Journal of Psychiatric Research 47 (2013) 1080e1087

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Journal of Psychiatric Research

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Review

VEGF and depression: A comprehensive assessment of clinical data

Anne Clark-Raymond, Angelos Halaris*
Stritch School of Medicine, Loyola University Chicago, Loyola University Medical Center, USA

a r t i c l e i n f o a b s t r a c t

Article history: Vascular Endothelial Growth Factor (VEGF), initially identied as an angiogenic mitogen, is believed to
Received 14 January 2013 play a role in hippocampal neurogenesis and response to stress. It exerts neuroprotective effects and
Received in revised form inuences synaptic transmission. The possible role of VEGF in depression has been hypothesized in the
4 April 2013
context of the neurotrophic model of depression, which postulates that stress can lead to decreased level
Accepted 11 April 2013
of neurotrophins. Since VEGF has emerged as a potential component in the pathophysiology of stress and
stress-related disorders, animal and clinical studies have attempted to delineate its precise role. In this
Keywords:
review article we provide a synopsis of basic studies that are of direct relevance to the clinical ndings in
Depression
VEGF
depression and antidepressant drug action. We have classied the studies on the basis of higher, lower or
Neurogenesis no different levels of VEGF as compared to control subjects. It became evident that there is conicting
Antidepressants data regarding VEGF levels in depressed patients. The fact that no denitive trend is apparent in the
published data is likely attributable to differences in study designs. However, promising leads have
emerged in our effort to understand and clarify this wide variation in results. Further study could
establish the potential use of VEGF as a biomarker to aid in making a correct diagnosis and a successful
treatment plan. Delineating the relationship of VEGF and depression ultimately has the potential to shed
light on the still elusive neural mechanisms underlying the pathophysiology of depression and the
mechanisms by which antidepressants exert their effects.
2013 Elsevier Ltd. All rights reserved.

1. Introduction antidepressants. Furthermore, given the dual role of VEGF in endo-

Vascular endothelial growth factor (VEGF) has in recent years
been the subject of psychiatric research with special emphasis on
Major Depressive Disorder (MDD) as a prime example of stress-
related disorder. VEGF may play a key role in mediating and/or pre-
dicting successful response to antidepressant treatment. VEGF was
originally described in 1989 by Leung et al. as an angiogenic mitogen,
and has since been extensively characterized as such. However, VEGF
is widely expressed, and recently much work has attempted to
characterize the role of VEGF in the brain. VEGF has been demon-
strated to play a role in hippocampal neurogenesis (Jin et al., 2002)
and response to stress (Heine et al., 2005), as well as in exerting
neuroprotective effects (Storkebaum et al., 2004) and inuencing
synaptic transmission (McCloskey et al., 2005). Additionally, its role
in synaptic plasticity involves hippocampus-dependent processes,
such as learning and memory (Cao et al., 2004).
The neurogenic role of VEGF is potentially critical in the
pathogenesis of MDD and in the efcacy of treatment with
* Corresponding author.
E-mail address: ahalaris@lumc.edu (A. Halaris).
thelial as well as neurological processes, VEGF may serve as a critical
link underlying the high co-morbidity of cardiovascular disease and
depression (Warner-Schmidt and Duman, 2008; Dome et al., 2009).
The role of VEGF in depression has been hypothesized under the
neurotrophic model of depression, which is based on the nding
that stress can cause a decreased level of neurotrophins, such as
Brain-derived Neurotophic Factor (BDNF) and VEGF. The model
suggests that this decline in neurotrophins may cause atrophy of
some limbic structures that control mood, resulting in symptoms of
depression, and that antidepressant treatment can reverse this
atrophy and restore physiological levels of neurotrophins (Duman
and Monteggia, 2006). However, this model has not been consis-
tently established to describe VEGF in clinical data of depression.
While this review will briey highlight a few of the most
inuential pre-clinical ndings on the topic, the primary focus will
be a critical assessment of the available clinical data pertaining to
VEGF and depression. The data amassed thus far has been contro-
versial. Four studies have found an increase in VEGF levels in
depressed patients compared to healthy controls. On the other
hand, three different studies have found no change in VEGF levels,
and one has demonstrated a decrease. In addition, while two
studies imply an increase in VEGF levels in depressed patients

