European Neuropsychopharmacology (]]]]) ], ]]]–]]]

www.elsevier.com/locate/euroneuro

Serotonin transporter gene expression

predicts the worsening of suicidal ideation
and suicide attempts along a long-term
follow-up of a Major Depressive Episode
Julia-Lou Consolonia,b,c, El Chérif Ibrahimb,c,d,
Marie-Noëlle Lefebvree, Xavier Zendjidjiana,f, Emilie Oliéc,g,h,
Pascale Mazzola-Pomiettod, Thomas Desmidti,j,
Ludovic Samalinc,k, Pierre-Michel Llorcac,k, Mocrane Abbarl,
Jorge Lopez-Castromanh,l, Emmanuel Haffenc,m,n,q,
Karine Baumstarckf, Jean Naudina, Jean-Michel Azorina,c,d,
Wissam El-Hagei,j,o, Philippe Courtetc,g,h,1,
Raoul Belzeauxa,b,c,p,n,1
a
APHM, Department of psychiatry, Marseille, France
b
Aix Marseille Univ, CNRS, CRN2M, UMR 7286, Marseille, France
c
Fondation FondaMental, Fondation de Recherche et de Soins en Santé Mentale, Créteil, France
d
Aix Marseille Univ, CNRS, INT, Inst Neurosci Timone, Marseille, France
e
CIC-CPCET, APHM, Hôpital La Timone, Marseille, France
f
Aix Marseille Univ, SPMC, EA 3279, Public Health, Chronic Diseases and Quality of Life - Research Unit,
Marseille, France
g
Department of Emergency Psychiatry and Acute Care, CHU Montpellier, France
h
Inserm, U1061, University of Montpellier, Montpellier, France
i
CHRU de Tours, Clinique Psychiatrique Universitaire, Tours, France
j
Inserm U1253 Imaging & Brain, Université de Tours, Tours, France
k
CHU Clermont-Ferrand, Department of Psychiatry, EA 7280, University of Clermont Auvergne, Clermont-
Ferrand, France
l
Department of Adult Psychiatry, CHRU Nimes, Nimes, France
m
Department of Clinical Psychiatry, University Hospital, Besançon, France
n
EA 481, Laboratory of Neurosciences, University of Franche-Comté, Besançon, France
o
Inserm CIC 1415, Centre d'Investigation Clinique, CHRU de Tours, Tours, France
p
McGill Group for Suicide Studies, Department of Psychiatry, McGill University, Douglas Mental Health University
Institute, Montreal, QC, Canada
q
CIC-1431 Inserm, University Hospital, Besançon, France

Received 16 June 2017; received in revised form 5 December 2017; accepted 8 December 2017

n
Correspondence to: Hôpital Sainte-Marguerite, Pavillon Solaris, 270 Bd. de Sainte-Marguerite, 13009 Marseille, France.
E-mail address: raoul.belzeaux@ap-hm.fr (R. Belzeaux).
1
These authors contributed equally to this work.

https://doi.org/10.1016/j.euroneuro.2017.12.015
0924-977X/& 2017 Elsevier B.V. and ECNP. All rights reserved.

Please cite this article as: Consoloni, J.-L., et al., Serotonin transporter gene expression predicts the worsening of suicidal ideation and
suicide attempts along a.... European Neuropsychopharmacology (2017), https://doi.org/10.1016/j.euroneuro.2017.12.015
2 J.-L. Consoloni et al.

KEYWORDS Abstract
Serotonin transporter; The quest for biomarkers in suicidal behaviors has been elusive so far, despite their potential
Suicide; utility in clinical practice. One of the most robust biological findings in suicidal behaviors is the
Major depression; alteration of the serotonin transporter function in suicidal individuals. Our main objective was
Gene expression; to investigate the predictive value of the serotonin transporter gene expression (SLC6A4) for
biomarker
suicidal ideation and as secondary, for suicide attempts in individuals with a major depressive
episode (MDE). A 30-week prospective study was conducted on 148 patients with a MDE and 100
healthy controls including 4 evaluation times (0, 2, 8 and 30 weeks). Blood samples and clinical
data were collected and SLC6A4 mRNA levels were measured from peripheral blood mono-
nuclear cells using RT-qPCR. We first demonstrated the stability and reproducibility of SLC6A4
mRNA expression measures over time in healthy controls (F= 0.658; p =0.579; η2 =0.008;
ICC =0.91, 95% CI [0.87–0.94]). Baseline SLC6A4 expression level (OR =0.563 [0.340–0.932],
p=0.026) as well as early changes in SLC6A4 expression between baseline and the 2nd week
(β =0.200, p= 0.042) predicted the worsening of suicidal ideation (WSI) in the following 8 weeks.
Moreover, changes in SLC6A4 expression between the 2nd and 8th weeks predicted the
occurrence of a suicide attempt within 30 weeks (OR =10.976 [1.438–83.768], p=0.021).
Altogether, the baseline level and the changes in SLC6A4 mRNA expression during a MDE might
predict the WSI and the occurrence of suicidal attempts and could be a useful biomarker in
clinical practice.
& 2017 Elsevier B.V. and ECNP. All rights reserved.

