What are the recommendations today concerning antidepressive treatment during lactation?/nBackgroun

Fråga: What are the recommendations today concerning antidepressive treatment during lactation?

Background: A mother is nursing her one-month-old infant. The patient is now mainly suffering from anxiety, but has previously been treated with nortriptyline (poor clinical response) and paroxetine (good clinical response) due to depression.

Sammanfattning: Prescription of an antidepressant for a breast-feeding woman implies a case specific risk-benefit decision. A tricyclic antidepressant is probably still drug of choice if nursing is wanted. Fluoxetine may be more prone to reach significant concentrations in the infant than citalopram, fluvoxamine, paroxetine and sertraline. However, the weight adjusted citalopram dose is close to that reported for fluoxetine. Therefore, it is suggested to also be cautious with citalopram treatment during lactation. By avoiding breast feeding during the peak absorption phase, the exposure of the infant can be reduced to some extent. During antidepressant treatment infants should be closely monitored for side effects. Although short-term adverse effects in infants from exposure through nursing is not reported, except for one fluoxetine case, future studies that assess the potential long-term consequenses are needed.

Svar: Antidepressants are lipophilic drugs that pass into breast milk. These drugs are well absorbed by the infant´s gastrointestinal tract, and elimination is mostly through hepatic metabolism. Therefore, concentration of drug in the infant´s plasma, rather than milk concentration, is the most relevant indicator of exposure to medication and hypothetical drug effect (1).

The plasma concentrations achieved in the infant vary with the maturity of the metabolic and excretory systems (2). Younger infants (less than 2 weeks old), metabolize and excrete drugs less efficiently than older infants, and would therefore be expected to have higher plasma concentrations (2,3). However, this system matures by 2-3 months of age to a metabolic rate two to six times faster than that of adults. The increased metabolic disposition rate begins to decline gradually at 2-3 years of age and reaches that of adults after puberty (3). In addition, glomerular filtration rate and tubular secretion are relatively low in neonates, about 30-40 per cent and 20-30 per cent lower than adult levels, respectively (4).

Although antidepressants are transferred to human milk, the doses delivered will always be low, because of the high volume of distribution that makes plasma concentrations and subsequent milk concentrations low in the mother (5).

For tricyclics only 1-2 per cent of the maternal dose/kg will pass into the breast milk (6). Data on infant tricyclic plasma levels suggest that full-term infants over 10 weeks of age have a low risk of negative effects secondary to maternal tricyclic treatment. No adverse effects have been reported and sometimes only very low drug concentrations have been found in infant plasma (3). The only exception is doxepin, which is not available on the Swedish market. Published studies support the possibility to use amitriptyline, nortriptyline, desipramine and clomipramine during breast-feeding (3,6).

There is less information concerning the excretion of the newer selective serotonin reuptake inhibitors into breast milk. In FASS it is stated that even in therapeutic doses, there is excretion of significant amounts of fluoxetine, fluvoxamine and paroxetine posing risk to the nursing infant. However, the documentation is insufficient for citalopram and sertraline to judge the risk in the nursing infant (7).

Fluoxetine has non-linear pharmacokinetics and the main metabolite norfluoxetine is pharmacologically active (6). The very long half-lives of fluoxetine and norfluoxetine are one to three days and seven to 15 days, respectively (7). Continuous exposure through breastmilk may give significant plasma concentrations in the infant of both compounds (3,8). A case report suggests a causal relationship between adverse symptoms and fluoxetine in milk. An infant became colic on a maternal dose of 20 mg for three days. Four days after switching to a formula, the symptoms subsided. However, the symptoms recurred when the six-week-old infant had breast milk again. Milk concentration showed 69 ng/ml fluoxetine and 90 ng/ml norfluoxetine. However, being breast-fed for one day, infant plasma concentrations of fluoxetine and norfluoxetine were as much as 340 ng/ml and 208 ng/ml, respectively (9)

On the other hand, in a study with ten breast-fed infants no adverse effects were observed. The daily infant fluoxetine dose was estimated to be about 4-8 per cent of the maternal dose (mg/kg) (7,9). In another study with ten nursing women the estimated infant doses of fluoxetine and norfluoxetine were 10.8 per cent or 6.5 per cent of the maternal dose. Adjusted on a mg/kg basis in a 4 kg infant, these estimates were calculated on a milk consumption of 1000 ml/day or 150 ml/kg/day, respectively (2,10).

