Rev Mex Med Forense, 2018, 3(1):27-39 ISSN: 2448-8011

Polymorphism of the SLC6A4 gene of the SERT transporter

in individuals with completed suicide
Original Article

Guillén-Rangel, Guadalupe C1; Contreras-Pérez, Carlos Manuel2;

Barrientos-Salcedo, Carolina3

SUMMARY Results: We included 9 individuals aged

Introduction. Suicide has been related to
diverse affective pathologies, including
depression; this entity has been linked to
polymorphisms of the genes that code for
the serotonin transporters and other
neurotransmitters, which could occur in
individuals with completed suicides.
Material and Methods: Blood samples
were taken from 9 individuals who died
due to suicide attempt in the Medical
Forensic Service of the Jaliscience
Institute of Forensic Sciences; DNA was
extracted by means of the Promega Wizard
Genomic DNA Purification Kit. For the
detection of the polymorphism the
endpoint PCR technique was performed
with specific primers for SCT6A4 of SERT,
for detection of the s / s and l / l
polymorphisms.
31 to 73 years, 8 male and 1 female, of
Mexican origin and 5 individuals as a
control group, who died due to non-
suicidal vehicular collision. Of the group
of suicides, in 7 (78%) the polymorphism l
/ l corresponding to the amplified product
of 512 bp was observed and in 2 (22%) the
s / s polymorphism corresponding to the
amplified product of 468 bp. In the control
group, the polymorphism l / l was
amplified in 4 individuals (80%) and the s
/ s in 1 (20%).
Conclusion: No statistically significant
differences were found between the
prevalence of polymorphisms of the
SCL6A4 gene in individuals with
completed suicide compared to the control
group. It is possible that SERT activity is
only a marker of sensitivity to
antidepressant treatment.
Palabras Clave: Violent death, homicide,
suicide, rural community

Received: September 13th, 2017; Accepted: October 10th, 2017; Published:Juanuary 15th, 2018
1
Clinical Chemist, Master in Forensic Medicine
2
Neuroetology Institute, University of Veracruz
3
Biomedical Research Institute, University of Veracruz
Corresponding author: Cuadalupe Concepción Guillén-Rangel, revmforense@uv.mx
 Guillen GC, Contreras CM, Barrientos C. Rev Mex Med Forense, 2018, 3(1): 27-39
INTRODUCTION
The nervous system, present in all
vertebrates and in many invertebrates, is
the anatomical and functional basis that
allows organisms to respond to changes in
the environmental stimuli. The stimuli can
be internal and external. The reaction that
occurs is known as response, which is an
adjustment that brings well-being to the
body. The stimulus-response reactions are
usually rapid and are an uninterrupted
mechanism for maintaining internal
consistency in the face of environmental
changes (Fried, 1990). All these reactions
are accompanied by a strong affective
component, which is often determinant, as
well as very varied vegetative
manifestations. Experimental observations
show that the coordination of this vast
complex of somatic, affective and visceral
components is carried out through the
functional mediation of the structures of
the limbic system (Bustamante, 1996). The
activity of these structures related to
emotional control supports and generates
not only our emotional feelings, but also a
set of motor, autonomic and endocrine
responses, which probably evolved to
dispose them to action and as way of social
signaling of intentionality (Llinás, 2002;
Velasco, 1998).
A group of molecules that fulfill
neurotransmitter function parameters in
the nervous system have been identified.
For a neuroactive molecule to be
considered a neurotransmitter, it must:
possess a mechanism for its synthesis in
presynaptic neurons; have a presynaptic
location; have a release mechanism; its
synaptic activity must be replicable
through the exogenous application of the
molecule; and have an identifiable effector
mechanism (receiver) and signal
determination (Toro, 2010).
Of great interest in suicidal
behavior, serotonin is a substance
belonging to the biogenic amines that acts
as a neurotransmitter and as a
neuromodulator, plays an important role in
mood, anxiety, sleep and is distributed
throughout the body. In the case of
mammals, it is 95% in the
enterochromaffin system of the
gastrointestinal tract and the rest in the
platelets and triptaminergic neurons of the
central nervous system and the enteric
nervous system. (Gershon, 2004). It has
been shown that 5-HT is involved in
different functions, including sleep,
appetite, temperature, anxiety, motor
activity, biological rhythm, learning and
memory. It is present in a wide variety of
areas of the brain. The alteration of
serotonergic activity in the CNS seems to
be involved in the appearance of various
neuropsychiatric pathologies, such as
affective disorders, obsessive-compulsive
behaviors, panic, depression and seasonal
affective disorder (Yura et al, 1996).