1. Introduction et al., 2010)). Associations with polymorphisms in genes

Suicide is a major cause of premature death worldwide and
a serious public health issue. Suicidal behaviors are the most
serious complications of mood disorders. Almost 90% of
suicide completers suffer from a psychiatric disorder, mainly
from a major depressive episode (MDE) (Arsenault-Lapierre
et al., 2004). Although efficient treatment of mood dis-
orders is an effective prevention strategy (Zalsman et al.,
2017), a worsening of suicidal ideation (WSI) occurs in up to
30% of patients with a MDE during antidepressant treatment
(Perroud et al., 2009; Zisook et al., 2009).
Many researches, over the past decades, focused on
identifying subgroups of patients with a higher risk of
suicidal ideation or behaviors, to predict and to prevent
these complications in the context of clinical care. Suicidal
behaviors have been associated with several risk factors
such as a previous psychiatric disorder, single marital status,
unemployment, childhood maltreatments, family history of
suicidal behaviors or previous suicide attempts, impulsivity
and alcohol use disorder (Fawcett et al., 1990; Fergusson
et al., 2000; Mann, 1998; McCauley et al., 1997; Tidemalm
et al., 2011). Moreover, depression severity, previous sui-
cide attempts, retirement, weight loss, vascular or neuro-
logical diseases and being widowed have also been
identified as risk factors for WSI during antidepressant
treatment (Brent, 2016; Coughlin et al., 2016; Perroud
et al., 2009). We notably reported that emergence or WSI
in the first weeks after initiating an antidepressant treat-
ment was mainly related to the worsening of depressive
symptoms (with a attributable risk of 67.5%) (Courtet et al.,
2014). Pharmacogenomics studies of antidepressant treat-
ment-emergent suicidal events have been performed in
large cohorts of depressed patients (reviewed in (Brent
involved in different systems have been reported but rarely
replicated. Despite all of these findings, to date, no specific
clinical or genetic markers or any combination has allowed
to effectively predict the WSI in the context of clinical care.
In such a context, biomarkers could help clinicians to
identify specific subpopulations at high risk for suicidality.
Based on the assumption that suicidality is a phenomenon
resulting from a complex interaction of genetic background,
early environmental stress and proximal biological variation
(Mann and Currier, 2010; Turecki, 2014), changes in gene
expression offer a good opportunity to capture biological
dysregulation associated with suicide risk. Several studies
examined gene expression differences in peripheral blood in
an attempt to describe biomarkers of MDE and antidepres-
sant response (Iga et al., 2008) but few of them regarding
suicide risk in depressed individuals (Chang et al., 2016).
Two types of methodology are used in this research area,
the hypothesis-free and candidate gene approaches. Inter-
estingly, three studies of the same team described changes
in blood expression levels that could predict suicidal idea-
tions states and future hospitalizations due to suicidal
behaviors using a hypothesis-free approach and different
cohorts of males and females patients independently with
heterogeneous psychiatric disorders (Le-Niculescu et al.,
2013; Levey et al., 2016; Niculescu et al., 2015b). Of note,
Mullins et al. did not replicate the results of one of these
previous studies (Mullins et al., 2014). Moreover, a cross-
sectional study that used a candidate gene-based approach
including mRNA expression of BDNF, FKBP5 and NR3C1 genes
in peripheral blood, did not find any differences between
depressed patients with and without suicidal ideation (Roy
et al., 2017).
To the best of our knowledge, no previous study focused
on the serotonin transporter gene expression variation. This

