The Interaction of Serotonin
Transporter Gene Polymorphisms
and Early Adverse Life Events on
Vulnerability for Major Depression
Derick E. Vergne, MD, and Charles B. Nemeroff, MD, PhD
Charles B. Nemeroff, MD, PhD
Reunette W. Harris Professor and Chairman, Department of
Psychiatry and Behavioral Sciences, Emory University School
of Medicine, Suite 4000 WMRB, 101 Woodruff Circle, Atlanta,
GA 30322, USA.
Current Psychiatry Reports 2006, 8:452–457
Current Science Inc. ISSN 1523-3812
Copyright © 2006 by Current Science Inc.
Considerable literature supports the hypothesis of
dysfunction in central nervous system serotonergic
circuits in the pathophysiology of mood disorders,
specifically major depression. Since the development
of the selective serotonin (5-HT) reuptake inhibitors, a
putative role for the 5-HT transporter (SERT) in the etiology
of depression has been explored. The discovery of a
functional SERT polymorphism has provided a novel
tool to further scrutinize the role of serotonergic neurons
in depression. This article reviews the burgeoning
evidence of an interaction between early life stress and
an SERT polymorphism on vulnerability to depression.
Of the major neurotransmitters, serotonin (5-HT),
norepinephrine (NE), acetylcholine, and dopamine (DA),
in the mammalian central nervous system (CNS) that
have been implicated in the biology of depression, the
available evidence supports a preeminent role for 5-HT.
Although this article focuses on the SERT, its polymor-
phism, early adverse life events, and depression, a very
brief review of 5-HT circuits and their role in depression
is of obvious relevance. Serotonin was named (from
“serum tonic”) after its vasoconstrictor characteristics
were discovered . The precursor to 5-HT is L-tryptophan,
an aromatic amino acid derived from the diet that is
transported across the blood–brain barrier into the CNS.
L-tryptophan availability is the rate-limiting step in
5-HT synthesis. It is converted to 5-hydroxytryptophan
(5-HTP) by tryptophan hydroxylase, and 5-HTP in turn
is converted to 5-HT by the nonspecific L-aromatic amino
acid decarboxylase. Serotonin influences a wide variety of
functions, including cardiovascular physiology, respira-
tion, thermoregulation, sleep, appetite, aggression, sexual
behavior, and impulsivity , many of which are altered
in depressed patients. The majority of the serotonergic
neuronal cell bodies are found in the raphe nuclei. From
there, 5-HT neurons project to the hypothalamus, cortex,
hippocampus, amygdala, and striatum, brain regions
implicated in the regulation of emotion, cognition,
memory, and the endocrine response to stress.
Some of the key evidence supporting a role for
a relative deficiency in serotonergic neurotransmis-
sion in the etiology of depression includes 1) reduced
plasma tryptophan concentrations in depressed patients;
2) decreased concentrations of 5-HT and its major metab-
olite, 5-hydroxyindole acetic acid, in cerebrospinal fluid
(CSF) of depressed patients and in postmortem brain
tissue of suicide victims; 3) increased 5-HT2 receptor
binding in postmortem brain tissue studies of depressed
patients and/or suicide victims and similar findings in
functional brain imaging investigations (vide infra);
and 4) effectiveness of drugs that increase serotonergic
neurotransmission in depression, such as the selective
serotonin reuptake inhibitors (SSRIs), tricyclic antide-
pressants, and monoamine oxidase inhibitors .
