Psychotropic drugs

Agomelatine

Agomelatine is characterized as a melatonin agent MT1/MT2-agonist and 5-HT2C-antagonist and is controversial with respect to its effectiveness. Due to the lack of sufficient data for a judgment, the better studied antidepressants are preferable.

Amitriptyline

Amitriptyline is a tricyclic antidepressant and has a half-life of 20 hours. It is up to 95% plasma protein-bound and is rapidly metabolized to the pharmacologically equally strong nortriptyline . Six breastfeeding women taking 75–175 mg of amitriptyline a day were studied (survey in ). The M/P ratio was 1. The relative dose for an exclusively breastfed infant, including the active metabolites should not, in light of current experience, exceed 2.5%. Amitriptyline and nortriptyline could not be detected in the infants’ serum, and the babies did not have any clinical symptoms.

The development in the first year of life among the 10 infants breastfed while their mothers were taking tricyclic antidepressants, did not differ from that of artificially fed infants in a control group ( ). Amitriptyline is the drug of choice among the tricyclic antidepressants during breastfeeding.

Atomoxetine

There are insufficient data on breastfeeding with atomoxetine, an SNRI. Better studied antidepressants are preferable.

Bupropion

A case study describes bupropion ( amfebutamone ), which is also used for smoking cessation. It acts as a serotonin and also as a noradrenaline and dopamine blocker. The half-life is 21 hours. An M/P ratio of 8 was calculated. The relative dose, including the only half-so-effective metabolites, erythro-hydro-bupropion, hydroxybupropion, and threohydrobupropion, should be considered to be 1% to a maximum of 3% (survey in ). Neither in this child nor in three additional children ( ) was the medication detected in the serum. A further study with 10 mothers, who received 150 mg for 3 days and 300 mg for a further 4 days, reported an average of 6.75 μg/kg of bupropion daily plus 10.8, 15.75 and 68.9 μg/kg of the above-mentioned metabolites daily. Considering bupropion alone, the relative infant dose was 0.14%. Including all the metabolites, the authors calculate a transfer of about 2% ( ). With a 6-month-old baby, who was partially breastfed and whose mother had begun taking 150 mg of bupropion 3 days earlier, a questionable seizure was observed ( ). In another article with some printing errors, four breastfed babies whose mothers took 150 or 300 mg of bupropion daily, the recalculated weight adjusted relative infant dose was <1%, without considering the metabolites. Only in one baby was bupropion found in the urine (41 μg/L) ( ).

With a readjustment, the better studied antidepressants are preferable.

Citalopram

The SSRI, citalopram , has a half-life of about 35 hours. The activity of the metabolites, norcitalopram and desmethylcitalopram , each amounts to 13% of citalopram. On the basis of more than 65 mother–baby pairs studied ( , , ), the following picture can be drawn: The relative dose of citalopram plus the effective metabolites for an exclusively breastfed baby is, on average, 3–5% with a maximum of 10%. The medication can either not be detected in the serum – or only in traces ( ). The highest values were ca. one-fifteenth of the therapeutic maternal concentration. Restless sleep was noted in one baby about 6 weeks old, whose mother received 40 mg a day. Citalopram (205 μg/L) was found in the milk and 12.7 μg/L in the infant’s serum. A relative infant dose of 5.4% was calculated. After halving the maternal dose and introducing two feeds of infant formula, the baby’s sleep pattern normalized ( ). In three of the 31 children studied ( ) insignificant and non-specific symptoms were found – for example, restlessness in a 2 month old baby which appeared after his mother began therapy. As a precautionary measure, this mother weaned after 2 weeks and the restlessness improved. In individual cases, somnolence in breastfed child has been reported. With the other children described in the literature, toxic symptoms were not mentioned. Also, further development up to the age of 1 year was mostly unremarkable ( , , ).

