I decided to address this question because one of our Members, a highly-experienced psychiatrist for whom I have high regard, asked a question about one of his patients with bipolar I disorder who was on lamotrigine monotherapy for maintenance treatment. When I expressed concern about lamotrigine monotherapy in bipolar I disorder, he asked if I don’t have confidence in its antimanic efficacy of lamotrigine.
Lamotrigine has specifically been shown to not work for acute mania and is specifically not recommended for acute mania by Practice Guidelines (e.g., Yatham et al., 2018; Fountoulakis et al., 2017). The lamotrigine Prescribing Information adds the following after listing the indications for lamotrigine: “Limitations of Use: Treatment of acute manic or mixed episodes is not recommended.”
But, what about for longer-term preventive (maintenance) treatment in a patient with bipolar I disorder? Lamotrigine does have an FDA indication for this—“Maintenance treatment of bipolar I disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy.”
What do Practice Guidelines say?
(Noted here in order of date of publication)
The Royal Australian and New Zealand College of Psychiatrists guideline (Malhi et al., 2015) notes the following and cites these references (emphasis in red added by us): “Lamotrigine has greater efficacy in the prevention of depressive relapse but relatively modest impact on risk of manic relapse (Level I) ).”
The British Association of Psychopharmacology’s guidelines note: “Lamotrigine…may be considered as monotherapy in bipolar II disorder. In bipolar I disorder, lamotrigine will usually require combination with an anti-manic long-term agent” (Goodwin et al., 2016).
Another international guideline, from an organization called CINP, does not recommend lamotrigine as a first-line choice for maintenance treatment but only as a second-line add on (CINP; Fountoulakis et al., 2017).
The guidelines from two major international societies (CANMAT and ISBD) recommend the following; “Responders to lamotrigine have a predominantly depressive polarity as well as comorbid anxiety. Lamotrigine monotherapy is not appropriate for patients with frequent manic episodes, as it has limited efficacy in preventing mania” (Yatham et al., 2018).
What did the clinical trials show?
As noted above, lamotrigine has an FDA indication for the “Maintenance treatment of bipolar I disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy.”
This makes it necessary for us to at least briefly look at the clinical trials that were the basis of this indication. Sorry, but unavoidable. 🙁
There were two key large randomized, double-blind, placebo-controlled clinical trials of using lamotrigine monotherapy for the maintenance treatment of bipolar I disorder (for up to 18 months) that led to that FDA approval of lamotrigine for maintenance treatment in bipolar I disorder (Bowden et al., 2003; Calabrese et al., 2003). In addition to having a placebo group, these studies also included a third group of patients who were on lithium monotherapy.
Who was enrolled?
1. One of these two key clinical trials included patients with bipolar I disorder who were currently or recently in an episode (“index episode”) of mania/ hypomania/ mixed episode (Bowden et al., 2003). In these studies, mixed episodes were considered to be equivalent to mania or hypomania.
2. The other clinical trial recruited patients with bipolar I disorder who were currently or recently in an episode (“index episode”) of bipolar depression (Calabrese et al., 2003).
Optional to read: The results of both studies were combined (“pooled analysis”) in a third paper (Goodwin et al., 2004).
What outcome measures were looked at in these studies?
Presumably because the exact start of an episode of bipolar disorder is hard to be sure of, the outcome measure in these studies was “time to intervention“. That is, how long was it until the person became sick and something more had to be done, either a change in the pharmacological treatment or addition of ECT.
The researchers looked at:
1. Time to intervention for “any episode” (depression/ mania/ hypomania/ mixed episode). This had been pre-defined as the “primary outcome measure”.
2. Time to intervention for mania/hypomania/ mixed episodes
3. Time to intervention for depression.
What were the main findings?
In both the studies, lamotrigine was better than placebo at delaying time to intervention for “any mood episode” or for depression, but lamotrigine was not better than placebo for delaying time to intervention for mania/hypomania/mixed episodes in either of the studies (Bowden et al., 2003; Calabrese et al., 2003).
