Candidate genes expression profile associated with antidepressants response in the gendep study: differentiating between baseline ‘predictors’ and longitudinal ‘targets’
Neuropsychopharmacology (2012), 1–9& 2012 American College of Neuropsychopharmacology. All rights reserved 0893-133X/12
Candidate Genes Expression Profile Associated withAntidepressants Response in the GENDEP Study: Differentiatingbetween Baseline ‘Predictors' and Longitudinal ‘Targets'
Annamaria Cattaneo1, Massimo Gennarelli1,2, Rudolf Uher3, Gerome Breen3, Anne Farmer3,
Katherine J Aitchison3,4, Ian W Craig3, Christoph Anacker5, Patricia A Zunsztain5, Peter McGuffin3 and
Carmine M Pariante*,5
Department of Biomedical Sciences and Biotechnology, Genetic and Biology Section, University of Brescia, Brescia, Italy; 2Genetic Unit, IRCCS
San Giovanni di Dio, Fatebenefratelli Centre, Brescia, Italy; 3Institute of Psychiatry, MRC Social, Genetic and Developmental Psychiatry, King's
College London, London, UK; 4Department of Psychiatry, University of Alberta, Edmonton, Canada; 5Department of Psychological Medicine,
Institute of Psychiatry, Section of Perinatal Psychiatry and Stress, Psychiatry and Immunology (SPI-lab), King's College London, London, UK
To improve the ‘personalized-medicine' approach to the treatment of depression, we need to identify biomarkers that, assessed before
starting treatment, predict future response to antidepressants (‘predictors'), as well as biomarkers that are targeted by antidepressants
and change longitudinally during the treatment (‘targets'). In this study, we tested the leukocyte mRNA expression levels of genes
belonging to glucocorticoid receptor (GR) function (FKBP-4, FKBP-5, and GR), inflammation (interleukin (IL)-1a, IL-1b, IL-4, IL-6, IL-7, IL-8,
IL-10, macrophage inhibiting factor (MIF), and tumor necrosis factor (TNF)-a), and neuroplasticity (brain-derived neurotrophic factor (BDNF),
p11 and VGF), in healthy controls (n ¼ 34) and depressed patients (n ¼ 74), before and after 8 weeks of treatment with escitalopram or
nortriptyline, as part of the Genome-based Therapeutic Drugs for Depression study. Non-responders had higher baseline mRNA levels
of IL-1b ( þ 33%), MIF ( þ 48%), and TNF-a ( þ 39%). Antidepressants reduced the levels of IL-1b ( 6%) and MIF ( 24%), and
increased the levels of GR ( þ 5%) and p11 ( þ 8%), but these changes were not associated with treatment response. In contrast,
successful antidepressant response was associated with a reduction in the levels of IL-6 ( 9%) and of FKBP5 ( 11%), and with an
increase in the levels of BDNF ( þ 48%) and VGF ( þ 20%)—that is, response was associated with changes in genes that did not predict, at
the baseline, the response. Our findings indicate a dissociation between ‘predictors' and ‘targets' of antidepressant responders. Indeed,
while higher levels of proinflammatory cytokines predict lack of future response to antidepressants, changes in inflammation associated
with antidepressant response are not reflected by all cytokines at the same time. In contrast, modulation of the GR complex and of
neuroplasticity is needed to observe a therapeutic antidepressant effect.
Neuropsychopharmacology advance online publication, 19 September 2012;
Keywords: antidepressant; depression; glucocorticoid receptor; inflammation; neuroplasticity; treatment response;
available, only a third of patients respond adequately totreatment, and up to half of them relapse within 1 year
Antidepressants are commonly prescribed drugs, but the
Unfortunately, we still cannot predict the
treatment protocols are dictated by clinical practice and
likelihood of response of an individual patient to a specific
personal preferences rather than by a ‘biomarker-based'
drug . Therefore, there is a pressing need to
personalized medicine approach (These drugs
identify biomarkers that, assessed before starting treatment,
are used in patients with major depression, one of the most
‘predict' future response, as well as biomarkers that are
common psychiatric disorders and a leading cause of
‘targeted' by antidepressants and change longitudinally
disability worldwide (). However,
during antidepressant treatment. In addition to fostering
despite the increasing variety of antidepressants currently
personalized medicine, establishing ‘predictors' and ‘target'biomarkers could lead to the identification of novel
*Correspondence: Professor CM Pariante, Department of Psycholo-
pathophysiological pathways relevant to depression, and
gical Medicine, Institute of Psychiatry, Section of Perinatal Psychiatry
thus novel mechanisms for designing therapeutic strategies.
