The impact of pregnancy on the pharmacokinetics of antidepressants: a systematic critical review and meta-analysis

ABSTRACT

Introduction: Pregnancy-related physiological changes exert a crucial impact on the pharmacokinetics of antidepressants; however, the current evidence presents inconsistencies. A clearer understanding of pregnancy-related effects on antidepressant disposition may facilitate the development of guidelines for appropriate dose adjustments during the course of pregnancy based on therapeutic drug monitoring.

Areas covered: We systematically reviewed studies comparing antidepressant levels in the same individuals during pregnant and non-pregnant states. Using dose-adjusted plasma concentration measurements, we estimated alteration ratios between the 3rd trimester and baseline (before or after pregnancy). Additionally, we performed a meta-analysis for changes in dose-adjusted concentrations to estimate mean differences.

Expert opinion: Data for several antidepressants display clear alteration patterns during pregnancy. On the basis of the alteration ratios trimipramine, fluvoxamine, and nortriptyline show a prominent decrease in dose-adjusted levels, especially in the 3rd trimester. Clomipramine, imipramine, citalopram, and paroxetine show smaller decreases in dose-adjusted concentrations in the third trimester. For escitalopram, venlafaxine and fluoxetine, changes are considered negligible. For sertraline, there was a tendency toward increased dose-adjusted concentrations in pregnancy. Available evidence suffers from major limitations and factors affecting pharmacokinetics have been insufficiently addressed. Further research is required to promote knowledge on pregnancy effects on antidepressant pharmacokinetics.

KEYWORDS:

• Antidepressants
• citalopram
• fluoxetine
• gestation
• pharmacokinetics
• pregnancy
• sertraline
• therapeutic drug monitoring
• venlafaxine
• women’s mental health

Acknowledgements

Pregnancy-related changes in disposition of psychotropic agents has been the topic of the doctoral thesis of one of the co-authors (Dr. A. A. Westin). Authors wish to thank Dr. Peter G. J. ter Horst, Department of Clinical PharmacyDepartment of Clinical Pharmacy, Isala Clinics, Zwolle, The Netherlands and University Centre for Pharmacy, Unit of Pharmacotherapy and Pharmaceutical Care, University of Groningen, Groningen, The Netherlands as well as Dr. Katherine L. Wisner, Asher Center for the Study and Treatment of Depressive Disorders, Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois and Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA, who provided valuable information regarding their studies. Authors are also indebted to Dr. Salmaan Kanji, Department of Pharmacy, The Ottawa Hospital and Ottawa Hospital Research Institute, Ottawa, Canada for the support in the application of the ClinPK statement checklist.

Article highlights

• Pregnancy-related physiological changes exert a crucial impact on the pharmacokinetics of several antidepressants.

• Due to pharmacokinetic changes during pregnancy dose adjustment may be required for some drugs.

• Limited data imply drops in dose-adjusted maternal plasma levels by 50% or even more in the 3rd trimester for fluvoxamine, nortriptyline, and trimipramine.

• For other antidepressants, changes in plasma concentrations during pregnancy are less pronounced or even show the contrary which may be a risk of high drug exposure to the infant.

• More quantitative and qualitative evidence is required for the further understanding of the pregnancy impact on the pharmacokinetics of antidepressants.

• We recommend thorough clinical follow-up and the use of therapeutic drug monitoring for all patients treated with antidepressants during pregnancy.

Declaration of interest

M Paulzen has received speaker’s fee from Neuraxpharma, Langenfeld, Germany. KM Deligiannidis has received research grant support as a site for the clinical trials of brexanolone and zuranolone and serves as a consultant for Sage Therapeutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

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Funding

This paper was not funded.