Melatonin Versus Placebo for Bipolar Disorder

Mood stabilization will be measured by a mood instability score reflecting the daily variability in self-monitored mood collected via the Monsenso system. Patients score their daily mood on a 9-point scale (-3 to +3); scores between -0.5 to 0.5 reflect normal variations, whereas scores of +1, +2 or +3 correspond to mildly, moderately, and severely increased mood and scores of -1, -2 or -3 correspond to mildly, moderately, and severely decreased mood. According to our established methodology, for each participant, we will estimate a mood instability score. Estimates of instability will be based on reading obtained via the Monsenso system which will prompt patients to complete daily mood ratings.

Change in sleep measured by change from baseline on the Pittsburgh Sleep Quality Index (min. value = 0; max. value = 21 with higher scores indicating poorer sleep quality) on 3 months visit and 6 months visit

The clinical rating of depression is assessed using the Hamilton Rating Scale for Depression, 6 items (HAM-D6), (min. value=0; max. value = 22 with higher scores reflecting more severe depression )

The clinical rating of (hypo)mania is assessed using the Young Mania Rating Scale (YMRS) (Min. value = 0; max. value = 60 with higher values reflecting more manic symptoms) [Clinically rated observer-based difference in scores over the 6 months trial, measured at baseline, 3 months and 6 months]

Functioning is assessed using the Functional Assessment Short Test (FAST) (Min. value = 0, max. value = 72 with higher values reflecting poorer function).

Assessed using Cohen's Perceived Stress Scale (PSS), a 10-item questionnaire. (Min. value = 0; max. value = 40, with higher values reflecting increased stress level)

Assessed using the self-administered questionnaire, Cognitive Complaints in Bipolar Disorder Rating Assessment (COBRA) (Min. value = 0; max. value = 48, the higher the score, the higher the number of subjective complaints)

Non-response to standard mood stabilizing treatment, where standard treatment is defined as lithium or lamotrigine.

If one of the following situations occurs after treatment allocation, the date is registrered as "non-response to treatment" defined as:

• Add-on of a second mood stabilizer (lithium or lamotrigine) in addition to the initial mood stabilizer (lithium or lamotrigine)
• Add-on of an antidepressant
• Add-on of quetiapine > 100 mg/day or another antipsychotic drug The patient will continue the trial follow-up in case of non-response

Assessed using the Morningness-Eveningness questionnaire (MEQ). (Min. value 16, max. value 86. A value of 41 or below indicate an "evening type". Value of 59 or above indicate a "morning type". Values between 42-58 indicate an "intermediate type")