Please cite this article as: Consoloni, J.-L., et al., Serotonin transporter gene expression predicts the worsening of suicidal ideation and
suicide attempts along a.... European Neuropsychopharmacology (2017), https://doi.org/10.1016/j.euroneuro.2017.12.015
5-HTT mRNA and suicide behaviors
gene has been robustly associated to suicidal behavior
(Antypa et al., 2013; Purselle and Nemeroff, 2003). The
serotonin transporter (5-HTT) is a major biological regulator
of the serotonergic system (Lesch et al., 1994; Rudnick,
2006), a dysfunction of which is one of the most studied
potential biological distal risk factor for suicide (Turecki,
2014). 5-HTT is a 7-transmembrane protein localized in
presynaptic neuron that regulates the serotonin action by
reuptaking the monoamine after its release in the synapse.
The 5-HTT is encoded by the SLC6A4 gene located on
chromosome 17. Post mortem studies revealed a decreased
concentration of the 5-HTT protein in the prefrontal cortex,
the hypothalamus and the brainstem of depressed patients
died by suicide compared to matched controls (Purselle and
Nemeroff, 2003; Stanley et al., 1982). In this context, some
authors have also compared the expression levels of SLC6A4
mRNA in post mortem brains between suicide completer and
healthy-matched control samples, without showing any
difference (Arango et al., 2001; Little et al., 1997;
Perroud et al., 2010). By quantifying regional brain 5-HTT
binding in vivo using PET, Miller et al. (2013) reported that
depressed suicide attempters had lower 5-HTT binding in
midbrain compared with depressed non-attempters and
healthy controls. They suggested that low 5-HTT binding
was more related to suicidal behavior than to depression
while another study did not replicate this finding (Oquendo
et al., 2016).
Although brain blood correlation is still a matter of
debate in biomarker development in psychiatry (Belzeaux
et al., 2017a), several lines of evidence demonstrate the
interest of studying SLC6A4 gene expression in blood
samples. Indeed, various investigators have reported differ-
ences of SLC6A4 mRNA levels expression between depressed
patients and controls (Belzeaux et al., 2012; Belzeaux
et al., 2014b; Iga et al., 2005; Lima et al., 2005; Tsao
et al., 2006). We previously demonstrated that SLC6A4
variation could be due to the occurrence and treatment of
MDE (Belzeaux et al., 2014a).
As a consequence, we aimed to investigate if SLC6A4
gene expression in peripheral mononuclear cells (PBMCs)
could predict the WSI during an 8-week follow-up among
patients with a severe MDE. First, we aimed to examine the
stability and reproducibility of SLC6A4 mRNA expression
over time in healthy control. A secondary aim of the study,
using a confirmatory approach, was to explore the link
between the variation in SLC6A4 gene expression and the
occurrence of suicide attempts in a 30-week follow-up
among the MDE patients.
2. Experimental procedures
2.1. Participants
Eligible study participants were 148 adults diagnosed with
current MDE and 100 age- and gender- matched healthy
controls from a study registered in ClinicalTrials.gov with ID:
NCT02209142.
Participants had a clinical evaluation using the Semi-
Structured Clinical Interview of the DSM-IV (First et al.,
2002). Patients were recently admitted in a psychiatric unit
or have been recently referred to a psychiatrist for a MDE.
Please cite this article as: Consoloni, J.-L., et al., Serotonin transporter gene expression predicts the worsening of suicidal ideation and
suicide attempts along a.... European Neuropsychopharmacology (2017), https://doi.org/10.1016/j.euroneuro.2017.12.015
3
The diagnosis of MDE was made by skilled psychiatrists
based on the DSM-IV criteria of mood disorders (American
Psychiatric Association, 2000) and the MDE severity was
evaluated by the 17-item Hamilton Depression Rating Scale
(HDRS; (Hamilton, 1960)). Patients were included if they
scored 19 or higher on the HDRS. Healthy controls were
evaluated by a trained psychologist or psychiatrist to
exclude subjects with any history of or current psychiatric
disorder screened by the SCID.
Exclusion criteria for both groups were a history of
substance use disorder in the past 12 months, a diagnosis
of schizophrenia, psychotic or schizoaffective disorder
according to the DSM-IV, a severe progressive medical
disease, pregnancy, vaccination within a month before the
inclusion in the study and being under 18.
Six patients and 3 healthy controls were excluded due to
the manifestation of exclusion criteria during the study
(diagnosis of severe medical conditions, consent withdra-
wal). Moreover, 35 patients and 5 healthy controls were
excluded from the analyses due to loss to follow-up,
unavailable gene expression data and/or main outcome
measures. Finally, data from 103 MDE patients and 92
healthy controls were included in the analyses. In compar-
ison to excluded patients, those included were not different
according to age (p= 0.784), gender (p= 0.097), number of
previous suicide attempts (p= 0.234) and initial MDE sever-
ity as evaluated by the HDRS (p= 0.405).
All participants received a full explanation of the proce-
dure and signed a written consent form before their
participation. This study received the local ethical commit-
tee approval (CPP Sud Méditerranée II, Marseille, France,
study registered under number 2011-A00661-40).
2.2. Study design and procedure
We conducted a prospective multi-centric study involving
8 departments of psychiatry in 6 different French cities
(Marseille, Montpellier, Nîmes, Tours, Besançon and Cler-
mont-Ferrand). The follow-up was divided into 2 periods. As
we aimed to predict the WSI, the first period allowed a
short-term follow-up of the subjects with 3 visits (Weeks 0,
2 and 8). The second period which extended from week 8 to
week 30, was used to register the potential occurrence of
suicidal attempts in patients who experienced a recent
MDE. In total, the participants attended 4 evaluation visits
during a 30-week period for blood sampling and clinical
assessments. Healthy controls were included to investigate
the stability over time and reproducibility of SLC6A4 mRNA
expression measures and to constitute a PCR calibration
measure.
2.2.1. Clinical assessment
2.2.1.1. Main outcome measures
2.2.1.1.1. Part 1 – WSI during the W0-W8 period. We
used the 12th item of the QIDS-SR-16 (Quick Inventory of
Depressive Symptomatology, self-rating; (Rush et al., 2003))
as the main outcome to evaluate suicidal ideation. This item
takes a value between 0 and 3. The QIDS-SR-16 is a 16-item
self-rating questionnaire with good psychometrics proper-
ties in patients with mood disorders (Rush et al., 2003;
Trivedi et al., 2004) which evaluates the 9 depression
4 J.-L. Consoloni et al.
criterion symptom domains of a MDE according to the DSM-
IV. Previous findings demonstrated that self-ratings of
suicidal ideation are equally or even more effective than
clinicians’ evaluations to assess suicidal ideation in adults
(Desseilles et al., 2012; Joiner et al., 1999). Moreover, using
a single item from a depression rating scale to assess
suicidal ideation is considered as a valid method
(Desseilles et al., 2012). Patients with MDE were divided
into two groups: those who experienced a WSI in the first
8 weeks of the follow up (WSI+ ) and those who did not
(WSI-). A WSI was defined by at least a 1-point increase at
the 12th item of the QIDS between two consecutive visits.
2.2.1.1.2. Part 2 – Suicide attempts during the W8-W30
period. Incidental suicide attempts among patients with
MDE were registered. When the clinician reported a suicide
attempt between two visits, the information was double-
checked by a careful examination of all available data for
each participant using the adverse events reports of the
protocol.
2.2.1.2. Other assessments. Patients with current MDE
were screened for psychiatric disorder and were asked for
prior suicide attempts, number of previous MDE, and their
medication using a standardized chart. Family history of
psychiatric disorders was screened with a validated chart,
the Family History-Research Diagnostic Criteria (Andreasen
et al., 1977). The severity, chronicity and melancholic
characteristics of current MDEs were also evaluated. At
each visit a mood assessment was made using the HDRS and
the self-rating questionnaire QIDS-SR-16 was realized.
Socio-demographics (age, gender, education level, and
marital status) and clinical information (body mass index,
current smoking status) were collected at the first visit.
The Childhood Trauma Questionnaire (CTQ; (Bernstein
et al., 1994)) was also administered in both healthy controls
and patients. The CTQ is a self-rating questionnaire that
allows investigating 5 dimensions of childhood trauma
(emotional and physical neglects, emotional and physical
abuses and sexual abuses). It has been validated in French
(Paquette et al., 2004), and shows good validity (Bernstein
et al., 2003; Paivio and Cramer, 2004) and good internal
consistency in heterogeneous populations (Bernstein et al.,
1997; Roy, 2003, 2004). In our study, we considered moder-
ate to severe childhood trauma based on the dimensional
approach (Tucci et al., 2010).
2.2.2. Biological procedure
Venous blood (8–9 ml) was drawn from fasting subjects in EDTA
tubes between 7:00 and 9:00 a.m. and processed within
40 min at inclusion (W0), 2 (W2), 8 (W8) and 30 (W30) weeks
after inclusion. Blood was passed through a LeukoLOCKTM filter
(Life Technologies, Ambion, Austin, TX), which captures the
total leukocyte population while eliminating red blood cells,
platelets, and plasma. After rinsing with phosphate-buffered
saline, the filter was flushed with RNAlaters solution to
stabilize the RNA in the captured leukocytes. The filter was
then stored at –80 1C before processing.
2.2.2.1. RNA isolation. Leukocytes trapped on LeukoLOCK
filters were lysed with TRI reagent (Ambion) and mixed with
Bromo-3-chloro-propane (Sigma). After centrifugation, total
RNA from the aqueous phase was precipitated with ethanol
and then purified on spin cartridge (Ambion). After washings,
Please cite this article as: Consoloni, J.-L., et al., Serotonin transporter gene expression predicts the worsening of suicidal ideation and
suicide attempts along a.... European Neuropsychopharmacology (2017), https://doi.org/10.1016/j.euroneuro.2017.12.015
total RNAs were eluted with 0.1 mM EDTA. Total RNA samples
were subsequently submitted to DNase treatment (DNA-freeTM
kit, Life Technologies, Ambion, Austin, TX). RNA concentration
and quality were determined using a nanodrop ND-1000
spectrophotometer (Thermo Scientific, Waltham, MA).
2.2.2.2. Real-time RT-PCR. 1 μg of total RNA was reverse
transcribed using the High-Capacity cDNA Reverse Transcrip-
tion kit (Life Technologies, Applied Biosystems, Foster City,
CA). Real-time PCR reactions were performed in duplicate
using the TaqMan Universal PCR Master Mix II with no UNG
(Life Technologies, Applied Biosystems, Foster City, CA) on
50 ng of the resulting cDNA, with an ABI PRISM 7900HT
thermocycler under the following conditions: 10 min at
95 1C, 50 cycles of 15 sec at 95 1C and 1 min at 60 1C.
Primers/TaqMan probe assays (Hs00169010_m1) purchased
from Applied Biosystems were used to determine the level
of expression of SLC6A4 transcripts. We used SV2A
(Hs00372069_m1) as a reference gene as previously
described (Belzeaux et al., 2012). Raw Ct values were
obtained with manual baseline settings on the RQ Manager
software (Applied Biosystems), and then the relative
expression level of each mRNA was quantified by using the
ΔΔCt method (Livak and Schmittgen, 2001), in which
SLC6A4 is quantified relative to SV2A and compared to a
calibrator sample defined by the mean of the samples from
the control subjects at baseline.
2.2.2.3. 5-HTTLPR genotyping. Genomic DNA was
extracted from EDTA-tubes venous blood using PureLink TM
genomic DNA mini kit (Invitrogen) and according to the
manufacturer's instructions. An analysis of the 5-HTTLPR
genotype was performed as previously described (Gudayol-
Ferre et al., 2013). The forward primer was 5-GGC GTT GCC
GCT CTG AAT TGC and the reverse primer was 5-GAG GGA CTG
AGC TGG ACA ACC CAC, and they were used to amplify a
region encompassing 5-HTTLPR to genotyping s and l alleles
(Heils et al., 1996). In a total volume of 20 ml containing
1.5 mM MgCl2, 0.2 mM each of dATP, dCTP and dTTP, 0.1 mM
of dGTP and 0.1 mM 7-deaza-dGTP, 1U Go Taq DAN Polymerase
(Promega), 0.25 mM of each primer, and 150 ng of genomic
DNA, after an initial 2-min denaturization step at 95 1C, 40
cycles were performed involving 30 s at 95 1C, 30 s at 62 1C,
and 1 min at 72 1C, followed by a final step of 5 min at 72 1C.
PCR products were resolved in 2.5% Utrapure agarose 1000
(Invitrogen) gels run in Tris-Borate EDTA buffer and visualized
under UV illumination after SYBR TM Safe staining (Invitrogen)
in a Ebox-VXS (Vilber Lourmat). Allele sizes (l allele: 529 bp; s
allele: 488 bp) were determined by comparison to a 50-bp
DNA ladder. The genotype distributions of 5-HTTLPR did not
differ significantly from the expected numbers calculated
according to the Hardy–Weinberg equilibrium in both, patients
and controls (p40.5).
2.3. Statistical analyses
Before exploring the variability of SLC6A4 mRNA expression
in the MDE patients, we first looked at the reproducibility of
the expression measure across the four visits in the healthy
participants group by the calculation of an Intra-Class
Correlation coefficient (ICC). ICC was estimated according
to an absolute agreement method and a one-way random
effects model. The stability of the expression over time in
5-HTT mRNA and suicide behaviors 5

