Antidepressants Promote and Prevent Cancers

Abstract

The review states that antidepressants (ADs) increase brain-derived neurotrophic factor (BDNF) transmission concomitantly in the brain and the blood: ADs increasing BDNF synthesis in specific areas of the central nervous system (CNS) could presumably affect megakaryocyte's production of platelets. ADs increase BDNF levels in the CNS and improve mood. In the blood, ADs increase BDNF release from platelets. The hypothesis presented here is that the release of BDNF from platelets contributes to the ADs effects on neurogenesis and on tumor growth in the cancer disease. Oncological studies indicate that chemicals ADs exert an aggravating effect on the cancer disease, possibly by promoting proplatelets formation and enhancing BDNF release from platelets in the tumor.

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Cancer Investigation
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Antidepressants Promote and Prevent Cancers
Francis Lavergne & Therese M. Jay
To cite this article: Francis Lavergne & Therese M. Jay (2020): Antidepressants Promote and
Prevent Cancers, Cancer Investigation, DOI: 10.1080/07357907.2020.1817481
To link to this article: https://doi.org/10.1080/07357907.2020.1817481
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REVIEW
Antidepressants Promote and Prevent Cancers
Francis Lavergne
a
and Therese M. Jay
a,b
a
Physiopathologie des maladies Psychiatriques, Institut de Psychiatrie et Neurosciences de Paris, UMR_S 1266 INSERM, Paris, France;
b
Facult
edeM

edecine Paris Descartes, Universit
e Paris Descartes, Paris, France
ABSTRACT
The review states that antidepressants (ADs) increase brain-derived neurotrophic factor
(BDNF) transmission concomitantly in the brain and the blood: ADs increasing BDNF synthe-
sis in specific areas of the central nervous system (CNS) could presumably affect mega-
karyocyte’s production of platelets. ADs increase BDNF levels in the CNS and improve
mood. In the blood, ADs increase BDNF release from platelets. The hypothesis presented
here is that the release of BDNF from platelets contributes to the ADs effects on neurogen-
esis and on tumor growth in the cancer disease. Oncological studies indicate that chemicals
ADs exert an aggravating effect on the cancer disease, possibly by promoting proplatelets
formation and enhancing BDNF release from platelets in the tumor.
ARTICLE HISTORY
Received 18 October 2019
Accepted 26 August 2020
KEYWORDS
Antidepressant; brain-
derived neurotrophic factor;
cancer; megakaryo-
cyte; platelet
Introduction
BDNF is a powerful neurotrophin that commands
the cell’sfate:lifeordeath.TheproBDNF/BDNF
neurotrophin system commands pharmacological
cascades down to the cell’sDNAtodirectthecells
toward regression or progression.
We show in the review that all ADs types can
finally, increase BDNF transmission (BDNF syn-
thesis and release) in the brain, and in the blood.
In the blood, the increasing BDNF transmission
aggravates cancers (since BDNF is an oncogene)
and contributes to mood regulation. In the brain
ADs increase BDNF transmission in a mood
pathway involving the hypothalamus and the pre-
frontal cortex. BDNF is a transducer that turns a
pharmacological signal into biology: BDNF com-
mand synaptogenesis and could, by this way,
contribute to reverse the behavioral states of
stress and depression. Literature supporting this
understanding is presented under three main
topics: 1) In the CNS, all ADs types increase
BDNF transmission. 2) In the blood all ADs
types increase plasmatic BDNF either directly,
e.g., ketamine, physical exercise, chemical antide-
pressants or indirectly by increasing physical
exercise as a consequence of clinical remission.
3) ADs increases plasmatic BDNF via a megakar-
yocyte/platelets pathway that enhances neurogen-
esis and cancer’s growth.
All types of ADs increase BDNF transmission in
the CNS
ADs and BDNF activities in the CNS show that
ADs and BDNF have similar effects in experi-
mental models related to depression. All AD
treatments (Acute electroconvulsive seizure,
rTMS, physical exercises, sleep deprivation,
chemical antidepressants, NMDA antagonists, D1
agonist) increase BDNF protein in the mood
pathway of the CNS and reduce behavioral stress
and depression.
ADs are drugs having various mechanisms of
action involving different systems of neurotrans-
mission: noradrenaline, 5HT, dopamine.
However, interestingly enough, all ADs mecha-
nisms induce dopamine increase in the prefrontal
cortex (1). Dopamine promotes NMDA antagon-
ism and BDNF secretion (2–4).
BDNF is a potent neurotrophine that promotes
the equilibrium between cell’s life and death fate.
BDNF activates the TrkB receptor, signaling in
CONTACT Therese M. Jay therese.jay@inserm.fr Institut de Psychiatrie et Neurosciences de Paris, UMR_S 1266 INSERM, 102-108 Rue de la Sant
e,
Paris, 75014, France
ß2020 Taylor & Francis Group, LLC
CANCER INVESTIGATION
https://doi.org/10.1080/07357907.2020.1817481

direction of cells life. Pro-BDNF, the obligatory
precursor of BDNF, activates the p75NT receptor
signaling in direction of cell’s death. BDNF
neurotrophic effects are seen in all cells with
TrkB membrane receptors. BDNF protein exists
at very low levels in the neurons and at extremely
high concentration in blood platelets.
ADs and BDNF have similar effects in
experimental models related to depression
BDNF appears to share the effects of ADs: Schmidt
and Duman (5) demonstrated that exogenous
BDNF administration to mice presents all the
known effects of ADs, i.e., acute administration of
BDNF increases mobility in the forced swim test,
attenuates the effects of chronic unpredictable stress
on sucrose consumption, decreases latency in the
novelty-induced hypophagia test and increases time
spent in the open arms of an elevated-plus maze.
Chronic BDNF administration, enhances, in the rat
hippocampus, neurogenesis, cyclic-AMP response
element-binding protein (CREB) and the enzyme
protein endoplasmic reticulum kinase (pERK) (5).
BDNF induces all the AD’s effects on behavior,
neurogenesis and molecular signaling, i.e., BDNF
activates the DNA in the nucleus, toward cell’ssur-
vival and reproduction. Similarly, neurogenesis is
the final biological step induced by all ADs.
Accordingly, when neurogenesis is suppressed ADs
can no longer achieve remission (6). Most ADs are
also known to promote the activation of the
BDNF/TrkB signaling cascade.
BDNF is recognized as a transducer, acting as
the link between the AD drug and the neuroplas-
tic effects such as synaptic long term potentiation
and neurogenesis (7). Moreover, response to ADs
is abolished by BDNF and TrkB conditional
knockout mice and by intra-cortical infusions of
BDNF-neutralizing antibodies (7). These findings
reinforce the neurotrophic hypothesis of depres-
sion in which ADs finally act through the BDNF/
pro-BDNF equilibrium.
All types of AD treatments increase BDNF
synthesis in the CNS mood pathway
ADs promote neurogenesis by increasing BDNF
synthesis in the brain. Animal studies show that
AD treatments augment BDNF’s synthesis as
expressed by an increase in messenger RNA
(mRNA) and protein expression. This increase is
observed with all types of AD treatments, in elec-
tro-convulsive treatment (ECT), repetitive trans-
cranial magnetic stimulation (rTMS), sleep
deprivation, physical exercise, chemical antide-
pressants, ketamine and D1 agonist.
Acute ECT
ECT is reported to increase BDNF mRNA
approximately twofold in rats’brain (8). After
ten seizures, BDNF protein increases in six brain
regions (9): parietal cortex (219%), entorhinal
cortex (153%), hippocampus (132%), frontal cor-
tex (94%), neostriatum (67%) and septum (29%).
BDNF increases gradually in the hippocampus
and frontal cortex, with a peak occurring 15 h
after the last seizures and lasting more than
3 days. A meta-analysis (10) performed in rats
shows that electroconvulsive seizures increase
BDNF levels in brain, with an effect size of 0.4
(g¼0.40, 95% CI ¼0.35-0.44, p<.0001). The
effect is higher in the dentate girus (g¼0.54)
compared to the hippocampus and the cortex (g:
0.38 and 0.41, respectively). The ECT effect size
is larger with BDNF’s mRNA (g: 0.46) compared
to BDNF protein (g: 0.35), although, the latter is
statistically significant. The BDNF increase
reported in the brain correlates positively with
the increased swimming time in the forced swim
test (r¼0.37, p<.001). ECT increases BDNF
synthesis, release and behavioral effects.
rTMS treatment
Repetitive transcranial magnetic stimulation
(rTMS) increases BDNF levels in the brain and
in the neuron. rTMS increases long term potenti-
ation in hippocampal CA3–CA1 synapses, in a
rat model of vascular dementia (11).
Physical exercise
Treadmill exercise in animal increases BDNF
mRNA in the brain (12) and upregulates BDNF
transcripts (13). Forced running exercise
increases hippocampal neurogenesis, elevates
BDNF-pCREB signaling and reverses the neuro-
genesis impairment and the downregulation of
the BDNF-pCREB signaling pathway induced by
2 F. LAVERGNE AND T. M. JAY

whole-brain irradiation (14). A month of volun-
tary physical exercise in mice increases BDNF
mRNA and protein in the neuronal somata of
the hippocampus (15).
Partial sleep deprivation
Partial sleep deprivation is associated to BDNF
synthesis in the pedunculopontine tegmentum
and subcoeruleus nucleus, areas which are deter-
minant for REM sleep drive (16). On the con-
trary, microinjections of TrkB receptor inhibitor
(K252a and ANA-12) dose-dependently reduced
the homeostatic responses to selective REM sleep
deprivation. TrkB inhibition reduces REM sleep
homeostatic drive and limits REM sleep
rebound (17).
Chemical ADs
Inhibition of mono-amine re-uptake ADs.
Imipramine (18), duloxetine (19), venlafaxine and
imipramine (20), desipramine (8), LPM580153
(21), reboxetine (15) increase BDNF transmission
in the brain. Imipramine (10 mg/kg) increases
BDNF gene expression in the hippocampus
(24.0%) and cerebral cortex (29.9%), compared to
the vehicle-treated rats (18). Duloxetine (10 mg/
kg) increases cortical and hippocampal mRNA
expression of BDNF and reduces the pro-apop-
tosis p53 protein expression, in qRT-PCR analysis
(19). Venlafaxine and imipramine (20) as well as
desipramine (8) significantly increase BDNF
mRNA expression in the dentate gyrus. The triple
uptake inhibitor, LPM580153 activates BDNF and
the downstream cascades as shown by an increase
in the protein levels of BDNF, p-ERK1/2, p-AKT,
p-CREB and p-mTOR (21). Reboxetine produces
a global increase of BDNF mRNA and protein in
the neuronal somata of the hippocampus (15).
Specific serotonin re-uptake inhibitors. Sertraline
(8), escitalopram (22), fluoxetine (15,23,24)
increase BDNF transmission. This increase in
BDNF mRNA is demonstrated after four days of
treatment with escitalopram in the frontal cortex
and hippocampus (22), in the hypothalamus and
habenula (23), in the neuronal somata of the
whole hippocampus. Fluoxetine increases BDNF
in the dendrites of CA3 neurons (15), in the pre-
frontal cortex (24) and reverses the BDNF
protein decrease induced by chronic unpredict-
able mild stress (24). However, fluoxetine did not
increase BDNF mRNA levels in the dentate
gyrus, contrary to venlafaxine and imipra-
mine (20).
Mono-amine oxydase inhibitor. Treatment with
tranylcypromine increases BDNF mRNA in the
hippocampus (8), with a bi-phasic and time-
dependent effect on BDNF gene expression (25).
ADs with other mechanisms of action.
Mirtazapine (19,20), mianserin (8), tianeptine
(26), augment BDNF transmission. Mirtazapine
(10 mg/kg) increases BDNF gene expression by
26.5% in the hippocampus and by 41.5% in the
cerebral cortex (18). Mirtazapine (3 mg/kg)
increases cortical and hippocampal mRNA
expression of BDNF and reduces the pro-apop-
tosis p53 protein expression (19). Mianserin,
increases BDNF mRNA in the hippocampus (8)
similarly to tianeptine (5, 10 and 15 mg/kg) (26).
Ketamine
Ketamine rapidly increases the BDNF-neuronal
transmission and the intra-cellular signaling in
the mTOR pathway, leading to an increase in the
number of new spine synapses in the prefrontal
cortex of rats. Moreover, blockade of mTOR
blocked ketamine induction of synaptogenesis
and behavioral responses in models of depres-
sion (27).
Dopamine D1agonist
D1 agonist treatment increases BDNF protein
and mRNA in neuronal and astroglia cultures of
the mouse striatum (28). On the contrary,
chronic administration of non-antidepressant
psychotropic drugs, including morphine, cocaine
or haloperidol, does not increase the levels of
BDNF mRNA in the brain (8).
These studies bring numerous evidences
strongly supporting that AD treatments enhance
BDNF transmission, as demonstrated by an upre-
gulation of BDNF mRNA and protein expression
in the CNS. However, this BDNF increase
presents regional specificity demonstrated by an
opposite effect of BDNF in the neural network
underlying stress and depression (29), i.e., BDNF
CANCER INVESTIGATION 3

administration induces an anti-depressive-like
activity in the hippocampus and prefrontal cortex
and a depression-like action in the nucleus
accumbens and the amygdala. Furthermore, stress
and depression induce dendritic atrophy in the
hippocampus and prefrontal cortex, while they
increase spine density in the amygdala. Thus, the
various effects of BDNF in the CNS depend on
their location in the neural mood circuit (29,30).
Many AD treatments are shown to increase
BDNF synthesis in the hippocampus and pre-
frontal cortex, but this effect is not observed in
all studies. For example, BDNF protein level is
increased by ECT but decreased by escitalo-
pram (31).
In summary, all types of ADs treatment have
been shown to augment BDNF synthesis in areas
of the brain. Detailed analysis reveals a regional
specificity and temporal distribution which differ
with the different ADs used and the different
BDNF transcripts involved (32).
ADs and BDNF reverse the state of stress
and depression
Stress and depression are associated with a low
BDNF transmission in the CNS mood circuitry.
Stress reduces BDNF synthesis in the hippocam-
pus and the prefrontal cortex. After acute
restraint stress, total BDNF mRNA levels and
BDNF transcripts 1, 2, 3, 4, 6, 7 are immediately
reduced and returned to control levels 24 h after
the stress session (13). Various models of stress,
restraint stress (13,33), exposition to a predator
scent stress for 10 min (12) reduce BDNF trans-
mission. ECT and AD drugs completely block the
downregulation of BDNF mRNA in the hippo-
campus induced by restraint stress (8), and
increase BDNF protein levels in the hippocampus
and prefrontal cortex of rats exposed to chronic
unpredictable mild stress (24).
In other areas involved in mood regulation,
stress may have opposite effects. Chronic stress
increases BDNF expression in the nucleus accum-
bens and the ventral tegmental area. In these
areas BDNF infusion exerts a pro-depression-like
effect demonstrated by an increased immobility
in the forced swim test. Blocking BDNF function,
in these areas, exert an antidepressant-like
effect (30).
Depression reduces BDNF synthesis in brain and
blood in animal models and patients
BDNF in the depressed brain
In a maternally deprived model of depression,
BDNF is reduced in the amygdala (p<.05) and
the immobility time is augmented in the forced
swim test (p<.05). Imipramine (30 mg/kg) treat-
ment reverses the effects of maternal deprivation
on immobility, and increases BDNF and cyto-
kines levels (p<.05) (34). Neonatal treatment of
rat pups with clomipramine has been shown to
cause long-lasting and persistent depression-
related behaviors and changes in sleep architec-
ture and in BDNF signaling in adult animals,
producing an animal model of depression.
Clomipramine-treated rats exhibited reduced lev-
els of BDNF and adenosine in the basal fore-
brain, whereas the levels of nitric oxide were
elevated (35).
Post-mortem brain tissue obtained from suicide
victims and normal controls confirm a low level
of BDNF in the brain at the time of death (36)
and show that both BDNF and TrkB levels are
significantly decreased in the prefrontal cortex
and hippocampus of depressed suicide
patients (37).
In major depressive disorder, brain atrophy is
observed in the hippocampus, the cerebral cortex
and the amygdala reflecting dendritic atrophy
occurring in the context of excitotoxicity,
decreased neurogenesis and impaired neuro-
trophic function (37–40). The hippocampus is
about 8–10% smaller than in healthy con-
trols (41).
BDNF in the blood of depressed patients
In clinical studies on depression, BDNF is meas-
ured in the blood, in the plasma and serum.
Plasma BDNF represents the “free,”active BDNF
in the blood. Serum BDNF represents the BDNF
stored in platelets and assessed after platelet
aggregation of the blood sample. Plasma and
serum BDNF are obviously related, but the inter-
pretation should be cautious. Serum BDNF is
likely to express BDNF synthesis and storage,
4 F. LAVERGNE AND T. M. JAY

