Original article 25
Fluoxetine response in impulsiveaggressive
behavior and serotonin transporter polymorphism
in personality disorder
Hernan Silvaa, Patricia Iturrab, Aldo Solaric, Juana Villarroela, Sonia Jereza,
Marco Jimenezb, Felipe Galleguillosb and Maria Leonor Bustamantea,b
Background Disturbances in central serotonin function
have been implicated in impulsive and aggressive
behavior. A deletion/insertion polymorphism within the
5-HT transporter promoter gene (5-HTTLPR) is thought to
be associated with disturbed impulse control, anxiety, and
depression. The serotonin transporter (5-HTT) is the
primary action site for selective serotonin reuptake
inhibitors (SSRIs). Several studies of major depression
have shown that the l allele of 5-HTTLPR is associated with
better SSRI antidepressant effects than the s allele.
Methods This study investigates the association between
c 2010 Wolters Kluwer Health | Lippincott
response of impulsivity to treatment with fluoxetine and
5-HTTLPR polymorphism in 49 personality disordered
patients. Additionally, we studied TPH1, 5HT1B and 5HT2C
receptor polymorphisms as predictors of response in this
population.
Results Results reveal that patients with the l/l genotype
of 5-HTTLPR had a significantly better response to
fluoxetine when compared to s allele carriers, as evaluated
on the basis of total (P < 0.05) and Aggression subscale
(P < 0.01) Overt Aggression Scale Modified-score
percentage change. There were no significant associations
between fluoxetine response and TPH1 (A218C) ( 6525
Introduction
There is strong evidence for central serotonergic dys-
function in impulsive behavior (Coccaro, 1989; Oquendo
and Mann, 2000; Carver and Miller, 2006). Reductions in
central serotonin function indices have been reported in
personality disordered individuals and other populations
with prominent histories of impulsiveaggressive beha-
vior (Brown et al., 1979; Brown et al., 1982; Coccaro
et al., 1989; OKeane et al., 1992). Patients suffering from
borderline personality disorder exhibit a broad spectrum
of symptoms and behaviors: affect lability, rapid mood
shifts from normal to depressive states, irritability, and
impulsive, aggressive and parasuicidal behavior. Several
open (Norden, 1989; Coccaro et al., 1990; Cornelius et al.,
1990; Cornelius et al., 1991; Markovitz et al., 1991;
Kavoussi et al., 1994) and double-blind, randomized
(Salzman et al., 1995; Coccaro and Kavoussi, 1997; Rinne
et al., 2002) studies of selective serotonin reuptake
inhibitors (SSRIs) suggest that the prescription of an
SSRI may be an effective pharmacological strategy to
0955-8829
c 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
A > G) ( 5806 G > T), HTR1B (G861C) and HTR2C (G68C)
genotype groups.
Conclusion This is the first study assessing the
association between these polymorphisms and
anti-impulsive response to fluoxetine in personality
disorder. As the s genotype is associated with a poorer
selective serotonin reuptake inhibitors response in
major depression, bulimia nervosa and borderline
personality disorder, it could represent a common
biological background for SSRI response. Psychiatr Genet
20:2530
Williams & Wilkins.
Psychiatric Genetics 2010, 20:2530
Keywords: aggressiveness, borderline, impulsivity, pharmacogenetics,
serotonin transporter, selective serotonin reuptake inhibitors
a
Psychiatric Clinic of University of Chile, Santiago de Chile, bProgram of Human
Genetics and cProgram of Cell and Molecular Biology, Biomedical Sciences
Institute, Faculty of Medicine University of Chile, Santiago de Chile, Chile
Correspondence to Hernan Silva, MD, Psychiatric Clinic of University of Chile,
Av. La Paz 1003, Santiago de Chile, 6871436, Chile
Tel: + 56 2 978 8601; fax: + 56 2 777 6786;
e-mail: hsilva@med.uchile.cl
Received 17 October 2008 Revised 1 July 2009
Accepted 16 August 2009
ameliorate the pathology of borderline personality dis-
order. Clinical improvement is associated with changes
in metabolic rate in prefrontal cortex, a region that has
been linked to impulsivity (New et al., 2004). On the
basis of these findings, SSRI treatment is recommended
for borderline personality disordered patients with affect
lability, impulsivity, and aggressiveness (Soloff, 2000).
