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What is the short- and long-term toxicity of paroxetine and escitalopram on breastfed infants whose mothers are on postpartum depression treatment? Using randomized,  double-blinded clinical trials. Essay Example

WHAT IS THE SHORT- AND LONG-TERM TOXICITY OF PAROXETINE AND ESCITALOPRAM ON BREASTFED INFANTS WHOSE MOTHERS ARE ON POSTPARTUM DEPRESSION TREATMENT?

Abstract

Medical literature describes three type of postpartum mood disorders, which are postpartum depression, postpartum blues and, and postpartum psychosis. Whereas the last two are relatively common, and account for nearly 80% of the postpartum mood disorder population, but resolve on their own and over a period of time; it is postpartum depression that offers a major clinical challenge since it is not self-limiting. Postpartum depression thus meets DSM-IV criteria for a major depressive episodes, lasting a few weeks (Campbell 1991). Women with major depressive history or history associated with previous pregnancy are at major risk. While the condition has been shown to have negative developmental impact on breastfed infants of these mothers, the use of antidepressants on them and their subsequent effects on infants through breast milk has always been a debate of concern. The risks have been shown to outweigh at least in case of short-term exposure to antidepressants during breastfeeding, where further investigation is on to determine the long-term effects on infants. Under this background this paper intends to determine both short and long-term effects of two such antidepressants, paroxetine and escitalopram on breastfed infants whose mothers are on postpartum depression treatment.

Introduction

On an average, around 13% of women who recently given birth, suffer from postpartum depression. Considered as a natural aftermath of the birth-giving process, it often goes unrecognized, underestimated, or undertreated. This can have a significant impact on the life of the infant being nursed , since studies have noted associations between maternal depression and impaired maternal-infant interactions(Murray at al 1996)), cognitive and emotional development(ref), and anxiety and lower self-esteem (Beck 1998)). When medical professional understand the need for treating postpartum depression in mothers, the only deterrent coming in the way of their use is about their potential adverse effects on the nursing infant (Politano et al 1992).

These concerns have been highlighted by several studies and behavioral outcomes and infant serum levels have been reported for breastfeeding newborns from mother treated by one or more types of antidepressants including selective serotonin reuptake inhihibtors (SSRIs) and tricyclic antidepressants (TCAs). These studies have reported infant serum levels of antidepressants, rather than anitdepressants’ concentrations in the breast milk. This is because serum levels as against breast milk are medically recognized as direct determinants of the drug exposure to antidepressants used on mother (Stowe et al 1997). This has prompted certain drug regulatory authorities, like USFDA, not to recommend any antidepressants to mothers when they are breastfeeding (Yoshida & Kumar 1996).

Several studies (Table 1) have provided information of clinical utility on transmission of antidepressants to nursing infants, even though there were some inherent methodological weaknesses associated with these studies, like low sample size, varying parameters between different studies even though goal to be established was one, and more importantly a relatively short-term follow up lasting from a week to a few month during the course of treatment but not beyond that period.


Table 1. Antidepressant Drug Therapy in Breastfeeding Mothers: Infant Serum Drug Levels and Behavioral Outcomes

No. of Infants

Maternal Dose

Infant Age (weeks)

Infant Serum Drug Levels (Lower Limit of Detection)*

Adverse Infant-Related Clinical Outcomes

What is the short- and long-term toxicity of paroxetine and escitalopram on breastfed infants whose mothers are on postpartum depression treatment? Using randomized,  double-blinded clinical trials.

