Serotonin Transporter Gene Polymorphisms,
Alcoholism, and Suicidal Behavior
Philip Gorwood, Philippe Batel, Jean Ade`s, Michel Hamon, and Claudette Boni
Background: Dysfunction of serotoninergic transmission
could predispose to excessive alcohol consumption and
dependence. The functional polymorphism of the serotonin
transporter gene (5-HTTLPR) has been associated with
different disorders, including alcoholism. Considering the
likelihood of heterogeneity in the “alcohol dependence”
phenotype, 5-HTTLPR may be more specifically
impli-cated in subsamples of patients or in related traits of
alcoholism, such as impulsivity.
Methods: We analyzed the role of this functional
poly-morphism in the risk for suicide attempt in a population of
male alcohol-dependent subjects. One hundred ten male
alcohol-dependent patients (DSM-III-R criteria), French
for at least two generations, were personally interviewed
with the Diagnostic Interview for Genetic Studies and
compared with 61 unaffected blood donors.
Results: The “short” (S) allele of the 5-HTTLPR
ap-peared to be unrelated to alcohol dependence and
comor-bid depression in our sample, but was found associated
with an increased risk for suicide attempts. This
associa-tion was predominantly observed in severe and repetitive
suicide attempts, with a significant dose effect of the S
allele (0, 1, or 2) on the number and the severity of suicide
attempts.
Conclusions: Mood disorders and alcohol dependence
may interact with a genetic (relative) deficiency in
sero-tonin reuptake, thereby increasing the risk for aggressive/
impulsive behaviors such as suicide attempts. Biol
Psy-chiatry 2000;48:259 –264 © 2000 Society of Biological
Psychiatry
Key Words: Suicide, serotonin, genetics, behavior,
im-pulsivity, addiction, dependence
Introduction
E
vidence has accumulated for the last years that
sero-tonergic neurotransmission is involved in alcoholism
(McBride et al 1993; Sellers et al 1992). Thus
alcohol-drinking behavior seems to be associated with low activity
levels of central serotonin (5-HT) systems (Ferreira and
Soares-Da-Silva 1991; LeMarquand et al 1994b; Zhou et
al 1994). Alterations in 5-HT uptake have also been
described in alcohol-dependent patients (Ernouf et al
1993; Heinz et al 1998) that may sustain such alcohol–
5-HT relationships because selective 5-HT reuptake
inhib-itors, such as fluoxetine, sertraline, and citalopram,
regu-larly produce a decrease in alcohol craving and drinking in
alcoholic patients (Balldin et al 1994a, 1994b; Higley et al
1998; Lejoyeux 1996; Lu et al 1994; Naranjo et al 1994).
Alcoholic subjects are dramatically exposed to suicidal
behavior (Kessler et al 1994) and suicide mortality
(Ros-sow and Amundsen 1995), which may also be causally
related to altered 5-HT neurotransmission. Indeed, low
levels of 5-HT and/or its metabolite 5-hydroxyindoleacetic
acid (5-HIAA) have regularly been found in blood and
cerebrospinal fluid (CSF) of subjects who attempted
sui-cide (Pihl and LeMarquand 1998). Interestingly,
alter-ations in 5-HT uptake have also been reported in these
subjects (Ellis and Salmond 1994; Meltzer et al 1981). The
interaction between alcoholism and 5-HT uptake may thus
be relevantly tested to explain the increased risk for
suicidal behavior in alcohol-dependent patients.
Polymorphism of the gene encoding the 5-HT
trans-porter (5-HTT) notably concerns its promoter (Heils et al
1996). The region between base pair (bp) 1376 and bp
1027 contains 16 tandem repeats of a 20- to 23-bp G
1
C
rich sequence. Two common forms of this region were
found in a white population: a 528-bp allele with 16
repeats (“long” [L] allele) and a 448-bp allele (“short” [S]
allele) with a deletion of 44 bp extending from bp 1255 to
bp 1212. The 528-bp long allele of the 5-HTT promoter is
two- to threefold more active in driving transcription than
the 484-bp allele in transfection experiments (Heils et al
1996). In addition, 5-HT uptake is twice as high in
lymphoblastoid cells from individuals homozygous for the
528-bp allele as in cells from individuals of the other
genotypes (Lesch et al 1996). The potential role that this
functional polymorphism in the 5-HTT promoter may play
in personality traits and psychiatric diseases has already
been the matter of numerous studies; however, to date,
rather controversial data have been reported regarding a
possible association of either the short or the long allele
with sometimes mood disorders and sometimes
anxiety-From Service de Psychiatrie, Hoˆpital Louis Mourier (AP-HP), Colombes (PG, JA), CNRS UMR 7593-Paris VII, Personnalite´ et Conduites Adaptatives, CHU Pitie´-Salpeˆtrie`re, Paris (PG, JA), Hoˆpital Beaujon (AP-HP), UTAMA, Clichy (PB), and INSERM U 288, Neuropsychopharmacologie, CHU Pitie´-Salpeˆt-rie`re, Paris (MH, CB), France.
