Pharmacokinetics of Quetiapine Across Pregnancy and Postpartum (Quetiapine)

The widespread and common use of quetiapine in childbearing and pregnant women demands more data to inform dosing and toxicity in pregnancy. The new FDA Pregnancy and Lactation Labeling Final Rule (PLLR) will go into effect on June 30th, 2015 and will replace the prior A, B, C, D, and X categories. Additionally, the PLLR will require information to aid prescribing decisions in three categories 1) Pregnancy (including labor and delivery), 2) Lactation, and 3) Females and Males of Reproductive Potential. The pregnancy category will include a subsection that will describe pharmacokinetic and pharmacodynamic characteristics of the medication in pregnancy, fetal risk, and data quality. The data collected in this study will update the FDA pregnancy pharmacokinetic section for quetiapine and inform physicians that prescribe to childbearing women.

Study Overview

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

Detailed Description

Bipolar Disorder (BD) and Schizophrenia (SCHZ) in pregnancy are associated with pregnancy complications and increased maternal mortality due to physiological and psychosocial changes independent of second-generation antipsychotic (SGA) use. Untreated BD and SCHZ have been associated with an increased risk of placental abnormalities, antepartum hemorrhage, preterm birth, pre-eclampsia, low birth-weight, intrauterine growth retardation, small for gestational age, fetal distress, neonatal hypoglycemia, stillbirth and congenital defects, and the potential for adverse neurodevelopmental outcomes. Severe maternal stress in pregnancy increases the risk for offspring mental disorders, and eye, ear, respiratory, digestive, skin, musculoskeletal, and genitourinary diseases and congenital malformations (i.e., cleft palate, cleft lip). Also, BD and SCHZ illness symptoms are linked to psychosocial consequences that result in poor perinatal outcomes including impulsivity that leads to reckless behavior such as increased indiscriminate sex and exposure to sexually transmitted infections, smoking, increased alcohol and drug use, less prenatal care, and poor nutrition. Furthermore, women with recurrence of mental illness in the perinatal period have increased risk for suicide, a leading cause of maternal death.

The only published case of quetiapine plasma concentrations in a pregnant woman included cross-sectional levels of a woman on 300 mg of quetiapine across pregnancy and postpartum. Compared to six months postpartum, the area under the curve decreased by 27%, 42%, and 18% in the first, second, and third trimester, respectively. Given the complexity of the metabolism of quetiapine to a very active metabolite, it is important to understand the altered metabolism of quetiapine and its active metabolite in pregnancy and the implication for dosing adjustments.

This study will investigate the longitudinal pharmacokinetics of quetiapine in pregnancy, delivery, and postpartum. The long-term goal of this line of research is to establish psychotropic medication dosing algorithms informed by longitudinal pharmacokinetic data to improve mental health and pregnancy outcomes for mothers with serious mental illness.

The primary aims are: 1) Determine the elimination clearance of quetiapine and its major active metabolite, 7-N-desalkyquetiapine, across pregnancy and postpartum; 2) Determine the effect of pharmacokinetic changes on symptoms and toxicity during pregnancy and postpartum, and; 3) Examine the maternal-to-cord plasma concentrations ratios of quetiapine and its major active metabolite, 7-N-desalkylquetiapine.

• Study Type: Observational
• Enrollment (Actual): 4

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

• Sampling Method: Non-Probability Sample

Study Population

Pregnant women taking quetiapine 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 18-45 years
• Pregnant, second trimester
• English-speaking
• DSM-V diagnosis of Bipolar Disorder or Schizophrenia, any subtype
• Medically healthy
• Singleton gestation

Exclusion Criteria:

• Chronic use of drugs for medical disorders, except thyroid replacement for stable hypothyroidism
• No psychiatrist or obstetrician
• QIDS-SR 16 positive answer 3 on item 12, "I have made specific plans for suicide or have actually tried to take my life" within the past week
• DSM-V diagnosis of substance abuse or dependence in last 6 months, with the exception of cannabis; positive urine drug screen

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Quetiapine; Patients taking quetiapine during pregnancy are eligible to participate in the study. Their dose and plasma concentration levels of quetiapine will be monitored throughout pregnancy and up to three months postpartum.	Drug: Quetiapine; Quetiapine concentrations will be observed in women who have already (under the guidance of a physician) decided to continue taking Quetiapine for the treatment of Bipolar Disorder (any subtype) or Schizophrenia during pregnancy.; Other Names: Seroquel

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in plasma concentration/elimination	For patients taking the immediate release formulation, plasma levels will be obtained beginning at time 0 and at hours, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16. For patients on the extended release formulation, plasma levels will be obtained at time 0 and at hours 0.5, 1, 1.5, 2, 2,5, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, and 24.	2 timepoints during pregnancy (second and third trimesters), and at four and twelve weeks postpartum

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Arterial and Venous Umbilical Cord Concentration of Quetiapine and 7-N-desalylquetiapine	Arterial and venous cord blood samples will be obtained immediately post-delivery and banked for later analysis	30 minutes
Cerebrospinal Fluid (CSF) Quetiapine and 7-N-desalkyquetiapine Concentrations		CSF to be obtained within 10 minutes of the epidural placement during labor
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 plasma levels. 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
Scores on anxiety scale, Generalized Anxiety Disorder (GAD-7)	To determine if there is a pattern of increasing scores on GAD-7 and declining plasma levels	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 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 plasma levels	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 Brief Psychosis Rating Scale (BPRS)	assessment to evaluate psychotic symptoms	Participants will complete these assessments an average of every 10 weeks from the time they enter the study, up to 12 weeks postpartum.
Positive responses on SAFTEE	surveys general and specific side effects including somatic, behavioral, and affective symptoms	Participants will complete these assessments an average of every 10 weeks from the time they enter the study, up to 12 weeks postpartum.
Delivery outcomes as determined by the Peripartum Events Scale (PES)	assessment to quantify stressful events related to delivery.	4 and 12 weeks postpartum
Scores on the separate domains of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health	Assesses patient perceptions in 5 domains:physical function, pain, emotional distress, social function, and fatigue.	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 Clak, MD, MSc, Northwestern University

Study record dates

Study Major Dates

• Study Start: March 1, 2016
• Primary Completion (Actual): August 1, 2020
• Study Completion (Actual): December 1, 2020

Study Registration Dates

• First Submitted: November 22, 2016
• First Submitted That Met QC Criteria: November 28, 2016
• First Posted (Estimate): December 1, 2016

Study Record Updates

• Last Update Posted (Actual): September 27, 2022
• Last Update Submitted That Met QC Criteria: September 26, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: quetiapine; postpartum; pregnant; female; women; bipolar; seroquel; perinatal; manic-depressive
• Additional Relevant MeSH Terms: Mental Disorders; Bipolar and Related Disorders; Bipolar Disorder; Physiological Effects of Drugs; Central Nervous System Depressants; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Antidepressive Agents; Quetiapine Fumarate
• Other Study ID Numbers: 00201540

Plan for Individual participant data (IPD)

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

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