0022-3956/$ e see front matter 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.jpsychires.2013.04.008
 A. Clark-Raymond, A. Halaris / Journal of Psychiatric Research 47 (2013) 1080e1087
following antidepressant treatment, three other studies have found
no change.
Differences in study designs and the numerous confounding
factors in patients medical histories and types of depression, length
of episodes and previous antidepressant drug exposures make
drawing denitive conclusions difcult. Yet the potential to harness
VEGF as a biomarker in depression remains great. Furthermore,
elucidation of the precise role of VEGF in depression may lead to a
better understanding of the pathophysiology of the disorder and
the mechanism of antidepressant drug action, and enhance our
ability to predict response to treatment.
2. Relevant pre-clinical data
An inuential early study addressing the role of angiogenic
factors and neurogenesis was performed by Palmer et al. (2000).
This study established that hippocampal neurogenesis occurs
within a vascular niche in the subgranular zone (SGZ) of the hip-
pocampus. Neurogenesis was found to occur in a cluster of cells that
includes neural progenitors, committed neuroblasts, glia, and
endothelial precursors; these proliferative clusters are themselves
located near capillaries.
Based on their ndings of an anatomic co-localization, Palmer
and colleagues postulated an intrinsic link between angiogenesis
and neurogenesis. A subsequent study by Jin et al. (2002) has
established that VEGF, mediated through the receptor VEGFR2/Flk-
1, is necessary for hippocampal neurogenesis in both in vitro and
in vivo studies using rat hippocampal tissue, thereby supporting
Palmers hypothesis.
It is well established that antidepressants induce hippocampal
cell proliferation and neurogenesis, and that this action very likely
contributes to the action of these drugs (Madsen et al., 2000;
Malberg et al., 2000; Kotama et al., 2004; Warner-Schmidt and
Duman, 2007). Importantly, this nding has also recently been
conrmed in humans: more neuronal precursor cells were found in
a post-mortem analysis of the dentate gyrus of MDD patients
treated with Selective Serotonin Reuptake Inhibitors (SSRIs) vs.
both control patients and untreated MDD patients (Boldrini et al.,
2012). Given the established link between VEGF and neuro-
genesis, a logical next step was to investigate the possible role of
VEGF in mediating antidepressant response.
In their elegant study, Warner-Schmidt and Duman (2007)
established that VEGF is a critical component of the neurogenic
action of antidepressants. Upon treatment with any of three
different antidepressant treatments (electroconvulsive seizure,
uoxetine, desipramine), the mRNA and protein levels of VEGF, in
addition to the proliferation of both neural and endothelial pro-
genitors in the SGZ, increased at time points consistent with the
action of these treatments (72 h for ECS, and 14 days for uoxetine
and desipramine). Furthermore, this proliferation could be thwar-
ted with an Flk-1 inhibitor. These investigators also demonstrated
the role VEGF plays in the behavioral effects of antidepressants.
Chronic treatment with desipramine induced a reversal of two
animal models of depression, novelty suppressed feeding and
chronic unpredictable stress, while administration of an Flk-1 in-
hibitor completely blocked this response. A similar result was
found when the learned helplessness and forced swim test models
were employed at a subchronic level of antidepressant treatment.
The experiments reported by Warner-Schmidt and collaborators
also support VEGF as a potential therapeutic target. Three-day
continuous infusions of VEGF produced results similar to those
obtained with desipramine treatment in the learned helplessness
and forced swim test models, thereby conrming that VEGF mimics
the action of an antidepressant. This study thus establishes VEGF to
be both necessary and sufcient for behavioral response in an
1081
antidepressant model, and identies VEGF signaling as a novel
target of antidepressants action.
Related pre-clinical studies have shown that other antidepres-
sants, as well as other psychotropic medications, can also produce
neurogenic effects. An increase in neurogenesis was previously
demonstrated upon treatment with the antidepressants, rebox-
etine and tranylcypromine (Malberg et al., 2000). Treatment with
the atypical antipsychotic drug, olanzapine, which can augment
antidepressant response in treatment-resistant depressed patients,
has been shown to increase neurogenesis as much as uoxetine
(Kotama et al., 2004).
Interestingly, VEGF has also been found to be a necessary
component for successful antidepressant response to lamotrigine,
an anti-convulsant and mood stabilizer (Sun et al., 2012). However,
neurogenesis was not seen upon chronic treatment with the typical
antipsychotic, haloperidol (Malberg et al., 2000) and opiates, in fact,
inhibited neurogenesis (Eisch et al., 2000). This may indicate that
the neurogenic effects seen in these studies are somehow specic
to relief from symptoms of depression.
Despite all that has been established regarding the role of VEGF
in neurogenesis and in mediating antidepressant effects, many
details remain to be elucidated. According to Warner-Schmidt and
Duman (2008), the ways in which VEGF could mediate the patho-
physiology of depression are numerous: neurogenesis, neuronal
cell survival, synaptic plasticity and/or antidepressant-induced in-
creases of endothelial cell number and function.
Since VEGF is implicated in a variety of disease entities of both
psychiatric and non-psychiatric etiologies, it will be important to
identify the brain regions and cell types that specically mediate
the antidepressant actions of VEGF. For instance, the source of the
measured VEGF in the studies cited above (endothelial, neural,
peripheral, or a combination thereof) is still unknown. Further-
more, Elfving et al. (2010) found lower hippocampal protein levels
of VEGF in a rat model of depression compared to healthy rats;
however, these authors found no difference in VEGF serum levels,
implying that peripheral levels of VEGF may not reect actual levels
in the CNS.
The action of VEGF in neurogenesis is direct, namely mitogenic
affecting neural progenitors directly, as well as indirect by inu-
encing endothelial cells, which in turn affect neurons. In a third
role, the action of VEGF on neurons has been shown to affect
endothelial cells. Much work has been accomplished establishing
the role of VEGF in neurogenesis, as well as the role of neurogenesis
in the treatment of depression. Hanson et al. (2011), Duric and
Duman (2013) and Nowacka and Obuchowicz (2012) have pro-
vided excellent and thorough reviews of in vitro and pre-clinical
animal studies on these topics.
In spite of a signicant body of preclinical knowledge about
VEGF, the clinical data has not yet established a clear trend. The
following section of this paper will provide a review of clinical
ndings to date and will attempt to reconcile the reported
controversial ndings.
3. Clinical data
In this section of this review article we will examine clinical
studies of VEGF in depressed individuals, and subdivide the studies
on the basis of higher or lower or no different levels of VEGF as
compared to control subjects. An overview and summary of these
studies is provided in Table 1.
3.1. VEGF levels are higher in depressed patients vs. control subjects
The study by Iga et al. (2007) expanded the eld of VEGF/
depression research to include human subjects. The study
1082 A. Clark-Raymond, A. Halaris / Journal of Psychiatric Research 47 (2013) 1080e1087

Table 1
Summary of clinical studies.

