Agent Detail - CITALOPRAM

Agent Summary

Quick take: Based on experimental animal studies and human reports, standard therapeutic use of citalopram is not expected to increase the risk of congenital anomalies. Use of serotonin reuptake inhibitors late in pregnancy can be associated with a mild transient neonatal syndrome of central nervous system, motor, respiratory, and gastrointestinal signs.

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Citalopram (Cipramil, Celexa) is a serotonin reuptake inhibitor used as an antidepressant. Escitaolpram, the active isomer, is marketed as Lexapro. Preclinical studies submitted by the sponsor (Forrest Labs) showed oral doses of 32 mg/kg/d to decrease mating in male and female rats. This dose is about five times the maximum recommended human dose on a mg/square meter basis. Administration to pregnant rats at 112 mg/kg/d produced maternal toxicity and an increase in cardiovascular and skeletal defects in the offspring. This dose is 18 times the maximum human dose on a surface area basis. No abnormalities in the offspring were seen with maternal doses of 56 mg/kg/d. In rabbits, there were no adverse developmental effects at a maternal dose of 16 mg/kg/d, which is five times the maximum human dose on a surface area basis. Administration to rats during late pregnancy and lactation of 24 mg/kg/d was associated with an increase in pup mortality and a decrease in pup growth.

The maternal:fetal transfer of citalopram has been studied in isolated human placentas (22). In comparison with fluoxetine, desmethylcitalopram, an active citalopram metabolite, had significantly lower placental transfer, suggesting to the investigators that, when used clinically, citalopram may produce lower fetal exposure than fluoxetine (22). There is a case report of a woman on 40 to 60 mg/d citalopram during the first six weeks of pregnant who underwent voluntary abortion at 12 weeks gestation. Examination of the fetus showed no abnormalities (1). One group identified nine pregnancies that included first trimester exposure to citalopram and resulted in normal offspring (13). Using a record-linkage approach, investigators prospectively identified 365 women who used citalopram during early pregnancy (6). The frequency of congenital anomalies among the infants of these women was no greater than expected (6). A review of the adverse reports submitted to the FDA after use of citalopram during gestation uncovered 94 reports, including congenital defects in 19 cases (23). In their abstract, the authors noted that 6 of these defects involved the eye. Although no risk estimates can be made with these data, the authors point out that about 20 percent of the defects were eye related, and they suggest this may have importance because long-term citalopram treatment in the rat has been reported to produce retinal and optic nerve changes (23).

A case control study from the Slone Epidemiology Center compared maternal antidepressant exposure in children with and without congenital malformations. There was no significant association between citalopram use and any of several categories of birth defect (27). There were too few exposures to escitalopram to permit analysis.

A teratogen information service study of 125 first trimester exposures to citalopram found no increased risk in malformations compared to an age-matched control group of pregnancies with what the authors considered to be trivial exposures and a control group of pregnancies exposed to fluoxetine, sertraline, and paroxetine (26). It is not known whether the groups were contemporaneous. Among the 108 infants born to women on citalopram, there were 4 congenital anomalies. The anomalies were atrial septal defect, hypospadias, Down syndrome, and umbilical and inguinal hernia. There were no differences between the three groups in gestational age or birth weight or in the rates of miscarriage. While the study reported an increased risk of neonatal complications related to 3rd trimester exposure to citalopram, methodologic limitations (for example, not controlling for maternal weight or tobacco use in relation to admission to special care nurseries) limit the reliability of the findings. Another report from this service identified 8 infants with malformations among 184 pregnancies with citalopram exposure and no infants with malformations among 21 pregnancies with escitalopram exposure (29). The malformations were umbilical hernia, duplex kidney, club foot, pyloric stenosis, neural tube defect, atrial septal defect, pneumothorax, and hypospadias. The reliability of the outcome information in this study is unknown.

A registry-linkage study from Denmark reported no significant association between citalopram use during pregnancy and total congenital malformations (OR 1.07, 95% CI 0.63-1.83) or total heart defects (OR 1.75, 95% CI 0.78-3.93). There was, however, a borderline significant association with septal defects (OR 2.52, 95% CI 1.04-6.10) (31). There were 460 citalopram-exposed pregnancies in this study.

