Abstract
Objectives CEQUEL (Comparative Evaluation of QUEtiapine plus Lamotrigine combination versus quetiapine monotherapy [and folic acid versus placebo] in bipolar depression) was a double‐blind, randomized, placebo‐controlled, parallel group, 2×2 factorial trial that examined the effect of adding lamotrigine and/or folic acid (FA) to quetiapine in bipolar depression. Lamotrigine improved depression, but its effectiveness was reduced by FA. We investigated the baseline predictors and correlates of clinical response, and the possible basis of the interaction.MethodsThe main outcome was change in depressive symptoms at 12 weeks, measured using the Quick Inventory for Depressive Symptoms—self report version 16 (QIDS‐SR16). We examined the relationship between symptoms and lamotrigine levels, and biochemical measures of one‐carbon metabolism and functional polymorphisms in catechol‐O‐methyltransferase (COMT), methylene tetrahydrofolate reductase (MTHFR) and folate hydrolase 1 (FOLH1).ResultsLamotrigine levels were unaffected by FA and did not differ between those participants who achieved remission and those with persisting symptoms. When participants with subtherapeutic serum levels were excluded, there was a main effect of lamotrigine on the main outcome, although this remained limited to those randomized to FA placebo. None of the biochemical measures correlated with clinical outcome. The negative impact of FA on lamotrigine response was limited to COMT Met carriers. FOLH1 and MTHFR had no effect.ConclusionsOur results clarify that FA's inhibition of lamotrigine's efficacy is not a pharmacokinetic effect, and that low serum lamotrigine levels contributed to lamotrigine's lack of a main effect at 12 weeks. We were unable to explain the lamotrigine−FA interaction, but our finding that it is modulated by the COMT genotype provides a starting point for follow‐on neurobiological investigations. More broadly, our results highlight the value of including biochemical and genetic indices in randomized clinical trials.
Highlights
Depression rather than mania accounts for the majority of the burden of increased mortality and long-term disability in bipolar disorder.[1]
We examined the relationship between symptoms and lamotrigine levels, and biochemical measures of one-carbon metabolism and functional polymorphisms in catechol-O-methyltransferase (COMT), methylene tetrahydrofolate reductase (MTHFR) and folate hydrolase 1 (FOLH1)
We recently reported the results of the CEQUEL trial (Comparative Evaluation of QUEtiapine plus Lamotrigine combination versus quetiapine monotherapy [and folic acid versus placebo] in bipolar depression).[4]
Summary
Depression rather than mania accounts for the majority of the burden of increased mortality and long-term disability in bipolar disorder.[1]. We recently reported the results of the CEQUEL trial (Comparative Evaluation of QUEtiapine plus Lamotrigine combination versus quetiapine monotherapy [and folic acid versus placebo] in bipolar depression).[4] CEQUEL was a multi-centre, double-blind, randomized clinical trial, with a 2×2 factorial design. It examined the efficacy of adding lamotrigine and/or folic acid (FA) to quetiapine monotherapy for depressive symptoms in participants with bipolar disorder. FA appeared to block the therapeutic effect of lamotrigine at 12 weeks, this interaction disappeared at later time points and lamotrigine was superior to placebo at 52 weeks.[4]
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