Drug Safety

, Volume 27, Issue 3, pp 173–184 | Cite as

Safety and Tolerability of Lamotrigine for Bipolar Disorder

  • Charles L. BowdenEmail author
  • Gregory M. Asnis
  • Lawrence D. Ginsberg
  • Beth Bentley
  • Robert Leadbetter
  • Robin White
Review Article


Tolerability and safety are important considerations in optimising pharmacotherapy for bipolar disorder. This paper reviews the tolerability and safety of lamotrigine, an anticonvulsant recommended in the 2002 American Psychiatric Association guidelines as a first-line treatment for acute depression in bipolar disorder and one of several options for maintenance therapy.

This paper reviews the tolerability and safety of lamotrigine using data available from a large programme of eight placebo-controlled clinical trials of lamotrigine enrolling a total of nearly 1800 patients with bipolar disorder. This review is the first to collate all the safety information from these clinical trials, including data from four unpublished studies.

The results these trials in which 827 patients with bipolar disorder were given lamotrigine as monotherapy or adjunctive therapy for up to 18 months for a total of 280 patient-years of exposure demonstrated that lamotrigine is well-tolerated with an adverse-event profile generally comparable with that of placebo. The most common adverse event with lamotrigine was headache. Lamotrigine did not appear to destabilise mood and was not associated with sexual adverse effects, weight gain, or withdrawal symptoms.

Few patients experienced serious adverse events with lamotrigine, and the incidence of withdrawals because of adverse events was low. Serious rash occurred rarely (0.1% incidence) in the clinical development programme including both controlled and uncontrolled clinical trials. These findings — considered in the context of data showing lamotrigine to be effective for bipolar depression — establish lamotrigine as a well-tolerated addition to the psychotropic armamentarium.


Bipolar Disorder Valproate Lamotrigine Toxic Epidermal Necrolysis Suicide Event 
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.



Dr Charles Bowden was a primary investigator in the clinical development programme for lamotrigine for bipolar disorder and has served as a consultant for GlaxoSmithKline. Dr Gregory Asnis and Dr Lawrence Ginsberg served as contributing investigators in the clinical development programme for lamotrigine for bipolar disorder. Dr Beth Bentley, Dr Robert Leadbetter and Dr Robin White are full-time employees of GlaxoSmithKline. The development of this manuscript was funded by an unrestricted grant from GlaxoSmithKline.

The authors thank Jane Saiers, PhD, for assistance with writing this manuscript.