the healthy participants group was assessed by conducting a
univariate repeated-measures ANOVA with the visit as the
single factor.
We compared socio-demographics and clinical character-
istics of MDE patients with or without WSI using univariate
analyses. For continuous variables, Student independent
t-tests or non-parametric Mann-Whitney tests were used
depending on the distribution of the variable while catego-
rical variables were compared with Chi-Square tests or
Fisher tests when the number of occurrence of a category
was o5.
In order to test whether mRNA expression levels of
SLC6A4 could predict the WSI in MDE patients between W0
and W8, we also performed a receiver operating character-
istic (ROC) curve analysis. Moreover, we confirmed the
results with a multiple logistic regression analysis with the
expression levels of SLC6A4 as the independent variable in
addition to clinical variables that could be potential con-
founding factors (i.e. age, gender, HDRS score at inclusion,
episode severity, diagnosis, current typical antipsychotic
medication). The predictive effect of SLC6A4 mRNA expres-
sion was quantified with the Area Under the Curve (AUC)
value and the optimal cut-off was determined by the Youden
index (i.e. index = sensitivity + specificity-1 for each ROC
curve point) to generate best specificity and sensitivity
values. The calculation of this index is recommended in the
context of biomarkers studies (Ray et al., 2010).
To determine if a variation in the expression level of
SLC6A4 mRNA is associated to the variation of suicidal
ideations, linear regression analyses were conducted.
The second period of the study allowed to examine
whether SLC6A4 mRNA expression levels could predict the
occurrence of suicide attempts. The expression level of
SLC6A4 mRNA at W8 was compared between the MDE
patients who attempted suicide during the second part of
the follow-up and those who did not. The same analyses
were conducted with the variation of SLC6A4 expression
between W0 and W8 and between W2 and W8. Then, a ROC
curve analysis were conducted to validate the predictive
effect of SLC6A4 expression. A multiple logistic regression
analysis to predict the status of MDE patients (suicide
attempters vs. non suicide attempters) allowed to control
this predictive effect by adding potential confounding
variables to the model (i.e. HDRS score at W8, previous
suicide attempts).
Statistical analyses were made using IBM SPSS version 20
and a po0.05 threshold was considered statistically
significant.
3. Results
3.1. Reproducibility and stability of SLC6A4 mRNA
measures
In preliminary analyses, we looked at the reproducibility of
SLC6A4 mRNA expression measures in healthy participants
across the 4 visits. We included in our study a group of 92
healthy controls, 57 women and 35 men, with a mean age of
44.2 (SD = 14.3).
The calculated ICC coefficient was 0.91, 95% CI [0.87–
0.94]. The repeated-measures ANOVA indicated no statisti-
cally significant effect of the visit (F= 0.658, p= 0.579;
η2 = 0.008). Altogether, these results suggest a remarkable
homogeneity and stability over a 30-week period in indivi-
duals without history and current psychiatric diagnosis (see
Figure 1).
The 5-HTTLPR polymorphism has been previously asso-
ciated in some but not all studies to a differences in
expression of SLC6A4 mRNA (Philibert et al., 2008). There-
fore, we explored this effect in control subjects with a new
general linear model. The repeated-measures ANOVA indi-
cated no statistically significant effect of the time
(F = 0.485, p= 0.694; η2 = 0.019), of the polymorphism
(F = 0.715, p= 0.400; η2 = 0.009) nor interaction between
time and polymorphism (F= 0.643, p= 0.589; η2 = 0.025).
3.2. Part 1 - W0–W8 period
Socio-demographics and clinical characteristics of both MDE
patients with or without WSI between W0 and W8 are
presented in Table 1. Twenty-seven (25.2%) patients experi-
enced a WSI in the first 8 weeks of the follow-up and no
suicidal attempt was reported.

Figure 1 Time course variation of SLC6A4 gene expression variation according to clinical group (i.e. healthy controls, patients with
or without Worsening Suicide Ideation, WSI) along 8 weeks. At W0, patients with WSI during the follow-up demonstrated a lower
level of expression in comparison to healthy controls (p=0.022) and patients without WSI (p= 0.032). We also conducted an ANOVA
for repeated measure including time (both visits) and group (WSI + or WSI -) and found a significant time by group interaction
(F =1.204, p=0.013; η2 =0.013).

Please cite this article as: Consoloni, J.-L., et al., Serotonin transporter gene expression predicts the worsening of suicidal ideation and
suicide attempts along a.... European Neuropsychopharmacology (2017), https://doi.org/10.1016/j.euroneuro.2017.12.015
 6
suicide attempts along a.... European Neuropsychopharmacology (2017), https://doi.org/10.1016/j.euroneuro.2017.12.015
Please cite this article as: Consoloni, J.-L., et al., Serotonin transporter gene expression predicts the worsening of suicidal ideation and

Table 1 Socio-demographic and clinical characteristics of both groups of depressed patients with (n =27) or without (n =80) a WSI between the first period of the follow-up
(Week 0–Week 8) and the appropriate univariate analyses. For continuous variables, Student independent t-tests or non-parametric Mann-Whitney tests were used depending
on the distribution of the variable while categorical variables were compared with Chi-Square tests or Fisher tests when the number of occurrence of a category was o5.
Statistically significant results are presented in bold.

