Lithium Therapy: Understanding Mothers, Metabolism and Mood (LiThiUM)

Lithium, the gold standard for treatment of Bipolar Disorder (BD) and a common augmentation to medication therapy for Major Depression, is commonly continued in pregnancy due to its therapeutic benefit and more recent data that suggests the teratogenic effects of lithium are less than historically believed. Due to the increased elimination of lithium during pregnancy, lithium concentration decreases in the blood and women with BD are vulnerable to BD episode recurrence in pregnancy. Uncontrolled symptoms of BD in pregnancy increase the risk for postpartum exacerbation of BD and psychosis. Our study will investigate the pharmacokinetics (PK) of lithium prior to pregnancy, during pregnancy, and postpartum. Twenty women taking lithium in pregnancy or planning to become pregnant and continue lithium will be invited to participate in a study to measure repeated blood levels of lithium at six time points between preconception and 3 months postpartum. The data collected will inform the dose, timing of dose, and frequency of dosing of lithium that will lead to fewer untoward effects for the mother and baby. Change in elimination clearance of lithium will be correlated with symptom worsening to develop a dosing algorithm that will help maintain wellness for pregnant women with mood disorders.

Study Overview

• Status: Completed
• Conditions: Bipolar Disorder
• Intervention / Treatment: Drug: Lithium

Detailed Description

There is an increased risk of recurrence of Bipolar Disorder (BD) episodes or worsening symptoms in pregnancy after the discontinuation of mood stabilizers. Similarly, changes in medication concentration due to the physiological changes in pregnancy may effectively reduce the medication dose and thus its efficacy in pregnancy. Therapeutic dose monitoring has proven to have great utility in preventing seizure recurrence in women with epilepsy (WWE). Similar guidelines to that of women with epilepsy would benefit pregnant women with BD who are taking mood stabilizing medications in pregnancy. Current evidence suggests that lithium has a more favorable reproductive profile than many mood stabilizing antiepileptic agents. However, the pharmacokinetics as well as the utility of therapeutic dose monitoring of lithium in pregnant patients with Bipolar Disorder has not been well studied.

This study is an observational protocol to explore the longitudinal pharmacokinetics (PK) of lithium during pregnancy and postpartum in 20 women with Bipolar Disorder. The correlation between changes in bioavailability and concentrations ratios and increases in symptoms of depression, mania and anxiety and recurrence of syndromal BD episodes that fulfill Diagnostic and Statistics Manual of Mental Disorders (IV) (DSM4) criteria will be investigated.

The primary aims of this study are 1.) To describe the changes in lithium elimination and serum concentration across pregnancy and postpartum to establish its efficacious use and dosing requirements during childbearing 2.) To evaluate the associations between maternal and umbilical cord lithium serum levels. 3.) To explore the relationship between declining lithium serum concentrations during pregnancy and the increase in psychiatric symptoms and recurrence of syndromal BD.

To optimize the research yield from this investigation, participants will have the option to allow banking of cerebrospinal (CSF) fluid and DNA for future analyses.

• Study Type: Observational
• Enrollment (Actual): 9

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern Memorial Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 53 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

• Sampling Method: Non-Probability Sample

Study Population

Pre-conception planning and pregnant women taking lithium for the purpose of mood stabilizing will be recruited broadly from Northwestern clinical services, including Internal Medicine, OB/GYN, Family Medicine, and Psychiatry, registries, and from the local Chicagoland community. Patients that sign consent, complete the evaluation and meet criteria will be enrolled into the study.

Description

Inclusion Criteria:

• Age 18 or older
• If Pregnant, equal to or less than 26 weeks
• English-speaking
• DSM-IV Bipolar Disorder, any subtype, Major Depressive Disorder, or Mood Disorder Not Otherwise Specified
• Able to provide informed consent
• Daily dosing of lithium

Exclusion Criteria:

• Active substance abuse within last 6 months and/or positive urine drug screen
• Active suicidality
• No obstetrical care
• Use of other drugs that affect metabolism of lithium
• Medications in FDA categories F or X that are not antimanic drugs
• Chronic Kidney Disease

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Serum concentration/elimination	For patients on 1x day dosing, serum levels will be obtained beginning at time 0 and at hours, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24 and L/D ratio will be determined at each time point. This series of serum levels will be completed an average of every 10 weeks across pregnancy, and postpartum. For patients on 2x dosing, serum levels will be obtained at time 0 and at hours 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12. All urine excreted during participant's overnight research visits will be collected to perform lithium and creatinine clearance tests.	An average of every 10 weeks, beginning at the preconception visit where a baseline concentration level will be established, at 3 timepoints throughout pregnancy, and at two and twelve weeks postpartum

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Scores on mania assessment, Young Mania Reporting Scale (YMRS)	To determine if there is a pattern of increasing scores on clinician administered mania assessment (YMRS) and declining L/D ratios.	Participants will complete these assessments an average of every 10 weeks from the time they enter the study, up to 12 weeks postpartum.
Scores on anxiety scale, Generalized Anxiety Disorder (GAD-7)		Participants will complete these assessments an average of every 10 weeks from the time they enter the study, up to 12 weeks postpartum.
Infant (umbilical cord)/Maternal ratio of lithium	Ratio of umbilical cord (infant) lithium serum level to maternal lithium serum level will be determined at delivery.	30 min
Scores on Depression assessment, Inventory of Depression Symptomatology- Self Report (IDS-SR)	To determine if there is a pattern of increasing scores on self-report depression assessment (IDS-SR) and declining L/D ratios. Increasing scores indicate worsening symptoms or depression episode recurrence.	Participants will complete these assessments an average of every 10 weeks from the time they enter the study, up to 12 weeks postpartum

Collaborators and Investigators

• Sponsor: Northwestern University
• Investigators: Principal Investigator: Crystal T Clark, MD, MSc, Northwestern University

Study record dates

Study Major Dates

• Study Start: April 1, 2015
• Primary Completion (Actual): December 1, 2019
• Study Completion (Actual): June 1, 2020

Study Registration Dates

• First Submitted: May 26, 2015
• First Submitted That Met QC Criteria: July 1, 2015
• First Posted (Estimate): July 3, 2015

Study Record Updates

• Last Update Posted (Actual): October 5, 2022
• Last Update Submitted That Met QC Criteria: October 3, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: lithium; pregnant; female; women; bipolar
• Additional Relevant MeSH Terms: Mental Disorders; Bipolar and Related Disorders; Bipolar Disorder; 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: 00200026

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No