
Hold the Folate With Adjunctive Lamotrigine
RESEARCH UPDATE
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,
So, a
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
Disclosures:
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.
References:
1. Calabrese JR, Huffman RF, White RL, et al.
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.
3. Taylor DM, Cornelius V, Smith L, Young AH.
4. NICE (National Institute for Clinical Excellence). Recommendation 1.6.3.
5. Nierenberg AA, McIntyre RS, Sachs GS.
6. Geddes JR, Gardiner A, Rendell J, et al.
7. Van der Loos MLM, Mulder PGH, Hartong EGTM, et al.
8. Taylor MJ, Carney SM, Goodwin GM, Geddes JR.
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