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BACKGROUND: Depression in people with bipolar disorder is a major cause of long-term disability, possibly leading to early mortality and currently, limited safe and effective therapies exist. Although existing monotherapies such as quetiapine have limited proven efficacy and practical tolerability, treatment combinations may lead to improved outcomes. Lamotrigine is an anticonvulsant currently licensed for the prevention of depressive relapses in individuals with bipolar disorder. A double-blinded randomized placebo-controlled trial (comparative evaluation of Quetiapine-Lamotrigine [CEQUEL] study) was conducted to evaluate the efficacy of lamotrigine plus quetiapine versus quetiapine monotherapy in patients with bipolar type I or type II disorders. OBJECTIVE: Because the original CEQUEL study found significant depressive symptom improvements, the objective of this study was to reanalyze CEQUEL data and determine an unbiased classification accuracy for active lamotrigine versus placebo. We also wanted to establish the time it took for the drug to provide statistically significant outcomes. METHODS: Between October 21, 2008 and April 27, 2012, 202 participants from 27 sites in United Kingdom were randomly assigned to two treatments; 101: lamotrigine, 101: placebo. The primary variable used for estimating depressive symptoms was based on the Quick Inventory of Depressive Symptomatology-self report version 16 (QIDS-SR16). The original CEQUEL study findings were confirmed by performing t test and linear regression. Multiple features were computed from the QIDS-SR16 time series; different linear and nonlinear binary classifiers were trained to distinguish between the two groups. Various feature-selection techniques were used to select a feature set with the greatest explanatory power; a 10-fold cross-validation was used. RESULTS: From weeks 10 to 14, the mean difference in QIDS-SR16 ratings between the groups was -1.6317 (P=.09; sample size=81, 77; 95% CI -0.2403 to 3.5036). From weeks 48 to 52, the mean difference was -2.0032 (P=.09; sample size=54, 48; 95% CI -0.3433 to 4.3497). The coefficient of variation (σ/μ) and detrended fluctuation analysis (DFA) exponent alpha had the greatest explanatory power. The out-of-sample classification accuracy for the 138 participants who reported more than 10 times after week 12 was 62%. A consistent classification accuracy higher than the no-information benchmark was obtained in week 44. CONCLUSIONS: Adding lamotrigine to quetiapine treatment decreased depressive symptoms in patients with bipolar disorder. Our classification model suggested that lamotrigine increased the coefficient of variation in the QIDS-SR16 scores. The lamotrigine group also tended to have a lower DFA exponent, implying a substantial temporal instability in the time series. The performance of the model over time suggested that a trial of at least 44 weeks was required to achieve consistent results. The selected model confirmed the original CEQUEL study findings and helped in understanding the temporal dynamics of bipolar depression during treatment. TRIAL REGISTRATION: EudraCT Number 2007-004513-33; (Archived by WebCite at

Original publication




Journal article


JMIR Ment Health

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CEQUEL study, bipolar disorder, data analysis, depressive symptoms, lamotrigine, time series