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The Role of Serotonin Transporter Protein Gene in Antidepressant-Induced Mania in Bipolar Disorder
Preliminary Findings
Emanuela Mundo, MD;
Melissa Walker, BSc;
Tasha Cate, BA;
Fabio Macciardi, MD, PhD;
James L. Kennedy, MD
Arch Gen Psychiatry. 2001;58:539-544.
ABSTRACT
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Background The occurrence of mania during antidepressant treatment is a key issue
in the clinical management of bipolar disorder (BP). The serotonin transporter
(5-HTT) is the selective site of action of most proserotonergic compounds
used to treat bipolar depression. The 5-HTT gene (SLC6A4) has 2 known polymorphisms. The aim of this study was to investigate
the role of the SLC6A4 variants in the pathogenesis
of antidepressant-induced mania in BP.
Methods Twenty-seven patients with a DSM-IV diagnosis
of BP I or II, with at least 1 manic or hypomanic episode induced by treatment
with proserotonergic antidepressants (IM+ group), were compared with 29 unrelated,
matched patients with a diagnosis of BP I or II, who had been exposed to proserotonergic
antidepressants without development of manic or hypomanic symptoms (IM-
group). The 2 known polymorphisms of the SLC6A4 were
genotyped, and allelic and genotypic association analyses were performed.
Results With respect to the polymorphism in the promoter region (5HTTLPR), IM+ patients had an excess of the short allele (n = 34 [63%])
compared with IM- patients (n = 17 [29%]) ( 21,
12.77; P < .001). The genotypic association analysis
showed a higher rate of homozygosity for the short variant in the IM+ group
(n = 10 [37%]) than in the IM- group (n = 2 [7%]) and a lower rate of
homozygosity for the long variant in the IM+ group (n = 3 [11%]) compared
with the IM- group (n = 14 [48%]) (22, 12.43; P = .002). No associations were found for the polymorphism
involving a variable number of tandem repeats.
Conclusion If these results are replicated, the 5HTTLPR
polymorphism may become an important predictor of abnormal response to medication
in patients with BP.
INTRODUCTION
THE INDUCTION of mania in patients treated with antidepressants is a
complex and not rare phenomenon that occurs with different frequencies in
patients with bipolar disorder (BP), unipolar disorder (UP), and obsessive-compulsive
disorder.1, 2, 3, 4, 5, 6, 7, 8
In patients with mood disorder, the frequency of antidepressant-induced mania
has been estimated to be 9.5% to 33%, varying across studies that included
different diagnoses (ie, UP and BP) and different antidepressant treatments.9, 10, 11 More recently, it
has become clearer that the phenomenon of antidepressant-induced mania was
strictly related to a diagnosis of BP, and that, in these patients, the switch
rate during antidepressant treatment was definitively higher than that in
patients with UP.12 Therefore, during the 1990s,
researchers have primarily focused on the occurrence of the phenomenon in
BP.
Whether the type of antidepressant treatment can influence the risk
for mood switches remains controversial. According to Solomon et al,2 a manic switch during antidepressant treatment occurs
in approximately 20% of the BP inpatient admissions, regardless of treatment
(tricyclic antidepressants, monoamine oxidase inhibitors, or electroconvulsive
therapy). On the other hand, some reports showed that the rate of induction
of mania is higher in patients with BP who are treated with tricyclic antidepressants
and monoamine oxidase inhibitors than in patients with BP who are treated
with selective serotonin reuptake inhibitors (SSRIs).8, 13
As the impact on the clinical management of BP created by the occurrence
of antidepressant-induced manic switches is quite high,1, 14
several studies have focused on the possible clinical predictors and features
of this phenomenon. A higher number of previous manic or hypomanic episodes
appeared to be the only clinical variable affecting the risk for development
of mania during antidepressant treatment.8, 12
Stoll et al15 reported that antidepressant-induced
manic or hypomanic episodes are clinically different from spontaneous ones,
having a shorter duration and less severe psychotic symptoms.15
The serotonin transporter (5-HTT) is the selective site of action of
several antidepressants commonly used to treat bipolar depression.16 Bipolar disorder has been shown to have a strong
genetic component,17, 18, 19
and thus, the 5-HTT protein gene (SLC6A4) has been
considered an ideal candidate for the investigation of the genetic component
of BP and the response to antidepressant medication.
