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Medical Hypotheses
journal homepage: www.elsevier.com/locate/mehy

Serotonin, pregnancy and increased autism prevalence: Is there a link?
Nouchine Hadjikhani *MGH/MIT/HMS Martinos Center for Biomedical Imaging, Charlestown, USA
Brain Mind Institute, EPFL Lausanne, Switzerlanda r t i c l e

i n f oArticle history:
Received 9 November 2009
Accepted 16 November 2009
Available online xxxx

s u m m a r y
The prevalence of autism, a neurodevelopmental condition resulting from genetic and environmental
causes, has increased dramatically during the last decade. Among the potential environmental factors,
hyperserotonemia during pregnancy and its effect on brain development could be playing a role in thisprevalence raise. In the rodent model developed by Whitaker-Azmitia and colleagues, hyperserotonemia
during fetal development results in a dysfunction of the hypothalamo–pituitary axis, affecting the amygdala as well as pro-social hormone oxytocin regulation.
Dysfunction of the amygdala and abnormal oxytocin levels may underlie many clinical features of ASD.
Selective serotonin reuptake inhibitors (SSRI) are the most widely used class of antidepressants drugs,
and they are not contraindicated during pregnancy. In this paper, we hypothesize that increased serotonemia during pregnancy, including due to SSRI intake, could be one of the causes of the raising prevalencein autism. If our hypothesis is conﬁrmed, it will not only shed light on one of the possible reason for autism prevalence, but also offer new preventive and treatment options.
Ó 2009 Elsevier Ltd. All rights reserved.

Introduction
Autism spectrum disorder (ASD) is a behaviorally deﬁned neurodevelopmental disorder affecting as many as 1 in 150 children
prevention [1], or even 1:91 according to the latest report of National Survey of Children’s Health [2]. Its deﬁning features include
mild to severe impairments in communication and reciprocal social interaction, as well as repetitive and stereotyped behaviors.
Reports of autism prevalence have increased dramatically during the past decade. This may be partly due to increased awarenessof ASD resulting in more diagnoses being made, but also to environmental factors [3,4]. Not much is known yet on the possible effect of certain drugs, food or environmental conditions on ASD
progression.
DHS model of autism
There is evidence that otr (coding for oxytocin, OT) and avpr
(coding for vasopressin) genes may be abnormal in some ASD individuals (for review, see [5]). However, decreased levels of OT could
also be the consequence of abnormal levels of serotonin (5HT) during brain development.
The developmental hyperserotonemia (DHS) model of autism
was ﬁrst hypothesized by Patricia Whitaker-Azmitia (reviewed in* Address: EPFL SV BMI AAB 133, Station 15, CH-1015 Lausanne, Switzerland.
Tel.: +41 216931807; fax: +1 5303094973.
E-mail address: nouchine@nmr.mgh.harvard.edu[6]), who based her theory on the observation that high levels ofserotonin is seen in the blood of a third of ASD children.
Hyperserotonemia is indeed the most consistent neurochemicalchange in autism [7–11]. Hyperserotonemia is also found in ﬁrstdegree relatives [12] and is associated with recurrence risk of autism within families [13–15].
It is important to keep in mind that in the mature brain, bloodlevels of serotonin are not an indicator of brain serotonin, because(1) serotonin does not cross the mature blood brain barrier (BBB)
and (2) the synthetic enzyme tryptophan hydroxylase is different
in the brain and in the periphery [16]. However, the immature
BBB allows the passage of 5HT and in infants, the BBB becomes
impermeable to serotonin at only 2 years of age.
The DHS model states that at early stages of development, whenthe BBB is not fully formed, high levels of maternal blood serotonin
could enter the brain of the developing fetus and cause loss of 5HT
terminals through negative feedback (Fig. 1).
Developmental hyperserotonemia was mimicked in the rat
from gestational day 12 to postnatal day 20 [6]. Changes were observed: (1) in columnar development in cortex (also seen in humans with ASD [17]), (2) in 5HT receptors and (3) in the
behavior of rats, that exhibited ‘autistic-like’ traits. In addition,changes were found (4) in the amygdala, with an increase of CGRP
(also seen in ASD [18]), and (5) in the paraventricular nucleus of
the hypothalamus (PVN), with as a consequence decreased OT levels (also seen in ASD [19,20]). Both changes in the amygdala andthe PVN could result from loss of 5HT innervation. Recently moreevidence has been produced supporting the DHS model, showing