A mother who took 40 mg in the evening, had up to 320 μg/L in the milk. For an exclusively breastfed baby, this is up to 6.6% as a relative dose ( ). The serum concentrations in the child corresponded to up to 1.8% of the maternal values. The abnormalities, such as irregular breathing, noted in the baby after birth, were attributed to adaptation difficulties, following intrauterine exposure. In another case, citalopram was adjusted and the baby was exclusively breastfed for 6 months. The neuropsychological development at a year and a half was judged as normal by the pediatrician ( ). Also, in a case with 60 mg of citalopram daily, the baby developed normally to the age of 6 months with primarily mother’s milk feeding ( ). Citalopram can be prescribed for appropriate indications during breastfeeding.

Clomipramine

Clomipramine , a tricyclic antidepressant, has a half-life of 32 hours. The pharmacologically active metabolites are N-desmethylclomipramine and two hydroxy-metabolites, 8-OH-clomipramine and 8-OH-desmethylclomipramine. Based on seven published reports on mother–child pairs, the average relative infant dose is 1.3% (survey in ).

In an infant who was already exposed during the pregnancy – the mother took 125 mg/day – 267 μg/L were measured in the plasma after birth. From the 7th day postpartum, the dose was increased to 150 mg/day. The maternal plasma concentration rose from 355 μg/L on day 10 to 510 μg/L on day 35. The concentration in the milk was between 270 and 624 μg/L. During the same period of time, concentrations measured in the infant’s serum declined from 45 μg/L to 9.8 μg/L (this was due to the breakdown of the drug transferred prenatally.) Assuming the highest value reported in the milk, the dose for an exclusively breastfed baby – without considering the metabolites – would be approximately 4% of the maternal weight-related dose ( ). In another study, four mother–child pairs were reported. The mothers took between 75 and 125 mg of clomipramine daily. Milk samples were not measured. Neither clomipramine nor its metabolites could be detected in the infants’ serum (< 10 μg/L; ).

Another study ( ) reported concentrations in the milk from two women similar to those reported by . The infants did not demonstrate any adverse signs from the medication. Clomipramine can be prescribed for appropriate indications during breastfeeding.

Desipramine

Desipramine , a tricyclic antidepressant, has a half-life ranging from 12 to 54 hours. It is the pharmacologically active metabolite of imipramine. Both substances are up to 95% bound to plasma proteins. On the basis of five published reports on mother–child pairs, there is an average relative infant dose of 1.6% (survey in ).

In a case report involving a daily dose of 300 mg, 381 μg/L of desipramine was measured in the milk. Mathematically, an infant would receive a maximum of 2.4% of the maternal weight-related dose if the metabolite, 2-hydroxydesipramine, was included ( ). In four additional children studied, only slight traces of the drug were measured in the serum. The infants demonstrated no adverse symptoms. Desipramine can be prescribed for appropriate indications during breastfeeding.

Dosulepine

Dosulepine (= dothiepin ), a tricyclic antidepressant, has a half-life of 9 hours and is metabolized to the three pharmacologically active metabolites, nordosulepine , dosulepine sulfoxide and nordosulepine sulfoxide . In two studies, eight and 20 breastfeeding mothers respectively, receiving dosulepine therapy are reported ( , ). The M/P ratio is about 1. With daily doses up to 225 mg, a maximum of 475 μg/L dosulepine plus 1,200 μg/L of the metabolites are reported. The highest values on the same order of magnitude were reported in another study of two women ( ). Based on these data, a maximum of 7% of the maternal weight-related dose was calculated for the infant when the metabolites were included. On average, however, it was less than 1% (survey in ). With one child, only traces of the active ingredient (4 μg/L) were detected in the serum (mother: 2.623 μg/L; ). No symptoms were reported. In a further study, prenatally exposed children aged 3 and 5 years were followed up. They demonstrated no abnormalities compared to a non-exposed control group ( ). Dosulepine can be prescribed for appropriate indications during breastfeeding.