Patients with or without WSI between weeks 0 and 8 Statistical test p-value Na

WSI (N =80) WSI + (N= 27)

Age Mean (SD) 43.93 (14.77) 45.22 (11.73) Student t test 0.680 107
Gender (Men/Women) N (%) 29 (36.3) /51 (63.8) 8 (29.6)/19 (70.4) Chi-square test 0.532 107

Education level N (%)

Elementary 4 (5.1) 0 (0.0) Chi-square test 0.569 105
High school 18 (23.1) 6 (22.2)
Baccalaureate or equivalent 18 (23.1) 5 (18.5)
Higher 38 (48.7) 16 (59.3)

Marital situation W0 N (%)

Married 31 (38.8) 16 (59.3) Chi-square test 0.063 107
Single 49 (61.3) 11 (40.7)
Body Mass Index W0 Mean (SD) 25.04 (5.25) 24.96 (4.35) Mann–Whitney test 0.514 95

Currently Smoking W0 N (%)

No 48 (60.8) 16 (59.3) Chi-square test 0.891 106
Yes 31 (39.2) 11 (40.7)

Family history (Close relatives) N (%)

Complete suicide or attempts 20 (25.3) 6 (23.1) Chi-square test 0.818 105
Psychiatric disorder 47 (59.5) 19 (70.4) Chi-square test 0.314 106
Affective disorder 43 (54.4) 16 (59.3) Chi-square test 0.663 106

Clinical data
Diagnostic Broad (U / B) N (%) 47 (58.8)/33 (41.2) 14 (51.9)/13 (48.1) Chi-square test 0.531 107
Mood Disorder N (%) 55 (68.8)/25 (31.2) 16 (59.3)/11 (40.7) Chi-square test 0.367 107

J.-L. Consoloni et al.

HDRS score W0 Mean (SD) 23.03 (3.22) 23.41 (3.60) Mann–Whitney test 0.827 107
QIDS-SR-16 score W0 Mean (SD) 17.04 (4.80) 18.54 (3.35) Mann–Whitney test 0.286 104
Number of previous MDE Mean (SD) 3.25 (2.73) 3.15 (2.62) Mann–Whitney test 0.941 95
Chronicity N (%) 8 (10.1) 4 (15.4) Fisher test 0.486 105
Severe MDE N (%) 52 (65.8) 19 (70.4) Chi-square test 0.664 106
Melancholic characteristics N (%) 27 (33.8) 6 (22.2) Chi-square test 0.262 107
History of suicide attempt N (%) 32 (44.4) 11 (55.0) Chi-square test 0.403 92
 5-HTT mRNA and suicide behaviors
suicide attempts along a.... European Neuropsychopharmacology (2017), https://doi.org/10.1016/j.euroneuro.2017.12.015
Please cite this article as: Consoloni, J.-L., et al., Serotonin transporter gene expression predicts the worsening of suicidal ideation and

Medication at the inclusionb N (%)

SSRI 26 (32.5) 10 (37.0) Chi-square test 0.666 107
SNRI 18 (22.5) 7 (25.9) Chi-square test 0.716 107
Tricyclic 10 (12.5) 2 (7.4) Chi-square test 0.726 107
MAOI 1 (1.3) 0 (0.0) Fisher test 1.00 107
Other kind of antidepressants 7 (8.8) 4 (14.8) Chi-square test 0.464 107
Benzodiazepine 59 (73.8) 22 (81.5) Chi-square test 0.418 107
Atypical antipsychotic 22 (27.5) 10 (37.0) Chi-square test 0.349 107
Typical antipsychotic 9 (11.3) 8 (29.6) Chi-square test 0.024 107
Lithium 10 (12.5) 5 (18.5) Fisher test 0.522 107
Sodium valproate 3 (3.8) 4 (14.8) Fisher test 0.066 107
Carbamazepine/Lamotrigine 10 (15.0) 1 (3.7) Fisher test 0.177 107
Other psychotropic medication 20 (25.0) 10 (37.0) Chi-square test 0.229 107
No specific medication at W0 N (%) 13 (16.3) 5 (18.5) Fisher test 0.772 107

Self-rating Questionnaires
CTQ – History of early trauma N (%) 41 (58.6) 10 (55.6) Chi-square test 0.817 88
CTQ - Emotional neglect N (%) 33 (47.1) 7 (38.9) Chi-square test 0.530 88
CTQ – Physical neglect N (%) 21 (30.0) 6 (33.3) Chi-square test 0.784 88
CTQ - Emotional abuse N (%) 27 (38.6) 6 (33.3) Chi-square test 0.682 88
CTQ – Physical abuse N (%) 14 (20.0) 2 (11.1) Chi-square test 0.508 88
CTQ - Sexual abuse N (%) 13 (18.6) 4 (22.2) Chi-square test 0.743 88
5-HTTLPR Genotype (s/s or s/l / l/l) 56 (70.0) / 24 (30.0) 20 (74.1) / 7 (25.9) Fisher test 0.808 107

Abbreviations: CTQ, Childhood Trauma Questionnaire; HDRS, Hamilton Depression Rating Scale; MAOI, Monoamine Oxidase Inhibitor ; MDE, Major Depressive Episode; QIDS-SR-16, Quick
Inventory of Depressive Symptomatology 16 items Self-Report; SNRI, Serotonin-Norepinephrine Reuptake Inhibitor; SSRI, Selective Serotonin Reuptake Inhibitor; WSI, Worsening of Suicidal
Ideation.
a
Maximum number of available data for each variable due to the presence of missing data.
b
Due to the naturalistic design of the study, patients could take more than one medication at the beginning and during the follow-up.

