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Neonatal signs following exposure to ssris
Hum Psychopharmacol Clin Exp 2005; 20: 522.
Neonatal signs following exposure to SSRIs
Moses-Kolko et al. (2005) reported that late (final tri-
acetylcholine (e.g., anti-muscarinic drugs)-related def-
mester of pregnancy) exposure of serotonin reuptake
icits such as memory and cognition in rodent models,
inhibitor (SRI) carries an overall risk ratio of 3.0 for
and are also effective in animal models of depression
a neonatal behavioral syndrome as compared with
(Hayashi and Su, 2004; Hashimoto and Ishiwata,
early gestational SRI exposure or no exposure. Eleven
2005). Additionally, fluvoxamine acts as an agonist at
(61%) of the 18 cases of SRI-related neonatal signs
sigma-1 receptors although it is unknown whether
were associated with paroxetine exposure. Further-
other SRIs are agonists at sigma-1 receptors (Hayashi
more, neonatal behavioral signs across the cohort stu-
and Su, 2004; Hashimoto and Ishiwata, 2005). Taken
dies and the case series were similar to those reported
together, it seems that agonistic activity of fluvoxamine
in the single case reports (Moses-Kolko et al., 2005).
at sigma-1 receptors might, in part, play a role in the
Furthermore, Sanz et al. (2005) reported recently the
lack of these side effects of fluvoxamine although
association between neonatal withdrawal syndrome
further studies using selective sigma-1 receptor ago-
and maternal use of SRIs, especially paroxetine. They
nists would be necessary. Therefore, it is likely that
identified a total of 102 cases of SRI use associated
SRIs (e.g., fluvoxamine) with high affinity at sigma-1
with either neonatal convulsions or withdrawal syn-
receptors might be useful for the treatment of perina-
drome. Paroxetine was the most commonly reported
SRI with these adverse side effects. Cases were alsoreported for fluoxetine, sertraline, and citalopram, butnot for any of the other SRIs including fluvoxamine
(Sanz et al., 2005). They conclude that paroxetine
Moses-Kolko EL, Bogen D, Perel J, et al. 2005. Neonatal signs after
should not be used in pregnancy or, if used, should
late in utero exposure to serotonin reuptake inhibitors-literature
be given at the lowest effective dose (Sanz et al.,
review and implications for clinical applications. JAMA 293:
2005). These two authors suggested that a moderate affi-
Narita N, Hashimoto K, Tomitaka S, et al. 1996. Interactions of
nity of paroxetine at muscarinic acetylcholine receptors
selective serotonin reuptake inhibitors with subtypes of sigma
could contribute to neonatal behavioral syndromes and
receptors in rat brain. Eur J Pharmacol 307: 117–119.
withdrawal syndrome associated with paroxetine use
Hashimoto K, Ishiwata K. 2005. Sigma receptor ligands: possible
(Moses-Kolko et al., 2005; Sanz et al., 2005).
application as therapeutic drugs and as radiopharmaceuticals.
Sigma-1 receptors are brain-enriched endoplasmic
Hayashi T, Su TP. 2004. Sigma-1 receptor ligands: potential in the
reticulum proteins that are implicated in certain psy-
treatment of neuropsychiatric disorders. CNS Drugs 18: 269–
chiatric disorders including depression and anxiety
(Hayashi and Su, 2004; Hashimoto and Ishiwata,
Sanz EJ, De-las-Cuevas C, Kiuru A, et al. 2005. Selective serotonin
2005). Sigma-1 receptors modulate a number of neu-
reuptake inhibitors in pregnant women and neonatal withdrawalsyndrome: a database analysis. Lancet 365: 482–487.
rotransmitter systems, including noradrenergic, gluta-matergic, and cholinergic systems (Hayashi and Su,2004; Hashimoto and Ishiwata, 2005). We reported
that SRIs possessed high to moderate affinities at
sigma-1 receptors in the brain (Narita et al., 1996).
Chiba University Center for Forensic Mental Health
The rank order of potency of drugs for sigma-1 recep-
tors was as follows: fluvoxamine (Ki ¼ 36 nmol/L) >
sertraline> fluoxetine> citalopram > paroxetine (Ki ¼
l893 nmol/L). Sigma-1 receptor agonists can improve
2005 John Wiley & Sons, Ltd.
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