ATORVASTATIN IN THE TREATMENT OF LITHIUM-INDUCED NEPHROGENIC DIABETES INSIPIDUS: THE PROTOCOL OF A RANDOMIZED CONTROLLED TRIAL

Jocelyn Fotso Soh,Francesco Trepiccione,Pablo Cervantes,Sybille Saury,Serge Beaulieu,Ayal Schaffer,Nathhan Hermann,Suzane Renaud,Nancy Low,Andrea Levinson,Annemiek Dols,Soham Rej,Outi Mantere,Gabriela Torres-Platas,Robert W Platt ,Birgitte Mønster Christensen ,Benoit H Mulsant ,Ana C Andreazza ,István Mucsi ,Tarek K Rajji ,Daniel J Müeller

doi:10.1016/j.jagp.2019.01.066

Abstract

Introduction Lithium is the gold-standard treatment for bipolar disorder, is highly effective in major depressive disorder, and is being investigated for therapeutic benefits in dementia, stroke, and even cancer. Approximately 350,000 Canadians use lithium and more could benefit. Despite this, clinicians are avoiding lithium, largely due to fear of renal toxicity, including irreversible chronic kidney disease (CKD). Nephrogenic Diabetes Insipidus (NDI) occurs in 20% of lithium users and independently predicts a 2-3 times increased risk of CKD. To date, amiloride is the only medication with randomized controlled trial (RCT) evidence for treating NDI, however it can increase lithium toxicity risk. There is a need for novel, well-tolerated treatments for NDI. We recently found that statins are associated with lower NDI risk in a cross-sectional study (n=71 lithium users). 0% (0/17) of statin users compared to 20.4% (11/54) of non-users had NDI (p=0.055), with atorvastatin 10-40mg/day being the main statin used. Mice studies from our collaborators have also been promising. We present the protocol for a pilot human RCT of statins in NDI to guide a larger confirmatory RCT. Methods We propose a 12-week, double-blind placebo-controlled pilot RCT of atorvastatin in patients with lithium-induced NDI. We will recruit 60 psychiatric patients, aged 18-85, who are on a stable lithium dose for ≥2 months and who have NDI, defined as a 10-hour fluid restriction urine osmolality (UOsm) Results The protocol of this study will be presented. Results will be ready in late 2019. Conclusions Atorvastatin is found to be useful in treating NDI, lithium could be used more safely in patients with a reduced subsequent risk of CKD, as well as hypernatremia, and acute kidney injury (AKI). This could also allow many additional patients with bipolar disorder, depression, and other psychiatric/neurological conditions to benefit from lithium. This could also potentially prevent medical health service utilization related to psychiatric, neurological, and renal disease, saving significant health costs. This research was funded by Kidney Foundation of Canada

Highlights

Lithium is the gold-standard treatment for bipolar disorder, is highly effective in treating major depressive disorder, and has anti-suicidal properties
We describe the first randomized controlled trial (RCT) to evaluate the effectiveness of atorvastatin for treating Nephrogenic Diabetes Insipidus (NDI) in a population of lithium users
We opted for a urinary osmolality of < 600 mOsm/Kg: patients with < 600 mOsm/kg are at risk of future NDI-related complications, such as chronic kidney disease (CKD) and they constitute a large percentage of lithium users (50% of patients)

Summary

Introduction

Lithium is the gold-standard treatment for bipolar disorder, is highly effective in treating major depressive disorder, and has anti-suicidal properties. We recently found that use of statins is associated with lower NDI risk in a cross-sectional study In this current paper, we describe the methodology of a randomized controlled trial (RCT) to treat lithium-induced NDI using atorvastatin. Despite the effectiveness of lithium, many clinicians avoid using it, with prescribing rates declining markedly in the past 2 decades, in America where only 8% of bipolar disorder patients receive lithium [9]. This is likely in large part due to the perception of serious potential adverse effects associated with lithium use compared to other treatment options [10]

Methods

Discussion

Conclusion