Adverse effects in neonates exposed prenatally to citalopram and other serotonin reuptake inhibitors prenatally have been described in a variety of reports, including individual cases, prospective studies, case-control studies, and a data mining investigation of the large WHO database of adverse drug reactions (13-17,25). The adverse effects describe include respiratory distress, jitteriness, irritability, vomiting and convulsions. Typically, these symptoms are mild and disappear by 2 weeks of age (17). Two studies have identified an increase in persistent pulmonary hypertension in infants exposed antenatally to serotonin reuptake inhibitors (24,28). Neonates exposed prenatally to citalopram and other serotonin re-uptake inhibitors can be evaluated for signs of adverse effects, but the incidence and severity of these effects do not appear to be so frequent or severe that women should avoid using these medications if they are otherwise indicated (18,19).  There is also a case report of necrotizing enterocolitis associated with escitalopram use (20 mg/d) throughout pregnancy and during lactation (30).

Citalopram and desmethylcitalopram are transferred to human milk (2,7-9,20). In one study, transfer of citalopram to milk was evaluated in three women, two of whom were patients on the medication and one of whom was a normal volunteer given a 40 mg dose (2). The women were 2, 4, and 10 months postpartum. Milk:plasma (M:P) ratios based on area under the time-concentration curve ranged from 1.16 to 1.88 in the patients. In the normal volunteer, the M:P ratio was 1. The estimated weight adjusted doses to the infants were 0.7 to 5.9% of maternal doses. Similar data were reported by a group of investigators who measured citalopram and its main metabolite in the breast milk and serum of seven exposed infants (7). They estimated that the combined dose of citalopram and desmethylcitalopram transmitted to infants via breast milk would correspond to 4.4 to 5.1% as citalopram equivalents. Most infants in this study did not have detectable serum levels of the drug or metabolite. None of the infants in the preceding studies showed abnormal physical or behavioral signs. In a Danish case report, however, a woman taking citalopram 40 mg/d found her infant was experiencing “uneasy sleep” (8). The infant’s serum level of citalopram was found to be 12.7 ng/mL, about one sixth that of its mother. Sleep was normalized when the dose was halved and two breast-feedings each day were replaced with artificial nutrition. In another case report, a milk-to-serum concentration ratio of approximately three was found for both citalopram and desmethylcitalopram (9). Peak milk concentrations of citalopram occurred 3 to 9 h after drug intake by the mother. These investigators also estimated that the infant received approximately 5% of the mother’s dose, adjusted for weight, and the serum level in the infant (7 nM) corresponded to approximately 1/15 of the trough serum concentration of the mother (104 nM). No signs of drug effects in the infant were observed. In two more recent cohort studies involving a total of 42 infants exposed to citalopram through breast milk, no significant elevation of adverse effects were found in the exposed infants (11,12) and development at one year was not notably different from that of non-exposed infants (12). Although these findings are reassuring, the small numbers of infants studied in these reports are not adequate to conclude that this agent will not have adverse effects in some exposed infants (11).

Citalopram has been reported to decrease libido (3-5), an effect also seen with other drugs in this class. One group has reported the successful use of citalopram in the treatment of premature ejaculation (21). A case series reported on three cases of clitoral priapism associated with treatment with citalopram (10).

For additional information and references on the serotonergic antidepressants, please see fluoxetine (#1898), paroxetine (#3590), sertraline (#3390), fluvoxamine (#3718), and venlafaxine (#3791).

Selected References

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2. Spigset O, Carieborg L, Ohman R, Norstrom A. Excretion of citalopram in breast milk. Br J Clin Pharmacol 1997;44:295-8.

3. Michael A, Herrod JJ. Citalopram-induced decreased libido. Br J Psychiatry 1997;171:90.

4. Naranjo CA, Sellers EM, Sullivan JT et al. The serotonin uptake inhibitor citalopram attenuates ethanol intake. Clin Pharmacol Therap 1987;41:266-74.

5. Nyth AL, Gottfries CG. The clinical efficacy of citalopram in the treatment of emotional disturbances in dementia disorders. A Nordic multicentre study. Br J Psychiatry 1990;157:894-901.

6. Ericson A, Källén B, Wiholm B-E: Delivery outcome after the use of antidepressants in early pregnancy. Eur J Clin Pharmacol 55:503-508, 1999.

7. Rampono J, Kristensen JH, Hackett LP, Paech M, Kohan R, Ilett KF: Citalopram and demethylcitalopram in human milk; distribution, excretion and effects in breast fed infants. Br J Clin Pharmacol 2000;50:263-8.

8. Schmidt K, Olesen OV, Jensen PN: Citalopram and breast-feeding: serum concentration and side effects in the infant. Biol Psychiatry 2000;47:164-5.

9. Jensen PN, Olesen OV, Bertelsen A, Linnet K: Citalopram and desmethylcitalopram concentrations in breast milk and in serum of mother and infant. Ther Drug Monit 1997;19:236-9.