and Stress, Psychiatry and Immunology, Kings College London, Room
Based on the current conceptualization of depression, we
2-055, The James Black Centre, 125 Coldharbour Lane, London SE5
suggest that hypothesis-driven, blood-based biomarker
9NU, UK, Tel: þ 44 0 20 7848 0807, Fax: þ 44 0 20 7848 0986,E-mail:
analysis should focus on the biological systems that
Received 30 April 2012; revised 13 July 2012; accepted 30 July 2012
have been more consistently described as abnormal in
Gene expression profile in the GENDEP study
depression: the glucocorticoid receptor (GR) complex,
serum and in the leukocytes mRNA of depressed patients,
inflammation, and neuroplasticity .
and that, in turn, pharmacological and non-pharmacologi-
One of the most consistent biological findings in depres-
cal antidepressant therapies increase BDNF to levels similar
sion is a hyperactivity of the hypothalamic–pituitary–
to those in healthy controls ;
adrenal (HPA) axis as
shown by a multitude of studies describing high levels of
levels of BDNF- and neuroplasticity-related genes are
cortisol, the main HPA axis hormone, in the context of
therefore another class of important candidate biomarkers
reduced function of the GR, the cortisol receptor primarily
in relation with antidepressant response.
involved in HPA axis regulation during stress. This reduced
In this study, to capture a comprehensive picture of the
GR function, or glucocorticoid resistance, is particularly
biological and clinical interaction between these three bio-
evident in patients with treatment-resistant depression
logical systems in relationship with antidepressant treat-
ment, we examined the gene expression (blood mRNA via
persistent glucocorticoid resistance during antidepressant
PaxGene tubes) of 15 genes belonging to the GR (three genes),
treatment is associated with early relapse ;
inflammation (nine genes), and neuroplasticity (three
Moreover, polymorphisms in the GR
genes) pathways. We studied a well-characterized group of
(or NR3C1) gene, and in the gene for the GR-associated,
depressed patients from the Genome-based Therapeutic
FKBP-5 co-chaperone protein, have been shown to regulate
Drugs for Depression (GENDEP) study
GR function and to predict antidepressant treatment response
), before and after 8 weeks of treatment with one of two
pharmacologically different antidepressants: the selective
). Therefore, the expression levels of GR-related genes
serotonin reuptake inhibitor, escitalopram, and the tricyclic
are important candidate biomarkers in relation with
noradrenaline reuptake inhibitor, nortryptline (and in a
group of matched controls). We selected all patients (n ¼ 74)
A second biological system potentially involved in
who were drug-free for at least 2 weeks before enrolling into
antidepressant response is inflammation. Pro-inflammatory
the trial, and had provided PaxGene tubes at both baseline
cytokines, and in particular interleukin (IL)-1b, IL-6, and
and follow-up (after 8 weeks of antidepressants). We mea-
tumor necrosis factor (TNF)-a, are increased in depressed
sured the transcriptional levels of the following genes:
patients as compared with controls in
for the GR complex, FKBP-4, FKBP-5, and GR; for the
turn, antidepressants have been shown to have anti-
inflammatory system, IL-1a, IL-1b, IL-4, IL-6, IL-7, IL-8,
inflammatory effects (), and anti-
IL-10, macrophage inhibiting factor (MIF), and TNF-a; and
inflammatory drugs, such as celecoxib and TNF-a antago-
for neuroplasticity, BDNF, p11, and VGF (non-acronymic).
nists, have been shown to have antidepressant properties or
We wished to answer three questions: first, which genes at
to improve antidepressant response (
baseline (ie, before starting antidepressant treatment)
Interestingly in this context, higher levels of inflammation
differentiate depressed patients vs controls; second, which
seem to identify depressed patients who are less likely to
genes, again at baseline, predict treatment response to
respond to antidepressant treatment ;
subsequent antidepressant treatment (‘predictors'); and
third, which genes, assessed prospectively (ie, at baseline
polymorphisms in immune genes, such as in IL-1b, IL-11,
and after 8 weeks of antidepressant treatment) change in
and TNF-a, have been associated with reduced responsive-
parallel with treatment response (‘targets').