while plasma BDNF, the active BDNF, depends
on platelet content and on the release from plate-
lets. BDNF could be leaking from the platelets or
released by drugs or released after platelet’s
aggregation. Relatively large cohorts are necessary
to identify significant differences, requiring a
group size of 60 to detect a 20% change.
Serum BDNF levels are reduced in patients
with major depressive disorders (42–45) not
treated with ADs, i.e., in the depressive group,
the mean plasmatic BDNF level (17.6 ng/mL;
SD ± 9.6) is half the one in the control group
(27.7 ng/mL; SD ± 11.4; p¼.002) and half the one
in patients treated with ADs (30.6 ng/mL;
SD ± 12.3; p¼.001). Serum BDNF presents a sig-
nificant negative correlation (r¼.350, p¼.045)
with the Hamilton-depression scale (HAM-D)
scores (42).
The balance between the proBDNF/receptor
75NT (75NTR)/sortilin and BDNF/TrkB signaling
pathways appears dysregulated in major depres-
sion. The serum levels of mature BDNF present a
negative correlation with the depression severity,
and, in the opposite direction, the levels of
proBDNF/p75NTR and sortilin are positively cor-
related with the scores of HAM-D (46). Major
depressive disorder can be described as a reduced
BDNF state or as an increased proBDNF state in
the brain and in the blood (46).
ADs reverse the low plasma or serum BDNF
observed in depression
Plasma BDNF is increased by S-escitalopram
(47), vortioxetine (48), sertraline, venlafaxine,
paroxetine, escitalopram (49) in depressed
patients. Besides the usual BDNF increase associ-
ated to AD treatments, one study (50) and meta-
analysis (10) show that plasma/serum BDNF are
higher in patients responding to treatment in
comparison to patients nonresponding to treat-
ment. ADs increase serum BDNF levels in major
depressive disorders in responders (Cohen’sd
(d)¼1.27, p¼4.4 E-07) and remitters (d¼0.89,
p¼.01), and significantly more than in nonres-
ponders. Pretreatment and post-treatment BDNF
levels were meta-analyzed according to treatment
response in 21 major depressive disorder studies
and 7 bipolar studies (10). Overall peripheral
BDNF (plasma BDNF in four studies and serum
BDNF in ten studies) was significantly increased
after ECT as compared to baseline (g¼0.35, 95%
CI ¼0.034–0.67, p¼.03) with a larger effect size
in responder (g: 0.4) compared to nonresponder
patients (g: 0.22). BDNF levels increased in
plasma (g¼0.72, 95% CI ¼0.22–1.23, p¼.004)
but not in serum (g¼0.14, 95% CI ¼
0.29–0.56, p¼.67). Serum/plasma BDNF might
be considered as a biomarker for a successful
ADs treatment. Clinical observations confirm
that global improvement with or without AD
treatments, reduce psycho-motor retardation and
increases physical activity. Since physical activity
enhances plasma BDNF, responding patients
should have higher BDNF levels than nonres-
ponding patients, as indicated by the ECT meta-
analysis. Physical activity (51) can release BDNF
by shear stress on the platelets. This would
explain why ECT and rTMS treatment induce
higher levels of plasma BDNF in responding
patients compared to nonresponding patients,
since responding patients have more physical
activity compared to nonresponding patients.
ECT, by itself, does not increase plasma BDNF.
There was no difference in plasma BDNF levels
(52–54) in patients following treatment with
ECT. In addition, a larger increase in plasma
BDNF and clinical improvement was observed
with the combination of ECT and physical exer-
cise, compared to ECT or physical exercise
alone (55).
How may ADs contribute to normalize serum/
plasma BDNF is unclear. Studies show that ADs
like sertraline (56) and ketamine (57) release
BDNF from platelets. The time course of plasma
BDNF concentration following the administration
of a single 10 mg/kg dose of ketamine in rats
shows a rapid and robust increase in plasma
BDNF concentration sustained for 240 min,
whereas during the same period of time, brain
BDNF concentrations were unchanged in the pre-
frontal cortex, hippocampus or cortex of rats and
no correlations between peripheral and central
BDNF concentration could be observed. ADs can
enhance BDNF release from platelets and could
(see below) increase platelets and megakaryocyte’s
production of BDNF from stem cells in the bone
marrow, ultimately increasing serum BDNF.
CANCER INVESTIGATION 5

ADs and BDNF activities at the periphery
BDNF is synthesized all over the body and
mainly in the bone marrow by the megakaryo-
cytes. Somme ADs increases stem cells prolifer-
ation and could enhance BDNF and
megakaryocyte’s production. Production of plate-
lets in the bone marrow is modulated by stress,
exercise and acts through the mono-aminergic
(noradrenaline, 5HT, dopamine) and NMDA sys-
tems. Several ADs and mood modulators increase
BDNF transmission in the blood.
Experimental evidences support the hypothesis
that ADs enhance BDNF transmission in the
body by increasing BDNF synthesis in the mega-
karyocytes and BDNF release from the platelets.
In this pathway, megakaryocytes and platelets
possess the same membrane, exhibiting receptors
to serotonin, noradrenaline, dopamine, NMDA,
which can be stimulated by ADs. Therefore, ADs
may regulate cell growth in cells exhibiting neu-
rotransmitters receptors but devoid of a role in
neurotransmission. ADs could affect the mega-
karyocyte synthesis of BDNF in the bone marrow
and affect the platelet’s BDNF release in the
blood, since in both cell types, similar membrane
with similar receptors are involved.
BDNF synthesis in the megakaryocytes
It has been recently demonstrated that megakar-
yocytes synthesize BDNF (58) which might be at
the origin of the large store of BDNF observed in
platelets. ADs may increase BDNF synthesis by
promoting the stem cell production of megakar-
yocytes in the bone marrow. ADs affect the
megakaryocytes differentiation and synthesis pre-
sumably via their membrane receptors. A gen-
ome-wide study has identified a plasma
membrane receptome for developing megakaryo-
cytes with 40 trans-membrane receptor genes
upregulated during the development of the mega-
karyocytes (59). The membrane contains many
receptors involved in mono-amine (MOA) trans-
mission: 5HT2 receptors and 5HT re-uptake
receptors in the 5HT system, alpha-2 adrenergic
receptors in the noradrenergic system, dopamine
D1 receptor and dopamine transporter receptor
in the dopamine system, N-Methyl-D-aspartate
(NMDA) receptor 1 and 2 in the glutamate sys-
tem (60). The later receptors are shown to be
functional, as demonstrated by the inhibition of
proplatelet formation by a selective NMDA
receptor antagonist, MK-801 (61).
ADs increase stem cell proliferation
Adding citalopram to a culture of human bone
marrow mesenchymal stem cells induces a sig-
nificant increase in stem cells proliferation. After
30 days of continuous exposure to citalopram and
retinoic acid, the proliferative increase of citalo-
pram-treated neural progenitors, was 7.41 (cumu-
lative population doubling level units) compared
to 5.63 (cumulative population doubling level
units) in the retinoic acid-treated cells. The pro-
liferation rate exhibited a plateau from day 15
onward in the retinoic acid-treated cells, while
the plateau phase was delayed by day 25 for ret-
inoic acid þcitalopram-treated cells (62). This
increase in stem cells proliferation, with ADs, is
confirmed with fluoxetine (20 microM) in neural
stem cells. Fluoxetine increases the proliferation
rate of neural stem cells (p<.05) isolated from
the hippocampus of adult rats (63).
The megakaryocytes and the neurons have
common membrane’s receptors stimulated by
noradrenaline, dopamine, serotonin, glutamate
systems. Studies show that noradrenaline acti-
vates the alpha2-adrenoreceptors and serotonin
activates the 5HT-2 receptors to promote propla-
telets formation in the bone marrow. It is likely
that ADs can affect the bone marrow production,
since thrombocytopenia or thrombopoiesis are
described as adverse effect of ADs, so several
ADs could enhance platelet number and increase
the detrimental effect of platelet on cancer cells.
The metastatic mammary adenocarcinoma cell
line 4T1, does not express functional adrenergic
receptors but the stimulation of adrenergic recep-
tor by ADs in vivo, aggravates 4T1 tumor pro-
gression. Chronic treatment with desipramine
and dexmedetomidine, highly selective a2-adren-
ergic receptors agonist, increase 4T1 growth. a2-
adrenoreceptor activation promote tumor pro-
gression in the absence of direct sympathetic
input to breast tumor cells (64). The tumor pro-
gression under a2-adrenergic stimulation could
6 F. LAVERGNE AND T. M. JAY

result from an increase in platelets production.
ADs present direct affinity for the megakaryocyte
membrane receptors and are likely to affect the
production of platelet in the bone marrow.
Nortriptyline and desipramine show a 30-fold
concentration increase in the bone marrow, com-
pared to the blood stream (65,66).
Stress, MOA systems and mood regulators
modulate the production of platelets
Stress modulates hematopoiesis
The bone marrow is innervated by the autonomic
nervous system. Sympathetic fibers are associated
with blood vessels and adventitial reticular cells
connected by gap junctions, thereby forming a
structural network, the neuro-reticular complex
in the bone marrow (67). This structurally niche
in the bone marrow is made of haematopoietic
and mesenchymal stem cells pairings and is regu-
lated by local input and by long-distance cues
from hormones and autonomic nervous system
(68). The staining of megakaryocytes in the bone
marrow reveals an increased number of megakar-
yocytes in close proximity to the vascular sinus-
oids (69), suggesting an interface between
nervous input and blood output.
Stress like sleep deprivation (70) increases
serum BDNF. Sympathetic stimulation, induced
via continual noise and exhaustive exercise,
enhances thrombopoiesis. Both stress stimula-
tions are shown to elevate peripheral platelet lev-
els at day 3 (p<.05) and day 7 (p<.01) in
normal mice. On the contrary, this effect was not
seen in mice lacking norepinephrine and epi-
nephrine due to dopamine b-hydroxylase–
deficiency (Dbh/)(69). In the bone marrow,
stress stimulates platelet production. This finding
is unexpected since stress usually decreases
neurogenesis in the brain, at least in the hippo-
campus and prefrontal cortex. Stress, in the bone
marrow, induces a defensive reaction, such as an
increase in platelet production.
Mono-amine systems modulate proplate-
let production
Both norepinephrine and epinephrine promote
proplatelet formation in addition to the expan-
sion of CD34þcells (CD34 is a marker for
multipotential hemopoietic stem cells). In vitro,
epinephrine stimulates the alpha2-adrenoceptor
on the megakaryocyte membrane, mediates extra-
cellular signal-regulated kinase ERK 1/2 (ERK1/2)
and promotes proplatelets formation (69).
Norepinephrine increases the proliferation of
neural precursor cells in mice’s hippocampus
(71) and rat’s dentate gyrus (72) and, both
norepinephrine and epinephrine increase the
proliferation of early progenitor cells, via
b2-adrenoreceptor stimulation, in adult hippo-
campus (72). In vivo studies show that norepin-
ephrine or epinephrine injections markedly
promote platelet recovery in mice with induced
thrombocytopenia due to 6.0 Gy of total-body X
ray irradiation (69). Serotonin (5HT) binds to
membrane receptors 5HT-2B/C and promotes
the differentiation and proliferation of megakar-
yocytes (73). 5HT at 200 nM significantly enhan-
ces the expansion of CD34þcells to early stem
cells progenitors. It increases CD34þcells, col-
ony-forming and multilineage committed progen-
itors: burst-forming unit; colony-forming unit-
erythroid; colony-forming unit-granulocyte
macrophage; colony-forming unit-megakaryocyte,
CD61þ, CD41þcells (CD61 and CD41 are
immune cells markers for megakaryocytes). 5HT
alone or in addition to fibroblast growth factor,
platelet-derived growth factor or vascular endo-
thelial growth factor stimulate bone marrow col-
ony-forming units. Ketanserin, a competitive 5-
HT2C antagonist, nullified the anti-apoptotic
effects of serotonin in cancer M-07e cells (74).
Mood regulators modulate proplatelet production
Valproic acid, a histone deacetylase inhibitor,
induces megakaryopoiesis as estimated by poly-
ploidy, proplatelet formation and elevated expres-
sion of the megakaryocytic markers CD41 and
CD61 (75). Lithium stimulates proliferation of
stem cells, in the bone marrow and in the brain.
In the bone marrow, lithium causes granulocyto-
sis. Clinicians have long used lithium to treat
granulocytopenia resulting from radiation and
cancer’s chemotherapy. Lithium reversibly pro-
motes the proliferation of human bone marrow-
derived mesenchymal stem cell in vitro. With
5 mm of lithium added to the culture, stem cells
proliferate more rapidly without undergoing
CANCER INVESTIGATION 7

apoptosis compared to the untreated cells (76,77).
Lithium upregulates nerve growth factor, neuro-
trophin-3, BDNF and their receptors (77). The
same lithium effects are seen in the brain.
Lithium expands the pools of adult hippocampal
progenitor and facilitates the production of neu-
rons at therapeutically relevant concentration.
These proliferative effects depend on the Wnt
pathway. Both downregulation of glycogen syn-
thase kinase-3beta, a lithium-sensitive component
of the canonical Wnt signaling pathway, and ele-
vated beta-catenin, a downstream component of
the same pathway produces effects similar to lith-
ium. In contrast, RNA mediated inhibition of
beta-catenin abolishes the proliferative effects of
lithium, suggesting that the Wnt signal transduc-
tion, underlie lithium’s therapeutic effect (78).
In summary, neurons and the megakaryocytes
are similarly modulated by neurotransmitters and
neurotrophins. ADs are likely to act equally on
both cell types. These effects on hematopoiesis,
likely depend on the ADs affinity for the mega-
karyocyte’s receptors. Women, who reported tak-
ing ADs, had a 40% higher risk of venous
thromboembolism compare to women not taking
ADs, regardless of the type of AD and the psy-
chotropic drug co-prescription. Women treated
for depression without ADs and co-prescription
did not experience a significant increase in ven-
ous thromboembolism risk. Consequently, the
primary driving force of venous thromboembol-
ism risk seems to lie on the AD or the psycho-
tropic drugs rather than on the depression itself
(79). ADs could enhance venous thromboembol-
ism risk by increasing the platelets count or by
increasing the platelet activation and aggregation.
Chemical ADs increase BDNF release
from platelets
Platelets are formed and released in the blood
stream without a nucleus. The message written in
the megakaryocyte, in the bone marrow, can be
delivered unchanged in the whole body through
the platelets in the vascular circulation. BDNF is
present in circulating platelets, at levels far higher
than in the brain. The average BDNF content in
human platelets is circa 92.7 pg per million plate-
lets, circa 22.6 ng/mL in serum and circa 92.5 pg/
mL in plasma. BDNF levels are a hundred fold
lower in plasma than in serum. Platelet’s BDNF
reflects physiological states since the BDNF levels
in platelets change during the menstrual cycle in
women (80). Platelets half-life is close to 10 days.
After secretion from neurons or release from the
platelets, BDNF acts as a local factor in the low
micrometer range (81) and once released from
platelets, BDNF circulates in the plasma during
an hour only (82). BDNF can be detected at con-
centration as low as 10 pg/mL (83).
ADs augment BDNF release from platelets in vitro
and in vivo
BDNF is released from the platelets through
pharmacological treatment (83,84) including ADs
(56). Other factors like thrombin, collagen, the
Ca
þþ
ionophore A23187, extracellular matrix
material and shear stress can also induce a rapid
release of BDNF from platelets. Shear stress is
due to the pressure on platelets. A pressure is a
force applies to a surface. Shear stress release
augments with increasing blood velocity and aug-
ments with decreasing surface, i.e., when cancer
cells invade the micro-vasculature. Upon agonist
stimulation, up to half the platelet BDNF content
is secreted. ADs have a powerful way to enhance
plasma BDNF throughout the body (49). They
can, like riluzole stimulate the secretion of the
BDNF stored in platelets (85). BDNF is released
from the a-granules in the platelets, mainly by
plasminogen-activator inhibitor 1 (86). Studies
with ADs (sertraline, paroxetine, fluvoxamine,
milnacipran) evoke BDNF release from platelets
in a dose-dependent manner. The BDNF release
is estimated about 20% of the platelets’content.
For sertraline, in vitro, the BDNF release is dose
dependent from 0.03 mM to 0.3 mM, in incubated
washed platelets prepared from rat blood (56). In
vivo, BDNF concentration gradually increases
from 1 h after injection and reaches a significant
difference 5 h post injection (56). This dosage
range corresponds to the AD levels used for
depression treatments. Some ADs increase BDNF
release from platelets in vitro and in vivo.In
another study, the BDNF increase was not signifi-
cant, in calcium free condition (87). Ketamine,
an NMDA ligand and fast acting AD, increases
plasma BDNF levels 2 h after administration in
8 F. LAVERGNE AND T. M. JAY

