Atorvastatin for the Treatment of Lithium-Induced Nephrogenic Diabetes Insipidus

• ClinicalTrials.gov Identifier: NCT02967653
• Recruitment Status: Completed
• First Posted: November 18, 2016
• Last Update Posted: September 16, 2020
• Sponsor: Lady Davis Institute
• Information provided by (Responsible Party): Dr. Karl Looper, Lady Davis Institute

Study Description

Brief Summary:

Lithium remains the gold-standard treatment for bipolar disorder, with 30-40% of patients with responding preferentially to this medication. Additionally, lithium is commonly used in treatment-resistant depression, and other psychiatric disorders (e.g. schizoaffective disorder). Lithium is especially valuable considering the great difficulty in achieving and maintaining symptomatic remission, the high rates of disability, as well as tremendous personal, family, and societal costs associated with bipolar disorder and treatment-resistant depression. Despite this, clinicians are increasingly avoiding lithium, largely due to fear of irreversible chronic kidney disease (CKD), particularly in North America.

It is well known that lithium exposure, even when dosed safely (<1.0mmol/L in adults 11 and <0.8mmol/L in geriatric patients 12,13), can increase the risk of CKD by 3 times, in large part through Nephrogenic Diabetes Insipidus (NDI) 14-19. NDI itself has also been associated with acute kidney injury 20, and life-threatening hypernatremia, which is an electrolyte imbalance characterized by high levels of blood sodium. Aside from hypertension, diabetes mellitus, aging, and other nonspecific CKD risk factors.

NDI is characterized by excessive thirst (polydipsia) due to increased production of dilute urine (polyuria). In NDI, lithium is believed to interact with the inositol monophosphate and protein kinase C pathways, thereby affecting calcium-related intracellular signaling, cyclic AMP (cAMP), inhibition of Glycogen Synthase Kinase-3 Beta (GSK3Beta), activation of MAP Kinase and many other pathways.

NDI occurs commonly in lithium users: 50% of chronic lithium users have urinary concentrating difficulties, with 12-19% have decreased urine osmolality (UOsm) <300mOsm/Kg).

To date, amiloride (5-20mg/day) is the only medication with prior evidence of therapeutic effectiveness in NDI from randomized clinical trials. However as a potassium-sparing diuretic 31, amiloride can lead to lithium-level elevations, and can thereby theoretically increase the risk of lithium-associated CNS and acute renal toxicity.

There is a need for novel, well-tolerated agents for the treatment of lithium-induced NDI.

We recently demonstrated that statins, which are well-tolerated and commonly used medications, are associated with low lithium-induced NDI risk in the first and only previous cross-sectional study examining statins and NDI in humans (n=71) 33. In this study we examined current lithium users aged 20-95, who had a mean lithium duration and serum lithium level of 10.6 years and 0.62mmol/L, respectively. Patients were assessed for UOsm following 10-hour water-restriction, a reliable measure of NDI. We found that 0% (0/17) of statin users compared to 20.4% (11/54) on non-users had UOsm <300mOsm/Kg following 10-hour water-restriction (Fisher's Exact p=0.055). The main statin prescribed in our previous study was atorvastatin 10-40mg/day (n=10) 33, which is the most widely used statin for cardiovascular disease. Atorvastatin and other statins are well-tolerated and have not been found to have adverse effects on mood, cognition, or renal function.

The mechanism by which statins may treat NDI is not yet known, but two independent mice studies have demonstrated the effectiveness of statins in treating genetic forms of NDI. In those mice models of genetic NDI, prostaglandin and intracellular cytoskeleton proteins pathways were thought to explain statins' activity on NDI.

In preparation for this project, our co-investigators Drs. Trepiccione and Christensen have initiated a pilot study in mice to investigate whether atorvastatin treatment could improve the lithium-induced NDI. NDI was induced in 10 mice by feeding mice with a LiCl-enriched diet for 15 days. After induction of NDI, a group of mice received intraperitoneal injection of atorvastatin (n=5) and a control group received vehicle (n=5) for additional 5 days in parallel with continued lithium treatment. Although our small statistical sample do not allow us to reach significance, (n=5 per group), the mice receiving atorvastatin showed a tendency to reduce polyuria.

In line with this research, our present research protocol aims at conducting a randomized controlled trial investigating a statin, such as atorvastatin, in the treatment of lithium-induced NDI.

Condition or disease	Intervention/treatment	Phase
Lithium Use, Nephrogenic Diabetes Insipidus	Drug: Atorvastatin	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Atorvastatin for the Treatment of Lithium-Induced Nephrogenic Diabetes Insipidus: A Randomized Controlled Trial
• Actual Study Start Date: July 13, 2017
• Actual Primary Completion Date: July 1, 2019
• Actual Study Completion Date: July 1, 2019

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: Placebo; Patients will be randomized to a placebo a day using simple 1:1 randomization using random.org, for 12 weeks.	Drug: Atorvastatin; Member of drug class called statins, primarily used as a lipid-lowering agent and the prevention of events associated with cardiovascular disease; Other Name: Lipitor
Experimental: Atorvastatin; Patients will be randomized to Atorvastatin 20mg/day for 12 weeks or pill placebo.	Drug: Atorvastatin; Member of drug class called statins, primarily used as a lipid-lowering agent and the prevention of events associated with cardiovascular disease; Other Name: Lipitor