ness to antidepressant therapy ; . Consistent with this notion, theelevated levels of IL-1b, IL-6, and TNF-a tend to diminish in
MATERIALS AND METHODS
parallel with antidepressant response (;
Of note is also the proposed modelthat the above-mentioned glucocorticoid resistance results
The GENDEP project is an open-label part-randomized
from the direct molecular action of the activated inflam-
multicentre pharmacogenetic study with two active phar-
matory pathways on the GR complex, and that, in turn, the
macological treatment arms
glucocorticoid resistance maintains the inflammatory status
It was designed to establish clinical and genetic
by reducing the inhibitory control of endogenous gluco-
determinants of therapeutic response to two antidepres-
corticoids on the immune system
sants with different primary modes of action: nortriptyline
This model suggests a common pathogenic process under-
and escitalopram. The overall study has been extensively
lying both the HPA axis and the inflammatory abnormal-
described before (see Supplementary Material for details).
ities in depression, and thus identifies expression levels of
In total, 9 psychiatric centers in 8 European countries
inflammatory genes as further important candidate bio-
recruited 811 adult outpatients (296 men and 514 women),
markers in relation with antidepressant response.
aged between 19 and 72 (mean age 42.5, SD ¼ 11.8) suffering
Finally, one of the potential mechanisms by which
from unipolar depression of at least moderate severity
excessive HPA axis activity and inflammatory responses
according to International Classification of Diseases 10/
may contribute to the pathogenesis of depression is through
Diagnostic and Statistical Manual of Mental Disorders,
inhibition of neurotrophic factors and disturbance of
fourth edition, and established by the semi-structured
neuroplasticity The neurotrophin,
brain-derived neurotrophic factor (BDNF), is the most
Severity of depressive symptoms and treatment response
studied molecule within the neuroplasticity network, and we
was assessed by weekly administration of three established
and others have shown that BDNF levels are reduced in the
measures of depression severity: the clinician-rated 10-item
Gene expression profile in the GENDEP studyA Cattaneo et al
Montgomery–Asberg Depression Rating Scale (MADRS;
), the 17-item Hamilton
Data were analyzed using the Statistical Package for Social
Rating Scale for Depression (HRSD–17; ),
Sciences, version 17.0 (SPSS). Continuous variables are
and the Beck Depression Inventory (BDI; ).
presented as mean±SD or SEM, as indicated. Categorical
The average participant in the original sample was in his/
variables were tested by means of w2 and Fisher's tests.
her second episode of depression and scored 28.7 (SD ¼ 6.7)
Univariate analysis of variance was used for comparing the
on the MADRS, 21.8 (SD ¼ 5.3) on the 17-item HDRS, and
mean values of the mRNA levels of the genes of interest, at
28.2 (SD ¼ 9.7) on the BDI.
baseline, in patients vs controls and in responders vs non-
A psychometric analysis has found that the MADRS was
responders. Changes over time were analyzed using the
the most internally consistent and informative of the three
repeated-measures General Linear Model with time (T0 and
scales , and therefore in the pharmaco-
T8) and response (yes/no) as factors. The Greenhouse–
genetic analyses already published and
Geisser correction was applied to degrees of freedom when
in the current gene expression study, we have used the
the sphericity assumption was violated. Parametric correla-
MADRS score as a primary outcome measure of ‘treatment
tion analyses using Pearson's coefficient were used to test
response'. Response to antidepressant medication was
the association between genes and the improvement in the
quantified as percentage reduction in the MADRS score
depressive symptoms measured as changes in the MADRS
from baseline to week 12, and responders were identified as
score. Linear regression analyses were used to test for
patients with a reduction in MADRS450%.
predictors of the treatment outcome.
For this study, we selected all patients who had been drug-free for at least 2 weeks before entering into the trial and
Biomarkers Differences between Patients at Baseline,
provided a baseline and a follow-up PaxGene tube (n ¼ 74).