Selective Serotonin Reuptake Inhibitors (SSRIs)

What is the short- and long-term toxicity of paroxetine and escitalopram on breastfed infants whose mothers are on postpartum depression treatment? Using randomized,  double-blinded clinical trials. 1

 Citalopram (Celexa)

  Jensen et al, 1997

20 mg/day

  Schmidt et al, 2000

40 mg/day

12.7 ng/mL

Uneasy sleep, normalized with dose reduction

  Rampono et al, 2000

0.36 mg/kg/day (median)

Not detected; 2.3 ng/mL (1 ng/mL)

  Spigset et al, 1997

20–40 mg/day

Not discussed

 Fluoxetine (Prozac)

  Brent & Wisner, 1998

20 mg/day

Limp, unresponsive, cyanotic (mother also taking carbamazepine and buspirone)

  Burch & Wells, 1992

20 mg/day

Not discussed

  Chambers et al, 1999

Not given

Not discussed

Lower growth curves (average deficit of 392 g)

  Hendrick et al, 2001

10–60 mg/day

Fluoxetine, <1–84 ng/mL; Norfluoxetine, <1 — 265 ng/mL (2 ng/mL)

  Isenberg, 1990

20 mg/day

Not discussed

Irritability

  Kristensen et al, 1999

0.24–0.94 mg/kg/day

Not detected; 252 ng/mL (10 ng/mL)

Colic in 2 infants; irritability, crying, and poor feeding in 2 infants (one of these also had methadone exposure)

  Lester et al, 1993

20 mg/day

Fluoxetine, 340 ng/mL; Norfluoxetine, 208 ng/mL

Crying, vomiting, diarrhea, and decreased sleep, problem reversed with formula feeding

  Taddio et al, 1996

0.17–0.85 mg/kg/day

Not detected in the one infant sampled (1 ng/mL)

  Yoshida et al, 1998

20–40 mg/day

Fluoxetine and nonfluoxetine not detectable (2 ng/mL)

 Fluvoxamine (Luvox)

  Hendrick et al, 2001

100–150 mg/day

Not detected (1 ng/mL)

  Piontek, 2001

300 mg/day

Not detected (2.5 ng/mL)

None, for up to 2–3 years after exposure

  Wright et al, 1991

200 mg/day

Not discussed

  Yoshida et al, 1997

100–200 mg/day

Not discussed

 Paroxetine (Paxil)

  Hendrick et al, 2001

5–30 mg/day

Not detected (1 ng/mL)

  Misri et al, 2000

10–40 mg/day

Not detected (0.1 ng/mL)

  Ohman et al, 1999

10–40 mg/day

Not discussed

  Stowe et al, 2000

10–50 mg/day

Not detected (2 ng/mL)

 Sertraline (Zoloft)

  Altshuler et al, 1995

100 mg/day

Not detected (0.5 ng/mL)

  Dodd et al, 2001

50–150 mg/day

Not detected (2 ng/mL)

  Epperson et al, 2001

25–200 mg/day

Not detected (2.5 ng/mL)

  Hendrick et al, 2001

25–200 mg/day

Not detected in 28; 2–8 ng/mL in 2 (1 ng/mL)

  Holland, 2000

Not discussed

Not discussed

Reduced breast milk supply

  Stowe et al, 1997

25–150 mg/day

Sertraline, undetectable or <3 ng/mL; desmethyl-sertraline, undetectable or <10 ng/mL (1 ng/mL)

  Wisner et al, 1998

50–200 mg/day

Sertraline, not detected or <64 ng/mL; N-desmethyl-sertraline, not detected or <68 ng/mL (2 ng/mL)

Tricyclic Antidepressants (TCAs)

 Amitriptyline (Elavil)

  Bader & Newman, 1980

100 mg/day

Not detected (10 ng/mL)

Not discussed

  Breyer-Pfaff et al, 1995

175 mg/day

Not detected (5 ng/mL)

  Brixen-Rasmussen et al, 1982

75–100 mg/day

Not detected (5 ng/mL)

  Erickson et al, 1979

150 mg/day

Not detected (28 ng/mL)

Not discussed

  Pittard & O’Neal, 1986

100 mg/day

Not discussed

Not discussed

  Yoshida et al, 1997

100–175 mg/day

Not detected in one, 7.5 ng/mL in one (0.1 ng/mL)

Probably none (1 infant was hypotonic before and after exposure)

 Clomipramine (Anafranil)

  Schimmell et al, 1991

125 mg/day

9.8–45.4 (20 ng/mL)

  Wisner et al, 1995

75–125 mg/day

Not detected or not quantifiable (10 ng/mL)

