Placental passage of tricyclic antidepressants.

BACKGROUND: The use of antidepressants during pregnancy continues to garner considerable attention, though there are limited investigations that have sought to quantify fetal exposure. METHODS: Maternal and umbilical cord sera were collected at delivery from ten women taking nortriptyline and seven taking clomipramine. Placental passage was calculated as the ratio of umbilical cord to maternal serum concentration. Obstetrical outcome data were gathered from subjects at delivery. RESULTS: The placental passage ratio of nortriptyline and its active metabolite, cis-10-hydroxynortriptyline, were .68 +/- .40, 1.40 +/- 2.40, respectively. Clomipramine and desmethylclomipramine ratios were .60 +/- .50, .80 +/- .60. Obstetrical complications, such as pre-term delivery and pregnancy induced hypertension, were increased compared to the national average. CONCLUSIONS: The in vivo ratios of umbilical cord to maternal serum drug concentrations demonstrate considerable fetal exposure and differ greatly from previous results utilizing ex vivo perfusion.     

Amniotic fluid and umbilical cord blood concentrations of antidepressants in three women.

BACKGROUND: Pregnancy and the postpartum period are a time of increased risk for women to develop mood disorders. As such, the reproductive safety data on antidepressant use during pregnancy have rapidly expanded over the last decade; however, there is relatively sparse information on maternal/fetal exchange of these medications and no data reporting their concentrations in amniotic fluid. METHODS: We report on three women treated during pregnancy with fluvoxamine, sertraline, and venlafaxine, respectively. Amniotic fluid at amniocentesis and umbilical cord blood and maternal blood at delivery were collected and analyzed for antidepressant concentrations using high performance liquid chromatography with UV detection. RESULTS: Antidepressant and metabolite concentrations were detectable in all amniotic fluid samples, though parent compound concentrations were less than maternal serum and umbilical cord blood concentrations. No adverse effects of the medication were reported. CONCLUSIONS: The presence of these antidepressants in amniotic fluid suggests that fetal exposure to these medications is continual and may occur through a variety of paths, thus accounting for increased fetal exposure. These paths include circulatory via placental passage, gastrointestinal via fetal swallowing, and respiratory secondary to fetal lung absorption.     

Pharmacokinetics of SSRI antidepressants: half-life and clinical applicability

The selective serotonin reuptake inhibitors (SSRIs) antidepressants are at present time the most useful for the treatment of depression. SSRIs exhibit differences in potency of inhibiting serotonin reuptake, although the differences do not correlate with clinical efficacy. There are substantial pharmacokinetic differences among the five SSRIs, fluvoxamine, fluoxetine, paroxetine, sertraline and citalopram. Optimum use of these drugs requires a working knowledge of these differences. Among these pharmacokinetic parameters, half-life and metabolism pathways are the most relevant. There are substantial differences in term of their half-life between fluoxetine and others SSRIs. The half-life of fluoxetine and its active metabolite norfluoxetine is respectively 2 to 4 days and 7 to 15 days, more extended than other SSRIs (approximately 1 day). The extended half-life of fluoxetine and its active metabolite may be an advantage in the poorly compliant patient and may offer a potential safety advantage over shorter-acting SSRIs, with respect to abrupt discontinuation of therapy. Conversely, this long half-life needs a long period of wash-out (5 weeks) before introducing other drugs (MAOIs, sumatriptan) which can interact with serotonin function and can lead to the serotoninergic syndrome. SSRIs are potent inhibitors of the hepatic isoenzyme P450-2D6 and would be expected to have effects on the clearance of drugs metabolized by this enzyme. Paroxetine is the most potent inhibitor, followed by fluoxetine, sertraline, citalopram and fluvoxamine. The metabolite elimination of citalopram, paroxetine and fluvoxamine is delayed by renal disease and dosages should be lowered in elderly patients. Conversely the pharmacokinetic of fluoxetine and sertraline are not affected by either age or renal impairment and, for fluoxetine, by obesity.     

Excretion of paroxetine into breast milk.