Patient population Number pts Measurement VEGF in depressed vs. Tx administered Effect of tx on VEGF
control

Iga MDD 32 mRNA Higher Paroxetine No change

Kahl MDD BPD 12 Serum Higher N/A N/A
Takebyashi MDD in remission 16 Plasma Higher N/A N/A
Lee and Kim MDD, Bipolar I 35 each Plasma Higher N/A N/A
Ventriglia MDD 24 Serum No change Escitalopram No change
Dome 09 MDD 33 Plasma No change N/A N/A
Kotan MDD w/melancholic features 40 Plasma No change N/A N/A
Dome 09 MDD 24 mRNA Decreased N/A N/A
Isung Suicide attemptors 58 Serum Decreased in N/A N/A
completed suicide
Dome 12 MDD 24 Plasma? N/A Various No change
Minelli MDD, tx resistant 19 Serum N/A ECT Increased
a
Ibrahim MDD 11 Plasma N/A Sleep deprivation

N/A Not applicable or not available.

a
Inverse correlation of VEGF levels and improvement in depression severity, thus implying an increase in VEGF levels following treatment.

represents an important step forward in evaluating VEGF levels as
they relate to MDD and antidepressant treatment. However, while
many ndings reached statistical signicance, their results have not
been replicated by all subsequent studies. This study was the rst of
many to begin to mount controversial evidence regarding the role
of VEGF in MDD. Based on previous ndings that VEGF mRNA levels
in peripheral leukocytes were found to be elevated in Alzheimers
disease patients, this seemed to be a suitable method to employ in
evaluating MDD patients. Peripheral leukocyte VEGF mRNA levels
were measured in 32 MDD patients and in 32 healthy controls
matched for age and sex with the patients. All patients were
treatment nave, and the majority were in their rst depressive
episode. Depression was assessed based on responses to the
Structured Interview Guide for the 17-item Hamilton Depression
Rating Scale (SIGH-D 17).
These investigators found VEGF mRNA levels to be signicantly
elevated at baseline in patients vs. controls (control 0.92
0.21;
baseline rst-episode patients 1.23
0.5; p 0.023). There was a
trend, though not statistically signicant, for VEGF levels to be
higher in the rst episode than in recurrent episodes (0.99
0.29 in
9 recurrent episode patients, p 0.077). No correlation was found
between VEGF levels and age, sex, leukocyte count, or baseline
depression severity.
While the difference in VEGF levels between baseline patients
and controls is technically signicant, the data sets for both groups
have large overlapping error bars. Additionally, there is such a small
absolute difference between the mean VEGF mRNA values between
the groups that any potential clinical signicance of these ndings
is doubtful.
The study by Kahl et al. (2009) demonstrated results similar to
those of Iga et al. Kahl et al. found an increase in serum VEGF levels
in 12 treatment-free female patients with a major depressive
episode in the context of borderline personality disorder (MDD/
BPD), compared to 12 healthy women. VEGF levels were measured
at T0, T 120 min and T 240 min following the rst serum
sampling to increase the validity of the experiment, and account for
possible diurnal changes in VEGF levels. VEGF levels at both T0 and
T 120 were signicantly higher in depressed patients than in
controls (T0 control 283
154 pg/ml, MDD/BPD 567
389 pg/ml,
p < 0.05; T 120 control 267
148 pg/ml, MDD/BPD 502
332 pg/
ml, p < 0.05; T 240 control 254
146 pg/ml, MDD/BPD
475
342 pg/ml; p NS). A signicant direct correlation was found
between VEGF levels and the Beck Depression Inventory (BDI)
scores. No correlation of these results was found with age or BMI.
While VEGF values at T0 and T 120 were higher in patients than
in controls, Kahl et al. were unable to account for the observation
that VEGF values in both controls and patients decreased at the time
points following T0. They speculated that this may be due to diurnal
changes in VEGF levels, or to effects of blood sampling. Furthermore,
it is puzzling that Kahl et al. found a direct correlation of VEGF levels
and depression severity, whereas other studies that did nd a cor-
relation, found an inverse one. However, this study employed a very
small sample size. In addition, while the patients in this study were
in a depressive episode, there may be differences in the patho-
physiology between MDD and BPD that would potentially confound
generalizing results in either of these disease entities.
The study by Takebyashi et al. (2010) demonstrated a signicant
increase in plasma VEGF levels in depressed patients in remission
compared to matched, healthy controls (78.4
55.6 pg/ml vs.
39.0
26.9 pg/ml, respectively; p < 0.05). This study is also the rst
to correlate VEGF levels and family history of psychiatric disorders,
demonstrating a signicant increase in VEGF levels in depressed
patients with family history compared to those with no family
history. The VEGF levels of those without family history were not
signicantly different from those of controls. Unfortunately, the
design of this study limits wider applicability of the reported re-
sults. The investigators evaluated only 16 patients with MDD under
partial or full remission. In addition, patients were currently taking
a wide variety of antidepressants and mood stabilizers: paroxetine,
uvoxamine, amoxapine, sulpiride, trazodone, milnacipran, imip-
ramine, clomipramine, amitriptyline, and lithium. All patients were
ostensibly taking equivalent doses, equivalent to 150 mg of imip-
ramine for each antidepressant. The mean age of the patients was
also ten or more years older than that of patients in the studies
cited above. Takebyashi et al. found no correlation of their results
with age, gender, age of onset of depression, length of period of
morbidity, or antidepressant dose.
Lastly, Lee and Kim (2012) also found increased VEGF levels in