Their average (SD) age was 38.3±10.9 and, there were 31males and 43 females. The average participant in our study
Patients (at baseline) and controls differed in the expression
was in his/her second episode of moderately severe
of most of the examined genes (Specifically, we
depression and scored, at baseline, 28.7 (SD ¼ 4.2) on the
found that depressed patients, as compared with controls,
MADRS, 20.7 (SD ¼ 4.1) on the HRSD–17, and 27.5
had higher FKBP-5 mRNA levels ( þ 27%, F ¼ 69.4,
(SD ¼ 10.2) on the BDI. There were no significant differ-
po0.0001) and lower GR mRNA levels ( 18%, F ¼ 63.2,
ences between patients treated with escitalopram (n ¼ 38) or
po0.0001). Moreover, they had higher mRNA levels of
nortryptiline (n ¼ 36), in age (38±12.4 vs 36±9.4, p ¼ 0.25),
IL-1b, ( þ 48%, F ¼ 117.9, po0.0001), IL-6 ( þ 24%, F ¼ 86.3,
gender (F/M was 20/18 vs 23/13, p ¼ 0.2), and in the
po0.0001), MIF ( þ 32%, F ¼ 34.8, po0.0001), and TNF-a
response rate (responders/non-responders was 26/12 vs 25/
( þ 58%, F ¼ 87.7, po0.0001), and lower levels of IL-4
11, p ¼ 0.6).
( 9%, F ¼ 5.6, p ¼ 0.02). Finally, depressed patients had
Controls were recruited in London (UK), through adver-
lower mRNA levels of BDNF ( 24%, F ¼ 46.5, po0.0001),
tisement in local newspapers, hospitals, and job centers, as
p11 ( 16%, F ¼ 12.1, p ¼ 0.001), and VGF ( 36%, F ¼ 37.3,
well as from existing volunteer databases. Controls were
screened using the Psychosis Screening Questionnaire), and were excluded if they
Baseline Differences in Biomarkers between Responders
met criteria for a present or past psychotic disorder, or if
and Non-Responders (‘Predictors')
taking any kind of hormonal treatment; their average agewas 35.2 (SD ¼ 8), and there were 19 males and 15 females.
As mentioned above, treatment response was defined as a
There were no significant differences in age and gender
percentage reduction 450% in the MADRS score from
between patients and controls (p ¼ 0.14 for age, and p ¼ 0.13
baseline to week 12. In this sample, we had 51 responders
for gender distribution).
and 23 non-responders: 26 responders to escitalopram, 12non-responders to escitalopram, 25 responders to nortrypt-
Gene Expression Analyses
line, and 11 non-responders to nortryptline. There were nodifferences in age (38.3±1.6 vs 38.4±2.2 years, Fo0.1,
We measured the leukocytes mRNA levels of the above-
p ¼ 0.98), gender distribution (F/M ¼ 31/20 vs 12/11, w2 ¼ 0.5,
mentioned candidate genes involved in GR function (FKBP-
p ¼ 0.3), or baseline MADRS (26.8±0.6 vs 25.0±0.8,
4, FKBP-5, and GR), inflammatory system (IL1-a, IL-1b, IL-
F ¼ 3.0, p ¼ 0.09) between responders and non-responders;
4, IL-6, IL-7, IL-8, IL-10, MIF, and TNF-a), and neuroplas-
moreover, study center also did not influence treatment
ticity (BDNF, p11, and VGF). Each sample was assayed in
response (p ¼ 0.3).
duplicate, and each target gene was normalized to the
We compared the baseline mRNA levels of each gene in
patients who did not respond to treatment vs patients who
3-phosphate dehydrogenase, beta-actin, and beta-2-micro-
did Only three genes were differentially
globulin. The expression levels of each target gene were
expressed: specifically, non-responders had higher mRNA
normalized to the geometric mean of all three reference
levels of the three pro-inflammatory cytokines, IL-1b ( þ 33%,
genes, and the Pfaffl method was used to determine relative
F ¼ 55.9, po0.0001), MIF ( þ 48%, F ¼ 14.6, po0.0001), and
target gene expression of each gene in patients as compared
TNF-a ( þ 39%, F ¼ 39.4, po0.0001). Moreover, for MIF
with controls (see Supplementary Material for details).
levels we observed a significant drug response interaction
Gene expression profile in the GENDEP study
Table 1 Expression Levels of Genes Belonging to GR Functionality (FKBP-4, FKBP-5, and GR), Inflammation (IL-1a, IL-1b, IL-4, IL-6, IL-7, IL-8,IL-10, TNF-a, and MIF), and Neuroplasticity (BDNF, p11, and VGF) in Controls and Depressed Patients with Statistics (p and F values andPercentage Changes)
Percentage change (%)
Table 2 Expression Levels of Genes Belonging to GR Functionality (FKBP-4, FKBP-5, and GR), Inflammation (IL-1a, IL-1b, IL-4, IL-6, IL-7, IL-8,IL-10, TNF-a, and MIF), and Neuroplasticity (BDNF, p11, and VGF) in Non-Responder and Responder Patients
Non-responder (n ¼ 23)
Responder (n ¼ 51)
Drug response interaction
Statistics (F and p values) are presented for both main effects and for the drug response interaction (26 responders to escitalopram, 12 non-esponders toescitalopram, 25 responders to nortryptline, and 11 non-responders to nortryptline).
