Antipsychotics and Breastfeeding

Chlorpromazine

Chlorpromazine is a classical phenothiazine. The literature on the use of chlorpromazine in nursing mothers is quite old, and milk and infant serum level data may not be accurate. Nevertheless, amounts in milk have been reported to be low with an RID of ∼2%. Most reports found no detectable drug in infant serum, but the drug has been detected in two infants’ urine where it may have concentrated. A few cases of infant drowsiness have been reported among infants whose mothers were taking chlorpromazine. In some cases, mothers were also taking other drugs that could cause sedation. Many reports found no discernable adverse effects, including some with some long-term follow-up.

In a small prospective study on the long-term effects of antipsychotics in breastfed infants, a decline in developmental scores was found at 12–18 months of age in three infants of mothers taking both chlorpromazine and haloperidol. Nine infants exposed to chlorpromazine, haloperidol, or trifluoperazine alone developed normally.

Other phenothiazines

Trifluoperazine and perphenazine have a few reports of milk levels. Milk concentrations were quite low to undetectable with an RID estimated to be <1%. Only a few exposed infants (4 with trifluoperazine and one with perphenazine) have been reported. One infant who was under 2 weeks of age had measurable amounts of serum trifluoperazine, but the mother had been taking the drug throughout pregnancy, so the contribution of breastfeeding is unknown. None of the five infants had any adverse effects, including long-term developmental effects at 30 months in two of them. These two phenothiazines are less sedating than chlorpromazine, which might account for the lack of infant drowsiness.

Haloperidol

Haloperidol is the only butyrophenone used in the United States to treat psychiatric conditions. Maternal doses of haloperidol up to 10 mg/day produced low levels in the milk of 15 mothers and in their infants’ serum. No adverse effects have been reported in breastfed infants when haloperidol was used alone, including limited long-term follow-up data that showed no adverse developmental effects. However, use with other antipsychotic drugs might occasionally negatively affect the infant as noted with chlorpromazine.

A woman diagnosed with schizophrenia was taking risperidone 1.5 mg/day during late pregnancy and postpartum while nursing her full-term infant. At 2 weeks postpartum, haloperidol 0.8 mg/day was added because of a recurrence of symptoms. At these dosages, no adverse effects were seen in the infant. Because of recurring symptoms, the dosage of haloperidol was increased to 1.5 mg/day. Three days later, the infant experienced excessive sedation, poor feeding, and slowing in motor movements. A pediatric assessment found no medical reason for these effects. Breastfeeding was stopped and the infant’s symptoms resolved completely in 5 days.

Flupenthixol and zuclopenthixol

These drugs are thioxanthenes that are only available outside of the United States. Flupenthixol (or flupentixol) was measured in the milk of four women and in the serum of one breastfed infant. Levels in milk were low, and the drug was undetectable in the infant’s serum. The infant was followed for 4 months, and no adverse effects were seen. A similar drug, zuclopenthixol (or zuclopentixol), has been studied after the oral and depot injection routes of administration. In the seven women who have been studied, milk levels were low and in six breastfed infants, five of whom were 2 months or under, no immediate adverse effects such as infant drowsiness were noted.

No breastfeeding information is available for any other first-generation antipsychotic drugs.

Clozapine

The first marketed atypical agent was clozapine, which is virtually free of extrapyramidal effects, but unfortunately can cause agranulocytosis. This adverse effect has caused a decrease in its prescribing, but it is still used with careful monitoring when other agents have failed. Clozapine has been measured in the milk of one mother. It appeared to have an RID of ∼1%, although the timing of sample collection was not described. In an infant partially breastfed by a mother taking clozapine during pregnancy and postpartum, the infant’s serum levels decreased from 56% of the mother’s serum level at birth to 6.5% at 33 hours postpartum.

Follow-up of infants exposed to clozapine through breast milk found drowsiness in one infant, agranulocytosis in another and delayed speech in a third. None of these could definitively be pinned to clozapine use, though. Two other infants were breastfed during maternal clozapine use and had no neurodevelopmental disorders at 6 months and 1 year of age.

Olanzapine

This is an early second-generation agent that has more extensive breastfeeding data than most other antipsychotics. Maternal doses of olanzapine up to 20 mg/day produced low levels in the milk of 25 patients and undetectable levels in the serum of 11 breastfed infants.

In all, 151 breastfed infants whose mothers were taking olanzapine have been reported in the literature. A few cases of dose-related infant drowsiness, irritability, tremor, and insomnia have been reported in the short term. Long-term follow-up found some cases of speech delay, motor development delay and failure to gain weight, but numerous cases of normal development have also been reported. Many of the infants were also exposed to olanzapine in pregnancy, so the adverse effects cannot necessarily be attributed to breastfeeding alone. Systematic reviews of second-generation antipsychotics have concluded that olanzapine is a first-line antipsychotic during breastfeeding.

A new olanzapine combination product contains samidorphan, an opioid partial agonist, which has not been studied during breastfeeding. The combination product appears to be acceptable during breastfeeding, but it might cause more drowsiness or respiratory depression than olanzapine alone.

Quetiapine

This drug is similarly data-rich compared with other antipsychotics. Maternal quetiapine doses of up to 400 mg/day produced doses in milk that had an RID of <1% in 31 patients. Limited long-term follow-up of infants exposed to quetiapine found that infants mostly developed normally. Systematic reviews of second-generation antipsychotics have concluded that quetiapine is a first- or second-choice antipsychotic agent during breastfeeding.