patients with treatment-resistant depression
(n¼22). At this time the plasma BDNF, presum-
ably released from the platelets, presents a very
strong correlation with the MADRS scores
(r¼0.897, p¼.002). Plasma BDNF levels were
highly negatively associated with MADRS scores
during 3 days (r¼0.897 at 4 h, r¼0.791 at
24 h, r¼0.944 at 48 h, r¼0.977 at 72 h) (88).
This confirms that platelets and neurons share
common receptors. These data suggest that plate-
let releases BDNF under AMPA Receptor-
mTOR activation.
BDNF can be released in plasma by pharmaco-
logical stimulation (platelets receptors recognize
many transmitters and glutamate compounds),
under shear stress pressure (platelets have very
different sizes and their membranes are not her-
metic) and under the aggregation process. When
platelet receptors recognize thrombin, collagen,
Ca
þþ
, extracellular matrix material, they trigger
platelet activation, adhesion, aggregation and sta-
bilization. Once activated, platelets change shape
and degranulate to release growth factors, bio-
active lipids into the blood stream. Platelet
degranulation releases three major forms of stor-
age granule, alpha-granules (n¼50–80 per
human platelet) dense granules (n¼3–8 per
human platelet) and lysosome. They contain
coagulation, angiogenic, inflammatory, trophic
factors, many immunological molecules, ions,
nucleotides, transmitters (5-HT, epinephrine, his-
tamine …), protease inhibitors (89). Thirty per-
cent of the platelet’s total BDNF content is
released from the alpha storage granule upon
platelet’s aggregation.
In summary, some ADs can increase BDNF
production, with a 2 weeks’delay, via proplatelets
formation in the bone marrow and other ADs
(physical exercise, chemical ADs) can promote
platelet’s BDNF release in the plasma with-
out delay.
ADs and BDNF in cancer disease
BDNF increases the cancer disease (in vitro and
in vivo studies). ADs aggravate the cancer’s dis-
ease but could also exert a protective effect on
cancer initiation (epidemiological studies showing
ADs aggravating and protective effect
on cancers).
BDNF in cancer disease
In cancer disease, when platelets aggregate to the
tumor, 70% of the BDNF platelet’s content, in
close contact with the tumor cells could exert
strong tumorigenic effects. After its secretion
from the neuron or after its release from the pla-
telets, BDNF acts as a local factor. Its biochemical
characteristics prevent a broad diffusion within
the target region: mature BDNF dimer is a sticky
protein of about 27 kDa, positively charged under
physiological conditions. The isoelectric point of
BDNF is close to 10. For this reason, local release
of BDNF affects synaptic plasticity on an exquis-
itely local scale in the low micrometer range (81),
and once released from platelets, BDNF circulates
in the plasma during an hour only (82). BDNF
has a short range and short time to act.
Properties of the BDNF molecule
BDNF is among the most potent endogenous
neuro-excitants in the mammalian CNS described
so far (90). BDNF, is a member of the neurotro-
phin family including nerve-growth factor, neuro-
trophin 3 and neurotrophin 4. BDNF depolarize
neurons just as rapidly as the neurotransmitter
glutamate, even at more than thousand-fold
lower concentration. Each neurotrophin has a
common receptor p75NTR and a specific tropo-
myosin-related kinase receptor (Trk). All neuro-
trophins are synthesized as 32 kD precursor
proteins called pro-neurotrophins. They are intra-
cellularly and extracellularly cleaved to produce
the mature neurotrophin form. Mature neurotro-
phins bind to Trk receptors with high affinity
(Figure 1) while pro-neurotrophins preferentially
bind to p75NTR. BDNF affects the cells fate. As
mentioned earlier, on one side BDNF/TrkB
receptor activation promotes cells proliferation
and migration through intracellular pharmaco-
logical cascades, on the other side, the pro-
BDNF, activates p75NTR receptor and promotes
cells death. The cell’s fate is controlled by this
BDNF-TrkB/pro-BDNF-p75NTR equilibrium.
BDNF administration to cancer cells culture pro-
motes cancer cells growth and migration in
CANCER INVESTIGATION 9

Figure 1. Schematic representation of the brain-derived neurotrophic factor (BDNF) signaling network. BDNF binds to tropomy-
osin-related kinase B (TrkB), which is a tyrosine kinase receptor. It also binds with low affinity to p75 neurotrophin receptor
(p75NTR). BDNF and its receptors are expressed throughout the central and peripheral nervous system. BDNF signaling is elicited
when it dimerizes and binds to TrkB, which results in the receptor dimerization and autophosphorylation. The activation of the
receptor results in its interaction with a number of molecules. The BDNF signaling pathway map contains 129 molecules for which
the PPIs, PTMs, translocation and activation/inhibition reactions are experimentally proven in BDNF signaling. The major signaling
modules activated by BDNF include PI3K/AKT, RAS/ERK, PLC/PKC, AMPK/ACC and JAK/STAT pathways. These signaling events in
neurons lead to various context-specific processes such as growth, cell proliferation, differentiation, maintenance of synaptic plasti-
city, microtubule assembly, fat metabolism, protection, survival, calcification, production of nitric oxide and apoptosis. A high confi-
dence version of this map is available at http://www.netpath.org/netslim/BDNF_pathway.html.
10 F. LAVERGNE AND T. M. JAY

neuronal and non-neuronal cells. TrkB signaling is
enough to transform a normal neural crest cell into
a carcinogenic phenotype characterized by cells
proliferation, migration and gene’sregulation(91).
Appropriate intracellular processes including tran-
scription from the BDNF gene (32), translation to
protein, BDNF protein sorting to secretory vesicles,
BDNF-containing vesicle transport and BDNF
secretion are essential to achieve normal BDNF
functions along with activating the signaling path-
ways after TrkB phosphorylation.
BDNF synthesis occurs throughout the body, in
neurons (92), in non-neuronal cells (93–95), in
white blood cells (96) and mostly in megakaryo-
cytes (58). In neurons, the biosynthesis of endogen-
ous BDNF is expressed at very low levels and is in
relation with the neuronal activity (activity-depend-
ent). The increase of neuronal activity increases
BDNF synthesis. BDNF, synthesized in the pre-
synaptic cell, is anterogradely transported to synap-
tic or extra-synaptic structures, stored in dense
core vesicles. The BDNF secretion occurs from
pre-synapses and is regulated by calcium ions. A
potential postsynaptic secretion is understood as a
BDNF exchange between neurons (81). BDNF gene
is expressed in human and rat megakaryocytes.
The rodent BDNF gene produces 22 different tran-
scripts with unclear functions, transcripts encoding
the 50exons 1, 2, 4 or 6 altogether represent 95%
of the total BDNF mRNA in rats and mice (32)
and in the human cortex (97).
Surprisingly, the pattern of mRNA transcripts in
megakaryocytes is similar to that of the neuronal
pattern.Inthepresenceofthapsigarginandexter-
nal calcium, the levels of the mRNA species leading
to efficient BDNF translation rapidly increase in
megakaryocytes. Under these conditions, pro-
BDNF, the obligatory precursor of biologically
active BDNF, becomes readily detectable and the
BDNF is observed in platelet’sa-granules. These
findings suggest that alterations of BDNF levels in
human serum may primarily reflect changes occur-
ring in megakaryocytes and platelets (58).
In vitro BDNF studies in oncology
BDNF increases tumor growth. Administration of
recombinant human BDNF promotes prolifer-
ation, migration, invasion and inhibition of anoi-
kis (detachment-induced apoptosis) (98).
Treatment with exogenous BDNF increases cell
proliferation (99) and antagonizes apoptosis in an
H2O2-induced apoptosis model (100) and ultim-
ately contributes to chemo-resistance in endomet-
rial carcinomas (101). On the contrary, inhibition
of endogenous TrkB signaling with the Trk
receptor inhibitor, K252a suppresses cell prolifer-
ation and increases apoptosis in cancer cell cul-
tures (98,102–106).
BDNF increases cancer cell’s migration. Increasing
TrkB signaling, promotes tumor formation and
metastasis. Activation of TrkB receptors acts as a
potent suppressor of anoikis, which is associated
with an aggressive tumorigenic and metastatic
phenotype in vivo (107). Administration of
exogenous BDNF increases anchor-independent
colony formation on soft agar gels in many cell
lines (91,104–106,108) and increases cell migra-
tion (109). Exogenous BDNF enhances cancer
cell metastasis in a large number of cancer cells
lines, in colon cancer (110,111), in chondrosar-
coma (112), in neuroblastoma (113–115), in head
and neck squamous cell carcinoma (116), in non-
small cell lung cancer (117), in NCI-H441 cancer
cells (118).
BDNF changes a normal cell into a cancer cell.
Strong TrkB signaling is able to transform a nor-
mal neural crest cell into a carcinogenic pheno-
type characterized by cell proliferation/migration
and gene’s regulation (91). BDNF is oncogenic.
On the contrary, inhibition of TrkB receptor sup-
presses the anchorage-independency (108) and
decreases the migratory and invasive capacity of
cancer cell lines (109,119). Moreover
“Knockdown of TrkB”receptor in human lung
cancer cell lines decreases the migratory and
metastatic ability of the cancer cells in vitro and
in vivo (120).
In vivo BDNF studies in oncology
BDNF is over-expressed in cancers. BDNF protein
and TrkB receptor are detected and over-
expressed in most cancer cell lines. Analysis in
the inflammatory exudates and transudates of
malignant and non-malignant tumor environ-
ment shows that the levels of nerve growth fac-
tor, BDNF and neurotrophin-3 are higher in the
CANCER INVESTIGATION 11

malignant tumor as compared with inflammatory
and transudative effusions in non-malignant
tumor. One will notice the high frequency of
BDNF over-expression in tumors. Expression of
neurotrophins mRNAs in 24 cell lines derived
from human malignant gliomas shows wide-
spread expression of neurotrophin genes with
BDNF being the most abundantly expressed.
Immunohistochemistry disclosed strong BDNF
reactivity in both tumor and endothelial cells.
Nearly all cell lines expressed BDNF (121). In
comparison to adjacent or normal tissues, BDNF
is over-expressed at the tumor site in colon can-
cer cells (122), human chondrosarcoma (112),
small and non-small cell lung cancer (123), pri-
mary tumor samples from uterine leiomyosar-
coma (102), gangliogliomas (124), endometrial
cancer (109), myeloma patients (125), pancreatic
ductal carcinoma (126), prostate cancer (127),
lung cancer (123) and in a multidrug-resistant
cell line obtained from patients with leiomyosar-
coma (102). The high frequency of BDNF over-
expression in cancer disease supports the mega-
karyocyte/platelet hypothesis in which BDNF
exert a global activating effect on most solid can-
cers, as soon as they invade the microvasculature.
These observations promote the hypothesis that
platelets release BDNF in all solid tumors.
Serum BDNF increases together with the can-
cer disease
Tumor development in the liver increases the
level of BDNF in serum samples. BDNF was
decreased after tumor’s lobectomy, and increased
again at the time of tumor recurrence. BDNF
and its receptor were solely expressed in the hep-
atocellular carcinoma generated by injection of
cancer cells into the left lobe of the liver (128).
BDNF was expressed in the cytoplasm of the
tumor cells. Higher tissue and serum levels of
BDNF are associated with more advanced tumor
status. The serum levels of BDNF were positively
correlated with the platelet counts, with the
tumor size (>5 cm), the presence of micro-satel-
lite, tumor nodules and poor cells differentiation
(in immuno-histochemistry and enzyme-linked
immunosorbent assay of hepatocellular carcin-
oma) (128).
BDNF over-expression at the tumor front is of
poor prognosis
BDNF expression is elevated at the invasive front
of primary tumors compared to the tumor core
and adjacent normal mucosa and correlates with
poor prognosis (98). BDNF is specifically over-
expressed at the cancer/blood interface where it
lights the cancer fire. BDNF/TrkB expression cor-
relates with metastasis, micro-vessel density,
lymph vessel density, lymph node metastasis,
lympho-vascular space involvement and poor
prognosis in patients (120). BDNF/TrkB corre-
lates with poor prognostic (109) in oral squa-
mous cell carcinoma (129), in hepatocellular
carcinoma (130) in neuroblastoma (131), in tran-
sitional cell carcinoma (110), in non-small cell
lung cancer (132). TrkB-positive tumors have a
significantly lower disease-free survival
(p¼.0094) and overall survival (p¼.0019) than
TrkB-negative tumors. TrkB expression was an
independent prognostic factor for disease-free
survival (HR 3.7, p¼.002) and overall survival
(HR 4.3, p¼.004) in multivariate analysis (132).
On the contrary, drugs that block the TrkB
receptor and drugs that impair the BDNF/TrkB/
mTOR extracellular signal-regulated kinase axis
reverse the aggressive and invasive phenotype
promoted at the invasive tumor front and reduce
distant dissemination in mice (101). Knockdown
of BDNF by short hairpin RNAs impairs tumor
growth and angiogenesis (130). TrkB antagonist
K252a, (98,123,133) reduces tumor growth
in vitro and in vivo. TrkB inhibitor, AZD6918,
antagonizes cell growth, invasion and colony for-
mation in xenograft model (134). The TrkB anti-
bodies at 0.5 mg/mL suppress migration and at
3mg/mL elicit cytotoxicity and apoptosis.
In summary high level of BDNF at the tumor
front is related to tumor growth, metastasis and
poor prognostic.
ADs in cancer disease
More than 20 years ago, Steingart (135) raised the
question: “Do antidepressants cause, promote or
inhibit cancers?”A literature search of MEDLINE
examined the association of ADs with cancer
between 1976 and 1993. The results were confus-
ing. Depending on the studies, amitriptyline was
12 F. LAVERGNE AND T. M. JAY

