Stimulant Therapy During Breastfeeding

Attention-Deficit Hyperactivity Disorder

ADHD is often thought of as a childhood disorder, but drug treatment can persist into adulthood, potentially in nursing mothers. Methylphenidate is a stimulant that is often considered first-line therapy for ADHD. It works primarily by inhibiting the reuptake of dopamine and norepinephrine in the central nervous system (CNS), but it also has stimulant activity at some serotonin receptors. It is available as a racemic mixture (methylphenidate), a single isomer product (dexmethylphenidate), and a dexmethylphenidate prodrug (serdexmethylphenidate).

Only racemic methylphenidate has been studied in nursing mothers, but the other forms would be expected to be clinically similar during breastfeeding. Seven mothers had their milk methylphenidate levels measured. In all cases, the estimated infant dosage was <3 mcg/kg per day, which was a relative infant dose of 0.2% or less of the maternal dosage. Consistent with this low dosage, five nursing infants whose mothers were taking methylphenidate had undetectable serum methylphenidate levels. The clinical outcomes of another 10 breastfed infants whose mothers were taking methylphenidate have been reported. None showed short-term adverse effects and all appeared to have normal growth and development. Methylphenidate reduces serum prolactin, so it might interfere with milk production, especially in women whose lactation is not well established. However, no studies or case reports have been found on the effect of methylphenidate on milk production.

Amphetamine and its active isomer, dextroamphetamine, are used to treat ADHD. Amphetamines stimulate the release of dopamine and norepinephrine from storage sites in the nerve terminal and block the reuptake of these amines by the presynaptic neuron. Amphetamine is available in several salt forms, but they all result in amphetamine in the bloodstream.

Very little information is available on the therapeutic use of amphetamine in nursing mothers. Only two women have had their milk amphetamine levels measured. In one mother the estimated infant dose was 11–12 mcg/kg per day and her infant had serum amphetamine levels between 5% and 15% of her serum levels on three occasions. Another infant had urinary amphetamine excretion measured, which ranged from 0.1% to 0.3% of the mother's urinary amphetamine excretion. These two infants had no immediate adverse effects and experienced normal growth and development. Amphetamine can decrease serum prolactin modestly, but no reports of lactation interference exist in mothers taking therapeutic doses. Amphetamine abusers have breastfeeding difficulties, but the role of amphetamine has not been isolated.

The nonstimulant drugs clonidine, guanfacine, and atomoxetine have been used to treat ADHD. Clonidine has been studied during breastfeeding and was found to provide the infant with doses of clonidine of ∼4–8% of the maternal dosage. Nine breastfed infants had serum clonidine levels that were about half of their mothers' serum levels. Although no adverse effects on breastfed infants have been reported, the extensive exposure of some breastfed infants is concerning. Guanfacine, which is pharmacologically similar to clonidine, has no information on the use in nursing mothers. It causes marked decreases in serum prolactin in men and non-nursing women, so it might interfere with breastfeeding. Atomoxetine likewise has no published data on its use during breastfeeding. One author reported that the manufacturer had received reports of two infants who slept longer than usual after being breastfed by mothers who were taking atomoxetine, but neither of the infants experienced any serious adverse events.

Narcolepsy

The most common form of narcolepsy is caused by a decrease or complete loss of the hypothalamic neurons that produce the orexin neuropeptides (also known as hypocretins). This deficiency, in turn, decreases production of histamine and other neurotransmitters that promote wakefulness. Cataplexy, defined as a sudden muscle weakness without a loss of consciousness, can accompany narcolepsy and is usually triggered by strong emotions. Individuals who have narcolepsy with cataplexy (type 1 narcolepsy) have very low or undetectable levels of orexins in their cerebrospinal fluid and a nearly complete loss of the orexin-producing neurons in the hypothalamus. Those with narcolepsy but no cataplexy (type 2 narcolepsy) usually have normal orexin levels. Another aspect of narcolepsy is disrupted sleep patterns, leading to daytime drowsiness. Sleep paralysis and hypnogogic hallucinations can occur. Drugs that address each of these issues are available.

Modafinil and its single active isomer, armodafinil, are considered the initial drugs of choice in treating narcolepsy. Methylphenidate and amphetamine products, discussed under ADHD, are alternatives. Solriamfetol is a newer stimulant drug used for daytime drowsiness, but no information is available on its use during breastfeeding.