7
8 J.-L. Consoloni et al.
Univariate analyses showed that patients with or without
WSI were comparable at baseline in terms of age, gender
repartition, education level, diagnosis, severity and chroni-
city of the MDE, number of previous MDE and past suicide
attempts (Table 1). However, MDE patients who experienced
a WSI during the first period of the study were most
frequently treated with typical antipsychotics (mainly cya-
memazine used as antihistaminic anxiolytic) at inclusion
(χ2 = 5.103, p= 0.024) compared to those who did not
(Table 1). Besides, WSI in MDE patients was not associated
with early childhood trauma (Table 1).
Reporting WSI was associated to a lower expression level
of SLC6A4 mRNA (t =2.170, p= 0.032) at baseline compared
to WSI- (Figure 1). Moreover, we found no significant
differences for SLC6A4 gene expression between patients
without worsening suicide ideation and healthy controls at
baseline (t = 0.034, p= 0.973), but we found a significant
Figure 2 Receiver operating characteristics (ROC) curve showing
the relationship between sensitivity and 1 – specificity in determin-
ing the predictive value of baseline SLC6A4 mRNA expression for
the WSI between W0 and W8 in MDE patients. The area under the
curve was 0.64 [0.51–0.77]. Calculation of the Youden index
allowed to determine a sensitivity value of 0.68 and a specificity
value of 0.62 for an optimal cut-off of 0.
Table 2 Multiple logistic regression analysis to predict the WSI during the W0-W8 period (N =103).
Predictorsa β p
Age 0.019 0.295
Sex 0.268 0.611
HDRS score at W0 0.033 0.686
Diagnosis 0.089 0.857
SLC6A4 expression W0 0.575 0.026
Typical antipsychotic medication 1.352 0.024
Abbreviations: HDRS, Hamilton Depression Rating Scale.
a
Statistically significant predictors are presented in bold.
Please cite this article as: Consoloni, J.-L., et al., Serotonin transporter gene expression predicts the worsening of suicidal ideation and
suicide attempts along a.... European Neuropsychopharmacology (2017), https://doi.org/10.1016/j.euroneuro.2017.12.015
differences between patients with worsening suicide idea-
tion and healthy controls with a lower level of expression in
patients at W0 (t = -2.328, p =0.022).
As represented in Figure 2, the expression level of SLC6A4
mRNA at baseline predicts the WSI between W0 and W8 with
a specificity of 0.62 and a sensitivity of 0.68 for the optimal
cut-off value determined by the Youden index. The AUC was
0.64, 95% CI [0.51–0.77], po0.05. This predictive effect
remained significant in the logistic regression (OR= 0.563
[0.340–0.932], p= 0.026) after adjustment for age, gender,
MDE severity at baseline, diagnosis and typical antipsycho-
tics consumption (Table 2).
To overcome a potential masked effect, we also included
the 5-HTTLPR polymorphism as a variable in our predictive
model of worsening suicide ideation. Interestingly, our main
results were unchanged and the genotype did not predict
WSI during the W0–W8 period (Table S1).
Given the potential link between BMI and gene expression
and potential interaction between suicide behavior and BMI,
we included BMI in the predictive model of worsening
suicide ideation. The predictive model was comparable
when including BMI, as detailed in the Table S2.
Moreover, it is worth noting that the expression level of
SLC6A4 mRNA at baseline was not correlated to the severity
of suicidal ideation at W0 according to the 12th item of the
QIDS scale (Spearman rho = 0.090; p= 0.311). In the same
vein, we observed only a trend for association between the
variation of SLC6A4 mRNA expression during the W0-W2
period and the concurrent variation of the suicidal ideation
within the same period (β = 0.174; p= 0.067) while an early
W0–W2 variation of SLC6A4 mRNA expression significantly
predicted the variation of suicidal ideation in the next
period, i.e. W2–W8 (β = 0.200, p= 0.042). More precisely, an
increase of SLC6A4 mRNA expression between W0 and W2
predicts a WSI between W2 and W8.
3.3. Part 2 - Week 8–30 period
During the second period of the study, 8 patients and
2 healthy controls were lost to follow-up. For this reason,
the data of only 95 MDE patients and 91 healthy controls
were available for the second part of the analyses. At W8,
MDE patients included 63 women and 32 men, with a mean
age of 43.7 (SD = 13.8) years. The mean HDRS total score of
MDE patients at W8 was 12.8 (SD =7.1) and 34 patients were
in remission (35.8%). During the W8-W30 period of the
follow-up, 5 patients attempted suicide (5.3%). Out of the
Adjusted Odds Ratio 95% Confidence Interval
1.020 0.983–1.057
0.765 0.272–2.147
0.967 0.823–1.137
0.915 0.347–2.415
0.563 0.340–0.932
0.259 0.080–0.835
5-HTT mRNA and suicide behaviors
5 patients who attempted suicide during the 30-week
follow-up, 2 of them have demonstrated an initial WSI
(WSI + ) during the first 8 weeks.
A Student t-test was conducted to determine if the
expression level of SLC6A4 mRNA at W8 was different between
the MDE patients who attempted suicide between W8 and W30
and those who did not. The analysis showed that the expres-
sion level of SLC6A4 mRNA at W8 was not different between
the two MDE patients groups (t= 0.898, p=0.371).
However, the variation of SLC6A4 mRNA expression
between W2 and W8 in the two groups was significantly
different (t = 4.616, po0.001), as expression levels
increased in suicide attempters (Figure S1). As repre-
sented in Figure 3, the variation of SLC6A4 mRNA expres-
sion between W2 and W8 predicted the occurrence of
suicide attempts between W8 and W30 with a specificity
of 0.78, a sensitivity of 1.00 and an AUC of 0.87, po0.05,
95% CI [0.69–0.97]. This predictive effect remained
Figure 3 Receiver operating characteristics (ROC) curve show-
ing the relationship between sensitivity and 1 – specificity in
determining the predictive value of SLC6A4 mRNA expression
variation between W2 and W8 for the occurrence of suicide
attempts between W8 and W30 in MDE patients. The area under
the curve was 0.87 [0.69–0.97]. Calculation of the Youden index
allowed to determine a sensitivity value of 1.00 and a specifi-
city value of 0.78 for an optimal cut-off of 0.43.
Table 3 Multiple logistic regression analysis to predict the occurrence of suicide attempts during the W8–W30 period
(n =95).
Predictorsa β p
History of previous SA 19.056
HDRS score at W8 0.179
SLC6A4 expression variation W8-W2 2.396
Abbreviations: HDRS, Hamilton Depression Rating Scale; SA, Suicide Attempts.
a
Statistically significant predictors are presented in bold.
Please cite this article as: Consoloni, J.-L., et al., Serotonin transporter gene expression predicts the worsening of suicidal ideation and
suicide attempts along a.... European Neuropsychopharmacology (2017), https://doi.org/10.1016/j.euroneuro.2017.12.015
9
significant (OR = 10.976 [1.438–83.768], p = 0.021) when
depression severity at W8 and the history of previous
suicide attempts were included in a multiple logistic
regression model (Table 3). Interestingly, the difference
of SLC6A4 mRNA expression between W0 and W8 also
predicted the occurrence of suicide attempts in MDE
patients during the long-term follow-up (OR = 3.624
[1.010–13.012], p = 0.048).
4. Discussion
With a prospective hypothesis-driven approach, we aimed
to investigate the predictive value of SLC6A4 mRNA levels
for suicide ideation and suicide attempts in patients with a
MDE. First of all, we demonstrated that SLC6A4 mRNA
expression is stable over time in subjects without any