As soon as serotonin is released
into the synaptic space, it is recaptured and
subsequently degraded to its inactive
metabolites. The serotonin transporter
(SERT) is the membrane protein
responsible for introducing 5-HT into the
cell, and consequently reduces the
availability of 5-HT in the extracellular
medium. This transporter has become the
main pharmacological target for the
treatment of psychiatric pathologies in
which the serotonergic system is altered.
This is the case of tricyclic
antidepressants, which prevent the
reuptake of noradrenaline and serotonin,
 Guillen GC, Contreras CM, Barrientos C. Rev Mex Med Forense, 2018, 3(1): 27-39
and selective inhibitors of serotonin
reuptake (SSRI). These inhibitors inhibit
the reuptake of serotonin immediately,
however, the therapeutic effect is reached
after a long and repetitive treatment for
reasons still unknown (Franzer, 1997).
Regulation of the extracellular
concentration of 5-HT is carried out by
means of a high affinity transporter,
dependent on Na + and energy. This
transporter allows to internalize part of the
5-HT released after the passage of
electrical impulses through the
serotonergic axons. Therefore, it is the
most effective mechanism to regulate the
accessibility of 5-HT to pre and
postsynaptic receptors, and ultimately, to
control the activity of the serotonergic
neurotransmission system (Moya, 2013).
By recapturing 5-HT, and thus regulating
the magnitude and range of responses to
the neurotransmitter, SERT participates in
the fine-tuning of cerebral serotonergic
synapses, as well as in their peripheral
actions. Interestingly, the greatest
expression of SERT is found in cortical
Figure 1. Microscopical structure of the SERT codifyng gene (obtained from Murphy et al, 2012)
Suicide is the self-inflicted act to
cause death voluntarily, deliberately, in
which three stages intervene successively,
called together a suicidal process: suicidal
desire, the suicidal idea and the suicidal act
itself (Durkheim, 1982; 2002). Suicide is
considered a multifactorial event in which
biological, individual and environmental
and limbic regions involved in behavior
and emotional states (Murphy, 2011).
The human SLC6A4 gene, which
encodes SERT, is a region of ~ 40 Kb,
located on chromosome 17q11.2 and
consists of fourteen exons (Figure 1). The
sequence of its transcript predicts a 630
amino acid protein containing twelve
transmembrane domains (Murphy, 2012).
There are variants of the SLC6A4
promoter: The first polymorphism in the 5
'region of SLC6A4 was described in 1996.
The authors named this polymorphism as
the "polymorphic region associated with
the serotonin transporter (5-HT
Transporter-Linked Polymorphic Region,
5 -HTTLPR). The L and S alleles of 5-
HTTLPR have different transcriptional
efficiencies, with S being comparatively
less effective than L. When the same
authors discovered that the S allele of 5-
HTTLPR is associated with personality
traits related to anxiety and depression,
this resulted in an advance in the area of
psychiatric genetics (Lesch, 1996).
social factors participate. Suicidal
behavior is preceded by some risk factors,
including the presence of psychiatric
illnesses, such as anxiety disorders,
depression, substance abuse, personality
disorders, schizophrenia and panic
disorders (Hernández, 2001; Purselley,
2003). Moderately severe affective anxiety
 Guillen GC, Contreras CM, Barrientos C. Rev Mex Med Forense, 2018, 3(1): 27-39
disorders, transient adjustment reactions,
anxiety as a personality trait and obsessive
characteristics are also considered suicide
risk factors (Gutiérrez-García, 2006,
Charlier, 2003, Perlis, 2007).
Suicidal behavior implies some
neurobiological processes already
identified. Alterations of the serotonergic
neurotransmission system (5HT) play an
important role in the pathogenesis of
suicide. The content of the main
metabolite of serotonin, 5-hydroxy-indole-
acetic acid (5-HIAA) is decreased in the
cerebrospinal fluid of some individuals
with violent suicide attempts, although
dysfunction of other neurotransmission
systems has also been found, such as
dopaminergic and noradrenergic (Weiss,
2010; Isung, 2012).
