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                    Antidepressant use during pregnancy

                                                             Patricia Boksa, PhD

Douglas Hospital Research Centre, Department of Psychiatry, McGill University, Montreal, Que.

This issue of the the Journal of Psychiatry & Neuroscience                       adaptation, including respiratory difficulty, cyanosis on
features an article by Einarson and colleagues1 describing                       feeding and jitteriness. The incidence of 3 or more minor
adverse effects in pregnant women who abruptly with-                             physical anomalies was also greater for 97 infants
draw from antidepressants (mainly selective serotonin                            exposed to fluoxetine during the first trimester of preg-
reuptake inhibitors [SSRIs]), benzodiazepines or both. A                         nancy, compared with controls.4 With regard to more
high incidence of side effects on abrupt withdrawal from                         long-term effects, Nulman et al.6 reported no abnormal-
these drugs among pregnant women would not be sur-                               ities in IQ, language or behavioural development in chil-
prising, given the well-documented abrupt withdrawal                             dren (mean age 33 months) born to 55 women who took
syndrome known to occur in nonpregnant women.2 Such                              fluoxetine during pregnancy; in this study, data were
side effects have led to the suggestion that these agents                        combined for children exposed to fluoxetine throughout
be discontinued on a tapering basis.                                             pregnancy or exposed during the first trimester only,
  The issue of potential risk to the infant of antidepres-                       and only 18 of the 55 children were exposed to fluoxe-
sant use during pregnancy remains controversial.                                 tine throughout pregnancy. Thus, although SSRI use
Indications from the manufacturers concerning anti-                              during pregnancy does not seem to have major terato-
depressants during pregnancy generally read: "Safety                             genic effects in humans, their use during pregnancy
during human pregnancy has not been established;                                 does appear to be associated with increased perinatal
should be used only if, in the physician's opinion, the                          complications and minor malformations, and possible
expected benefits outweigh (or markedly outweigh) the                            long-term effects require further study.
possible risks to the fetus." In some cases, it is men-                             A limitation of human studies is the level of resolution
tioned that animal studies indicate no teratogenic effects.                      of outcome measures that can be achieved. We know
  Sources of evidence to assess "possible risks to the                           that disorders such as depression, anxiety and schizo-
fetus" come from human and animal studies. For SSRIs,                            phrenia are not generally associated with gross morpho-
3 human studies concur that SSRI use during pregnancy                            logical changes in brain, but likely involve subtle altera-
confers no increased risk for miscarriage or major mal-                          tions in brain biochemistry or morphology. There is
formations.3­5 Looking at subtler measures, however,                             increasing evidence that early developmental insults
Chambers and colleagues4 reported that a sample of 73                            (e.g., obstetric complications, low birth weight) may
infants exposed to fluoxetine, either throughout preg-                           contribute to psychopathology that is expressed only
nancy or during only the last trimester, had increased                           later in life (e.g., schizophrenia) because of interactions
rates of premature delivery and admission to special                             with ongoing brain development, aging, or stressors.
care nurseries, lower birth weight and poor neonatal                             Thus, early insults may produce increased vulnerability

Correspondence to: Dr. Patricia Boksa, Douglas Hospital Research Centre, 6875 LaSalle Blvd., Verdun QC  H4H 1R3; fax 514 762-

Medical subject headings: antidepressive agents; pregnancy; risk factors; serotonin; serotonin uptake inhibitors; substance withdrawal syndrome; teratogens

J Psychiatry Neurosci 2001;26(1):17-9.

© 2001 Canadian Medical Association

Vol. 26, no 1, 2001                                  Journal of Psychiatry & Neuroscience                                                               17



