Citalopram Risk Summary

Risk Factor: CM
Class: CENTRAL NERVOUS SYSTEM DRUGS / Antidepressants

Fetal Risk Summary

The antidepressant, citalopram, is a selective serotonin reuptake inhibitor (SSRI) that has a chemical structure unrelated to those of other antidepressants (1). All the antidepressant agents in this class (citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline) share a similar mechanism of action, although they have different chemical structures. These differences could be construed as evidence against any conclusion that they share similar effects on the embryo, fetus, or newborn. In the mouse embryo, however, craniofacial morphogenesis appears to be regulated, at least in part, by serotonin. Interference with serotonin regulation by chemically different inhibitors produces similar craniofacial defects (2). Regardless of the structural differences, therefore, some of the potential adverse effects on the pregnancy may also be similar.

Both mating and fertility were reduced in male and female rats at oral doses of 32 mg/kg/d (approximately five times the maximum recommended human daily dose of 60 mg/day on a surface area [mg/m2] basis [MRHD]) (1). The duration of gestation was increased at 48 mg/kg/day (approximately eight times the MRHD).

Citalopram demonstrated dose-related embryo and fetal growth retardation, reduced survival, and teratogenicity in rats dosed during organogenesis with 112 mg/kg/day (approximately 18 times the MRHD) (1). The developmental no-effect dose was 56 mg/kg/day. Fetal malformations included cardiovascular and skeletal defects. The 112 mg/kg/day dose was also maternal toxic (clinical signs, decreased weight gain) (1). In contrast, no developmental adverse effects were observed in the offspring of pregnant rabbits given doses up to 16 mg/kg/day (approximately five times the MRHD) (1).

Increased offspring mortality during the first 4 days after birth and persistent growth retardation were observed when pregnant rats were dosed with 24 mg/kg/day throughout gestation and early lactation. Similar effects were observed with a 32 mg/kg/day dose administered in late gestation through weaning. The no-effect dose in this group was 12.8 mg/kg/day (approximately twice the MRHD) (1).

No reports describing the placental transfer of citalopram in animals or humans have been located. The molecular weight of the agent (about 405 for the hydrobromide salt), however, is low enough that transfer to the fetus should be expected.

Citalopram is at least eight times more potent in the inhibition of serotonin reuptake than its four metabolites (1). It has an elimination half-life of approximately 35 hours. This is in the same general range as the other SSRI agents with weakly active or inactive metabolites (elimination half-lifes of parent compounds in parentheses): fluvoxamine (15.6 hours), paroxetine (21 hours), and sertraline (26 hours). All have much shorter elimination half-lifes than fluoxetine (46 days) or fluoxetine's active metabolite (416 days).

A brief 1993 case report described a woman who was treated with citalopram for major depression during the first 6 weeks of an undiagnosed pregnancy (3). She received 40 mg/day during the first 3 weeks, and then the dose was increased to 60 mg/day. She also took thioridazine, etilefrine, and dihydroergotamine for coexisting panic disorder and migraine headaches. All medication was stopped in the sixth week of gestation when the pregnancy was diagnosed. Because of her deteriorating mental status and anxiety concerning fetal development, she requested an abortion which was performed at 12 weeks' gestation. At autopsy, a thorough macroscopic and microscopic evaluation, including a detailed neuropathological examination, found no evidence of malformation (3).

In 1999, the Swedish Medical Birth Registry published the results of a study on the use of antidepressants in early pregnancy and delivery outcome for the years 19951997 (4). During the period, 281,728 infants were registered, 531 of whom had been exposed in utero to SSRI antidepressants, 15 to SSRIs plus a non-SSRI antidepressant, and 423 to non-SSRI antidepressants. Of the 376 women who used citalopram, 364 used it alone, 1 used it in combination with sertraline, and 11 used it in combination with non-SSRI antidepressants (clomipramine, amitriptyline, or imipramine). There was no significant differences in relative risk (RR = observed/expected) for birth defects between those exposed to any depressant (total 39; RR 1.13), SSRIs only (total 21; RR 1.12), and non-SSRIs only (total 18; RR 1.15). Similarly, no significant differences in infant survival were observed among the groups. A shorter gestational duration (<37 weeks) was observed for any antidepressant exposure (OR 1.43, 95% Confidence Interval [CI] 1.141.80), but no difference between SSRI and non-SSRI antidepressants. Moreover, antidepressant exposure was not associated with an increased risk of low birth weight (defined as<2500 g) among singletons as the crude OR 1.32, 95% CI 0.96 1.80, decreased to 1.03 after adjustment for confounders (4). Fifteen (4.0%) of the citalopram -exposed infants had anomalies, but one was a trisomy 13 syndrome and five were classified as uncertain anomalies (laryngeal/bronchial anomaly [N=1]; undescended testicle [N=4]) (4). No signals of teratogenicity or patterns of defects were observed in the other 10 citalopram-exposed infants.