found to promote tumor growth. Fluoxetine and
clomipramine were reported to be both tumor
promoters and antineoplastic agents, and imipra-
mine and citalopram both demonstrated antineo-
plastic properties. In today’s literature, we find
support for the ideas that 1) ADs have a
“protective”effect on cancer before cancer initi-
ation, 2) ADs have an “aggravating”effect on the
cancer disease when given after the can-
cer’s initiation.
Epidemiological studies showing ADs protective
effect on cancers
Recent studies in Taiwan suggest that ADs have a
protective value against cancer’s initiation. The
following studies examine the use of ADs in daily
dosage x days (ddd) before the cancer diagnosis
(index date) in groups of cancer patients and
matched controls. The cancer risk was assessed as
a function of cumulative dosage (ddd) for the
AD prescription. Before a cancer diagnosis, previ-
ous use of ADs reduces or do not increase the
incidence of cancers (136–140). These findings
raise the possibility that ADs protect from cancer
initiation. In 8392 endometrial cancer cases and
82,432 matched controls, conditional logistic
regression analysis shows no association between
ADs prescription (in the year preceding the can-
cer diagnosis) and endometrial cancer: null asso-
ciation for specific serotonin re-uptake inhibitors
(SSRI) (OR ¼0.98) and for SNRI (OR ¼1.14)
(140). In 49,342 cases with colorectal cancer and
240,985 controls, similar results were found
(136). In 49,998 cases with hepatocellular carcin-
oma, paired with 244,236 randomly selected con-
trols, use of tricyclic ADs (p<.0001), SSRI ADs
(p<.0001), trazodone (p<.006) and mirtazapine
(p<.03) was associated with a lower risk for hep-
atocellular carcinoma (138). In 26,262 cases with
invasive cervical cancer and 129,490 controls, all
ADs presented a null risk except for trazodone
(OR ¼1.22, 95% CI ¼1.03–1.43) that
increased cervical cancer incidence (137). A
slightly decreased risk for cancer was found in
gastric cancer (139) for SSRI’s (OR ¼0.87, in ⭌
28 ddd). Other ADs presented a null risk.
Interestingly, lithium could reduce overall can-
cer risk in patients with bipolar disorder. A retro-
spective cohort study evaluated the hazard ratios
(HRs) for risk of cancer in bipolar patients
treated by lithium or by anticonvulsants only.
Compared to anticonvulsant-only, lithium expos-
ure was associated with a significantly lower can-
cer risk (HR ¼0.735, 95% CI 0.554-0.974) with a
dose–response relationship for cancer risk reduc-
tion (141).
Repairing effects of ADs on cancer’s cells
In vitro studies show that ADs can act on the
mitochondrial DNA and on the cellular DNA in
the direction of repairing dysfunctions or induc-
ing apoptosis. ADs improve the mood state and
potentially the general health. The main effect of
ADs is in a pro-life direction toward neurogen-
esis and synaptogenesis. ADs promote cells repli-
cation but also, possibly, repair the errors in cells
replication and induce apoptosis in abnormal
cells situations. Many in vitro studies show bene-
ficial effects of ADs, i.e., fluoxetine-induces apop-
tosis in hepatocellular carcinoma cells through
the loss of mitochondrial membrane and forma-
tion of reactive oxygen species (142). Sertraline
induces apoptosis in HepG2 cancer cells at least
partially via the activation of the mitogen-acti-
vated protein kinase pathway and the activation
of tumor necrosis factor and cascade signaling
pathway (143). In three human tumor cell lines:
H460 (lung cancer), HeLa (cervical cancer) and
HepG2 (hepatoma), amitriptyline produces the
highest cellular damage in comparison with three
commonly used chemotherapeutic drugs: campto-
thecin, doxorubicin and methotrexate.
Amitriptyline induces a high level of intracellular
reactive oxygen species followed by irreversible
serious mitochondrial damage. This decrease in
the antioxidant machinery was observed only for
amitriptyline (144). Few mechanisms may explain
a beneficial effect of ADs in the cancer’s disease.
Chronic administration of SSRIs may reduce
platelet aggregation secondary to depletion of
platelets’serotonin stores. SSRIs inhibit serotonin
uptake into presynaptic neurons as well as they
inhibit serotonin uptake in platelets. SSRI treat-
ment in 14 patients shows a lower platelet sero-
tonin content (66%; p<.05) and lower reactivity
to adenosine diphosphate, collagen or epineph-
rine-induced platelet aggregation (10–52%;
p<.05) in comparison to controls (145). SSRI
CANCER INVESTIGATION 13

could deplete platelets 5HT and in doing so, sta-
bilize platelets, instead of leading them to aggre-
gation. These protective effects are intriguing but
have not been developed as a potential anti-can-
cer treatment.
Epidemiological studies showing ADs aggravating
effects on cancers
The use of ADs near the cancer’s incidence
(index date) increases patient’s mortality. AD
prescriptions 3 years before the cancer diagnosis
slightly increase breast cancer’s mortality in
women with late-stage breast cancer (146). AD
prescriptions a year or more before cancer’s diag-
nosis increase by 20 cases the incidence of non-
Hodgkin’s lymphoma (966 cases vs. 946, the
expected risk estimated in the population) (147).
In a prospective study, that cumulated 3.3 million
person-year with an average follow-up of 4 years,
AD users are paired with non-AD users and are
followed-up for cancers diagnosis. Cancer cases
19,365 were observed during the follow-up
period. Jari Haukka proposes that the ADs effect
on cancer is mainly due to the growth rate of
unobservable preclinical tumors rather than the
initiation of new tumors (148). Cancer’s inci-
dence was higher in AD groups, in general. The
incidence was larger for brain cancer (adjusted
RR: 1.91, CI: 1.34–2.74). Significantly higher inci-
dence was associated with the highest cumulative
exposure to SSRI for breast cancer (RR: 1.53, CI:
1.14–2.03) and to non-SSRI ADs for colon cancer
(RR: 2.35, 1.04–5.35). Another study in Denmark,
shows that women treated for depression with
ADs (n¼6068) before a primary early-stage
breast cancer diagnosis (n¼45,325) exhibit an
increased risk for poorer survival (hazard ratio
1.21; 95% CI, 1.14 to 1.28) (146).
When ADs are administered less than a year
before diagnosis the cancer’s morbidity is higher.
Closer the AD’s treatment is to the cancer diag-
nosis, larger is the probability that ADs are pre-
scribed during early tumor development. In a
nested case-control study made of 109,096 cancer
patients and 426,402 matched controls, the risk
for lung cancers is higher for SSRI ADs (OR ¼
2.26; 95% CI 2.00–2.54) and for tricyclic ADs
(OR ¼2.93; 95% CI 2.6–3.3). Risk increases
(p<.0001) in patients renewing the ADs
prescription (current users). Odd ratios for can-
cer incidence in ADs users are higher in 14
groups out of 15 when “ADs are prescribed less
than a year before cancer diagnosis”in compari-
son to “more than a year”(149).
In the “Cancer Mortality in People treated
with ADs before Cancer Diagnosis”study, the
one-year mortality rate increases by 32% when
ADs were pursued during the cancer’s disease.
The mortality increases by 54% when ADs were
initiated during the 4 months preceding the can-
cer diagnosis (in a population-based cohort study
with cancer from January 2003 to December
2010 in Denmark (150,151).
When ADs are prescribed during the cancer
disease, mortality is strongly increased. In a dou-
ble blind controlled study, 189 advanced cancer
patients were randomly assigned to sertraline
50 mg (n¼95) or to placebo (n¼94). Primary
analyses were done by intention to treat.
Sertraline had no significant effect on depression,
anxiety, fatigue, overall quality of life. Sertraline
was discontinued more often and earlier than
was the placebo (hazard ratio 1.46 [1.03–2.06],
p¼.03) and showed shorter survival in patients
(unadjusted hazard ratio 1.60 [95% CI 1.04–2.45],
log-rank p¼.04; adjusted hazard ratio 1.62
[1.06–2.41], Cox model p¼.02). The trial was
closed at the planned interim analysis
(n¼150) (152).
ADs aggravate the cancer disease in animal studies
ADs increase tumor growth and metastasis in
some animal studies. Melanoma tumor cells were
inoculated after AD treatments with desipramine
or fluoxetine (10 mg/kg, ip, for two weeks) in
mice. In young males, pretreatment with desipr-
amine dramatically promoted metastasis forma-
tion and increased mortality rate but inhibited
primary tumor growth. In aged animals both
ADs increased primary tumor growth, whereas
metastasis was only moderately promoted (153).
In glioblastoma-astrocytoma cell culture, addition
of paroxetine increases BDNF mRNA and protein
expression. The effects were evidenced at 6 h after
incubation for BDNF mRNA and 12 h after for
BDNF protein (154). BDNF/TrkB signaling cas-
cade inhibited apoptosis and increased cell
growth and migration. The pro-BDNF/p75NTR
14 F. LAVERGNE AND T. M. JAY

pathway induced exactly the opposite effect and
inhibits malignant glioma cell growth and migra-
tion, in C6 glioma cancer cells (155). Increasing
BDNF signaling promotes the cancer cells DNA
in direction of growth and space invasion.
In summary, these epidemiological and clinical
findings point toward an aggravating effect of AD
treatments during the cancer’sdisease.Inour
understanding, ADs present a global effect increas-
ing cancer’s morbidity (tumor grow, metastasis,
morbidity) when administered after cancer’siniti-
ation. On the contrary, ADs could partly protect
from cancer when prescribed before cancer’siniti-
ation. The global ADs effect promoting cancer
morbidity could be mediated by platelets and
BDNF, since BDNF is an oncogene and since these
effects are suppressed by TrkB antagonists and
TrkB antibodies; these observations suggest the
hypothesis that ADs, potentially by increasing
BDNF synthesis in megakaryocytes or BDNF
release in the blood, increase cancer pathophysi-
ology via BDNF signaling. Coexistence of cancers
andADtreatmentsisdetrimental.
Discussion
The herein presented hypothesis states that ADs
increase BDNF transmission in the blood as well as
in the areas of the CNS involved in mood regula-
tion. Both BDNF from the blood and from the
CNS could contribute to the clinical effects of ADs.
Theincreaseinplateletproductionandtherelease
of trophic factors from platelets, including BDNF,
explains the aggravating effect of ADs on the can-
cer disease.
The megakaryocyte/platelet pathway
in oncology
Platelets are detrimental in the cancer’s disease
In vivo, the platelets promote survival of circulating
tumor cells in the bloodstream by conferring resist-
ance to immunological attack from natural killer
cells and by maintaining the state of epithelial to
mesenchymal transition (89,156). Circulating cancer
cells and the cancer tumor capture platelets and
build a protective shield. When a cancer has started
to invade the micro-vasculature, the platelets aggre-
gate at the tumor front. The invasive front
promotes platelet’s aggregation by releasing cells
cytoplasmic material, collagen and extra cellular
matrix. The cancer’s distorted vessels, at the tumor
front, provoke shear stress and reinforce BDNF
release and platelet aggregation. In cancers biopsies,
platelets surrounding the primary tumor predict
resistance to chemotherapy. Platelets coating was
observed in 59% of the primary breast cancer
biopsy and those cells were less responsive to neo-
adjuvant chemotherapy (p<.0001) (157).
Clopidogrel, an inhibitor of platelet aggregation,
potentiates cisplatin nano-formulation by reducing
the platelet’s coating. After clopidogrel pretreat-
ment, a fourfold greater delivery of cisplatin to
tumor tissue was obtained. It reduced the tumor
growth and increased survival rate, in a murine
4T1 breast cancer model (158).
Platelet extract is a strong trophic factor, with a
global effect toward cells regeneration and survival,
including cancer cells. In vitro studies show that
platelet extracts enhance cells growth and decrease
apoptosis by enhancing phospho-ERK and phos-
pho-JNK signaling in human hepatocellular carcin-
oma cell lines (159). Other factors contribute to
platelet toxicity: platelets induce a pro-inflamma-
tory program involving the aberrant expression of
cyclooxygenase (COX)-2, leading to increased tissue
concentrations of the pro-inflammatory and pro-
tumorigenic prostaglandin E2. (160). An autocrine
loop between platelets and cancer cells inflates the
cancer’s invasiveness: the platelets and the tumor
entertain a reinforcing autocrine loop (161)in
which the platelets release serotonin, Ca
þþ
ions,
trophic factors including BDNF, finally, increasing
tumor growth and metastasis, and in which, the
tumor growth releases extra cellular material and
distorts the micro-vasculature, enhancing shear
stress on platelets and platelet’s aggregation.
The platelet content lights the cancer’s fire:
platelets promote cancer cells production, protect
the tumor and the circulating cancer cells from
immunological defenses, promote metastasis,
reduce treatment efficacy and increase mortality.
Treating the cancer disease in the
megakaryocyte/platelet pathway
Thrombocytosis (high platelet count) is associ-
ated with shorter survival in many types of solid
CANCER INVESTIGATION 15

tumors (162). An overview of 25 studies, each
with more than 100 patients, confirms that
thrombocytosis is an adverse prognostic factor in
cancers (162). On the contrary, low platelet count
is related to reduced cancer disease.
Thrombocytopenia (low platelet count) is associ-
ated with smaller tumor’s size as shown in 430
hepato-cellular carcinomas (163,164). From the
understanding that platelets light and entertain
the cancer’s fire, cancer treatments should reduce
the platelets production or reduce the aggregation
process with anticoagulant drugs. Another strat-
egy would be to deliver apoptotic factors to the
tumor via the platelets.
Anti-mitotic drugs reduce the platelet production
Cancer’s treatments decrease platelets count and
this decrease contributes to overall patient’s sur-
vival. Two hundred six patients, treated for
advanced squamous cell head and neck cancer
with two cancer treatment show a larger 5-year
overall survival: 49% versus 34%, (p: .03), in the
treated group that induced neutropenia (72%),
likely to reflect low megakaryocyte count (165).
Anticoagulants reduce the cancer disease
Anti-coagulant drugs reduce the platelet’s
involvement in cancers. The use of anti-platelet
agents, like aspirin, reduces the cancer mortality
and metastasis. Low-dose aspirin causes an irre-
versible inactivation of platelet’s cyclooxygenase
COX-1 activity and the synthesis of thromboxane
A2 (160). Aspirin shows an anti-cancer effect
even at the low doses used for the prevention of
thrombosis. Aspirin and clopidogrel prevent
tumor growth and reduce metastasis. Using an
imaging system based on a bioluminescence tech-
nology, tumors and metastasis were monitored
for 2 months in mice. Twenty eight days’treat-
ment with clopidogrel or aspirin daily reduces
the growth of the primary tumor. Metastases
were detected in the lungs and spleens of 100%
of the untreated mice and only in 40% of the
treated mice (166). The prevention of vascular
events with 75 mg/d of aspirin was assessed in
large controlled trials (17,285 participants) and
long follow-up period in which new cancers were
observed. During the follow-up period of
6.5 years, the aspirin group presented less distant
metastasis (HR¼0.64, 95% CI 0.48–0.84,
p¼.001) and reduced deaths for all types of can-
cer (167). Other large randomized trials with reli-
able post-trial follow-up confirm the protective
effect of aspirin on cancers (a: The British
Doctors Aspirin Trial 5139 subjects and b:
UK-TIA Aspirin Trial 2449 subjects) (168). In
six trials in primary thrombosis prevention, with
35,535 participants, daily low-dose aspirin
reduces the incidence of cancers by roughly 25%
(324 vs. 421 cancers cases), after 3 years’follow-
up, in women (p¼.01) and men (p¼.008) (167).
Risk reduction with aspirin is close to 40% for
adenocarcinoma (HR 054) (167) and for
oesophageal, gastric, biliary, breast and gastro-
intestinal cancers (OR ¼062) (169). Allocation
to aspirin reduces cancer deaths, particularly
from 5 years onwards (OR ¼063, 92 deaths vs.
145 deaths) in 69,224 participants (167). All anti-
coagulants reduce the risk for cancer. In 5955
men with localized adenocarcinoma of the pros-
tate, patients treated with anticoagulants (war-
farin, clopidogrel, enoxaparin, with or without
aspirin) presented a lower risk (p<.01) for pros-
tate cancer-specific mortality: 3% deaths in the
anticoagulant group compared to 8% deaths in
the non-anticoagulant group, after 10 years’fol-
low-up (170). Heparin also improves survival and
reduces metastasis in cancer patients (171). On
long-term follow-up of 183,912 subjects, aged 
50 years, aspirin reduces cancer incidence (HR¼
0.46) compared to no anti-platelet therapy.
Combined clopidogrel and aspirin treatment low-
ers cancer risk (HR 0.92) in comparison to
aspirin alone (172). Interestingly, a single oral
dose of clopidogrel, but not aspirin, significantly
reduces the release of BDNF from platelets in
healthy volunteers (84). Aspirin has the potential
for being clinically used as an adjuvant in cancer
therapy (173).
Use of platelets for drug delivery at the
cancer’s front
Platelets can uptake drugs and release them upon
activation. Doxorubicin-loaded platelets were sig-
nificantly more cytotoxic, in vitro and in vivo,as
16 F. LAVERGNE AND T. M. JAY