Doxepin

Doxepin , a tricyclic antidepressant, and its equally strong active metabolite N-desmethyldoxepin , are up to 80% bound to plasma proteins. The half-life of doxepin ranges from 8 to 25 hours; that of N-desmethyldoxepin is 33 to 81 hours. In a study of two breastfeeding mothers, one of whom received 150 mg and the other 75 mg of doxepin daily, an average of 0.3–1% of the maternal weight-related dose, including the metabolite, N-desmethyldoxepin, are reported for the infant ( ). Another breastfed baby has been treated for depressed breathing and sedation. Values of 2.2 μg/L doxepin are measured in his plasma and – corresponding to the maternal concentration – 66 μg/L N-desmethyldoxepin are measured in the serum ( ). The symptoms improve after changing to artificial feeding. It would seem that an accumulation must be expected in an infant. A further case report described a 9-day-old boy with a weak suck, muscular hypotonia and vomiting. His mother took 35 mg of doxepin a day. The relative infant dose reported, including the metabolite, was only 2.5%. Doxepin was found in the infant’s serum just at detection level (10 μg/L). The metabolite was not detectable. The symptoms disappeared 48 hours after changing to artificial feeding ( ). During breastfeeding, better studied antidepressants should be given preference.

Duloxetine

There are case reports on the SNRI, duloxetine, for eight women: After 3.5 days of taking duloxetine (40 mg/day), milk samples from six women who were in the process of weaning are reported. The highest value was observed about 6 hours after the last intake. A maximum of 15 μg of duloxetine was found in the total milk supply for a day. From this, the authors calculate a maximum relative infant dose of 0.25%. The M/P ratio was 0.26. The inactive metabolites were not reported ( ). In another report on a woman taking 60 mg duloxetine daily, 64 μg/L was measured in the milk 6 hours after intake. From this, the authors calculate a 0.8% relative dose for the breastfed baby 4 hours after the last breastfeed. In turn 8 hours after the last dose, no duloxetine was detectable in the serum (detection limit 1 μg/L; ). A relative infant dose of 0.8% and a concentration in the breastfed baby, which also corresponds to 0.8% of the maternal concentration, was found in a further case report ( ). During breastfeeding, the better studied antidepressants should be given preference.

Escitalopram

The SSRI, escitalopram , is an active isomer of citalopram with a molecular mass of 414. At 56%, the protein binding is lower than that of citalopram (80%) and could, theoretically, facilitate a transfer to the milk. A case report describes a 3-week-old baby, whose weight gain was insufficient from the beginning of the maternal therapy until the age of 4 months and whose slightly elevated transaminases (liver enzymes), increased muscle tonus (hypertonia) in the upper extremities and frequent crying and hyperirritability were striking. The symptoms improved after supplementation in the fifth month of life ( ). We received a report on a newborn, who begin high-pitched crying 2 hours after a breastfeed or 5 to 6 hours after maternal intake of escitalopram every afternoon. When the intake of the tablet was switched to the morning, the symptoms also occurred in the morning. This behavior improved after supplementation and disappeared after weaning.

With eight women who took 10–20 mg/day, an average of 7.6 μg/kg plus 3 μg/kg of the metabolite, desmethylescitalopram , was calculated for the infant under steady-state conditions. This represented a total relative infant dose of around 5%. No medication was found in the blood of three of the breastfed babies (detection limit <1 μg/L). For the other five babies, the values were under 5 μg/L. The maternal values for escitalopram and its metabolites were 24 or 20 μg/L on average. Measured against the Denver developmental tests, the children developed normally ( ). Also, the baby of a woman who first took 5 and then 10 mg daily, had developed normally at 8 weeks. The authors calculated a relative dose of up to 7.7% ( ). For another woman, a relative infant dose of 4.6%, including desmethylescitalopram, was reported ( ). This child also seemed normally developed at 9 months, according to the Denver test, as did a further baby whose mother had 20 mg daily of the therapy ( ). A 5-day-old baby, whose mother took 20 mg of escitalopram during the pregnancy and during breastfeeding, developed necrotizing enterocolitis after he had already been treated in the first 2 days of life for respiratory distress syndrome ( ). The authors discuss the effect of the medication on the thrombocyte function as a cause, but an effect via mother’s milk should be viewed cautiously. With a readjustment, the better tested antidepressants should be given preference.