Address reprint requests to Philip Gorwood, M.D., Ph.D., CNRS UMR 7593, CHU Louis Mourier, 178, rue des Renouillers, 92700 Colombes, France. Received July 1, 1999; revised October 11, 1999; accepted February 2, 2000.
related disorders (Ball et al 1997; Bellivier et al 1997;
Collier et al 1996; Ewald et al 1998; Gutie´rrez et al 1998;
Jorm et al 1998; Kunugi et al 1997; Lesch et al 1996;
Matsushita et al 1997; McDougle et al 1998; Nakamura et
al 1997; Rees et al 1997).
Similarly, conflicting data have been reported about the
possible association of polymorphism of the 5-HTT gene
promoter with alcoholism. Thus, Sander et al (1998) and
Schmidt et al (1997) found that the frequency of the short
allele is significantly increased in alcoholic patients with
severe dependence as compared with nonalcoholic control
subjects. On the other hand, Tu¨rker et al (1998) noted the
existence of a significant association between the short
allele of the 5-HTT gene promoter and high ethanol
tolerance in young adults. In contrast, Edenberg et al
(1998) and Jorm et al (1998) could not find any
associa-tion between polymorphism of the 5-HTT gene promoter
and alcohol misuse and dependence.
Because heterogeneity in the population of alcoholic
patients might have contributed to these discrepancies,
further investigations on a possible association between
this polymorphism and various subgroups of alcoholics
have been performed. Distinction of subgroups based on
the presence and type of suicidal behavior allowed the
discovery of a significant association between the
pres-ence of the short allele of the 5-HTT gene promoter and
severe suicide attempts in alcoholic-dependent patients.
Methods and Materials
Seventy male control subjects, recruited from a blood transfusion center, were at least 35 years old and French for at least two generations, without any substance dependence (DSM-III-R). The age of 35 was considered as a cutoff to reduce the risk that control subjects may lately develop alcohol dependence. Using the same clinical instruments as for the patients, we eliminated four subjects who fulfilled the DSM-III-R alcohol dependence or abuse criteria, and three others because they made a suicide attempt at least once in their life. In addition, two subjects refused to participate. Finally, 61 control subjects were included in this study.
We recruited 110 male alcoholics from two general hospitals that specialize in the treatment of alcoholism, in Paris and its suburbs. Inclusion criteria consisted of DSM-III-R criteria of alcohol dependence, French origin for at least two generations, and no comorbid dementia. Schizophrenia and bipolar manic– depressive disorder were exclusion criteria. The lifetime psychi-atric and addictive diagnoses were made by face-to-face inter-view using the Diagnostic Interinter-view for Genetic Studies (DIGS; Nurnberger et al 1994). The alcoholic patients were seen on average at 43.6 years of age (SD510.5), alcohol dependence occurring on average at 26.0 years (SD58.6). The average score in the Michigan Alcoholic Screening Test (Selzer 1971, derived from the DIGS) was 32.5 (SD511.7). The psychiatric comor-bidities were mainly major depressive disorder (N 5 27),
antisocial personality disorder (N522), pathological gambling (N520), agoraphobia (N519), other dependence such as for cannabis (N512), opiates (N512), sedatives (N511), and cocaine (N5 6). In this sample 181 suicides were attempted, involving 55 patients. The degree of lethality (rated from 0 to 6 according to the DIGS) was “severe” in 13 patients (e.g., cut throat) and “very severe” (with respiratory arrest or prolonged coma) in two cases.
