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Clinical and pre-clinical investigation of sertraline use in pregnancy: bioavailability and risk to offspring
Phogole, C. M. 2025. Clinical and pre-clinical investigation of sertraline use in pregnancy: bioavailability and risk to offspring. Unpublished doctoral dissertation. Stellenbosch: Stellenbosch University [online]. Available: https://scholar.sun.ac.za/items/09f65288-4b2f-4c4a-96d2-c21eba79bef4
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Stellenbosch : Stellenbosch University
2025
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| access_status_str | Open Access |
| author | Phogole, Cassius Maapea |
| author2 | Kellermann, Tracy |
| author_browse | Kellermann, Tracy Phogole, Cassius Maapea |
| author_facet | Kellermann, Tracy Phogole, Cassius Maapea |
| author_sort | Phogole, Cassius Maapea |
| collection | Thesis |
| dc_rights_str_mv | Stellenbosch University |
| description | Phogole, C. M. 2025. Clinical and pre-clinical investigation of sertraline use in pregnancy: bioavailability and risk to offspring. Unpublished doctoral dissertation. Stellenbosch: Stellenbosch University [online]. Available: https://scholar.sun.ac.za/items/09f65288-4b2f-4c4a-96d2-c21eba79bef4 |
| format | Thesis |
| id | oai:scholar.sun.ac.za:10019.1/132504 |
| institution | Stellenbosch University (South Africa) |
| language | English |
| last_indexed | 2026-06-10T12:40:58.715Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from SUNScholar — Stellenbosch University Repository |
| publishDate | 2025 |
| publishDateRange | 2025 |
| publishDateSort | 2025 |
| publisher | Stellenbosch : Stellenbosch University |
| publisherStr | Stellenbosch : Stellenbosch University |
| record_format | dspace |
| source_str | SUNScholar — Stellenbosch University Repository |
| spelling | oai:scholar.sun.ac.za:10019.1/132504 Clinical and pre-clinical investigation of sertraline use in pregnancy: bioavailability and risk to offspring Phogole, Cassius Maapea Kellermann, Tracy Smith, Carine Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medicine. Division of Clinical Pharmacology. Pregnancy -- Psychological aspects Serotonin uptake inhibitors -- Side effects Sertraline -- Bioavailability UCTD Phogole, C. M. 2025. Clinical and pre-clinical investigation of sertraline use in pregnancy: bioavailability and risk to offspring. Unpublished doctoral dissertation. Stellenbosch: Stellenbosch University [online]. Available: https://scholar.sun.ac.za/items/09f65288-4b2f-4c4a-96d2-c21eba79bef4 Thesis (PhD)--Stellenbosch University, 2025. ENGLISH ABSTRACT: Globally, over 10% of pregnant women are estimated to experience depression. Gestational depression poses significant risks, including maternal suicidal behaviour, non-adherence to prenatal guidelines, and impulsivity, all of which can jeopardize the health of both mother and baby. Consequently, practitioners often prescribe antidepressants, as psychotherapy alone is deemed ineffective. Among these, selective serotonin reuptake inhibitors (SSRIs), particularly sertraline (SER), are commonly chosen due to their relatively favourable safety profile. However, emerging literature suggests a potential association between SSRI use during pregnancy and an increased risk of neurodevelopmental disorders and congenital defects in exposed offspring. Despite these concerns, the mechanisms by which SSRIs, particularly SER, exert their effects on foetal development remain poorly understood. This knowledge gap extends to the concentrations of SER and its active metabolite, desmethylsertraline (DES), to which the foetus is exposed. This study aimed to conduct clinical and preclinical investigations to evaluate placental transfer of SER and DES and assess their potential risks to developing offspring using larval zebrafish. To elucidate this, we developed and validated a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous quantification of SER and DES in human plasma, following regulatory guidelines. This method was successfully applied to clinical samples, analyzing SER and DES in maternal and umbilical cord plasma collected at delivery from 20 pregnant women treated with SER during gestation, to establish their placental transfer. Both analytes exhibited a one-third placental transfer relative to maternal plasma exposure. To further understand the effects of these analytes at the observed concentrations during developmental stages in