Journal of Affective Disorders 133 (2011) 221–226
Contents lists available at ScienceDirect
Journal of Affective Disorders
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j a d
Research report
The 5-HTTLPR polymorphism, impulsivity and suicide behavior in euthymic
bipolar patients☆
Leandro Fernandes Malloy-Diniz a,e,⁎, Fernando Silva Neves b,1, Paulo Henrique Paiva de Moraes a,2,
Luiz Armando De Marco c,e,3, Marco Aurélio Romano-Silva b,e,4,
Marie-Odile Krebs d, Humberto Corrêa b,e,4
a
Departamento de Psicologia da Universidade Federal de Minas Gerais, Avenida Antonio Carlos 6627, Faculdade de Filosofia e Ciências Humanas, Sala 4010,
Belo Horizonte, Minas Gerais, Brazil
b
Departamento de Saúde mental, Universidade Federal de Minas Gerais, Faculdade de Medicina, Avenida Alfredo Balena, 190 sala 240, Santa Efigênia, 30130-100,
Belo Horizonte, MG, Brazil
c
Departamento de Cirurgia, Universidade Federal de Minas Gerais, Faculdade de Medicina, Avenida Alfredo Balena 190, Sala 325, Santa Efigênia, 30130-100 Belo Horizonte, MG, Brazil
d
Descartes University; INSERM, U894 Laboratoire de Pathophysiology of Psychiatric, Disorders; Sainte-Anne Hospital, 7 rue Cabanis 75674 Paris, CEDEX 14, France
e
INCT de Medicina Molecular, Faculdade de Medicina, Universidade Federal de Minas Gerais, Av Alfredo Balena, 190, Belo Horizonte-MG, CEP 30130-100, Brazil
a r t i c l e
i n f o
Article history:
Received 12 September 2010
Accepted 31 March 2011
Available online 6 May 2011
Keywords:
Bipolar disorder
Suicide
Impulsivity
5-HTTLPR
Neuropsychology
Decision-making
a b s t r a c t
Background: Suicide behavior is very frequent in Bipolar Disorder (BD) and they are both closely
associated with impulsivity. Furthermore they are, impulsivity, BD and suicide behavior,
associated with serotonergic function, at least partially, under genetic determinism and somewhat
associated with the serotonin transporter gene polymorphism, the 5-HTTLPR. We aimed to assess
different impulsivity components in BD sub-grouped by suicidal attempt and healthy controls. We
hypothesized that the non-planning/cognitive impulsivity, could be more closely associated with
suicidal behavior. We further associated 5-HTTLPR genotypes with neuropsychological results to
test the hypothesis that this polymorphism is associated with cognitive impulsivity.
Method: We assessed 95 euthymic bipolar patients sub-grouped by suicidal attempt history in
comparison with 94 healthy controls. All subjects underwent a laboratory assessment of
impulsivity (Continuous Performance Test and Iowa Gambling Test). Furthermore the genotyping
of 5-HTTLPR was performed in all subjects.
Results: We found that bipolar patients are more impulsive than healthy controls in all impulsivity
dimensions we studied. Furthermore bipolar patients with a suicide attempt history have a
greater cognitive impulsivity when compared to both bipolar patients without such a history as
well when compared to healthy controls. No association was found between 5-HTTLPR genotypes
and neuropsychological measures of impulsive behavior.
Limitations: The sample studied can be considered small and a potentially confounding variable –
medication status – was not controlled.
Conclusion: A lifetime suicide attempt seems associated with cognitive impulsivity independently
of the socio-demographic and clinical variables studied as well with 5-HTTLPR genotype. Further
studies in larger samples are necessary.
© 2011 Elsevier B.V. All rights reserved.
☆ The work was conducted between the month of January (year 2006) and
January (year 2010).
⁎ Corresponding author. Tel.: + 55 31 34095027.
E-mail address: [email protected] (L.F. Malloy-Diniz).