The Serotonin Transporter and Depression
Since the introduction of the SSRIs in the late 1980s and
demonstration of their clinical efficacy in the treatment
of depression and certain anxiety disorders, much effort
has been devoted to understanding their major target, the
SERT. SSRIs are, of course, believed to exert their primary
antidepressant action by blocking the SERT and thereby
preventing the uptake of 5-HT into the presynaptic sero-
tonergic nerve terminal. The immediate consequence of
the SSRI is to increase the concentration of 5-HT in the
SERT Polymorphism, Early Life Trauma, and Depression Vergne and Nemeroff 453
synaptic cleft, which presumably increases the occupancy
of one or more postsynaptic 5-HT receptors, thereby
increasing serotonergic neurotransmission. As previously
noted, a multitude of abnormalities of 5-HT function have
been reported in patients with mood and anxiety disor-
ders . Moreover, corticolimbic structures and circuits
regulating behavior and emotionality receive a dense
5-HT innervation. The hypothesized reduction in the
availability of 5-HT would be expected to be associated
with an increase in postsynaptic 5-HT2 receptor binding
density, and that has been reported in platelets, post-
mortem brain tissue, and in functional imaging studies
of depressed patients . In addition, a multitude of
studies have repeatedly documented reductions in SERT
binding in drug-free depressed patients in platelets, post-
mortem brain tissue, and functional imaging studies
[4–8]. Parsey et al. , using positron emission tomogra-
phy, recently reported reduced SERT binding potential in
drug-naïve depressed patients. Reduced SERT binding in
prefrontal cortex has been noted repeatedly in postmortem
studies in depressed patients who committed suicide .
The SERT Gene Polymorphism
Evidence is accumulating suggesting that the pathophysi-
ology of certain depressions, as well as the clinical response
to SSRIs, may be determined in part by a polymorphism
in the promoter region of the SERT. First identified 10
years ago independently by Bradley and Blakely  and by
Heils and Lesch , the SERT is encoded in humans by a
single gene (SLC6A4) located on chromosome 17q11.1-q12.
A functional three-base pair repeat polymorphism has
been identified in the promoter region of this gene and
termed 5-HTTLPR. The short variant of the polymor-
phism was called “s” for “short arm,” and the long variant
“l” for “long arm.” The presence of the s allele in the s/s
and s/l genotype is associated with reduced transcription
of the SERT gene and reduced 5-HT uptake when com-
pared with the l/l genotype [9–12]. Since the description
of this polymorphism, considerable scrutiny has been
devoted to seeking an association between the s allele
and a depressive phenotype. For example, Gonda et al.
 measured affective temperaments, including depres-
sive, cyclothymic, hyperthymic, irritable, and anxious, in
139 subjects and reported an association of the s/s and s/l
genotypes in individuals with high scores on an affective
Roiser et al.  utilized a cued reinforcement reaction
task, a measure of motivational processing, to show that
in individuals subjected to tryptophan (and, therefore,
5-HT) depletion, the s/s genotype conferred a vulnerability
to loss of motivational speed. The authors suggested that
depression with anhedonia and impaired motivation is at
least partly predicted by the s/s genotype . Hariri et al.
 confirmed and extended findings from a previous
study  by screening 92 individuals for the SERT
genotype and then evaluating them for fear and anxiety
traits. They then utilized functional MRI to measure
amygdala activity. An association between increased
amygdala activity, high anxiety traits, and “s” allele
carriers was observed.
Poststroke depression also has been linked to sero-
tonergic dysfunction and the SERT polymorphism.
Ramasubbu et al.  studied 28 patients postcerebrovas-
cular accident (post-CVA) with comorbid mood disorders
and matched controls. An association between the s/s and
s/l genotype and a depressive phenotype poststroke was
observed. Post-CVA patients with the s/s or s/l genotype
were more likely to develop symptoms of depression than
patients with the l/l genotype.
Although limited by a relatively small sample, Joiner et al.
 observed correlations between a positive family
history of depression and the s/s or s/l genotype.
The SERT Polymorphism and
Following the discovery of the SERT polymorphism
and its association with susceptibility to depressive
mood states, the question as to whether it predicts
response to one or another class of antidepressants
was investigated. Space constraints preclude a detailed
review of this burgeoning literature, but taken together,
the results have been mixed [18–24], with some studies
describing failure to attain remission in a trial of
citalopram in patients with the s/s genotype , and
another study reporting no association between the
SERT genotype and clinical response to sertraline .
Moreover, in two studies, superior clinical responses to
paroxetine and fluvoxamine were observed in patients
with the l/l genotype [20,21]. In contrast, a superior
response to SSRIs also was reported in patients with
the s/s genotype [22,23]. Interestingly, we observed an
association between an NE transporter polymorphism
and the antidepressant response to the dual 5-HT/NE
reuptake inhibitor milnacipran .