BACKGROUND: The study was carried out to quantify the excretion of the selective serotonin reuptake inhibitor paroxetine in breast milk. METHOD: In 6 lactating women, the concentrations of paroxetine in breast milk and serum were studied at the times for assumed minimum (24 hours after dose intake) and maximum (4-7 hours after dose intake) drug levels in milk. Moreover, a seventh subject was studied with frequent and regular sampling throughout a dose interval of 24 hours at 2 different dose levels. RESULTS: The mean milk/serum concentration ratios in the first 6 subjects ranged from 0.39 to 1.11 (overall mean +/- SD = 0.69 +/- 0.29), and the mean estimated dose to the infants ranged from 0.7% to 2.9% (overall mean +/- SD = 1.4% +/- 0.79%) of the weight-adjusted maternal dose. Based on area-under-the-curve data from the seventh subject, the milk/serum concentration ratio was 0.69 at a dose of 20 mg/day and 0.72 at a dose of 40 mg/day; the estimated relative doses to the infant were 1.0% and 2.0%, respectively. The mean increase in milk paroxetine concentrations from assumed minimum to assumed maximum was 61% (range, 4%-172%; p < .01). The mean paroxetine concentration in hindmilk was 78% higher than in foremilk (range, 16%-169%; p < .01), an increase that was parallel to the increase in milk triglyceride levels (r = 0.83, p = .005). No adverse drug reactions or unusual behaviors were reported in the infants. CONCLUSION: The study indicates that the relative dose to a suckling infant for paroxetine is lower than that reported for fluoxetine and citalopram and higher than that reported for sertraline and fluvoxamine.     

Pooled analysis of antidepressant levels in lactating mothers, breast milk, and nursing infants

OBJECTIVE: The available data on antidepressant levels in nursing infants were analyzed in order to calculate average infant drug levels and determine what factors influence plasma drug levels in breast-feeding infants of mothers treated with antidepressants. METHOD: Electronic searches of MEDLINE, PreMEDLINE, Current Contents, Biological Abstracts, and PsycINFO from 1966 through July 2002 followed by bibliographic searches identified 67 relevant studies (two unpublished). By consensus the authors identified 57 studies of maternal plasma, breast milk, and/or infant plasma antidepressant levels from nursing mother-infant pairs, measured by liquid chromatography. RESULTS: Infants with recent prenatal exposure and symptomatic infants included in case reports were analyzed separately. Infant plasma levels were standardized against the average maternal level for each drug. The average infant-maternal plasma ratio was calculated for each drug, and correlations of infant plasma level to maternal dose, maternal plasma level, and breast milk level were calculated. Nortriptyline, paroxetine, and sertraline usually produce undetectable infant levels. Of drugs currently used, fluoxetine produces the highest proportion (22%) of infant levels that are elevated above 10% of the average maternal level. Based on smaller numbers, the data on citalopram indicate that it produces elevated levels in 17% of infants. The milk-to-plasma ratios for 11 antidepressants had a statistically significant negative association with the percentage of the drug bound to protein. CONCLUSIONS: Nortriptyline, paroxetine, and sertraline may be preferred choices in breast-feeding women. Minimizing the maternal dose may be helpful with citalopram. Current data do not support monitoring breast milk levels in individual patients. Future researchers should report maternal, breast milk, and infant antidepressant levels along with other appropriate variables.     

Antidepressants in amniotic fluid: another route of fetal exposure

OBJECTIVE: The authors' goal was to determine the concentration of antidepressants in amniotic fluid during maternal treatment of depression. METHOD: Women treated with antidepressants undergoing amniocentesis for obstetrical reasons were enrolled. Antidepressant concentrations in amniotic fluid and maternal serum were determined with high-performance liquid chromatography. RESULTS: Amniotic fluid was obtained from 27 women, and the amniotic fluid's antidepressant concentrations were highly variable. For the parent compounds, the amniotic fluid concentrations of selective serotonin uptake inhibitors averaged 11.6% (SD=9.9%) of maternal serum concentrations (N=22). Amniotic fluid to maternal serum ratios were higher for venlafaxine: 172% (SD=91%) (N=3). Of interest, the amniotic fluid to maternal serum ratios for the metabolites (N=19) did not demonstrate a consistent pattern compared to the parent compound ratios. In 10 subjects, the amniotic fluid to maternal serum ratio for the metabolites was higher than the parent compound and lower in the remaining nine subjects. CONCLUSIONS: The pattern of antidepressant concentrations in amniotic fluid is similar to recent data for placental passage. Although the significance of amniotic fluid exposure remains to be determined, these results demonstrate that maternally administered antidepressants are accessible to the fetus in a manner not previously appreciated.     

Selective serotonin-reuptake inhibitors: an update.