  Yoshida et al, 1997

75–125 mg/day

Not detected in one; 3.2–5.5 ng/mL in one (0.1 ng/mL)

 Desipramine (Norpramin)

  Stancer & Reed, 1986

300 mg/day

Not detected (1 ng/mL)

 Doxepin (Sinequan)

  Frey et al, 1999

35 mg/day

Doxepin, 10 µg/L; N-desmethyldoxepin not detected (10 ng/mL)

Poor suckling and swallowing, drowsiness, hypotonia, vomiting, weight loss

  Kemp et al, 1985

150 mg/day

Not detected (5 ng/mL)

  Matheson et al, 1985

75 mg/day

Doxepin, 3 µg/L; N-desmethyldoxepin, 58–66 µg/L (7 ng/mL)

Sedation, respiratory depression

 Imipramine (Tofranil)

  Erickson et al, 1979

150 mg/day

Not detected (28 ng/mL)

Not discussed

  Sovner & Orsulak, 1979

200 mg/day

Not discussed

  Yoshida et al, 1997

75–150 mg/day

Not detected in 2; 0.6–7.4 ng/mL in two (0.1 ng/mL)

 Nortriptyline (Pamelor)

  Altshuler et al, 1995

125 mg/day

Not detected (10 ng/mL)

  Mammen et al, 1997

Not discussed

Nortriptyline not detected; E-10-hydroxynortriptyline, <4 (2 ng/mL)

  Matheson & Skjaeraasen, 1988

75–100 mg/day

Not discussed

  Wisner & Perel, 1991

50–80 mg/day

Nortriptyline, not detectable; 10-hydroxynortriptyline, 5–11 ng/mL in 2 infants (4–5 ng/mL)

  Wisner & Perel, 1996

75–110 mg/day

Not detected (<4 ng/mL)

  Wisner et al, 1997

60–150 mg/day

0–10 ng/mL in 6 term infants; 16 ng/mL in the single preterm infant (4 ng/mL)

Other Antidepressants

 Buproprion (Wellbutrin)

  Briggs et al, 1993

100 mg/day

Not detected (25 ng/mL)

 Nefazodone (Serzone)

  Yapp et al, 2000

300 mg/day

1270 ng/mL (lower limits of detection not given)

Drowsiness, lethargy, hypothermia, and poor feeding (preterm infant)

 Venlafaxine (Effexor)

  Ilett et al, 1998

3–8 mg/kg/day

Venlafaxine, not detected (4 ng/mL); O-desmethyl-venlafaxine, 23–225 ng/mL (3 ng/mL)

  Ilett et al, 2002

225–300 mg/day

Venlafaxine, not detected; 5 ng/mL; O-desmethyl-venlafaxine, 1.5–5.7 ng/mL (1 ng/mL)

Discussion

Recent information suggests that depression itself has a major negative impact for infants and that it may interfere with optimal parenting producing significant neurobehavioral delay in infants. Many women presenting with depressive symptoms may not require pharmacotherapy. Early postpartum, sleep deprivation, and stress are clearly normal and general support may be all that is required. But in some patients with severe depression, therapy is clearly indicated. For these reasons it is important that major depression in breastfeeding women be closely monitored and if necessary, be treated.

In understanding the problems related to possible toxicity that gets passed on from the mother to the breastfeeding infant it becomes important that one understand the fact that breastfeeding is an important process that is beneficial to the mother as well as the infant. The process and breast milk have been termed as a source of irreplaceable nutrition for the infant by the American Academy of Pediatrics (AAP). Also to be noted is the fact that in comparison to infants that are higher bottle-fed, breast-fed infants are known to have comparatively lower rates of, respiratory difficulties, gastrointestinal disease, and allergies among other problems (Chen et al1988, Rogan and Gladden 1993). Also noteworthy is the fact that breast-feeding ends up contributing to the healthy development of a bond between the mother and the infant besides ensuring healthy development of the infant itself.