Depressive affective disorder is
characterized by emotional dysregulation
and is one of the clinical entities that is
most often associated with suicide. On the
other hand, antidepressants have actions
on the neuronal activity of these structures,
in addition to the lateral septal nuclei. And,
finally, serotonin is one of the
neurotransmitters involved in the actions
of antidepressants and possibly in suicide.
But the results have not been conclusive; it
is mandatory to know the role of SERT
gene polymorphisms in the cerebral cortex
of suicide victims.
METHODS
To identify the presence of the
SERT polymorphism, blood samples were
taken at the Forensic Medical Service of
the Jalisco Institute of Forensic Sciences,
located in the city of Tlaquepaque, Jalisco.
For the extraction of DNA, the protocol
established by the Promega Wizard®
Genomic DNA Purification Kit was
followed.
To carry out the detection of the
polymorphism, the PCR technique was
carried out. The primers specific for
SLC6A4 of SERT (GenBank:
EU035982.1) were designed for the
amplification of the insertion / deletion
polymorphic sequence. The size of the
product obtained is 468 bp for the deletion
allele (s) and 512 bp for the insertion allele
(l). The SERT polymorphism in the
SLC6A4 gene; the shortest variant (short /
short or s / s) results in less transcriptional
activity and greater vulnerability to
affective disorders. In contrast, the longer
variant (insertion) (long / long or l / l)
results in a higher transcriptional activity
(Heils et al, 1996). The amplification was
performed under the following conditions:
an initial denaturation cycle at 95 ° C for 3
minutes, 35 cycles of: 1 minute of
denaturation at 95 ° C, 1 minute of
annealing at 61 ° C and 1 minute of
extension at 72 ° C and 10 minutes of final
extension at 72 ° C.
The PCR amplification products
obtained were subjected to electrophoresis
in a 3% agarose gel at 120 V for 30
minutes. From the total reaction volume of
12.5 μl of the PCR, 5 μl were taken for the
run, and a molecular weight marker of
1000 bp was loaded. It was treated with
ethidium bromide at 20 mg / ml for 20
minutes. The amplified products were
observed in a transilluminator with UV
light.
RESULTS
The samples used in this study
were taken within a period of 8 hours after
death, both in patients and controls, to
guarantee the reliability of the test, even
 Guillen GC, Contreras CM, Barrientos C. Rev Mex Med Forense, 2018, 3(1): 27-39

though the collection tube of the sample
contains the anticoagulant EDTA. Natural
decomposition of the body can alter the
integrity of the sample as well as
fragmentation in the DNA which affects
the effectiveness of the PCR.
We included 9 blood samples of
consummate suicidal individuals aged
between 31 and 73 years, 8 of the male sex
and 1 of the female sex. Of the group of
suicidal individuals, in 7 (78%) the
polymorphism l / l corresponding to the
amplified product of 512 bp was observed
and in 2 (22%) the s / s polymorphism
corresponding to the amplified product of
468 bp was obtained (Figure 2).

Figure 2. Alleles of suicide samples. Column 1, molecular weight marker; column 2, 5-10, presence
of the insertion polymorphism (l / l) of 512 bp with higher transcription; columns 3 and 4, presence
of the deletion polymorphism (s / s) of 468 bp with decreased transcrption

As a control group, 5 blood polymorphism l / l and 1 (20%)

samples from individuals with an etiology polymorphism s / s were observed (figure
of death were included; their cause of 3).
death was overcrowding; ages between 30
and 74 years, 3 of the male sex and 2 of the
female sex. In 4 (80%) of them the

Figure 3. Control sample alleles. Column 1, molecular weight marker; columns 2, 3, 5 and 6
presence of insertion polymorphism (l / l); column 4, presence of deletion polymorphism (s / s).
 Guillen GC, Contreras CM, Barrientos C. Rev Mex Med Forense, 2018, 3(1): 27-39
DISCUSSION
It has long been shown that
antidepressant treatments modify the
functioning of the serotonergic system
(Blier, 1987, Contreras, 1993, Contreras,
1994). For this reason, the serotonergic
system has been involved in the
pathophysiology of depression. In this
sense, it is important to reconsider the fact
that about one third of these patients
develop suicidal thoughts and, on many
occasions, they try to achieve it. That is
why it is relevant to study this system in
individuals suffering from depression and
particularly in the victims of suicide.