Selective serotonin-reuptake inhibitors (SSRIs), including fluoxetine, sertraline, paroxetine, fluvoxamine, and citalopram, represent an important advance in the pharmacotherapy of mood and other disorders. They are chemically unrelated to tricyclic, heterocyclic, and other first-generation antidepressants. SSRIs are the treatment of choice for many indications, including major depression, dysthymia, panic disorder, obsessive-compulsive disorder, eating disorders, and premenstrual dysphoric disorder, because of their efficacy, good side-effect profile, tolerability, and safety in overdose, as well as patient compliance. A review of the literature was conducted using Medline and the terms "SSRIs," "fluoxetine," "sertraline," "paroxetine," "fluvoxamine," and "citalopram." Articles were limited to those published in English within the last 15 years. The search revealed that indications for antidepressants include unipolar depression, dysthymia, bipolar depression, treatment-resistant depression, depression in the medically ill, panic disorder, obsessive-compulsive disorder, eating disorders, social phobia, and premenstrual dysphoric disorder. One SSRI, fluoxetine, has demonstrated safety in pregnancy. Side effects of SSRIs include gastrointestinal disturbances, headache, sedation, insomnia, activation, weight gain, impaired memory, excessive perspiration, paresthesia, and sexual dysfunction.     

Effects of exposure to selective serotonin reuptake inhibitors during pregnancy on serotonergic symptoms in newborns and cord blood monoamine and prolactin concentrations

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) have gained wide acceptance in the treatment of mental disorders in pregnant women, but there seems to be an increased risk for neonatal adaptation problems after exposure to SSRIs in late pregnancy. We aimed to investigate the perinatal sequelae of infants exposed to SSRIs during their fetal life and the relationship of these symptoms to the cord blood monoamine and prolactin concentrations. METHODS: We conducted a prospective, controlled, follow-up study with 20 mothers taking 20 to 40 mg/d of either citalopram or fluoxetine for depression (n = 10) or panic disorder (n = 10) and their infants and 20 matched controls not receiving psychotropic medication for confounding obstetric characteristics. Maternal cord blood and infant citalopram, fluoxetine, and norfluoxetine, cord blood monoamine and metabolite, and prolactin concentrations were measured. The newborns underwent standard clinical examination and specific assessment of serotonergic symptoms during the first 4 days of life and at the ages of 2 weeks and 2 months. RESULTS: There was a statistically significant (P =.008, V = 15, n = 20 for both groups), 4-fold difference in the serotonergic symptom score during the first 4 days of life between the SSRI group and the control group. The SSRI-exposed infants had significantly lower cord blood 5-hydroxyindoleacetic acid (5-HIAA) concentrations (P =.02, t31 = 2.57) compared with the control group. A significant inverse correlation (rs = -0.66, P =.007, n = 15) was seen between the serotonergic symptom score and the umbilical vein 5-HIAA concentrations in the SSRI-exposed but not the control infants. CONCLUSIONS: Infants exposed to SSRIs during late pregnancy are at increased risk for serotonergic central nervous system adverse effects, and the severity of these symptoms is significantly related to cord blood 5-HIAA levels.     

Breastfeeding during maternal antidepressant treatment with serotonin reuptake inhibitors: infant exposure, clinical symptoms, and cytochrome p450 genotypes

BACKGROUND: The aims of the study were to quantify the drug exposure in breastfed infants of antidepressant-treated mothers, to identify possible adverse events, and to correlate these variables to maternal and infant drug metabolism-relevant genotypes and milk triglyceride content. METHOD: The study included 25 lactating women treated with citalopram (N = 9), sertraline (N = 6), paroxetine (N = 6), fluoxetine (N = 1), or venlafaxine (N = 3) and their 26 breastfed infants. Drug concentrations in maternal and infant serum and milk were analyzed using liquid chromotography mass spectrometry methods; milk triglyceride levels were measured with a commercial kit. Cytochrome P450 (CYP) 2D6 and CYP2C19 activity was determined by polymerase chain reaction-based genotyping of the mothers and infants. An infant adverse event questionnaire was completed by the medication-treated mothers as well as by a control group of medication-free breastfeeding mothers of 68 infants. RESULTS: Sertraline and paroxetine were not detected in any of the drug-exposed infants. The infant serum level of citalopram was either undetectable (N = 4) or low (N = 6). All venlafaxine-exposed infants had measurable drug concentrations. We identified a paroxetine-treated mother and her infant who were both CYP2D6 poor metabolizers, as well as a citalopram-treated mother with CYP2C19 poor metabolizer status, but the serum drug levels of their infants were still either undetectable (paroxetine) or low (citalopram). There was no evidence of adverse events in the drug-exposed infants. CONCLUSION: Serum drug levels in breastfed infants of antidepressant-treated mothers were undetectable or low. This study adds further evidence to previously published data indicating that breastfeeding should not be generally discouraged in women using serotonin reuptake inhibitor anti-depressants.     

