and lamotrigine in healthy subjects. Clin Pharmacol Ther 1996 Aug; 60: 145–56PubMedCrossRefGoogle Scholar
Böttiger Y, Ståhle L. Lamotrigine drug interactions in a TDM material [abstract no. 84]. Ther Drug Monit 1997 Oct; 19: 568CrossRefGoogle Scholar
Edelbroek PM, Segers JP, Gilissen KGPM, et al. Population pharmacokinetics of lamotrigine to evaluate interaction with concommitant antiepileptic drugs. Epilepsia 1996; 37 Suppl. 4: 64Google Scholar
Hossain M, Chen C, Ette E. Characterization of lamotrigine (LTG) drug interactions using the population approach [abstract no. 3148]. Pharm Res 1997 Nov; 14(11 Suppl.): S515Google Scholar
May TW, Rambeck B. Influence of oxcarbazepine and methsuximide on LTG concentrations [abstract]. Epilepsia 1998; 39 Suppl. 2: 25Google Scholar
Calabrese JR, Bowden CL, Sachs G, et al. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder. J Clin Psych 2003; 64(9): 1013–24CrossRefGoogle Scholar
Bowden CL, Calabrese JR, Sachs G, et al. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. Arch Gen Psychiatry 2003 Apr; 60(4): 392–400PubMedCrossRefGoogle Scholar
Calabrese JR, Bowden CL, Fieve R, et al. Lamotrigine or lithium in the maintenance treatment of bipolar I disorder [abstract no. P.1.115 plus poster]. Presented at the 15th Congress of the European College of Neuropsychopharmacology; 2002 Oct 5–9; Barcelona. Eur Neuropsychopharmacol 2002; 12Suppl. 3: S217Google Scholar
Calabrese JR, Bowden CL, Sachs GS, et al. A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. J Clin Psychiatry 1999 Feb; 60(2): 79–88PubMedCrossRefGoogle Scholar
Frye MA, Ketter TA, Kimbrell TA, et al. A placebo-controlled study of lamotrigine and gabapentin monotherapy in refractory mood disorders. J Clin Psychopharmacol 2000 Dec; 20(6): 607–14PubMedCrossRefGoogle Scholar