In summary, citalopram does not appear to be a major human teratogen, although the data are still limited. The Swedish study discussed above observed no increase in defects or pattern of major anomalies over that expected in a nonexposed population. An increase in minor malformations and severe perinatal complications has been observed with another SSRI antidepressant (see Fluoxetine), but the relationship of these observations to citalopram and other SSRIs is unknown. In that study, both fluoxetine-exposed and control infants were specifically examined in a blind manner for minor anomalies, which might have been missed by a less intensive examination. Such an examination was not described in the Swedish study. Moreover, the increase in perinatal complications was related to the use of fluoxetine late in pregnancy. The prolonged elimination half-lifes of fluoxetine and its active metabolite may have contributed to these complications.

A 1999 review of SSRI antidepressants concluded that if therapy was required during pregnancy, the SSRIs were a good choice because of their side-effect profile and safety in overdose (5). Because fluoxetine had been studied the most during pregnancy, the reviewers recommended it as their first choice. Additional research, however, is needed on all SSRIs, including citalopram, to better define their relationship to minor malformations and perinatal morbidity. In addition, investigations are needed on the potential of SSRIs for neurobehavior teratogenicity that might not become evident for years after birth.

Breast Feeding Summary

Citalopram is excreted into human milk (1,6,7,8 and 9). A 1997 report described breast milk concentrations of the antidepressant in two lactating women under treatment for depression and one healthy lactating volunteer (6). All three subjects were extensive metabolizers of citalopram with respect to the liver enzymes (CYP2C19 and CYP2D6) involved in the metabolism of the drug. The two women with depression were being treated with 20 mg/day and 40 mg/day at 2 and 4 months postpartum, respectively. The healthy volunteer was given a single dose of 40 mg at 10 months postpartum. The milk:serum ratio in the two women ranged from 1.16 to 1.88, whereas in the volunteer, the ratio was 1.00, based on the area-under-the-time-concentration curve (AUC) (6). The dose ingested by an infant was calculated to range from 4.3 to 17.6 g/kg/day (0.7% 5.9% of the weight-adjusted maternal dose) in the two women on chronic therapy and 11.2 g/kg/day (1.8% of the weight-adjusted maternal based on AUC). The two mothers on chronic therapy observed no adverse effects in their nursing infants. Compared with other SSRI antidepressants, the relative dose to the infant from citalopram (0.7%5.9%) was comparable to fluoxetine and its active metabolite (1.2%6.5%) but higher than that for fluvoxamine (0.5%), sertraline (0.45%), and paroxetine (0.34%) (6). Based on these data, the authors recommended that caution be used with the administration of citalopram during lactation (6).

In a second 1997 report, a 21-year-old mother developed severe depression 2 months after delivery of a female infant and was begun on citalopram (7). Blood and milk samples were collected after 15 days of treatment following 8 days of a continuous 20 mg/day dose. The mean milk:serum ratio over a 24-hour period was approximately 3 for both citalopram and its inactive metabolite. The investigators estimated that the weight-adjusted dose of citalopram received by the infant was 4.8% of the mother's dose. After 3 weeks of therapy, a blood sample was obtained from the infant. The serum concentration of citalopram in the infant (the concentration of the metabolite was to low to measure) was about 1/15th of the mother's level just before a dose. These low levels indicate that no accumulation of citalopram or the metabolite occurred in the baby. Furthermore, no immediate adverse effects or unusual behavior were observed in the infant (7).

A 2000 report measured citalopram concentrations in the milk and plasma of seven women who were nursing their infants (mean age 4.1 months) (8). The median citalopram dose was 0.36 mg/kg/day. The mean milk:plasma ratios of citalopram and the metabolite, demethylcitalopram, were 1.8 (range 1.23) and 1.8 (range 1.02.5), respectively. Citalopram was detected in the plasma of three infants (2.02.3 ng/mL), two of which also had detectable levels of the metabolite (2.2 ng/mL). The mean combined dose of citalopram and metabolite (expressed as a percentage of the maternal weight-normalized dose) was 4.4%5.1%. No adverse effects were observed in the infants and all had normal Denver developmental quotients. Because the dose was less then the 10% notional level of concern and the absence of adverse effects, the authors concluded that citalopram was safe to use during breast feeding (8).