This recommendation has also been incorporated into the
American Psychiatric Associations practice guidelines on
borderline personality disorder (American Psychiatric
Association, 2001).
Furthermore, SSRIs are currently the first-line medica-
tion for the treatment of major depression. The response
varies among patients, which may be explained partly by
the genetic factors. Identification of the genetic factors
underlying response to SSRI therapy may help to predict
therapeutic response and facilitate optimal drug selection
(Kircheiner et al., 2003). Recent pharmacogenetic SSRI
research has focused on possible associations between
DOI: 10.1097/YPG.0b013e328335125d
26 Psychiatric Genetics 2010, Vol 20 No 1
polymorphisms in candidate genes related to SSRI
therapeutic effects and clinical response (Serretti et al.,
2002; Peters et al., 2004; Serretti and Artioli, 2004). The
serotonin transporter (5-HTT) is the primary target
for SSRI action. Its role is to uptake 5HT into the
presynaptic neuron, which thus terminates the synaptic
actions and recycles it into the neurotransmitter pool. A
polymorphism in the promoter region of the human
5HTT gene (5-HTTLPR) has been described (Heils
et al., 1996). It consists of a 44-base pair deletion (short or
s variant) or insertion (long or l variant) endowed with
functional consequences. The s form is associated with
lower transcriptional activity and reduced 5HT re-uptake
efficiency (Rausch, 2005). In 1998, Smeraldi et al.
(Smeraldi et al., 1998) first showed an association
between antidepressant fluvoxamine response and the
5-HTTLPR polymorphism, with a better response to
fluvoxamine showed for l-allele carriers compared with
s-variant homozygotes. Several subsequent studies have
shown either better response or more rapid response with
the 5HTTLPR-l allele (Arias et al., 2003; Serretti and
Artioli, 2004; Lesch and Gutknecht, 2005; Serretti et al.,
2005) although these results have not always been
replicated (Kraft et al., 2007). Two Asian studies had
contrasting findings too (Kim et al., 2000; Yoshida et al.,
2002). A possible explanation for these discrepancies is
the low frequency of the l allele in Asian population
(Yoshida et al., 2002). Using mega-analytical (Serretti
et al., 2006), and meta-analytical techniques (Serretti
et al., 2007) that gather data from many patients, the
association of the l variant with a better SSRI response
has been confirmed.
Genetic studies have shown an association between
5-HTTLPR and impulsivity (Lesch et al., 1996; Lee
et al., 2003), suicide (Bellivier et al., 2000; Bondy et al.,
2000; Courtet et al., 2004) and eating disorders (Di Bella
et al., 2000; Gorwood, 2004; Monteleone et al., 2006),
suggesting that 5-HTTLPR may represent a vulnerability
factor common to those clinical conditions in which
a dysregulation of 5HT transmission seems to occur.
Functional variants have been identified in the l allele,
which have been designated lG and lA (Hu et al., 2006).
lG and s alleles have comparable levels of serotonin
transporter expression (Hu et al., 2006). Therefore
individuals may be classified on the basis of their levels
of expression as lower and higher, and lG and s individuals
should be considered as a whole and separated from lA
individuals.