1
Tel./fax: + 55 31 34099785.
2
Tel.: + 55 31 34095027.
3
Tel./fax: + 55 31 34099134.
4
Tel.: + 55 31 34992719; fax: + 55 31 34992695.
0165-0327/$ – see front matter © 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jad.2011.03.051
1. Introduction
Impulsivity, defined as a process that includes a swift action
without conscious judgment, a behavior without adequate
thought and a tendency to act with less forethought despite
normal intelligence (Moeller et al., 2001) is considered a core
222
L.F. Malloy-Diniz et al. / Journal of Affective Disorders 133 (2011) 221–226
characteristic of Bipolar Disorder (BD). It is present in maniac/
hypomaniac, depressive and/or euthymic affective phases (Najt
et al., 2007; Swann et al., 2008). Impulsivity can be rather
deleterious in BD since it has been associated with substance
abuse (Allen et al., 1998) as well as increased morbidity,
accidents and familial and social troubles (Hollander et al.,
2001). The most dramatic consequence of impulsivity in BD is
suicidal behavior (Turecki, 2005). Nearly one third of patients
acknowledge at least one suicide attempt and 10% to 20%
commit suicide. In those patients, suicide rates average
approximately 1% annually, about 60 times higher than in the
general population (Müller-Oerlinghausen et al., 2002).
To our knowledge few studies specifically addressed the
issue of impulsivity and suicidal behavior in BD (Najt et al.,
2007, Swann et al., 2008) and those that did, overall reported
an association between impulsivity and suicide. However,
comparison between the results of those studies can be
misleading. First, impulsivity was assessed using questionnaire responses in the majority of the studies. Behavior
laboratory tests are more reliable since they can be independent of recall and interpretation of past behavior. Second,
impulsivity is a complex construct and there are many
controversies about how to define and measure it, leading to
obvious differences in the results depending on the questionnaires used. Furthermore, some authors argue that impulsivity can be divided into at least three different dimensions
(attentional, motor and non-planning/cognitive impulsiveness) with distinct neuro-anatomical and functional substract
(Patton et al., 1995; Bechara and Van der Linden, 2005).
It is known that BD, suicidal behavior and impulsivity are,
at least partially, genetically determined and somewhat under
serotonergic modulation (Turecki, 2005). The 5-HTTLPR
polymorphism of the serotonin transporter has been extensively analyzed in several psychiatric conditions. Probably, the
most consistent finding is an association between the S allele
(a mutation that reduces transporter expression, reducing
serotonin re-uptake) and suicidal behavior, regardless of
diagnosis (Campi-Azevedo et al., 2003; Neves et al., 2008;
Neves et al., 2009). The association studies between the
5-HTTLPR polymorphism and impulsivity are rarer and to our
knowledge there are no previous studies in BD. Furthermore,
it has been shown recently that 5-HTTLPR is functionally
triallelic (La, Lg, and S) (Hu et al. 2006). The L allele with an
A-to-G substitution (Lg) has a lower expression than La and a
nearly equivalent expression as the S allele (Rocha et al.,
2008). In view of the strong links between impulsivity, BD and
suicide the present study assessed impulsivity in a sample of
BD patients sub-grouped by suicidal attempt history compared to healthy controls. We hypothesized that nonplanning/cognitive, would be more closely associated with
suicidal behavior. We further associated 5-HTTLPR genotypes
with our neuropsychological results to test the hypothesis
that this polymorphism is associated with non-planning/
cognitive impulsivity.
2. Materials and methods
2.1. Subjects
Study participants were 95 BD patients (41 with lifetime
history of suicide attempt) recruited from the Núcleo de
Transtornos Afetivos from the Psychiatric Service of the
Hospital das Clínicas, Universidade Federal de Minas Gerais.