offspring, umbilical cord plasma concentrations were translated into equivalent zebrafish doses for preclinical risk assessment studies. Since SSRIs target the serotonin transporter (SERT) to exert their therapeutic effects, we began by investigating the impact of early chronic exposure to these analytes on the serotonergic system of zebrafish. This was achieved by exposing zebrafish from embryonic to larval stages and subsequently quantifying SERT, serotonin (5-HT), and vesicular monoamine transporter-2 (VMAT-2), using immunofluorescence staining. Behavioural assessments were conducted using the light-dark transition test (LDTT). Both analytes resulted in an aberrant serotonergic system, as evidenced by elevated expression levels of 5-HT and VMAT-2, reduced expression of SERT, and alterations in normal behaviour. To obtain a holistic understanding of other affected pathways, a whole proteome analysis of treated larvae was conducted using label-free LC-MS, with protein interrogation performed against human databases given the high homology between these species. A total of 9/616 identified proteins were significantly downregulated in the DES-treated group, while no differentially regulated proteins were observed in the SER-treated group. DES specifically caused downregulation of proteins, including DDX39A (ATP-dependent RNA helicase), CLUH (clustered mitochondria protein homolog), HSPB1 (heat shock protein beta-1), MYL2 (myosin regulatory light chain 2), MATN1 (cartilage matrix protein), PHB1 (prohibitin 1), RPL30 (ribosomal protein L30), DRAP1 (Dr1-associated corepressor), and DHRS11 (dehydrogenase/reductase SDR family member 11). These proteins are integral to key biological pathways, including cardiovascular function, steroid biosynthesis, adherens junctions, and mitochondrial function. Moreover, these identified protein biomarkers in zebrafish model correlate directly with clinically reported congenital defects, particularly cardiac malformations, in offspring exposed to SSRIs during pregnancy. In conclusion, SER and DES demonstrated considerable placental transfer, with approximately 30% of maternal plasma exposure reaching the foetus, consistent with historical data. Both analytes caused dysfunction in the developing zebrafish serotonergic system and altered behaviours in standardized assays. Proteomic data implicate DES as the primary contributor to adverse clinical outcomes associated with gestational SSRI use. Although SER is known to exhibit linear pharmacokinetics, suggesting that dose reduction could effectively lower foetal exposure and minimize the risk of congenital defects, its variable plasma exposures during pregnancy pose challenges for optimizing dosing strategies. AFRIKAANSE OPSOMMING: Ongeveer 10% van swanger vroue wêreldwyd ervaar depressie. Depressie verwante gedragspatrone tydends swangerskap hou beduidende risiko in vir beide die moeder en die ongebore baba. Gevolglik word daar alleenlik antidepressante as spigoterapeutise behandelling vir swanger vroue voorgeskryf, wat oneffektief mag wees. Sertraline (SER), ‘n selektiewe serotonien heropname inhibeerder (SSRI), word gereeld voorgeskryf as gevolg van die se gunstige veiligheidsprofiel. Ontluikende literatuur stel voor dat daar ‘n potensiele verwantskap tussen SSRI gebruik tydens swangersakap en verhoogde risiko van neuroontwikkelingsafwykings asook ander aangebore afwykings mag wees na blootstelling aan die middels. Die meganismes verantvoordelik vir die negatiewe gevolge op fetaleontwikkeling volgende SSRI (spesifiek SER) gebruik word nog nie ten volle verstaan nie. Die onsekerheid van die konsentrasies SER en sy aktiewe metaboliet desmethysetraline (DES) waaraan die fetus blootgstel word maak deel uit van die huidige kennisleemtes wat oorbrug moet word. Hierdie studie was gerig daarop om deur middel van kliniese en pre-kliniese ondersoeke die plasenta-oordag van SER en DES te evalueer en verder die potensiele risikos wat SER en DES blootstelling vir die onwikkelende fetus inhou in sebravisse te onsoek. ‘n vloeistofchromatografie-tandem massaspektrometrie (LC-MS/MS) metode was ontwikkel en gevalideer (in gevolge regulasie riglyne) vir die gelyktydige kwantifiseeing van SER en DES in menslike plasma. Plasma monsters van 20 swanger vroue wat met SER behandel is tydens swangerskap is ten tyde die bevalling van beide die moeder en die naelstring geneem. Die voorafgenoemde metode was gebruik om die plasma te analiseer en die plastenta-oordrag