European Journal of Clinical Pharmacology

, Volume 72, Issue 12, pp 1417–1425 | Cite as

The quality of lactation studies including antipsychotics

  • Hazel Hummels
  • Daphne Bertholee
  • Douwe van der Meer
  • Jan Pieter Smit
  • Bob Wilffert
  • Peter ter HorstEmail author


The aim of the study

The aim of this study is to determine the quality of lactation studies that investigated antipsychotics in breast milk according to the Food and Drug Administration (FDA) and International Lactation Consultant Association (ILCA) draft guidelines.

Materials and methods

We used the draft FDA and ILCA guidelines to review the quality of articles including antipsychotic use during breastfeeding. We used PubMed and Lactmed for the literature search. Furthermore, cross references were searched for additional studies.


Of the 51 studies, only one olanzapine and one quetiapine study calculated the milk to plasma ratio (M:P ratio), the Absolute Infant Dose (AID), and the Relative Infant Dose (RID) correctly. In the remaining studies, at least one of the three endpoints was not determined properly. No correct endpoints were calculated in studies containing chlorpromazine, chlorprothixene, clozapine, haloperidol, sulpiride, trifluoperazine, ziprasidone, zonisamide, and zuclopenthixol.

This review investigated that there was a lack of information on the sampling methods of breast milk. Furthermore, the concentrations needed for the calculations of the three endpoints were mainly based on single measurements instead of at least five measurements during one dose interval. In many studies, the RID was not calculated correctly due to the fact that the RID was not normalized by the maternal weight or an average maternal weight of 70 kg was used as a standard.


Except for two studies, most studies about the safety of antipsychotic use during lactation did not meet the criteria of the draft FDA and ILCA guidelines. Further research is mandatory to assess the safety of using antipsychotics while breastfeeding.