psychiatric disorders. We also demonstrated that a low
baseline SLC6A4 mRNA expression level as well as an early
increase in SLC6A4 mRNA expression predicted the WSI in
the following 8 weeks. Furthermore, increase in SLC6A4
expression between baseline and the 8th week or between
the 2nd week and the 8th week (W0 and W8 or W2 and W8)
predicted the occurrence of a suicide attempt within a 30-
week follow-up period. Of note, clinical variables previously
associated to suicide risk did not predict neither WSI nor the
occurrence of suicidal attempts in this cohort (i.e. depres-
sion severity, previous history of suicide attempts, child-
hood trauma). These negative findings reinforce the utility
of adequate biomarkers to prevent such behaviors.
To the best of our knowledge, we present the first
evidence of a difference in SLC6A4 mRNA expression levels
between depressed patients with and without suicidal
behaviors. Although several previous post mortem studies
assessed the role of regulation of expression of this candi-
date gene, they provided conflicting results (Arango et al.,
2001; Little et al., 1997; Perroud et al., 2010). However,
previous post mortem studies have the inconvenience of
being static, allowing a single-point measure at the time of
death in cases-controls study design which are known to be
less powerful than prospective studies. Moreover, these
studies were not able to control for a potential confounding
effect of the diagnosis of depression as they usually
compared brains of depressed suicide victims to those of
healthy controls that were not depressed at the time of
their death.
We have chosen a prospective study design that allowed
us to make four different time points measures in a 30-week
period and consequently to investigate within-subjects
Adjusted odds ratio 95% Confidence Interval
0.997 0.000
0.095 1.196 0.970–1.476
0.021 10.976 1.438–83.768
10
variations of mRNA expression across time. In fact, in the
context of the prediction of the response to antidepressant
medication, some authors have postulated that early varia-
tions of peripheral mRNA gene expression could predict a
phenotypic outcome better than static measures (Leuchter
et al., 2009). Interestingly, our findings support this idea.
Although baseline SLC6A4 mRNA expression level efficiently
predicted the WSI, an early increase expression in the
beginning of the follow-up was also a good predictor.
Moreover, a similar early variation of SLC6A4 mRNA expres-
sion predicted the occurrence of a suicide attempt.
It seems important to note that other prospective studies
have tried to identify genetic biomarkers of suicidal idea-
tion increase and suicidal behaviors based on a hypothesis-
free approach but did not evidence SLC6A4 gene expression
differences (Le-Niculescu et al., 2013; Niculescu et al.,
2015b). Changes in blood expression levels of 6 genes (i.e.
SAT1, PTEN, MAP3K3, MARCKS, UBA6 and MT-ND6) have
been proposed as biomarkers for suicidality in a first study
from Le-Niculescu and colleagues based on a discovery
cohort of 9 bipolar disorder male patients (Le-Niculescu
et al., 2013). However, two studies failed to replicate these
findings in depressed individuals (Mullins et al., 2014;
Niculescu et al., 2015a). In a second study, using a discovery
cohort of 37 males with heterogeneous psychiatric disor-
ders, the authors identified genes whose expression could
be used as biomarkers for the emergence of suicidal
ideation or suicidal behaviors and combined them with
clinical information using homemade validated scales
(Niculescu et al., 2015b). More recently, the authors used
the same approach in a discovery cohort of 12 women that
led them to highlight different biomarkers (Levey et al.,
2016). While it is a promising approach, biomarkers appear
to be related to a specific diagnosis, so it can be hypothe-
sized that the authors did not highlight SLC6A4 as a
candidate due to the heterogeneity of their discovery
cohort.
Although our findings yield new perspectives in the field
of suicide prevention during MDE, our study has several
limitations. Firstly, the AUC value accounting for the pre-
diction of the WSI between baseline and the 8th week by
SLC6A4 mRNA expression at baseline was low. Usually
biomarkers are considered to have a good discriminative
ability and to be clinically relevant when the AUC is higher
than 0.75 (Ray et al., 2010). An explanation for this low
value could be that we chose to focus on one single
potential candidate biomarker whereas it could be of great
interest to search for a combination of biological and/or
clinical biomarkers to predict more precisely such a com-
plex phenomenon (Blasco-Fontecilla et al., 2013). Never-
theless, the predictive value of SLC6A4 mRNA expression
variations on the occurrence of a suicide attempt was high
with an AUC of 0.87, indicating good discriminative capa-
city. While this result needs to be considered with caution
due to the small number of events (5 patients attempted
suicide between the 8th and 30th weeks) that could have
dimly emphasize its predictive value (Button et al., 2013;
Seeley et al., 1984), it is worth noting that the proportion of
suicide attempters in our cohort of depressed individuals
was concordant with the expected rates in a context of
clinical care (Nicoli et al., 2012; Weissman et al., 1999). It is
Please cite this article as: Consoloni, J.-L., et al., Serotonin transporter gene expression predicts the worsening of suicidal ideation and
suicide attempts along a.... European Neuropsychopharmacology (2017), https://doi.org/10.1016/j.euroneuro.2017.12.015
J.-L. Consoloni et al.
also of interest to note that Blasco-Fontecilla et al.
reported an AUC value of 0.92 for the prediction of suicide
attempts based on selected items from clinical scales in an
heterogeneous psychiatric population (Blasco-Fontecilla
et al., 2012), that is relatively close to our predictive value.
Secondly, it is worth noting that generalizability of our
findings should be limited due to our relative small sample
size, specifically regarding the occurrence of suicide
attempts. As reported in the results Section, 2 patients
demonstrated an initial WSI during the first 8 weeks and
have attempted suicide in the second part of the study.
Probably due to an underpowered statistical analysis, we
did not find any association between patients with an initial
WSI and suicide attempters (Fisher Exact Test; p= 0.294).
Although previous studies describing potential biomarker of
suicide risk have been based on smaller sample sizes,
shorter follow-up duration and/or without several time
points, larger study with similar design and based on
representative cohort of patients are needed to replicate
our findings.
Although our findings appear in contradiction with pre-
vious observations, several methodological hypotheses
could explain these discrepancies. First of all, our data
described dynamic changes of gene expression level follow-
ing a long time period that might be difficult to compare to
a single time point comparison in post mortem brain
studies. This unique time point is close to suicide and
death, and could not capture all biological changes that
predispose to suicidal behaviors. Moreover, to the best of
our knowledge, post mortem brain studies of SLC6A4 mRNA
only compared healthy controls to suicide individuals, with-
out MDD control groups. It is worth noting that post mortem
brain studies mainly include male subjects, while in our