Other genes have also shown associations with impulsi-
vity. Tryptophan hydroxylase (TPH1) is the rate-limiting
enzyme in the synthesis of serotonin, and the TPH1
genotype has been associated with suicidality and
impaired impulse control (Nielsen et al., 1998; Rotondo
et al., 1999; Turecki et al., 2001) and impulsiveaggressive
behavior (New et al., 1998; Staner et al., 2002). After the
finding that mice genetically deficient for TPH had
normal amounts of 5-HT in the brain and showed no
behavioral differences with wild-type animals, a second
isoform of the enzyme was discovered, which is known as
TPH2, this variant is expressed exclusively in the brain
(Walther et al., 2003). A functional TPH2 polymorphism
(G1463A) has been identified and association with major
depression has been proposed (Zhang et al., 2005). The
5HT1B receptor is thought to mediate aggression and
impulse control as studied in 5HT1B knockout mice and
in aggressive and impulsive behavior in humans with
alcoholism (Lappalainen et al., 1998; Bouwknecht et al.,
2001). Other candidate genes for impulsive personality
traits include genotypes of the 5HT2C receptors, as
studied in cases of deliberate self-harm (Evans et al.,
2000). Polymorphisms of those genes and others could be
useful for predicting the therapeutic response of im-
pulsivity to SSRIs. These genes have been studied earlier
in antidepressant response to SSRIs (Peters et al., 2004;
Serretti and Artioli, 2004; Serretti et al., 2005).
The aim of this study is to investigate the association
between the response of impulsivity to fluoxetine treat-
ment and 5-HTTLPR polymorphism in personality
disordered patients. Preliminary analysis of our data
indicates that s allele carriers show a different temporal
pattern of response (Silva et al., 2007). Additionally, we
studied the TPH1, and 5HT1B and 5HT2C receptors
polymorphisms as predictors of response in this popula-
tion. TPH2 functional polymorphism was not included in
this study because, as earlier reported by our group, we
did not find any carriers of the minor allele A among
the borderline personality disorder patients (Bustamante
et al., 2006).
To the best of our knowledge, no study has assessed
the association between those polymorphisms and anti-
impulsive response to fluoxetine in personality disorder.
Methods and materials
Participants
The study population consisted of 59 patients, aged
1865 years, enrolled at the Psychiatric Clinic of the
University of Chile. The group of patients represents
the sociogenetic strata II of the contemporary Chilean
population, which is considered the most representative
strata of the Chilean Admixture Population (Amerindian
people and Caucasian settlers). All participants met the
DSM-IV diagnostic criteria of borderline personality
disorder according to the International Personality Dis-
orders Examination (Loranger, 1999). The Structured
Clinical Interview for DSM-IV Axis I Disorders Patient
Edition (First et al., 1995) was used to rule out any Axis I
diagnoses. Participants with a history of organic mental
syndrome, psychosis, mania, eating disorders, substance
abuse or dependence or significant physical illness
according to anamnesis were excluded. Patients with a

history of depressive or anxious symptoms were included
if they were asymptomatic at the moment of the study.
All participants were drug-free or had abstained from
drugs for at least 2 weeks, or 4 weeks if they had
been taking fluoxetine. Informed consent was obtained
from all participants. The study approval was obtained
from the local ethics committee, and the study was
carried out according to the principles of the Declaration
of Helsinki.
All participants were treated with fluoxetine in doses of
20 mg/day in the beginning; based on clinical response
after a 2-week treatment, investigators could increase
the dosage to 40 mg/day. Additional increases were made
if clinical response was considered insufficient. Plasma
fluoxetine levels were assessed at 12 weeks of treatment
and assayed by use of a liquid chromatographic method
and fluorescence detection (Suckow et al., 1992). No
other psychotropic medications were permitted; however
anxiolytic alprazolam and hypnotic zolpidem were allowed.
Responders were defined as patients with at least 75%
reduction in baseline Overt Aggression Scalemodified
(OAS-M) ratings after 12 weeks of fluoxetine treatment
(Coccaro et al., 1991). This definition was consistent with
the criteria commonly used in antidepressant treatment
response evaluation. A full 12 weeks period was con-
sidered necessary to define an adequate antiaggressive or
anti-impulsive trial with fluoxetine (American Psychiatric
Association, 2001).