0306-9877/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.mehy.2009.11.015

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N. Hadjikhani / Medical Hypotheses xxx (2009) xxx–xxx

that pups, similarly to ASD children, exhibit increased tendency toseizures, are less social, and show fewer olfactory-based social
interactions [21].
In the human brain, serotoninergic neurons appear at ﬁve
weeks of gestation [22]. Serotonin ﬁbers grow continuously prenatally, and brain serotonin levels increase until a peak is reached atabout 2 years of age, after which they decline until adult levels arereached, which represent 50% of the peak values (reviewed in [6]).
Serotonin exerts a negative feedback on the development ofserotonin neurons, mediated by 5HT1A receptors [23]. Serotonin
terminals innervate both the central nucleus of the amygdala andthe paraventricular nucleus of the hypothalamus, and the releaseof CGRP and OT is mediated by 5HT1a and 5HT2 receptors [24].

Increased serotonin during pregnancy
In humans, increased levels of serotonin during pregnancy
could have several distinct etiologies, including increased internal
release, increased intake and decreased metabolism. As mentioned
above, it is known that ﬁrst-degree relative hyperserotonemia increases the risk of autism [13–15].
Drugs that release 5HT, such as cocaine, have been shown todramatically increase the prevalence of autism, with 11.4% of children exposed in utero being affected [25]. However, in the light ofrecent prevalence increases, can we think of another substancethat was newly introduced and could be playing a role?

SSRIs and autism – is there a link?
Prozac was introduced in the USA in 1987. SSRIs are the third
most prescribed antidepressant [26], with over 22.2 million prescriptions in the US in 2007. SSRIs are not contraindicated during
pregnancy, and as high as 2.3% of mothers report using SSRIs fromone month before to 3 months after conception [27–29].
Several studies have examined the teratogenic effects of SSRIs[30,31], and some have concluded to an association with slightly
increased risks of cardiac abnormalities. Those studies examined
the potential effects of SSRI exposure in utero on the presence of
fetal malformation, and the effect of withdrawal syndrome after
birth. However, they did not address the long-term effect of SSRI
exposure on cognition and, to our knowledge, no study has so far
explored the presence of a correlation between SSRIs intake andautism prevalence. SSRIs remain the treatment of choice of depression during pregnancy.
Borue et al. [32], recently reviewed the possible effects of SSRIs
on cognitive development in rodents, and have shown that administration of SSRIs during a key developmental window createschanges in brain circuitry and maladaptive behaviors that persist
into adulthood, including increased anxiety, aggression anddepression.
Epidemiological data may shed some light on a putative connection between SSRIs and autism. In 2007, Utah was the statewith the highest rate of depression in the USA [33], and Utah is
number one in prescription for depression. In 2009, a study published by the US Center for Disease Control and Prevention revealed that Utah has the third highest rate among 14 states
examined, with prevalence rates 12% higher than national averages, and that increased twentyfold in 20 years. While no causality
can be drawn from these epidemiological observations, and while
we are lacking speciﬁc data on the prevalence of SSRI intake by
pregnant women in Utah, the coincidence of highest SSRI intake
and top ten autism rates in the same state, given what we havelearned from the rodent model, certainly warrants further
investigation.

Other factors can be suspected, including high tryptophan containing food intake. Tryptophan is present in dietary supplements,
but also in many different foods like soybeans, turkey andchocolate.

Evidence supporting the DHS model of autism
In line with the DHS model, decreased levels/activity of serotonin have been described in ASD brains: PET studies have revealed
decreased activity of radiolabeled serotonin in the frontal cortex
and thalamus [34] and decreased serotonin synthesis [35] in autistic children, and a recent SPECT study has shown lowered serotonin binding potential in several brain areas in Asperger
individuals, including the superior temporal cortex [36].
In addition, it is known that drugs that increase serotonin availability in the brain can be therapeutically helpful in ASD [37], andthat tryptophan depletion worsens autistic symptomatology [38].
Tryptophan depletion has also recently been shown to disrupt
emotion processing in healthy controls [39].
Noteworthily, both thalidomide and valproic acid exposure,commonly used in animal models of autism, produce hyperserotonemia [40] and alter serotoninergic neurons [41].

