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Functional Connectivity between Task-Positive Networks and the Left Precuneus as a Biomarker of Response to Lamotrigine in Bipolar Depression: A Pilot Study.

ABSTRACT: Treatment of bipolar depression poses a significant clinical challenge. Lamotrigine is one of a few efficacious drugs, however, it needs to be titrated very slowly and response can only be assessed after 10-12 weeks. With only a proportion of patients responding, an exploration of factors underlying treatment responsivity is of paramount clinical importance, as it may lead to an allocation of the drug to those most likely to respond to it. This study aimed at identifying differences in patterns of pre-treatment resting state functional connectivity (rsFC) that may underlie response to lamotrigine in bipolar depression. After a baseline MRI scan, twenty-one patients with bipolar depression were treated with lamotrigine in an open-label design; response, defined as ≥50% decrease in Hamilton Depression Rating Scale (HAMD) score, was assessed after 10-12 weeks of treatment. Twenty healthy controls had a baseline clinical assessment and scan but did not receive any treatment. Fifteen out of 21 (71%) patients responded to lamotrigine. Treatment responsivity was associated with enhanced pre-treatment rsFC of the right fronto-parietal network (FPN) and dorsal attention network (DAN) with left precuneus. The lack of treatment response was additionally characterised by reduced rsFC: of the DAN with right middle temporal gyrus; of the default mode network (DMN) with left precuneus; of the extended sensory-motor area with areas including the left hippocampus/left amygdala and left subcallosal cortex/nucleus accumbens; and of the left FPN with left inferior temporal gyrus/occipital fusiform gyrus/lateral occipital cortex. The results suggest that preserved rsFC between the FPN and DAN, the networks involved in cognitive control, and the hub of the posterior DMN, the left precuneus, may be critical for good response to lamotrigine as an add-on treatment in patients with bipolar depression. The study also suggests a more general decrease in rsFC to be related to poor treatment responsivity.

SUBMITTER: Martens M

PROVIDER: S-EPMC8229811 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundDepression 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.ObjectiveBecause 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.MethodsBetween 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.ResultsFrom 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.ConclusionsAdding 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 registrationEudraCT Number 2007-004513-33; https://www.clinicaltrialsregister.eu/ctr-search/trial/2007-004513-33/GB (Archived by WebCite at http://www.webcitation.org/73sNaI29O).

Project description:Bipolar disorder is a highly recurrent disease and has great impact on the function of patients. Depressive symptoms consist of more than 50% of life time during the illness and may lead to self harm or suicidal behaviors. Little is known about the antidepressant effects of olanzapine, an atypical antipsychotic, as monotherapy despite its indication for preventing manic episodes. In contrast, lamotrigine, a mood stabilizer, has been proven to be effective in preventing depression in patients with bipolar disorder. However, no studies have compared the efficacy between lamotrigine and olanzapine in the maintenance treatment of bipolar disorder. This enriched naturalistic study was implemented to assess the effectiveness of olanzapine and lamotrigine as monotherapy in the prevention of recurrence of bipolar disorder.Patients with bipolar disorder in a euthymic state (Young's Mania Rating Scale (YMRS) score <12, and 21-item Hamilton Depression Rating Scale (HAM-D) score <7) for at least two months, having already received either olanzapine or lamotrigine as the maintenance treatment were recruited. The patients maintained with olanzapine (n?=?22) were applied to olanzapine group whereas those maintained with lamotrigine (n?=?29) were applied to lamotrigine group. They were followed up for 12 months. Differences in the efficacy between olanzapine and lamotrigine in recurrence prevention were analyzed. The Kaplan-Meier method was used to generate time-to-recurrence curves, and differences between the two groups were compared using the log-rank test.Olanzapine had a significantly lower recurrence rate of depressive episodes than lamotrigine (20.0% vs. 57.7%, ?2?=?6.62, p?=?.010). However, olanzapine and lamotrigine had similar mania (15.0% vs. 0%, ?2?=?4.17, p?=?.075, Fisher's exact test) and any mood episode (35.0% vs. 57.7%, ?2?=?2.33, p?=?.127) recurrence rates. Olanzapine was significantly superior to lamotrigine in the time to recurrence of depressive episodes (?2?=?4.55, df?=?1, p?=?.033), but there was no difference in the time to recurrence of any mood episode (?2?=?1.68, df?=?1, p?=?.195).This prospective naturalistic study suggests that olanzapine is more effective than lamotrigine in the prevention of depressive episodes in patients with bipolar disorder. Future large-scale randomized studies are warranted to validate our results.ClinicalTrials.gov ID NCT01864551.

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Functional Connectivity between Task-Positive Networks and the Left Precuneus as a Biomarker of Response to Lamotrigine in Bipolar Depression: A Pilot Study.

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