Fluoxetine

The oldest SSRI, fluoxetine , and its active metabolite, norfluoxetine , are up to 94% bound to the plasma protein. The half-life of fluoxetine is 4 days and that of norfluoxetine is 7 days. Thereby, it has the longest half-life of the antidepressants. The M/P ratio is 0.25. Experience with 16 mother–baby pairs in two studies shows that the relative dose of fluoxetine plus norfluoxetine taken in by the breastfed baby is, on average, 6.5% with a maximum of 17%. The babies are unremarkable ( , , ). Another case report describes an infant with screaming attacks, watery stools and vomiting, whose symptoms disappeared upon weaning to infant formula. When he was put to the breast again, the symptoms reappeared ( ). The mother took 20 mg fluoxetine daily. A relative dose of around 8%, including norfluoxetine, was calculated. Fluoxetine (340 μg/L) and norfluoxetine (208 μg/L) was reported in the serum of the 10-week-old baby – therapeutic concentrations, which would be expected in an adult treated with 20 mg daily. In another case with an irritable infant (maternal dose 20 mg/day), fluoxetine (28.8 μg/L) and norfluoxetine (41.6 μg/L) were found in the milk ( ). From this, a dose for the baby of about 11 μg/kg/day was calculated, corresponding to 3.2% of the maternal weight-related dose. Another case report describes an infant with questionable convulsive-like symptoms and a cyanotic attack, whose mother had taken carbamazepine and buspirone in addition to fluoxetine. Further development of the child was reported to be normal up to the end of the first year of life. The authors are, with justification, hesitant to conclude that there was a connection between the medication and the symptoms ( ). Four additional children, who were followed up neurologically until the age of one, were unremarkable ( ).

reports a statistically significant lower weight gain of about 9% in a group of 28 breastfed babies whose mothers were taking fluoxetine, by comparison to a control group of 34 breastfed babies without psychoactive medication. No other symptoms were reported.

In a study of the serotonin metabolism, only in one of five newborns studied was any effect through fluoxetine via the mother’s milk determined, measured vicariously via a lowering in whole-blood (platelet) 5-HT transporters. The affected baby did not have any symptoms ( ). There are theoretical concerns because an SSRI-induced serotonin transport disturbance could also have an effect on the CNS with consequences for brain development.

All in all, among 80 mother–child pairs studied, five babies had symptoms for which a connection with fluoxetine was mentioned. The vast majority of the babies were unremarkable ( , ). On the other hand, symptomatic children are even rarer with the other SSRIs. The relative infant dose is the highest with fluoxetine and the half-life is the longest. Both could contribute to a comparatively poorer tolerance by the infant. During breastfeeding, the better tolerated antidepressants are preferable.

Fluvoxamine

The half-life of the SSRI, fluvoxamine , is 16 hours. In a breastfeeding mother who took 200 mg of fluvoxamine daily, 310 μg/L were reported in the serum and 90 μg/L in the milk. Based on this, an M/P ratio of 0.3 can be calculated. Thereby, the infant would receive 13.5 μg/kg/ fluvoxamine daily, which corresponds to 0.5% of the maternal, weight-related dose ( ). A second case report observed proportionally lower concentrations when the dose was 100 mg daily. Mathematically, this too corresponded to a relative dose of 0.5%. The cognitive and motor development of the baby, who was breastfed for 5 months, and then tested at 4 and 21 months, was unremarkable ( ).

In a third mother–baby pair, with a maternal dose of 200 mg fluvoxamine daily, 48 μg/kg/ a day corresponding to a relative dose for the clinically unremarkable infant of 1.6%, was calculated ( ). A further group of authors reported on the determination of fluvoxamine levels in the serum of 10-week-old breastfed baby receiving a relative dose of only 0.6% based on the maximum active ingredient concentration in the milk. Nevertheless, 45% of the maternal serum concentration was measured in his serum. During the period of observation, up to 4 months of age, the baby’s development was unremarkable ( ). With five additional symptom-free children, no medication was detected in the blood ( , ). Fluvoxamine may be prescribed for appropriate indications during breastfeeding.