depressed patients. They evaluated plasma VEGF levels of 35 MDD
patients currently in a depressive episode, 35 bipolar I patients with
a most recent manic episode (BM) and 60 healthy controls. Patients
were either treatment nave or were medication-free for at least
four weeks prior to beginning the study. Approximately half of the
MDD patients were in a recurrent episode; the remaining were in a
rst episode. Plasma VEGF levels in each cohort were: MDD:
163.28
135.33 pg/ml; BM: 199.82
182.59 pg/ml; control:
110.05
109.57 pg/ml. MDD patients had signicantly higher VEGF
levels than controls (p 0.023), as did BM patients (p 0.018).
VEGF levels were not different in MDD vs. BM patients. There was
no correlation of the results with age or depression severity. BMI
was, however, a signicant covariate, but the results held true when
it was controlled for.
 A. Clark-Raymond, A. Halaris / Journal of Psychiatric Research 47 (2013) 1080e1087
3.2. VEGF levels are similar in depressed patients and healthy
controls
In contrast to the above results, Ventriglia et al. (2009) found no
difference in VEGF serum levels in depressed patients. They
assessed 24 MDD patients, the majority of whom had had
prior antidepressant treatment, who were matched with 24
healthy controls for age, sex, BMI, and smoking status. They found
no difference in serum VEGF levels compared to healthy controls
(patients: 403.8
243.4 pg/ml, controls: 405.0
215.6 pg/ml,
p 0.984), even after accounting for confounding factors, gender
(p 0.004) and smoking habits (p 0.005). Age and BMI did not
confound the results.
Dome et al. (2009) included 33 patients with a current episode
of MDD and 16 healthy controls matched for age, gender and
smoking status. Patients were currently taking a variety of psy-
chotropic medications: anxiolytics, second-generation antipsy-
chotics, mood stabilizers, hypnotics, SSRIs, SNRIs, and other
antidepressants. According to Dome et al., none of these medica-
tions have known effects on EPC levels, an assertion that may
require further verication in future studies. With respect to
plasma protein levels of VEGF, their results are similar to those of
Ventriglia et al. in that they found no signicant difference between
MDD patients and controls (patients 19.37
3.83 pg/ml; controls
17.35
3.82 pg/ml; p 0.1).
Kotan et al. (2012) likewise found no difference in VEGF levels in
depressed patients. These authors evaluated 40 MDD patients with
melancholic features and 40 matched controls. The patients had
been drug-free for at least three months: 35% of patients had their
rst depressive episode and never used antidepressants while 50%
had their second, and 15% had their third depressive episode.
Plasma VEGF levels were not found to be signicantly different
between the two groups (patients 300
158 pg/ml, controls
358
217 pg/ml; p > 0.05). These results did not correlate with sex,
age, or BMI. A decline in VEGF levels did, however, correlate to
severity of depression: VEGF levels were negatively correlated with
HDRS scores (p 0.043) in the patient group.
3.3. VEGF levels are decreased in depressed patients vs. healthy
controls
Assessments of plasma VEGF levels in the 2009 study by Dome
et al. paralleled the results of the previous work of Ventriglia et al.
and the subsequent study by Kotan et al. Domes assessment of
VEGF mRNA levels, however, contradicted the results of Iga et al. In
contrast to Iga et al., who demonstrated an increase, VEGF mRNA
levels were found to be signicantly decreased in MDD patients
(P < 0.01). Dome also found VEGF mRNA levels to be signicantly
but inversely correlated with BDI scores (p < 0.01). VEGF mRNA
levels were not found to correlate with smoking status.
A fascinating clinical study by Isung et al. (2011) takes the study
of VEGF levels in depression in a different direction. Isung et al.
investigated serum VEGF levels as they relate to suicide attempts
and completion by comparing levels between surviving suicide
attempters and suicide victims. They found low VEGF levels to be
a signicant predictor for suicide (p 0.045). Their study evalu-
ated 58 suicide attempters using the Montgomery-Asberg
Depression Rating Scale (MADRS) and the Suicide Intent Scale
(SIS). All patients were followed up for cause of death. Signicantly
lower levels of VEGF were found in the seven patients who after a
mean follow-up of 13 years had completed suicide (suicide
attempters 24.9
19.5 pg/ml, suicide victims 14.58
6.03 pg/ml;
p 0.033). VEGF also showed a trend for negative correlation with
the planning subscale of SIS; the suicide attempters with the lowest
levels of VEGF had made more planned suicide attempts.
1083
This study found no signicant effect of severity of depression
(MADRS score), co-morbid diagnosis of personality disorder or
substance abuse diagnosis on cytokine levels in the suicide
attempters. In addition, the low levels of VEGF in suicide victims
remained signicant even after controlling for age, sex and BMI.
Interestingly, the data also showed a trend for lower IL-2 and for
higher IFNG levels in suicide victims, strongly implicating a role for
inammatory biomarkers in suicide risk.
4. Effects of antidepressant treatment on VEGF levels
4.1. VEGF levels do not change upon antidepressant treatment
While Iga et al. did nd an increase in VEGF mRNA levels in
depressed patients vs. controls, in the same study they found no
difference in VEGF levels following antidepressant treatment. Pa-
tients were given paroxetine in doses up to 60 mg (mean dose
31.0
9.1 mg/day for 8 weeks). Twenty four of the initial 32 MDD
patients completed eight weeks of paroxetine treatment. Following
the eight weeks of treatment, the patients saw a signicant
improvement in depressive symptoms (SIGH-D scores at baseline
