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Fulltext The Risk of Congenital Heart Anomalies Following Prenatal Exposure to Serotonin Reuptake Inhibitors-Is Pharmacogenetics the Key?

Daud AN, Bergman JE, Kerstjens-Frederikse WS, Groen H, Wilffert B

Int J Mol Sci, 2016 Aug 13;17(8).
PMID: 27529241 DOI: 10.3390/ijms17081333

Serotonin reuptake inhibitors (SRIs) are often prescribed during pregnancy. Previous studies that found an increased risk of congenital anomalies, particularly congenital heart anomalies (CHA), with SRI use during pregnancy have created concern among pregnant women and healthcare professionals about the safety of these drugs. However, subsequent studies have reported conflicting results on the association between CHA and SRI use during pregnancy. These discrepancies in the risk estimates can potentially be explained by genetic differences among exposed individuals. In this review, we explore the potential pharmacogenetic predictors involved in the pharmacokinetics and mechanism of action of SRIs, and their relation to the risk of CHA. In general, the risk is dependent on the maternal concentration of SRIs and the foetal serotonin level/effect, which can be modulated by the alteration in the expression and/or function of the metabolic enzymes, transporter proteins and serotonin receptors involved in the serotonin signalling of the foetal heart development. Pharmacogenetics might be the key to understanding why some children exposed to SRIs develop a congenital heart anomaly and others do not.

Matched MeSH terms: Serotonin Uptake Inhibitors/adverse effects*
Serotonin Selective Reuptake Inhibitors (SSRIs) and Female Sexual Dysfunction (FSD): Hypothesis on its Association and Options of Treatment

Rappek NAM, Sidi H, Kumar J, Kamarazaman S, Das S, Masiran R, et al.

Curr Drug Targets, 2018;19(12):1352-1358.
PMID: 28025939 DOI: 10.2174/1389450117666161227142947

Sexual dysfunctions are commonly seen in women on selective serotonin reuptake inhibitors (SSRIs). The complexities of female sexual functioning are reflected through modulation of inter- playing factors like the neuropsychophysiological factors, inter-personal and relationship issue, psychiatric co-morbidities and physical disorder. The incidence of SSRIs-induced FSD is difficult to estimate because of the potential confounding effects of SSRIs, presence of polypharmacy, marital effect, socio-cultural factors and due to the design and assessment problems in majority of the studies. The exact mechanism of FSD-induced SSRIs is unknown. It has been postulated that although SSRIs may modulate other neurotransmitter system such as nitric oxide (NO), noradrenergic and dopamine in inducing FSD. In the present review, we highlight current evidence regarding potential mechanism of SSRIs in causing FSD, which include low sexual desire (low libido), arousal difficulties (lack of lubrication), and anorgasmia. The specific association of FSD to SSRI use, has not been ellucidated. The relationship is dose-dependent, and may vary among the groups with respect to mechanism of serotonin and dopamine reuptake, induction of release of prolactin from the pituitary gland, anticholinergic side-effects, inhibition of NO synthesis and emotional-memory circuit encryption for sexual experiences. Various interventional strategies exist regarding the treatment of SSRI-induced FSD and this includes tolerance, titration dosage, substitution to another antidepressant drug and psychotherapy. There is a need of better understanding of SSRIs-induced FSD for better treatment outcome.

Matched MeSH terms: Serotonin Uptake Inhibitors/adverse effects*
Female sexual dysfunction in patients with major depressive disorder (MDD) treated with selective serotonin reuptake inhibitor (SSRI) and its association with serotonin 2A-1438 G/A single nucleotide polymorphisms

Masiran R, Sidi H, Mohamed Z, Mohd Nazree NE, Nik Jaafar NR, Midin M, et al.

J Sex Med, 2014 Apr;11(4):1047-1055.
PMID: 24533444 DOI: 10.1111/jsm.12452

INTRODUCTION: Selective serotonin reuptake inhibitors (SSRIs) are known for their sexual side effects. Different SSRIs may affect different areas of sexual function at different rates.
AIMS: The study aimed to determine the prevalence of female sexual dysfunction (FSD), its clinical correlates, and association with 5HT2A (rs6311) single nucleotide polymorphisms (SNPs) in patients with major depressive disorder (MDD) who were on SSRI therapy.
METHODS: This was a cross-sectional study on 95 female outpatients with MDD treated with SSRI. The patients were in remission as determined by Montgomery-Asberg Depression Rating Scale. Genomic DNA was isolated from buccal swabs and samples were processed using a real time polymerase chain reaction.
MAIN OUTCOME MEASURES: The presence or absence of FSD as measured by the Malay Version of Female Sexual Function Index and 5HT2A-1438 G/A (rs6311) SNP.
RESULTS: The overall prevalence of FSD was 32.6%. After controlling for age, number of children, education level, total monthly income, SSRI types, and SSRI dosing, being employed significantly enhanced FSD by 4.5 times (odds ratio [OR] = 4.51; 95% confidence interval [CI] 1.00, 20.30; P = 0.05). Those having marital problems were 6.7 times more likely to have FSD (OR = 6.67; 95% CI 1.57, 28.34). 5HT2A-1438 G/A (rs6311) SNP was not significantly associated with FSD.
CONCLUSION: There was no significant association between FSD and the 5HT2A (rs6311) SNP in patients with MDD on SSRI therapy. Employment status and marital state were significantly associated with FSD among these patients.
Study site: Psychiatry clinics, Pusat Perubatan Universiti Kebangsaan Malaysia (PPUKM), University Malaya Medical Centre (UMMC), Kuala Lumpur, Malaysia

Matched MeSH terms: Serotonin Uptake Inhibitors/adverse effects
Female sexual dysfunction in patients treated with antidepressant-comparison between escitalopram and fluoxetine

Sidi H, Asmidar D, Hod R, Guan NC

J Sex Med, 2012 May;9(5):1392-9.
PMID: 21477024 DOI: 10.1111/j.1743-6109.2011.02256.x

Selective serotonin reuptake inhibitor is one of the most widely used antidepressant and commonly associated with female sexual dysfunction (FSD).

