Antidepressants During Pregnancy and Lactation: Pharmacokinetics and Clinical Implications

NCT01796132 | Unknown Phase 4

• 3 other identifiers: SSRI-Milk320030_1356502012-004509-29
• Study Type: interventional
• Target: 500
• Locations: 2 countries
• Sites: 5

Brief Summary

Background: The childbearing years are a time of increased vulnerability to the onset of mood disorders in women and a high prevalence of exposure to antidepressant drugs during pregnancy and postpartum has been reported. However, the lack of information regarding the milk transfer and the safety of these drugs in breastfed infants and the related fear of adverse events for the sucking infant are some of the factors responsible for stopping prematurely breast-feeding or avoiding drug therapy. Selective serotonin reuptake inhibitors (SSRI) and selective serotonin and noradrenaline reuptake inhibitors (SNRI) are the most frequently prescribed antidepressant drugs during pregnancy and the post-partum period. They exhibit a wide interpatient variability in their concentration profiles that has been related to numerous environmental, stereochemical, demographic and genetic influences that might alter the level of exposure of breastfed newborns. Limited information is available regarding the safety of use of these antidepressant drugs during lactation, and is generally derived from small studies. A comprehensive description of their distribution and quantification in milk in a larger cohort of patients under various influences and the resulting impact on milk concentrations is lacking. Objectives: The current proposal addresses the primary objectives of quantifying the range of concentration to citalopram, escitalopram, sertraline, fluoxetine, paroxetine, fluvoxamine, duloxetine and venlafaxine in mother plasma and breast milk in relation to genetic polymorphisms, stereochemistry, demographics and environmental factors in a large cohort of depressive mothers. This will enable to derive the exposure to the breast-fed child taking into account this variability and therefore better adjust treatment to potential influences. As secondary objectives, we will examine the neurodevelopmental outcome of a sub-set of infants subjected to SSRI/SNRI in utero and/or during breastfeeding at birth, 6, 18 and 36 months, and compared to that of a control population of infants not subjected to this treatment. Expected Results: The proposed strategy will offer new information regarding the expected level of drug exposure associated with each or with a combination of risk factors and help for optimizing the security and rationalizing the use of antidepressant treatment in lactating women. Hence, research on the safety of use of these drugs for the developing child is an area of great public health significance.

Conditions

Depressive Disorder; Lactation

Keywords

Depression; Lactation; Breastfeeding; Pharmacokinetics; Antidepressant

Outcome Measures

Primary Outcomes (1)

• Evaluate the pharmacokinetics of SSRI/SNRI antidepressant drugs in breast milk secretion

  The principal aim is to derive exposure to the breast-fed child by simulation while integrating influencing factors on pharmacokinetics (as genetic polymorphism, stereochemistry, demographics or environmental aspects). 5ml blood, 10ml fore-milk and 10ml hind-milk are taken from the mother during the same feed at week 1 and week 4-6 postpartum. Antidepressant drug concentrations are determined by LC-MS/MS and milk composition by human milk analyzer.Pharmacogenetic tests are performed with PCR-Taqman on maternal blood samples and cover genes involved in the metabolism (e.g CYP) and distribution (e.g. p-Gp) of antidepressants. Simulation of antidepressant drug secretion into breast milk will take into account all this information and will be performed with non-linear mixed effects modelling techniques.

  week 1 and week 4-6 postpartum

Secondary Outcomes (4)

• Examine neonatal adaptation

  delivery and week 1 postpartum

• Examine neurodevelopment

  week 1, month 6, 18 and 36 postpartum

• Study of growth

  birth, month 6, 18 and 36 postpartum

• Examine early mother-infant relationship

  Month 6 postpartum

Study Arms (2)

Control

NO INTERVENTION

Pregnant and/or nursing mothers not taking a SSRI or SNRI antidepressant are recruited in a non-exposed group (Control or no SSRI/SNRI). Control group participates only in the sub-studies related to neonatal adaptation, neurodevelopment, growth and early mother-infant relationship.

SSRI/SNRI exposure

EXPERIMENTAL

Pregnant and/or nursing mothers under SSRI or SNRI treatment are recruited in an exposed group (SSRI/SNRI exposure). Drug regimen including dosage, frequency and duration is not modified by the study.