The SERT Polymorphism and Early Life
Stress (ELS) in the Genesis of Depression
Although the available evidence does suggest an asso-
ciation between the s allele of the SERT genotype and
a predisposition to depression, not all individuals with
an s/s or s/l genotype develop the phenotype of major
depression. Other factors (genetic and environmental)
have long been hypothesized to be critical risk factors
that collectively increase an individual’s susceptibility
to develop major depression. A now-remarkably robust
database supports the hypothesis that adverse events
early in life increase an individual’s likelihood of devel-
oping depression in adulthood.
454 Mood Disorders
In the nonhuman primate, Sanchez et al.  has
demonstrated that ELS in the form of maternal separation
leads to an overactive hypothalamic-pituitary-adrenal
(HPA) axis in adult animals; moreover, this effect is most
pronounced in rhesus monkeys with the s/s genotype .
Bennett et al.  reported that rhesus monkeys with a
variation of the human SERT polymorphism termed rh5-
HTTLPR exhibited decreased concentrations of CSF 5-HT
metabolites when exposed to peer rearing, a paradigm
analogous to ELS in humans. This is consistent with a
SERT transporter polymorphism-ELS interaction. In light
of previous studies in humans demonstrating increased
HPA responses in patients with a history of depression
and ELS , Barr et al.  assessed the influence of
rearing conditions and the rh5-HTTLPR polymorphism
on adrenocorticotropic hormone (ACTH) release. The
authors found that the s allele coupled with ELS led to
increased plasma ACTH concentrations, confirming the
findings of Sanchez et al.  cited previously.
Many studies have demonstrated an association between
ELS and the development of depression [28,30]. Recently,
the precise neurobiological mechanisms by which early
untoward life experience in combination with specific genetic
vulnerabilities increase the probability of depression have
been the subject of intense scrutiny. One fruitful line of this
research has concentrated on interactions between the SERT
polymorphism, ELS, and depression. In a groundbreaking
study, Caspi et al. [31••] sought to determine if there was an
association between depression, ELS, and the 5-HTTLPR
genotype. The authors reported that the number of stressful
life events positively correlated with subjects’ self-report of
depressive symptoms, and moreover, that individuals with
the s/s or s/l genotype reported more severe depressive symp-
toms in response to stressful life events (Fig. 1). The authors
Figure 1. Results of multiple regression analyses estimating the association between the number of stressful life events (between ages 21 and
26 years) and depression outcomes at age 26 as a function of serotonin transporter (SERT) genotype. (A) Self-reports of depression symptoms.
The interaction showed that the effect of life events on self-reports of depression symptoms was stronger among individuals carrying an s
allele than among l/l homozygotes. (B) Probability of major depressive episode. Life events predicted a diagnosis of major depression among
s carriers but not among l/l homozygotes. (C) Probability of suicide ideation or attempt. Life events predicted suicide ideation or attempt
among s carriers but not among l/l homozygotes. (D) Informant reports of depression. The effect of life events on depression was stronger
among s carriers than among l/l homozygotes. (From Caspi et al. [31••]; with permission.)
SERT Polymorphism, Early Life Trauma, and Depression Vergne and Nemeroff 455
also found a similar association between the s/s and
s/l genotypes and the probability of major depres-
sive episodes and suicidal ideation or attempts. More
specifically, those individuals exposed to childhood
maltreatment who possessed the s/s genotype had
the highest probability of developing a major depres-
sive episode, followed by the s/l genotype [31••].
Remarkably, subjects with the l/l genotype were pro-
tected from the “depressogenic” effects of severe ELS.