The effects that medication has on the infant are determined by the absorption levels and the metabolism have on the infant. Also it is to be noted that children that are younger than 6 months tend to possess a longer gastric drainage time. This ends up allowing the drug to get more degraded ultimately translate into lowering the absorption. Also important is the fact that infants possess a gastric pH which means that the more basic compounds tend to remain un-ionized, and therefore work along the lines of a higher absorption rates as compared with acidic compounds. These patterns are more often to be found in younger infants.

As described, psychotropic medications that are present in maternal serum diffuse into breast milk to varying degrees. The concentration of medication in milk is frequently compared with the concentration in maternal serum to quantify the extent of passage, which is known as the milk-to-plasma ratio (M/P). In general, compounds that are weakly protein-bound, highly lipid-soluble, weakly basic, and small in size have higher M/P ratios. Ratios greater than 1 indicate that the medication is present in higher concentrations in breast milk than in maternal serum. The higher the M/P, the greater the infant exposure to medication.

In the past years, the older tricylic antidepressants were the mainstay of depressive therapy. While they have been thoroughly studied in breastfeeding mothers are generally considered safe, poor patient compliance and a high side effect profile generally preclude their use. With the introduction of the SSRIs like paroxtine and escitalopram , the use of antidepressants has increased enormously.

In general the SSRIs are well tolerated and highly effective and increasingly a number of studies demonstrate that they are relatively safe in breastfeeding mothers. According to research, a selective serotonin-reuptake inhibitor should be the first-line drug because such agents carry a low risk of toxic effects in patients who take an overdose and are easy to administer, and have been used relatively frequently in breast-feeding women. Any drug should be initiated at half the usual starting dose (Wisner et al., 2002).

Paroxetine a typical SSRI with inactive metabolites. Paroxetine is a lipophilic agent and has a large volume of distribution, so plasma concentrators are low and breast milk concentrations are 7-8 ug.L. The estimated dose to the infant is only 0.34 per cent of the mother’s dose. In some studies, the drug was not detected in the plasma of 7-8 infants, and no adverse effects have been reported in any of the other nursing infants whose mothers have taken paroxetine.

Clinical studies clearly suggest that transfer of these agents into milk is quite minimal and virtually no side effects have been reported in breastfeeding infants (Stowe et al 1997). One of the better known studies that sought to understand the short term impact of paroxetine on a breastfeeding infant was undertaken by Misri (2000). The study tries to analyze the concentrations of the drug in the maternal serum, infant serum samples, and the breast milk so that it could estimate immediate infant exposure through breastfeeding. The study was based on a randomized trial method along a sample size of 25 infants, and found that the drug, like the other selective serotonin reuptake inhibitors, which have already been the subject of studies, gets transferred from the breast milk of nursing mothers to the nursing infant.

According to research, a standard dose of paroxetine transferred was estimated to be about 1.1 per cent of the maternal dose (Hendrick et al 2001). This also translated to the fact that in the immediate term no major adverse effects were found in any of the infants of the study. However, the conclusion stood that more studies were needed for devising a more systematic method for observing and recording any adverse effects, particularly to assess the long-term ipact of these drugs on breastfeeding infants. This was also reflected in a study by Gjerdingen (2003), who reported that for most of the infants, serum levels of antidepressant drugs were either not detectable or very low, which would translate into the fact that there would be no short term impacts.

The aforementioned study by Stowe et al (2000) also found that the amount of paroxitine that is transferred by the mother’s milk to the breastfeeding infant is too negligible for it to have any substantial adverse event on the infant. The objective of the study was to finalise the amount of exposure to medication that an infant must have undergoes because of breastfeeding during maternal treatment with paroxetine. The study made use of breastmilk which was collected after 10 days of maternal treatment with paroxetine at a stable daily dose. The samples were put through an analysis through high-performance liquid chromatography with ultraviolet detection and a limit of detection. The study found that the result was an extension of earlier data given the fact that it demonstrated that the excretion of the medicine through breast milk sera was too negligible for it to have any major short term impact on the infant. The low concentrations of paroxetine in infant serum and lack of any observable adverse effects after maternal use of this medication.