and 8-week, 20.8
7.2 and 7.8
6.5, respectively; P < 0.001).
However, no signicant change in VEGF levels was seen
following treatment (1.37
0.49 at baseline; 1.34
0.69 at 8-week;
p 0.763). No signicant correlation was found between VEGF
mRNA levels at baseline and at eight weeks of treatment with
paroxetine (p 0.466). This result did not correlate with paroxetine
concentrations or leukocyte count.
By contrast, Iga et al. did nd a signicant correlation between a
decline in VEGF mRNA levels with paroxetine treatment and a
decrease in SIGH-D scores (Pearson correlation r 0.41 P 0.049).
However, the correlation is evidently low. Furthermore, it calls into
question the signicance of the correlation of VEGF levels with
SIGH-D scores after treatment when the VEGF levels themselves
did not signicantly change with treatment. Iga et al. surmise that
the lack of change in VEGF mRNA levels in MDD patients e even
upon antidepressant treatment and even when treatment is suc-
cessful in alleviating symptoms e may, in fact, underlie the known
co-morbidity of depression and cardiovascular disease. The high
VEGF level in depressed patients may pre-dispose them to car-
diovascular disease. This is an intriguing proposition that merits
further study.
In their 2009 study, Ventriglia et al. not only found no change in
depressed patients vs. healthy controls, but also no change in VEGF
levels after eight or twelve weeks of escitalopram treatment.
Treatment with escitalopram was effective, based on HDRS scores
(at T0 19.68
2.76; at T8 10.44
6.31; at T12 6.68
3.73;
p < 0.001). However, no change in VEGF levels was found after
treatment (at T0 403.8
243.4 pg/ml, at T8 409.0
273.7 pg/
ml, at T12 426.3
262.8 pg/ml; p 0.383).
In their study Ventriglia et al. stratied their patient cohort into
responders (>50% reduction in HDRS) and non-responders. Thir-
teen of the 24 patients were classied as responders to treatment at
eight weeks; 18 were responders at 12 weeks. Even when evalu-
ating VEGF levels only among responders, no difference was
found over the course of treatment (for the responders, serum
VEGF at T0 367.2
234.2 pg/ml, at T8 344.5
221.3, at
T12 377.8
255.2; p 0.274; for the non-responders, serum
VEGF at T0 400.26
252.7 pg/ml, at T8 396.5
265.9 pg/ml, at
T12 413.3
258.3 pg/ml; p 0.601). Furthermore, no correlation
was seen between a change in VEGF levels and an improvement in
depressive symptoms.
Another study by Dome et al. (2012) also detected no change in
VEGF levels following antidepressant treatment. This study
enrolled 24 MDD patients who were treatment-free at the
1084 A. Clark-Raymond, A. Halaris / Journal of Psychiatric Research 47 (2013) 1080e1087
beginning of the study; patients were then individually placed on
different antidepressants that were not specied in the paper. Pa-
tients were also taking a variety of other psychotropic medications,
similar to the Dome et al. previous study. After 30 days of antide-
pressant treatment, VEGF levels did not signicantly change (T 0
68.5
55.7 pg/ml, T 30 days 79.6
66.8 pg/ml; p 0.123),
despite signicant improvements in depressive symptoms (>50%
change in MADRS score, p < 0.001).
4.2. VEGF levels increase upon antidepressant treatment
In contrast to the above studies, a study by Minelli et al. (2011)
found a signicant increase in serum VEGF levels following anti-
depressant treatment, specically, ECT. VEGF serum levels of 19
treatment-resistant depressed patients were assessed before
treatment (T0), the day after the end of ECT (T1) and one month
after the end of ECT (T2). ECT treatment improved depression
symptoms as assessed by MADRS scores (p < 0.0001). No changes
occurred in serum VEGF between T0 and T1, but a signicant in-
crease was observed between T0 and T2 (p 0.042). Furthermore,
Minelli et al. observed a signicant correlation between the VEGF
increase at T2 and the reduction in MADRS scores (p 0.049,
r 0.047).
Importantly, these investigators found no correlation of VEGF
levels at baseline with age, gender, smoking, BMI, or depression
severity. No correlation of VEGF levels at baseline, change in VEGF
levels upon ECT, or change in MADRS scores was found with con-
current use of psychiatric medications including antidepressants
and antipsychotics during ECT treatment or presence of psychotic
symptoms. A trend toward a correlation was seen between baseline
VEGF and change in MADRS scores upon treatment (p 0.053
r 0.45).
The ndings from the pilot study by Ibrahim et al. (2011) parallel
the effects reported by Minelli et al. While Ibrahim et al. did not
report a signicant increase in VEGF levels following antidepres-
sant treatment, they did demonstrate an inverse correlation of
VEGF levels and improvement in depression severity, thus implying
an increase in VEGF levels following treatment.
The antidepressant treatment employed was sleep deprivation
(SD), a method shown to produce a rapid antidepressant response,
typically within a day, in many patients with MDD. Following a
wash-out of all psychotropic medications, 11 MDD patients un-
derwent total SD for 39 h. The patients were largely experiencing a
recurrent episode. The current episode was, on average, almost a
year in length, and patients were only included in the study if
HAMD scores at the time of screening were greater or equal to 18.
Depression was evaluated in both the morning and evening of
days 1 and 2 of SD using HAMD-6 scores, which it decreased
signicantly after SD. A negative correlation was found between
change in VEGF levels and change in morning HAMD-6 scores
(r 0.64; p 0.047), indicating that as depression scores
decreased following SD, VEGF plasma levels increased.
In spite of the fact that a correlation can be made, taken
together, this data seems inconclusive. Among the 11 patients, six