Inclusion criteria included a BD diagnosis according to DSM-IV
and determined using a structured interview (MINI-PLUS)
and euthymic at the moment of neuropsychological assessment. The Brazilian version of the Beck Depression Inventory
(BDI) (Gorestein and Andrade, 1998) and the Young Mania
Rating Scale (YMRS) (Vilela et al., 2005) were used. Subjects
were classified as euthymic if they had both a BDI score lower
than 12 points and a YMRS lower than 13. Additional inclusion
criteria included at least eight years of formal education and
normal intelligence as measured by the Test of Raven's
Progressive Matrices (percentile N10) (Raven, 2008).
The control group consisted of 94 subjects recruited from
the community. No subject had a history of an Axis 1 psychiatric
illness according to DSM-IV criteria and assessed by the MINIPLUS. All controls had at least eight years of formal education
and normal intelligence as measured by the Test of Raven's
Progressive Matrices.
Lifetime history of suicide was assessed using a semistructured interview plus a review of medical records as
previously described (Campi-Azevedo et al., 2003). Furthermore, a supplementary interview with at least one close
relative and a review of medical records were undertaken to
confirm the patient's information. Suicide attempt was defined
as a conscious intent of the patient to end his/her life, even if
ambivalent, through means that the patient believed could
result in death (Asberg et al., 1976).
2.2. Neuropsychological assessment
Two different tests were used, the Continuous Performance
Test (CPT-II) (Epstein et al., 2003) that provides measures of
sustained attention and impulsiveness, and a computerized
Brazilian version of the Iowa Gambling Test (IGT) (Bechara
et al., 2000; Malloy-Diniz et al., 2008). In the CPT-II, subjects
have to press the spacebar when any letter (except the letter X)
appears on screen. Omission errors occur when the individual
does not press the spacebar when a letter (except X) appears on
screen and reflect instances when a patient is not attentive to
the target stimuli. A commission error occurs when the subject
presses the spacebar when the letter X appears on screen,
reflecting flaws in motor response inhibition. These two
concepts correspond to attentional and motor impulsiveness,
respectively, of Barratt's model of impulsiveness (Malloy-Diniz
et al., 2007). Thus, we used commission and omission errors as
dependent measures to evaluate motor and attentional
impulsivity.
In the IGT, subjects have to choose one card at a time from
four available decks (A, B, C and D). The task requires the
subjects to make 100 choices (100 trials), and in each trial
subjects may win or lose a certain amount of money. During
the instructions, subjects are told that some decks are more
advantageous than others but they do not know which decks
are better. After each choice, subjects receive feedback on the
computer screen telling them how much money they won or
lost. Using the feedback, the subject has to avoid decks that
yield high immediate gains but lead to large future losses
(decks A and B) and choose the decks that lead to small
immediate gains but avoids substantial losses throughout the
task (decks C and D). One hundred choices are divided into
L.F. Malloy-Diniz et al. / Journal of Affective Disorders 133 (2011) 221–226
five blocks, with twenty choices each. This kind of register is
important to verify changes in the pattern of choices during
the task, such as observing the learning curve. For each block,
the net score was used (number of cards selected from the
advantageous “good” decks minus the disadvantageous “bad”
decks) as the dependent measure. A total net score from all
blocks was also obtained. This test is a good model for
studying non-planning/cognitive impulsivity (Malloy-Diniz
et al., 2007).
A neuropsychologist administered the tests in a laboratory
in a fixed order, beginning with CPT-II. During the administration of the tests and scales the examiner was unaware of
the subject's diagnosis and also blind to molecular results.
2.3. Genotyping
DNA extraction and bilallelic amplification were performed as previously described (Campi-Azevedo et al., 2003).
To identify Lg the amplified product was digested with MspI
restriction enzyme (New England Biolabs, Ipswich, MA)
which allows the detection of the A/G (rs25531) SNP. The
digestion products were visualized by 3.5% agarose gel
electrophoresis stained with ethidium bromide under UV
light, as previously described (Rocha et al., 2008).