Genetic analysis
DNA was extracted from peripheral blood leukocytes
using the Ultra Clean DNA Blood Spin kit (Mo Bio
Laboratories Inc., Carlsbad, California, USA) according
to the manufacturers instructions. Polymerase chain
reaction (PCR) amplification was carried out using the
primers designed by (Gelernter et al., 1997). Amplifica-
tion reaction was carried out in a final volume of 15 ml
consisting of 100 ng of genomic DNA, 0.15 mmol/l dNTP,
0.2 mmol/l of sense and antisense primers, and 1.8 mmol/l
MgCl2 and 1.5 U of Taq DNA polymerase (Biotools,
Madrid, Spain). Reaction was initiated by 3 min 951C
denaturation, followed by 40 cycles of denaturation at
951C for 30 s; anealing at 571C for 30 s; extension at 721C
for 60 s. A final extension at 721C for 10 min was carried
out as well. The long (419 bp) and short (375 bp) alleles
were then analyzed in 22.5% Metaphor agarose gels
stained with ethidium bromide. To identify the SNP that
occurs in the l allele, l carriers samples were digested in
MspI, as described by (Stein et al., 2006), which allowed
to identify the A-G substitution since it creates an
additional site for this enzyme.
Variants of TPH1 A218C, TPH16526A>G, and TPH1
5806G>T were genotyped by PCR-restriction fragment
length polymorphism (RFLP) methods. The PCR reac-
tion was carried out as described earlier (Rotondo et al.,
Fluoxetine response in impulsiveaggressive behavior Silva et al. 27
1999; Serretti et al., 2001; Turecki et al., 2001). Restriction
fragments were separated in a 2% agarose gel and stained
with ethidium bromide.
Variants of HTR1B (G861C) were typed by PCR-RFLP
as described by (Lappalainen et al., 1998). Essentially
PCR products were digested with HincII (BioEngland
New Lab, New England Bio Labs: Beverly, Massachusetts,
USA) and electrophoresed on a 2% agarose gel.
Variants of HTR2C (X linked) were genotyped by
PCR-RFLP, which detects a Cys23(C) to Ser23(S)
substitution. The standard PCR assay was performed,
and amplicons were digested using HinfI (BioEngland
New Lab) as described by (Lappalainen et al., 1995). The
resulting fragments were separated in a 3.5% agarose
(Methafor) gel and visualized with ethidium bromide
staining.
Statistical analysis
Statistical analysis was performed using the Statistical
Package for the Social Sciences (SPSS, version 11.5, SPSS
Inc., Chicago, 1999). The difference in baseline clinical
and demographic characteristics between groups (re-
sponder and nonresponder patients) was tested with
Students t-test. The presence of HardyWeinberg
equilibrium was examined using the Chi-square test for
goodness of fit. We estimated the genotypic and allelic
frequencies of each polymorphism for the impulsive
sample participants. Comparisons between responder and
nonresponder impulsive patients were carried out using
the Fishers test. The odds ratio with a 95% confidence
interval was calculated.
Results
A total of 59 patients were enrolled in the study. Forty-
nine patients (83%) completed a 12-week course of
fluoxetine (female/male: 36/13; mean age: 30.0, SD: 9.5
years). At the beginning of the study the ratings were:
OAS-M total 38.1 (SD: 16.4), Aggression subscale 28.6
(SD: 15.1), Irritability subscale 6.7 (SD: 1.9), Suicidality
subscale 2.8 (SD: 3.3). At 12 weeks the ratings were:
OAS-M total 14.0 (SD: 10.7), Aggression subscale 8.5
(SD: 8.9), Irritability subscale 4.4 (SD: 2.6), Suicidality
subscale 1.1 (SD: 2.0). The mean fluoxetine dose was
36.9 mg/day (SD: 12.8).
There were no significant differences in sex, age,
fluoxetine dosage or baseline OAS-M score between the
responder and nonresponder groups. We further evalu-
ated fluoxetine response for total OAS-M and for each
subscale (Table 1).