There are several limitations in the
case of the study of the necropsy of suicide
victims. Although the identification of the
cause of death is evident, many other
aspects are unknown. For example, it is
relevant and it is a confusion factor when
interpreting the results, the existence of a
previous treatment and especially its
duration. The same applies to the accuracy
of obtaining information about a previous
diagnosis. These observations always
prevent us from having a clear
interpretation of the results.
A fundamental characteristic of the
nervous system is its plasticity, understood
as a capacity of neural networks to make
constant adjustments in their function that
in some cases can be related to the
development and manifestations of
diseases. For the particular case of our
suicidal individuals, it is unknown if there
was a previous diagnosis of depression or
any other diagnosis. It is not possible to
identify if those changes could be
attributed to the development of the
disease or to any specific treatment.
It is important to take into account
that serotonin is not the only
neurotransmitter involved in suicide. In
fact, there is an association between high
levels of glutamate in cerebrospinal fluid
and suicidal ideation; these levels decrease
after the correct pharmacological
treatment (Garakani, 2013). Apparently,
certain epigenetic alterations in the spindle
and the kinetocoro associated with the so-
called protein-2 are a good biological
marker of suicidal behavior; this gene is
related to the transactivation of the nuclear
glucocorticoid receptor (Kaminsky, 2015),
which evidently will alter the function of
the hypothalamic-pituitary-adrenal axis
and modify cortisol secretion patterns,
which in turn is related to suicidal ideation
and behavior (Li, 2013); we cannot rule
out the participation of other systems such
as the prolactin system, whose increased
release in conjunction with cortisol can
promote the formation of cytosines, which
have also been linked to suicidal behavior
(Pompili, 2013). The regulating properties
of the serotonergic system influence the
GABA system, particularly in the regions
of the frontal middle cortex (Zhong, 2004).
The results of any study may also depend
on the stage of the disease in which the
analysis is performed. In this sense, it is
notable that the actions of fluoxetine, a
prototype antidepressant, may depend on
age, which may be explained by
differential actions of fluoxetine on
neuroplasticity, especially in the amygdala
of the temporal lobe (Homberg, 2011);
there may be some differences in the
expression of symptoms of depression and
sensitivity to antidepressant treatments,
genetically determined, especially when
applied to models of depression that
appears in the later stages of life, at least
experimentally (Perez-Caceres, 2013).
This data is of interest due to the high
suicide rate that occurs in the
 Guillen GC, Contreras CM, Barrientos C. Rev Mex Med Forense, 2018, 3(1): 27-39
elderly.
In recent years, studies have been
conducted in which the hypothesis was
whether the polymorphisms in the SERT
gene are associated with suicide. Some
studies have not shown any relationship
between suicidal behavior and the SERT
genotype. Ohara et al in 1998 and Geijer et
al in 2000 studied the relationship of the
genotype with depressed patients and with
different forms of polymorphism (l / s,
heterozygous form of the gene) finding no
significant differences between patients
and controls, concluding that the presence
of polymorphism does not affect affective
disorders. In 1999 Du et al. Carried out a
study that showed a higher frequency of
allele I in depressed suicide victims
compared to non-suicidal controls. In
2015, Yi-Wei Yeh and colleagues, through
a positron emission tomography study,
confirmed the reduction of SERT in
depressed patients with suicide attempts
compared to depressed patients without
previous attempts, which relates to the
pathophysiology of behavior suicide.
More recently and using positron
emission tomography techniques,
associated with radioligands, it has been
established that the regions rich in SERT
are the same as the antidepressant
treatments, such as the cingulum, the
amygdala and the raphe nuclei. This
occupation is related to the content of
antidepressants in plasma, which seems to
be related to the sensitivity and efficacy of
antidepressant treatments, since the first
step in the actions of antidepressants is to
establish a blockade of SERT (Baldinger,
2014). There is a possibility that
deficiencies in serotonin
neurotransmission are underlying only the
depressive process. This has been
demonstrated by the use of positron
emission tomography and specific
markers; the function of the 5-HT1A
receptor is decreased in patients with
major depression, about 26% in the
mesiotemporal cortex and in almost half
(43%) in the nuclei of the raphe (Drevets,
2007). The neonatal administration of
chlorimipramine produces behaviors
suggestive of despair in the adult stage
(Limon, 2014). In suicide victims, a
reduction in the number of
somatodendritic receptors and post-
synaptic 5-HT1A receptors has been
found; these observations have been
replicated in positron emission
tomography studies, associated with
reduction of the binding capacity of the 5-
HT1A receptor binding in specific areas of
the dorsal raphe nucleus, the medial
prefrontal cortex (mPFC), the amygdala
and the hippocampus, structures related to
the control of emotional behavior.