compared to the free drug. The method can be
personalized as patient’s own platelet can be used
to deliver various drugs with improved efficacy
(174). The platelets treatments could include
many apoptotic factors, like stimulation of the
p75NT receptor and antagonism of the TrkB
receptor. Treatments could focus on cells apop-
tosis or on inhibition of angiogenesis (175).
In summary, treatments could focus on reduc-
ing platelet count (similarly to anti-mitotic treat-
ments), on reducing platelet’s aggregation and
release (similarly to anticoagulant drugs) and on
delivery of apoptotic factors via platelet’s drug
uptake and release.
Plasmatic BDNF effects on mood, cognition
and neurogenesis
Physical exercise releases BDNF from platelets by
shear stress: shear stress release is due to the
vibrations and pressure supported by the platelet
in the vascular bed. Once released BDNF acts as
a local factor (81) and circulates in the plasma
during an hour only (82). In the blood, ADs
increase BDNF transmission. In contrast, anti-
mitotics reduce BDNF transmission and indu-
ces anhedonia.
Low plasmatic BDNF levels are found in dis-
eases characterized by low physical activity, such
as psycho-motor retardation, apathy, immobiliza-
tion. Low plasmatic BDNF is observed in relation
with psycho-motor retardation in major depres-
sive episode (42–46,48,176) with apathy in
Alzheimer disease (177) with reduced mobility in
Parkinson disease (178,179) and in overweight
type 2 diabetes with complete immobilization in
spinal cord injury (180). One day after spinal
cord injury, the average BDNF level is 4919 pg/
mL and continues to decrease after 7 days
(3285 pg/mL, p<.05), to half the level of healthy
subjects (7020 pg/mL) (181).
Low plasmatic BDNF is associated with anhe-
donia. The depressive effects of anti-mitotic drugs
could be mediated by platelet and peripheral
BDNF decrease: the combination of doxorubicin
(2 mg/kg) and cyclophosphamide (50 mg/kg)
injected i.p. to rats once a week for 4 weeks pro-
duces anhedonia-like and anxiety-like behaviors,
and spatial cognitive impairments. Chemotherapy
induces both a decrease in platelet levels and in
the number of proliferating cells in the subgranu-
lar zone of the hippocampus and in the dentate
gyrus. However, hippocampal BDNF levels and
BDNF mRNA levels were not decreased by this
treatment (182), suggesting that the main effects
of antimitotic drugs on mood depends from its
effects on the bone marrow and not of its direct
effects in the CNS.
High plasmatic BDNF levels are found in
remitters from depression compared to non-
remitters (176,183), possibly due to an increased
mobility in remitters. Attention Deficit and
Hyperactivity Disorder, have high BDNF levels
(p<.0001) compared to controls (184–186), sig-
nificantly higher in males compared with controls
(p¼.006), but not in females.
Effects of physical exercise on mood, memory
functioning and neurogenesis
The idea that neurogenesis is regulated by blood
components is raised by the observation that
dividing cells in the hippocampus are found in
dense clusters associated with the vasculature.
There is evidence that adult neurogenesis occurs
within an angiogenic niche. This environment
may provide a novel interface where blood circu-
lating factors influence plasticity in the adult
CNS more precisely in the thin lamina between
the hippocampal hilus and granule cell layer or
subgranular zone, an area known to generate new
neurons throughout adult life (187).
The effect of exercise on mood is demonstrated
in depressed patients. Meta-analysis, of 23
randomized controlled trials with 977 partici-
pants; show that physical exercise is an effective
treatment for depression and an adjunct treat-
ment in combination with chemical ADs.
Physical exercise has a moderate to large signifi-
cant effect on depression compared to control
conditions (g¼–0.68) or compared to no inter-
vention (g¼–1.24) or compared to usual care (g
¼–0.48). Exercise as an adjunct to AD medica-
tions yields a moderate effect (g¼–0.50) that
trends toward significance (188) . Physical exer-
cise augments remission in late-life major depres-
sion. When looking at the end of a sertraline
study, 45% of the participants in the sertraline
CANCER INVESTIGATION 17

group and 81% of the participants in the sertra-
line group þprogressive aerobic exercise of high
intensity, achieved remission (p¼.001) (189).
Exercise improves memory functioning in
depressed patients and in healthy adolescents. In
depressed patients, progressive aerobic exercise
with sertraline displays greater improvements on
cognitive assessment (effect size ¼0.37), execu-
tive functions (effect size ¼0.13) and disability
questionnaire (effect size ¼–0.31) compared to
sertraline alone (190). In adolescents (n¼40),
aerobic exercise of moderate to high intensity
increases levels of serum BDNF at rest and
enhances cognitive functioning. Exercise was per-
formed 4 times per week for 12 weeks. The high
intensity group showed a more significant BDNF
increase compared to the low intensity aerobic
and stretching groups. Working memory signifi-
cantly increases in the high intensity exercise
group compared to the low intensity aerobic
group (191). The positive effect of exercise on
memory is demonstrated in 3/3 studies in the
depressed population and in 10/14 studies (71%)
in the nondepressed population (192).
Plasmatic BDNF effects with exogenous BDNF
administration
BDNF administration modulates mood, memory
and neurogenesis in the brain. Intra-peritoneal
administration of the TAT-BDNF fusion peptide
(the core functional domain of BDNF and the
membrane-penetrating TAT) improves learning
and memory in two Alzheimer disease-like
rodent models. Spatial learning and memory
were tested using the Morris water maze test.
Administration of the TAT-BDNF peptide
reduces the latency to find the platform and
increases the time and path length in the target
quadrant. The number of dendritic spines and
the percentage of mushroom-shaped spines were
significantly increased in treated rats. TAT-BDNF
peptide can remodel synaptic plasticity. The
mechanisms involve activation of the TrkB/Erk/
Akt signaling pathway (193). These effects are
similar to the effects of physical exercise on
mood, memory and neurogenesis.
Conclusion
We propose the hypothesis that ADs modulate
mood and neurogenesis, at least partly, by
increasing BDNF signaling (synthesis and release)
in the brain, in the bone marrow and in
the blood.
Chemical ADs increase BDNF signaling to
tumor’s cells via megakaryocytes and platelets;
this mechanism induces more growth, metastasis
and patient’s morbidity. In vitro and in vivo
oncological studies demonstrated that BDNF and
platelets aggravate cancers. Moreover, epidemio-
logical studies in oncology showed that ADs use
promoted the cancer mortality, although, it did
not increase the cancer’s incidence. Therefore,
during a cancer disease, chemical ADs should not
be prescribed.
Acknowledgments
The authors thank G. Fillion for his helpful comments on
the manuscript.
The article is dedicated to the memory of E. Holtzer.
Disclosure statement
The research was conducted in the absence of any commer-
cial or financial relationships that could be construed as a
potential conflict of interest.
Funding
This work was supported by grants from INSERM (Institut
National de la Sant
e et de la Recherche M
edicale) and
Universit
e Paris Descartes.
References
1. Lavergne F, Jay TM. A new strategy for antidepres-
sant prescription. Front Neurosci. 2010;4:192. doi:10.
3389/fnins.2010.00192.
2. Sun X, Zhao Y, Wolf ME. Dopamine receptor stimu-
lation modulates AMPA receptor synaptic insertion
in prefrontal cortex neurons. J Neurosci. 2005;
25(32):7342–7351. doi:10.1523/JNEUROSCI.4603-04.
2005.
3. Bustos G, Abarca J, Campusano J, Bustos V, Noriega
V, Aliaga E. Functional interactions between somato-
dendritic dopamine release, glutamate receptors and
brain-derived neurotrophic factor expression in mes-
encephalic structures of the brain. Brain Res Brain
18 F. LAVERGNE AND T. M. JAY

Res Rev. 2004;47(1–3):126–144. doi:10.1016/j.brain-
resrev.2004.05.002.
4. Stewart CV, Plenz D. Inverted-U profile of dopa-
mine-NMDA-mediated spontaneous avalanche
recurrence in superficial layers of rat prefrontal cor-
tex. J Neurosci. 2006;26(31):8148–8159. doi:10.1523/
JNEUROSCI.0723-06.2006.
5. Schmidt HD, Duman RS. Peripheral BDNF produces
antidepressant-like effects in cellular and behavioral
models. Neuropsychopharmacology. 2010;35(12):
2378–2391. doi:10.1038/npp.2010.114.
6. Eliwa H, Belzung C, Surget A. Adult hippocampal
neurogenesis: is it the alpha and omega of anti-
depressant action? Biochem Pharmacol. 2017;141:
86–99. doi:10.1016/j.bcp.2017.08.005.
7. Bj€
orkholm C, Monteggia LM. BDNF - a key trans-
ducer of antidepressant effects. Neuropharmacology.
2016;102:72–79. doi:10.1016/j.neuropharm.2015.10.
034.
8. Nibuya M, Morinobu S, Duman RS. Regulation of
BDNF and trkB mRNA in rat brain by chronic elec-
troconvulsive seizure and antidepressant drug treat-
ments. J Neurosci. 1995;15(11):7539–7547. doi:10.
1523/JNEUROSCI.15-11-07539.1995.
9. Altar CA, Whitehead RE, Chen R, W€
ortwein G,
Madsen TM. Effects of electroconvulsive seizures
and antidepressant drugs on brain-derived neuro-
trophic factor protein in rat brain. Biol Psychiatry.
2003;54(7):703–709. doi:10.1016/s0006-
3223(03)00073-8.
10. Polyakova M, Schroeter ML, Elzinga BM, Holiga S,
Schoenknecht P, de Kloet ER, et al. Brain-derived
neurotrophic factor and antidepressive effect of elec-
troconvulsive therapy: systematic review and meta-
analyses of the preclinical and clinical literature.
PLoS One. 2015;10(11):e0141564. doi:10.1371/jour-
nal.pone.0141564.
11. Zhang N, Xing M, Wang Y, Tao H, Cheng Y.
Repetitive transcranial magnetic stimulation enhan-
ces spatial learning and synaptic plasticity via the
VEGF and BDNF-NMDAR pathways in a rat model
of vascular dementia. Neuroscience. 2015;311:
284–291. doi:10.1016/j.neuroscience.2015.10.038.
12. Hoffman JR, Ostfeld I, Kaplan Z, Zohar J, Cohen H.
Exercise enhances the behavioral responses to acute
stress in an animal model of PTSD. Med Sci Sports
Exerc. 2015;47(10):2043–2052. doi:10.1249/MSS.
0000000000000642.
13. Ieraci A, Mallei A, Musazzi L, Popoli M. Physical
exercise and acute restraint stress differentially
modulate hippocampal brain-derived neurotrophic
factor transcripts and epigenetic mechanisms in
mice. Hippocampus. 2015;25(11):1380–1392. doi:10.
1002/hipo.22458.
14. Ji J, Ji S, Sun R, Li K, Zhang Y, Zhang L, Tian Y.
Forced running exercise attenuates hippocampal
neurogenesis impairment and the neurocognitive
deficits induced by whole-brain irradiation via the
BDNF-mediated pathway. Biochem Biophys Res
Commun. 2014;443(2):646–651. doi:10.1016/j.bbrc.
2013.12.031.
15. Baj G, D’Alessandro V, Musazzi L, Mallei A, Sartori
CR, Sciancalepore M, et al. Physical exercise and
antidepressants enhance BDNF targeting in hippo-
campal CA3 dendrites: further evidence of a spatial
code for BDNF splice variants.
Neuropsychopharmacology. 2012;37(7):1600–1611.
doi:10.1038/npp.2012.5.
16. Datta S, Knapp CM, Koul-Tiwari R, Barnes A. The
homeostatic regulation of REM sleep: a role for
localized expression of brain-derived neurotrophic
factor in the brainstem. Behav Brain Res. 2015;292:
381–392. doi:10.1016/j.bbr.2015.06.038.
17. Barnes AK, Koul-Tiwari R, Garner JM, Geist PA,
Datta S. Activation of brain-derived neurotrophic
factor-tropomyosin receptor kinase B signaling in
the pedunculopontine tegmental nucleus: a novel
mechanism for the homeostatic regulation of rapid
eye movement sleep. J Neurochem. 2017;141(1):
111–123. doi:10.1111/jnc.13938.
18. Rog
oz Z, Skuza G, Legutko B. Repeated treatment
with mirtazepine induces brain-derived neurotrophic
factor gene expression in rats. J Physiol Pharmacol
off J Pol Physiol Soc. 2005;56:661–671.
19. Engel D, Zomkowski ADE, Lieberknecht V,
Rodrigues AL, Gabilan NH. Chronic administration
of duloxetine and mirtazapine downregulates proa-
poptotic proteins and upregulates neurotrophin gene
expression in the hippocampus and cerebral cortex
of mice. J Psychiatr Res. 2013;47(6):802–808. doi:10.
1016/j.jpsychires.2013.02.013.
20. Larsen MH, Hay-Schmidt A, Rønn LCB, Mikkelsen
JD. Temporal expression of brain-derived neuro-
trophic factor (BDNF) mRNA in the rat hippocam-
pus after treatment with selective and mixed
monoaminergic antidepressants. Eur J Pharmacol.
2008;578(2–3):114–122. doi:10.1016/j.ejphar.2007.08.
050.
21. Zhang F, Shao J, Tian J, Zhong Y, Ye L, Meng X,
et al. Antidepressant-like effects of LPM580153, a
novel potent triple reuptake inhibitor. Sci Rep. 2016;
6:24233. doi:10.1038/srep24233.
22. Kozisek ME, Middlemas D, Bylund DB. The differ-
ential regulation of BDNF and TrkB levels in juven-
ile rats after four days of escitalopram and
desipramine treatment. Neuropharmacology. 2008;
54(2):251–257. doi:10.1016/j.neuropharm.2007.08.
001.
23. Sachs BD, Caron MG. Chronic fluoxetine increases
extra-hippocampal neurogenesis in adult mice. Int J
Neuropsychopharmacol. 2014;18. doi:10.1093/ijnp/
pyu029.
24. Zhang Y, Gu F, Chen J, Dong W. Chronic anti-
depressant administration alleviates frontal and
CANCER INVESTIGATION 19