The SLC6A4 is located on chromosome 17 and
has 2 common polymorphisms. One is in the promoter region (5HTTLPR), consisting of a 44–base pair (bp) insertion or deletion.20 The long variant (l) has
been reported to generate more gene expression than the short one (s).20
Investigation into the involvement of the 5HTTLPR polymorphism in the pathogenesis of BP has led to conflicting results.
Among the several case-control association studies performed, only 2 studies
detected a positive association between the s variant
of the gene and BP,21, 22 whereas
2 recent linkage studies yielded negative findings.23, 24
The other polymorphism in the SLC6A4 consists of
a variable number of tandem repeats (VNTR) in the
second intron, with 3 alleles (STin2*9, STin2*10, and STin2*12).25
Recent studies appear to exclude any associations between this polymorphism
and BP.26, 27, 28, 29
With respect to the role of the 5HTTLPR polymorphism
in antidepressant response, patients with major depression who are homozygous
or heterozygous for the l variant appear to show
a better response to fluvoxamine maleate30
and paroxetine.31 Patients with bipolar depression
who are homozygous for the l variant of the 5HTTLPR polymorphism have been found to have a better clinical
response to total sleep deprivation.32
To date, there are no studies on the involvement of the 5HTTLPR polymorphism in the induction of mania during antidepressant
treatment, but a recent report from a pilot investigation suggested an association
with the s variant.33
The aim of the present study was to investigate further the role of the 5HTT
protein gene in the pathogenesis of manic or hypomanic switches in patients
with BP treated with proserotonergic agents.
SUBJECTS AND METHODS
SUBJECTS
The subjects undergoing investigation for the purpose of this study
have been selected from a larger sample of 300 patients with BP I or BP II
recruited from hospital clinics and newspaper advertisements in Toronto, Ontario,
and across central Canada, within the research protocols of our group. All
of these patients had been administered the Diagnostic Structured Interview
for DSM-IV Axis I diagnoses (SCID-I)34
and the Family Interview for Genetic Studies (FIGS)35
by trained interviewers. From all patients and their parents, we obtained
written informed consent to participate in the genetic studies ongoing in
our research group, which also included the use of personal and clinical data
and blood drawing for genotyping.
The SCID-I, the FIGS, the clinical and life charts available, and all
information about past and current pharmacological treatment recorded during
the interviews were blindly and independently reviewed by 2 trained psychiatrists
(E.M. and J.L.K.). Considering the retrospective nature of this study, to
avoid investigators' biases, only information and life charts that existed
before the design of the present investigation have been used.
Based on this review, from the original sample of 300 patients with
BP I and BP II, we were able to select 2 groups of unrelated patients. The
first group consisted of 27 subjects with a positive history for antidepressant-induced
mania (IM+ group). It included patients with the following characteristics:
(1) a confirmed DSM-IV diagnosis of BP I or BP II,
(2) at least 1 depressive episode treated with proserotonergic antidepressants,
and (3) at least 1 manic or hypomanic episode induced by treatment with these
compounds (ie, 1 episode fulfilling DSM-IV criteria
for mania or hypomania, which developed during antidepressant treatment).
The second group, without the history of antidepressant-induced mania (IM-
group), consisted of 29 patients with the following characteristics: (1) a
confirmed diagnosis of BP I or BP II, (2) at least 1 depressive episode treated
with proserotonergic antidepressants, and (3) no antidepressant-induced manic
or hypomanic episodes.
Patients within the IM- group were matched by sex, age (±
5 years), and ethnicity (including preimmigration roots) with the patients
of the IM + group. The matching procedure we used implied the possibility
of using more than 1 control subject per case subject, when available.
We excluded subjects with (1) uncertain DSM-IV
diagnosis of BP (including patients with only 1 manic or hypomanic episode
induced by antidepressant treatment and no spontaneous ones, for whom there
is to date no consensus about the diagnosis of BP); and/or (2) unavailable,
inadequate, or unreliable information on past and current psychopharmacological
treatments (eg, report of exposure to antidepressant treatment but no information
about the type of antidepressant); and/or (3) no history of exposure to proserotonergic
antidepressants.
