Practical Implications for Treating Women with Bipolar Disorder, Depression Across Pregnancy

In part 2 of this podcast series, Dorothy Sit, MD shares her current research on obstetrical and psychiatric care drug concentrations, in addition to the practical implications of her findings for clinicians treating patients with bipolar disorder.

Dr Sit discusses her research examining the changes in antidepressant concentrations throughout pregnancy, and future avenues for related studies.

Listen to part 1 of this series here.

Read the Transcript:

Dr Sit: The other component of the work I've done in my research career involves a focus on the phenomenology, pathophysiology, and pharmacological responses in women across their life cycle. Some of the work that I have done have encompassed studies that examined the changes in antidepressant concentrations across pregnancy.

What these studies have accomplished is to illustrate the mean drug concentration to dose ratios. So, the drug concentration's control for dose for the common antidepressants used for the treatment of depression and anxiety that include fluoxetine, sertraline, citalopram, and escitalopram.

The concentration or the drug concentration-to-dose ratios for these drugs seem to decrease in the second and third trimesters of pregnancy. It's presumably from the changes in induction of hepatic metabolism.

When we looked at pregnant women treated with citalopram, the parent drug and its metabolite, the drug concentration decreased substantially. In fact, looking at the ratios first of sertraline in the earlier publications, the concentrations of sertraline decreased by an average of 60% between 20 weeks of pregnancy and delivery.

By 4 to 6 weeks postpartum, the ratios of sertraline were similar to that in early pregnancy. When we looked at fluoxetine, the mean ratios of the parent drug to the metabolite—the parent drug, meaning fluoxetine, and the metabolite, norfluoxetine—concentrations decreased across pregnancy.

In fact, there was a negative relationship or a negative association between the depression scores and the dose-corrected concentrations, meaning that as the scores were higher, the concentrations on corrected for dose were lower.

Thirdly, pregnant women treated with citalopram or escitalopram, the drugs and the metabolite concentrations decreased between 20 weeks gestation and delivery and returned to baseline by the 12th week postpartum.

What these studies illustrate is that the concentration-to-dose ratios for these drugs—sertraline, fluoxetine, and citalopram or escitalopram—would decrease in the second half of pregnancy and the third trimester presumably due to an increased hepatic metabolism.

What this translates to in clinical care is that we need to monitor the dosing and the treatment's response very carefully in pregnancy and postpartum and be aware that when mood symptoms start to increase and depression scores increase, it may be a time to up the dose and increase the dose of antidepressant treatment to compensate for the reduction in this concentration-to-dose ratio that we were seeing in these earlier studies.

That has also translated into upcoming and ongoing studies that are building on these earlier findings. From our group, we have investigators that include my mentor, Dr. Katherine Wisner, Northwestern University Feinberg School of Medicine, Chicago, Illinois our colleagues, Dr. Catherine Stika, State University of New York, Syracuse, and Dr. Alfred George, Northwestern University Feinberg School of Medicine.

Together, they are conducting a National Institutes of Health, Bethesda, Maryland, sponsored study, sponsored by the National Institute of Child Health and Human Development, Bethesda, Maryland, and the Obstetric-Fetal Pharmacology Research Center, Galveston, Texas, to examine optimal medication management of mothers with depression. This is also known as the OptiMUM study.

In this study, they're examining data, collecting data that can be used to construct a guideline for optimal antidepressant drug dosing across pregnancy and postpartum to reduce disease burden and minimize adverse effects looking at these specific drugs.

In future studies, exploring the possibility of developing a center of excellence through the p50 structure to examine more carefully and to map the activities of the cytochrome hepatic enzymes throughout childbearing, with a particular careful attention at examining the progressive changes in drug and metabolite concentrations across pregnancy in the first 3 to 6 months after birth.

To determine, longitudinally, the monthly concentrations of drugs that should be used in obstetrical and psychiatric care, particularly with respect to the antidepressant drugs.

What are some of the practical implications from our findings for clinicians who are treating patients with bipolar disorder? The important several implications with bipolar disorder, just being aware that patients may be experiencing depression in a vast majority of the mood episodes that they're having.

They can present as purely major depressive episodes with bipolar disorder or mixed episodes, so a mixture of depression, but also hypomanic and manic symptoms.

Knowing this, because bright light therapy is primarily an antidepressant response and there's no indication that it produces a mood-stabilizing effect, it will be important for patients and their clinicians to be aware that they should be optimally treated with their antimanic drug therapy before adding in an antidepressant somatic therapy such as bright light or antidepressant drug. Ensuring that the mixed symptoms and the hypomanic residual symptoms are under good control before adding bright light.

In the study, exclusion criteria included patients who had any form of hypomania who are not maintained on a proper antimanic treatment, other patients who had any type of psychotic features.

Keep in mind that this is a study that recruited patients who have purely bipolar depression. Also know that with this approach, we introduce midday light as a safer option. We will discuss a little bit more about ways to manipulate the dose, the timing, and other aspects of the dosing of light therapy to improve outcome.

The understanding is that light therapy is primarily affected through the circadian system. However, we do not have sufficient data to support that we are making changes or producing changes in the circadian rhythms of patients who are receiving light therapy.

Even so, it may provide a benefit to improve the sleep phase, possibly the consolidation sleep quality.

The other aspect to this is that we still need replication data, particularly for our study. This is the one clinical trial conducted on midday light for this type of patient population. We definitely need replication studies.

We'll talk about what other groups have found and compare their outcomes to provide a more balanced understanding of the outcomes to expect and also the possible avenues for future research related to what we discovered.

Dorothy Sit, MD, received her medical degree at the University of Toronto, School of Medicine, Canada. She completed residencies in family medicine and general psychiatry, and a fellowship in psychopharmacology. Dr. Sit is an associate professor at Northwestern University, Feinberg School of Medicine, Chicago, Illinois. She provides clinical care and training of residents, fellows, and medical students at the Asher Center for the Research and Treatment of Depressive Disorders, Chicago, Illinois. Dr. Sit studies the phenomenology, pathophysiology, and pharmacologic responses of women across the lifespan, especially in the perinatal period. She investigates novel somatic therapies including bright light therapy for patients with bipolar illness, epilepsy, and complex mood disorders.