Matched MeSH terms: Serotonin Uptake Inhibitors/adverse effects*
Association of brain-derived neurotrophic factor valine to methionine polymorphism with sexual dysfunction following selective serotonin reuptake inhibitor treatment in female patients with major depressive disorder

Nazree NE, Mohamed Z, Reynolds GP, Mohd Zain S, Masiran R, Sidi H, et al.

Asia Pac Psychiatry, 2016 Dec;8(4):260-268.
PMID: 27787964 DOI: 10.1111/appy.12210

INTRODUCTION: The occurrence of female sexual dysfunction (FSD) in patients with major depressive disorder (MDD) receiving selective serotonin reuptake inhibitors (SSRIs) treatment gives negative impacts on patients' quality of life and causes treatment discontinuation. We aimed to investigate whether genetic polymorphism of identified candidate gene is associated with FSD in our study population.
METHODS: This is a cross-sectional study. A total of 95 female patients with MDD who met the criteria of the study were recruited and were specifically assessed on the sexual function by trained psychiatrists. Patients' DNA was genotyped for BDNF Val66Met polymorphism using real-time polymerase chain reaction.
RESULTS: The prevalence of FSD in this study is 31.6%. In the FSD group, patients with problematic marriage were significantly more frequent compared with patients who did not have problematic marriage (P = 0.009). Significant association was detected in the lubrication domain with BDNF Val66Met polymorphism (P = 0.030) using additive genetic model, with even stronger association when using the recessive model (P = 0.013).
DISCUSSION: This study suggested that there was no significant association between BDNF Val66Met with FSD. However, this polymorphism is significantly associated with lubrication disorder in patients treated with SSRIs.

Matched MeSH terms: Serotonin Uptake Inhibitors/adverse effects*
Fulltext Prenatal exposure to serotonin reuptake inhibitors and congenital heart anomalies: an exploratory pharmacogenetics study

Daud ANA, Bergman JEH, Kerstjens-Frederikse WS, van der Vlies P, Hak E, Berger RMF, et al.

Pharmacogenomics, 2017 Jul;18(10):987-1001.
PMID: 28639488 DOI: 10.2217/pgs-2017-0036

AIM: To explore the role of pharmacogenetics in determining the risk of congenital heart anomalies (CHA) with prenatal use of serotonin reuptake inhibitors.
METHODS: We included 33 case-mother dyads and 2 mother-only (child deceased) cases of CHA in a case-only study. Ten genes important in determining fetal exposure to serotonin reuptake inhibitors were examined: CYP1A2, CYP2C9, CYP2C19, CYP2D6, ABCB1, SLC6A4, HTR1A, HTR1B, HTR2A and HTR3B.
RESULTS: Among the exposed cases, polymorphisms that tended to be associated with an increased risk of CHA were SLC6A4 5-HTTLPR and 5-HTTVNTR, HTR1A rs1364043, HTR1B rs6296 and rs6298 and HTR3B rs1176744, but none reached statistical significance due to our limited sample sizes.
CONCLUSION: We identified several polymorphisms that might potentially affect the risk of CHA among exposed fetuses, which warrants further investigation.

Matched MeSH terms: Serotonin Uptake Inhibitors/adverse effects*
Association between 5HT2A polymorphism and selective serotonin re-uptake inhibitor (SSRI)-induced sexual desire disorder (SDD) among Malaysian women

Masiran R, Sidi H, Mohamed Z, Mohamed Saini S, Nik Jaafar NR

Asia Pac Psychiatry, 2013 Apr;5 Suppl 1:41-9.
PMID: 23857836 DOI: 10.1111/appy.12043

SSRIs are known for their sexual side-effects with a variable rate of sexual dysfunction (SD). 5HT2A (rs6311) single nucleotide polymorphism (SNP) was found to have significant association with SD. The purpose of this study was to determine the prevalence of female SDD, its clinical correlates and association with 5HT2A (rs6311) SNP in patients with major depressive disorder (MDD) treated with SSRIs.

Matched MeSH terms: Serotonin Uptake Inhibitors/adverse effects*
Hypoactive sexual desire among depressed female patients treated with selective serotonin reuptake inhibitors: a comparison between escitalopram and fluoxetine

Sidi H, Asmidar D, Hod R, Jaafar NR, Guan NC

Int J Psychiatry Clin Pract, 2012 Mar;16(1):41-7.
PMID: 22122658 DOI: 10.3109/13651501.2011.617457

To determine the risk of hypoactive sexual desire (HSD) in depressed female patients treated with selective serotonin reuptake inhibitors, comparing escitalopram and fluoxetine. The associated factors were also examined.

Matched MeSH terms: Serotonin Uptake Inhibitors/adverse effects