Imipramine

Imipramine , a tricyclic antidepressant, has a half-life of 6 to 20 hours. It is metabolized to the pharmacologically equally strong-acting desipramine. With a dose of 200 mg /day, a maximum of 29 μg/L imipramine and 35 μg/L desipramine has been measured in the mother’s milk ( ). By contrast, in four other mothers taking 75–150 mg/day, active ingredient concentrations of up to approximately 600 μg/L has been reported. Most of the values, however, were significantly under 300 μg/L ( ). A maximum value of 90 μg/L per day or 7% of the maternal weight-related dose is calculated for an infant. On average, however, it was significantly below 2% of the maternal weight-related dose (survey in ). Imipramine may be prescribed for appropriate indications during breastfeeding.

Maprotiline

Following treatment with 100–150 mg daily of maprotiline , a tetracyclic antidepressant, a relative dose of 1.6% was reported, without taking into account the active metabolites (survey in ). With a readjustment, better tested antidepressants should be given preference.

Mianserin

Mianserin is among the tetracylic antidepressants. It is up to about 90% bound to plasma protein and it has a half-life of about 22 hours. The primary active metabolite is desmethylmianserin . Two breastfeeding women have been studied. They had taken 40 and 60 mg, respectively, of mianserin daily. Twenty and 80 μg/L, respectively, of mianserin and 20 or 10 μg/L of desmethylmianserin were reported in the milk. Including the metabolites, this is, mathematically, a maximum of 1.5% of the weight-related dose for an infant. No medication was detectable in the serum of the first baby. With the second baby, 12 μg/L of mianserin and 14 μg/L of desmethylmianserin were measured in the urine ( ). With a readjustment, better tested antidepressants should be given preference.

Mirtazapine

Mirtazapine , along with noradrenaline and selective serotonin-inhibitors, which resemble the tetracyclic antidepressants or mianserin, has a plasma protein binding of up to 85%. The half-life is 20–40 hours. Three weeks after the birth of her child, a mother was switched from sertraline to 30 mg of mirtazapine daily. After reaching steady state, a level of 25 μg/L was measured in the maternal plasma. In the milk it was a maximum of 34 μg/L and in the baby’s serum, 0.2 μg/L were measured. Accordingly, the relative infant dose was a maximum of 1%. After 6 weeks of breastfeeding with this therapy, the baby was functionally normally developed, and weight gain was regular ( ). With eight mothers who took between 30 and 120 mg/day, an average of 8 μg/kg/day plus 3 μg/kg of the metabolite, desmethylmirtazapine , were calculated for the breastfed baby. From this, a relative infant dose between 1 and 3%, including metabolites, resulted. With four of these babies, no medication was found in the serum (detection limit 1 ng/mL). With one baby, whose mother took quite a high dose of 2 mg/kg, 1.5 ng/mL were measured in the serum. By contrast, the metabolite was not detectable. Measured against the Denver test, the seven children studied for between 1.5 and 13 months had unremarkable development ( ). In one patient who took 22.5 mg daily, a maximum of 145 μg/L was measured in the milk ( ). Based on this maximum value, a relative dose of 6% was calculated. No active ingredient was detectable in the baby’s serum. By contrast, 2 hours after the morning feed, or 14 hours after the mother had taken the medication, 10 μg/L were found in the serum of a 2-month-old baby, whose mother took 15 mg/day. This corresponded to 37% of the maternal serum concentration ( ). No specific abnormalities were observed in these children.

Mirtazapine is acceptable during breastfeeding but careful monitoring of the infant is necessary.

Moclobemide

The reversible MAO-inhibitor, moclobemide , was studied in six mother–baby pairs. An M/P ratio of 0.7 and a relative infant dose of 1.2% were reported ( ). In another study with eight mothers who took between 300 and 900 mg daily, up to 5.3 mg/L (with a daily dose of 900 mg) was measured in the milk ( ), from which a maximum relative infant dose of 2–6% was calculated. The breastfed babies were unremarkable. Also, in a further publication on four mothers, normal development of the children up to the age of 1 year was reported. Nevertheless, one mother was weaned at 2 months because of gastroesophageal reflux in her baby ( ). With a readjustment, the better studied antidepressants should be given preference.

