Bipolar disorder (BD) is a severe brain disorder characterized by the recurrence of mood episodes. About 1% to 4% of the worldwide population suffers from BD, ranking as the fourth most important contributor to the global disease burden among mental, neurological and substance-use disorders [1,2]. BD is associated with a 10-20 years decrease in life expectancy, which has not improved over recent decades, unlike the pattern seen in the general population [3,4]. This severity of BD is closely associated with a high relapse rate, with 60-80% of relapses occurring within 2 years after a manic or depressive episode [5-7].

Patients presenting with BD spend more time with depressive symptoms than with manic ones, which have a major impact on the quality of life and is associated with poorer outcomes including recurrences and suicide. Indeed, a 13-year follow-up study of patients with BD type I demonstrated that depressive symptoms predominated over (hypo)manic symptoms (32% vs. 9% of total follow-up weeks, respectively) [8]. Similarly, patients with BD type II suffer more from depressive symptoms than (hypo)manic symptoms (50% vs. 1% of total follow-up weeks, respectively) [9]. These observations are confirmed up to 20 years of follow-up, both in BD type I and II, with a clear predominance of depressive symptoms during 59% of the follow-up versus 2% for (hypo)manic symptoms [10]. However, in bipolar depression, available antidepressant strategies show low efficacy apart from electroconvulsive therapy (ECT) [11,12]. Mood stabilizers in monotherapy rarely suffices to treat depression and conventionnal antidepressant are added but carry the risk of serious side effects, including an affective switch from depression to hypomania/mania, rapid cycling, and suicidality [11,12]. Given this rather bleak therapeutic landscape, there is an urgent need to develop new antidepressant treatments in BD.

The use of light for its antidepressant action dates back to the beginnings of civilization [13], and a growing body of evidence has been generated over the last decade about bright light therapy (BLT, also named phototherapy) evolving as an effective depression treatment not only to be used in seasonal affective disorder [14] (SAD, a syndrome defined by recurrent depressions that occur annually at the same time each year [15]), but also in non-seasonal depression both in unipolar and bipolar disorders [13]. Indeed, BLT is the cornerstone treatment of seasonal affective disorders since more than two decades [16,17] with a first case series published in 1984 by Rosenthal and colleagues [15]. Artificial bright light appeared more effective than dim light, but also showed the effects of lengthening the photoperiod (defined as the length of light period during a night/day cycle) and suppressing the melatonin secretion [15]. BLT is the first line treatment for depression with seasonal patterns with an efficacy equivalent to typical antidepressants like selective serotonin reuptake inhibitors (SSRIs) [18]. This benefit was confirmed in meta-analyses of randomized trials evaluating BLT versus placebo in subjects with seasonal unipolar depression [19], and seasonal bipolar depression [20]. Interestingly, it has been recently demonstrated that BLT may also be useful in non-seasonal depression. Indeed, BLT appeared efficacious and well tolerated in the treatment of adults with non-seasonal unipolar depression, of moderate to severe intensity, with an effect size equal or superior to SSRIs [19,21], and was confirmed in a meta-analysis [22].

Despite these new insights about light antidepressant action, the management of BLT continues to be a point of debate, especially for BD with non-seasonal pattern [13]. There is only one randomized negative study in BD that recruited 44 non-seasonal patients but whose analyzes focused on the comparison of 10 patients treated with BLT versus 11 patients treated with placebo [23]. However, 10 subjects per group is probably insufficient as sample size to test the therapeutic efficacy of BLT. For example, Lam et al. [21] could identify that 54 subjects per comparison group allowed a statistical power of 80% to detect a mean difference with placebo on the MADRS depression scale of 3.5 points or an effect size of 0.4, considered as mild to moderate therapeutic effect. In addition, an older randomized controlled trial of Kripke et al. [24], that included both BD and non-BD patients (n=25) versus placebo (n=26), observed that non-seasonal patients with BD had a greater decreased of depressive symptoms than non-BD patients, although not significant. This is confirmed by a study that focused specifically on comparing the effects of light therapy on non-seasonal bipolar versus non-bipolar depressions [25]. These authors observe, in a small sample of 17 patients, that BLT is significantly more effective on bipolar than non-bipolar non-seasonal depressive symptoms, with an antidepressant effect maintained at 3 months [25].

