Lithium Therapeutic Drug Monitoring; Once Daily Vs Twice Daily Dosing and the Impact of Kidney Function

Lithium is a mainstay in the treatment of bipolar disorder, and a frequently used adjunctive therapy for major depressive disorder. It is accepted practice to monitor lithium serum levels to monitor for efficacy and toxicity. However, studies on the difference in lithium levels between once and twice daily dosing, which also assess the impact of kidney function are scarce. The aim of this study is to quantify this pharmacokinetic difference, identify the impact of kidney function, in the context of estimating effects to inform feasibility and sample size needed for a larger well-powered study.

Study Overview

• Status: Unknown
• Conditions: Bipolar Disorder; Major Depressive Disorder
• Intervention / Treatment: Diagnostic test: Lithium level; Diagnostic test: Serum Creatinine

Detailed Description

Bipolar disorder is a chronic and recurring condition which causes functional impairment and increases lifetime suicide risk. Major depressive disorder likewise confers a high burden of illness on the affected population, and treatment is complicated by the fact 50-70% of patients treated with an initial agent do not achieve full remission of symptoms. There are numerous clinical practice guidelines which support the use of lithium as a first-line agent for bipolar disorder, and as an adjunctive therapy for major depressive disorder. Therapeutic ranges for lithium were established in the 1970s using multiple daily dose regimens, and therefore should not be directly applied to patients taking lithium once daily. The current standard of practice is to measure levels 12 hours post dose irrespective of once or twice daily administration. There is some evidence that lithium levels drawn 12 hours post dose are 10 - 26% higher when dosing lithium once daily compared to twice daily, however, the impact of kidney function on this difference has not been studied, and this difference in 12h post levels has not been confirmed via prospective data. Guidance on therapeutic drug monitoring (TDM) is vague with respect to interpretation of specific lithium blood levels for once daily dosing. Physicians may reduce a patient's dose based on a lithium level that is seemingly higher that target, even if the patient is clinically stable, putting the patient at risk for re-emergence of symptoms. Though it is known that lithium is excreted by the kidney, the impact of kidney function on the difference in lithium levels when dosed once daily compared to twice daily is not well understood. The results of this pilot study will help identify the impact of kidney function on lithium therapeutic drug monitoring in current practice, and potentially lead to a larger multi-center study.

• Study Type: Interventional
• Enrollment (Anticipated): 15
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Virginia Fernandes, PharmD; Phone Number: 416-586-4800; Email: virginia.fernandes@sinaihealthsystem.ca
• Study Contact Backup: Name: Dario A Moscoso, PharmD; Phone Number: 416-586-4800; Email: dario.moscoso@sinaihealthsystem.ca

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X5
      • Recruiting
      • Mount Sinai Hospital
      • Contact: Virginia Fernandes, PharmD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Adult patients admitted to the inpatient psychiatry unit at Mount Sinai Hospital treated with lithium therapy (i.e. taking lithium before admission, or initiated on lithium therapy during hospitalization)

Exclusion Criteria:

• any patients who are currently pregnant
• patients taking lithium three times daily
• patients taking lithium with a specific dosing frequency for a documented clinical reason.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Once Daily Dosing; In this arm of the study, participants receive the prescribed dose of lithium once daily at bedtime. After 4-6 days, a steady state lithium serum level and serum creatinine are taken, and they crossover to the other arm (twice daily dosing, if they have not already done so). Frequency of selected medication use is noted.	Diagnostic test: Lithium level; The level of lithium in the serum; Diagnostic test: Serum Creatinine; The level of creatinine (as an indicator of kidney function, to approximate GFR) in the serum
Active Comparator: Twice Daily Dosing; In this arm of the study, participants receive the prescribed dose of lithium divided into two daily doses. After 4-6 days a steady state lithium serum level and serum creatinine are taken, and they crossover to the other arm (once daily dosing, if they have not already done so).Frequency of selected medication use is noted.	Diagnostic test: Lithium level; The level of lithium in the serum; Diagnostic test: Serum Creatinine; The level of creatinine (as an indicator of kidney function, to approximate GFR) in the serum

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference in lithium levels between once and twice daily dosing	The average of the difference in 12 hour post-dose serum level between the two dosing regimens (once daily and twice daily dosing)	once 2 steady state levels have been taken (4-12 days of intervention)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation between renal function and difference in lithium level	Calculated correlation coefficient (r) for renal function (as estimated by calculation of creatinine clearance via Cockroft Gault) and mean percent change in serum lithium concentration when transitioning between once and twice daily dosing	once 2 steady state levels have been taken (4-12 days of intervention) and average creatinine clearance has been calculated
Frequency of selected concurrent medication use	Frequency of thiazide diuretic, loop diuretic, NSAID, and ACE inhibitor/ARB use	recorded upon enrollment, and every 4-6 days until study completion, up to 12 months

Collaborators and Investigators

• Sponsor: Mount Sinai Hospital, Canada

Study record dates

Study Major Dates

• Study Start (Actual): February 6, 2019
• Primary Completion (Anticipated): September 1, 2019
• Study Completion (Anticipated): December 1, 2019

Study Registration Dates

• First Submitted: January 10, 2019
• First Submitted That Met QC Criteria: January 18, 2019
• First Posted (Actual): January 22, 2019

Study Record Updates

• Last Update Posted (Actual): March 8, 2019
• Last Update Submitted That Met QC Criteria: March 6, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Keywords: renal; pharmacokinetics; lithium; kidney
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Mood Disorders; Bipolar and Related Disorders; Depressive Disorder; Disease; Bipolar Disorder; Depressive Disorder, Major; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Tranquilizing Agents; Psychotropic Drugs; Antidepressive Agents; Antimanic Agents; Lithium Carbonate
• Other Study ID Numbers: 18-0289-A

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: There is no such plan

Drug and device information, study documents

• 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