A 29-year-old woman, 4 weeks after delivery, was started on citalopram (40 mg/day) for postpartum depression (9). Eight days later, at steady state, single samples of milk and serum (time from last dose not specified) yielded concentrations of 205 ng/mL and 98.9 ng/mL, respectively. Uneasy sleep was noted in the breast-fed infant starting about 2 to 3 days after initiation of drug therapy. The citalopram concentration in the infant's serum after 16 days of maternal therapy was 12.7 ng/mL. Reducing the dose to 20 mg/day and substituting two breast-feedings with artificial nutrition normalized the infant's sleeping. One week later, the serum concentrations of citalopram in the mother and infant were 49.0 ng/mL and 4.5 ng/mL, respectively (9).

In their product information, the manufacturer describes two infants with excessive somnolence, decreased feeding, and weight loss associated with nursing from mothers receiving citalopram (1). Both cases involved reports to the manufacturer that apparently were not published. Although the information is incomplete, the manufacturer was able to obtain partial details of these cases (G. Fagen, personal communication, Forrest Pharmaceuticals, 2000). One full-term infant was born to a Danish woman who had been started on citalopram, 40 mg/day, shortly before delivery. The infant was presumably breast-fed. When the adverse effects were noted 3 to 4 days after birth, the mother stopped the drug. The infant made a full recovery. The second case involved an 8-day-old Swedish baby who developed tiredness, weight loss, and decreased suckling. The mother had started taking citalopram, 20 mg/day, approximately 1 year earlier. She was also taking an antihistamine. Five days before the onset of the adverse symptoms, without medical advice, she increased her dose to 30 mg/day. A single milk sample (timing in relationship to the dose not specified) yielded a drug concentration of 377 nmol/L (about 0.122 g/mL) (1 mol of citalopram = 324.4 g [6]). The concentration of the metabolite was 111 nmol/L. These amounts are very close to those reported in the above published cases. No other details of the case were available, although it is known that the infant was doing well at 4 years of age.

A recent review of SSRI agents concluded that if there were compelling reasons to treat a mother for postpartum depression, a condition in which a rapid antidepressant effect is important, the benefits of therapy with SSRIs would most likely outweigh the risks (10). Based on the data cited previously, however, nursing women receiving citalopram, in particular those taking doses >20 mg/day or concurrently with other sedative agents, should be warned of the potential for toxicity in their infants. Moreover, because the long-term consequences of exposure to SSRI antidepressants in breast milk on the infant's neurobehavior development are unknown (no such adverse effects have been reported to date, but additional research is needed), stopping or reducing the frequency of breast feeding should be considered if therapy with these agents is required. Avoiding nursing around the time of peak maternal concentrations (about 4 hours after a dose) may limit infant exposure. However, the long elimination half-lifes of all SSRIs and their weakly basic properties which are conducive to ion trapping in the relatively acidic milk probably will lessen the effectiveness of this strategy. The American Academy of Pediatrics classifies antidepressants as drugs whose effect on the nursing infant may be of concern (11). The mother should be provided with all of this information so that she can actively participate in any decision.

References

1. Product information. Celexa. Forest Pharmaceuticals, 2000.
2. Shuey DL, Sadler TW, Lauder JM. Serotonin as a regulator of craniofacial morphogenesis: site specific malformations following exposure to serotonin uptake inhibitors. Teratology 1992;46:36778.
3. Seifritz E, Holsboer-Trachsler E, Haberthur F, Hemmeter U, Poldinger W. Unrecognized pregnancy during citalopram treatment. Am J Psychiatry 1993;150:14289.
4. Ericson A, Kallen B, Wiholm BE. Delivery outcome after the use of antidepressants in early pregnancy. Eur J Clin Pharmacol 1999;55:5038.
5. Masand PS, Gupta S. Selective serotonin-reuptake inhibitors: an update. Harvard Rev Psychiatry 1999;7:6984.
6. Spigset O, Carleborg L, Ohman R, Norstrom A. Excretion of citalopram in breast milk. Br J Clin Pharmacol 1997;44:2958.
7. Jensen PN, Olesen OV, Bertelsen A, Linnet K. Citalopram and desmethylcitalopram concentrations in breast milk and in serum of mother and infant. Therap Drug Monitor 1997;19:2369.
8. 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;50:2638.
9. Schmidt K, Olesen OV, Jensen PN. Citalopram and breast-feeding: serum concentration and side effects in the infant. Biol Psychiatry 2000;47:1645.
10. Edwards JG, Anderson I. Systematic review and guide to selection of selective serotonin reuptake inhibitors. Drugs 1999;57:50733.
11. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:13750.

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