Hold the Folate With Adjunctive Lamotrigine



Three medications frequently appear in guidelines for bipolar depression treatment: lithium, lamotrigine, and quetiapine. Which one to start with? That depends on whether the choice among medication options is made based on efficacy or tolerability.

Most practitioners have seen patients recoil when informed of the risk of weight gain from quetiapine or lithium. By contrast, lamotrigine is generally regarded as weight neutral, but doubts have been raised about its effectiveness.1-3

Some reviews place it low among treatment options (eg, National Institute for Clinical Excellence 2014).4 Sometimes lamotrigine is not even among the top 3 at all, when efficacy data are allowed to trump other considerations.5

So, a new study6 showing that lamotrigine clearly outperforms placebo is welcome, even if only in an adjunctive role (adding to a previous study, in which adjunctive lamotrigine paired with lithium outperformed placebo thus paired).7 In the new study, lamotrigine was added to quetiapine and was clearly better in this role than a placebo-unless subjects were also given folate!

Folate? Where did that contraindication come from? To understand this result requires a look at the study design. First, this is one of those very welcome “real-life” studies with almost no exclusion criteria, provided the intended treatments were appropriate for the patients.

Although investigators were encouraged to withdraw other medications before entry into the study, some could be continued as clinically indicated; after 12 weeks into lamotrigine-or-placebo, clinicians were at liberty to add other medications as well if necessary.

Second, once the study was under way, patients were followed up for an entire year-remarkably long for clinical trials. The investigators deserve a medal just for holding together a complex protocol over nearly 4 years of recruitment in 27 sites in the United Kingdom.

[[{"type":"media","view_mode":"media_crop","fid":"48162","attributes":{"alt":"bipolar","class":"media-image media-image-right","id":"media_crop_3574532234308","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"5790","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"width: 196px; height: 130px; float: right;","title":"©IrinaBraga/ Shutterstock","typeof":"foaf:Image"}}]]Once randomized to adjunctive lamotrigine or placebo, patients were then also randomized to receive, in addition, folate or a placebo version of folate. Why folate? Some of the principal investigators had just completed a review of folate as an adjunct in unipolar depression, finding some limited evidence for its efficacy and very little risk.8 Perhaps they wished patients in the lamotrigine trial to have a strong chance at response, given the long trial and complex randomization.

Using the the Quick Inventory of Depressive Symptomatology 16-Item Self-Report (QIDS-SR16, a self-rated depression scale), lamotrigine patients lowered their scores 2.69 points more than did the corresponding placebo (no lamotrigine) patients (P < .017). But when the lamotrigine group was subdivided by folate status, a striking and unanticipated result emerged.

At 12 weeks, patients on lamotrigine without folate reduced their QIDS-SR16 score 4.14 points relative to placebo; but those on lamotrigine with folate lowered their QIDS-SR16 score only 0.12 points.

"The investigators deserve a medal just for holding together a complex protocol over nearly 4 years of recruitment in 27 sites in the United Kingdom."

Does folate really interfere with lamotrigine’s action? Or perhaps its absorption? The authors found no previous reports of this problem. But they noted that “there are grounds to consider such an interaction biologically plausible.

Lamotrigine was originally synthesised as one of a series of folate antagonists on the grounds that folate was thought to be pro-convulsant. Hence, it is possible that lamotrigine and folate both bind such interactions to a common receptor or enzyme site.”6

The bottom line

How should clinicians proceed now? These data further support the efficacy of lamotrigine in bipolar depression-contravening some guidelines, as the study’s authors note.6 They further conclude, “. . . if a patient with bipolar disorder needs folic acid therapy, then lamotrigine should be avoided (and vice versa [emphasis added]).”6


Dr Phelps is Director of the Mood Disorders Program at Samaritan Mental Health in Corvallis, Ore. He is the Bipolar Disorder Section Editor for Psychiatric Times. Dr Phelps stopped accepting honoraria from pharmaceutical companies in 2008.


1. Calabrese JR, Huffman RF, White RL, et al. Lamotrigine in the acute treatment of bipolar depression: results of five double-blind, placebo-controlled clinical trials. Bipolar Disord. 2008;10:323-333.
2. Ghaemi SN, Shirzadi AA, Filkowski M. Publication bias and the pharmaceutical industry: the case of lamotrigine in bipolar disorder. Medscape J Med. 2008;10:211. http://www.medscape.com/viewarticle/579046. Accessed May 10, 2016.
3. Taylor DM, Cornelius V, Smith L, Young AH. Comparative efficacy and acceptability of drug treatments for bipolar depression: a multiple-treatments meta-analysis. Acta Psychiatr Scand. 2014;130:452-469.
4. NICE (National Institute for Clinical Excellence). Recommendation 1.6.3. https://www.nice.org.uk/guidance/cg185/chapter/1-recommendations#managing-bipolar-depression-in-adults-in-secondary-care-2. Published September 2014. Updated February 2016. Accessed May 10, 2016.
5. Nierenberg AA, McIntyre RS, Sachs GS. Improving outcomes in patients with bipolar depression: a comprehensive review.J Clin Psychiatry. 2015;76:e10.
6. Geddes JR, Gardiner A, Rendell J, et al. Comparative evaluation of quetiapine plus lamotrigine combination versus quetiapine monotherapy (and folic acid versus placebo) in bipolar depression (CEQUEL): a 2 × 2 factorial randomised trial. Lancet Psychiatry. 2016;3:31-39.
7. Van der Loos MLM, Mulder PGH, Hartong EGTM, et al. Efficacy and safety of lamotrigine as add-on treatment to lithium in bipolar depression: a multicenter, double-blind, placebo-controlled trial. J Clin Psychiatry. 2009;70:223-231.
8. Taylor MJ, Carney SM, Goodwin GM, Geddes JR. Folate for depressive disorders: systematic review and meta-analysis of randomized controlled trials. J Psychopharmacol. 2004;18:251-256.


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