Specific concerns also exist in BD antidepressant strategies, such as the manic switch, and so warrant specific safety studies [14]. Depending on the clinical assessment (no systematic report, clinical examination, or rating scales) and clinical characteristics of studied subjects, the rate of manic switches went from 0% to 18.8% [26]. Preliminary reports suggest that morning exposure may induce manic switches, and that mid-day exposures may be associated with a decreased risk of manic switch [27]. A 6-week randomized double-blind placebo-controlled trial provided new evidence to support mid-day BLT as an efficient therapy in BD, but also a safety one since no manic switches were observed [28]. Nevertheless, most of the BD patients (82%) had BD with seasonal pattern, and no comparisons of seasonal and non-seasonal patients were possible. Moreover, whereas an historical review suggested that manic switches occurred independent of treatment modality [26], different dose-titration protocols have not been directly compared and data are lacking in order to provide reliable evidence-based therapeutic guidelines.

In this context, the originality of this study protocol will be to evaluate, in patients with BD and non-seasonal depression, using a rigorous approach, the characteristics of BLT administration that are not codified (duration, escalation, morning and mid-day exposure) depending on the tolerance (hypomanic symptoms) from an intra-subject dose escalation scheme of the efficacy of this therapy, in two groups exposed either during the morning or at mid-day. This phase I/II study will also provide an estimate of the potential size effect of BLT, which is necessary for the secondary planning of a randomized, placebo-controlled efficacy trial.

Taken as a whole, this study will aim to identify the best modalities of the therapeutic escalation according to the tolerance of morning and mid-day BLT in patients with nonseasonal bipolar depression. In each parallel group (morning vs. mid-day), an inter-subject (with cohorts of 3) and intrasubject (with a potential of 5 dose levels) dose escalation schemes will be used to determine the maximum tolerated dose (MTD) of BLT in BD. The dose is defined here by the duration of the exposure to the intensity of the glasses (equivalent to 10,000 Lux on traditional light therapy). This scheme takes into account the inter and intra-individual variability of tolerance and response, to model cumulative toxicity and to maximize the probability for each patient to receive an effective dose. It is based on the definition of an intra-subject dose escalation scheme, with different initiation doses and a total of 5 dose levels (7.5, 10, 15, 30, and 45 min), and one dose target ceiling dose (TCD) defined according to previous observations during escalation.

This study will propose an antidepressant strategy other than electroconvulsive therapy or antidepressants, in patients who do not respond to well-managed mood stabilization therapy. Light therapy also improves sleep and abnormal circadian rhythms such as phase shift [35-39]. These abnormalities in circadian rhythms and sleep are present in all phases of BD, particularly during depressive phases [40-46].

Concerning the predictive risks, light therapy is rather very well tolerated [47]. More specifically, the possibility exist of hypomanic switch in patients with BD with possible symptoms such as tachypsychia, logorrhea, increased energy and activity, irritability or aggression [27,48]. The other rare side effects of light therapy are: headache, eye strain, nausea and agitation [38,49,50]. In addition, despite traditionnal precautions in BLT studies including what we planned for this LuBi study, there does not seem to be any retinal toxicity associated with light therapy [51]. Regarding the issue of suicidal behavior, which may be a problem with conventional antidepressants, a previous report of 3 cases treated with light therapy alone (2 subjects with BD suffering from seasonal depression and 1 unipolar subject with seasonnal affective disorder) observed in these subjects the emergence of suicidal ideation during the first week, complicated of a suicide attempt for 2 of these 3 subjects [52]. Nevertheless, a more recent study focused specifically on suicidality effect of light therapy in patients with seasonal affective disorder (both unipolar and bipolar) and rather observed a protective effect: almost half of the 191 subjects had a decrease in suicidal ideation and only 6 subjects showed worsening of these [53]. This anti-suicidal protective effect has also been observed in two studies associating light therapy with other therapeutic strategies in unipolar disorder [54] and bipolar disorder [55]. Thus, light therapy may precipitate or aggravate suicidal ideations sporadically, but seems to have a protective effect suicidal in the vast majority of patients.

Results from this study would help to better determine how to prescribe light therapy in patients with BD to ensure a good initiation and tolerance, in order to help developing a nondrug therapeutic strategy in a field where significant progress is expected since standard therapies are not very effective outside electroconvulsive therapy. Moreover, this study innovates in the field of light therapy with a device in the form of glasses that may be more ergonomic and acceptable.