(F ¼ 4.4, p ¼ 0.04): this was due to the difference between
as changes in the MADRS score between week 0 and week
non-responders and responders being larger for non-
12 (DMADRS), both in the overall sample and separately
responders to nortriptyline ( þ 56%, F ¼ 73.2, po0.0001)
based on the drug used. As expected, the expression
than for those non-responders to escitalopram ( þ 39%,
levels of IL-1b, MIF, and TNF-a at baseline were all strongly
F ¼ 36.9, po0.0001). There was no drug response inter-
and negatively correlated with the treatment outcome,
action for any of the other genes.
both in the entire group (IL-1b, r ¼ 0.56; MIF, r ¼ 0.62;
We further examined the relative contributions of the
and TNF-a, r ¼ 0.44; all po0.0001), and also separately
three cytokines in predicting treatment response measured
in the two samples based on the drug used (for
Gene expression profile in the GENDEP studyA Cattaneo et al
escitalopram: IL-1b, r ¼ 0.54, p ¼ 0.001; MIF, r ¼ 0.73,
(F ¼ 4.4, p ¼ 0.039) interactions. Namely, IL-6 levels
po0.0001; and TNF-a, r ¼ 0.39, p ¼ 0.016; and for
decreased significantly in responders ( 9%, F ¼ 20.3,
nortriptyline, IL-1b, r ¼ 0.65 po0.0001; MIF, r ¼ 0.56
po0.0001), and this was present for both responders to
po0.0001; and TNF-a, r ¼ 0.68, po0.0001). We then run
escitalopram ( 12%, F ¼ 14.0, p ¼ 0.001) and to nortripty-
a linear regression model to identify the relative contribu-
line ( 6%, 0.2, F ¼ 6.6, p ¼ 0.02). In non-responders there
tions of the three cytokines to the prediction of response. As
was no overall effect ( þ 1%, F ¼ 0.4, p ¼ 0.5) but, when the
shown in the best predictive model was obtained
two drugs were analyzed separately, IL-6 did not change in
when the three cytokines were all included in the model,
the non-responders to escitalopram ( 2%, F ¼ 0.5, p ¼ 0.5)
both in the overall samples (46% of the variance) and
and increased in the non-responders to nortriptyline
separately in the escitalopram-treated group (53% of the
( þ 7%, F ¼ 5.8, p ¼ 0.037).
variance) and in nortriptyline-treated group (48% of the
Finally, four genes were regulated by antidepressant
treatment, irrespective of the antidepressant used or oftreatment response, as shown by a main effect of time in theabsence of any response time or drug timeinteractions.
Change in Biomarkers and Relationship with Treatment
Specifically, antidepressant treatment significantly reduced
the expression levels of IL-1b ( 6%, F ¼ 7.9, p ¼ 0.006) and
To investigate the effect of 8 weeks of antidepressant treat-
MIF ( 24%, F ¼ 16.4, po0.0001), and increased GR mRNA
ment with escitalopram or nortriptyline on gene expression
levels ( þ 5%, F ¼ 7.3, p ¼ 0.009) and p11 levels ( þ 8%,
(and its relationship with treatment response), we compared
F ¼ 8.4, p ¼ 0.005).
the change in mRNA levels of each gene between baseline(T0) and week 8 (T8). These data are presented in
Three genes were regulated by antidepressant treatment
but in responders only, and regardless of the antidepressant
To provide evidence supporting a personalized-medicine
used, as shown by significant response time interactions
approach to the treatment of depression, we have assessed
but no drug time interactions. Specifically, antidepressant
the blood mRNA expression of 15 candidate genes across
treatment significantly reduced FKBP5 levels only in
three biological systems implicated in the pathogenesis of
patients who responded to the treatment ( 11%, F ¼ 16.4,
depression and in the action of antidepressants: GR
po0.0001), whereas no effect was observed in non-res-
complex, inflammation, and neuroplasticity. We have used
ponders ( 2%, F ¼ 0.6, p ¼ 0.45; response time interaction,
a well-characterized group of drug-free depressed patients
F ¼ 4.4, p ¼ 0.04; drug timeinteraction, F ¼ 0.05, p ¼ 0.8).
