Melatonin and Response to Lithium (MeLiR)

A Case-control Study Comparing Melatonin Nocturnal Secretion Between Lithium Responders Versus Non Responders in Type 1 Bipolar Disorder.

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.

Study Overview

• Status: Recruiting
• Conditions: Bipolar Disorder I
• Intervention / Treatment: Diagnostic test: urine collection; Diagnostic test: Level of Protein 14.3.3; Diagnostic test: Level of miR-451

Detailed Description

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.

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
• 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)

• Study Type: Observational
• Enrollment (Estimated): 60

Contacts and Locations

• Study Contact: Name: Vincent Hennion, MD; Phone Number: +33 01 40 05 42 08; Email: vincent.hennion@aphp.fr

Study Locations

• France
  • Ile De France
    • Paris, Ile De France, France, 75010
      • Recruiting
      • Hôpital Fernand-Widal
      • Contact: Vincent Hennion, MD; Phone Number: +33 01 40 05 42 08; Email: vincent.hennion@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: N/A

• Sampling Method: Non-Probability Sample

Study Population

Euthymic BD-1 patients treated by lithium

Description

Inclusion Criteria:

• BD-1 as defined by DSM-5
• Age : 18 to 60
• 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

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
good-responders (GR) to lithium in euthymic BD-1 individuals	Diagnostic test: urine collection; Urine collection will be made on a 12 hours period (20h00-8h00), the night before V2; at V2 : 2 mL urinal sample for measure of 6-SMT concentration (ng/mL) and creatinin (mg/mL); Measure of 6-SMT will be made by a validated radio-immunology assay; Diagnostic test: Level of Protein 14.3.3; blood sample at V2 (2x7mL ACD tubes); measured by ELISA; Diagnostic test: Level of miR-451; blood sample at V2 (2.5mL PAX-gene tube); measured by quantitative RT-PCR
non-responders (NR) to lithium in euthymic BD-1 individuals	Diagnostic test: urine collection; Urine collection will be made on a 12 hours period (20h00-8h00), the night before V2; at V2 : 2 mL urinal sample for measure of 6-SMT concentration (ng/mL) and creatinin (mg/mL); Measure of 6-SMT will be made by a validated radio-immunology assay; Diagnostic test: Level of Protein 14.3.3; blood sample at V2 (2x7mL ACD tubes); measured by ELISA; Diagnostic test: Level of miR-451; blood sample at V2 (2.5mL PAX-gene tube); measured by quantitative RT-PCR

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ratio between 6-sulfatoxy-melatonin (6-SMT) concentration and creatinin concentration on a 12-hours nocturnal urine collection	Ratio between 6-sulfatoxy-melatonin (6-SMT) concentration and creatinin concentration on a 12-hours nocturnal urine collection (8pm to 8am) : Urine collection will be made on a 12 hours period (20h00-8h00), the night before D30; at D30 : 2 mL urinal sample for measure of 6-SMT concentration (ng/mL) and creatinin (mg/mL); Measure of 6-SMT will be made by a validated radio-immunology assay	at day 30

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Level of Protein 14.3.3	Level of Protein 14.3.3 in ng/mL : blood sample at D30 (2x7mL ACD tubes); measured by ELISA	at day 30
Level of miR-451	Level of miR-451; blood sample at D30 (2.5mL PAX-gene tube); measured by quantitative RT-PCR	at day 30
Level of plasmatic lithium	Level of plasmatic lithium (mmol/L); blood sample at D30 (mmol/L); 5mL tube with sodium heparinate	at day 30
Level of intraerythrocytic lithium	Level of intraerythrocytic lithium (mmol/L); blood sample at D30 (mmol/L); 4mL EDTA tube	at day 30

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Actual): July 26, 2023
• Primary Completion (Estimated): July 1, 2025
• Study Completion (Estimated): July 1, 2025

Study Registration Dates

• First Submitted: May 19, 2023
• First Submitted That Met QC Criteria: May 19, 2023
• First Posted (Actual): May 26, 2023

Study Record Updates

• Last Update Posted (Actual): July 28, 2023
• Last Update Submitted That Met QC Criteria: July 27, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: lithium
• Additional Relevant MeSH Terms: Mental Disorders; Mood Disorders; Bipolar and Related Disorders; Bipolar Disorder
• Other Study ID Numbers: APHP221168; 2022-A02550-43 (Other Identifier: ID RCB Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No