2.4. Statistical analysis
Descriptive statistics (mean and standard deviation) for
socio-demographic variables were used to compare the
individuals. Due to the non-normal distribution of the CPT-II
test results of the groups (measured by Kolmogorov–Smirnov
test) the Mann–Whitney nonparametric test was employed to
compare the group's differences (bipolar vs. healthy controls
and suicide attempters vs. non attempters). We also used
Pearson coefficient analyses to verify correlations between the
measures and the number of suicide attempts.
A comparison between suicide attempters vs. nonattempters was conducted using a generalized linear model
analyses to assess interaction between clinical features (BDI
and YMRS scores, illness subtype and intellectual level), sociodemographic aspects (age, gender and educational level) and
genotypes. In these analyses impulsivity measures were
considered dependent variables. Independent variables included bipolar subtype (I or II), lifetime history of suicide
attempt (present and absent), gender and educational level
(high school and college graduate) as factors and intelligence
(Raven's raw score), age, depression (BDI score) and mania
(YMRS score) as covariates.
We grouped S- and/or Lg-carriers in view of the fact that Sand/or Lg allele acts in a nearly dominant way. This group was
named the “low expression group” and participants with the
La/La genotype comprised the “high expression group” as
previously described (Rocha et al., 2008). Genotype frequencies between groups were compared using the chi-square test.
Results were considered significant when p b 0.05.
3. Results
Bipolar patients and healthy controls had comparable
demographic characteristics concerning gender distribution,
formal education levels as well as comparable intelligence
223
performance but bipolar patients were older than healthy
controls.
Regarding impulsivity, the bipolar group as a whole had a
statistically significant worse performance than controls on
almost all measures of impulsiveness (except for the first and
second blocks of IGT). Table 1 illustrates these results.
Bipolar patients were further sub-grouped according to
suicide behavior. The socio-demographic parameters and
intelligence levels were comparable between the two groups
and comparable to healthy controls, except that bipolar
patients were older than controls. On impulsivity tasks, suicide
attempters were different than non-attempters on the IGT task
(second, third, fourth and fifth blocks and net score) (Fig. 1) but
no differences were found between these two groups on CPT-II.
Furthermore, a significant inverse correlation between number
of suicide attempts and IGT score (p= 0.001) was seen.
Genotype comparison between groups was performed. All
groups tested within Hardy–Weinberg equilibrium. No statistical differences were observed between bipolar patients and
control subjects [high expression group (30 vs. 24) and the low
expression group (65 vs. 70), X2 = 0.42], nor between bipolar
patients with and without a lifetime suicide attempt [high
expression group (12 vs. 18) and low expression group (29 vs.
36), X2 = 0.178]. No association was found between 5-HTTLPR
genotypes and neuropsychological measures of impulsive
behavior.
A generalized linear regression analysis was performed to
examine the relationship between clinical, socio-demographic
and genetic variables and the impulsivity measures that show
differences according to lifetime history of suicide attempt
(non-planning impulsivity). Considering non-planning impulsivity (IGT net score results), the best model included only
lifetime history of suicide attempt (coefficient B = 17.121;
SE = 4.777; Wald chi-square = 12,843, 2.37; p b 0.001; and 95%
CI= 7.7 to 26.4) and no other clinical, socio-demographic or
genetic variables.
4. Discussion
The primary objective of the present study was to address
three facets of impulsivity: non-planning/cognitive, attentional
and motor impulsivity in bipolar disordered patients subgrouped by suicide attempt history. A well-characterized
sample of adults with bipolar disorder was evaluated and it
showed that bipolar patients were more impulsive than healthy
controls on all three dimensions, despite the absence of
differences in intellectual level. Furthermore, bipolar patients
with a history of suicide attempt had higher non-planning/
cognitive impulsivity compared to non-attempters. This relationship was found in a previous study in type I BD patients
(Malloy-Diniz et al., 2009) and was reinforced by the
correlation between the disadvantageous choices reflected in
the IGT net score and suicide attempts. Such differences were
not seen in CPT-II omission and commission errors.
