Tricyclic Antidepressants: Teratology

2015

Antidepressants comprise only a small portion in the vast assortment of drugs that may be taken by pregnant women. In a sample of 3,072 subjects, the number of gravid women receiving antidepressant drugs was estimated to be in the order of 0.1 % (). Similar to other drugs that are used much more frequently during pregnancy (), particularly during the first trimester (the most sensitive period of embryonal development), some antidepressants have been suspected to carry a teratogenic risk.

In a short note published 1972, McBride reported on one child with amelia and mentioned two others with a similar limb deformity he felt were caused by imipramine taken by the mothers in early pregnancy. Two further cases were subsequently reported (). Doubt was, however, cast upon the validity of the McBride’s notion of a causal relation between imipramine or other tricyclic antidepressants such as amitriptyline and congenital abnormalities. The Australian Drug Evaluation Committee (1973) and the results of further clinical and epidemiologic studies failed to associate the ingestion of these drugs in early pregnancy with malformations (). Likewise, neither on account of the review presented by one manufacturer () nor on the basis of the survey of a series of 15,000 pregnancies in Scotland () and the review of 2,784 cases of birth defects in Finland (), was it inferred that imipramine or amitriptyline were causally related to congenital abnormalities. More recently, the results of an extensive surveillance program in the United Kingdom, relating to drug histories for the first trimester of pregnancy for mothers of congenitally malformed children and for an equal number of control mothers of normal babies, presented no evidence that antidepressants (tricyclics or MAO inhibitors) were teratogenic ().

It is of interest to survey the experimental studies that were conducted to determine the effects of various antidepressants on the embryonal and foetal development of laboratory animals. A review of the literature pertaining to the various groups of antidepressant drugs is given by Tuchmann-Duplessis () and by Schardein (). In the following, a survey is given of studies conducted in the laboratory animal with tricyclic antidepressants in therapeutic use.

The basic principles for testing for teratogenicity are similar to those underlying the detection of general toxicity except that two interdependent variables are involved, the pregnant female and the embryo. The reaction of each may be entirely different. According to present knowledge, rodents (rats or mice) and/or a lagomorph (the rabbit) can be expected to yield results that are of relevance to man. The predictive value of studies in these species appears to be at least as great as that of experiments in other species, including nonhuman primates. The rationale for testing and the present methods used in teratogenicity studies have been summarized by an expert committee of the Swiss Academy of Medical Sciences (1974).

Imipramine has been extensively studied in a variety of animal species. In the rat, a species in which the metabolism of imipramine has a certain resemblance to that of man (), the drug was shown to be toxic to the mother animal and to the embryo or fetus at daily oral dose levels of 10 – 50 mg/kg body weight (). Toxicity was increased about twofold by s.c. administration () and by i.p. administration. Reduction in litter size was observed when 5 mg/kg was given continuously to rats prior to and during pregnancy (). In none of these studies was teratogenicity produced and the effects were ascribed mainly to toxic effects on the mother animal (). In contrast to the rat, pregnant mice proved resistant and doses up to 150 mg/kg were without effect ().

Whereas oral doses of imipramine (up to 50 mg/kg) given to pregnant rabbits were without effect on the foetus (), the application of high parenteral doses (10-50 mg/kg) caused maternal toxicity and abnormalities in the fetuses, in a dose related fashion (). Malformations of the CNS, the extremities, and of other parts of the skeleton being predominant. These findings corroborate to some extent earlier observations in this species by Larsen () and by Robson and Sullivan (). Their significance is doubtful, however, since in contrast to the human and the rat, the rabbit produces large amounts of 2-hydroxy-imipramine, which is the metabolite held responsible for the maternal and foetal toxicity and in consequence, for the teratogenic effects in this species ().

On the basis of these data, imipramine produces maternal toxicity when given in high enough doses to the pregnant animal. Only when this effect prevails, may embryotoxicity and abnormal development be induced. Nontoxic doses to the mother animal are without effect on the fetus. It is of interest to compare this secondary or nonspecific action in rats and rabbits to the results of experiments conducted in non-human primates. Hendrickx () administered imipramine hydrochloride to bonnet and Rhesus monkeys during the critical periods of organogenesis, including limb development and palatal closure, at daily oral doses ranging from 100 to 1000 mg, i.e., from 19 to 244 mg/kg per day. Signs of maternal toxicity (convulsions) occurred at the high dose level but no teratologic changes were produced. By and large, results similar to imipramine were also obtained with its desmethyl metabolite desipramine ().

Of other antidepressants in therapeutic use, the information available in the literature is less extensive. Amitriptyline was reported to induce malformations in rabbits, but it produced no such effects in mice () or rats (). This drug and butriptyline were reported to cause an increasing degree of retardation of skeletal ossification in rats at doses of 5-25 mg/kg. Apart from this entirely nonspecific effect, no maternal or fetal toxicity was observed (). Maprotiline, an antidepressant dibenzobicyclo-octadiene, likewise caused slight retardation of fetal growth when administered orally throughout the organogenetic phase at a dose level of 10 mg/kg (i.e., about five times the maximum therapeutic dose). No effects whatever were observed in pregnant mice. In rabbits, at a dose that produced maternal toxicity (6 mg/kg), the offspring were unaffected. The compound did not adversely effect fertility, general reproductive performance, perinatal behavior and lactation in rats ().