Outcome Measures

Primary Outcome Measures :

1. Raw Urine Osmolality value at 12 week follow-up, adjusted for baseline (UOsm in mOsm/Kg) [ Time Frame: 12 weeks follow-up ]
   Urine Osmolality value at 12 week follow-up

Secondary Outcome Measures :

1. Raw aquaporins-2 (AQP-2) values at 12 week follow-up, adjusted for baseline [ Time Frame: 12 weeks follow-up ]
   aquaporins-2 measurement as adjusted for baseline
2. Raw Urine Volume (mL/24h) value at 12 week follow-up, adjusted for baseline [ Time Frame: 12 weeks follow-up ]
   24h urine volume values measured as adjusted for baseline
3. Raw Self-Reported Fluid Intake value 12 week follow-up, adjusted for baseline [ Time Frame: 12 weeks follow-up ]
   self-reported fluid intake #measurement as adjusted for baseline

Other Outcome Measures:

1. Raw value of Cognition in the domain of executive function at 12 week follow-up, adjusted for baseline [ Time Frame: 12 weeks follow-up ]
   Using Screen for Cognitive Impairment in Psychiatry (SCIP), Stroop, Trials A/Trials B tests
2. Safety Measures [ Time Frame: 12 weeks follow-up ]
   Creatine kinase (CK) and Low Density Lipoprotein (LDL) Liver function tests Thyroid function (TSH) Calcium levels eGFR
3. Subgroup Analyses - Raw Urine Osmolality value at 12 week follow-up, adjusted for baseline in patients UOsm <300mOsm/Kg [ Time Frame: 12 weeks follow-up ]
   Subgroup analyses

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 85 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Individuals between 18 and 85 years of age

• Individuals with any psychiatric disorder who are taking lithium

  o Patients will be recruited from the Douglas Mental Health University Institute, Jewish General Hospital and McGill University Health Centre.

• Able and willing to give informed consent.
• Chronic and current lithium users (at least 2 months of Lithium use).
• Stable dose of lithium for the past 2 months.
• Patients taking any lithium level will be included.
• Patients with any psychiatric diagnosis will also be included.
• NDI defined as a 10-hour water restriction UOsm <600mOsm/Kg.

Exclusion Criteria:

• Patients allergic to Statins
• Patients with statin use within 6 weeks prior to the study
• Patients with a past history of severe adverse reaction to statins.
• Patients with a baseline Low Density Lipoprotein (LDL) level <1.5.
• Relative contraindications to statin use 42: pregnancy or lactation, concurrent use of fibrates, heavy ethanol consumption (>50 units/week).
• Incapacity to consent
• Deemed by the treating physician to have a severe cognitive or behavioural disturbance such as acute delirium or moderate-severe DSM5 Neurocognitive Disorder (dementia), preventing their ability to complete safely the study questionnaire and/or to provide blood and urine test.

Contacts and Locations

Locations

Canada, Quebec

McGill University Health Centre

Montréal, Quebec, Canada, H3A1A1

Jewish General Hospital

Montréal, Quebec, Canada, H3T1E4

Douglas Mental Health University Institute

Montréal, Quebec, Canada, H4H1R3

Sponsors and Collaborators

Lady Davis Institute

Investigators

• Principal Investigator: Soham F Rej, MD, M.Sc.; Jewish General Hospital

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Fotso Soh J, Beaulieu S, Trepiccione F, Linnaranta O, Torres-Platas G, Platt RW, Renaud S, Su CL, Mucsi I, D'Apolito L, Mulsant BH, Levinson A, Saury S, Müller D, Schaffer A, Dols A, Low N, Cervantes P, Christensen BM, Herrmann N, Rajji T, Rej S. 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.

Fotso Soh J, Torres-Platas SG, Beaulieu S, Mantere O, Platt R, Mucsi I, Saury S, Renaud S, Levinson A, Andreazza AC, Mulsant BH, Müller D, Schaffer A, Dols A, Cervantes P, Low NC, Herrmann N, Christensen BM, Trepiccione F, Rajji T, Rej S. Atorvastatin in the treatment of Lithium-induced nephrogenic diabetes insipidus: the protocol of a randomized controlled trial. BMC Psychiatry. 2018 Jul 16;18(1):227. doi: 10.1186/s12888-018-1793-9.

• Responsible Party: Dr. Karl Looper, Psychiatrist-in-Chief, Associate Professor, Dept. of Psychiatry, McGill University; Co-Lead, Geri-PARTy Research Group, Lady Davis Institute
• ClinicalTrials.gov Identifier: NCT02967653
• Other Study ID Numbers: 16/02
• First Posted: November 18, 2016
• Last Update Posted: September 16, 2020
• Last Verified: September 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:

Diabetes Insipidus; Diabetes Insipidus, Nephrogenic; Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Kidney Diseases; Urologic Diseases; Pituitary Diseases; Atorvastatin; Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Enzyme Inhibitors