After this seminal study, a relatively large number of
subsequent studies addressing this finding have been
conducted . In a longitudinal study  using a
cohort of 165 adults followed since 1978, self-reports
and semistructured interviews were used to account for
the subjects’ behavioral and psychological state every
5 years. The ability to cope with stress, depression,
and adversity was measured. In 2003, 128 members
of the original cohort were tested for the 5-HTTLPR
genotype. Individuals with an s/s and s/l genotype
had a greater propensity to develop major depression
in the presence of adverse life events. This was con-
firmed in another sample  in which the probability
of experiencing an episode of major depression was
proportional to the number of adverse life events. As
has been noted by many clinicians, patients with a
significant history of adversity often exhibit a cumula-
tive effect of stress that eventually triggers a depressive
episode, especially those with a genetic predisposition.
This raises an interesting question, namely whether
we are able to predict the occurrence of depression
based on genotype and a history of stressful/traumatic
life events. In an attempt to answer this question,
Kendler et al. [33•] randomly selected 549 partici-
pants and collected data regarding the occurrence of
stressful life events, including a history of assault,
divorce, separation, and major financial problems.
The subjects were administered structured interviews
to measure anxiety and depression symptom severity,
genotyped for the SERT, and stratified for gender.
Individuals with stressful life events and the s/s geno-
type were more likely to develop depression within 2
months of a stressful life event. Female gender added
to the risk of developing depressive symptoms. This
study and others raise the question as to whether
genotyping patients for the SERT, and perhaps other
important clinical polymorphisms in those with a
history of ELS, may be cost effective when conducted
as an integral component of a complete psychiatric
evaluation when major depression is suspected as
the primary diagnosis. This may, in some patients,
eliminate the economic and psychosocial burden
associated with delayed treatment, with the lack of
follow-up in patients who upon first evaluation may
not fulfill DSM criteria for major depression but will
likely develop a full-blown episode based on geno-
type and a history of ELS.
The SERT Polymorphism and ELS in the
Genesis of Depression in Children
Previous work by our group and others has repeatedly
highlighted the contributing effect of ELS and trauma on
the subsequent development of depression . The effects
of ELS and SERT genotype on susceptibility to depression
have been studied in children. As in adults, SERT geno-
type influenced the development of depressive symptoms
in children, with the s allele predominant in children with
major depressive disorder . Kaufman et al.  studied
the effect of ELS and the SERT genotype in children aged
5 to 15 years. They hypothesized that both genotype
and social support would exert a strong influence on the
development of depressive symptoms. Remarkably, a sup-
portive environment appeared to protect children with the
s/s genotype and a history of maltreatment from developing
depression . A subsequent study by the same group
[36•] confirmed and extended this finding by documenting
important gene-environment interactions between SERT
and brain-derived neurotrophic factor (BDNF) polymor-
phisms, childhood maltreatment, and depression and the
salutary effects of social support. These findings point to
an early intervention strategy for children with a known
history of abuse. Armed with the knowledge that psycho-
social support is beneficial in children with a predisposing
SERT and BDNF genotype, child psychiatrists and other
mental health care providers could suggest early interven-
tion in such individuals.
From genotype to behavior:
What is going on in the brain?
In this article, the functions of 5-HT, the SERT, and its
polymorphism, as well as its interactions with ELS, have
been described. The question remains: What is the nature
of that association? In other words, what occurs in the
CNS of depressed patients with the s/s genotype of the
SERT? Moreover, what are the biological consequences
of ELS when combined with the s/s SERT genotype? In
the concluding portion of this review, these questions are
The amygdala is a key brain structure, an integral com-
ponent of the limbic system that has been shown to play a
key role in the emotional processing of incoming stimuli
. The amygdala is overactive in patients carrying the
s allele [6,15]. Connections from cerebrocortical brain
regions help to regulate the activity of the amygdala when
an aversive/stressful stimulus is processed. Functional
imaging studies indicate a dysfunctional connectivity
between regions of the frontal cortex, specifically the pre-
frontal and anterior cingulate cortices, and the amygdala
in depressed patients with the s/s and s/l SERT genotype
[38,39]. Theoretically, malfunction of frontal inhibitory
structures could lead to amygdala hyperactivity and the
accompanying stress/depressive symptoms. In fact, Hariri
and Holmes  have proposed a model in which miscom-
munication between subregions of the prefrontal cortex
456 Mood Disorders
and the central nucleus of the amygdala occur, which
results in a diminished ability to integrate, plan, and
execute complex behaviors in response to environmental
stimuli in individuals with the s/s and s/l genotype.