van die middels te bepaal. Beide analiete het 'n een-derde plasenta-oordrag getoon relatief tot die moederplasma konsentrasies. Om die uitwerking van hierdie analiete op die ontwikkeling van die fetus beter te verstaan was die vasgestelde nealstringplasma konsentrasies herlei na ekwivalente sebravisdosisse vir ‘n prekliniese risikoassesseringsstudies. SSRI bring terapeutise effekte mee deur die serotonienvervoerder (SERT) te teiken. Om hierdie rede is die impak van vroeë chroniese blootstelling aan die analiete op die serotonergiese sisteem van sebravisse ondersoek. Dit is bewerkstellig deur sebrasvissies van embrioniese tot larwe ontwikkelingsfases aan die analiete bloot te stel en daarna met behulp van immuunfluoressensie tegnieke SERT, serotonien (5-HT), en vesikulêre monoamienvervoerder-2 (VMAT-2) te kwantifiseer. Gedragsassesserings is ook uitgevoer met behulp van die lig-donker oorgangstoets (LDTT). ‘n Toename in 5-HT en VMAT-2 uitdrukking, https://scholar.sun.ac.za ix afname in SERT uitdrukking, en veranderinge in normale gedragspatrone dui daarop dat beide die analiete moontlike afwykings in die serotonergiese stelsel meebring. Om afwykings in ander sisteme wat moontlik geaffekteer is in geheel beter verstaan is ‘n heel proteoom analiese op behandelde sebravislarwe uigevoer. Merker-vrye LC-MS was gebruik en proteïen-analise was met menslike databasisse vergelyk, gegewe die hoë homologie tussen hierdie spesies. 'n Totaal van 9/616 geïdentifiseerde proteïene was beduidend afgereguleer in die DES-behandelde groep, terwyl geen proteïene in die SER-behandelde groep afwykings in regulasie getoon het nie. DES het ‘n afname in protiene soos DDX39A (ATP-afhanklike RNA-helikase), CLUH (gebondelde mitochondria protien homoloog), HSPB1 (Heat shock protein beta-1), MYL2 (myosin regulatory light chain 2), MATN1 (cartilage matrix protein), PHB1 (prohibitin 1), RPL30 (ribosomal protein L30), DRAP1 (Dr1-associated corepressor), and DHRS11 (dehydrogenase/reductase SDR family member 11) veroorsaak. Hierdie protiene maak ‘n belangrike deel uit van ‘n versameling biologiese weë wat kardiovaskulêre funksie, steroid biosintese en mitochondriale funksie insluit. Die protienbiomerkers wat in die sebravis model geidentifiseer is stem ooreen met die aangebore defekte wat voorheen in die kliniese omgewing geraporteer is. Meer spesifiek verwys na kardiale misvorming nadat die ongebore fetus aan SSRIs blootgestel is. Ten slotte het SER en DES beduidende plasenta-oordrag getoon, met 30% van moederplasma-blootstelling wat die fetus bereik. Beide analiete het wanfunksie veroorsaak in die ontwikkelende serotonergiese stelsel van sebrasvislarwe en gedragsveranderinge in gestandaardiseerde toetse veroorsaak. Proteomiese data dui daarop dat DES verantwoordelik is vir nadelige kliniese uitkomste wat gerapporteer is ná die gebruik van SSRI’s tydens swangerskap. Doctoral 2025-06-10T08:17:07Z 2025-06-10T08:17:07Z 2025-03 Thesis https://scholar.sun.ac.za/handle/10019.1/132504 en Stellenbosch University xi, 137 pages : illustrations application/pdf Stellenbosch : Stellenbosch University |
| spellingShingle | Pregnancy -- Psychological aspects Serotonin uptake inhibitors -- Side effects Sertraline -- Bioavailability UCTD Phogole, Cassius Maapea Clinical and pre-clinical investigation of sertraline use in pregnancy: bioavailability and risk to offspring |
| title | Clinical and pre-clinical investigation of sertraline use in pregnancy: bioavailability and risk to offspring |
| title_full | Clinical and pre-clinical investigation of sertraline use in pregnancy: bioavailability and risk to offspring |
| title_fullStr | Clinical and pre-clinical investigation of sertraline use in pregnancy: bioavailability and risk to offspring |
| title_full_unstemmed | Clinical and pre-clinical investigation of sertraline use in pregnancy: bioavailability and risk to offspring |
| title_short | Clinical and pre-clinical investigation of sertraline use in pregnancy: bioavailability and risk to offspring |
| title_sort | clinical and pre clinical investigation of sertraline use in pregnancy bioavailability and risk to offspring |
| topic | Pregnancy -- Psychological aspects Serotonin uptake inhibitors -- Side effects Sertraline -- Bioavailability UCTD |
| url | https://scholar.sun.ac.za/handle/10019.1/132504 |
| work_keys_str_mv | AT phogolecassiusmaapea clinicalandpreclinicalinvestigationofsertralineuseinpregnancybioavailabilityandrisktooffspring |