10. Berk M, Acton M: Citalopram-associated clitoral priapism: a case series. Int Clin Psychopharmacol 1997;12:121-2.

11. Lee A, Woo J, Shinya I: Frequency of infant adverse events that are associated with citalopram use during breast-feeding. Am J Obstet Gynecol 190:218-21, 2004.

12. Heikkinen T, Ekblad U, Kero P, Ekblad S, Laine K: Citalopram in pregnancy and lactation. Clin Pharmacol Ther 2002;72:184-91.

13. Laine K, Effects of exposure to selective serotonin reuptake inhibitors during pregnancy on serotonergic symptoms in newborns and cord blood monoamine and prolactin concentrations. Arch Gen Psychiatry 60:720-6, 2003.

14. Nordeng H, Lindemann R, Perminov KV, Reikvam A: Neonatal withdrawal syndrome after in utero exposure to selective serotonin reuptake inhibitors. Acta Paediatr 90:288-291, 2001.

15. Oberlander TF, Misri S, Fitzgerald CE, Kostaras X, Rurak D, Riggs W: Pharmacologic factors associated with transient neonatal symptoms following prenatal psychotropic medication exposure. J Clin Psychiatry 2004;65:230-7.

16. Sanz EJ, De-las-Cuevas C, Kiuru A, Bate A, Edwards R: Selective seratonin reuptake inhibitors in pregnant women and neonatal withdrawal syndrome: a database analysis. Lancet 2005;365:482-7.

17. Moses-Kolko EL, Bogen D, Perel J, Bregar A, Uhl K, Levin B, Wisner KL. Neonatal signs after late in utero exposure to serotonin reuptake inhibitors. Literature review and implications for clinical applications. J Am Med Assoc 2005;293:2372-2383.

18. Ruchkin V, Martin A: SSRIs and the developing brain. Lancet 2005;365:451-3.

19. Gentile S: The safety of newer antidepressants in pregnancy and breastfeeding. Drug Saf. 2005;28(2):137-52.

20. Berle JO, Steen VM, Aamo TO, Breilid H, Zahlsen K, Spigset O: Breastfeeding during maternal antidepressant treatment with serotonin reuptake inhibitors: infant exposure, clinical symptoms, and cytochrome p450 genotypes. J Clin Psychiatry 2004;65:1228-34.

21. Atmaca M, Kuloglu M, Tezcan E, Semercioz A: The efficacy of citalopram in the treatment of premature ejaculation: a placebo-controlled study. Int J Impot Res 2002;14:502-5.

22. Heikkine T, Ekblad U, Laine K: Transplacental transfer of citalopram, fluoxetine and their primary demethylated metabolites in isolated perfused human placenta. BJOG 2002;109:1003-8.

23. Tabacova SA, McCloskey CA, Fisher Jr JE: Adverse developmental events reported to FDS in association with maternal citlopram treatment in pregnancy. Birth Defects Research 70:361, 2004.

24. Chambers CD,Hernandez-Diaz S, Van Marter LJ et al: Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N Engl J Med 2006;354: 579-87.

25. Levinson-Castiel R, Merlob P, Linder N, Sirota L, Klinger G: Neonatal abstinence syndrome after in utero exposure to selective serotonin reuptake inhibitors in term infants. Arch Pediatr Adolesc Med 2006;160:173-6.

26. Sivojelezova A, Shuhaiber S, Sarkissian L, Einarson A, Koren G. Citalopram use in pregnancy: prospective comparative evaluation of pregnancy and fetal outcome. Am J Obstet Gynecol 2005.193:2004-9.

27. Louik C, Lin AE, Werler MM, Hernandez-Diaz S, Mitchell AA, First-trimester use of selective serotonin-reuptake inhibitors and the risk of birth defects. N Engl J Med 2007;356:2675-2683.

28. Källén B, Otterblad Olausson P. Maternal use of selective serotonin re-uptake inhibitors and persistent pulmonary hypertension of the newborn. Pharmacoepidemiol Drug Saf 2008;17:801-806.

29. Einarson A, Choi C, Einarson TR, Koren G. Incidence of major malformations in infants following antidepressant exposure in pregnancy: results of a large prospective cohort study. Can J Psychiatry 2009;54(4):242–246.

30. Potts AL, Young KL, Carter BS, Shenai JP.  Necrotizing enterocolitis associated with in utero and breast milk exposure to the selective serotonin reuptake inhibitor, escitalopram. J Perinatol 2007; 27(2): 120-2.

31. Pedersen LH, Henriksen TB, Vestergaard M, Olsen J, Bech BH. Selective serotonin inhibitors in pregnancy and congenital malformations: population based cohort study. BMJ 2009;339:b3569 doi: 10.1136/bmj.b3569.