Occupancy of the serotonin transporter by fluoxetine,paroxetine, and sertraline: In vivo studies with [125i]rti-55

[¹²⁵I]RTI-55 was used in tracer doses to label serotonin (5-HT) transporters in vivo in the mouse brain. Fluoxetine, paroxetine, and sertraline, potent antidepressants and selective inhibitors of serotonin transporter sites, were administered in various doses and at various times. The doses and times that result in significant binding of the drugs to transporters correspond to doses and times where they are reported to have physiological effects. Estimates of occupancy rate and duration of binding to serotonin transporters were made. The rate of occupancy of the 5-HT transporter site was fastest for sertraline, intermediate for paroxetine and slowest for fluoxetine. Similarly, the duration of occupancy was significantly shorter for sertraline and paroxetine (approximately 10 h) than for fluoxetine (approximately 50 h). The results indicate that in competition studies, [¹²⁵I]RTI-55 can be used to identify doses of drugs that are physiologically effective, to determine their relative rate of occupancy, and most importantly, to measure the residency time on the central serotonin transporter in vivo. © 1994 Wiley-Liss, Inc.     

Fluoxetine and norfluoxetine concentrations in nursing infants and breast milk.

BACKGROUND: This study's goal was to characterize nursing infants' exposure to fluoxetine through breast milk and to identify variables for minimizing such exposure. METHODS: Nursing women on stable daily doses of fluoxetine were recruited into the study. Breast milk, maternal and infant serum concentrations of fluoxetine and norfluoxetine were determined with high-performance liquid chromatography. RESULTS: Nineteen nursing women one with a pair of dizygotic twins participated in the study. The women were on stable daily doses of fluoxetine (10-60 mg/day) and all but two took the medication during the last trimester of pregnancy. Fluoxetine was detectable in 30% (n = 6) of the nursing infant sera (< 1-84 ng/mL), whereas norfluoxetine was found in 85% (N = 17) (< 1-265 ng/mL). Peak breast milk concentrations occurred approximately 8 hours after maternal dosing and predicted norfluoxetine concentrations in infant serum. Maternal serum fluoxetine and norfluoxetine concentrations correlated highly with infant norfluoxetine concentrations. A daily maternal fluoxetine dosage of 20 mg or lower was significantly less likely to produce detectable concentrations of either fluoxetine or norfluoxetine in infants compared to higher daily dosages. No adverse effects were reported in any infant. CONCLUSIONS: Our findings demonstrate that maternal serum and peak breast milk concentrations of fluoxetine and norfluoxetine predict nursing infant serum norfluoxetine concentrations. In nursing women taking 20 mg/day or less of fluoxetine, infant serum concentrations were typically low.     

Antidepressants in epilepsy

People with epilepsy (PWE) frequently suffer from comorbid mood and anxiety disorders. Depression is one of the major psychiatric comorbidities having a negative impact on the quality of life in people with epilepsy. A review of the literature indicates that the majority of antidepressant-related seizures have been associated with either ultra-high doses or overdosing and, generally, the risk of antidepressant-associated seizures is low. Correspondingly, there is some evidence indicating that antidepressants of most widely used groups may additionally lower the risk of triggering seizures. Four antidepressants are not recommended for patients with epilepsy, i.e.: amoxapine, bupropion, clomipramine and maprotiline. Clinicians applying first line of depression treatment in patients with epilepsy should consider use of SSRIs or SNRIs, particularly sertraline, citalopram, mirtazapine, reboxetine, paroxetine, fluoxetine, escitalopram, fluvoxamine, venlafaxine, duloxetine. Implementation of anticonvulsive drugs in depressed patients should include valproate, carbamazepine, lamotrigine, gabapentin, pregabalin. The paper reviews the evidence for the clinical use of antidepressants in PWE.     