hippocampal BDNF deficits in CUMS rat. Brain Res.
2010;1366:141–148. doi:10.1016/j.brainres.2010.09.
095.
25. Coppell AL, Pei Q, Zetterstr€
om TSC. Bi-phasic
change in BDNF gene expression following anti-
depressant drug treatment. Neuropharmacology.
2003;44(7):903–910. doi:10.1016/S0028-
3908(03)00077-7.
26. Della FP, Abelaira HM, R
eus GZ, Ribeiro KF,
Antunes AR, Scaini G, et al. Tianeptine treatment
induces antidepressive-like effects and alters BDNF
and energy metabolism in the brain of rats. Behav
Brain Res. 2012;233(2):526–535. doi:10.1016/j.bbr.
2012.05.039.
27. Zhou W, Wang N, Yang C, Li XM, Zhou ZQ, Yang
JJ. Ketamine-induced antidepressant effects are asso-
ciated with AMPA receptors-mediated upregulation
of mTOR and BDNF in rat hippocampus and pre-
frontal cortex. Eur Psychiatry. 2014;29(7):419–423.
doi:10.1016/j.eurpsy.2013.10.005.
28. K€
uppers E, Beyer C. Dopamine regulates brain-
derived neurotrophic factor (BDNF) expression in
cultured embryonic mouse striatal cells.
Neuroreport. 2001;12(6):1175–1179. doi:10.1097/
00001756-200105080-00025.
29. Yu H, Chen Z. The role of BDNF in depression on
the basis of its location in the neural circuitry. Acta
Pharmacol Sin. 2011;32(1):3–11. doi:10.1038/aps.
2010.184.
30. Berton O, McClung CA, Dileone RJ, Krishnan V,
Renthal W, Russo SJ, et al. Essential role of BDNF
in the mesolimbic dopamine pathway in social defeat
stress. Science. 2006;311(5762):864–868. doi:10.1126/
science.1120972.
31. Jacobsen JPR, Mørk A. The effect of escitalopram,
desipramine, electroconvulsive seizures and lithium
on brain-derived neurotrophic factor mRNA and
protein expression in the rat brain and the correl-
ation to 5-HT and 5-HIAA levels. Brain Res. 2004;
1024(1–2):183–192. doi:10.1016/j.brainres.2004.07.
065.
32. Aid T, Kazantseva A, Piirsoo M, Palm K, Timmusk
T. Mouse and rat BDNF gene structure and expres-
sion revisited. J Neurosci Res. 2007;85(3):525–535.
doi:10.1002/jnr.21139.
33. Ueyama T, Kawai Y, Nemoto K, Sekimoto M, Ton
e
S, Senba E. Immobilization stress reduced the
expression of neurotrophins and their receptors in
the rat brain. Neurosci Res. 1997;28(2):103–110. doi:
10.1016/s0168-0102(97)00030-8.
34. Rus GZ, dos Santos MAB, Abelaira HM, Ribeiro KF,
Petronilho F, Vuolo F, et al. Imipramine reverses
alterations in cytokines and BDNF levels induced by
maternal deprivation in adult rats. Behav Brain Res.
2013;242:40–46. doi:10.1016/j.bbr.2012.11.044.
35. Savelyev SA, Rantam€
aki T, Rytk€
onen KM, Castren E,
Porkka-Heiskanen T. Sleep homeostasis and
depression: studies with the rat clomipramine model
of depression. Neuroscience. 2012;212:149–158. doi:
10.1016/j.neuroscience.2012.03.029.
36. Kim YK, Lee HP, Won SD, Park EY, Lee HY, Lee
BH, et al. Low plasma BDNF is associated with sui-
cidal behavior in major depression. Prog
Neuropsychopharmacol Biol Psychiatry. 2007;31(1):
78–85. doi:10.1016/j.pnpbp.2006.06.024.
37. Sheldrick A, Camara S, Ilieva M, Riederer P, Michel
TM. Brain-derived neurotrophic factor (BDNF) and
neurotrophin 3 (NT3) levels in post-mortem brain
tissue from patients with depression compared to
healthy individuals - a proof of concept study. Eur
Psychiatry. 2017;46:65–71. doi:10.1016/j.eurpsy.2017.
06.009.
38. Koolschijn PCMP, van Haren NEM, Lensvelt-
Mulders GJLM, Hulshoff Pol HE, Kahn RS. Brain
volume abnormalities in major depressive disorder: a
meta-analysis of magnetic resonance imaging studies.
Hum Brain Mapp. 2009;30(11):3719–3735. doi:10.
1002/hbm.20801.
39. Stratmann M, Konrad C, Kugel H, Krug A,
Sch€
oning S, Ohrmann P, et al. Insular and hippo-
campal gray matter volume reductions in patients
with major depressive disorder. PLoS One. 2014;9(7):
e102692. doi:10.1371/journal.pone.0102692.
40. Rajkowska G. Postmortem studies in mood disorders
indicate altered numbers of neurons and glial cells.
Biol Psychiatry. 2000;48(8):766–777. doi:10.1016/
s0006-3223(00)00950-1.
41. Videbech P, Ravnkilde B. Hippocampal volume and
depression: a meta-analysis of MRI studies. Am J
Psychiatry. 2004;161(11):1957–1966. doi:10.1176/
appi.ajp.161.11.1957.
42. Shimizu E, Hashimoto K, Okamura N, Koike K,
Komatsu N, Kumakiri C, et al. Alterations of serum
levels of brain-derived neurotrophic factor (BDNF)
in depressed patients with or without antidepres-
sants. Biol Psychiatry. 2003;54(1):70–75. doi:10.1016/
s0006-3223(03)00181-1.
43. Karege F, Perret G, Bondolfi G, Schwald M, Bertschy
G, Aubry JM. Decreased serum brain-derived neuro-
trophic factor levels in major depressed patients.
Psychiatry Res. 2002;109(2):143–148. doi:10.1016/
S0165-1781(02)00005-7.
44. Karege F, Bondolfi G, Gervasoni N, Schwald M,
Aubry JM, Bertschy G. Low brain-derived neuro-
trophic factor (BDNF) levels in serum of depressed
patients probably results from lowered platelet
BDNF release unrelated to platelet reactivity. Biol
Psychiatry. 2005;57(9):1068–1072. doi:10.1016/j.biop-
sych.2005.01.008.
45. Cunha ABM, Frey BN, Andreazza AC, Goi JD, Rosa
AR, Gonc¸alves CA, et al. Serum brain-derived
neurotrophic factor is decreased in bipolar disorder
during depressive and manic episodes. Neurosci Lett.
20 F. LAVERGNE AND T. M. JAY

2006;398(3):215–219. doi:10.1016/j.neulet.2005.12.
085.
46. Zhou L, Xiong J, Lim Y, Ruan Y, Huang C, Zhu Y,
et al. Upregulation of blood proBDNF and its recep-
tors in major depression. J Affect Disord. 2013;
150(3):776–784. doi:10.1016/j.jad.2013.03.002.
47. Serra-Mill
as M, L
opez-V
ılchez I, Navarro V, Gal
an
AM, Escolar G, Penad
es R, et al. Changes in plasma
and platelet BDNF levels induced by S-citalopram in
major depression. Psychopharmacology (Berl). 2011;
216(1):1–8. doi:10.1007/s00213-011-2180-0.
48. Sagud M, Nikolac Perkovic M, Vuksan-Cusa B,
Maravic A, Svob Strac D, Mihaljevic Peles A, et al.
prospective, longitudinal study of platelet serotonin
and plasma brain-derived neurotrophic factor con-
centrations in major depression: effects of vortioxe-
tine treatment. Psychopharmacology (Berl). 2016;
233(17):3259–3267. doi:10.1007/s00213-016-4364-0.
49. Zhou C, Zhong J, Zou B, Fang L, Chen J, Deng X,
et al. Meta-analyses of comparative efficacy of anti-
depressant medications on peripheral BDNF concen-
tration in patients with depression. PLoS One. 2017;
12(2):e0172270. doi:10.1371/journal.pone.0172270.
50. Katsuki A, Yoshimura R, Kishi T, Hori H, Umene-
Nakano W, Ikenouchi-Sugita A, et al. Serum levels
of brain-derived neurotrophic factor (BDNF), BDNF
gene Val66Met polymorphism, or plasma catechol-
amine metabolites, and response to mirtazapine in
Japanese patients with major depressive disorder
(MDD). CNS Spectr. 2012;17(3):155–163. doi:10.
1017/S109285291200051X.
51. Kallies G, Rapp MA, Fydrich T, Fehm L, Tschorn
M, Ter
an C, et al. Serum brain-derived neurotrophic
factor (BDNF) at rest and after acute aerobic
exercise in major depressive disorder.
Psychoneuroendocrinology. 2019;102:212–215. doi:
10.1016/j.psyneuen.2018.12.015.
52. Ryan KM, Dunne R, McLoughlin DM. BDNF plasma
levels and genotype in depression and the response
to electroconvulsive therapy. Brain Stimul. 2018;
11(5):1123–1131. doi:10.1016/j.brs.2018.05.011.
53. Allen AP, Naughton M, Dowling J, Walsh A, Ismail
F, Shorten G, et al. Serum BDNF as a peripheral bio-
marker of treatment-resistant depression and the
rapid antidepressant response: a comparison of keta-
mine and ECT. J Affect Disord. 2015;186:306–311.
doi:10.1016/j.jad.2015.06.033.
54. Rapinesi C, Kotzalidis GD, Curto M, Serata D, Ferri
VR, Scatena P, et al. Electroconvulsive therapy
improves clinical manifestations of treatment-resist-
ant depression without changing serum BDNF levels.
Psychiatry Res. 2015;227(2–3):171–178. doi:10.1016/j.
psychres.2015.04.009.
55. Salehi I, Hosseini SM, Haghighi M, Jahangard L,
Bajoghli H, Gerber M, et al. Electroconvulsive ther-
apy and aerobic exercise training increased BDNF
and ameliorated depressive symptoms in patients
suffering from treatment-resistant major depressive
disorder. J Psychiatr Res. 2014;57:117–124. doi:10.
1016/j.jpsychires.2014.06.018.
56. Watanabe K, Hashimoto E, Ukai W, Ishii T,
Yoshinaga T, Ono T, et al. Effect of antidepressants
on brain-derived neurotrophic factor (BDNF) release
from platelets in the rats. Prog
Neuropsychopharmacol Biol Psychiatry. 2010;34(8):
1450–1454. doi:10.1016/j.pnpbp.2010.07.036.
57. Le Nedelec M, Glue P, Winter H, Goulton C,
Broughton L, Medlicott N. Acute low-dose ketamine
produces a rapid and robust increase in plasma
BDNF without altering brain BDNF concentrations.
Drug Deliv Transl Res. 2018;8(3):780–786. doi:10.
1007/s13346-017-0476-2.
58. Chac
on-Fern
andez P, S€
auberli K, Colzani M,
Moreau T, Ghevaert C, Barde YA. Brain-derived
neurotrophic factor in megakaryocytes. J Biol Chem.
2016;291(19):9872–9881. doi:10.1074/jbc.M116.
720029.
59. Sun S, Wang W, Latchman Y, Gao D, Aronow B,
Reems JA. Expression of plasma membrane receptor
genes during megakaryocyte development. Physiol
Genomics. 2013;45(6):217–227. doi:10.1152/physiol-
genomics.00056.2012.
60. Genever PG, Wilkinson DJ, Patton AJ, Peet NM,
Hong Y, Mathur A, et al. Expression of a functional
N-methyl-D-aspartate-type glutamate receptor by
bone marrow megakaryocytes. Blood. 1999;93(9):
2876–2883.
61. Hitchcock IS, Skerry TM, Howard MR, Genever PG.
NMDA receptor-mediated regulation of human meg-
akaryocytopoiesis. Blood. 2003;102(4):1254–1259.
doi:10.1182/blood-2002-11-3553.
62. Verdi J, Mortazavi-Tabatabaei SA, Sharif S, Verdi H,
Shoae-Hassani A. Citalopram increases the differen-
tiation efficacy of bone marrow mesenchymal stem
cells into neuronal-like cells. Neural Regen Res.
2014;9(8):845–850. doi:10.4103/1673-5374.131601.
63. Chen SJ, Kao CL, Chang YL, Yen CJ, Shui JW,
Chien CS, et al. Antidepressant administration mod-
ulates neural stem cell survival and serotoninergic
differentiation through bcl-2. Curr Neurovasc Res.
2007;4(1):19–29. doi:10.2174/156720207779940707.
64. Szpunar MJ, Burke KA, Dawes RP, Brown EB,
Madden KS. The antidepressant desipramine and a2-
adrenergic receptor activation promote breast tumor
progression in association with altered collagen
structure. Cancer Prev Res (Phila). 2013;6(12):
1262–1272. doi:10.1158/1940-6207.CAPR-13-0079.
65. Winek CL, Morris EM, Wahba WW. The use of
bone marrow in the study of postmortem redistribu-
tion of nortriptyline. J Anal Toxicol. 1993;17(2):
93–98. doi:10.1093/jat/17.2.93.
66. Winek CL, Westwood SE, Wahba WW. Plasma ver-
sus bone marrow desipramine: a comparative study.
CANCER INVESTIGATION 21

Forensic Sci Int. 1990;48(1):49–57. doi:10.1016/0379-
0738(90)90271-y.
67. Yamazaki K, Allen TD. Ultrastructural morphomet-
ric study of efferent nerve terminals on murine bone
marrow stromal cells, and the recognition of a novel
anatomical unit: the “neuro-reticular complex”.AmJ
Anat. 1990;187(3):261–276. doi:10.1002/aja.
1001870306.
68. M
endez-Ferrer S, Michurina TV, Ferraro F,
Mazloom AR, Macarthur BD, Lira SA, et al.
Mesenchymal and haematopoietic stem cells form a
unique bone marrow niche. Nature. 2010;466(7308):
829–834. doi:10.1038/nature09262.
69. Chen S, Du C, Shen M, Zhao G, Xu Y, Yang K,
et al. Sympathetic stimulation facilitates thrombopoi-
esis by promoting megakaryocyte adhesion, migra-
tion, and proplatelet formation. Blood. 2016;127(8):
1024–1035. doi:10.1182/blood-2015-07-660746.
70. Schmitt K, Holsboer-Trachsler E, Eckert A. BDNF in
sleep, insomnia, and sleep deprivation. Ann Med.
2016;48(1–2):42–51. doi:10.3109/07853890.2015.
1131327.
71. Jhaveri DJ, Mackay EW, Hamlin AS, Marathe SV,
Nandam LS, Vaidya VA, Bartlett PF. Norepinephrine
directly activates adult hippocampal precursors via
beta3-adrenergic receptors. J Neurosci. 2010;30(7):
2795–2806. doi:10.1523/JNEUROSCI.3780-09.2010.
72. Masuda T, Nakagawa S, Boku S, Nishikawa H,
Takamura N, Kato A, et al. Noradrenaline increases
neural precursor cells derived from adult rat dentate
gyrus through b2 receptor. Prog
Neuropsychopharmacol Biol Psychiatry. 2012;36(1):
44–51. doi:10.1016/j.pnpbp.2011.08.019.
73. Cheng YS, Liu YS, Yang M. Effect of 5-hydroxtrypt-
amine on megakaryocytopoiesis–review. Zhongguo
Shi Yan Xue Ye Xue Za Zhi. 2006;14:403–407.
74. Yang M, Li K, Ng PC, Chuen CKY, Lau TK, Cheng
YS, et al. Promoting effects of serotonin on hemato-
poiesis: ex vivo expansion of cord blood CD34þ
stem/progenitor cells, proliferation of bone marrow
stromal cells, and antiapoptosis. Stem Cells. 2007;
25(7):1800–1806. doi:10.1634/stemcells.2007-0048.
75. Schweinfurth N, Hohmann S, Deuschle M,
Lederbogen F, Schloss P. Valproic acid and all trans
retinoic acid differentially induce megakaryopoiesis
and platelet-like particle formation from the mega-
karyoblastic cell line MEG-01. Platelets. 2010;21(8):
648–657. doi:10.3109/09537104.2010.513748.
76. Zhu Z, Yin J, Guan J, Hu B, Niu X, Jin D, et al.
Lithium stimulates human bone marrow derived
mesenchymal stem cell proliferation through GSK-
3b-dependent b-catenin/Wnt pathway activation.
FEBS J. 2014;281(23):5371–5389. doi:10.1111/febs.
13081.
77. Young W. Review of lithium effects on brain and
blood. Cell Transplant. 2009;18(9):951–975. doi:10.
3727/096368909X471251.
78. Wexler EM, Geschwind DH, Palmer TD. Lithium
regulates adult hippocampal progenitor development
through canonical Wnt pathway activation. Mol
Psychiatry. 2008;13(3):285–292. doi:10.1038/sj.mp.
4002093.
79. Branchford BR. Venous thromboembolism risk with
antidepressants: driven by disease or drugs? J Am
Heart Assoc Cardiovasc Cerebrovasc Dis. 2017;6(5):
e006293. doi:10.1161/JAHA.117.006293.
80. Lommatzsch M, Zingler D, Schuhbaeck K,
Schloetcke K, Zingler C, Schuff-Werner P, et al. The
impact of age, weight and gender on BDNF levels in
human platelets and plasma. Neurobiol Aging. 2005;
26(1):115–123. doi:10.1016/j.neurobiolaging.2004.03.
002.
81. Sasi M, Vignoli B, Canossa M, Blum R.
Neurobiology of local and intercellular BDNF signal-
ing. Pflugers Arch. 2017;469(5–6):593–610. doi:10.
1007/s00424-017-1964-4.
82. Poduslo JF, Curran GL. Permeability at the blood-
brain and blood-nerve barriers of the neurotrophic
factors: NGF, CNTF, NT-3, BDNF. Brain Res Mol
Brain Res. 1996;36(2):280–286. doi:10.1016/0169-
328X(95)00250-V.
83. Radka SF, Hoist PA, Fritsche M, Altar CA. Presence
of brain-derived neurotrophic factor in brain and
human and rat but not mouse serum detected by a
sensitive and specific immunoassay. Brain Res. 1996;
709(1):122–301. doi:10.1016/0006-8993(95)01321-0.
84. Stoll P, Plessow A, Bratke K, Virchow JC,
Lommatzsch M. Differential effect of clopidogrel and
aspirin on the release of BDNF from platelets. J
Neuroimmunol. 2011;238(1–2):104–106. doi:10.1016/
j.jneuroim.2011.06.015.
85. T€
urck P, Frizzo ME. Riluzole stimulates BDNF
release from human platelets. BioMed Res Int. 2015;
2015:1–6. doi:10.1155/2015/189307.
86. Tamura S, Suzuki H, Hirowatari Y, Hatase M,
Nagasawa A, Matsuno K, et al. Release reaction of
brain-derived neurotrophic factor (BDNF) through
PAR1 activation and its two distinct pools in human
platelets. Thromb Res. 2011;128(5):e55–e61. doi:10.
1016/j.thromres.2011.06.002.
87. Hochstrasser T, Ehrlich D, Sperner-Unterweger B,
Humpel C. Antidepressants and anti-inflammatory
drugs differentially reduce the release of NGF and
BDNF from rat platelets. Pharmacopsychiatry. 2013;
46(1):29–34. doi:10.1055/s-0032-1314843.
88. Haile CN, Murrough JW, Iosifescu DV, Chang LC,
Al Jurdi RK, Foulkes A, et al. Plasma brain derived
neurotrophic factor (BDNF) and response to keta-
mine in treatment-resistant depression. Int J
Neuropsychopharmacol. 2014;17(2):331–336. doi:10.
1017/S1461145713001119.
89. Menter DG, Tucker SC, Kopetz S, Sood AK,
Crissman JD, Honn KV. Platelets and cancer: a cas-
ual or causal relationship: revisited. Cancer
22 F. LAVERGNE AND T. M. JAY