For IM+ and IM- groups, we collected the following demographic
and clinical variables from the SCID-I and the FIGS: age at time of the interview,
age at onset of BP, diagnostic subtype of BP, comorbid Axis I diagnoses, family
history of mood disorders, number of spontaneous manic or hypomanic episodes,
number of depressive episodes, presence or absence of psychotic symptoms during
the mood episodes, presence or absence of rapid cycling, and presence or absence
of suicidal behavior. Information about current or past treatment with mood
stabilizers was also recorded from the clinical charts, where available.
GENOTYPING
Genomic DNA was extracted from blood samples using a nonenzymatic procedure.36 All genotyping procedures have been performed without
the researchers aware of the aim and design of this study and the clinical
diagnoses of the subjects investigated.
SLC6A4 PROMOTER REGION
Polymerase chain reaction (PCR) was used to amplify a segment of genomic
DNA containing the insertion or deletion polymorphism in the promoter region
of the SLC6A4 using primers with the sequences reported
by Cook et al.37 The PCR was performed in a
25-µL volume containing 200 ng of genomic DNA; 10-mmol/L Tris hydrochloride;
50-mmol/L potassium chloride; 1.5-mmol/L magnesium dichloride; 5% dimethyl
sulfoxide; 200 µmol/L each of deoxyadenosine triphosphate (dATP), deoxythymine
triphosphate (dTTP), and deoxycytosine triphosphate (dCTP); 100 µmol/L
of deoxyguanosine triphosphate (dGTP); 100 µmol/L of 7-deaza-dGTP; 1
µmol/L of each primer; and 1 U of AmpliTaq
DNA polymerase (Applied Biosystems Inc, Foster City, Calif). The genomic DNA
was denatured at 95°C for 3 minutes, then the remaining reaction components
were added. The reaction consisted of 40 cycles of 95°C for 30 seconds,
61°C for 30 seconds, and 71°C for 60 seconds, followed by extension
at 72°C for 10 minutes. The PCR products were visualized on a 2.5% agarose
gel and visualized under UV light in the presence of ethidium bromide. The
DNA bands were assigned allele numbers based on their size (allele 1 [l], 450 bp; allele 2 [s], 406
bp).
SLC6A4 VARIABLE NUMBER OF TANDEM REPEATS
The 25-µL reaction modified from that of Cook et al37
consisted of 200 ng of template; 0.8 µmol/L of each primer; 10-mmol/L
Tris hydrochloride; 50-mmol/L potassium chloride; 1-mmol/L magnesium dichloride;
200 µmol/L each of dATP, dCTP, and dTTP; 150-µmol/L dGTP; 50-µmol/L
7-deaza-dGTP; 8% dimethyl sulfoxide; and 1 U of AmpliTaq DNA polymerase (Applied Biosystems Inc). Cycling conditions consisted
of initial denaturation for 3 minutes at 95°C, followed by 40 cycles of
45-second denaturation at 95°C, 30-second annealing at 56°C, and a
45-second extension at 72°C, ending with a final 7-minute extension at
72°C. After separation on a 2.5% agarose gel for 2 hours at 100 V, the
3 alleles produced bands at 345 bp (9 repeats), 360 bp (10 repeats), and 390
bp (12 repeats).
STATISTICAL ANALYSIS
All demographic and clinical variables available were tabulated and
compared between both samples of patients studied. The t test (2-tailed) for independent samples was used for the continuous
variables, whereas the 2 test was used for the dichotomous
ones.
The genotype data for both polymorphisms were analyzed using Pearson 2 tests. Allele and genotype frequencies were compared between the IM+
and IM- groups. The  level of significance used was set at .05,
and was not adjusted. All the statistical analyses were performed using commercially
available software (SPSS for Windows, version 10.1; SPSS Inc, Chicago, Ill).
RESULTS
The main demographic (including ethnic background) and clinical variables
for both patient groups are summarized in Table 1. No significant differences were found between groups for
the variables considered.