Breastfeeding Asthma Food and Drug Administration 


  1. 1.
    Hoddinott P, Tappin D, Wright C (2008) Breast feeding. BMJ 336(7649):881–887CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Ip S, Chung M, Raman G, Chew P, Magula N, DeVine D, et al. (2007) Breastfeeding and maternal and infant health outcomes in developed countries. Evid Rep Technol Assess (Full Rep) (153):1–186Google Scholar
  3. 3.
    World Health Organisation and UNICEF (2003) Global strategy for infant and young child feedingGoogle Scholar
  4. 4.
    World Health Organisation (2009) Infant and young child feeding. Model chapter for textbooks for medical students and allied health professionalsGoogle Scholar
  5. 5.
    Infant care (2014) Increase the proportion of infants who are ever breastfed [Internet]. Available from:
  6. 6.
    Hale TW (2014) Medications and mothers’ milk. Hale Publishing, AmarilloGoogle Scholar
  7. 7.
    Cookson J, Hodgson R, Wildgust HJ (2012) Prolactin, hyperprolactinaemia and antipsychotic treatment: a review and lessons for treatment of early psychosis. J Psychopharmacol 26(5 Suppl):42–51CrossRefPubMedGoogle Scholar
  8. 8.
    Barnes TR (2011) Schizophrenia consensus Group of British Association for psychopharmacology. Evidence-based guidelines for the pharmacological treatment of schizophrenia: recommendations from the British Association for Psychopharmacology. J Psychopharmacol 25(5):567–620CrossRefPubMedGoogle Scholar
  9. 9.
    Kendell RE, Chalmers JC, Platz C (1987) Epidemiology of puerperal psychoses. Br J Psychiatry 150:662–673CrossRefPubMedGoogle Scholar
  10. 10.
    Kumar R (1994) Postnatal mental illness: a transcultural perspective. Soc Psychiatry Psychiatr Epidemiol 29(6):250–264CrossRefPubMedGoogle Scholar
  11. 11.
    Okano T, Nomura J, Kumar R, Kaneko E, Tamaki R, Hanafusa I, et al. (1998) An epidemiological and clinical investigation of postpartum psychiatric illness in Japanese mothers. J Affect Disord 48(2–3):233–240CrossRefPubMedGoogle Scholar
  12. 12.
    Dean C, Kendell RE (1981) The symptomatology of puerperal illnesses. Br J Psychiatry 139:128–133CrossRefPubMedGoogle Scholar
  13. 13.
    Meltzer ES, Kumar R (1985) Puerperal mental illness, clinical features and classification: a study of 142 mother-and-baby admissions. Br J Psychiatry 147:647–654CrossRefPubMedGoogle Scholar
  14. 14.
    Klompenhouwer JL, van Hulst AM (1991) Classification of postpartum psychosis: a study of 250 mother and baby admissions in the Netherlands. Acta Psychiatr Scand 84(3):255–261CrossRefPubMedGoogle Scholar
  15. 15.
    Kumar R, Marks M, Platz C, Yoshida K (1995) Clinical survey of a psychiatric mother and baby unit: characteristics of 100 consecutive admissions. J Affect Disord 33(1):11–22CrossRefPubMedGoogle Scholar
  16. 16.
    Dean C, Williams RJ, Brockington IF (1989) Is puerperal psychosis the same as bipolar manic-depressive disorder? A family study. Psychol Med 19(3):637–647CrossRefPubMedGoogle Scholar
  17. 17.
    Robling SA, Paykel ES, Dunn VJ, Abbott R, Katona C (2000) Long-term outcome of severe puerperal psychiatric illness: a 23 year follow-up study. Psychol Med 30(6):1263–1271CrossRefPubMedGoogle Scholar
  18. 18.
    Robertson E, Jones I, Haque S, Holder R, Craddock N (2005) Risk of puerperal and non-puerperal recurrence of illness following bipolar affective puerperal (post-partum) psychosis. Br J Psychiatry 186:258–259CrossRefPubMedGoogle Scholar
  19. 19.
    Jones I, Craddock N (2001) Familiality of the puerperal trigger in bipolar disorder: results of a family study. Am J Psychiatry 158(6):913–917CrossRefPubMedGoogle Scholar
  20. 20.
    Sit D, Rothschild AJ, Wisner KLA (2006) Review of postpartum psychosis. J Women’s Health (Larchmt) 15(4):352–368CrossRefGoogle Scholar
  21. 21.
    Gentile S (2010) Antipsychotic therapy during early and late pregnancy. A systematic review. Schizophr Bull 36(3):518–544CrossRefPubMedGoogle Scholar
  22. 22.
    Neville MC WC (1996) Effects of drugs on milk secretion and composition. In: Bennett PN, editor. Drugs and Human Lactation. Elsevier. p. 15–46Google Scholar
  23. 23.
    Polin RA, Abman SH, Rowitch D, Benitz WE (2011) Fetal and neonatal physiology. Elsevier Saunders, Philadelphia, p. 292Google Scholar