Drug: SSRI/SNRI

Interventions

SSRI/SNRI DRUG

Exposed group of mothers taking one of the mentioned antidepressant drugs of the class of selective serotonin reuptake inhibitors (SSRI) or serotonin/noradrenalin reuptake inhibitors (SNRI).

Also known as: citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine

SSRI/SNRI exposure

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients planning to deliver in the 5 maternities involved in the study;
• Mothers under treatment by any SSRI/SNRI (fluvoxamine, fluoxetine, paroxetine, duloxetine, citalopram, escitalopram, sertraline or venlafaxine);
• Mothers who intent to breastfeed their child;
• Ability to understand and willingness to sign a written informed consent document for plasma and milk withdrawal and pharmacogenetic testing.
• For the neurodevelopment follow-up part,all babies of the Maternity of Lausanne, Morges or Geneva exposed to SSRI/SNRI will be enrolled. A control group of infants of the same socio-economic status as the subset of exposed patients will be recruited in the Maternity Hospital of Lausanne.

You may not qualify if:

• Mothers \<18 years of age patients;
• Infants of gestational age \< 34 weeks;
• Mothers giving birth to infants with major malformations;
• Inability to communicate due to language problems for the mother;
• Patients with a socio-economic context making close monitoring of the child by the mother or a relative not possible.

Sponsors & Collaborators

• Centre Hospitalier Universitaire Vaudois: lead
• University Hospital, Geneva: collaborator
• Hospices Civils de Lyon: collaborator
• Central Hospital, Nancy, France: collaborator

Study Sites (5)

Service d'Obstétrique, Service de Néonatologie; Centre Hospitalier Universitaire Nancy

Nancy, Meurthe-et-Moselle, France

RECRUITING

Service d'Obstétrique, Service de Néonatologie; Hospices civiles de Lyon (HCL)

Lyon, Rhône, France

RECRUITING

Service d'Obstétrique, Service du Développement et de la Croissance; Hopitaux Universitaires Genevois (HUG)

Geneva, Canton of Geneva, Switzerland

RECRUITING

Division de Pharmacologie Clinique, Service d'Obstétrique, Service de Néonatologie, Service de Pédopsychiatrie de liaison, Unité de Pharmacogénétique et Psychopharmacologie Clinique; Centre Hospitalier Universitaire Vaudois (CHUV)

Lausanne, Canton of Vaud, Switzerland

RECRUITING

Service d'Obstétrique, Service de Pédiatrie; Ensemble Hospitalier de la Côte (EHC)

Morges, Canton of Vaud, Switzerland

RECRUITING

Related Publications (12)

• McNamara PJ, Abbassi M. Neonatal exposure to drugs in breast milk. Pharm Res. 2004 Apr;21(4):555-66. doi: 10.1023/b:pham.0000022401.14710.c5.

  PMID: 15139511 BACKGROUND

• Goldman AS, Hopkinson JM, Rassin DK. Benefits and risks of breastfeeding. Adv Pediatr. 2007;54:275-304. doi: 10.1016/j.yapd.2007.03.014.

  PMID: 17918475 BACKGROUND

• Marcus SM, Flynn HA, Blow FC, Barry KL. Depressive symptoms among pregnant women screened in obstetrics settings. J Womens Health (Larchmt). 2003 May;12(4):373-80. doi: 10.1089/154099903765448880.

  PMID: 12804344 BACKGROUND

• Bennett HA, Einarson A, Taddio A, Koren G, Einarson TR. Prevalence of depression during pregnancy: systematic review. Obstet Gynecol. 2004 Apr;103(4):698-709. doi: 10.1097/01.AOG.0000116689.75396.5f.

  PMID: 15051562 BACKGROUND

• Poobalan AS, Aucott LS, Ross L, Smith WC, Helms PJ, Williams JH. Effects of treating postnatal depression on mother-infant interaction and child development: systematic review. Br J Psychiatry. 2007 Nov;191:378-86. doi: 10.1192/bjp.bp.106.032789.

  PMID: 17978316 BACKGROUND

• di Scalea TL, Wisner KL. Pharmacotherapy of postpartum depression. Expert Opin Pharmacother. 2009 Nov;10(16):2593-607. doi: 10.1517/14656560903277202.