who entered a randomized trial with two different anti-
Moreover, antidepressant treatment significantly increased
depressants, and we have assessed genes that differentiate
VGF expression only in responders ( þ 20%, F ¼ 15.4,
patients from controls, predict future antidepressants response,
po0.0001) but not in non-responders ( 3%, F ¼ 0.002,
or change in association with response. The main finding is
p ¼ 0.97; response time interaction, F ¼ 4.4, p ¼ 0.039;
a dissociation between genes that predict treatment response
drug timeinteraction, F ¼ 0.03, p ¼ 0.8). Finally, antide-
(‘predictors') and genes that change longitudinally in patients
pressant treatment increased BDNF expression more in the
who respond (‘targets'). Specifically, among the 15 genes,
responders ( þ 48%, F ¼ 126.4, po0.0001) than in the non-
only higher levels of the three inflammation-related genes,
responders ( þ 21%, F ¼ 49.4, po0.0001; response time
IL-1b, MIF, and TNF-a, predict lack of response to
interaction, F ¼ 17.8, po0.0001; drug time interaction,
antidepressants, and successful antidepressant response is
F ¼ 3.6, p ¼ 0.062).
not associated with a reduction in the levels of these genes.
IL-6 was regulated by antidepressant treatment but in a
In contrast, successful antidepressant response is associated
drug- and response-specific way, that is, in the presence of
with a reduction in the levels of the inflammation-related
both response time (F ¼ 10.0, p ¼ 0.002) and drug time
gene, IL-6, and of the GR-associated gene, FKBP-5; and with
Table 3 Adjusted R2 Values and Significance of Linear Regression Model to Assess the Contribution of TNF-a, MIF, and IL-1b, Alone or inCombination, in Predicting the Treatment Response in the Whole Sample, in the Escitalopram-Treated Group and in the Nortriptyline-Treated Group
Whole sample (n ¼ 74)
Escitalopram-treated group (n ¼ 38)
Nortriptyline-treated group (n ¼ 36)
Effects of each single cytokine as predictor of treatment response
Adjusted R2 ¼ 0.19, po0.0001
Adjusted R2 ¼ 0.13, p ¼ 0.016
Adjusted R2 ¼ 0.45, po0.0001
Adjusted R2 ¼ 0.37, po0.0001
Adjusted R2 ¼ 0.51, po0.0001
Adjusted R2 ¼ 0.29, po0.0001
Adjusted R2 ¼ 0.31, po0.0001
Adjusted R2 ¼ 0.27, p ¼ 0.001
Adjusted R2 ¼ 0.41, po0.0001
Combined effects of cytokines as predictor of treatment response
Adjusted R2 ¼ 0.19, po0.0001
Adjusted R2 ¼ 0.13, p ¼ 0.016
Adjusted R2 ¼ 0.45, po0.0001
Adjusted R2 ¼ 0.40, po0.0001
Adjusted R2 ¼ 0.50, po0.0001
Adjusted R2 ¼ 0.47, po0.0001
TNF-a þ MIF þ IL-1b
Adjusted R2 ¼ 0.46, po0.0001
Adjusted R2 ¼ 0.53, po0.0001
Adjusted R2 ¼ 0.48, po0.0001
Gene expression profile in the GENDEP study
Table 4 Expression Levels of Genes Belonging to GR Functionality (FKBP-4, FKBP-5, and GR), Inflammation (IL-1a, IL-1b, IL-4, IL-6, IL-7, IL-8,IL-10, TNF-a, and MIF), and Neuroplasticity (BDNF, p11, and VGF) in Depressed Patients before (Patients T0) and after 8 Weeks ofAntidepressant Treatment (Patients T8)
Time response interaction
Time drug interaction
Statistics (F and p values) are presented for the time effect as well as the time response and time drug interactions. The numbers of patients for each group were:26 responders to escitalopram, 12 non-responders to escitalopram, 25 responders to nortryptline, and 11 non responders to nortryptline).
an increase in the neuroplasticity-associated genes, VGF
sants have anti-inflammatory properties ;
and BDNF—that is, in genes that are not associated with the
here we also demonstrate that the changes
baseline prediction of treatment response.