  24. 24.
    Food and Drug Administration (2005) Clinical lactation studies – study design, data analysis and recommendations for labelingGoogle Scholar
  25. 25.
    Begg EJ, Duffull SB, Hackett LP, Ilett KF (2002) Studying drugs in human milk: time to unify the approach. J Hum Lact 18(4):323–332CrossRefPubMedGoogle Scholar
  26. 26.
    Hill RC, McIvor RJ, Wojnar-Horton RE, Hackett LP, Ilett KF (2000) Risperidone distribution and excretion into human milk: case report and estimated infant exposure during breast-feeding. J Clin Psychopharmacol 20(2):285–286CrossRefPubMedGoogle Scholar
  27. 27.
    Ilett KF, Hackett LP, Kristensen JH, Vaddadi KS, Gardiner SJ, Begg EJ (2004) Transfer of risperidone and 9-hydroxyrisperidone into human milk. Ann Pharmacother 38(2):273–276CrossRefPubMedGoogle Scholar
  28. 28.
    Matheson I, Skjaeraasen J (1988) Milk concentrations of fluphentixol, nortriptyline and zuclopenthixol and between-breast differences in two patients. Eur J Clin Pharmacol 35:217–220CrossRefPubMedGoogle Scholar
  29. 29.
    Var L, Ince I, Topuzoglu A, Yildiz A (2013) Management of postpartum manic episode without cessation of breastfeeding: a longitudinal follow up of drug excretion into breast milk. Eur Neuropsychopharmacol 23(Suppl 2):S382CrossRefGoogle Scholar
  30. 30.
    Aydin B, Nayir T, Sahin S, Yildiz A (2015) Olanzapine and quetiapine use during breastfeeding: excretion into breast milk and safe breastfeeding strategy. J Clin Psychopharmacol 35(2):206–208CrossRefPubMedGoogle Scholar
  31. 31.
    Yoshida K, Smith B, Craggs M (1998) Neuroleptic drugs in breast-milk: a study of pharmacokinetics and of possible adverse effects in breast-fed infants. PsycholMed 28:81–91Google Scholar
  32. 32.
    Sugawara K, Shimoyama R, Ohkubo T (1999) Determinations of psychotropic drugs and antiepileptic drugs by high-performance liquid chromatography and its monitoring in human breast milk. Hirosaki Med J 51(Suppl):S81–S86Google Scholar
  33. 33.
    Aichhorn W, Stuppaeck C, Whitworth AB (2005) Risperidone and breast-feeding. J Psychopharmacol 19(2):211–213CrossRefPubMedGoogle Scholar
  34. 34.
    Gardiner SJ, Kristensen JH, Begg EJ, Hackett LP, Wilson DA, Ilett KF, et al. (2003) Transfer of olanzapine into breast milk, calculation of infant drug dose, and effect on breast-fed infants. Am J Psychiatry 160(8):1428–1431CrossRefPubMedGoogle Scholar
  35. 35.
    Rampono J, Kristensen JH, Ilett KF, Hackett LP, Kohan R (2007) Quetiapine and breast feeding. Ann Pharmacother 41(4):711–714CrossRefPubMedGoogle Scholar
  36. 36.
    Weggelaar NM, Keijer WJ, Janssen PKA (2011) Case report of risperidone distribution and excretion into human milk: how to give good advice if you have not enough data available. J Clin Psychopharmacol 31(1):129–131CrossRefPubMedGoogle Scholar
  37. 37.
    Ilett KF, Watt F, Hackett LP, Kohan R, Teoh S (2010) Assessment of infant dose through milk in a lactating woman taking amisulpride and desvenlafaxine for treatment-resistant depression. Ther Drug Monit 32(6):704–707CrossRefPubMedGoogle Scholar
  38. 38.
    Teoh S, Ilett KF, Hackett LP, Kohan R (2011) Estimation of rac-amisulpride transfer into milk and of infant dose via milk during its use in a lactating woman with bipolar disorder and schizophrenia. Breastfeed Med 6(2):85–88CrossRefPubMedGoogle Scholar
  39. 39.
    Nordeng H, Gjerdalen G (2014) Brede WRea. Transfer of aripiprazole to breast milk: a case report. J Clin Psychopharmacol 34:272–275CrossRefPubMedGoogle Scholar
  40. 40.
    Olesen OV, Bartels U, Poulsen JH (1990) Perphenazine in breast milk and serum. Am J Psychiatry 147(10):1378–1379CrossRefPubMedGoogle Scholar
  41. 41.
    Lee A, Giesbrecht E, Dunn E, Ito S (2004) Excretion of quetiapine in breast milk. Am J Psychiatry 161(9):1715–1716CrossRefPubMedGoogle Scholar
  42. 42.
    Schlotterbeck P, Leube D, Kircher T, Hiemke C, Grun d G (2007) Aripiprazole in human milk. Int J Neuropsychopharmacol 10:433CrossRefPubMedGoogle Scholar
  43. 43.
    Lutz U, Hiemke C, Wiatr G (2010) Aripiprazole in pregnancy and lactation a case report. J Clin Psychopharmacol 30:204–205CrossRefPubMedGoogle Scholar