Genotype distributions for all genetic polymorphisms
were in HardyWeinberg equilibrium. There were no
significant associations between fluoxetine response and
TPH1 (A218C) ( 6525 A > G) ( 5806 G > T), HTR1B
(G861C) and HTR2C (G68C) genotype groups (Table 2).
28 Psychiatric Genetics 2010, Vol 20 No 1

Table 1 Descriptive statistics on demographic and OAS-M data However, for 5-HTTLPR genotypes l/l carriers had a
in responders (n = 22) and nonresponders (n = 27) to a 12-week significantly better response to fluoxetine than patients
fluoxetine treatment
carrying an s allele (Table 3). The odds ratio for l/l carriers
Responders Nonresponders P value was 14.857 (95% CI, 1.02482.414 P = 0.017). Patients
Sex (F/M) 15/7 21/6 0.525 with the l/l genotype had significantly lower scores on the
Mean age (years) (SD) 29.1 (8.1) 30.7 (10.7) 0.540
Fluoxetine dosage (mg/day) (SD) 34.1 (15.3) 39.3 (9.9) 0.181
OAS-M and on the Aggression subscale at week 12 of
Plasma fluoxetine levels (ng/ml) 194.3 (104.2) 174.6 (101.4) 0.674 treatment with fluoxetine. All of the l allele carriers, that
Baseline OAS-M 39.7 (17.2) 36.8 (15.8) 0.546 is, l/l and l/s individuals, carried the lA variants, and are
12-week OAS-M 6.2 (4.7) 20.4 (9.9) < 0.001
Baseline aggression 30.2 (15.8) 27.3 (14.7) 0.509
therefore assumed to have comparable levels of serotonin
12-week aggression 1.8 (2.3) 13.9 (8.7) < 0.001 transporter expression.
Baseline irritability 6.7 (2.3) 6.8 (1.5) 0.867
12-week irritability 3.5 (2.6) 5.1 (2.5) 0.038
Baseline suicidality 2.8 (3.2) 2.8 (3.5) 0.965
12-week suicidality 0.8 (1.2) 1.4 (2.4) 0.247
Discussion
The main finding of this study is that the l/l genotype
OAS-M responders: defined by a reduction of at least 75% on the OAS-M total
score compared to baseline.
of the 5-HTTLPR is associated with better anti-
F, female; M, male. impulsive response to fluoxetine in borderline personality
disordered patients. The short form of 5-HTTLPR is
associated with a poorer response. The effect of flu-
Table 2 Genotype frequencies in responders (n = 22) and oxetine was primarily on the Aggression subscale of the
nonresponders (n = 27) to a 12-week fluoxetine treatment OAS-M. The reduction in aggressiveness and impulsivity
Responders Nonresponders is consistent with findings from earlier studies suggesting
Genotypes (n %) (n %) P r 0.05 that SSRI treatment is an effective pharmacological
SERTLPR strategy in borderline personality disorder (Norden,
l/l 8 (88.9) 1 (11.1) 0.013 1989; Coccaro et al., 1990; Cornelius et al., 1990; Cornelius
l/s 9 (39.1) 14 (60.9)
s/s 5 (29.4) 12 (70.6) et al., 1991; Markovitz et al., 1991; Kavoussi et al., 1994;
TPH1 A218C Salzman et al., 1995; Coccaro and Kavoussi, 1997; New
A/A 6 (54.4) 5 (45.5) 0.609
A/C 8 (36.4) 14 (63.6)
et al., 1998; Soloff, 2000; American Psychiatric Association,
C/C 8 (50.0) 8 (50.0) 2001; Rinne et al., 2002).
TPH1 6525 A > G
A/A 8 (66.7) 4 (33.3) 0.126 These results cannot be explained by differences in
A/G 11 (44.0) 14 (56.0)
G/G 3 (25.0) 9(75.0)
compliance, because responders were similar to non-
TPH1 5806 G > T responders in average fluoxetine dose and plasma flu-
G/G 13 (56.5) 10 (43.5) 0.157 oxetine levels. Nor can they be explained by age and sex,
G/T 9 (34.6) 17 (65.4)
T/T as these were similar in both groups. Earlier studies have
HTR1B G861C shown that age may affect therapeutic response to SSRIs
G/G 7 (41.2) 10 (58.8) 1.000
G/C 11 (45.8) 13 (54.2)
and others antidepressants (Morishita and Arita, 2004).