Therefore, there is the possibility that
some mechanism related to episodes of
major depression and other alterations
related to stress are dysfunctions in the 5-
HT1A receptor (Savitz, 2009). These
effects that are found with
pharmacological treatments are also
observed with other techniques, such as
electroshock (Lanzenberger, 2013).
In the present study, the I / I
polymorphism was found in both
experimental groups, which is relevant
given that serotonin uptake is
approximately twice as high in cells that
contain the l / l form as in the s / s form
(Lesch, 1998), but there was no difference
between the groups. The relevance of
studying polymorphisms lies in the fact
that the existence of these peculiarities,
can explain the difference in the responses
associated with prolonged stress or
affiliative behaviors, such as cortisol
(Berger, 2016), which is regulated by the
action of the 5-HT2C receptor, which is
located in the hypothalamus (Way, 2016).
 Guillen GC, Contreras CM, Barrientos C. Rev Mex Med Forense, 2018, 3(1): 27-39
Moreover, the risk of hypersecretion of
cortisol and other forms of
psychopathology related to stress increase
with the genotype in which variations
occur (Sorenson, 2013). In the present
study, a case of completed suicide, which
presented the short polymorphism
SLC6A4 of the SERT gene, had multiple
previous suicide attempts; the possibility
of a relationship with the presence of the
polymorphism of the short gene (s / s) and
suicide can not be ruled out yet.
In fact, in those cases closer to
suicide, as in treatment-resistant
depression, the neuroplasticity of the
serotonergic system seems to be
compromised, possibly due to an excess in
the secretion of glutamate, serotonin,
noradrenaline and histamine, which can
cause an inhibitory effect on the release of
serotonin. A relevant aspect that may
aggravate this scheme is the presence of
the short arm of the serotonin transporter
gene (Coplan, 2014), which would explain
the resistance to treatment and the very
possible aggravation of suicidal ideation.
However, these data seem to
indicate that the efficiency of the serotonin
transporter gene is more related to the
possible efficacy of some antidepressant
pharmacological treatment, rather than
being a characteristic of the subject who
will develop suicidal behavior.
REFERENCES
1. Ali, S. O., et al. (2000). A preliminary
study of the relation of
neuropsychological performance to
neuroanatomic structures in bipolar
disorder. Neuropsychiatry
Neuropsychol Behav Neurol, 13(1):
20-8.
2. Baldinger, P., Kranz, G. S., Haeusler,
D., Savli, M., Spies, M., Philippe, C.,.
. . Kasper, S. (2014). Regional
differences in SERT occupancy after
acute and prolonged SSRI intake
investigated by brain PET.
Neuroimage, 88, 252-262.
doi:10.1016/j.neuroimage.2013.10.00
2
3. Berecek, B. M., Brody, M. J. (1982).
Evidence for a neurotransmitter role
for epinephrine derived from the
adrenal medulla. Am J Physiol 242
(4): H593-H601.
4. Berger, J., Heinrichs, M., von
Dawans, B., Way, B. M., & Chen, F.
S. (2016). Cortisol modulates men's
affiliative responses to acute social
stress. Psychoneuroendocrinology,
63, 1-9.
doi:10.1016/j.psyneuen.2015.09.004
5. Blier, P., & de Montigny, C. (1987a).
Antidepressant monoamine oxidase
inhibitors enhance serotonin but not
norepinephrine neurotransmission.
Psychopharmacol Ser, 3, 127-134.
6. Blier, P., & de Montigny, C. (1987b).
Modification of 5-HT neuron
properties by sustained administration
of the 5-HT1A agonist gepirone:
electrophysiological studies in the rat
brain. Synapse, 1(5), 470-480.
doi:10.1002/syn.890010511
7. Blier, P., de Montigny, C., & Chaput,
Y. (1987). Modifications of the
serotonin system by antidepressant
treatments: implications for the
therapeutic response in major
depression. J Clin Psychopharmacol,
7(6 Suppl), 24S-35S.