  44. 44.
    Watanabe N, Kasahara M, Sugibayashi R, et al. (2011) Perinatal use of aripiprazole: a case report. J Clin Psychopharmacol 31:377–379CrossRefPubMedGoogle Scholar
  45. 45.
    Blacker KH, Weinstein BJ, Ellman GL (1962) Mother’s milk and chlorpromazine. Am J Psychiatry 119:178–179CrossRefGoogle Scholar
  46. 46.
    Uhlir F, Ryznar J (1973) Appearance of chlorpromazine in the mother’s milk. Acta Nerv Super (Praha) 15:106Google Scholar
  47. 47.
    Wiles DH, Orr MW, Koakowska T (1978) Chlorpromazine levels in plasma and milk of nursing mothers. Br J Clin Pharmacol 5:272–273CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Ohkubo T, Shimoyama R, Sugawara K (1993) Determination of chlorpromazine in human breast milk and serum by high-performance liquid chromatography. J Chromatogr 614(328):332Google Scholar
  49. 49.
    Lacey JH (1971) Dichloralphenazone and breast milk. Br Med J 4:684CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Matheson I, Evang A, Overo KF, Syversen G (1984) Presence of chlorprothixene and its metabolites in breast milk. Eur J Clin Pharmacol 27(5):611–613CrossRefPubMedGoogle Scholar
  51. 51.
    Barnas C, Bergant A, Hummer M, Saria A, Fleischhacker WW (1994) Clozapine concentrations in maternal and fetal plasma, amniotic fluid, and breast milk. Am J Psychiatry 151(6):945CrossRefPubMedGoogle Scholar
  52. 52.
    Kirk L, Jorgensen A (1980) Concentrations of cis(Z)-flupenthixol in maternal serum, amniotic fluid, umbilical cord serum, and milk. Psychopharmacology 72:107–108CrossRefPubMedGoogle Scholar
  53. 53.
    Stewart RB, Karas B, Springer PK (1980) Haloperidol excretion in human milk. Am J Psychiatry 137:849–850CrossRefPubMedGoogle Scholar
  54. 54.
    Whalley LJ, Blain PG, Prime JK (1981) Haloperidol secreted in breast milk. Br Med J 282:1746–1747CrossRefGoogle Scholar
  55. 55.
    Kuniyoshi M, Inanaga K (1985) Haloperidol and biperiden plasma levels in a pregnant atypical psychotic woman and a neonate—a case report. Kurume Med J 32:199–202CrossRefPubMedGoogle Scholar
  56. 56.
    Ohkubo T, Shimoyama R, Sugawara K (1992) Measurement of haloperidol in human breast milk by high-performance liquid chromatography. J Pharm Sci 81:947–949CrossRefPubMedGoogle Scholar
  57. 57.
    Ambresin G, Berney P, Schulz P, Bryois C (2004) Olanzapine excretion into breast milk: a case report. J Clin Psychopharmacol 24(1):93–95CrossRefPubMedGoogle Scholar
  58. 58.
    Croke S, Buist A, Hackett LP, Ilett KF, Norman TR, Burrows GD (2002) Olanzapine excretion in human breast milk: estimation of infant exposure. Int J Neuropsychopharmacol 5(3):243–247CrossRefPubMedGoogle Scholar
  59. 59.
    Lutz UC, Wiatr G, Orlikowsky T, Gaertner HJ, Bartels M (2008) Olanzapine treatment during breast feeding: a case report. Ther Drug Monit 30(3):399–401CrossRefPubMedGoogle Scholar
  60. 60.
    Whitworth A, Stuppaeck C, Yazdi K, Kralovec K, Geretsegger C, Zernig G, et al. (2010) Olanzapine and breast-feeding: changes of plasma concentrations of olanzapine in a breast-fed infant over a period of 5 months. J Psychopharmacol 24(1):121–123CrossRefPubMedGoogle Scholar
  61. 61.
    Stiegler A, Schaletzky R, Walter G, Wust R, Abele H, Goelz R, et al. (2014) Olanzapine treatment during pregnancy and breastfeeding: a chance for women with psychotic illness? Psychopharmacology 231(15):3067–3069CrossRefPubMedGoogle Scholar
  62. 62.
    Kirchheiner J, Berghofer A, Bolk-Weischedel D (2000) Healthy outcome under olanzapine treatment in a pregnant woman. Pharmacopsychiatry 33(2):78–80CrossRefPubMedGoogle Scholar
  63. 63.
    Misri S, Corral M, Wardrop AA, Kendrick K (2006) Quetiapine augmentation in lactation: a series of case reports. J Clin Psychopharmacol 26(5):508–511CrossRefPubMedGoogle Scholar
  64. 64.
    Kruninger U, Meltzer V, Hiemke C, Herpich S, Schreiber W (2007) Schwangerschaft und Stillzeit unter Behandlung mit Quetiapin—eine Kasuistik. Psychiatr Prax 34(Suppl 1):S75–S76CrossRefGoogle Scholar
  65. 65.
    Yazdani-Brojeni P, Taguchi N, Garcia-Bournissen F, Moretti M, Verjee Z, Koren G, et al. (2010) Quetiapine in human milk and stimulation-based assessment of infant exposure. Clin Pharmacol Ther 87(Suppl 1):S3–S4Google Scholar
