Bright Light Therapy in the Morning or at Mid-Day in the Treatment of Non-Seasonal Bipolar Depressive Episodes (LuBi): Study Protocol for a Dose Research Phase I / II Trial

Pierre Alexis Geoffroy, El Mountacer Billah El Abbassi, Julia Maruani, Bruno Etain, Michel Lejoyeux, Ali Amad, Philippe Courtet, Caroline Dubertret, Philip Gorwood, Guillaume Vaiva, Frank Bellivier, Sylvie Chevret, Pierre Alexis Geoffroy, El Mountacer Billah El Abbassi, Julia Maruani, Bruno Etain, Michel Lejoyeux, Ali Amad, Philippe Courtet, Caroline Dubertret, Philip Gorwood, Guillaume Vaiva, Frank Bellivier, Sylvie Chevret

Abstract

Objective This study protocol aims to determine, using a rigorous approach in patients with bipolar disorder (BD) and non-seasonal major depressive episode (MDE), the characteristics of bright light therapy (BLT) administration (duration, escalation, morning and mid-day exposures) depending on the tolerance (hypomanic symptoms). Methods Patients with BD I or II and treated by a mood stabilizer are eligible. After 1 week of placebo, patients are randomized between either morning or mid-day exposure for 10 weeks of active BLT with glasses using a dose escalation at 7.5, 10, 15, 30 and 45 minutes/day. A further follow-up visit is planned 6 months after inclusion. Patients will be included by cohorts of 3, with at least 3 days of delay between them, and 1 week between cohorts. If none meet a dose limiting toxicity (DLT; i.e hypomanic symptoms), the initiation dose of the next cohort will be increased. If one patient meet a DLT, an additionnal cohort will start at the same dose. If 2 or 3 patients meet a DLT, from the same cohort or from two cohorts at the same dose initiation, the maximum tolerated dose is defined. This dose escalation will also take into account DLTs observed during the intra-subject escalation on previous cohorts, with a "Target Ceiling Dose" defined if 2 DLTs occured at a dose. Discussion Using an innovative and more ergonomic device in the form of glasses, this study aims to better codify the use of BLT in BD to ensure a good initiation and tolerance. Trial registrationaaClinicalTrials.gov Identifier: NCT03396744.

Keywords: Bipolar depression; Bipolar disorders; Bright light therapy; Circadian rhythms; Major depressive episode; Phototherapy.

Figures

Figure 1.
Figure 1.
Study design and global organization of the LuBi study. YMRS: Young Mania Rating Scale.
Figure 2.
Figure 2.
Correct placement of the Luminette® device.
Figure 3.
Figure 3.
Diagram of the inter-subject or inter-cohorts’ escalation. DLT: dose-limiting toxicity, MTD: maximum tolerated dose, BLT: Birght Light Therapy, YMRS: Young Mania Rating Scale.
Figure 4.
Figure 4.
Diagram of the the intra- and inter-subject escalation decision rule for a cohort. The diagram schematizes the intra-cohort and inter-cohort escalation rules for a cohort of 3 patients (number 1, 2, and 3) treated at an initial dose dx. The inter-subject escalation is based on the observation of no DLT on the 3 subjects of this cohort (or at most on 1/6); the intra-subject escalation is performed in the absence of DLT at the initial dose, and it will stop if the subject is experimenting with a DLT at the dose dx+a. Intra-subject escalation or the initial dose for future cohorts will then be limited to the dose immediately below the target ceiling dose (TCD) as soon as it has been reached for at least two patients. DLT: dose-limiting toxicity, TCD: target ceiling dose.
Figure 5.
Figure 5.
Theoretical distribution of doses between the randomized groups, morning and mid-day. Randomization is only used to test the effect of BLT conditions, ie morning vs. midday. The choice of doses is based on the observed responses of patients previously included in a sequential pattern called “adaptive”. BLT: bright light therapy.

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