Nefazodone

Nefazodone , a 5-HT2-receptor-antagonist with a half-life of 17 hours, was studied in three samples with two patients. With a daily dose of between 100 and 400 mg, concentrations of 50–700 μg/L of the active ingredient, including the active metabolite, hydroxynefazodone , were found in the milk. However, the sampling was done before the patients took the tablets (two single doses daily). At the time of the study, the patients had already been in treatment for at least 3 weeks ( ). From these measurements, a relative dose for an exclusively breastfed baby of between <1 and 7% was calculated. A further case report described a premature infant who, mathematically speaking, only received 0.5% of the maternal weight-related dose (300 mg) and was still admitted to the hospital because of lethargy, weak suck and problems with temperature regulation. The symptoms improved within 72 hours after weaning ( ). Nefazodone was taken off the market in 2003 due to a case of liver failure and thus, no longer plays any role in breastfeeding.

Nortriptyline

Nortriptyline , a tricyclic antidepressant with a half-life of 37 hours, is the active metabolite of amitriptyline . Experience with a total of 27 mother–baby pairs, where the mothers were taking 50–175 mg of nortriptyline a day, showed that acute toxic symptoms among the breastfed infants would hardly be expected. The M/P ratio (about 1) and the relative infant dose (not over 2–3%) corresponded to the values with amitriptyline (survey in , ). Only in the case of a 4-week-old baby, whose mother took 60 mg a day and had a serum concentration of only 42 μg/L, was nortriptyline measured in the serum at 10 μg/L. With other infants only minute amounts of a 10-hydroxy-metabolite were found. Nortriptyline can be prescribed for appropriate indications during breastfeeding.

Opipramol

For opipramol , a tricyclic antidepressant, an older study of 10 women reported an M/P ratio of 0.1 and a relative infant dose of only 0.3% ( ). With a readjustment, better tested antidepressants should be given preference.

Paroxetine

The half-life of the SSRI paroxetine is 22 hours. Based on a study of a total of 110 mother–baby pairs, the relative dose for an exclusively breastfed baby is about 1%. No paroxetine could be detected in the serum of almost all of the infants studied. No clinical abnormalities were observed ( , , , ). Peak values in the milk correlated with the dose. The highest value was 101 μg/L with a maternal dose of 50 mg daily. This represents a relative infant dose of less than 2% ( ). With a daily dose of 20 mg paroxetine, 7.6 μg per liter is found in mother’s milk. For the infant, that had a value of 1.14 μg/kg/day, and this represented about 0.4% of the maternal weight-related dose ( ). The concentrations in the serum of 16 infants, whose mothers took 10–50 mg daily, were under the detection level (<2 μg/L). In a further study with 40 mother–baby pairs and a maternal daily dose of 10–40 mg, only minimal amounts could be detected and only traces – if that – could be detected in the infants’ serum. However, the concentration in the mothers’ milk at 153 μg/L was more than five-fold above the average (cited in , ).

found no statistically significant deviations in the development and weight gain of 27 infants followed up to the age of 1, compared to a control group. Paroxetine can be prescribed for appropriate indications during breastfeeding. However, for a possible new pregnancy, it is not appropriate.

Reboxetine

With four women who took between 4 and 10 mg of the SNRI, reboxetine , daily, the highest concentrations in the milk −10–21 μg/L – were measured, on average 4 hours after taking the medication. Correspondingly, 7–16 μg/L was found in the mothers’ serum. The relative infant dose was calculated at 1.4–2.5%. Among the four babies, a maximum of 5 μg/L was found in the serum – in so far as it was detectable at all ( ). Three of the four children developed normally measured against the Denver test. The fourth baby had delayed development; however, this had already been noticed before the start of the maternal medication. With a readjustment, the better tested antidepressants should take precedence.

St. John’s wort (Hypericin)

This substance is discussed in Chapter 4.13 .