8. Borges, G., Medina-Mora, M. E.,
Orozco, R., Ouéda, C., Villatoro, J.,
Fleiz, C. (2009). Distribución y
determinantes sociodemográficos de
 Guillen GC, Contreras CM, Barrientos C. Rev Mex Med Forense, 2018, 3(1): 27-39
la conducta suicida en México. Salud
Ment. 32: 413-425.
9. Bustamante, B. Jairo. (1996).
Neuroanatomía funcional (2ª ed.).
Bogotá: Librería medica Celsus.
10. Carlson, N. R. (2009). Fisiología de la
conducta. Octava edición. Pearson
Addison Wesley.
11. Charlier, C., Broly, F., Lhermitte, M.,
et al. (2003). Polymorphisms in the
CYP 2D6 gene: association with
plasma concentrations of fluoxetine
and paroxetine. Ther Drug Monit.
25:738-742.
12. Chávez-León, E., Ontiveros-Uribe,
M. P., Serrano-Gómez, C. (2008). Los
antidepresivos inhibidores selectivos
de recaptura de serotonina (ISRS,
ISR-5HT) Salud Ment; 31(4) :307-
319
13. Contreras, C. M., Marvan, M. L., &
Munoz-Mendez, A. (1993).
Clomipramine increases the
responsiveness of raphe-cortical
neurons in the rat.
Neuropsychobiology, 27(4), 199-203.
doi:118981
14. Contreras, C. M., Sanchez Estrada, G.,
Molina Hernandez, M., & Marvan, M.
L. (1994). Electroconvulsive shock
decreases excitatory responses to
serotonin in the caudate nucleus of the
rat. Prog Neuropsychopharmacol Biol
Psychiatry, 18(1), 193-199.
15. Coplan, J. D., Gopinath, S., Abdallah,
C. G., & Berry, B. R. (2014). A
neurobiological hypothesis of
treatment-resistant depression - Antidepresants and suicide risk in the
mechanisms for selective serotonin
reuptake inhibitor non-efficacy. Front
Behav Neurosci, 8, 189.
doi:10.3389/fnbeh.2014.00189
16. Drevets, W. C., Thase, M. E., Moses-
Kolko, E. L., Price, J., Frank, E.,
Kupfer, D. J., & Mathis, C. (2007).
Serotonin-1A receptor imaging in
recurrent depression: replication and
literature review. Nucl Med Biol,
34(7), 865-877.
doi:10.1016/j.nucmedbio.2007.06.00
8
17. Durkheim, E. (1982). El suicidio.
Madrid: Akal Universitaria, 5-6.
18. Frazer, A. (1997). Pharmacology of
antidepressants. J. Clin.
Psychopharmacon. 17(suppl.1): 2S-
18S.
19. Garakani, A., Martinez, J. M.,
Yehuda, R., & Gorman, J. M. (2013).
Cerebrospinal fluid levels of
glutamate and corticotropin releasing
hormone in major depression before
and after treatment. J Affect Disord,
146(2), 262-265.
doi:10.1016/j.jad.2012.06.037
20. García de Jalon-Aramayo, E., Peralta,
V. (2002). Suicidio y riesgo de
suicidio. Anales Sis, San Navarra. Vol
25.
21. Gartner, L. P, Hiatt, J. L. (1997).
Histologia, texto y atlas. McGraw Hill
Interamericana.
22. González-Garrido, A. A., Ramos-
Loyo, J. (2006). La atención y sus
alteraciones: del cerebro a la
conducta. México. Ed. El manual
moderno; UNAM, Facultad de
psicología.
23. Grunebaum, M. F., et al. (2004).
United States, 1985-1999. J Clin
Psychiatry. 65(11):1456-1462.
24. Gutierrez-Garcia, A. G., Contreras, C.
M. (2006). El suicidio, conceptos
 Guillen GC, Contreras CM, Barrientos C. Rev Mex Med Forense, 2018, 3(1): 27-39
actuales. Salud Mental, Vol. 29, No. 5,
septiembre-octubre.
25. Gutiérrez-García, A. G., Contreras, C.
M. (2008). El suicidio y algunos de
sus correlatos neurobiológicos. Salud
Mental. 31: 321-330.
26. Hansen, R. A., et al. (2005).
Treatment of major depressive
disorder. Ann Intern Med;
143:415:426.
27. Healy, D. (2009). The Antidepressant
Era, Paperback Edition, Harvard
University Press.
28. Heils, A., Teufel, A., Petri, S., Stober,
G., Riederer, P., Bengel, D., et al.
