Agent Detail

NORTRIPTYLINE

Agent Number 1150
CAS Number 72-69-5
Last Updated 02/12/2022

Agent Summary

Quick take: Nortriptyline did not increase birth defects in human studies.


Nortriptyline is a tricyclic antidepressant, marketed as the hydrochloride under the name Pamelor. Nortriptyline is a metabolite of amitriptyline #1019.

Experimental animal studies

Exposure to amitriptyline was associated with malformations in hamsters, 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/.

A study of ten infants exposed in utero to nortriptyline demonstrated placental passage with a mean ratio of umbilical cord blood concentration to maternal serum concentration of nortriptyline of 0.68 and of the 10-hydroxy metabolites of 1.40 (24).

There are reports tricyclic antidepressants might cause congenital malformations (3-6). Human studies did not associations between nortriptyline and other tricyclic antidepressants and birth defects (7,23,28). 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).

Two infants had lethargy and poor suck with one requiring NICU care after tricyclic exposure, but there were no associations with the among of transfer of the parent drug or the metabolite (24). 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.
Neonatal complications were seen in newborns who were exposed in utero to other tricyclic antidepressants. The symptoms included colic, cyanosis, rapid breathing, and irritability (9-11, 25). Nortriptyline 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 another three 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). Nortriptyline was identified in one nursing infant, and a 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 at 2-15 weeks of age (15). Maternal doses ranged from 50 to 100 mg/day. 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). There was concern that exposure to nortriptyline and related drugs might have long term effects on neonatal brain development (17,18). Exposure during pregnancy is greater than through breastfeeding and stopping an effective medication may increase depression relapse (31).

Reproductive effects

Nortriptyline and other tricyclic antidepressants reduced libido and were associated with erectile and ejaculatory dysfunction in some men (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.

  31. Lusskin SI, Khan SJ, Ernst C, Habib S, Fersh ME, Albertini ES. Pharmacotherapy for perinatal depression. Clin Obstet Gynecol. 2018. doi:10.1097/grf.0000000000000365.

/rtc