Melatonin and Response to Lithium

Bipolar disorders are mental illnesses characterized by the recurrence of mood-episodes, that can have a severe impact on the life of individuals. The effect of lithium, one of the main medications used to treat acute episodes or prevent them from happening, is very different from one individual to an-other. So far, there is no way to predict in advance for whom patient this treatment will be effective or for whom it will not.

Finding markers that can predict as early as possible the efficiency of this treatment is a major field of current research in psychiatry, in order to avoid maintaining an inefficient treatment for several years that can have negative side-effects.

Over the past decades, it has been shown by multiple studies that lithium can act on the biological clock, that regulates circadian rhythmicity of the body (i.e. rhythms that presents a 24 hours periods, such as rhythms of sleep and activity, feeding, social activities...). But it is still very unclear whether the effect of lithium in regulating the mood in bipolar disorders is mediated by this action.

Melatonin is one of the key-regulator of circadian rhythmicity of the human body. Our hypothesis, based on some previous studies, is that the action of lithium in type-1 bipolar disorder (BD-I) is related to an action on melatonin secretion.

To test that, we want in this study to compare the noctunal secretion of melatonin between BD-I individuals with a good response to lithium versus with a poor response to lithium.

The study is a monocentric case-control study comparing the level of urinary nocturnal secretion of 6-sulfatoxy-melatonin between good-responders (GR) and non-responders (NR) to lithium in euthymic BD-1 individuals.

The study will also compare the levels of 14-3-3 proteins and miR-451 between these two groups. They are regulators of melatonin-synthesis, that on one hand have been previously associated in autism spectrum disorders to melatonin level modifications and on the other hand have been shown in one preclinical study in rat to be regulated by a lithium treatment.The study also compare the levels of other proteins and mRNA of interest related to ciracdian regulatory pathways.

Euthymic BD-1 patients treated by lithium will be pre-selected and lithium response will be assessed by clinicians using the validated ALDA-scale.

V1 = inclusion (D0) :

* assessment of inclusion and exclusion criteria
* written consent
* collection of socio-demographic data, clinical data
* questionaries : MADRS (Montgomery-Absberg Depressive scale for depressive symptoms), YMRS (Young Mania Rating Scale for manic symptoms), Berlin score (risk of undiagnosed obstructive sleep apnea)
* ALDA scale for assessment of lithium response
* information and furniture for one-night urine collection and one-week sleep diary
* planning of V2, the day after diurnal urine collection

V2 (D8 to D30):

* collection of the urine collection and the sleep diary
* blood sample for measure of plasmatic level of lithium, 14.3.3 proteins and miR-451, mRNA or proteins of interest
* Self-questionaries : PSQI (Pittsburg Sleep Quality Index for sleep assesment), CSM (Composite Scale of Morningness for assessment of morning vs evening chronotype), CTI (Circadian Type Inventory for assessment of chronotype)

Eligibility Criteria:
Inclusion Criteria:

* BD-1 as defined by DSM-5
* Age : 18 to 70
* Current treatment by lithium for more than one year
* Euthymia defined by : MADRS \<8 and YMRS \<8 at inclusion ; no hospitalization or change in mood-stabilizing treatment in the previous 3 months
* Health condition compatible with blood and urinal sampling
* Being affiliated to french social security
* Written consent

Exclusion Criteria:

* Treatment by : melatonin, agomelatin, benzodiazepines or hypnotic in the last 15 days
* Treatment by a strong CYP1A2 inducer in the last month : ciprofloxacine, dihydralazine, fluvoxamine, norfloxacine
* Current substance use disorder except for tobacco
* Chronic renal failure with glomerular filtration rate \<60mL/min
* Jetlag in the last 15 days or life-event impacting circadian rhythmicity (birth, grief, night-work...)
* Sleep disorders such as Obstructive Sleep-Apnea, restless leg syndrome, narcolepsy
* Pregnancy, breastfeeding
* Guardianship
* Inability to understand french, illiteracy