  1. 1.
    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; 60: 79–88PubMedCrossRefGoogle Scholar
  2. 2.
    Kusumakar V, Yatham LN. Lamotrigine treatment of rapid cycling bipolar disorder. Am J Psychiatry 1997; 154: 1171–2PubMedGoogle Scholar
  3. 3.
    Sporn J, Sachs GS. The anticonvulsant lamotrigine in treatment-resistant manic-depressive illness. J Clin Psychopharmacol 1997; 17: 185–9PubMedCrossRefGoogle Scholar
  4. 4.
    Walden J, Hesslinger B, van Calker D, et al. Addition of lamotrigine to valproate may enhance efficacy in the treatment of bipolar affective disorder. Pharmacopsychiatry 1996; 29: 193–5PubMedCrossRefGoogle Scholar
  5. 5.
    Calabrese JR, Suppes T, Bowden CL, et al. A double-blind, placebo-controlled, prophylaxis study of lamotrigine in rapid-cycling bipolar disorder. J Clin Psychiatry 2000; 61: 841–50PubMedCrossRefGoogle Scholar
  6. 6.
    Frye MA, Ketter TA, Kimbrell TA, et al. A placebo-controlled study of lamotrigine and gabapentin monotherapy in refractory mood disorders. J Clin Psychopharm 2000; 20: 607–14CrossRefGoogle Scholar
  7. 7.
    Bowden CL, Calabrese JR, McElroy SL, et al. The efficacy of lamotrigine in rapid cycling and non-rapid cycling patients with bipolar disorder. Biol Psychiatry 1999; 45: 953–8PubMedCrossRefGoogle Scholar
  8. 8.
    Calabrese JR, Bowden CL, McElroy SL, et al. Spectrum of activity of lamotrigine in treatment-refractory bipolar disorder. Am J Psychiatry 1999; 156: 1019–23PubMedGoogle Scholar
  9. 9.
    Berk M. Lamotrigine and the treatment of mania in bipolar disorder. Eur Neuropsychopharmacol 1999; 9Suppl. 4: S119–23PubMedCrossRefGoogle Scholar
  10. 10.
    Ichim L, Berk M, Brook S. Lamotrigine compared with lithium in mania: a double-blind randomized controlled trial. Ann Clin Psychiatry 2000; 12: 5–10PubMedGoogle Scholar
  11. 11.
    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; 60: 392–400PubMedCrossRefGoogle Scholar
  12. 12.
    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 Psychiatry 2003; 64: 1013–24PubMedCrossRefGoogle Scholar
  13. 13.
    Howland RH. Induction of mania with serotonin reuptake inhibitors. J Clin Psychopharmacol 1996; 16: 425–7PubMedCrossRefGoogle Scholar
  14. 14.
    Himmelhoch JM, Thase MD, Mallinger AG, et al. Tranylcypromine versus imipramine in anergic bipolar depression. Am J Psychiatry 1991; 148: 910–6PubMedGoogle Scholar
  15. 15.
    Wehr TA, Goodwin FK. Can antidepressants cause mania and worsen the course of affective illness? Am J Psychiatry 1987; 144(11): 1403–11PubMedGoogle Scholar
  16. 16.
    Sachs GS, Lafer B, Stoll AL, et al. A double-blind trial of bupropion versus desipramine for bipolar depression. J Clin Psychiatry 1994; 55: 391–3PubMedGoogle Scholar
  17. 17.
    Nemeroff CB, Evans DL, Gyulai L, et al. Double-blind, placebo-controlled comparison of imipramine and paroxetine in the treatment of bipolar depression. Am J Psychiatry 2001; 15(8): 906–12Google Scholar
  18. 18.
    American Psychiatric Association. Practice guidelines for the treatment of patients with bipolar disorder. Am J Psychiatry 2002; 159: 1–50Google Scholar
  19. 19.
    Scott J, Pope M. Self-reported adherence to treatment with mood stabilizers, plasma levels, and psychiatric hospitalization. Am J Psychiatry 2002; 159: 1927–9PubMedCrossRefGoogle Scholar
  20. 20.
    Jamison KR, Gerner RH, Goodwin FK. Patient and physician attitudes toward lithium: relationship to compliance. Arch Gen Psychiatry 1979; 36: 866–9PubMedCrossRefGoogle Scholar
  21. 21.
    Brodie MJ, Richens A, Yuen AWC, et al. Double-blind comparison of lamotrigine and carbamazepine in newly diagnosed epilepsy. Lancet 1995; 345: 476–9PubMedCrossRefGoogle Scholar
  22. 22.
    Steiner TJ, Dellaportas CI, Findley LJ. Lamotrigine monotherapy in newly diagnosed untreated epilepsy: a double-blind comparison with phenytoin. Epilepsia 1999; 40: 601–7PubMedCrossRefGoogle Scholar
  23. 23.
    Messenheimer JA, Mullens EL, Giorgi L, et al. Safety review of adult clinical trial experience with lamotrigine. Drug Saf 1998; 18(4): 281–96PubMedCrossRefGoogle Scholar
  24. 24.
    Uvebrant P, Bauzien PR. Intractable epilepsy in children: the efficacy of lamotrigine treatment, including non-seizure-related benefits. Neuropediatrics 1994; 25: 284–9PubMedCrossRefGoogle Scholar
  25. 25.
    Biton V, Mirza W, Montouris G, et al. Weight change associated with valproate and lamotrigine monotherapy in patients with epilepsy. Neurology 2001; 56: 172–7PubMedCrossRefGoogle Scholar
  26. 26.
    Lamictal® (lamotrigine) product information. Research Triangle Park (NC): Glaxo Wellcome Inc, 2001 MayGoogle Scholar