cohort, we included 65% of women which corresponds to the
usual sex-ratio of patients suffering from MDD. Although we
did not find any gender effect, such a difference may also
influence the interpretation of the results. Lastly,
post mortem brain results could be affected by several
biases difficult to control such as the influence of post
mortem brain intervals or brain pH.
Moreover, another limitation of this study could be that
pharmacological treatment may affect mRNA level of
SLC6A4 and add some bias to our results. In recent years
evidence has accumulated that some antidepressants but
also drugs of abuse such as cocaine or amphetamines impact
on several pathways, which modulate serotonin transporter
cell surface expression by influencing its cellular distribu-
tion (Lau, 2012). However, it is not clear in the literature if
this protein dysregulation also involves the gene expression
level or not. As a matter of fact, we found several evidence
that this hypothesis is unlikely. Based on an animal model of
depression in mice, namely Unpredicted Chronic Mild Stress,
we recently described gene expression differences between
mice treated with fluoxetine and untreated ones, using
microarrays (Herve et al., 2017). When specially focusing on
SLC6A4 mRNA level of expression in blood, we found no
differences between untreated and “responders mice” (t-
test; FC = 1.14 p= 0.60) as well as between untreated and
“non-responders mice” (t-test; FC = 1.02 p= 0.66). This
result has been also confirmed in a comparable study from
another team (Yamagata et al., 2017) in which the authors
5-HTT mRNA and suicide behaviors
described no differences for SLC6A4 gene expression (Hir-
otaka Yamagata, personal communication). Based on brain
tissue, another research team described also that SSRIs
induced a decrease in protein density in hippocampus not
caused by gene expression regulation (Benmansour et al.,
1999). Moreover, while several studies have described gene
expression changes after antidepressant treatment in dif-
ferent human cell lines (Breitfeld et al., 2016; Morag et al.,
2011; Probst-Schendzielorz et al., 2015), to the best of our
knowledge, none of them demonstrated any dysregulation
of SLC6A4 gene expression. Consistently, we ran a query on
the Drug Signature Database (Yoo et al., 2015) and found no
evidence of SLC6A4 mRNA variation induced by any anti-
depressants. Finally, several studies have described blood
gene expression variations after antidepressant response
(for review see Belzeaux et al., 2017a). None of these
studies described a significant gene expression variation of
SLC6A4 associated with antidepressant treatment. The lack
of information regarding the length of medication use in our
cohort could be considered as a supplementary limitation.
As our analyses revealed a significant effect of typical
antipsychotics, it could have been of interest to control
for this duration when comparing the SLC6A4 mRNA expres-
sion level at baseline.
The lack of mechanistic exploration of SLC6A4 mRNA
expression variation could also be considered as a limita-
tion. In fact, several epigenetic factors may cause variation
in gene expression level including DNA methylation, histone
modification and miRNAs, but evidence of biological inter-
action between these factors and SLC6A4 mRNA remains
scarce (Belzeaux et al., 2017a). First of all, methylation of
CpG motifs within the exon DNA region is a potential
important mechanism of SLC6A4 expression changes. Methy-
lation could be induced by environmental factors and
represent one of the potential physical substrate of gene
environment interaction in pathophysiology of psychiatric
phenotype and treatment response (Philibert et al., 2008).
miRNAs are also considered as meta-regulator of gene
expression and protein expression (Belzeaux et al.,
2017b). Initially, miR-16 has been described to regulate
serotonin transporter expression (Baudry et al., 2010) but
several works suggest that other miRNAs such as mir-15a
and miR-24 could also been involved in such regulation (Liao
et al., 2016; Moya et al., 2013). It would be an important
added-value to include such biomarkers in future studies.
Finally, another limitation of our study is the absence of
plausible neurobiological interpretations of the association
between changes in SLC6A4 mRNA expression in white blood
cells and suicide risk since brain blood correlations had not
been clearly defined. Even if the underlying neurobiological
mechanisms are still unknown, this biomarker has been
selected on the basis of an important literature that linked
the SLC6A4 gene to suicidality in line with the predictive
value we observed. Moreover, the SLC6A4 mRNA expression
was stable over time across the healthy participants group
suggesting that SLC6A4 variations seem specific to the
suicide phenotype. However, future studies are needed to
explain why such a variation in blood cells could be relevant
in suicide phenotype.
In conclusion, many researches have implicated seroto-
ninergic functioning in suicidality and especially the 5-HTT
but no previous study revealed an association between
Please cite this article as: Consoloni, J.-L., et al., Serotonin transporter gene expression predicts the worsening of suicidal ideation and
suicide attempts along a.... European Neuropsychopharmacology (2017), https://doi.org/10.1016/j.euroneuro.2017.12.015
11
SLC6A4 mRNA expression and suicidal risk in the follow-up
of depressed individuals. SLC6A4 mRNA expression at base-
line but also SLC6A4 expression variations predicted the
worsening of suicidal ideation. SLC6A4 course during a MDE
could thus be a good biomarker of future suicide attempts.
Funding sources
Funding for this study was provided by a national hospital
clinical research program (PHRC, No. 2010-19) as well as by
the French Government (National Research Agency, ANR)
through the VASPAC (ANR-13-SAMA-0002). RB received a
grant from FondaMental foundation (Postdoc fellowship
FondaMental Servier (2015)). The funders had no further
role in study design; in the collection, analysis and inter-
pretation of data; in writing of the report; and in the
decision to submit the paper for publication.
Authors' contributions
RB, PC and ECI designed the study and wrote the protocol.
JLC, RB, ECI and PC managed the literature searches and
analyses. ECI and JLC realized the biological analyses. JLC
undertook the statistical analyses, and wrote the first draft
of the manuscript. All authors contributed to and have
approved the final manuscript.
Conflicts of interest
The authors declare that they have no conflicts of interest.
Acknowledgements
The authors thank Samira Miloudi, Aurélie Cazals, Olivier Blanc,
Chrystelle Cappe, Bérangère Goemaere, Annabelle Pin for their
help in administrating the study and contacting the participants;
Henri Dor, Muriel Ruffier, Magali Scotto, Lydie Berger, Hélène
Bansard for the collection of the biological samples; Dr. Damien
Jouvenoz, Dr. Julien Testart, Dr. Pierre Arquillière, Dr. Marguerite
Serres, Dr. Chloé Jover, Dr. Fayçal Goumeidane for their help with
the clinical evaluations. They also thank Mélanie Broutin, Mohama-
dou Diarra, Eva Massé and Claire Zimberger for their contributions
to the biological analyses.
Appendix A. Supporting information
Supplementary data associated with this article can be
found in the online version at doi:10.1016/j.euroneuro.
2017.12.015.
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