Twelve women treated with sertraline doses of 25 to 200 mg/day had sertraline and desmethylsertraline milk concentrations with a gradient from fore milk to hind milk. The highest concentrations of sertraline were observed in the hind milk 7-10 hours after maternal dose. All plasma samples from the infants were obtained 2-4 hours after morning nursing. Sertraline levels were detectable in three infants and six had detectable concentrations of the less active metabolite desmethylsertraline (4). In another study including 9 nursing mother-infant pairs, the maternal doses ranged from 50 to 200 mg/day. Infant sertraline levels were very low (less than 2 ng/ml) in 7 of the 9 infants and low (3 ng/ml) in one. N-desmethylsertraline were also low (6 ng/ml or less) in 7 of the 9 infants (11). In both studies no adverse effects were observed in the infants.

In addition, a 24-hour analysis of sertraline levels in breast milk showed to be lowest within the 2 hours before and one hour after ingestion of the drug. The highest levels were seen 5 to 9 hours after drug intake (12).

The effects of 5-hydroxytryptamine (5-HT) transport on early neurodevelopment is unknown. In humans, platelet and neuronal 5-HT transporters are identical, and animal studies indicate that reuptake inhibitors cause similar central and peripheral blockade. In a study 5-HT levels in whole blood from 4 mothers and their nursing infants were measured before and after sertraline treatment. Two had 100 mg daily for 9 weeks and the other two 50 mg daily for 12 weeks. Platelet 5-HT declined to approximately 10 per cent of the base-line level in the mothers after treatment, while little or no change was seen in the infants. This indicates that platelet 5-HT levels and transport were not reduced in the infants. The authors conclude this to be consistent with the low plasma concentrations of sertraline in the nursing infants (13).

Fluvoxamine has non-linear pharmacokinetics and a terminal half-life of 15 hours (6). A mother who breast-fed her child during treatment with fluvoxamine 100 mg/day, had a maternal plasma concentration of 0.17 mg/l and 0.05 mg/l in breast milk. The ratio of milk/plasma concentration was 0.29. The infant´s dose through breast milk was estimated to about 0.5 per cent of the maternal dose (14). The same milk/plasma ratio was previously found when a mother took 200 mg fluvoxamin daily. The infant was followed up to 21 months and showed no toxic effects of fluvoxamine. Based on these two cases so far, the authors suggest no contraindication for breast-feeding during fluvoxamin treatment (14).

Citalopram is a weak base (pKa 9.5), which tends to concentrate in milk with a lower pH than that of plasma. The excretion of citalopram in breast milk was studied in two patients and the estimated relative dose ingested by the infants was 0.7-5.9 per cent of the weight adjusted maternal dose. Because the weight adjusted dose of citalopram is close to that reported for fluoxetine, the authors suggest caution with the administration of citalopram to lactating mothers (15). However, for fluvoxamine, sertraline and paroxetine, the weight adjusted dose to the infant has been calculated to be 0.5 per cent, 0.45 per cent and 0.34 per cent, respectively (15). In another case, the milk/plasma ratio was about 3 for both citalopram and desmethylcitalopram. The peak milk concentration of citalopram occurred 3-9 hours after drug intake by the mother. The infant received about 5 per cent of the weight adjusted maternal dose (16).

Paroxetine has a half-life of about 24 hours and linear kinetics at recommended doses. Low concentrations of paroxetin in milk have been measured in four lactating mothers after single doses of 50 mg. The weight adjusted dose that reaches the infant was estimated to 1-3 per cent of the maternal dose (6). In Drugline a case report describes that the weight adjusted dose to an infant was 0.5 per cent of the maternal dose. No negative effects were observed in this infant (17).

It should be pointed out that the long-term effects on neurobehavior and development from exposure to these potent serotonin uptake blockers during a period of rapid central nervous system development have not been studied (18))