(1996). Allelic variation of human
serotonin transporter gene expression.
Journal of neurochemistry. Jun;
66(6):2621/4.
29. Hernández-Palazuelos, G. (2011).
Conductas suicidas. Hipoc Rev Med
Vol 2 Nún 27-2 Oct-Dic.
30. Holmans, P., et al. (2007). Genetics of
early-onset major depression
(GenRED): Final genome scan report.
Am J Psychiatry; 64:248-258.
31. Homberg, J. R., Olivier, J. D., Blom,
T., Arentsen, T., van Brunschot, C.,
Schipper, P.,. . . Reneman, L. (2011).
Fluoxetine exerts age-dependent
effects on behavior and amygdala
neuroplasticity in the rat. PLoS One,
6(1), e16646.
doi:10.1371/journal.pone.0016646
32. Isung, J., et al. (2012). Low vascular
endothelial growth factor and
interleukin-8 in cerebrospinal fluid of
suicide attempters. Transl Psychiatry;
2:e196.
33. Kaminsky, Z., Wilcox, H. C., Eaton,
W. W., Van Eck, K., Kilaru, V.,
Jovanovic, T., . . . Smith, A. K. (2015).
Epigenetic and genetic variation at
SKA2 predict suicidal behavior and
post-traumatic stress disorder. Transl
Psychiatry, 5, e627.
doi:10.1038/tp.2015.105
34. Kendler, K. S., et al. (2006). A
Swedish national twin study of
lifetime major depression. Am J
Psychiatry; 163:109-114.
35. Kosfeld, M., et al. (2005). Oxytocin
increases trust in humans. Nature
435:673-676.
36. Krishnan, K. R. R., et al. (1991).
Hipocampal abnormalities in
depression. J Neuropsychiatry; 3: 387
37. Lanzenberger, R., Baldinger, P.,
Hahn, A., Ungersboeck, J.,
Mitterhauser, M., Winkler, D., . . .
Frey, R. (2013). Global decrease of
serotonin-1A receptor binding after
electroconvulsive therapy in major
depression measured by PET. Mol
Psychiatry, 18(1), 93-100.
doi:10.1038/mp.2012.93
38. Lesch, K. P., Bengel, D., Heils, A.,
Sabol, S. Z., Greenberg, B. D., Petri,
S., et al. (1996). Association of
anxiety‐related traits with a
polymorphism in the serotonin
transporter gene regulatory region.
Science. Nov 29. 274(5292):1527‐31.
39. Li, H., Gao, Z., Wu, Q., Huang, P.,
Lin, C., & Chen, G. (2013).
Relationship of hypothalamus-
pituitary-adrenal (HPA) axis function
and suicidal behavior in patients with
depression. Shanghai Arch
Psychiatry, 25(1), 32-39.
doi:10.3969/j.issn.1002-
0829.2013.01.007
40. Limon-Morales, O., Soria-Fregozo,
C., Arteaga-Silva, M., Vazquez-
Palacios, G., & Bonilla-Jaime, H.
(2014). Altered expression of 5-HT1A
 Guillen GC, Contreras CM, Barrientos C. Rev Mex Med Forense, 2018, 3(1): 27-39
receptors in adult rats induced by
neonatal treatment with
clomipramine. Physiol Behav, 124,
37-44.
doi:10.1016/j.physbeh.2013.10.026
41. Llinás, R. R. (2002). El cerebro y el
mito del yo. El papel de las neuronas
en el pensamiento y el
comportamiento humanos. Bogotá:
Editorial Norma S. A.
42. Mann, J. J., Kapur, S. (1991). The
emergence of suicidal ideation and
behavior during antidepressant
pharmacotherapy. Arch Gen
Psychiatry. 48:1027-1033.
43. Moya, P. R. (2013). El transportador
de serotonina: variantes genéticas y
trastornos neuropsiquiatricos. Rev.
Farmacol. Chile. 6(3): 19.
44. Murphy, D. L., Lesch, K. P. (2008).
Targeting the murine serotonin
transporter: insights into human
neurobiology. Nature reviews
Neuroscience. Feb; 9(2):85‐96.
45. Murphy, D. L., Moya, P. R.,
Wendland, J. R., Timpano, K. R.
(2012). Genetic contributions to
obessive‐compulsive disorder (OCD)
and OCDrelated disorders In:
Nurnberger J, Berrettini W, editors.
