Quality of Lactation Studies Investigating Antidepressants Daphne den Besten-Bertholee, Douwe Hedzer van der Meer, and Peter Gerrit Johannes ter Horst Abstract Introduction: The aim of this study was to determine the quality of lactation studies investigating antide- pressants in breast milk according to the Food and Drug Administration (FDA) draft guidelines and the article of Begg, published in the official journal of the International Lactation Consultant Association (ILCA). Materials and Methods: We used PubMed and LactMed Ò for the literature search. Furthermore, cross refer- ences were searched for additional studies. Results: A total number of 60 articles were included for review. For selective serotonin reuptake inhibitors and venlafaxine, only two studies correctly assessed the absolute infant dose and milk to plasma ratio; one sertraline and one fluoxetine study. Of all tricyclic antidepressants, one study for amitriptyline and one for nortriptyline assessed these endpoints correctly. We found a lack of information on breast milk sampling methods in many studies. Concentrations needed for the calculations were based on single measurements instead of at least five measurements during one dose interval, and the relative infant dose was not normalized by maternal weight, or an average maternal weight of 70 kg was used as a standard. Discussion: We conclude that the quality of the current literature on this topic does not meet the standards of the FDA. Studies of higher quality are needed to determine the extent of drug transfer to breast milk for antidepressants, so an adequate recommendation about use of these drugs during lactation can be given. Keywords: antidepressants, lactation, pharmacokinetics, review Introduction T he percentage of mothers who breastfeed their child has increased the last years up to 75%. 1 Human milk provides essential nutrients for the infant and provides health benefits for both mother and child. Breast milk increases the mother–child bonding, strengthens the immune system and stimulates the gastrointestinal function of the newborn. 2,3 Because of these health benefits and the low costs of breastfeeding, the World Health Organization recommends exclusive breastfeeding during the first 6 months of life and up to 2 years as supplement. 4 The prevalence of depression is 10–15% in pregnant women, 5–7 5–29% in the postpartum period, 8–10 and 2.9–5.5% of nursing mothers use antidepressants. 11,12 Reported side ef- fects in the neonate due to possible exposure of antidepressant medication through breast milk are somnolence, lethargy, fe- ver, reduced postnatal growth, and excessive infant crying. 13–15 On the contrary, discontinuing antidepressants during breast- feeding, which seems to overcome adverse drug reactions in the suckling infant, may lead to bonding problems, adverse child development, excessive infant crying, and a possible relapse of maternal depression. 16,17 Investigating the risks of anti- depressant use while breastfeeding is difficult because it is unethical to conduct randomized, placebo-controlled, double- blind trials in pregnant and lactating women treated with an- tidepressants. The guidelines of the Food and Drug Administration (FDA) and the European Medicine Agency (EMA), intro- duced four major elements for risk assessment of using medication during breastfeeding, which consist of the esti- mated infant dose, the infant plasma concentration, the ob- served adverse effects of the infant, and the follow-up of breast-fed infants. 18,19 This review will focus on the first el- ement, the estimated infant dose. Therefore, we use the ar- ticle of Begg et al., 20 published in the official journal of the International Lactation Consultant Association (ILCA) and also the FDA guidelines as we did in our previous studies on anticonvulsants, 21 antipsychotics, 22 and antibiotics. 23 To assess the safety of antidepressants, it is of great im- portance to distinguish between direct pharmacological ef- fects of antidepressants and possible developmental disorders in the suckling infants because of the psychiatric condition of the mother. Therefore, it is highly important to assess the infant dose of antidepressants in breast milk. Both FDA guidelines and the article of Begg state which parameters Department of Clinical Pharmacy, Isala, Zwolle, the Netherlands. BREASTFEEDING MEDICINE Volume XX, Number XX, 2019 ª Mary Ann Liebert, Inc. DOI: 10.1089/bfm.2019.0021 1 Downloaded by University of Groningen Netherlands from www.liebertpub.com at 04/26/19. For personal use only.