The groups were comparable on all socio-demographic
variables studied except that bipolar patients were older than
healthy controls. The development of executive functions,
including some types of impulsivity improves from childhood
to adulthood and becoming less efficient at the end of
adulthood and early old age (Zelazo et al., 2004). Despite the
age difference between the study groups, the mean age of the
224
L.F. Malloy-Diniz et al. / Journal of Affective Disorders 133 (2011) 221–226
Table 1
Comparison between control and bipolar subjects in sociodemographic, genetic and impulsivity measures.
Age
Gender
Female N (%)
Educational level
University N (%)
Genotype
LaLa
Raven score (mean and SD)
CPT — II (omission errors) (mean and SD)
CPT — II (commission errors)
(mean and SD)
CPT hit reaction time (mean and SD)
IGT block 1 (mean and SD)
IGT block 2 (mean and SD)
IGT block 3 (mean and SD)
IGT block 4 (mean and SD)
IGT block 5 (mean and SD)
IGT net score (mean and SD)
Healthy controls (n = 94)
Bipolar disorder patients (n = 95)
Mean or
count
Mean or
count
32
53
56
24
47.2
3.47
10.26
383.52
− 1.20
2.14
5.68
6.93
6.78
20.57
Standard deviation
or N%
(13)
(56. 4%)
(59.6%)
(25.5%)
(5.3)
5.38
7.20
71.03
5.99
6.80
6.84
8.07
9.13
23.61
controls and bipolar subjects was in middle adulthood and,
therefore, this difference probably did not affect the impulsivity results, as further supported by the lack of a relationship found between impulsivity measures and age in our
study.
The frequency of the 5-HTTLPR genotype was not different
between bipolar patients and healthy controls or in subjects
according to suicide attempt history. An association between
the short form of the 5-HTTLPR and suicide behavior is well
established (Bondy et al., 2006) and the current researchers
have published results confirming this association in different
diagnostic groups as well as in bipolar patients (CampiAzevedo et al., 2003; Neves et al., 2008). Nevertheless, it has
been shown that the association effect in smaller and larger
samples is needed to observe this association. The negative
association seen in the present study probably reflects a Type
II error.
The same argument regarding sample size could explain the
lack of an association between the 5-HTTLPR and impulsivity
seen here. However, in a previous study involving a sample of
only 49 obsessive–compulsive disorder (OCD) patients, we
8.0
Bipolar Disorder
without lifetime
history of suicide
attempt
6.0
4.0
Bipolar Disorder with
lifetime history of
suicide attempt
2.0
0.0
-2.0
Control Group
IGT
IGT
IGT
IGT
IGT
Block 1 Block 2 Block 3 Block 4 Block 5
-4.0
Fig. 1. Comparison between bipolar subjects (according to lifetime history of
suicide attempt) and control group.
Z our x2
P
Standard deviation
or N%
41
66
44
30
44.8
9.31
16.17
12
69.5%
46.3%
31.6%
3.8
15.68
8.76
4.473
3472
3.334
0.847
− 1.379
− 4.755
− 4.743
0.000
N.S.
N.S.
N.S.
N.S.
0.000
0.000
427.10
− 1.87
0.49
1.20
1.40
1.52
3.89
89.34
4.47
5.18
6.72
7.68
8.92
24.28
− 3.866
− 0.571
− 1.455
− 4.812
− 4.314
− 3.890
− 4.555
0.000
N.S.
N.S.
0.000
0.000
0.000
0.000
were able to show a higher non-planning cognitive impulsivity
in low-expression allele carriers than in those with high
expression (Rocha et al., 2008).
