Article

Neurodevelopmental effects of prenatal exposure to psychotropic medications

Department of Mental Health, ASL "Salerno", Mental Health Center, Cava de' Tirreni, Salerno, Italy.
Depression and Anxiety (Impact Factor: 4.29). 07/2010; 27(7):675-86. DOI: 10.1002/da.20706
Source: PubMed

ABSTRACT Until now, studies on the reproductive safety of psychotropics have typically assessed the risk of congenital malformations and perinatal complications associated with in utero exposure to such medications. However, little is known of their inherent potential neurobehavioral teratogenicity. The objective is to analyze available data from studies investigating developmental outcome of children exposed prenatally to psychotropics. A computerized Medline/PubMed/TOXNET/ENBASE search (1960-2010) was conducted using the following keywords: pregnancy, child/infant development/neurodevelopment, antidepressants, benzodiazepines, mood stabilizers, and antipsychotics. A separate search was also run to complete the safety profile of single specific medications. Resultant articles were cross-referenced for other relevant articles not identified in the initial search. A noncomputerized review of pertinent journals and textbooks was also performed. All studies published in English and reporting primary data on the developmental outcome of infants exposed in utero to psychotropics and born without malformations were collected. As regards antiepileptic drugs, only studies that provided data on specific medications approved for psychiatric practice use (carbamazepine, lamotrigine, and valproate) were considered. Data were extracted from 41 articles (38 identified electronically and 3 nonelectronically), which met the inclusion criteria. Despite reviewed studies showing relevant methodological limitations, concordant, albeit preliminary, information seems to exclude that prenatal exposure to both selective serotonin reuptake inhibitors and tricyclic antidepressants may interfere with the infants' psychological and cognitive development. Conversely, information on valproate strongly discourages its use in pregnant women. Moreover, although data on carbamazepine remain controversial, information on whole classes of drugs and single medications is either absent (second-generation antipsychotics) or too limited (first-generation antipsychotics, benzodiazepines, lithium, and lamotrigine) to inform the decision-making process. For all classes of psychotropics, new and/or further studies are warranted to answer definitively the urgent question about the impact of prenatal exposure to such medications on infant development.