had an increase in VEGF levels upon SD, while ve actually had a
decrease or no change. However, since this is a preliminary study,
more data must be collected before an accurate assessment of the
effect of SD on VEGF levels can be made.
5. Discussion
The discrepancies among the above referenced studies raise
questions about the true meaning of peripheral measures of VEGF
as they may or may not relate to the pathophysiology and treat-
ment of MDD patients. The clinical studies discussed in this article
span work from 2006 through the current year. At this point a clear
trend has not emerged, and the most recent studies discussed here
only add to the controversy of earlier results.
Before any denitive conclusions can be drawn from the re-
ported studies, major differences in experimental design which
differs widely between studies, must be taken into consideration.
First of all, it is impossible to truly compare results among studies,
as the method of measurement of VEGF e mRNA, serum, or plasma
e was not consistent across studies. Blood levels and mRNA and do
not necessarily correlate, nor do they represent the same cellular
events. Furthermore, differences may exist when comparing serum
and plasma levels of VEGF; this difference may reect the contri-
bution of platelet concentrations of VEGF. Importantly, Ventriglia
et al. found a signicant correlation between VEGF serum levels in
the patient group and blood platelet count (r 0.542; p 0.005).
When comparing the actual VEGF concentrations measured
in the various studies, there appears to be a range of values.
Serum measurements of VEGF in healthy control subjects are fairly
uniform, ranging from approximately 283.0
154 pg/ml to
405.0
215.6 pg/ml; however, there appears to be a wider range
among plasma measurements, ranging from 17.35
3.82 pg/ml to
110.05
109.57 pg/ml in healthy controls. Likewise values vary
among the different cohorts of patients. In addition, Kahl et al.
found a signicant variation in VEGF serum levels at different times
of the day. By contrast, Iga reported no difference. Thus, there is a
potential for a variation in VEGF levels based on time of day and
sampling procedure that may confound results.
Interestingly, the clinical results from studies that employed
non-pharmacologic antidepressant treatments mirror the results of
pre-clinical studies, whereas all studies to date employing chemical
antidepressants contradict the pre-clinical data. This observation
implies that pharmacologic agents act more complexly in humans
than in animals compared to non-chemical treatments such as ECT.
Additionally, it cannot be ruled out that the discrepancy is due to
differences in protocol between animal and human studies. It
should always be kept in mind that animal models of depression are
just models, and the human condition is far more complex geneti-
cally and pathophysiologically than any animal model can simulate.
Furthermore, the antidepressants used in the clinical studies were
not the same ones as were used in the pre-clinical studies. Thus it
cannot be ruled out denitely that the discrepancy is due to dif-
ferences in the pharmacodynamic proles among the antidepres-
sants studied that may differentially affect VEGF levels.
Furthermore, the cohorts in the Dome and Takebyashi studies
were not only treated with antidepressants, but with other psy-
chotropic drugs as well. It must be acknowledged that there may be
unknown and unpredictable effects of the different chemical anti-
depressants on VEGF levels in clinical studies, even when
comparing different SSRIs, let alone other psychotropic medica-
tions. Clearly, these controversial ndings will require clarication
in future studies of peripheral measures of VEGF in psychiatric
populations.
The exclusion criteria utilized in all of the above studies
included some of the same basic items, namely, excluding subjects
with existing medical problems, pregnancy, etc., and matched
control subjects were meticulously screened. Nevertheless, it is to
be expected that different patient cohorts will vary to a greater or
lesser degree in terms of age, gender, BMI, ethnicity, smoking and
drinking habits. A few studies did nd some of these confounding
factors to signicantly affect VEGF values. Given the wide array of
roles VEGF plays as both a vascular factor and neurotrophin, it is
logical to anticipate that such parameters would signicantly affect
VEGF levels.
There are a host of other factors, however, that must be assessed
in studies investigating psychiatric illnesses that are often difcult
 A. Clark-Raymond, A. Halaris / Journal of Psychiatric Research 47 (2013) 1080e1087
and time-consuming to ascertain from patients, and even more
difcult to quantify and standardize in order to allow for mean-
ingful comparisons between studies. Some of these include the
assessment of the severity of depression, previous use of psycho-
tropic medication, concurrent use of other psychotropic medica-
tions, age of onset of disease, number of previous episodes of
depression, length of the current depressive episode, co-morbid
psychiatric diagnoses or psychotic features, suicidality, and family
history of depression, bipolar disorder, or other psychiatric ill-
nesses. These factors though, must not be assessed only as potential
confounders of the data. More importantly, a thorough assessment
of such factors and their effects on VEGF expression and periph-
erally measured levels may aid in understanding the precise
contribution of VEGF regulation to the underlying pathophysiology
of depression and response to antidepressant treatments.
Based on the eleven clinical studies published to date, the effect
of depression as well as antidepressant treatment on VEGF levels is