in inflammation associated with antidepressant response
The baseline levels of TNF-a, IL1-b, and MIF, together
are not reflected by all cytokines at the same time. This is
predict the treatment outcome for both antidepressants, with
perhaps not surprising, because the action of a single
clinically significant effect sizes of around 50% of the
cytokine is regulated within a complex network, where
variance (Moreover, although each single
multiple pro-inflammatory cytokines maybe involved in the
cytokine strongly correlates with the treatment response, the
antidepressant response, and a reduction in inflammation
best predictive model is present when we include all three
may be signaled by an increase in the expression of negative
cytokines in the linear regression, suggesting that each
regulators of cytokine action as well as by a reduction in
cytokine taps also in non-shared molecular mechanisms. For
cytokines level. It is also possible that a simple reduction in
example, IL1-b and TNF-a, but not MIF, activate the
the levels of some inflammatory biomarkers, such as IL1-b
indoleamine 2,3-dioxygenase pathway
and MIF, is not sufficient for reversing the biological
), which is responsible for the
changes underlying the depressive symptoms, because
catabolism of tryptophan to kynurenine, and results in the
potentially downstream effectors pathways, such as MAPK
production of the neurotoxic and depressogenic metabolites,
and nuclear factor kappa B, remain abnormal
3-hydroxykynurenine and quinolinic acid
). At the opposite end, persistently high levels of other
Indeed, we have recently shown that this pathway is
inflammatory cytokines, such as TNF-a, may be a marker of
activated by IL-1b also in human neurons (
specific forms of depression that are less responsive to
In contrast, MIF, but not IL-1b and TNF-a, is released
antidepressant treatment, eg, depressed patients with a
in response to glucocorticoids, and, when secreted, it
history of childhood trauma tend to have higher inflam-
renders immune cells less sensitive to the anti-inflammatory
matory biomarkers and to be less
effects of glucocorticoids (
responsive to pharmacological intervention
It is also of note that antidepressant treatment in our
; in this case, the increased
study reduces the levels of IL1-b and MIF, but this reduction
cytokine levels may be an underlying ‘trait feature' conferring
is not associated with treatment response. In contrast, levels
treatment resistance, and may not be modifiable by
of TNF-a, which are elevated in non-responders, are not
modified by antidepressant treatment; and levels of IL-6
The expression of four genes changes only in patients
decrease following antidepressants, but in responders only.
who respond to treatment, but not in those who do not
Of note, this last finding is remarkably consistent with the
respond. These genes are across the three biological systems
previous paper by , who also found
investigated: the GR-associated gene, FKBP-5; the pro-
that IL-6 plasma levels after 8 weeks of antidepressant
inflammatory cytokine, IL-6 (as mentioned above); and the
treatment were reduced in responders only. Although these
neuroplasticity associated genes, VGF and BDNF. The
data confirm previous evidence showing that antidepres-
association between reduction in FKBP-5 and response to
Gene expression profile in the GENDEP studyA Cattaneo et al
antidepressants has never, to our knowledge, been de-
the two drugs, that is, belonging to the serotonergic and the
scribed before; but previous studies have demonstrated that
noradrenergic pathways, respectively. This is also in line
polymorphisms in the gene encoding this co-chaperone are
with the results of our previous genetic study in the same
associated with antidepressant response
The main limitation of this study is that our finding
have recently shown that the pattern of
cannot yet be used to change clinical practice. Notwith-
RNA levels of GR-stimulated genes, including FKBP-5,
standing the strengths of the randomized, longitudinal design,
discriminate between patients and controls
these findings need to be replicated in an independent sample.
Taken together, our data (see also the changes in GR
Moreover, the predictive biomarkers that we have identified
discussed below) suggest that depression is characterized by
are not specific to one or the other of the antidepressants,
the coexistence of higher FKBP-5 and lower GR, leading to
and as such could not be used to guide the choice of anti-
GR resistance, and that successful antidepressant treatment
depressants but rather to identify patients that potentially
requires normalization of GR function. Finally, treatment
may be helped by early access to adjuvant therapies.
response was associated with an increase in BDNF and VGF.