In comparison, in both these studies, lithium was more effective than placebo for delaying time to intervention for any mood episode, depression, and mania/hypomania/mixed episodes.
Bottom line and Clinical recommendations
In my opinion, the broad FDA indication for lamotrigine was not justified by the research data. Since the researchers had said in advance that the primary outcome measure would be time to intervention for “any episode”, that included depression, mania, hypomania, and mixed episodes, and so the FDA indication includes all four types of episodes.
Lamotrigine is an important medication for bipolar disorder, both bipolar I and bipolar II. I prescribe it all the time.
But, in my clinical practice, if a patient has had even one episode of clear-cut moderate or severe mania, I do NOT use lamotrigine monotherapy. My reasoning has been that in bipolar II disorder, the consequences of having a hypomanic episode are typically not serious, but in bipolar I disorder, having another manic episode could have very serious consequences.
I think that despite the FDA indication, given that lamotrigine is not great at preventing mania, it is risky to try to prevent future episodes of the illness with lamotrigine alone.
My conclusion is that it is yet another “psychopharMYTH” that lamotrigine can be used as monotherapy for maintenance treatment in bipolar I disorder.
Expert commentary
Below are some comments on this issue from Joseph Goldberg, MD (bio), a leading psychopharmacology expert who is internationally-recognized for his special expertise in bipolar disorder:
Regarding the two clinical trials of lamotrigine monotherapy for the maintenance treatment of bipolar I disorder (Bowden et al., 2003; Calabrese et al., 2003), it is important to note that lamotrigine was not efficacious for preventing mania/hypomania/mixed episodes in either of the clinical trials. Let me explain why this is important.
Methodological tip
In clinical trials in patients with bipolar disorder, the current or most recent episode at the start of the study, when the patient is recruited into the study, is called the “index episode“. The “polarity” of the index episode refers to whether the current or most recent episode was one of depression or a mania/hypomania/mixed episode.
It has been shown that in clinical trials of maintenance treatments for bipolar disorder, the polarity of the index episode predicts the polarity of relapse. For example, if a study recruits patients whose current or most recent episode was one of bipolar depression, then if they relapse during follow-up, it is more likely they will have bipolar depression than a manic/ hypomanic/ mixed episode. This issue is a huge deal in maintenance clinical trials in bipolar disorder.
Now, let’s see how this methodological tip applies to the two key clinical trials of lamotrigine monotherapy for the maintenance treatment of bipolar I disorder. One of these two clinical trials was done on patients whose index episode was one of bipolar depression (Calabrese et al., 2003). A criticism could be levied against this study that the expected rate of relapse into manic/ hypomanic/ mixed episodes would be expected to be lower. And, this would be expected to make it harder for the study to find lamotrigine to be effective for delaying time to intervention for manic/ hypomanic/ mixed episodes.
But, in the other study (Bowden et al., 2003), patients were recruited whose index episodes were manic/ hypomanic/ mixed episodes. This study can be said to have been “enriched” for the possibility of manic/ hypomanic/ mixed episodes if they relapsed during the follow-up period. The higher incidence of manic/ hypomanic/ mixed episodes in the placebo group would be expected to increase the chances of finding that the treatment was effective for delaying time to intervention for manic/ hypomanic/ mixed episodes. But, even in this study, lamotrigine was not better than placebo for delaying time to intervention for manic/ hypomanic/ mixed episodes. In this case, we can’t say that this was an artifact of the design of that study.
Bottom line: Clinicians should be aware that lamotrigine is widely considered not to be an efficacious preventative treatment for bipolar I mania.
[Optional to read: It should not be surprising to us that lamotrigine is efficacious for preventing or delaying episodes of bipolar depression but not manic/ hypomanic/ mixed episodes. Mechanistically, lamotrigine doesn’t have GABA-ergic properties and, as an anti-glutamatergic drug, lamotrigine is conceptually thought to be more relevant for bipolar depression than for mania. In fact, part of the inspiration for examining ketamine for the treatment of depression came from earlier observations with lamotrigine as a prototype anti-glutamatergic drug.]