unclear. Results differ even when comparing apples to apples, so
to speak: for instance, the results of Kotan and Lee and Kim differ
even though both studies included a sizable number of medication-
free, currently depressed cohorts of MDD patients, the majority of
whom were in recurrent episodes.
Thus a denitive link between the actions of antidepressants
and VEGF has yet to be elucidated, but likely this link relates to their
established roles in neurogenesis. A neurotrophic model of
depression implicates a stress-induced decline in neurotrophins,
such as VEGF, and in the atrophy of limbic structures, which ulti-
mately results in a mood disorder (Duman and Monteggia, 2006).
Indeed Heine et al. (2005) demonstrated that rats exposed to
chronic unpredictable stress had lower hippocampal protein levels
of VEGF than healthy control rats.
With respect to the neurotrophic model of depression, the
clinical evidence to date does not unequivocally support such a
model. The model also stipulates that antidepressant treatment
would reverse the expected effect of stress, i.e. reverse the decline
of VEGF levels. Yet this nding, while well-documented in pre-
clinical studies, has not been replicated in clinical data. Given this
discrepancy, we therefore propose an alternate explanation. We
speculate that, as Lee and Kim hypothesized, the higher levels of
VEGF seen in depressed patients in several studies may indicate an
attempted neuroprotective effect by specic brain structures in
response to the perceived stress leading to and associated with the
illness of depression. This neuroprotective potential may be
conferred by a higher VEGF level, or may be a result of it.
Furthermore, we propose that VEGF levels may in fact be
decreased in patients whose depression is not relieved by antide-
pressant treatment. This may indicate an inability of the brain to
undergo neurogenesis, a process that seems to be required for the
successful action of antidepressants. We could potentially interpret
the ndings of Isung et al. to support this theory, if the patients
suicidality were to indicate a long-term, non-remitting depression.
However, only one study discussed here (Ventriglia) actually
assessed a potential difference in VEGF levels in patients who did
not respond to antidepressant treatment vs. those who remit;
however, no difference was found between the two groups. In order
to truly explore the clinical potential of VEGF, more data must be
collected that specically assesses VEGF levels in patients unre-
sponsive to treatment.
Following our hypothesis of low VEGF levels in patients unre-
sponsive to treatment, it is possible that such patients VEGF levels
are so low that they, in fact, mimic healthy controls. Therefore, no
difference would be seen when comparing the VEGF levels of these
depressed patients to controls. This may account for the lack of
difference in the patients VEGF levels seen in some of the studies
discussed here. Additionally, if all patient baseline values are
1085
averaged without regard to treatment outcome, the average is
skewed and falsely presents lack of difference between depressed
patients and healthy control subjects.
We further postulate that factors such as depression severity,
previous psychotropic medication use, previous episodes of
depression, length of the current depressive episode, and family
history of depression and other psychiatric conditions have the
potential to inuence the neuronal environment and the potential
for neurogenesis, thus affecting patients VEGF levels measured at
study time. If a higher level of VEGF in depressed patients would
indicate an attempted neuroprotective effect to counteract the
stress of depression, then we would hypothesize that VEGF values
would be skewed in the direction of an increase if patients were
severely depressed, in longer, recurrent episodes, had previously
used medication, and had a family history of mental illness.
Supportive evidence for this contention can be found in the
study by Takebyashi et al. who found a signicant increase in VEGF
levels in depressed patients with a family history compared to
those with no family history. Other factors, however, were found to
be signicant, but not necessarily in the way we would predict. Iga
et al. found a trend (although it was not statistically signicant)
toward lower VEGF levels in the small number of patients in a
recurrent episode that the study included, compared to patients in
a rst episode. Furthermore, Dome et al. (2009), Kotan, Iga, Minelli,
and Ibrahim all found an inverse correlation of VEGF levels and
severity of depression (for some of these, following antidepressant
treatment), indicating a lower VEGF level in a more severely
depressed patient. We would want to ascertain the number of
patients in these studies who were treatment-resistant, which
according to our hypothesis, may account for the lower VEGF
levels.
Another factor potentially contributing to contradictory results
may be genetic polymorphisms of the VEGF gene (VEGFA) in the
study populations. A recent study by Viiki et al. (2010) found the
VEGF 2578 C/A polymorphism to be associated with occurrence of
treatment-resistant depression. However, the polymorphism did
not correlate to response to ECT or SSRIs. A study by Tsai et al.
(2009) likewise found no association of VEGF genetic poly-
morphisms and response to SSRIs.
Viiki et al. also found a trend correlation of the polymorphism
and MDD vs. healthy controls, but this nding did not reach sta-
tistical signicance. Similarly, a study by Iga et al. (2007) failed to
detect an association between MDD and the studied polymorphism
in a Japanese population. Admittedly, it is difcult to compare these
three studies, as the cohorts are of different ethnicities, a factor
