Lithium (Li) is the leading treatment for BD, protecting against both maniac and depressive relapse, and reducing the risk of suicide and mortality. However, despite this major clinical efficacy, the use of lithium is limited by its narrow therapeutic index and by its side effects. Li induces a vasopressin-resistant urinary concentration defect, with resulting nephrogenic diabetes insipidus (NDI) in 12-50 % of patients. This feature is more frequent after 5 years of treatment with lithium. Polyuria and subsequent thirst might affect patients' quality of life, but also cause potentially life-threatening hypernatremia if free access to water is impaired. Thus, we aim at evaluating the efficacy of amiloride on urine concentrating ability in patients with nephrogenic diabetes insipidus due to chronic lithium treatment.

Patients will be referred to the nephrology or the renal physiology department for the usual follow-up of the lithium treatment. After verification of eligilibity criteria, information and collection of consent, patient will be randomized.

During the first phase, patients will be randomized in two parallel groups: the experimental arm will receive 5mg of amiloride twice daily during 2 months and the control arm will receive a placebo twice daily during 2 months.

Measures of fasting urine osmolality will be performed at baseline, 2 months, at 6 months and at 12 months, in order to compare the difference of urine osmolality before and after treatment between the two-randomization arms. Other baseline explorations are as follows: mean number of nocturnal voids, SF-36 questionnaire, thirst intensity and distress scales, YMRS/MADRS mood scale, GAD7 anxiety scale, PSQI sleep scale, GFR measurement and estimation, 24h urine for the quantification of the polyuria and osmolality, plasma and erythrocyte lithium level, serum osmolality, natremia, kaliemia, urea, chlore level, complete blood count, plasma copeptine and vasopressin.

A nephrologist visit will take place 15 days after the initiation of the treatment along with a new measure of plasma lithium level.

Patients will be evaluated at 1 month only if a change in posology is required after the first measurement at day 15 and then at 2, 6 and 12 months.

In parallel, patients will be evaluated by at the psychiatry clinic at 1 month, 2, 6 and 12 months, and in any condition requiring additional visit as usual in standard care (follow-up of anxiety, sleepiness, suicidal ideation, depression).

After the completion of this first phase, the open label second phase will begin. Unblinding the trial will allow the treatment allocation being available for the participants and health care professionals. Amiloride will be continued in participants in the experimental group, and the remaining participants will be followed-up without treatment. This phase will last for 10 months (total trial duration: 12 months).

At one year, renal functions (GFR, urine concentration and 24h urine production) will be assessed along with report of events including hospital admission.

The safety of the experimental treatment will be assessed by regular evaluations of plasma lithium and potassium level, beginning at 2 weeks after treatment initiation and after 2 months. The main risk of amiloride is hyperkalemia, which occurs in patients with severe renal insufficiency. These patients will not be included in our study. Otherwise, the treatment is generally safe and well-tolerated. Plasma lithium level will be measured at the first month clinical evaluation if a change in posology is required after the first measurement at day 15.

Inclusion Criteria:

• Adults between 18 and 70 years (age ≥ 18 years and <70 years)
• Patient with bipolar disorder
• Patient treated with lithium for at least 5 years
• Patient with a urine concentration defect defined by a maximal urine osmolality < 600 mOsm/kg
• Woman of childbearing age agreeing to use an efficient contraceptive method for 12 months

Exclusion Criteria:

• Renal failure defined as eGFR < 30 ml/min/1.73m² estimated by the CKD-EPI equation
• Kalemia > 5 mmol/l
• Hypersensitivity or known allergy to amiloride
• Hypersensitivity to lactose
• Known adrenal insufficiency
• Concomitant use of other potassium-sparing treatment (e.g. spironolactone, angiotensin converting enzyme inhibitors (ACE), angiotensin II receptor (AT2R) antagonists, calcineurin inhibitors tacrolimus and ciclosporin)
• Acute ongoing infection (less than 3 days before inclusion)
• Severe heart failure (NYHA > II)
• Rhythm, conduction or repolarisation disorder present on an ECG done within 12 months prior to inclusion
• Acute phase of mood disorder
• Uncontrolled diabetes mellitus or diabetes with hyporeninism hypoaldosteronism
• Potassium supplements
• Use of heparins
• Use of trimethoprim
• Cirrhosis
• Oedemas
• Previous use of amiloride use in the 6 months prior to randomisation)
• Pregnant or breastfeeding women
• Participation in another clinical study involving investigational medicinal product or patient being in the exclusion period at the end of a previous study
• Patient refusal to participate
• Non-affiliation to a social security regimen or CMU
• Patient under State Medical Aid
• Subject deprived of freedom, subject under a legal protective measure