A double-blind, randomized, placebo-controlled pilot trial of atorvastatin for nephrogenic diabetes insipidus in lithium users

Bipolar Disord. 2021 Feb;23(1):66-75. doi: 10.1111/bdi.12973. Epub 2020 Jul 16.


Objective: Lithium remains an important treatment for mood disorders but is associated with kidney disease. Nephrogenic diabetes insipidus (NDI) is associated with up to 3-fold risk of incident chronic kidney disease among lithium users. There are limited randomized controlled trials (RCT) for treatments of lithium-induced NDI, and existing therapies can be poorly tolerated. Therefore, novel treatments are needed for lithium-induced NDI.

Method: We conducted a 12-week double-blind pilot RCT to assess the feasibility and efficacy of 20 mg/d atorvastatin vs placebo in the treatment of NDI in chronic lithium users. Patients, recruited between September 2017 and October 2018, were aged 18 to 85, currently on a stable dose of lithium, and determined to have NDI.

Results: Urinary osmolality (UOsm) at 12 weeks adjusted for baseline was not statistically different between groups (+39.6 mOsm/kg [95% CI, -35.3, 114.5] in atorvastatin compared to placebo groups). Secondary outcomes of fluid intake and aquaporin-2 excretions at 12 weeks adjusted for baseline were -0.13 L [95% CI, -0.54, 0.28] and 98.68 [95% CI, -190.34, 387.70], respectively. A moderate effect size was observed for improvements in baseline UOsm by ≥100 mOsm/kg at 12 weeks in patients who received atorvastatin compared to placebo (38.45% (10/26) vs 22.58% (7/31); Cohen's d = 0.66).

Conclusion: Among lithium users with NDI, atorvastatin 20 mg/d did not significantly improve urinary osmolality compared to placebo over a 12-week period. Larger confirmatory trials with longer follow-up periods may help to further assess the effects of statins on NDI, especially within patients with more severe NDI.

Trial registration: ClinicalTrials.gov NCT02967653.

Keywords: bipolar disorder; kidney function; lithium use; nephrogenic diabetes insipidus.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Atorvastatin
  • Bipolar Disorder*
  • Diabetes Insipidus, Nephrogenic* / chemically induced
  • Diabetes Insipidus, Nephrogenic* / drug therapy
  • Diabetes Mellitus*
  • Humans
  • Lithium
  • Middle Aged
  • Pilot Projects
  • Young Adult


  • Lithium
  • Atorvastatin

Associated data

  • ClinicalTrials.gov/NCT02967653