Impulsivity is accepted as a good endophenotype candidate in suicide behavior (Mann et al., 2009). Therefore, an
association between suicide behavior and 5-HTTLPR genotypes being intermediated by impulsivity, more particularly
non-planning cognitive impulsivity, could be expected. If this
view is correct, the association effect of this polymorphism
would be greater and smaller samples would be necessary to
find an association. The fact that we did not find this association suggests a different mechanism linking impulsivity to
suicide behavior in BD.
The 5-HTTLPR seems not to be a specific marker of suicide
behavior but a more general vulnerability factor in subjects
carrying S-allele that activates amygdala (Hariri et al., 2002),
reduces the coupling between pre-frontal cortex and amygdala (Pezawas et al., 2005) and increases autonomic response
and cortisol secretion in response to stress (Gotlib et al., 2008).
Individuals with the 5-HTTLPR genotype are prone to overreact in response to stressful events and as a consequence are
more vulnerable to developing depression, anxiety, and also
suicide behavior (Caspi et al., 2003). It could be speculated
that if those vulnerable individuals are indeed more impulsive, the risk of suicidal behavior increases. However, cognitive impulsivity seems to be determined by other mechanisms
and not by 5-HTTLPR.
Another study (Jollant et al., 2007) found a relationship
between IGT results and 5-HTTLPR variants in a sample of 162
subjects with multiple diagnoses (major depression, bipolar
disorder, OCD, eating disorders and substance abuse/dependence). The present study considered BD patients exclusively
so a comparison with Jollant et al's results would be hazardous
since the latter did not analyze groups by diagnosis. Furthermore, the authors in the Jollant et al. study found that LL and LS
carriers had better performance in learning ability across
choices compared to SS carriers. Nevertheless, in the L allele, a
functional variant (an ANG SNP) that reduces its mRNA production and thus changes its functionality was described (Hu
et al., 2006). In the present study participants were grouped
L.F. Malloy-Diniz et al. / Journal of Affective Disorders 133 (2011) 221–226
differently, those with high 5HTT expression (LaLa carriers)
vs. those with low 5HTT expression (all other genotypes).
The current study has certain limitations that must be
noted. The sample could be considered small, reducing statistical power when performing comparisons between suicide
attempters and non-attempters and according to different
genotypes. Therefore, a β-error cannot be excluded. Another
limitation is that all bipolar subjects were undergoing pharmacological therapy during the study and these treatments
may have influenced study results. However, Ancin et al.
(2010) suggested that cognitive alterations in bipolar patients
cannot be explained by medication because the alterations
remained after controlling for medication variables in the
statistical analyses of several studies (Fleck et al., 2001), as
well as in drug-free euthymic bipolar patients (Goswami et al.,
2009). Finally, bipolar disorder is a heterogeneous disorder
and several clinical features could mediate its course and
prognosis including co-morbidities.
Despite these limitations, to the best of our knowledge, this
is the first study assessing the association between 5-HTTLPR,
suicidal behavior and different types of impulsivity in a sample
of BD patients. The nature of impulsivity in BD and in suicidal
behavior and its probable role as a possible endophenotype
should be investigated further. Future research should include
neuropsychological variables and the study of other genetic
polymorphisms in affected bipolar patients and their unaffected relatives.
Role of funding source
This study was supported by Grant INCT-MM FAPEMIG: CBB-APQ-0007509 / CNPq 573646/2008-2 and FAPEMIG SHA-APQ-00741-09. Dr. Humberto
Correa is supported by CNPq's Postdoctoral fellowship program. CNPq, MCT
and Fapemig had no further role in study design; in the collection, analysis
and interpretation of data; in the writing of the report; and in the decision to
submit the paper for publication.
Conflict of interest
No conflict declared.
Acknowledgment
Programa de Institutos Nacionais de Ciência e Tecnologia
(CNPq, MCT and FAPEMIG) and FAPEMIG SHA-APQ-00741-09;
Dr. Humberto Correa is supported by CNPq's Postdoctoral
fellowship program.
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