Effects of hyperserotonemia on oxytocin
Oxytocin (OT) is a nanopeptide produced in the magnocellular
neurosecretory cells in the supraoptic nucleus and the paraventricular nucleus (PVN) of the hypothalamus. It is released into theblood from the posterior lobe of the hypophysis, as well as directlyfrom the perikarya, dendrites or axon collaterals of magnocellular
neurons. OT ﬁbers have endings in a variety of different brain
areas, including the thalamus, the hippocampus, the amygdala,
the pineal gland and the cerebellum [42].
OT is involved in many aspects of mammalian social behavior,including social recognition and anxiety [43]. OT KO mice have reduced social recognition, and central OT administration into theamygdala restores social cognition [44]. Rodents with abnormal
OT have been proposed as potential animal models for autism[45–47].
In the DHS model, a loss of OT-containing cells in the hypothalamus as well as a loss of OT projections towards the amygdala isassociated with an abnormal social behavior [6].
In humans, OT regulates social interactions, social cognition, social behavior and fear [5,48–51]. In particular, in healthy controls
OT increases gaze to the eye region of the face [52], and attenuates
amygdala response to emotional faces regardless of valence [53].
Intranasal administration of OT speciﬁcally improves recognition
memory for faces, but not for non-social stimuli in healthy humans[54]. Studies done in ASD children have shown decreased plasmatic OT [19,20].

Effects of hyperserotonemia on the amygdala
The amygdala plays an important role in the perception of emotion, and there are indications from several neuropathology, lesion
and neuroimaging studies that it plays a role in the social cognitiondeﬁcits in autism. Altered connections between the amygdala andother components of the emotional processing network could leadto an aberrant emotional response. Several anatomical studies
have found abnormalities in the amygdala of autistic subjects,
although their results do not allow any conclusion regarding an increase or a decrease of amygdala volume in autism [55–61]. Cellpacking density has been described as abnormal [55]. In addition,
a number of functional studies have reported abnormal amygdala

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Fig. 1. Developmental hyperserotonemia model of autism [6]. Panel A: during gestation, the blood brain barrier is still permeable to 5HT. An increase in the maternal blood of
5HT could be caused by several factors: Cocaine [25]; constitutive high HT level [12]; food-related 5HT intake, SSRIs intake [32]. Increased maternal plasma 5HT results inincreased 5HT in the fetal brain. Panel B: Increased 5HT in the fetal brain provokes a loss of 5HT terminals through a negative feedback mechanism. Panel C: As a consequence,in the developed brain we can observe an abnormal cortical columnar architecture, decreased oxytocin production from the hypothalamus, and increased production of
calcitonin-gene related peptide (CGRP) in the amygdala.

activation (e.g. [62,63] and some have proposed that the amygdala
may play a pivotal role in autism [64].
Calcitonin-gene related peptide (CGRP) projections to theamygdala are involved in conditioned response to acoustic andsomatosensory stimuli and play a role in fear conditioning [65],and an increase in CGRP increases fear responding (Fig. 1).
SigniﬁcanceThe dramatic rise in autism prevalence may not only be due toan increased awareness and broader deﬁnition, but also to somefactors in the environment. Among these factors, an elevated levelof serotonin during pregnancy could play an adverse role in brain
development. Elevated serotonin could be caused by intake ofdrugs elevating serotonin levels, and by the consumption of foods
rich in serotonin. If our hypotheses are conﬁrmed, our data would
have consequences not only in our understanding of the pathophysiology of autism, but also in the development of preventive actions meant to limit the amount of serotonin intake during
pregnancy. In addition, if further studies are consistent with a dysfunctional oxytocin production in the brain of ASD individuals,
they will open the way for new therapeutical approaches basedon oxytocin administration.
Conﬂicts of interest statement
None declared.
Acknowledgments
This work was supported by the Swiss National Foundation
Grant PP00B-110741 to NH.
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