Pharmacokinetics of clomipramine during pregnancy.

PURPOSE: Clomipramine is one of the drugs for depression during pregnancy; however, pharmacokinetic data of clomipramine and its active metabolite desmethylclomipramine in this vulnerable period are lacking. In this study, we describe clomipramine and desmethylclomipramine concentrations including their ratios during pregnancy. Second, we describe Center for Epidemiologic Studies Depression scale (CES-D) scores during pregnancy. METHODS: During 13 pregnancies, every trimester and 3 months after pregnancy, the clomipramine and desmethylclomipramine concentrations were measured with LC-MSMS and the severity of depression was assessed by taking the CES-D score. All concentrations used in our calculations were in fact the ratio between actual plasma concentration (µg/l) and the actual dose (mg). We compared differences in ratios between trimesters by using the Friedman test. RESULTS: Studying 12 women and 13 pregnancies, we found no changes in mean clomipramine concentrations, a statistically significant decrease in mean desmethylclomipramine concentrations (p = 0.014) and a significant decrease in the ratio of desmethylclomipramine/clomipramine mean concentrations during pregnancy (p = 0.014) compared to the post-partum period. Sub-therapeutic concentrations of clomipramine and desmethylclomipramine were found in three patients during whole pregnancy. CONCLUSIONS: The mean concentrations of the pharmacologically active metabolite of clomipramine and desmethylclomipramine changes during pregnancy, where a decrease in mean concentrations was found during pregnancy. In case of recurrent disease, we recommend to control clomipramine and its metabolite concentrations, while both are active.

Concentrations of venlafaxine and its main metabolite O-desmethylvenlafaxine during pregnancy.

WHAT IS KNOWN AND OBJECTIVE: Depression during pregnancy is common and includes risks for mother and child. Pharmacokinetics of venlafaxine may be changed during pregnancy. This study aimed to describe changes in metabolic ratios and concentrations of venlafaxine and its main metabolite O-desmethylvenlafaxine during and after pregnancy. METHODS: To study this, we used data from our study of compliance to Antidepressants During Pregnancy (the ADAP study) to investigate the course of venlafaxine and O-desmethylvenlafaxine concentrations during pregnancy and in the period post-partum. RESULTS AND DISCUSSION: We found that the venlafaxine concentration significantly changed during pregnancy when compared to the post-partum period (P = 0·028). The median concentration of venlafaxine in the first trimester was 98·9% (54·2-292·0%), the second 100·0% (46·5-264·0%) and the third trimester 87·0% (61·5-217·2%). We did not found differences in O-desmethylvenlafaxine concentrations in the different trimesters of pregnancy compared with the post-partum period, P = 0·565. Also the ratio of O-desmethylvenlafaxine/venlafaxine concentrations increased significantly from 76·9% (range 32·8-142·0%) in the first trimester to 196·7% (range 83·3-427·6%) in the third trimester compared with the post-partum period, P = 0·004. Further, three of seven patients had concentrations below the therapeutic reference range (100-400 µg/L) in any period of pregnancy, whereas no one had subtherapeutic concentrations in the post-partum period. WHAT IS NEW AND CONCLUSION: Venlafaxine concentrations decreases during pregnancy, and the ratio of the concentrations of O-desmethylvenlafaxine/venlafaxine increases during pregnancy. Pregnant women using venlafaxine are at risk for subtherapeutic concentrations, therefore routine monitoring of concentrations venlafaxine and O-desmethylvenlafaxine is recommendable during pregnancy.

In utero exposure to antidepressants and the use of drugs for pulmonary diseases in children.

PURPOSE: The use of antidepressants during pregnancy is common. Some studies suggest an association between in utero exposure to antidepressants and the occurrence of pulmonary diseases like asthma later in life. Serotonin reuptake inhibitors (SSRIs) as well tricyclic antidepressants (TCAs) are thought to be involved in the development of the respiratory rhythm generator (RRG) and the maturation of the formation of surfactant. In this study the use of drugs for pulmonary diseases in children who were exposed to antidepressants in utero were compared with non-exposed children. METHODS: The pharmacy prescription database IADB.nl was used for a cohort study in which the use of drugs for pulmonary disease in children after in utero exposure to antidepressants (TCAs, SSRIs) was compared with children with no antidepressant exposure in utero. Drugs for pulmonary diseases were applied as a proxy for disturbed development of the respiratory tract. RESULTS: A small though significant increase in the incidence risk ratio (IRR) of the use of drugs for pulmonary disease was found after any-time in utero exposure to SSRIs, adjusted for maternal use of antibiotics, of 1.17 (95 % CI 1.16-1.18). An increase was also seen when we looked specifically for the use of SSRIs in at least the first trimester (IRR = 1.18, 95 % CI 1.17-1.20). An increased IRR in the use of drugs for pulmonary disease was also seen when children were exposed to TCAs, but this was not statistically significant. However, in both groups our sample size was rather small. The effect size is modest and may also be confounded by maternal smoking. CONCLUSIONS: In utero exposure to SSRIs leads to a statistically significant increase in the use of drugs for pulmonary diseases, especially when exposure occurred during the first trimester of pregnancy. The increase in the use of drugs for pulmonary disease may also be related to other factors. Therefore, further study is recommended.