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Table 1. Demographic and Clinical Variables in Patients With and Without
Antidepressant-Induced Manic/Hypomanic Episodes*
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Data regarding past or current treatment with mood stabilizers (lithium
carbonate, carbamazepine, or valproate sodium) were available for 50 patients,
23 in the IM+ group and 27 in the IM- group. In the IM+ group, information
was available for 10 patients regarding the time of the induction of mania
during the exposure to antidepressants: 5 were receiving mood stabilizers,
and 5 were not. In the IM- group, 20 patients were receiving mood stabilizers
at the time of the exposure to the antidepressant treatment (when mania did
not develop), and 13 of them had spontaneous manic episodes while receiving
mood stabilizers. Reliable data on daily doses and plasma levels at the time
of the exposure to the antidepressants were available for only a few patients
and thus, also considering that these variables were not standardized, no
analysis was performed.
In the IM+ group, the ongoing antidepressant treatments during the development
of manic or hypomanic episodes included fluoxetine hydrochloride (n = 8),
fluvoxamine (n = 6), a combination of fluoxetine and fluvoxamine (n = 3),
paroxetine (n = 2), nefazodone hydrochloride (n = 2), moclobemide (n = 2),
venlafaxine hydrochloride (n = 1), imipramine hydrochloride (n = 2), and sertraline
hydrochloride (n = 1). Reliable data on daily doses and treatment duration
at the time of the induction of mania were not available.
Genotypes and allele frequencies for the 2 polymorphisms studied in
the total sample and in the IM+ and IM- groups are shown in Table 2.
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Table 2. Genotype and Allele Frequencies for the Polymorphisms of the
Serotonin Transporter Gene in Both Groups of Patients*
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The whole sample and both subsamples defined by the diagnosis were within
the equilibrium of the Hardy-Weinberg law for both polymorphisms studied.
Results of the association analysis performed with the alleles and genotypes
of the VNTR polymorphism did not show any significant
difference between the patient groups. On the other hand, with respect to
the 5HTTLPR polymorphism, the allelic association
analysis showed that among IM+ patients, there was an excess of the s allele (Pearson 21, 12.77; P < .001). The association analysis performed with the
genotypes was also significant, showing a higher rate of homozygosity for
the s variant and a lower rate of homozygosity for
the l variant among IM+ patients (Pearson 22, 12.43; P = .002).
The odds ratio associated with the presence of the s variant was 4.1 (95% confidence interval, 1.84-8.65) (Table 2). Given a disease allele frequency of approximately 60%
and a genotype relative risk of 2, with our sample it is possible to detect
a significant allelic effect with a power ranging from 0.65 to 0.96 at
= .05, depending on the expected effect size.
COMMENT
The main finding from this study suggests a role for the s variant of the 5HTTLPR polymorphism in conferring
a higher risk for development of antidepressant-induced mania in patients
with BP treated with proserotonergic compounds. This result appears to confirm
a previous finding from a pilot investigation, in which the genotype and allele
frequencies for the 5HTTLPR polymorphism were compared
between a smaller sample of patients with BP and antidepressant-induced manic
or hypomanic episodes and a larger group of unmatched patients with BP and
only spontaneous episodes.33
We hypothesized that patients with BP who are homozygous for the s variant, having lower gene expression and, thus, fewer
5-HTT sites, could be more sensitive to the block of serotonin reuptake or
to the increase of serotinin availability. A lower number of 5-HTT sites would
imply higher levels of serotonin in the synaptic cleft as a consequence of
a lower reuptake rate. Thus, these subjects would be more likely to exhibit
an enhanced response to compounds that block serotonin reuptake and increase
further synaptic serotonin levels. Both effects were induced in our IM+ sample
during treatment with SSRIs, imipramine, nefazodone, venlafaxine, or moclobemide.
These compounds act directly or indirectly on serotonin neurotransmission,16, 38, 39 and thus can be referred
to as proserotonergic antidepressants.
If our hypothesis is true, and if the induction of mania represents
only an exaggeration of the expected response to antidepressants, patients
with the ss genotype should be more likely to respond
to proserotonergic antidepressants or to show a shorter latency for the response.
On the contrary, the s variant of the 5HTTLPR polymorphism has been associated with poor response to SSRIs30, 31 or to total sleep deprivation.32 However, the relationship between the 5HTTLPR polymorphism and the expected antidepressant response remains
controversial, considering that a recent report40
associates good response to SSRIs with the ss genotype.