Metastasis Rev. 2014;33(1):231–269. doi:10.1007/
s10555-014-9498-0.
90. Kafitz KW, Rose CR, Thoenen H, Konnerth A.
Neurotrophin-evoked rapid excitation through TrkB
receptors. Nature. 1999;401(6756):918–921. doi:10.
1038/44847.
91. Dewitt J, Ochoa V, Urschitz J, Elston M, Moisyadi S,
Nishi R. Constitutively active TrkB confers an
aggressive transformed phenotype to a neural crest-
derived cell line. Oncogene. 2014;33(8):977–985. doi:
10.1038/onc.2013.39.
92. Adachi N, Numakawa T, Richards M, Nakajima S,
Kunugi H. New insight in expression, transport, and
secretion of brain-derived neurotrophic factor: impli-
cations in brain-related diseases. World J Biol Chem.
2014;5(4):409–428. doi:10.4331/wjbc.v5.i4.409.
93. Lommatzsch M, Braun A, Mannsfeldt A, Botchkarev
VA, Botchkareva NV, Paus R, et al. Abundant pro-
duction of brain-derived neurotrophic factor by
adult visceral epithelia. Implications for paracrine
and target-derived Neurotrophic functions. Am J
Pathol. 1999;155(4):1183–1193. doi:10.1016/S0002-
9440(10)65221-2.
94. Kajitani N, Hisaoka-Nakashima K, Morioka N,
Okada-Tsuchioka M, Kaneko M, Kasai M, et al.
Antidepressant acts on astrocytes leading to an
increase in the expression of neurotrophic/growth
factors: differential regulation of FGF-2 by noradren-
aline. PLoS One. 2012;7(12):e51197. doi:10.1371/
journal.pone.0051197.
95. Hisaoka-Nakashima K, Kajitani N, Kaneko M,
Shigetou T, Kasai M, Matsumoto C, et al.
Amitriptyline induces brain-derived neurotrophic
factor (BDNF) mRNA expression through ERK-
dependent modulation of multiple BDNF mRNA
variants in primary cultured rat cortical astrocytes
and microglia. Brain Res. 2016;1634:57–67. doi:10.
1016/j.brainres.2015.12.057.
96. Braun A, Lommatzsch M, Mannsfeldt A, Neuhaus-
Steinmetz U, Fischer A, Schnoy N, et al. Cellular
sources of enhanced brain-derived neurotrophic fac-
tor production in a mouse model of allergic inflam-
mation. Am J Respir Cell Mol Biol. 1999;21(4):
537–546. doi:10.1165/ajrcmb.21.4.3670.
97. Pruunsild P, Kazantseva A, Aid T, Palm K,
Timmusk T. Dissecting the human BDNF locus:
bidirectional transcription, complex splicing, and
multiple promoters. Genomics. 2007;90(3):397–406.
doi:10.1016/j.ygeno.2007.05.004.
98. Okugawa Y, Tanaka K, Inoue Y, Kawamura M,
Kawamoto A, Hiro J, et al. Brain-derived neuro-
trophic factor/tropomyosin-related kinase B pathway
in gastric cancer. Br J Cancer. 2013;108(1):121–130.
doi:10.1038/bjc.2012.499.
99. Akil H, Perraud A, M
elin C, Jauberteau MO,
Mathonnet M. Fine-tuning roles of endogenous
brain-derived neurotrophic factor, TrkB and sortilin
in colorectal cancer cell survival. PLoS One. 2011;
6(9):e25097. doi:10.1371/journal.pone.0025097.
100. Chen JY, Liu J, Wang RH, Peng WZ, Liu ZM, Wang
XM, et al. Suppressive effect of brain derived neuro-
trophic factor on H2O2-induced apoptosis in human
lung cancer cell YTMLC-90. Ai Zheng Aizheng Chin
J Cancer. 2003;22:938–942.
101. Alonso-Alconada L, Eritja N, Muinelo-Romay L,
Barbazan J, Lopez-Lopez R, Matias-Guiu X, et al.
ETV5 transcription program links BDNF and pro-
motion of EMT at invasive front of endometrial car-
cinomas. Carcinogenesis. 2014;35(12):2679–2686.
doi:10.1093/carcin/bgu198.
102. Makino K, Kawamura K, Sato W, Kawamura N,
Fujimoto T, Terada Y. Inhibition of uterine sarcoma
cell growth through suppression of endogenous tyro-
sine kinase B signaling. PLoS One. 2012;7(7):e41049.
doi:10.1371/journal.pone.0041049.
103. Ricci A, Greco S, Mariotta S, Felici L, Bronzetti E,
Cavazzana A, et al. Neurotrophins and neurotrophin
receptors in human lung cancer. Am J Respir Cell
Mol Biol. 2001;25(4):439–446. doi:10.1165/ajrcmb.25.
4.4470.
104. Douma S, Van Laar T, Zevenhoven J, Meuwissen R,
Van Garderen E, Peeper DS. Suppression of anoikis
and induction of metastasis by the neurotrophic
receptor TrkB. Nature. 2004;430(7003):1034–1039.
doi:10.1038/nature02765.
105. Glass DJ, Nye SH, Hantzopoulos P, Macchi MJ,
Squinto SP, Goldfarb M, et al. TrkB mediates
BDNF/NT-3-dependent survival and proliferation in
fibroblasts lacking the low affinity NGF receptor.
Cell. 1991;66(2):405–413. doi:10.1016/0092-
8674(91)90629-d.
106. Klein R, Nanduri V, Jing SA, Lamballe F, Tapley P,
Bryant S, et al. The trkB tyrosine protein kinase is a
receptor for brain-derived neurotrophic factor and
neurotrophin-3. Cell. 1991;66(2):395–403. doi:10.
1016/0092-8674(91)90628-c.
107. Desmet CJ, Peeper DS. The neurotrophic receptor
TrkB: a drug target in anti-cancer therapy? Cell Mol
Life Sci. 2006;63(7–8):755–759. doi:10.1007/s00018-
005-5490-8.
108. Odate S, Onishi H, Nakamura K, Kojima M,
Uchiyama A, Kato M, et al. Tropomyosin-related
kinase B inhibitor has potential for tumor regression
and relapse prevention in pulmonary large cell neu-
roendocrine carcinoma. Anticancer Res. 2013;33(9):
3699–3703.
109. Bao W, Qiu H, Yang T, Luo X, Zhang H, Wan X.
Upregulation of TrkB promotes epithelial-mesenchy-
mal transition and anoikis resistance in endometrial
carcinoma. PLoS One. 2013;8(7):e70616. doi:10.1371/
journal.pone.0070616.
110. Huang SM, Lin C, Lin HY, Chiu CM, Fang CW,
Liao KF, et al. Brain-derived neurotrophic factor reg-
ulates cell motility in human colon cancer. Endocr
CANCER INVESTIGATION 23

Relat Cancer. 2015;22(3):455–464. doi:10.1530/ERC-
15-0007.
111. Yu Y, Zhang S, Wang X, Yang Z, Ou G.
Overexpression of TrkB promotes the progression of
colon cancer. APMIS. 2010;118(3):188–195. doi:10.
1111/j.1600-0463.2009.02577.x.
112. Lin CY, Chen HJ, Li TM, Fong YC, Liu SC, Chen
PC, et al. b5 integrin up-regulation in brain-derived
neurotrophic factor promotes cell motility in human
chondrosarcoma. PLoS One. 2013;8(7):e67990. doi:
10.1371/journal.pone.0067990.
113. Matsumoto K, Wada RK, Yamashiro JM, Kaplan
DR, Thiele CJ. Expression of brain-derived neuro-
trophic factor and p145TrkB affects survival, differ-
entiation, and invasiveness of human neuroblastoma
cells. Cancer Res. 1995;55(8):1798–1806.
114. Hecht M, Schulte JH, Eggert A, Wilting J,
Schweigerer L. The neurotrophin receptor TrkB
cooperates with c-Met in enhancing neuroblastoma
invasiveness. Carcinogenesis. 2005;26(12):2105–2115.
doi:10.1093/carcin/bgi192.
115. Cimmino F, Schulte JH, Zollo M, Koster J, Versteeg
R, Iolascon A, et al. Galectin-1 is a major effector of
TrkB-mediated neuroblastoma aggressiveness.
Oncogene. 2009;28(19):2015–2023. doi:10.1038/onc.
2009.70.
116. Kupferman ME, Jiffar T, El-Naggar A, Yilmaz T,
Zhou G, Xie T, et al. TrkB induces EMT and has a
key role in invasion of head and neck squamous cell
carcinoma. Oncogene. 2010;29(14):2047–2059. doi:
10.1038/onc.2009.486.
117. Zhang S, Guo D, Luo W, Zhang Q, Zhang Y, Li C,
et al. TrkB is highly expressed in NSCLC and medi-
ates BDNF-induced the activation of Pyk2 signaling
and the invasion of A549 cells. BMC Cancer. 2010;
10:43. doi:10.1186/1471-2407-10-43.
118. G€
otz R, Sendtner M. Cooperation of tyrosine kinase
receptor TrkB and epidermal growth factor receptor
signaling enhances migration and dispersal of lung
tumor cells. PLoS One. 2014;9(6):e100944. doi:10.
1371/journal.pone.0100944.
119. Odate S, Nakamura K, Onishi H, Kojima M,
Uchiyama A, Nakano K, et al. TrkB/BDNF signaling
pathway is a potential therapeutic target for pulmon-
ary large cell neuroendocrine carcinoma. Lung
Cancer. 2013;79(3):205–214. doi:10.1016/j.lungcan.
2012.12.004.
120. Sinkevicius KW, Kriegel C, Bellaria KJ, Lee J, Lau
AN, Leeman KT, et al. Neurotrophin receptor TrkB
promotes lung adenocarcinoma metastasis. Proc Natl
Acad Sci USA. 2014;111(28):10299–10304. doi:10.
1073/pnas.1404399111.
121. Hamel W, Westphal M, Sz€
onyi E, Escand
on E,
Nikolics K. Neurotrophin gene expression by cell
lines derived from human gliomas. J Neurosci Res.
1993;34(2):147–157. doi:10.1002/jnr.490340202.
122. Yang X, Martin TA, Jiang WG. Biological influence
of brain-derived neurotrophic factor (BDNF) on
colon cancer cells. Exp Ther Med. 2013;6(6):
1475–1481. doi:10.3892/etm.2013.1330.
123. Ricci A, De Vitis C, Noto A, Fattore L, Mariotta S,
Cherubini E, et al. TrkB is responsible for EMT tran-
sition in malignant pleural effusions derived cultures
from adenocarcinoma of the lung. Cell Cycle. 2013;
12(11):1696–1703. doi:10.4161/cc.24759.
124. Aronica E, Leenstra S, Jansen GH, van Veelen CW,
Yankaya B, Troost D. Expression of brain-derived
neurotrophic factor and tyrosine kinase B receptor
proteins in glioneuronal tumors from patients with
intractable epilepsy: colocalization with N-methyl-D-
aspartic acid receptor. Acta Neuropathol. 2001;
101(4):383–392. doi:10.1007/s004010000296.
125. Ai LS, Sun CY, Wang YD, Zhang L, Chu ZB, Qin Y,
et al. Gene silencing of the BDNF/TrkB axis in mul-
tiple myeloma blocks bone destruction and tumor
burden in vitro and in vivo. Int J Cancer. 2013;
133(5):1074–1084. doi:10.1002/ijc.28116.
126. Miknyoczki SJ, Chang H, Klein-Szanto A, Dionne
CA, Ruggeri BA. The Trk tyrosine kinase inhibitor
CEP-701 (KT-5555) exhibits significant antitumor
efficacy in preclinical xenograft models of human
pancreatic ductal adenocarcinoma. Clin Cancer Res
off J Am Assoc Cancer Res. 1999;5:2205–2212.
127. Montano X, Djamgoz MBA. Epidermal growth fac-
tor, neurotrophins and the metastatic cascade in
prostate cancer. FEBS Lett. 2004;571(1–3):1–8. doi:
10.1016/j.febslet.2004.06.088.
128. Yang ZF, Ho DW, Lau CK, Tam KH, Lam CT, Yu
WC, et al. Significance of the serum brain-derived
neurotrophic factor and platelets in hepatocellular
carcinoma. Oncol Rep. 2006;16(6):1237–1243. doi:10.
3892/or.16.6.1237.
129. Sasahira T, Ueda N, Yamamoto K, Bhawal UK,
Kurihara M, Kirita T, Kuniyasu H. Trks are novel
oncogenes involved in the induction of neovasculari-
zation, tumor progression, and nodal metastasis in
oral squamous cell carcinoma. Clin Exp Metastasis.
2013;30(2):165–176. doi:10.1007/s10585-012-9525-x.
130. Lam CT, Yang ZF, Lau CK, Tam KH, Fan ST, Poon
RTP. Brain-derived neurotrophic factor promotes
tumorigenesis via induction of neovascularization:
implication in hepatocellular carcinoma. Clin Cancer
Res. 2011;17(10):3123–3133. doi:10.1158/1078-0432.
CCR-10-2802.
131. Brodeur GM, Minturn JE, Ho R, Simpson AM, Iyer
R, Varela CR, et al. Trk receptor expression and
inhibition in neuroblastomas. Clin Cancer Res. 2009;
15(10):3244–3250. doi:10.1158/1078-0432.CCR-08-
1815.
132. Okamura K, Harada T, Wang S, Ijichi K, Furuyama
K, Koga T, et al. Expression of TrkB and BDNF is
associated with poor prognosis in non-small cell
24 F. LAVERGNE AND T. M. JAY