Escitalopram, on the other hand, is the S-isomer of citalopram, widely used antidepressant. While only a small amount of information is available on the fact that doses of up to 20 mg daily of escitalopram enable the production of low levels of breast milk, it is also found that the institutionalization of the drug in small doses does not have any significant short term impact on the infant, especially if he is more than two months old. In essence the medicine is a form of citalopram that is taken in a lower dose; hence it is preferred over citalopram. Experience with it during breastfeeding is very limited, but no adverse effects have been reported either.

One study found that racemic citalopram serum levels in infants were determined by their CYP2C19 genotype, with slow metabolizers more likely to have detectable serum levels.

In 8 breastfed infants whose mothers were taking an average of 199 mcg/kg daily of escitalopram (10 or 20 mg daily), escitalopram and desmethylescitalopram were undetectable in the serum of 3 infants (<1 mcg/L). The drug and metabolite serum levels were less than 5 mcg/L in all the other infants. Their mothers’ serum levels of the drug and metabolite averaged 24 and 20 mcg/L, respectively.

At 5 days of age, an infant was readmitted to the neonatal intensive care unit with a diagnosis of necrotizing enterocolitis. The infant, whose mother had taken escitalopram 20 mg daily throughout pregnancy and while breastfeeding, was for the first two days following birth in intensive care because of respiratory distress. It was deduced that escitalopram might have been responsible for the enterocolitis because of its effect on platelet aggregation; a possible case of drug reaction (Potts et al 2007).

Studies in most cases have shown that escitalopram when instituted in small amounts in any given mother who is breastfeeding does not have an impact, given the fact that the amount of escitalopram seeping through in the breastmilk serum is anyways small. Some of the studies have been cited herewith to prove the hypothesis.

There are several published reports on escitalopram and breastfeeding. Very small amounts of escitalopram are found in breast milk but no serious harmful effects have been found in breastfed babies . Rampono and colleagues (2006) investigated transfer of escitalopram and its demethyl metabolite into milk, the relative and absolute infant doses via milk to assess any adverse effects in the breastfed infant.

Women took a median dose of 10 mg day(-1) for escitalopram and absolute infant doses were 7.6 microg kg(-1) day(-1) for the drug. Infants had met normal developmental milestones with no history of adverse effects. Rampono and colleagues concluded that escitalopram was a safe drug for use during breastfeeding since its absolute infant dose is lower than that for any equivalent antidepressant.

Conclusions and future directions

Many medical professional and lactating mothers alike are hesitant to use of antidepressant treatment for postpartum depression because of previously documented adverse effect histories on infants. When medical literature is scanned for use of these drugs in postpartum depression, it is hard to find conclusive litratur on randomized controlled trials in breast-fed infants and studies that establish long-term follow up results. At the same time among SSRIs drugs like escitalopram may not be considered as drugs of choice since the information, even though appearing as compatible, may not be so as the overall knowledge of antidepressants’ use on postpartum depression is still very scarce and largely inconclusive. Many studies have documented the favourable use of these drugs but given the proportion of research needed to form a firm opinion, the studies conducted can be said as too little. The studies have documented that only low doses of these drugs are transferred to infants, but that doesn’t offer a justification of their use even in infants who are either premature, have some neonatal disorder or any metabolic disturbances; as such infants can be grossly vulnerable to adverse events associated with these drugs.

Despite this since the pharmacological intervention in severe postpartum depression in lactating mothers forms the only option available, the recommendation in such clinical conditions would be first to establish safety of infants whose mothers are on antidepressant treatment. This can be done by establishing a safety index that can be established by assessing the degree adverse events in infants whose mothers are on antidepressants and frequencies associated with the same by comparing previous adverse reports of infants exposed to antidepressants through breast milk and combined total healthy outcomes achieved in these. The former can be taken as the numerator and the latter a denominator; and the sum divided by 100. If the value that I got is < or =2, it would indicate the drug to be administered to mother is relatively safe for the infant; if it is 2.1-10, then it must be used with caution; and if the value is >10, then the drug must be contraindicated for use.

References

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