It is quite likely that the lack of homogeneity across these different studies,
with respect to the diagnosis (BP or UP), the compounds administered, or the
definition of the antidepressant response, have been reflected in discordant
results. In addition, the involvement of targets other than the 5-HTT in the
response to proserotonergic compounds is quite likely. The critical role of
serotonin presynaptic autoreceptors (ie, serotonin1A) in determining
the timing and the extent of the antidepressant response to medication has
been pointed out16 and discussed with respect
to the recent associations between the SLC6A4 variants
and the response to SSRIs.41
Several limitations of this study should be considered. Whether antidepressant-induced
manic switches in BP are phenomena quantitatively or qualitatively different
from the expected antidepressant response is still unclear. The natural course
of BP is characterized by the spontaneous recurrence of episodes of depression
and mania or hypomania, and this could be a confounding factor in the detection
of the rates and of the predisposing factors to antidepressant-induced phenomena,
such as manic or hypomanic switches and rapid cycling courses. As stated by
Coryell et al,42 in BP, the occurrence of a
major depressive episode may naturally anticipate a switch and, at the same
time, may induce treatment with antidepressants, leading to an apparent, but
not true, causal connection between the two events. Thus, the phenomenon of
antidepressant-induced mania should be defined and investigated with controlled
prospective studies in which all clinical and pharmacological variables known
to be predictive factors are controlled a priori. Our study was performed
according to a retrospective design, and although the review of the clinical
information and the genotyping have been performed blindly, the lack of a
prospective design represents a limitation. The doses and the treatment duration
for the proserotonergic antidepressants administered were not controlled for
in this study, and the information available did not allow us to verify whether
these variables were comparable between IM+ and IM- patients. On the
other hand, to our knowledge, there are no studies showing that antidepressant-induced
manic or hypomanic episodes are related to these variables. According to the
information extracted from the sample, there were no differences between IM+
and IM- groups with respect to the pharmacological variable that would
have the most significant impact on the risk for development of manic switches
during the antidepressant treatment, ie, the concomitant treatment with mood
stabilizers. Unfortunately, given that reliable information was not available
for all patients, data could only be reported and commented on descriptively.
Nonetheless, even though the percentage of patients in the IM- group
receiving mood stabilizers at the time of the exposure to antidepressant treatment
was higher than that in the IM+ group, spontaneous manic or hypomanic episodes
developed in most of the IM- patients.
Ideal study designs would imply the exposure of drug-naïve patients
with BP to antidepressants and mood stabilizers randomly and blindly, but
these studies have obvious ethical and practical limitations. This is the
main reason why the investigations of predictors and clinical characteristics
of antidepressant-induced mania have been performed according to retrospective
or naturalistic designs.8, 12, 15
Finally, it could be argued that the s allele
of the 5HTTLPR polymorphism might be associated primarily
with clinical characteristics other than antidepressant-induced manic switches
that confer severity to the illness and predispose patients to development
of mania when exposed to antidepressants. In our sample, we did not find statistically
significant differences in any of the clinical variables compared between
IM+ and IM- patients. These included the presence of suicidal behaviors
that have been associated with the presence of the s
variant of the 5HTTLPR polymorphism.43
However, given the complexity of the clinical picture of BP, further studies
on the predictive role of genetic factors in antidepressant-induced mania
should consider matching patients for clinical variables that affect illness
severity.
CONCLUSIONS
Despite the limitations, including small size of the samples studied,
our study suggests a role of the 5HTTLPR polymorphism
in the pathogenesis of antidepressant-induced mania in BP. Further investigations
are needed to confirm this result and to build comprehensive explanatory hypotheses
for the complex mechanisms involved in determining the normal and the abnormal
clinical responses to antidepressants.
If these preliminary results are confirmed in additional samples, the 5HTTLPR polymorphism may become an important predictor
of antidepressant-induced manic switches, which are among the most clinically
damaging adverse effects of antidepressant treatment in patients with BP.
AUTHOR INFORMATION
Accepted for publication January 23, 2001.
From the Neurogenetics Section, Centre for Addiction and Mental Health,
University of Toronto, Toronto, Ontario.
Corresponding author: James L. Kennedy, MD, Neurogenetics Section,
R-31, Centre for Addiction and Mental Health, Clarke Site, 250 College St,
Toronto, Ontario, Canada M5T 1R8 (e-mail: James_Kennedy{at}CAMH.net).
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