Moreover, it is possible that these gene expression changes
The evidence for a role of BDNF in depression is abundant
are not causally involved in the treatment response, and
It is also of note that the
indeed we have not investigated potential biological mechan-
recent study from describing patients
isms that are changed by antidepressants and may underlie
who responded to an open-labeled treatment with venlafax-
the gene expression changes that we have described, such as
ine, also showed an increase in serum BDNF by week 3 of
changes in immune cells composition or in cortisol levels.
treatment. Also of interest is a large cross-sectional study
In conclusion, our findings identify for the first time that
again showing that depressed
the baseline levels of MIF, IL1-b, and TNF-a are ‘predictors'
patients had lower levels of serum BDNF, whereas remitted
of antidepressant treatment response. Moreover, we show
patients (a different group) had normal levels. There are less
that an enhancement of GR function and an improvement
data on the role of VGF in depression, but previous studies
in neuroplasticity are needed to observe a response to
have shown that VGF modulates hippocampal function and
antidepressant therapies, suggesting that future antidepres-
behavior through an effect that is BDNF-dependent and that
sant strategies should specifically target these pathways.
it is involved both in the pathogenesis of depression and inthe effects of antidepressants
We also find that GR and p11 levels are lower in depressed
patients compared with controls, and that their levels
The GENDEP project was supported by a European Commis-
increase after antidepressants, but not in relationship with
sion Framework 6 grant (contract reference: LSHB-CT-2003-
treatment response. Both lower levels of GR and lower levels
503428). This specific project has been supported by a grant
of p11, which is considered a GR-target gene via two specific
from the Commission of European Communities Seventh
glucocorticoid response elements in its promoter
Framework Programme (Collaborative Project Grant Agree-
, have been described before in depressed
ment no. 22963, Mood Inflame) and a Clinician Scientist
Fellowship from the Medical Research Council, UK (G108/
knowledge, this is the first report describing prospective
603) to CMP; by a NARSAD young investigator award to
changes in p11 levels; and only one previous study has
PAZ; by a grant from the Psychiatry Research Trust, UK
assessed GR expression prospectively using radioactive
(McGregor 97) to CMP and AC; by grants from the Italian
dexamethasone binding in peripheral blood mononuclear
Ministry of Health (Ricerca Corrente) and Regione Lom-
cells, and, again, found a reduction of GR density in depressed
bardia (ID:17387Sal-13) to MG; and by salary support to
patients (compared with controls) and an increase after
CMP, GB, and PZ, and a Studentship to CA, from the
antidepressant treatment ). Of note, we
National Institute for Health Research Mental Health
have consistently shown that antidepressants regulate the
Biomedical Research Centre at South London and Maudsley
function and the expression of the GR
NHS Foundation Trust and King's College London.
Moreover, a recent study in rats has shown that
escitalopram increases brain p11 levels concomitantly to adecrease in the p11 promoter methylation (
All funding regarding this project is described in the
Indeed, our own research in human neuronal stem
acknowledgment section. Dr Pariante in the last 3 years has
cells has recently shown that antidepressants directly increase
received fees as a speaker or as a member of advisory board,
the function of the GR and, via a GR-dependent mechanism,
as well as research funding, from pharmaceutical companies
the expression of p11: an action that is required for the effects
that commercialize or are developing antidepressants, such
of antidepressants on neurogenesis
as Lilly, Servier, and Janssen. All other authors declare no
It is interesting to note that, except for IL-6, we have
conflict of interest.
found that all the examined genes are modulated in thesame way by both drugs, even if escitalopram and nortry-ptiline have different modes of action. We believe this is due
to the fact that we have examined genes that belong to
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This work is licensed under the Creative
Spijker AT, van Rossum EF (2012). Glucocorticoid sensitivity in
mood disorders. Neuroendocrinology 95: 179–186.
Derivative Works 3.0 Unported License. To view a copy
Taler M, Gil-Ad I, Lomnitski L, Korov I, Baharav E, Bar M et al
(2007). Immunomodulatory effect of selective serotonin reup-
Supplementary Information accompanies the paper on the Neuropsychopharmacology website )
APPENDIX 1 Levels and effects of persistent organic pollutants (POPs) in seabirds Retinoids and α-tocopherol – potential biomarkers of POPs in birds? Kari Mette Murvoll Doctoral thesis for the degree of Philosophiae Doctor (PhD) Norwegian University of Science and Technology Faculty of Natural Sciences and Technology
My Health, My Choice, My Child, My Life! Women demand the roll out of a comprehensive national action plan to end vertical transmission of HIV in India Globally, momentum has been built to reinvigorate efforts to reduce maternal and infant mortality and improve maternal health including for women living with HIV. Nationally, women and children have been the stated priority of the government HIV programme since the beginning. The Indian Constitution guarantees the right to equality for all women and the right to life and health of all. In order to succeed in meeting these goals, civil society, especially women and mothers living with HIV, must be engaged and listened to, as we know the ground realities in the communities we live and work in.