Risperidone

Data from six women indicate that maternal risperidone doses of up to 6 mg/day produce an RID of just under 5%. Reports of four breastfed infants found no risperidone in serum, but its active metabolite was found in one. Sedation, failure to thrive, jitteriness, tremors, abnormal muscle movements, and respiratory depression have been reported in infants exposed to risperidone in milk. Systematic reviews of second-generation antipsychotics concluded that risperidone is a second-line agent during breastfeeding because of the limited data available and higher excretion into milk compared with other drugs.

In an interesting case report, a woman in India who was diagnosed with undifferentiated schizophrenia took risperidone 4–5 mg/day and trihexyphenidyl 2 mg/day throughout five pregnancies. She breastfed each infant for 20–24 months. No adverse developmental consequences were noted in any of the children. At the time of publication, the oldest three children, aged 26, 23, and 22 years, had completed their education and were employed, while the youngest two were 15 and 19 years old and doing well academically.

Paliperidone

Paliperidone or 9-hydroxyrisperidone is the active metabolite of risperidone. No studies have measured paliperidone in breast milk after administration of paliperidone itself. However, 9-hydroxyrisperidone has been measured in milk and serum during risperidone therapy and one can estimate an RID of ∼1% for paliperidone using these data. Paliperidone is available only as long-acting products. Long-acting injectable formulations may continue to deliver small amounts to breast milk for many months.

Iloperidone

This is a newer drug that is chemically similar to risperidone and paliperidone. No data are available on its use during lactation.

Lurasidone

This drug is also chemically similar to risperidone. Only one mother-infant pair has been reported. A woman with depressive type schizoaffective disorder was taking lurasidone 40 mg at night and desvenlafaxine 50 mg in the morning after giving birth. She exclusively breastfed her infant and provided single milk samples on days 5 and 41 postpartum, which precluded RID determination. At 5 hours after the mother’s dose, the infant had a lurasidone blood concentration that was 1.4% of the mother’s simultaneous blood level. The infant’s growth and development were good during a follow-up period of 39 days.

Lumateperone

This is another risperidone-like drug that has no published data in breastfeeding mothers. But the manufacturer reports an unpublished lactation study in 17 women who took a single 42 mg dose of lumateperone. The estimated daily infant dose of lumateperone in human milk was 0.0004 mg/kg with an assumed average daily milk consumption of 200 mL/kg. The mean RID was 0.06%. Several major circulating metabolites were also present in breast milk at an estimated daily infant dose of 0.0004 mg/kg. These low drug levels in milk appear to indicate the acceptability of lumateperone during breastfeeding, but no infant outcomes have been reported.

Ziprasidone

In one woman, ziprasidone was started at 9 days postpartum. The dosage was not stated, but it was presumably started at a low dose and titrated upward. Maternal serum and milk concentrations were obtained 10 minutes before the morning dose every day for 16 days. By day 7 of therapy, the patient was taking 80 mg of ziprasidone twice daily. Ziprasidone was not detectable in milk until day 10 of therapy when the milk concentration was 11 µg/L; thereafter, the milk concentrations were not quantifiable (<10 µg/L). No other information is available on ziprasidone during breastfeeding.

Aripiprazole

Aripiprazole has relatively high levels reported in the milk, with RIDs of 8.3% and 12.7% reported in two women. Other reports have found lower amounts in milk. Only one infant has had serum levels reported. A woman was taking aripiprazole 18 mg/day during pregnancy and postpartum. On day six her breastfed infant had a serum concentration of 7.6 µg/L, which was almost 20% of the maternal serum concentration. Because of the drug’s long half-life, some of the infant’s serum concentration could have been from transplacental transmission.

Brexpiprazole

This is another dopamine D₂ agonist similar to aripiprazole. Only one mother–infant pair has been reported. A woman with schizophrenia received brexpiprazole 2 mg once daily, risperidone 2 mg twice daily, and quetiapine 12.5 mg twice daily during pregnancy and postpartum. Concentrations of brexpiprazole in breast milk ranged from 1 to 6 µg/L at various times and the authors estimated the RID to be ∼0.7%. The neonate had a cord blood level of 3.9 µg/L and ingested small volumes of colostrum and milk 12 times from 46–86.5 hours after birth. Serum levels declined with a half-life of 45.9 hours. By about 115 hours postpartum, brexpiprazole was undetectable in the infant’s serum.

Cariprazine

This is the third dopamine D₂ agonist. It has not been studied during breastfeeding, but cariprazine and its active metabolites are >90% protein bound, so it is unlikely that clinically important amounts are excreted into milk.

Xanomeline

This drug is a new cholinergic antipsychotic drug that is available only in combination with the anticholinergic drug trospium, which is used to counteract xanomeline’s peripheral cholinergic effects. No information is available on the clinical use of xanomeline or trospium during breastfeeding. Because trospium is a charged molecule, it is unlikely to pass well into milk.

Amisulpride

Amisulpride is a dopamine D₂ and D₃ antagonist. It is only approved in the United States as an injection for postoperative nausea and vomiting, but it is used orally as an antipsychotic abroad. With RIDs ranging from 4.7% to 10.7% in various patients, excretion of amisulpride into breast milk is higher than most other antipsychotics. Infant serum concentrations were 3.9% and 10.5% of their mothers’ serum levels in two cases, although no adverse effects were reported, including at 13 months of age in one infant.

Sulpiride

Another dopamine D₂ and D₃ antagonist, sulpiride, is excreted into breast milk far above the RID value of 10% in some reports. Serum concentrations in breastfed infants have not been evaluated. Unfortunately, this drug has found use as a galactogogue in some countries because of its prolactin-elevating property. Two studies found no adverse effects in breastfed infants whose mothers were treated with sulpiride for 2–4 weeks as a galactogogue, although other investigators estimated that the dose in milk was high enough to increase serum prolactin in breastfed infants. Infant and maternal sedation has been reported.