Lithium Use, Nephrogenic Diabetes Insipidus Clinical Trial
Official title:
Atorvastatin for the Treatment of Lithium-Induced Nephrogenic Diabetes Insipidus: A Randomized Controlled Trial
| NCT number | NCT02967653 |
| Other study ID # | 16/02 |
| Secondary ID | |
| Status | Completed |
| Phase | Phase 2 |
| First received | |
| Last updated | |
| Start date | July 13, 2017 |
| Est. completion date | July 1, 2019 |
| Verified date | September 2020 |
| Source | Lady Davis Institute |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | |
| Study type | Interventional |
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.
| Status | Completed |
| Enrollment | 60 |
| Est. completion date | July 1, 2019 |
| Est. primary completion date | July 1, 2019 |
| Accepts healthy volunteers | No |
| Gender | All |
| Age group | 18 Years to 85 Years |
| Eligibility |
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. |
| Country | Name | City | State |
|---|---|---|---|
| Canada | Douglas Mental Health University Institute | Montréal | Quebec |
| Canada | Jewish General Hospital | Montréal | Quebec |
| Canada | McGill University Health Centre | Montréal | Quebec |
| Lead Sponsor | Collaborator |
|---|---|
| Lady Davis Institute |
Canada,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Other | Raw value of Cognition in the domain of executive function at 12 week follow-up, adjusted for baseline | Using Screen for Cognitive Impairment in Psychiatry (SCIP), Stroop, Trials A/Trials B tests | 12 weeks follow-up | |
| Other | Safety Measures | Creatine kinase (CK) and Low Density Lipoprotein (LDL) Liver function tests Thyroid function (TSH) Calcium levels eGFR | 12 weeks follow-up | |
| Other | Subgroup Analyses - Raw Urine Osmolality value at 12 week follow-up, adjusted for baseline in patients UOsm <300mOsm/Kg | Subgroup analyses | 12 weeks follow-up | |
| Primary | Raw Urine Osmolality value at 12 week follow-up, adjusted for baseline (UOsm in mOsm/Kg) | Urine Osmolality value at 12 week follow-up | 12 weeks follow-up | |
| Secondary | Raw aquaporins-2 (AQP-2) values at 12 week follow-up, adjusted for baseline | aquaporins-2 measurement as adjusted for baseline | 12 weeks follow-up | |
| Secondary | Raw Urine Volume (mL/24h) value at 12 week follow-up, adjusted for baseline | 24h urine volume values measured as adjusted for baseline | 12 weeks follow-up | |
| Secondary | Raw Self-Reported Fluid Intake value 12 week follow-up, adjusted for baseline | self-reported fluid intake #measurement as adjusted for baseline | 12 weeks follow-up |