ELS has been shown to be a major predictor of vul-
nerability for anxiety and depression and also to be
associated with hyperactivity of the HPA axis, including
hypercortisolemia . Increased cortisol availability has
been reported to lead to down-regulation of hippocampal
SERT binding and resultant dysregulation of serotonergic
transmission . Whether this effect of HPA axis hyper-
activity on SERT function is influenced by the 5-HTTLPR
polymorphism remains to be determined.
In addition, mice lacking the SERT exhibit 5-HT1A
receptor down-regulation, and 5-HT2C up-regulation in
the amygdala associated with amygdala hyperexcitability
. Neuropeptides are well-known modulators of the
classical neurotransmitters, and many of them interact
directly or indirectly with 5-HT–containing circuits.
Two of the best studied are neuropeptide Y (NPY) and
corticotropin-releasing factor (CRF). The role of CRF in
the genesis of depression and/or anxiety [28,40] is well
established, and interactions between these two peptides
and 5-HT neurons have been described [42,43]. Although
CRF has a preeminent role in the consequences of ELS
and the biology of depression, a role for NPY remains to
There is convincing evidence of an association between
the SERT gene polymorphism and depression and perhaps
even nonsyndromal depressive symptomatology and
treatment response to antidepressants. We can suggest
three major research directions among many that could
be proposed. First, the thorough evaluation of patients
with a history of trauma is imperative in order to closely
follow such “high-risk” individuals to prevent the mor-
bidity and mortality associated with depression. This
is also particularly relevant to children because of the
evidence that psychosocial intervention can mitigate the
effects of genetic vulnerability, at least as it regards the
SERT polymorphism. Second, we have raised the issue of
how genotyping may well be cost effective by helping to
prevent development of a full-blown syndromal illness.
Third, as discussed in the last section, ELS is associated
with a multitude of brain changes that interact with
genetic vulnerability. The precise biological basis of such
gene-environment interactions needs to be elucidated in
order to develop novel treatment strategies for these highly
Dr. Vergne was supported by an APIRE Research
Fellowship (521990). Dr. Nemeroff is supported by
National Institutes of Health MH-42088, MH-39415,
MH-52899, MH-069056, MH-077083, and RR-000039.
In the last 3 years, Dr. Nemeroff has consulted to, served
on the speakers’ bureau and/or board of directors for, been a
grant recipient, and/or owned equity in the following: Abbott
Laboratories (consultant, speakers’ bureau), ACADIA
Pharmaceuticals, Inc. (consultant, stockholder), American
Foundation for Suicide Prevention (grants/research, board
of directors), American Psychiatric Institute for Research
and Education (board of directors), AstraZeneca Inter-
national (grants/research), BMC-JR, LLC (equity),
Bristol-Myers Squibb (grants/research,
CeNeRx BioPharma (equity), Corcept Therapeutics (con-
sultant, stockholder), Cypress Bioscience, Inc. (consultant,
stockholder), Cyberonics, Inc. (consultant), Eli Lilly and
Co. (consultant), Entrepreneur’s Fund (consultant), Forest
Laboratories, Inc. (grants/research, consultant), George
West Mental Health Foundation (board of directors),
GlaxoSmithKline (consultant, speakers’ bureau), i3 DLN
(consultant), Janssen Pharmaceutica (grants/research,
consultant, speakers’ bureau), Lundbeck (consultant),
the National Alliance for Research on Schizophrenia
and Depression (grants/research), the National Institute
of Mental Health (grants/research), the National Foun-
dation for Mental Health (board of directors), NovaDel
Pharma, Inc. (stockholder, board of directors), Otsuka
America Pharmaceutical, Inc. (consultant), Pfizer, Inc.
(grants/research, consultant, speakers’ bureau), Quin-
tiles Transnational Corp. (consultant), Reevax Pharma
(equity), UCB Pharma (consultant), and Wyeth-Ayerst
Laboratories (grants/research, consultant).
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