  66. 66.
    Tanoshima R, Yazdani-Brojeni P, Taguchi N, Garcia-Bournissen F, Moretti M, Verjee Z, et al. (2012) Quetiapine in human breast milk—population PK analysis of milk levels and simulated infant exposure. J Popul Ther Clin Pharmacol 19:e267–e268Google Scholar
  67. 67.
    Van Boekholt AA, Hartong EG, Huntjens-Fleuren H, Grootens KP, Semmekrot BA (2015) Quetiapine concentrations during exclusive breastfeeding and maternal quetiapine use. Ann Pharmacother 49(6):743–744CrossRefPubMedGoogle Scholar
  68. 68.
    Aono T, Shioji T, Aki T, Hirota K, Nomura A, Kurachi K (1979) Augmentation of puerperal lactation by oral administration of sulpiride. J Clin Endocrinol Metab 48(3):478–482CrossRefPubMedGoogle Scholar
  69. 69.
    Polatti F (1982) Sulpiride isomers and milk secretion in puerperium. Clin Exp Obstet Gynecol 9(3):144–147PubMedGoogle Scholar
  70. 70.
    Birnbaum CS, Cohen LS, Bailey JW, Grush LR, Robertson LM, Stowe ZN (1999) Serum concentrations of antidepressants and benzodiazepines in nursing infants: a case series. Pediatrics 104(1):e11CrossRefPubMedGoogle Scholar
  71. 71.
    Schlotterbeck P, Saur R, Hiemke C, Grunder G, Vehren T, Kircher T, et al. (2009) Low concentration of ziprasidone in human milk: a case report. Int J Neuropsychopharmacol 12(3):437–438CrossRefPubMedGoogle Scholar
  72. 72.
    Ando H, Matsubara S, Oi A, Usui R, Suzuki M, Fujimura A (2014) Two nursing mothers treated with zonisamide: should breast-feeding be avoided? J Obstet Gynaecol Res 40(1):275–278CrossRefPubMedGoogle Scholar
  73. 73.
    Shimoyama R, Ohkubo T, Sugawara K (1999) Monitoring of zonisamide in human breast milk and maternal plasma by solid-phase extraction HPLC method. Biomed Chromatogr 13(5):370–372CrossRefPubMedGoogle Scholar
  74. 74.
    Kawada K, Itoh S, Kusaka T, Isobe K, Ishii M (2002) Pharmacokinetics of zonisamide in perinatal period. Brain and Development 24(2):95–97CrossRefPubMedGoogle Scholar
  75. 75.
    Ohman I, Tomson T (2011) Pharmacokinetics of zonisamide in neonatal period and during lactation. Basic Clin Pharmacol Toxicol 109(Suppl 1):73Google Scholar
  76. 76.
    Aaes-Jorgensen T, Bjorndal F, Bartels U (1986) Zuclopenthixol levels in serum and breast milk. Psychopharmacology 90(3):417–418CrossRefPubMedGoogle Scholar
  77. 77.
    Briggs GG, Samson JH, Ambrose PJ, Schroeder DH (1993) Excretion of bupropion in breast milk. Ann Pharmacother 27(4):431–433PubMedGoogle Scholar
  78. 78.
    Bennett PN (1996) Use of monographs on drugs. In: Bennett PN (ed) Drugs and human lactation. Elsevier, Amsterdam, pp. 67–74Google Scholar
  79. 79.
    Hotham N (2015) Drugs in breastfeeding. Aust Prescr 38:156–159CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    McCloughen A, Foster K (2011) Weight gain associated with taking psychotropic medication: an integrative review. Int J Ment Health Nurs 20(3):202–222CrossRefPubMedGoogle Scholar
  81. 81.
    Fortinguerra F, Clavenna A, Bonati M (2009) Psychotropic drug use during breastfeeding: a review of the evidence. Pediatrics 124:e547–e556CrossRefPubMedGoogle Scholar
  82. 82.
    Ohman R, Hagg S, Carleborg L, Spigset O (1999) Excretion of paroxetine into breast milk. J Clin Psychiatry. 60(8):519–523CrossRefPubMedGoogle Scholar
  83. 83.
    Stowe ZN, Hostetter AL, Owens MJ, Ritchie JC, Sternberg K, Cohen LS, et al. (2003) The pharmacokinetics of sertraline excretion into human breast milk: determinants of infant serum concentrations. J Clin Psychiatry 64(1):73–80CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Hazel Hummels
    • 1
    • 2
  • Daphne Bertholee
    • 1
  • Douwe van der Meer
    • 1
  • Jan Pieter Smit
    • 3
  • Bob Wilffert
    • 2
    • 4
  • Peter ter Horst
    • 1
    Email author
  1. 1.Isala, Department of Clinical PharmacyZwolleThe Netherlands
  2. 2.University of Groningen, University Centre for Pharmacy, Unit of Pharmacotherapy, Epidemiology and EconomicsGroningenthe Netherlands
  3. 3.Isala Department of PsychiatryZwolleThe Netherlands
  4. 4.Department of Hospital and Clinical PharmacyUniversity Medical Centre GroningenGroningenthe Netherlands

Personalised recommendations