Department of Psychiatry, University of Oxford, Oxford, UK.
Oxford Health NHS Foundation Trust, Oxford, UK.
Bipolar Disord. 2017 Sep;19(6):477-486. doi: 10.1111/bdi.12531. Epub 2017 Aug 20.
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.
The 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).
Lamotrigine 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.
Our 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.
CEQUEL（喹硫平联合拉莫三嗪与喹硫平单药治疗双相抑郁的比较评估[叶酸与安慰剂]）是一项双盲、随机、安慰剂对照、平行组、2×2 析因试验，旨在研究在双相抑郁中添加拉莫三嗪和/或叶酸（FA）对喹硫平的影响。拉莫三嗪改善了抑郁症状，但 FA 降低了其疗效。我们调查了临床反应的基线预测因子和相关性，以及可能的相互作用基础。
主要结局是使用 16 项快速抑郁症状自评量表（QIDS-SR16）评估的 12 周时的抑郁症状变化。我们检查了症状与拉莫三嗪水平之间的关系，以及一碳代谢的生化指标和儿茶酚-O-甲基转移酶（COMT）、亚甲基四氢叶酸还原酶（MTHFR）和叶酸水解酶 1（FOLH1）的功能多态性。
FA 对拉莫三嗪水平没有影响，并且在达到缓解和持续症状的参与者之间没有差异。当排除血清水平低于治疗范围的参与者后，拉莫三嗪对主要结局有主要影响，尽管这仅限于随机分配到 FA 安慰剂的参与者。生化指标与临床结局均无相关性。FA 对拉莫三嗪反应的负面影响仅限于 COMT Met 携带者。FOLH1 和 MTHFR 没有影响。
我们的结果阐明了 FA 抑制拉莫三嗪疗效不是药代动力学效应，并且低血清拉莫三嗪水平导致拉莫三嗪在 12 周时缺乏主要作用。我们无法解释拉莫三嗪-FA 相互作用，但我们发现它受 COMT 基因型调节，为后续神经生物学研究提供了起点。更广泛地说，我们的结果强调了在随机临床试验中纳入生化和遗传指标的价值。