  27. 27.
    Matsuo F. Lamotrigine. Epilepsia 1999; 40Suppl. 5: S30–6PubMedCrossRefGoogle Scholar
  28. 28.
    GlaxoSmithKline Study SCAB2005, 2001. (Data on file)Google Scholar
  29. 29.
    GlaxoSmithKline Study SCAA2010, 1999. (Data on file)Google Scholar
  30. 30.
    GlaxoSmithKline Study SCAA2008, 2000. (Data on file)Google Scholar
  31. 31.
    GlaxoSmithKline Study SCAB2009, 1999. (Data on file)Google Scholar
  32. 32.
    American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: American Psychiatric Association, 1994Google Scholar
  33. 33.
    Kupfer DJ, Frenk E, Grochocinski VJ, et al. Demographic and clinical characteristics of individuals in a bipolar disorder case registry. J Clin Psychiatry 2002; 63: 120–5PubMedCrossRefGoogle Scholar
  34. 34.
    GlaxoSmithKline 2002. (Data on file)Google Scholar
  35. 35.
    Jamison KR. Suicide and bipolar disorder. J Clin Psychiatry 2000; 61Suppl. 9: 47–51PubMedGoogle Scholar
  36. 36.
    Khan A, Warner HA, Brown WA. Symptom reduction and suicide risk in patients treated with placebo in antidepressant clinical trials. Arch Gen Psychiatry 2000; 57: 311–7PubMedCrossRefGoogle Scholar
  37. 37.
    Calabrese JR, Rapport DJ, Kimmel SE, et al. Controlled trials in bipolar I depression: focus on switch rates and efficacy. Eur Neuropsychopharmacol 1999; 9Suppl. 4: S109–12PubMedCrossRefGoogle Scholar
  38. 38.
    Compton MT, Nemeroff CB. The treatment of bipolar depression. J Clin Psychiatry 2000; 61Suppl. 9: 57–67PubMedGoogle Scholar
  39. 39.
    Peet M. Induction of mania with selective serotonin reuptake inhibitors and tricyclic antidepressants. Br J Psychiatry 1994; 164: 549–50PubMedCrossRefGoogle Scholar
  40. 40.
    Guberman AH, Besag FMC, Brodie MJ, et al. Lamotrigine-associated rash: risk/benefit considerations in adults and children. Epilepsia 1999; 40: 985–91PubMedCrossRefGoogle Scholar
  41. 41.
    Gitlin MJ. Psychotropic medications and their effects on sexual function: diagnosis, biology, and treatment approaches. J Clin Psychiatry 1994; 55: 406–13PubMedGoogle Scholar
  42. 42.
    Ferguson JM. The effects of antidepressants on sexual functioning in depressed patients: a review. J Clin Psychiatry 2001; 62Suppl. 3: 22–34PubMedGoogle Scholar
  43. 43.
    McIntyre RS. Psychotropic drugs and adverse events in the treatment of bipolar disorders revisited. J Clin Psychiatry 2002; 63Suppl. 3: 15–20PubMedGoogle Scholar
  44. 44.
    Vieta E, Reinares M, Corbella B, et al. Olanzapine as long-term adjunctive therapy in treatment-resistant bipolar disorder. J Clin Psychopharmacol 2001; 21: 469–73PubMedCrossRefGoogle Scholar
  45. 45.
    Roy Chengappa KN, Levine J, Rathore D, et al. Long-term effects of topiramate on bipolar mood instability, weight change and glycemic control: a case-series. Eur Psychiatry 2001; 16: 186–90PubMedCrossRefGoogle Scholar
  46. 46.
    Jallon P, Picard F. Bodyweight gain and anticonvulsants: a comparative review. Drug Saf 2001; 24(13): 969–78PubMedCrossRefGoogle Scholar
  47. 47.
    Devinsky O, Vuong A, Hammer A, et al. Stable weight during lamotrigine therapy: a review of 32 studies. Neurology 2000; 54: 973–5PubMedCrossRefGoogle Scholar
  48. 48.
    Sachs GS, Guille C. Weight gain associated with use of psychotropic medications. J Clin Psychiatry 1999; 60(S21): 16–9PubMedGoogle Scholar
  49. 49.
    Odishaw J, Chen C. Effects of steady-state bupropion on the pharmacokinetics of lamotrigine in healthy subjects. Pharmacotherapy 2000; 20: 1448–53PubMedCrossRefGoogle Scholar
  50. 50.
    Chen C, Veronese L, Yin Y. The effects of lamotrigine on the pharmacokinetics of lithium. Br J Clin Pharmacol 2000; 50: 193–5PubMedCrossRefGoogle Scholar
  51. 51.
    Besag FM, Berry DJ, Pool F, et al. Carbamazepine toxicity with lamotrigine: pharmacokinetic of pharmacodynamic interaction? Epilepsia 1998; 39: 183–7PubMedCrossRefGoogle Scholar
  52. 52.
    Kanner AM, Frey M. Adding valproate to lamotrigine: a study of their pharmacokinetic interaction. Neurology 2000; 55: 588–91PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2004

Authors and Affiliations

  • Charles L. Bowden
    • 1
    Email author
  • Gregory M. Asnis
    • 2
  • Lawrence D. Ginsberg
    • 3
  • Beth Bentley
    • 4
  • Robert Leadbetter
    • 4
  • Robin White
    • 4
  1. 1.Department of PsychiatryUniversity of Texas Health Science Center at San AntonioSan AntonioUSA
  2. 2.Department of PsychiatryAlbert Einstein College of Medicine, Montefiore Medical CenterBronx, New YorkUSA
  3. 3.Red Oak Psychiatric AssociatesHoustonUSA
  4. 4.GlaxoSmithKline, Research Triangle ParkNorth CarolinaUSA

Personalised recommendations