Modafinil and armodafinil promote wakefulness, but by a different mechanism from methylphenidate and amphetamines. Modafinil inhibits the release of gamma-aminobutyric acid and increases the release of glutamate in the CNS. It does not appear to be an indirect- or direct-acting dopamine-receptor agonist nor to act as a sympathomimetic agent, but it may block dopamine transporters and increase dopamine concentrations in the brain. Only a minimal amount of information on modafinil is available in nursing mothers. One woman with narcolepsy had milk levels of armodafinil measured. Based on the average amount in milk of 1.2 mg/L at 19 days postpartum, the daily infant dosage was estimated to be 0.18 mg/kg, which corresponded to a weight-adjusted infant dosage of 5.3% of the maternal dosage. In a case–control study of women having type 1 narcolepsy, a few women breastfed their infants while taking modafinil. No adverse effects were noted. The article's authors felt that the infant risk from the medication is low.

Oxybate is a CNS depressant that is taken twice nightly to improve the sleep architecture in patients with narcolepsy and to reduce the frequency of cataplexy. Oxybate and its salts are chemically gamma-hydroxybutyrate (GHB), which has been abused as a street drug. But, GHB is an endogenous substance and low amounts are normally found in breast milk with a proposed normal range of 0.13–1.03 mg/L. With therapeutic doses of 4.5 g, milk levels were considerably higher than normal in one woman: 23.2 mg/L 1 hour after the dose, decreasing to 3.1 mg/L 4 hours after the dose, and back to the normal range of 1 mg/L 5 hours after the dose. In another woman, at 4 hours after the first 4.5 g dose, the breast milk level was 2.5 mg/L; the milk level at 3–4 hours after the second dose was 2.9 mg/L. Breast milk levels had returned to normal physiologic levels by 6–7 hours after the second dose.

Two other mothers reportedly breastfed their infants, at least one of them exclusively, while taking oxybate for narcolepsy. Neither infant had any short-term adverse effects, and the exclusively breastfed infant showed normal growth and development. Because the drug is so short acting and taken only at night, it may be relatively easy to avoid exposing older breastfed infants to excessive amounts of the drug. Some have recommended that with the typical two doses per night treatment regimen, nursing be withheld from the time of the first dose to 4–6 hours after the second dose with normal breastfeeding during the day.

Pitolisant is a new drug that binds selectively to central histamine H₃ receptors, increasing histamine levels in the hypothalamus, thereby bypassing the orexin pathway. It is used for both excessive daytime drowsiness and cataplexy. No information is available on its use during breastfeeding, but it is not contraindicated while nursing according to product labeling.

Several traditional antidepressants are used off label for cataplexy and are often taken together with drugs from other classes. Clomipramine is a tricyclic antidepressant that has relatively low levels in the milk of mothers taking it (∼1.3–2.3% of the maternal dose) and is usually undetectable in the serum of breastfed infants. Although clomipramine has not been studied extensively in nursing mothers, breastfed infants of mothers taking other tricyclic antidepressants have found no adverse effects on growth and development.

Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) that has been used for cataplexy associated with narcolepsy. The average amount of drug in breast milk is higher with fluoxetine than with most other SSRIs and the long-acting active metabolite, norfluoxetine, is detectable in the serum of most breastfed infants during the first 2 months postpartum and in a few thereafter. Adverse effects such as colic, fussiness, and drowsiness have been reported in some breastfed infants. Decreased infant weight gain was found in one study, but not in others. No adverse effects on development have been found in a small number of infants followed for up to a year.

Venlafaxine is a serotonin norepinephrine reuptake inhibitor. Infants receive venlafaxine and its active metabolite in breast milk, and the metabolite of the drug can be found in the serum of most breastfed infants. Sedation and slow weight gain have been reported in a few breastfed infants, but most infants appear to grow and develop normally. Expert opinion varies on the acceptability of venlafaxine during breastfeeding, If it is used, breastfed infants, especially newborn or preterm infants, should be monitored for excessive sedation and adequate feeding and weight gain.

Summary

For mothers with ADHD, methylphenidate appears to be preferable to other drug therapies. Amphetamine can be used, but infant drug exposure is greater. Based on currently available information, it is best to avoid clonidine, guanfacine, and atomoxetine, if possible.

Mothers with narcolepsy can be treated with the first-line drugs modafinil or armodafinil, although the relatively low amount of documentation indicates a need for close infant monitoring. Oxybate is acceptable for nursing mothers, but nighttime breastfeeding is generally discouraged. Of the antidepressants used for cataplexy, clomipramine is preferred, but fluoxetine can be used with close infant monitoring.