Clomipramine concentration and withdrawal symptoms in 10 neonates


  • Trial registry: EudraCT, number 2006–002122-28.

Dr Peter G. J. ter Horst PharmD, Isala Klinieken, Department of Clinical Pharmacy, Groot Wezenland 20, 8011 JW Zwolle, The Netherlands. Tel.: +31 38 424 7244, Fax: +31 38 424 7685. E-mail:



• Antidepressants are associated with withdrawal symptoms after in utero exposure.

• Half-life of clomipramine in neonates is prolonged compared with that in adults.


• We present 10 cases of neonates exposed in utero to clomipramine, with detailed information about withdrawal symptoms and pharmacokinetics.

• There is a high and severe complication rate in our cohort regarding the mother and the neonate.

AIM After in utero exposure to tricyclic antidepressants, neonatal withdrawal symptoms have been reported with an estimated incidence between 20 and 50%; however, few data are available for clomipramine. This could also be the case for neonatal pharmacokinetic clomipramine parameters and so this study was set up.

METHODS Babies exposed to clomipramine in utero were included in an observational study, approved by the local ethics committee, after written informed consent. Withdrawal symptoms were scored at 12, 24 and 48 h after birth using the Finnegan score. Plasma concentrations were determined using an in-house-developed, validated liquid chromatography with mass detection (LC-MSMS) method at 0, 12, 24 and 48 h after birth.

RESULTS We found that three of 11 pregnancies were complicated with pre-eclampsia. Ten neonates were observed for clomipramine withdrawal symptoms. The observed withdrawal symptoms were too short a period of sleep after feeding (6), poor feeding (3), mild to severe tremors (6), hyperactive Moro reflex (3) and respiratory rate >60 breaths min−1. Serious withdrawal reactions, such as tachycardia and cyanosis, were seen. We calculated a half-life value of 42 ± 16 h for clomipramine in neonates. Only a weak correlation was found between withdrawal reactions and clomipramine plasma concentration or desmethylclomipramine plasma concentration.

CONCLUSIONS In neonates, clomipramine is eliminated with a half-life value of 42 h, compared with 20 h in adults. In two of 10 neonates, tachycardia and cyanosis were seen as serious withdrawal symptoms after maternal use of clomipramine.