lung cancer. Lung Cancer. 2012;78(1):100–106. doi:
10.1016/j.lungcan.2012.07.011.
133. Dubanet L, Bentayeb H, Petit B, Olivrie A, Saada S,
de la Cruz-Morcillo MA, et al. Anti-apoptotic role
and clinical relevance of neurotrophins in diffuse
large B-cell lymphomas. Br J Cancer. 2015;113(6):
934–944. doi:10.1038/bjc.2015.274.
134. Nakamura Y, Suganami A, Fukuda M, Hasan MK,
Yokochi T, Takatori A, et al. Identification of novel
candidate compounds targeting TrkB to induce
apoptosis in neuroblastoma. Cancer Med. 2014;3(1):
25–35. doi:10.1002/cam4.175.
135. Steingart AB, Cotterchio M. Do antidepressants
cause, promote, or inhibit cancers? J Clin Epidemiol.
1995;48(11):1407–1412. doi:10.1016/0895-
4356(95)00545-5.
136. Lee HC, Chiu WC, Wang TN, Liao YT, Chien IC,
Lee Y, et al. Antidepressants and colorectal cancer: a
population-based nested case-control study. J Affect
Disord. 2017;207:353–358. doi:10.1016/j.jad.2016.09.
057.
137. Chan HL, Hsieh YH, Lin CF, Liang HY, Huang KY,
Chiu WC, et al. Invasive cervical cancer and antide-
pressants: a nationwide population-based study.
Medicine (Baltimore). 2015;94(42):e1866. doi:10.
1097/MD.0000000000001866.
138. Chen VCH, Lin CF, Hsieh YH, Liang HY, Huang
KY, Chiu WC, et al. Hepatocellular carcinoma and
antidepressants: a nationwide population-based
study. Oncotarget. 2017;8(18):30464–30470. doi:10.
18632/oncotarget.12826.
139. Hsieh YH, Chiu WC, Lin CF, Chan HL, Liang HY,
Lee Y, et al. Antidepressants and gastric cancer: a
nationwide population-based nested case-control
study. PLoS One. 2015;10(11):e0143668. doi:10.1371/
journal.pone.0143668.
140. Lin CF, Chan HL, Hsieh YH, Liang HY, Chiu WC,
Huang KY, et al. Endometrial cancer and antidepres-
sants: a nationwide population-based study.
Medicine (Baltimore). 2016;95(29):e4178. doi:10.
1097/MD.0000000000004178.
141. Huang RY, Hsieh KP, Huang WW, Yang YH. Use
of lithium and cancer risk in patients with bipolar
disorder: population-based cohort study. Br J
Psychiatry. 2016;209(5):393–399. doi:10.1192/bjp.bp.
116.181362.
142. Mun AR, Lee SJ, Kim GB, Kang HS, Kim JS, Kim
SJ. Fluoxetine-induced apoptosis in hepatocellular
carcinoma cells. Anticancer Res. 2013;33(9):
3691–3697.
143. Chen S, Xuan J, Wan L, Lin H, Couch L, Mei N,
et al. Sertraline, an antidepressant, induces apoptosis
in hepatic cells through the mitogen-activated pro-
tein kinase pathway. Toxicol Sci. 2014;137(2):
404–415. doi:10.1093/toxsci/kft254.
144. Cordero MD, S
anchez-Alc
azar JA, Bautista-Ferrufino
MR, Carmona-L
opez MI, Illanes M, R
ıos MJ, et al.
Acute oxidant damage promoted on cancer cells by
amitriptyline in comparison with some common
chemotherapeutic drugs. Anticancer Drugs. 2010;
21(10):932–944. doi:10.1097/CAD.0b013e32833ed5f7.
145. Bismuth-Evenzal Y, Gonopolsky Y, Gurwitz D,
Iancu I, Weizman A, Rehavi M. Decreased serotonin
content and reduced agonist-induced aggregation in
platelets of patients chronically medicated with SSRI
drugs. J Affect Disord. 2012;136(1–2):99–103. doi:10.
1016/j.jad.2011.08.013.
146. Liang X, Margolis KL, Hendryx M, Reeves K,
Wassertheil-Smoller S, Weitlauf J, et al. Effect of
depression before breast cancer diagnosis on mortal-
ity among postmenopausal women. Cancer. 2017;
123(16):3107–3115. doi:10.1002/cncr.30688.
147. Dalton SO, Johansen C, Mellemkjaer L, Sørensen
HT, McLaughlin JK, Olsen J, Olsen JH.
Antidepressant medications and risk for cancer.
Epidemiol Camb Mass. 2000;11:171–176.
148. Haukka J, Sankila R, Klaukka T, Lonnqvist J,
Niskanen L, Tanskanen A, et al. Incidence of cancer
and antidepressant medication: record linkage study.
Int J Cancer. 2010;126(1):285–296. doi:10.1002/ijc.
24537.
149. Boursi B, Lurie I, Mamtani R, Haynes K, Yang YX.
Anti-depressant therapy and cancer risk: a nested
case-control study. Eur Neuropsychopharmacol.
2015;25(8):1147–1157. doi:10.1016/j.euroneuro.2015.
04.010.
150. Sun Y, Vedsted P, Fenger-Grøn M, Wu CS, Bech
BH, Olsen J, et al. Cancer mortality in people treated
with antidepressants before cancer diagnosis: a popu-
lation based cohort study. PLoS One. 2015;10(9):
e0138134. doi:10.1371/journal.pone.0138134.
151. Sun Y, Vedsted P, Fenger-Grøn M, Wu CS, Bech
BH, Olsen J, et al. Correction: cancer mortality in
people treated with antidepressants before cancer
diagnosis: a population based cohort study. PLoS
One. 2016;11(5):e0155453. doi:10.1371/journal.pone.
0155453.
152. Stockler MR, O’Connell R, Nowak AK, Goldstein D,
Turner J, Wilcken NRC, et al. Effect of sertraline on
symptoms and survival in patients with advanced
cancer, but without major depression: a placebo-con-
trolled double-blind randomised trial. Lancet Oncol.
2007;8(7):603–612. doi:10.1016/S1470-
2045(07)70148-1.
153. Kubera M, Grygier B, Arteta B, Urba
nska K, Basta-
Kaim A, Budziszewska B, et al. Age-dependent
stimulatory effect of desipramine and fluoxetine pre-
treatment on metastasis formation by B16F10 melan-
oma in male C57BL/6 mice. Pharmacol Rep. 2009;
61(6):1113–1126. doi:10.1016/s1734-1140(09)70174-4.
154. Angelucci F, Croce N, Spalletta G, Dinallo V,
Gravina P, Boss
u P, et al. Paroxetine rapidly
modulates the expression of brain-derived neuro-
trophic factor mRNA and protein in a human
CANCER INVESTIGATION 25

glioblastoma-astrocytoma cell line. Pharmacology.
2011;87(1–2):5–10. doi:10.1159/000322528.
155. Xiong J, Zhou L, Lim Y, Yang M, Zhu YH, Li ZW,
et al. Mature BDNF promotes the growth of glioma
cells in vitro. Oncol Rep. 2013;30(6):2719–2724. doi:
10.3892/or.2013.2746.
156. Leblanc R, Peyruchaud O. Metastasis: new functional
implications of platelets and megakaryocytes. Blood.
2016;128(1):24–31. doi:10.1182/blood-2016-01-
636399.
157. Ishikawa S, Miyashita T, Inokuchi M, Hayashi H,
Oyama K, Tajima H, et al. Platelets surrounding pri-
mary tumor cells are related to chemoresistance.
Oncol Rep. 2016;36(2):787–794. doi:10.3892/or.2016.
4898.
158. Pandey A, Sarangi S, Chien K, Sengupta P, Papa AL,
Basu S, et al. Anti-platelet agents augment cisplatin
nanoparticle cytotoxicity by enhancing tumor vascu-
lature permeability and drug delivery.
Nanotechnology. 2014;25(44):445101. doi:10.1088/
0957-4484/25/44/445101.
159. Carr BI, Cavallini A, D’Alessandro R, Refolo MG,
Lippolis C, Mazzocca A, Messa C. Platelet extracts
induce growth, migration and invasion in human
hepatocellular carcinoma in vitro. BMC Cancer.
2014;14:43. doi:10.1186/1471-2407-14-43.
160. Guillem-Llobat P, Dovizio M, Alberti S, Bruno A,
Patrignani P. Platelets, cyclooxygenases, and colon
cancer. Semin Oncol. 2014;41(3):385–396. doi:10.
1053/j.seminoncol.2014.04.008.
161. Goubran HA, Burnouf T, Radosevic M, El-Ekiaby
M. The platelet-cancer loop. Eur J Intern Med. 2013;
24(5):393–400. doi:10.1016/j.ejim.2013.01.017.
162. Buergy D, Wenz F, Groden C, Brockmann MA.
Tumor-platelet interaction in solid tumors. Int J
Cancer. 2012;130(12):2747–2760. doi:10.1002/ijc.
27441.
163. Carr BI, Guerra V, De Giorgio M, Fagiuoli S,
Pancoska P. Small hepatocellular carcinomas and
thrombocytopenia. Oncology. 2012;83(6):331–338.
doi:10.1159/000341533.
164. Carr BI, Lin CY, Lu SN. Platelet-related phenotypic
patterns in hepatocellular carcinoma patients. Semin
Oncol. 2014;41(3):415–421. doi:10.1053/j.seminoncol.
2014.04.001.
165. Rivera F, Vega-Villegas ME, L
opez-Brea M, Isla D,
Mayorga M, Gald
os P, et al. Randomized phase II
study of cisplatin and 5-FU continuous infusion (PF)
versus cisplatin, UFT and vinorelbine (UFTVP) as
induction chemotherapy in locally advanced squa-
mous cell head and neck cancer (LA-SCHNC.
Cancer Chemother Pharmacol. 2008;62(2):253–261.
doi:10.1007/s00280-007-0599-0.
166. Mezouar S, Darbousset R, Dignat-George F, Panicot-
Dubois L, Dubois C. Inhibition of platelet activation
prevents the P-selectin and integrin-dependent accu-
mulation of cancer cell microparticles and reduces
tumor growth and metastasis in vivo. Int J Cancer.
2015;136(2):462–475. doi:10.1002/ijc.28997.
167. Rothwell PM, Wilson M, Price JF, Belch JFF, Meade
TW, Mehta Z. Effect of daily aspirin on risk of can-
cer metastasis: a study of incident cancers during
randomised controlled trials. Lancet Lond Engl.
2012;379(9826):1591–1601. doi:10.1016/S0140-
6736(12)60209-8.
168. Flossmann E, Rothwell PM. British doctors aspirin
trial and the UK-TIA aspirin trial. Effect of aspirin
on long-term risk of colorectal cancer: consistent
evidence from randomised and observational studies.
Lancet Lond Engl. 2007;369(9573):1603–1613. doi:10.
1016/S0140-6736(07)60747-8.
169. Algra AM, Rothwell PM. Effects of regular aspirin
on long-term cancer incidence and metastasis: a sys-
tematic comparison of evidence from observational
studies versus randomised trials. Lancet Oncol. 2012;
13(5):518–527. doi:10.1016/S1470-2045(12)70112-2.
170. Choe KS, Cowan JE, Chan JM, Carroll PR, D’Amico
AV, Liauw SL. Aspirin use and the risk of prostate
cancer mortality in men treated with prostatectomy
or radiotherapy. J Clin Oncol. 2012;30(28):
3540–3544. doi:10.1200/JCO.2011.41.0308.
171. Borsig L. Antimetastatic activities of heparins and
modified heparins. Experimental evidence. Thromb.
Res. 2010;125(Suppl 2):S66–S71. doi:10.1016/S0049-
3848(10)70017-7.
172. Leader A, Zelikson-Saporta R, Pereg D, Spectre G,
Rozovski U, Raanani P, et al. The effect of combined
aspirin and clopidogrel treatment on cancer inci-
dence. Am J Med. 2017;130(7):826–832. doi:10.1016/
j.amjmed.2017.01.022.
173. Mitrugno A, Sylman JL, Rigg RA, Tassi Yunga S,
Shatzel JJ, Williams CD, et al. Carpe low-dose
aspirin: the new anti-cancer face of an old anti-plate-
let drug. Platelets. 2018;29(8):773–778. doi:10.1080/
09537104.2017.1416076.
174. Li J, Ai Y, Wang L, Bu P, Sharkey CC, Wu Q, et al.
Targeted drug delivery to circulating tumor cells via
platelet membrane-functionalized particles.
Biomaterials. 2016;76:52–65. doi:10.1016/j.biomateri-
als.2015.10.046.
175. Li N, Lu Y, Li D, Zheng X, Lian J, Li S, et al. All-
trans retinoic acid suppresses the angiopoietin-Tie2
pathway and inhibits angiogenesis and metastasis in
esophageal squamous cell carcinoma. PLoS One.
2017;12(4):e0174555. doi:10.1371/journal.pone.
0174555.
176. Kreinin A, Lisson S, Nesher E, Schneider J, Bergman
J, Farhat K, et al. Blood BDNF level is gender spe-
cific in severe depression. PLoS One. 2015;10(5):
e0127643. doi:10.1371/journal.pone.0127643.
177. Alvarez A, Aleixandre M, Linares C, Masliah E,
Moessler H. Apathy and APOE4 are associated with
reduced BDNF levels in Alzheimer’s disease. J
26 F. LAVERGNE AND T. M. JAY

Alzheimers Dis. 2014;42(4):1347–1355. doi:10.3233/
JAD-140849.
178. Wang Y, Liu H, Zhang BS, Soares JC, Zhang XY.
Low BDNF is associated with cognitive impairments
in patients with Parkinson’s disease. Parkinsonism
Relat Disord. 2016;29:66–71. doi:10.1016/j.parkreldis.
2016.05.023.
179. Khalil H, Alomari MA, Khabour OF, Al-Hieshan A,
Bajwa JA. Relationship of circulatory BDNF with
cognitive deficits in people with Parkinson’s disease.
J Neurol Sci. 2016;362:217–220. doi:10.1016/j.jns.
2016.01.032.
180. Zhen YF, Zhang J, Liu XY, Fang H, Tian LB, Zhou
DH, et al. Low BDNF is associated with cognitive
deficits in patients with type 2 diabetes.
Psychopharmacology (Berl). 2013;227(1):93–100. doi:
10.1007/s00213-012-2942-3.
181. Paczkowska E, Rogi
nska D, Pius-Sadowska E,
Jurewicz A, Piecyk K, Safranow K, et al. Evidence
for proangiogenic cellular and humoral systemic
response in patients with acute onset of spinal cord
injury. J Spinal Cord Med. 2015;38(6):729–744. doi:
10.1179/2045772314Y.0000000227.
182. Kitamura Y, Hattori S, Yoneda S, Watanabe S,
Kanemoto E, Sugimoto M, et al. Doxorubicin and
cyclophosphamide treatment produces anxiety-like
behavior and spatial cognition impairment in rats:
possible involvement of hippocampal neurogenesis
via brain-derived neurotrophic factor and cyclin D1
regulation. Behav Brain Res. 2015;292:184–193. doi:
10.1016/j.bbr.2015.06.007.
183. Fernandes BS, Molendijk ML, K€
ohler CA, Soares JC,
Leite CMGS, Machado-Vieira R, et al. Peripheral
brain-derived neurotrophic factor (BDNF) as a bio-
marker in bipolar disorder: a meta-analysis of 52
studies. BMC Med. 2015;13:289. doi:10.1186/s12916-
015-0529-7.
184. Zhang J, Luo W, Li Q, Xu R, Wang Q, Huang Q.
Peripheral brain-derived neurotrophic factor in
attention-deficit/hyperactivity disorder: a compre-
hensive systematic review and meta-analysis. J Affect
Disord. 2018;227:298–304. doi:10.1016/j.jad.2017.11.
012.
185. Shim SH, Hwangbo Y, Kwon YJ, Jeong HY, Lee BH,
Lee HJ, et al. Increased levels of plasma brain-
derived neurotrophic factor (BDNF) in children with
attention deficit-hyperactivity disorder (ADHD).
Prog Neuropsychopharmacol Biol Psychiatry. 2008;
32(8):1824–1828. doi:10.1016/j.pnpbp.2008.08.005.
186. Amiri A, Torabi Parizi G, Kousha M, Saadat F,
Modabbernia MJ, Najafi K, et al. Changes in plasma
Brain-derived neurotrophic factor (BDNF) levels
induced by methylphenidate in children with
Attention deficit-hyperactivity disorder (ADHD).
Prog Neuropsychopharmacol Biol Psychiatry. 2013;
47:20–24. doi:10.1016/j.pnpbp.2013.07.018.
187. Kvam S, Kleppe CL, Nordhus IH, Hovland A.
Exercise as a treatment for depression: a meta-ana-
lysis. J Affect Disord. 2016;202:67–86. doi:10.1016/j.
jad.2016.03.063.
188. Belvederi Murri M, Amore M, Menchetti M, Toni
G, Neviani F, Cerri M, et al. Physical exercise for
late-life major depression. Br J Psychiatry. 2015;
207(3):235–242. doi:10.1192/bjp.bp.114.150516.
189. Neviani F, Belvederi Murri M, Mussi C, Triolo F,
Toni G, Simoncini E, et al. Physical exercise for late
life depression: effects on cognition and disability.
Int Psychogeriatr. 2017;29(7):1105–1112. doi:10.1017/
S1041610217000576.
190. Jeon YK, Ha CH. The effect of exercise intensity on
brain derived neurotrophic factor and memory in
adolescents. Environ Health Prev Med. 2017;22(1):
27. doi:10.1186/s12199-017-0643-6.
191. Palmer TD, Willhoite AR, Gage FH. Vascular niche
for adult hippocampal neurogenesis. J Comp Neurol.
2000;425(4):479–494. doi:10.1002/1096-
9861(20001002)425:4<479::AID-CNE2>3.0.CO;2-3.
192. Loprinzi PD, Frith E, Edwards MK, Sng E, Ashpole
N. The effects of exercise on memory function
among young to middle-aged adults: systematic
review and recommendations for future research.
Am J Health Promot. 2018;32(3):691–704. doi:10.
1177/0890117117737409.
193. Wu Y, Luo X, Liu X, Liu D, Wang X, Guo Z, et al.
Intraperitoneal administration of a novel TAT-
BDNF peptide ameliorates cognitive impairments via
modulating multiple pathways in two Alzheimer’s
rodent models. Sci Rep. 2015;5:15032. doi:10.1038/
srep15032.
CANCER INVESTIGATION 27