  PMID: 19874247 BACKGROUND

• Sie SD, Wennink JM, van Driel JJ, te Winkel AG, Boer K, Casteelen G, van Weissenbruch MM. Maternal use of SSRIs, SNRIs and NaSSAs: practical recommendations during pregnancy and lactation. Arch Dis Child Fetal Neonatal Ed. 2012 Nov;97(6):F472-6. doi: 10.1136/archdischild-2011-214239.

  PMID: 23080479 BACKGROUND

• Horstmann S, Binder EB. Pharmacogenomics of antidepressant drugs. Pharmacol Ther. 2009 Oct;124(1):57-73. doi: 10.1016/j.pharmthera.2009.06.007. Epub 2009 Jun 27.

  PMID: 19563827 BACKGROUND

• Baumann P, Eap CB. Enantiomeric antidepressant drugs should be considered on individual merit. Hum Psychopharmacol. 2001 Dec;16(S2):S85-S92. doi: 10.1002/hup.336.

  PMID: 12404713 BACKGROUND

• Panchaud A, Garcia-Bournissen F, Csajka C, Kristensen JH, Taddio A, Ilett KF, Begg EJ, Ito S. Prediction of infant drug exposure through breastfeeding: population PK modeling and simulation of fluoxetine exposure. Clin Pharmacol Ther. 2011 Jun;89(6):830-6. doi: 10.1038/clpt.2011.23. Epub 2011 Apr 27.

  PMID: 21525869 BACKGROUND

• Lobo ED, Quinlan T, O'Brien L, Knadler MP, Heathman M. Population pharmacokinetics of orally administered duloxetine in patients: implications for dosing recommendation. Clin Pharmacokinet. 2009;48(3):189-97. doi: 10.2165/00003088-200948030-00005.

  PMID: 19385712 BACKGROUND

• Weisskopf E, Guidi M, Fischer CJ, Bickle Graz M, Beaufils E, Nguyen KA, Morisod Harari M, Rouiller S, Rothenburger S, Gaucherand P, Kassai-Koupai B, Borradori Tolsa C, Epiney M, Tolsa JF, Vial Y, Hascoet JM, Claris O, Eap CB, Panchaud A, Csajka C. A population pharmacokinetic model for escitalopram and its major metabolite in depressive patients during the perinatal period: Prediction of infant drug exposure through breast milk. Br J Clin Pharmacol. 2020 Aug;86(8):1642-1653. doi: 10.1111/bcp.14278. Epub 2020 Apr 14.

  PMID: 32162723 DERIVED

MeSH Terms

Conditions

Depressive Disorder; Breast Feeding; Depression

Interventions

Citalopram; Duloxetine Hydrochloride; Escitalopram; Fluoxetine; Fluvoxamine; Paroxetine; Sertraline; Venlafaxine Hydrochloride

Condition Hierarchy (Ancestors)

Mood Disorders; Mental Disorders; Feeding Behavior; Behavior; Behavioral Symptoms

Intervention Hierarchy (Ancestors)

Propylamines; Amines; Organic Chemicals; Nitriles; Benzofurans; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Thiophenes; Sulfur Compounds; Heterocyclic Compounds, 1-Ring; Oximes; Hydroxylamines; Piperidines; 1-Naphthylamine; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds; Cyclohexanols; Hexanols; Fatty Alcohols; Alcohols; Phenethylamines; Ethylamines; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Lipids

Study Officials

• Chantal Csajka, Prof PhD

  Centre Hospitalier Universitaire Vaudois (CHUV)

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Chantal Csajka, Prof PhD

CONTACT

0041 21 314 42 63; chantal.csajka@chuv.ch

Alice Panchaud, PhD

CONTACT

0041 21 314 42 76; alice.panchaud@chuv.ch

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NON RANDOMIZED
• Masking: NONE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof PhD

Study Record Dates

• First Submitted: February 4, 2013
• First Posted: February 21, 2013
• Study Start: August 1, 2012
• Primary Completion: December 1, 2016
• Study Completion: December 1, 2018
• Last Updated: July 28, 2015

Record last verified: 2015-07

Locations

CH (3); FR (2)