Principles of Psychiatric Genetics.
Cambridge, UK: Cambridge
University Press. p. 121‐33.
46. Nemeroff, C. B., et al. (2007). Impact
of publicity concerning pediatric
suicidality data on physician practice
patterns in the United States. Arch
Gen Psychiatry. 64:466-472.
47. Nutt, D. J. (2003). Death and
dependence: current controversies
over the selective serotonin reuptake
inhibitors. J Psychopharmacol,
17:355-364.
48. Perez-Caceres, D., Ciudad-Roberts,
A., Rodrigo, M. T., Pubill, D.,
Camins, A., Camarasa, J.,. . . Pallas,
M. (2013). Depression-like behavior
is dependent on age in male SAMP8
mice. Biogerontology, 14(2), 165-
176. doi:10.1007/s10522-013-9420-0
49. Perlis, R. H., et al. (2007). Association
between treatment-emergent suicidal
ideation with citalopram aond
polymorphisms near cyclic adenosine
monophosphate response element
binding protein in the STAR*D study.
Arch Gen Psychiatri, 64:689-697.
50. Pompili, M., Serafini, G., Palermo,
M., Seretti, M. E., Stefani, H.,
Angeletti, G.,. . . Girardi, P. (2013).
Hypothalamic pituitary adrenal axis
and prolactin abnormalities in suicidal
behavior. CNS Neurol Disord Drug
Targets, 12(7), 954-970.
51. Rodríguez-Hernández, C., et al.
(2013). Avances en la etiología
genética de la depresión. Psiquis
(México), May-Jun, Vol 22, Num
3:75-81
52. Savitz, J., Lucki, I., & Drevets, W. C.
(2009). 5-HT (1A) receptor function
in major depressive disorder. Prog
Neurobiol, 88(1), 17-31.
doi:10.1016/j.pneurobio.2009.01.009
53. Schillani, G., Goljevscek, S., Carlino,
D., De Vanna, M., Aguglia, E.,
Giraldi, T. (2009). Repeated suicidal
behaviour: Stressful life events and 5-
HTTLPR genetic polymorphism. Int J
Psychiatry Clin Pract, 13(3): 229-32.
54. Sorenson, A. N., Sullivan, E. C.,
Mendoza, S. P., Capitanio, J. P., &
Higley, J. D. (2013). Serotonin
transporter genotype modulates HPA
axis output during stress: effect of
stress, dexamethasone test and ACTH
challenge. Transl Dev Psychiatry, 1,
21130. doi:10.3402/tdp.v1i0.21130
 Guillen GC, Contreras CM, Barrientos C. Rev Mex Med Forense, 2018, 3(1): 27-39

55. Toro, G. J., Yepes, S. M., Palacios, E.
(2010). Neurología (2 ed.). Bogotá:
Manual Moderno Ltda
56. Velázquez, P. L., et al. (2009).
Farmacología Básica y Clínica (18
ed.). Madrid: Medica Panamericana.
57. Way, B. M., Brown, K. W., Quaglia,
J., McCain, N., & Taylor, S. E. (2016).
Nonsynonymous HTR2C
polymorphism predicts cortisol
response to psychosocial stress II:
Evidence from two samples.
Psychoneuroendocrinology, 70, 142-
151.
doi:10.1016/j.psyneuen.2016.04.022
58. Weiss, N., et al. (2010). IL8 and
CXCL13 are potent chemokines for
the recruitment of human neural
precursor cells across brain
endothelial cells. J Neuroimmunol,
223:131–134.
59. Yi-Wei, Y., et al (2015). Incongruent
Reduction of Serotonin Transporter
Associated with Suicide Attempts in
Patients with Major Depressive
Disorder: A Positron Emission
Tomography Study with 4-[18F]-
ADAM. International Journal of
Neuropsychopharmacology, 1–9.
60. Yura, A., et al. (1996). Possible
involment of calmodulin-dependent
kinases in Ca (2+)-dependent
enhancement of [3H] 5-
hydroxytryptamine uptake in rat
cortex, Brain Res, 738(1): 96-102.
61. Zhong, P., & Yan, Z. (2004). Chronic
antidepressant treatment alters
serotonergic regulation of GABA
transmission in prefrontal cortical
pyramidal neurons. Neuroscience,
129(1), 65-73.
doi:10.1016/j.neuroscience.2004.06.0
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