C/C 4 (50.0) 4 (50.0) Furthermore, the reduction in aggressiveness and im-
HTR2C G68C pulsivity could not be accounted for by the antidepressant
G/G 14 (45.2) 17 (54.8) 0.519
G/C 1 (20.0) 4 (80.0) activity of fluoxetine. In this study, no participant met
C/C criteria for a current major depression. Moreover, accord-
G 7 (53.8) 6 (46.2) ing to other studies, antiaggressive response to fluoxetine
C
is not associated with any systematic changes in depres-
sion, even in participants with history of dysthymia or
depressive disorder (Coccaro and Kavoussi, 1997).
Table 3 Distribution of responder and nonresponder patients
(n = 49) to a 12-week fluoxetine treatment, by 5-HTTLPR genotype
Associations between the s allele and a poorer SSRI
group, and OAS-M subscale response have been repeatedly reported in participants
Responders Nonresponders P value
with major depression (Smeraldi et al., 1998; Serretti and
Artioli, 2004; Lesch and Gutknecht, 2005; Serretti et al.,
OAS-M
l/l 8 1 0.007
2005), but this association has not been investigated in
l/s + s/s 14 26 depth regarding anti-impulsive response in borderline
Aggression personality disorder. It is likely that a single polymorph-
l/l 8 1 0.023
l/s + s/s 17 23 ism explains only part of the observed variations in SSRI
Irritability anti-impulsive response. Further studies analyzing multi-
l/l 1 8 1.000
l/s + s/s 6 34
ple genes implicated in the therapeutic effect of SSRI
Suicidality may give a better prediction for response to treatment.
l/l 5 4 0.465 Furthermore, it is likely that multiple genes contribute to
l/s + s/s 15 25
complex traits such as aggressiveness and impulsivity, and
 Fluoxetine response in impulsiveaggressive behavior Silva et al. 29
the association of any specific gene with such a trait
may be quite modest. Genetic vulnerability is likely to be
compounded by environmental factors in the expression
of impulsive aggression, which may further contribute to
a modest gene-trait relationship.
It is intriguing that the same 5-HTTLPR genotype is
associated with a poorer SSRI response in major depres-
sion, bulimia nervosa (Monteleone et al., 2005) and
borderline personality disorder. All of these conditions are
related to serotonergic dysfunction. If similar findings are
reported in other serotonergic-related syndromes such
as panic disorders and obsessive-compulsive disorder
in which SSRIs are currently used as a first-line treat-
ment, this genotype could represent a common biological
background for SSRI response.
TPH1 (A218C) ( 6525 A > G) ( 5806 G > T), HTR1B
(G861C) and HTR2C (G68C) genotypes have been
associated with suicidality, self-harm and impulsive
aggressive behavior (Lappalainen et al., 1998; New et al.,
1998; Nielsen et al., 1998; Rotondo et al., 1999; Evans et al.,
2000; Bouwknecht et al., 2001; Turecki et al., 2001; Staner
et al., 2002), characteristic manifestations of borderline
personality disorder. However, these genes were not
found to be related to fluoxetine response in this study.
A limitation of this study is the relatively low number of
participants. We believe that the highly characterized
phenotypes used in the study help to compensate for this
limitation. Also, the predominance of women in this work
limits the extrapolation of results to other populations.
Further research with larger populations and using differ-
ent serotonergic antidepressants is required.
Acknowledgements
This work was supported by the Fondo Nacional
de Desarrollo Cientfico y Tecnologico (FONDECYT
1030305). Giovanna Otalora provided excellent technical
assistance.
Conflicts of interest: none declared.
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