Agent Detail

NORTRIPTYLINE

Agent Number 1150
CAS Number 72-69-5
Last Updated 12/29/2016

Cross References

PAMELOR (894-71-3)    

Agent Summary

Quick take: Nortriptyline did not appear to increase the risk of birth defects in humans. Tricyclic antidepressants including nortriptyline have been associated with neonatal complications of varying severity but limited long-term follow-up data has not shown neurodevelopmental delays in these babies. Infants exposed through breastfeeding have low or undetectable concentrations of nortriptyline and its metabolites.


Nortriptyline is a tricyclic antidepressant, marketed as the hydrochloride under the name Pamelor. Nortriptyline is a metabolite of amitriptyline (#1019), which is also used in the treatment of depression.

Experimental animal studies

Exposure to these compounds has been associated with teratogenic effects in the hamster, especially when chlordiazepoxide (#1058), a benzodiazepine, is coadministered. Cranial malformations and encephalocele were predominant among the anomalies reported (1,2).

Human pregnancy reports

A pregnancy registry for psychiatric medications has been organized at the Massachusetts General Hospital. Contact the registry at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.

Some clinical reports have suggested that nortriptyline and other tricyclic antidepressants might cause congenital malformations (3) with specific attention focused on limb reduction defects (4-6), but retrospective studies of large populations have failed to show a preponderance of nortriptyline users among mothers of children with congenital limb defects (7). Successful pregnancies involving first trimester exposure to nortriptyline have also been reported (23). A study using US Medicaid claims data did not find an increase in any cardiac malformation, right ventricular outflow tract obstruction, or ventricular septal defect associated with prescription of a tricyclic antidepressant during the first trimester of pregnancy after adjustment for maternal illness (28). Individual tricyclics were not listed, and it is not known how many, if any, of the exposures included nortriptyline. In another publication from this study, exposure to a non-serotonin reuptake inhibitor antidepressant in the third trimester was not associated persistent pulmonary hypertension of the newborn when the results were adjusted for depression severity; there were 367 patients exposed to nortriptyline in this combined group of more than 26,000 patients (29).

A study of ten infants exposed in utero to nortriptyline demonstrated placental passage (mean ratio of umbilical cord blood concentration to maternal serum concentration) of nortriptyline of 0.68 (SD 0.40) and of its 10-hydroxy metabolites of 1.40 (SD 2.40) (24). Two infants had neonatal complications (lethargy, poor sucking) with one requiring NICU care, but there were no correlations with the placental passage of either the parent drug or the metabolite. A healthy infant was born at term without neonatal complications following exposure to nortriptyline (75 mg/day) beginning in the second trimester (27). The cord-maternal concentration ratios were 0.47 for nortriptyline and 0.65 for the metabolite E-10-hydroxynortriptyline. The mother did not smoke.

Withdrawal symptoms have been observed in newborns who were exposed to other tricyclic antidepressants in utero. The symptoms included colic, cyanosis, rapid breathing, and irritability (9-11, 25). The pediatrician who will care for a newborn exposed to this compound can be advised in advance that the mother has been taking nortriptyline. This agent was associated with urinary retention in one newborn (12).

Neurobehavioral testing of 80 children with first-trimester exposure to tricyclic antidepressants (of whom 8 had been exposed to nortriptyline) showed no differences in IQ, language, or behavior compared to 55 children with exposure to fluoxetine (#1898) or 84 children without antidepressant exposure during gestation (21). The children ranged in age from 16 to 86 months at the time of testing. A follow-up study that examined those children who had been exposed to antidepressants throughout gestation (and incorporated new subjects, for a total of 3 exposed to nortriptyline) demonstrated that the duration of maternal depression in pregnancy and number of episodes postpartum had a negative impact on IQ and language development, independent of medication exposure (26).

Lactation

Tricyclic antidepressants enter human milk (13,14,19,20,22). Two studies measuring serum concentrations of nortriptyline and certain metabolites in lactating women and their infants identified nortriptyline in one suckling infant, but one less active metabolite was detected in the serum of three of thirteen exposed newborns (19,22). No adverse effects were noted in any infants. Infant serum concentrations were measured in 10 breastfed infants (15). Maternal doses ranged from 50 to 100 mg/day. Infant samples were obtained at 2-15 weeks of age. Nortriptyline concentrations were approximately 2 ng/mL in 2/10 infants and undetectable in the remainder. Concentrations of the 10-hydroxy metabolites ranged from undetectable to less than 10 ng/mL. Combined infant concentrations were less than 10% of maternal concentrations (15). No adverse events were reported.

The American Academy of Pediatrics classified nortriptyline among agents for which the effects on nursing infants are unknown but might be of concern (16). Some clinicians have focused attention on the possibility that exposure to nortriptyline and related drugs might have long term effects on neonatal brain development (17,18). The long-term neurodevelopmental study described above included breastfed infants exposed to tricyclic antidepressants or fluoxetine and found no overall differences between the groups based on breastfeeding status; conclusions about individual tricyclic antidepressants were not possible due to the small sample sizes (26). Additional prospective studies are needed to characterize the risks if any associated with low-dose exposure through breastfeeding (15).

Reproductive effects

Some small clinical reports suggested that nortriptyline and other tricyclic antidepressants may reduce libido and cause erectile and ejaculatory dysfunction in males (8). Euprolactinemic galactorrhea occurred in a 21 year old woman after two weeks of treatment with nortriptyline 25 mg/day; galactorrhea resolved within one week of discontinuation of the medication (30).

Selected References

  1. Beyer BK et al.: Incidence and potentiation of external and internal fetal anomalies from chlordiazepoxide and amitriptyline alone and in combination. Teratology 30:39-45, 1984.