Simple and Practical Medical Education thanks Joseph Goldberg, MD (bio) for his very helpful expert comments and for peer reviewing and approving this article (in October 2020).
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References
Practice guidelines
Fountoulakis KN, Grunze H, Vieta E, Young A, Yatham L, Blier P, Kasper S, Moeller HJ. The International College of Neuro-Psychopharmacology (CINP) Treatment Guidelines for Bipolar Disorder in Adults (CINP-BD-2017), Part 3: The Clinical Guidelines. Int J Neuropsychopharmacol. 2017 Feb 1;20(2):180-195. doi: 10.1093/ijnp/pyw109. Review. PubMed PMID: 27941079; PubMed Central PMCID: PMC5408976.
Goodwin GM, Haddad PM, Ferrier IN, Aronson JK, Barnes T, Cipriani A, Coghill DR, Fazel S, Geddes JR, Grunze H, Holmes EA, Howes O, Hudson S, Hunt N, Jones I, Macmillan IC, McAllister-Williams H, Miklowitz DR, Morriss R, Munafò M, Paton C, Saharkian BJ, Saunders K, Sinclair J, Taylor D, Vieta E, Young AH. Evidence-based guidelines for treating bipolar disorder: Revised third edition recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2016 Jun;30(6):495-553. doi: 10.1177/0269881116636545. Epub 2016 Mar 15. PubMed PMID: 26979387; PubMed Central PMCID: PMC4922419.
Grunze H, Vieta E, Goodwin GM, Bowden C, Licht RW, Möller HJ, Kasper S; WFSBP Task Force on Treatment Guidelines for Bipolar Disorders. The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of bipolar disorders: update 2012 on the long-term treatment of bipolar disorder. World J Biol Psychiatry. 2013 Apr;14(3):154-219. doi: 10.3109/15622975.2013.770551. PubMed PMID: 23480132.
Malhi GS, Bassett D, Boyce P, Bryant R, Fitzgerald PB, Fritz K, Hopwood M, Lyndon B, Mulder R, Murray G, Porter R, Singh AB. Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders. Aust N Z J Psychiatry. 2015 Dec;49(12):1087-206. doi: 10.1177/0004867415617657. Review. PubMed PMID: 26643054.
Yatham LN, Kennedy SH, Parikh SV, Schaffer A, Bond DJ, Frey BN, Sharma V, Goldstein BI, Rej S, Beaulieu S, Alda M, MacQueen G, Milev RV, Ravindran A, O’Donovan C, McIntosh D, Lam RW, Vazquez G, Kapczinski F, McIntyre RS, Kozicky J, Kanba S, Lafer B, Suppes T, Calabrese JR, Vieta E, Malhi G, Post RM, Berk M. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord. 2018 Mar;20(2):97-170. PubMed PMID: 29536616; PubMed Central PMCID: PMC5947163.
Randomized, double-blind clinical trials
Bowden CL, Calabrese JR, Sachs G, Yatham LN, Asghar SA, Hompland M, Montgomery P, Earl N, Smoot TM, DeVeaugh-Geiss J; Lamictal 606 Study Group. 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):392-400. doi: 10.1001/archpsyc.60.4.392. Erratum in: Arch Gen Psychiatry. 2004 Jul;61(7):680. PMID: 12695317.
Calabrese JR, Bowden CL, Sachs G, Yatham LN, Behnke K, Mehtonen OP, Montgomery P, Ascher J, Paska W, Earl N, DeVeaugh-Geiss J; Lamictal 605 Study Group. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder. J Clin Psychiatry. 2003 Sep;64(9):1013-24. doi: 10.4088/jcp.v64n0906. PMID: 14628976.
Goodwin GM, Bowden CL, Calabrese JR, Grunze H, Kasper S, White R, Greene P, Leadbetter R. A pooled analysis of 2 placebo-controlled 18-month trials of lamotrigine and lithium maintenance in bipolar I disorder. J Clin Psychiatry. 2004 Mar;65(3):432-41. doi: 10.4088/jcp.v65n0321. PMID: 15096085.
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