Fifteen years' experience with methylphenidate for attention-deficit disorder during pregnancy: Effects on birth weight, Apgar score and congenital malformation rates.

BACKGROUND: Methylphenidate (MPD) is increasingly prescribed to fertile women with Attention-Deficit Disorder (AD(H)D), with or without hyperactivity, despite advice for discontinuation during pregnancy. Few studies report on results concerning safety after methylphenidate exposure during pregnancy for the offspring. AIM: Safety for the offspring of exposure to MPD during pregnancy. METHODS: This is an observational retrospective cohort study in a population of pregnant women and their offspring, treated with MPD for ADHD in the Psychiatry-Gynaecology-Pediatrics outpatient clinic between 1 January 2005 and 1 June 2020 at Isala hospital. The primary endpoints were birth weight and Apgar score in offspring exposed to MPD during pregnancy, compared to offspring unexposed to MPD. Birth weight was analysed using linear mixed model analysis. Apgar score and (secondary endpoint) neonatal malformations, at 20 week ultrasound, were analysed using basic univariate statistical analysis. RESULTS: MPD continuation, compared to discontinuation, was associated with higher neonatal birth weight (p = 0.049), but lost statistical significance after incorporating covariates (p = 0.079). There were no significant differences in Apgar scores and congenital malformations between neonates exposed and unexposed to MPD. CONCLUSIONS: MPD does not seem to affect birth weight, Apgar score and the frequency of neonatal malformations at the 20 week ultrasound.

[Antidepressants during pregnancy and lactation]. / Antidepressiva tijdens zwangerschap en borstvoeding.

BACKGROUND: It is difficult to find well-grounded advice about the pharmacotherapeutic treatment of anxiety and depression before, during and after pregnancy. Furthermore, in the literature pharmacotherapeutic advice relating to the various periods (pre-conception, pregnancy and lactation) is often contradictory. AIM: By reviewing the literature, to arrive at a recommendation for the pharmacotherapeutic treatment of depression during and after pregnancy and to compare and weigh up the various risks involved in treatment. METHOD: A literature search in PubMed and Embase with search terms 'antidepress*', 'anxiol*', 'pregnan*', 'depressi*', 'anxiet*', 'guideline', 'lactation', 'breastfeeding' and 'milk'. The National Guideline Clearinghouse database was used to find guidelines. results The literature reveals that the medical treatment of a depression during pregnancy and lactation is not without risks. However, there are also risks involved in not treating depression during these periods. These risks cannot be assessed at group-level but have to be weighed up for each individual separately. The patient needs to be informed about the risks she runs in connection with a particular treatment so that a well-considered decision can be made about whether to treat or not treat depression with antidepressants during pregnancy. CONCLUSION: If the decision is made to treat depression during pregnancy and in the lactation period, it is advisable to choose an antidepressant from the safest category; in most countries this means opting for tricyclic antidepressants.

Simultaneous determination of levomepromazine, midazolam and their major metabolites in human plasma by reversed-phase liquid chromatography.

A sensitive and reliable high-performance liquid chromatographic (HPLC) assay is a prerequisite for pharmacokinetic analysis of continuous infusion of levomepromazine adjuvant to midazolam. We developed such a method to determine the levels of levomepromazine, midazolam and their major metabolites (levomepromazinesulfoxide, desmethyl-, didesmethyllevomepromazine, O-desmethyllevomepromazine and alpha-hydroxy-midazolam) simultaneously. Desmethylclomipramine was used as an internal standard (I.S.). The lower limit of quantification of this assay was set for levomepromazine 4.1 microg/l, levomepromazinesulfoxide 4.9 microg/l, O-desmethyllevomepromazine 18.4 microg/l, alpha-hydroxymidazolam 26.6 microg/l, midazolam 23.4 microg/l, didesmethyllevomepromazine 15.8 microg/l, and desmethyllevomepromazine 6.6 microg/l. The between- and within day assay variations were commonly below 5%. The recovery in human plasma for the different analytes varied between 85 and 11%. The accuracy of this assay varied between 95 and 105% for the different concentrations. The linearity of this assay was set between 25 and 800 microg/l (r(2)>0.999 of the regression line). The first results of pharmacokinetic analysis of midazolam indicated that half-life varied between 1.1 and 1.9 h. Pharmacokinetic analysis using a one-compartment model of levomepromazine revealed that the apparent volume of distribution was 4.1+/-2.4 l per kg lean body mass and the metabolic clearance was 309+/-225 l per hour per 70 kg. This assay proved to be robust and reproducible. It can reliably be used for further study of the pharmacokinetics of continuous infusion of levomepromazine.