  2. Guram MS et al.: Comparative teratogenicity of chlordiazepoxide, amitriptyline, and a combination of the two compounds in the fetal hamster. Neurotoxicology (Park Forest IL) 3:83-90, 1982.

  3. Bracken MB and Holford TR: Exposure to prescribed drugs in pregnancy and association with congenital malformations. Obstet Gynecol 58:33 6-44, 1981.

  4. McBride WG: Limb deformities associated with iminodibenzyl hydrochloride. Med J Aust 1:492, 1972.

  5. Barson AJ: Malformed infant. Br Med J 2:45, 1972.

  6. Freeman R: Limb deformities: possible association with drugs. Med J Aust 1:606-7, 1972.

  7. Heinonen OP et al.: Birth Defects and Drugs in Pregnancy, Littleton, Publishing Sciences Group, 1977, pp. 336-337.

  8. Mitchell JE and Popkin MK: Antidepressant drug therapy and sexual dysfunction in men: a review. J Clin Psychopharm 3:76-79, 1983.

  9. Webster PA: Withdrawal symptoms in neonates associated with maternal antidepressant therapy. Lancet 2:318-9, 1973.

  10. Eggermont E: Withdrawal symptoms in neonate associated with maternal imipramine therapy. Lancet 2:680, 1973.

  11. Shrand H: Agoraphobia and imipramine withdrawal? Pediatrics 70:825, 1982.

  12. Shearer WT et al.: Urinary retention in a neonate secondary to maternal ingestion of nortriptyline. J Pediatr 81:570-2, 1972.

  13. Bader TF and Newman K: Amitriptyline in human breast milk and the nursing infant's serum. Am J Psychiatry 137:855-6, 1980.

  14. Brixen-Rasmussen L et al.: Amitriptyline and nortriptyline excretion in human breast milk. Psychopharmacology (Berlin) 139:679-81, 1982.

  15. Weissman AM, Levy BT, Hartz AJ, Bentler S, Donohue M, Ellingrod VL, Wisner KL: Pooled analysis of antidepressant levels in lactating mothers, breast milk, and nursing infants. American Journal of Psychiatry 2004; 161(6):1066-78

  16. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human breast milk. Pediatrics 108:776-89, 2001.

  17. Nurnberg HG and Prudic J: Guidelines for treatment of psychosis during pregnancy. Hosp Community Psychiatry 35:67-71, 1984.

  18. Matheson I, Skjaeraasen J: Milk concentrations of flupenthixol, nortriptyline and zuclopenthixol and between-breast differences in two patients. Eur J Clin Pharmacol 35:217-20, 1988.

  19. Wisner KL, Perel JM: Serum nortriptyline levels in nursing mothers and their infants. Am J Psychiatry 148: 1234-6, 1991.

  20. Breyer-Pfaff U, Nill K, Entenmann KN, Gaertner HJ: Secretion of amitriptyline and metabolites into breast milk. Am J Psychiatry 152: 812-3, 1995.

  21. Nulman I, Rovet J, Stewart DE, Wolpin J, Gardner HA, Theis JGW, Kulin N, Koren G. Neurodevelopment of children exposed in utero to antidepressant drugs. N Engl J Med 1997;336:258-62.

  22. Wisner KL, Perel JM, Findling RL, Hinnes RL: Nortriptyline and its hydroxymetabolites in breastfeeding mothers and newborns. Psychopharmacol Bull 33:249-51, 1997.

  23. Brunel P, Vial T, Roche I, et al.: [Follow-up of 151 pregnant women exposed to antidepressant treatment (MAOI excluded) during organogenesis.] Therapie 49:117-122, 1994.

  24. Loughhead AM, Stowe ZN, Newport DJ, Ritchie JC, DeVane CL, Owens MJ: Placental passage of tricyclic antidepressants. Biological Psychiatry 2006;59(3):287-90.

  25. Misri S, Sivertz K: Tricyclic drugs in pregnancy and lactation: a preliminary report. International Journal of Psychiatry in Medicine 1991; 21(2):157-71.

  26. Nulman I, Rovet J, Stewart DE, Wolpin J, Pace-Asciak P, Shuhaiber S, Koren G: Child development following exposure to tricyclic antidepressants or fluoxetine throughout fetal life: a prospective, controlled study. American Journal of Psychiatry 2002; 159(11):1889-95.

  27. Sit D, Perel JM, Wisniewski SR, Helsel JC, Luther JF, Wisner KL. Mother-infant antidepressant concentrations, maternal depression, and perinatal events. J Clin Psychiatry. 2011;72(7):994-1001.

  28. Huybrechts KF, Palmsten K, Avorn J, Cohen LS, Holmes LB, Franklin JM, Mogun H, Levin R, Kowal M, Setoguchi S, Hernandez-Diaz S. Antidepressant use in pregnancy and the risk of cardiac defects. N Engl J Med. 2014;370(25):2397-407. doi:10.1056/NEJMoa1312828.

  29. Huybrechts KF, Bateman BT, Palmsten K, Desai RJ, Patorno E, Gopalakrishnan C, Levin R, Mogun H, Hernandez-Diaz S. Antidepressant use late in pregnancy and risk of persistent pulmonary hypertension of the newborn. Jama. 2015;313(21):2142-51. doi:10.1001/jama.2015.5605.

  30. Kukreti P, Ali W, Jiloha RC. Rising trend of use of antidepressants induced non- puerperal lactation: A Case report. J Clin Diagn Res: JCDR. 2016;10(6):Vd01-vd2. doi:10.7860/jcdr/2016/19266.7928.

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