for psychopathology related to subtle neurochemical              rats increases mRNA for brain-derived neurotrophic
imbalances at much later periods in the lifespan.                factor (BDNF) and for its receptor, trkB, in the hip-
  In animal studies, the evidence of "no teratogenicity"         pocampus.15 BDNF is a neurotrophin that promotes
indicated by pharmaceutical manufacturers routinely              development of immature neurons and enhances the
consists of survival studies and gross morphological             survival and function of mature neurons;
studies showing no major malformations. However,              * chronic SSRI treatment also increases mRNA for the
there are indications from animal studies that prenatal          nuclear transcription factor, cAMP response element
exposure to SSRIs or benzodiazepines does have long-             binding protein (CREB), in rat hippocampus, as well
term effects on specific neurotransmitter systems and            as the expression and function of the CREB protein,
behaviours. For example, administration of fluoxetine to         which can upregulate a variety of target genes;16
pregnant rats during part of their pregnancy has been         * the human placenta possesses an active 5-HT trans-
shown to alter brain serotonin (5-HT) uptake sites, hypo-        porter that is potently inhibited by SSRIs such as flu-
thalamic 5-HT receptor levels and responses, and 5-HT-           oxetine (IC50 = 17 nM) and paroxetine (IC50 = 23 nM),
mediated phosphoinositide turnover in cortical slices in         and less potently by cocaine (IC50 = 182 nM).17 5-HT
adolescent or adult offspring.7­9 Since rats are born            profoundly affects vascular function by contracting
immature relative to humans, mimicking drug adminis-             vascular smooth muscle and enhancing the effects of
tration equivalent to an entire human pregnancy would            other vasoconstrictors. Thus, clearance of 5-HT by
require giving drug to the rat from conception until             the placental 5-HT transporter plays an important
about postnatal day 10. However, even these studies              role in optimizing uteroplacental blood flow. Co-
administering fluoxetine to rats during a fraction of the        caine produces placental ischemia, depriving the
pregnancy show lasting effects on 5-HT systems. Recent           fetus of oxygen and nutrients,18 and it has been sug-
studies by Coleman et al.10 report that administration of        gested that "impairment of such a vital function
paroxetine to mice throughout gestation results in               [placental 5-HT transport] by cocaine is expected to
increased anxiety in infant offspring and increased              be highly relevant to the pathogenesis of fetal and
aggressive behaviour in adult male offspring. In the case        placental complications of cocaine abuse during
of the benzodiazepines, a rich history of animal studies         pregnancy."17 Such concerns are even more relevant
has documented effects of prenatal and early postnatal           to SSRIs because they inhibit placental 5-HT trans-
benzodiazepines on gamma-aminobutyric acid,                      port much more potently than cocaine does;
monoamine and opioid neurochemistry, as well as last-         * fluoxetine reduces hunger and food intake in hu-
ing behavioural effects on learning, social interactions,        mans,19 produces hypophagia in rats20 and increases
aggression and anxiety (reviewed in Schroeder et al.11).         resting energy expenditure and basal body temper-
  It is reasonable to hypothesize that SSRIs may affect          ature in humans.21
fetal brain development because 5-HT is thought to be           Hopefully, these few thoughts can serve as a reminder
an important regulator of early brain development. For        that the use of antidepressants during pregnancy is a
example, 5-HT promotes the differentiation of CNS tar-        complex and controversial issue. The fact that antide-
get cells and autoregulates growth of 5-HT neurons in         pressants are not major teratogens does not prove that
culture.12 Also, 5-HT systems are very plastic. After cer-    they are without effect on the developing CNS - these
tain CNS lesions, immense hyperinnervation of various         drugs are more likely to affect CNS biochemistry or the
brain regions by 5-HT terminals occurs, especially in         microscopic organization of brain circuits, rather than
the neonate.13 The mechanism of 5-HT hyperinnerva-            gross brain structure. The role of 5-HT in normal CNS
tion involves the activation of 5-HT1A receptors by 5-HT,     development, as well as the effects of altering 5-HT
which causes the release of protein S-100  from astro-        transmission at critical periods, remain to be further
cytes.14 Thus, S-100  may be viewed as a serotonergic         clarified. Although my comments have concentrated on
sprouting factor whose release is mediated via 5-HT           fetal risk, the decision to use antidepressants during
itself.                                                       pregnancy is a multifaceted problem, involving benefits
  In addition to effects on 5-HT, other documented ef-        and risks of either using or abstaining from the medica-
fects of chronic SSRI treatment could also affect fetal       tion to both mother and child. Given our current level
brain development. For example:                               of uncertainty, we can only benefit from more individ-
* chronic administration of the SSRI, sertraline, to adult    uals performing their own critical appraisals of the

18                                      Revue de psychiatrie et de neuroscience                       Vol. 26, no 1, 2001



existing literature, and from further research, to reach                          to paroxetine (Paxil). Am J Obstet Gynecol 1999;181:1166-71.
the goal of a truly informed decision as to relative ben-                    11. Schroeder H, Humbert A-C, Desor D, Nehlig A. Long-term
                                                                                  consequences of neonatal exposure to diazepam on cerebral
efits and risks of antidepressant use during pregnancy.                           glucose utilization, learning, memory and anxiety. Brain Res
References                                                                   12. Azmitia EC, Frankfurt M, Davila M, Whitaker-Azmitia PM,
                                                                                  Zhou FC. Plasticity of fetal and adult CNS serotonergic neu-
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2. Black K, Shea C, Dursun S, Kutcher S. Selective serotonin reup-                Ultrasructural analysis of the serotonin hyperinnervation in
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                         2001 Canadian College of Neuropsychopharmacology
                                             Annual Meeting Announcement

                       The 24th Annual Meeting of the Canadian College of Neuropsychopharmacology
                       (CCNP) will be held June 16­20, 2001, at the Banff Centre for the Arts in Banff, Alta.,
                       in the Canadian Rockies. This meeting will be held jointly with the British
                       Association for Psychopharmacology and the Japanese Society for Neuropsycho-
                       pharmacology. Symposia, plenary lectures and award lectures will be included.

                                                  Abstract deadline: April 15, 2001

                       For information, please contact Ms. Rachelle Anderson: tel 780 407-6576; fax 780

Vol. 26, no 1, 2001                                   Journal of Psychiatry & Neuroscience                                                        19