which may largely inuence genetic polymorphisms. Thus, while
there is a possibility that VEGF genetic polymorphisms contribute
to pharmacologic treatment resistance, such a correlation has not
yet been found with treatment response.
Another potentially confounding factor is the varying diagnoses
of some patient cohorts studied (i.e. MDD, MDD with melancholic
features, bipolar disorder, borderline personality disorder), as un-
derlying differences in the pathophysiology of these diagnostic
entities may be inuencing the results. It is interesting to note,
however, that Lee and Kim found that both MDD and BM patients
had higher VEGF levels than healthy controls, but no signicant
difference was seen between MDD and BM patients.
At this point, it is not known what effects the different diag-
nostic entities and endophenotypes of depression may have on
VEGF values. VEGF values have also been assessed in autism and
schizophrenia. Emanuele et al. (2010) found lower serum VEGF
levels in patients with severe autism compared to controls. Fulzele
and Pillai (2009) found lower VEGF mRNA levels in the pre-frontal
cortex of schizophrenic patients. Interestingly, these ndings
represent the opposite result of patients with depression in many
1086 A. Clark-Raymond, A. Halaris / Journal of Psychiatric Research 47 (2013) 1080e1087
studies discussed here, which demonstrate an increase in VEGF
levels in depressed patients vs. controls.
In this context, Domenici et al. (2010) conducted a study to
identify candidate biomarker signatures for depression and
schizophrenia, potentially ones distinguishing the two disorders.
VEGF, however, was not identied among the signicant bio-
markers for depression or schizophrenia in an immunoassay sam-
pling of a large case-control population.
In spite of the discrepant ndings and the design and diagnostic
issues discussed in this review, we believe there remains signicant
potential to utilize VEGF not solely as a biomarker of depression,
but also to distinguish between different psychiatric conditions or
even endophenotypes of depression. Schmidt et al. (2011) have
actually discussed this possibility. Since a plasma protein concen-
tration e such as VEGF e is by nature, not a binary quantity like the
presence or absence of an SNP, but rather a value that must be
evaluated on a continuum, the identication of value ranges of this
biomarker that would distinguish between very similar syndromes
would be a delicate task. Likely a panel of biomarkers, rather than a
single one, would be necessary in order to accomplish this goal.
The availability of such a biomarker, with established sensitivity
and specicity, would be an enormously useful clinical tool in
diagnosing not only different disorders, but even subtypes of a
heterogeneous psychiatric illness that displays similar phenotypes
in the clinical presentation. The availability of such a biomarker
tool would also lead to more precise and effective treatment
strategies.
6. Conclusion
VEGF has emerged as a potential component in the patho-
physiology of stress and stress-related disorders, notably depres-
sive illness. Animal and clinical studies have attempted to delineate
the precise role of this compound. As has become evident in this
review, there is conicting data regarding VEGF levels in depressed
patients vs. control subjects. The fact that no denitive trend is
apparent in the published data is a bit discouraging. However, the
reported variation in results may be likely due, at least in part, to
differences in study designs.
The reported studies provide useful leads for the design of
future studies. Consistency in choice of medium analyzed (serum
vs. plasma) and precise documentation of the patients personal
and family history of psychiatric illness, length and severity of
depression and treatment employed are some of the critical vari-
ables that must be taken into account in stratifying VEGF measures.
Additionally, more data is needed to denitively assess: (1) if there
is a difference in VEGF levels in un-medicated depressed patients
vs. controls, (2) if antidepressant treatment changes VEGF levels,
(3) the relationship between VEGF levels and response to antide-
pressant treatment, and (4) the mechanism of the interaction be-
tween VEGF and antidepressant function. VEGF could prove to be a
useful biomarker for identifying depression, understanding treat-
ment resistance, distinguishing endophenotypes of the disorder,
and even distinguishing depression from other mental illnesses.
Last but not least, VEGF levels could be used to predict response
to treatment. Further study could indicate the potential to use VEGF
as a biomarker to aid in making a correct diagnosis as well as a
successful treatment plan. Delineating the relationship of VEGF and
depression ultimately has the potential to shed light on the still
elusive neural mechanism underlying the pathophysiology of this
highly prevalent disorder, and the mechanism by which antide-
pressants exert their effects. The possibility to effectively utilize
known differences in biomarkers, such as VEGF, for early and ac-
curate diagnosis or to choose appropriate antidepressant treatment
e in essence, personalized psychiatry e is an exciting prospect.
Role of funding source
The authors were supported by their institution (Loyola Uni-
versity Chicago Stritch School of Medicine) during the time they
worked on the preparation of this manuscript.
Contributors
Anne Clark-Raymond, a medical student, and Angelos Halaris,
MD, PhD, Professor of Psychiatry, are the sole contributors to this
work.
Conict of interest
The authors have no conict of interest to report.
Acknowledgments
The authors have no acknowledgments to report.
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