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Available from: Salvatore Gentile, Aug 04, 2014
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    • "Administration of psychotropic drugs during pregnancy requires great caution and benefits must be weighed against potential risks, especially in the first trimester (Stewart and Erlick Robinson 2001). Although evidence for psychotropic medication teratogenicity is generally lacking or limited (Gentile 2010), mood stabilizers such as lithium and valproate are strongly discouraged (Berle and Spigset 2003; Gentile 2010) and carbamazapine controversial (Gentile 2010; Stewart and Erlick Robinson 2001). As for antidepressants, a recent population-based cohort study data from the Danish Fertility Database has found no associated risk with use of SSRIs during pregnancy (Jimenez-Solem et al. 2013). "
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    ABSTRACT: This study aims to explore practice, use, and risk of electroconvulsive therapy (ECT) in pregnancy. A systematic search was undertaken in the databases Medline, Embase, PsycINFO, SveMed and CINAHL (EBSCO). Only primary data-based studies reporting ECT undertaken during pregnancy were included. Two reviewers independently checked study titles and abstracts according to inclusion criteria and extracted detailed use, practice, and adverse effects data from full text retrieved articles. Studies and extracted data were sorted according to before and after year 1970, due to changes in ECT administration over time. A total of 67 case reports were included and studies from all continents represented. Altogether, 169 pregnant women were identified, treated during pregnancy with a mean number of 9.4 ECTs, at mean age of 29 years. Most women received ECT during the 2nd trimester and many were Para I. Main diagnostic indication in years 1970 to 2013 was Depression/Bipolar disorder (including psychotic depression). Missing data on fetus/child was 12 %. ECT parameter report was often sparse. Both bilateral and unilateral electrode placement was used and thiopental was the main anesthetic agent. Adverse events such as fetal heart rate reduction, uterine contractions, and premature labor (born between 29 and 37 gestation weeks) were reported for nearly one third (29 %). The overall child mortality rate was 7.1 %. Lethal outcomes for the fetus and/or baby had diverse associations. ECT during pregnancy is advised considered only as last resort treatment under very stringent diagnostic and clinical indications. Updated international guidelines are urgently needed.
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    • "In a population-based cohort study in Netherlands, the exposure rate to SSRIs increased from 12.2 to 28.5 pregnancies per 1000 in 8 years (Bakker et al., 2008). Safety concerns are continually being expressed regarding the use of SSRIs, serotonin–norepinephrine reuptake inhibitors (SNRIs), antiepileptic drugs, mood stabilizers , benzodiazepines, and antipsychotics during pregnancy (Way, 2007; Gentile and Bellantuono, 2009; Sackett et al., 2009; Tuccori et al., 2009; Gentile, 2010). "
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    ABSTRACT: This study explored the affect expression and self-regulation capacities of 8-month-old infants exposed in utero to psychotropic medications. This was a continuation of our previous study conducted on the same cohort when the infants were 3 months old. Psychotropics implicated included selective serotonin reuptake inhibitors (SSRIs), and a benzodiazepine derivative anxiolytic (clonazepam). The three comparison groups were: control (n = 23; infants not exposed to psychotropics in utero), SSRI-alone (n = 22; infants exposed to SSRIs only and having mothers who had a primary diagnosis of depressive disorder without having comorbid anxiety disorder), and SSRI+ group (n = 15; infants gestationally exposed to SSRIs and clonazepam and having mothers that had both clinical depression and anxiety disorder). Using the Parent-Child Early Relational Assessment Scale, infants were assessed in a dyadic context during free play and a structured task. There were significant differences in psychotropic exposed and non-exposed dyads regarding infant negative affect management. There were significant associations between the SSRI+ group of mothers and infant negative affect. This group of mothers also showed significant associations with infants' averting and avoiding behaviors in both play situations. The SSRI-alone group was similar to the control group and showed variable associations with infant's positive, negative, and sober moods unlike the SSRI+ group. There were no differences in infants' capacity for self-regulation in psychotropic exposed and non-exposed groups. Increased awareness of these vulnerable subgroups (SSRI-alone and SSRI+) is needed, in order to safeguard these dyads through better support systems and improved management.
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    • "Giventhatmanyearly-onsetneuropsychiatricdisor- dersareetiologicallyheterogeneousandinvolve multiplesusceptibilitygenes,havingmodelsystems thattargetspecificneuronsorbraincircuitsmaybe invaluable(Arenkieletal.,2007;Thompson&Levitt, 2010;Zhangetal.,2010).Inthiscontext,theuseof advancedgenomictechnologiesandnovelcomputa- tionalapproacheshasbeguntoyielddividendsin definingthegeneticmechanismsatworkwithinspe- cificbrainregionsduringparticulardevelopmental periods(Bill&Geschwind,2009;Johnsonetal., 2009). AndersenandNavaltacontinuethefocusonani- malmodelsastheyexploretheirhopethatagreater understandingofneurodevelopmentwillleadto improvedtreatmentoptionsandthepossibilitythat earlypharmacologicalinterventionsmaybeusedto preventtheemergenceoffullsyndromes.Whilewe sharetheiroptimism,thiswillbeachallenge.Timely interventionswillrequireidentifyingindividualswho areinaprodromalstate,i.e.,anearly,nonspecific setofsymptomsthatindicatetheonsetofdisease beforespecific,diagnosablesymptomsoccur.Butas reviewedinthe2010AnnualResearchReview,in ordertoidentifyaprodromewewillneedtohavean accurateunderstandingofdevelopmentalpatho- physiologyunderlyingspecificdisorders(Costello& Angold,2010;Leckman&Yazgan,2010).Andersen andNavaltathengoontoenumeratetheadvantages ofusingpreclinicalstudiesinanimalstoinform clinicalpracticeaswellasnotingtheirinherent limitations.Giventheincreasinguseofpsychotropic medicationsoverthepastthreedecadesinpregnant andlactatingwomenandthatinanimalstudies thereisevidenceofserious,delayed,anduntoward behaviouralconsequences(Andersen,Greene-Collozi ,&Sonntag,2010;Ansorge,Morelli,&Gingrich, 2008),itisunfortunatethatsolittleinformationis availabletoguidetheuseoftheseagentsineveryday clinicalpractice.Inbrief,thereisevidencethat antidepressanttreatmentduringlatepregnancymay increasetheratesofpoorpregnancyoutcomeand neonatalwithdrawal/toxicreactions(Gentile, 2010a).Nolong-termfollow-upstudiesofchildren exposedtoantidepressantsduringpregnancyhave beendonebeyond48–72months,althoughthe adversephenotypesinanimalswere'delayed'and evidentinadulthood(Gentile,2010b).Thusfar,the humandataconcerninglonger-termoutcomesare mixed(Gentile,2010b).Onerecentstudyfoundthat theexposuretoprenatalSSRIsandmaternalmood haddistincteffectsonchildbehaviorat3yearsof age,reflectedinanincreasedlevelofinternalizing behaviors.Althoughthereisreasonforconcern, thereisalsoreasonforoptimismthatsafeandnovel interventionsthattargetand'drive'GABA,glutamate ,andneuropeptides(oxytocinanddynorphin) andbiogenicamine(serotonin,norepinephrine,and dopamine)pathwayswillbedevelopedinthefuture. Thefinalcontributionofthe2011annualresearch reviewissueisthefuturisticarticlebyVaccarinoand colleagues(2011)whichinsomesensemayallow scientiststostudytheneuraldevelopmentof patient-specificcelllinesusingstemcellsderived fromskinfibroblasts.Whileitisclearthatitisvir- tuallyimpossibletostudythedynamicaspectsof humanneurodevelopmentatthecellularand molecularlevel,arecenttechnicaladvancemay allowustobegintoapproachthischallenge.This advanceisthedevelopmentofinducedpluripotent stemcell(iPSC)technology.iPSCscanbeusedto deriveneuronsusingtissueobtainedfromaliving person,andmaintainhisorhergeneticconstitution anddiversity.Whenproperlyused,thederivationof iPSCsfromskinorotherdifferentiatedsomaticcells shouldallowthestudyofhumanneuraldevelopmentforindividualgenomesinvitro .Theapplication ofthistechnologytodevelopmentalneuropsychiatric disorderssuchasASD,ADHD,Tourettesyndrome, andlanguageandlearningdisabilitiesisparticularly promisingasitmaybepossibletodetectdeviations ofdevelopmentinpatient-derivediPSCsthatwill informourbasicunderstandingofthesedisorders. "
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