Plasma concentrations of clozapine and its major metabolites during combined treatment with paroxetine or sertraline

The effect of paroxetine or sertraline on steady-state plasma concentrations of clozapine and its major metabolites was studied in 17 patients with schizophrenia or schizoaffective disorder stabilized on clozapine therapy (200-400 mg/day). In order to treat negative symptomatology or concomitant depression, 9 patients received additional paroxetine (20-40mg/day) and 8 patients sertraline (50-100 mg/day). After 3 weeks of paroxetine administration, mean plasma concentrations of clozapine and norclozapine increased significantly by 31% (p<0.01) and by 20% (p<0.05), respectively, while levels of clozapine N-oxide remained almost unchanged. The mean plasma norclozapine/clozapine and clozapine N-oxide/clozapine ratios were not modified during paroxetine treatment. No significant changes in plasma concentrations of clozapine and its major metabolites were observed after 3 weeks of combined therapy with sertraline. Clozapine coadministration with either paroxetine or sertraline was well tolerated. Our findings suggest that the metabolism of clozapine is not affected by sertraline treatment at typical therapeutic doses, while paroxetine, a potent inhibitor of CYP2D6, appears to inhibit the metabolism of clozapine, possibly by affecting pathways other than N-demethylation and N-oxidation. While sertraline may be added safely to patients on maintenance treatment with clozapine, careful clinical observation and monitoring of plasma clozapine levels may be useful whenever paroxetine is coadministered with clozapine.     

SSRI efficacy-finding the right dose

The selective serotonin reuptake inhibitors (SSRIs) are a class of effective, well-tolerated antidepressants. They have a number of benefits compared with the tricyclic antidepressants (TCAs) including improved safety in overdose, reduced side-effect burden, and uncomplicated dosing regimens. To avoid the potential for troublesome side effects with TCAs, doses should be gradually increased over several weeks. Dose titration can be associated with several drawbacks such as patients discontinuing therapy due to a prolonged time to therapeutic response, additional visits to a prescribing healthcare provider, or additional hospitalizations. In contrast, the SSRIs typically do not require dose titration since many patients find the initial dose effective. The ability to prescribe an initial optimum therapeutic dose while avoiding dose-related side effects is important in the treatment of major depression. With this in mind, the authors consider the recommended dose ranges for the five SSRIs: citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline.     

Use of unbound drug concentrations to determine neonatal anticonvulsant exposure

Unbound and total concentrations of several anticonvulsant drugs were measured by liquid chromatography in maternal and neonatal cord serum collected at birth from 16 women being treated for epilepsy and their newborns. Maternal and neonatal unbound drug concentrations agreed closely for phenobarbital (n = 6), phenytoin (n = 7), carbamazepine (n = 8), and its epoxide metabolite. Mean maternal total drug concentrations were higher than neonatal concentrations in the cases of phenobarbital, carbamazepine, its epoxide and diol metabolites. The differences were due to greater protein binding in maternal serum. Measurement of total anticonvulsant concentrations in newborns may be misleading, because of altered protein binding in the neonate. For the medications tested, neonatal and maternal exposures to unbound drug appear to be equivalent.     

Transplacental passage of oxcarbazepine and its metabolites in vivo

PURPOSE: The purpose of this study was to investigate human fetal exposure to oxcarbazepine (OCBZ) in vivo. METHODS: Transplacental passage and placental tissue concentrations of OCBZ and its metabolites were determined. Maternal venous blood, cord blood, and placental tissue samples from 12 mothers using OCBZ during pregnancy alone or in combination with other antiepileptic drugs were collected. Samples were analyzed with high-performance liquid chromatography. RESULTS: Maternal venous concentrations of OCBZ and its major metabolites were at same range as cord blood concentrations (OCBZ in maternal serum, 0.19 +/- 0.16 microg/ml, and in cord serum, 0.21 +/- 0.19 microg/ml; 10-hydroxy-10,11-dihydrocarbamazepine (10-OH-CBZ) in maternal serum, 5.69 +/- 2.49 microg/ml, and in cord serum, 5.23 +/- 1.44 microg/ml; 10,11-trans-dihydroxy-10,11-dihydrocarbamazepine (10,11-D) in maternal serum, 0.29 +/- 0.22 microg/ml, and in cord serum, 0.28 +/- 0.14 microg/ml). OCBZ (0.17 +/- 0.16 microg/g placental tissue), 10-OH-CBZ (3.49 +/- 1.34 microg/g placental tissue) and 10,11-D (0.25 +/- 0.11 microg/g placental tissue) were detected in the placental tissue. The amount of OCBZ detected from placental tissue was 0.01% of the daily dose. CONCLUSIONS: OCBZ, like other antiepileptic drugs, is transferred significantly through the placenta in humans.