Genomic DNA was extracted from anticoagulated venous blood samples (Loparev et al 1991). The serotonin transporter gene (5-HTTLPR) of the 5-HTT gene regulatory region was amplified (Heils et al 1996) by polymerase chain reaction with oligonucleotide primers srtp5 (59 -GGCGTTGCCGCTCT-GAATGC-39) and srtp3 (59 -GAGGGACTGAGCTGGACAAC-CAC-39). Polymerase chain reaction reactions were performed with 50 ng genomic DNA, 10 pmol of each primer, 20 mmol/L KCl, 10 mmol/L Tris-HCl (pH 8.8), 16 mmol/L (NH4)2SO4,
0.01% Tween 20, 1.5 mmol/L MgCl2, 200 mmol/L of
de-oxynucleotides, 5% dimethyl sulfoxide, and 1 unit of Eurobiotaq polymerase, in a total volume of 25mL.
Cycling conditions were preceded by a denaturation step at 85°C for 20 min, followed by 35 cycles of denaturation at 95°C for 1 min, annealing at 61°C for 1 min, and synthesis at 72°C for 1 min. Amplification products were separated by electrophoresis in a 2% agarose gel and visualized by UV after ethidium bromide staining. The 484-bp fragment of the biallelic polymorphism was designated as “S” and the 528-bp fragment as “L.” Genotyping was carried out blindly, without knowledge of the diagnostic status.
Allele and genotype frequencies were compared withx2
tests, and the test for Hardy–Weinberg equilibrium was performed for each sample. Linear trend in variation of frequencies of the involved allele with respect to the number (or severity) of suicide attempts was evaluated with the Armitage test (Armitage 1955). Because of the quantitative impact of the S allele on the transcription level (Heils et al 1996) of the 5-HTT gene (subjects with at least one S allele having less 5-HTT binding sites and messenger RNA in the midbrain than homozygous “LL” subjects [Little et al 1998]), nonparametric correlation analyses (Spear-man test) were performed (with the appropriate corrections for equal values) between quantitative variables and the number of S allele (0, 1, or 2). The impact of mood disorders in the relation found between “5-HTT polymorphisms” and “suicide attempts” was analyzed through an analysis of variance.
Results
No difference in genotype counts was found between
alcoholics and control subjects [
x
2(2)
5
1.61, p
5
.45].
The same conclusion applied between subjects with or
without the S allele [
x
2(2)
5
1.54, p
5
.21]. Both control
subjects and alcohol-dependent patients were in
accor-dance with Hardy–Weinberg equilibrium for the
polymor-phisms tested [respectively,
x
2(1)
5
0.7, p
5
.39 and
x
2(1)
5
0.1, p
5
.55].
subjects (without suicidal behavior), 61.8% in alcoholics
without suicidal behavior, and 78.2% in alcoholics who
tried at least once to commit suicide (Table 1). Thus,
alcoholics with suicidal behavior have different genotypes
than normal control subjects and a tendency for different
genotypes than alcoholics with no history of suicidal
behavior (Table 1).
Number and lethality of suicide attempts were then
compared between alcoholic patients according to the
presence of the short variant of the 5-HTT gene promoter.
We noted a regular increase in the frequency of the S allele
with the number of suicide attempts for each subject:
61.8% for patients with no suicide attempt, 74.2% for
patients who committed a suicide attempt once or twice,
82.3% for those who tried three or four times, and 83.3%
for patients with more than four suicide attempts. The
linear trend for increased S allele frequency according to
the number of suicide attempts (none, once or twice, three
or four times, and more than four) was significant [
x
2(1)
5
3.89, p
5
.05, Armitage test]. Furthermore, a “dose effect”
of the S allele was observed, with a significant positive
correlation between the number of suicide attempts and
the number of the S allele (0, 1, or 2;
r 5
.193, p
5
.04).
We also observed an increase in the presence and the
frequency of the S allele in alcohol-dependent patients
according to the lethality of suicide attempts. Sixty-two
percent of patients with no suicide attempt (N
5
55) had
the S allele; this percentage increased to 78% for patients
with moderate lethality suicide attempts (N
5
40) and to
80% for those with more severe suicide attempts (N
5
15).
In this last group, the two patients with very severe suicide
attempts both had the S allele. In this view, we found a
significant increase in the S allele frequency according to
the lethality of suicide attempts [i.e., no suicide attempt, at
least a suicide attempt, at least one severe suicide attempt,
and at least one very severe attempt;
x
2(1)
5
4.41, p
5
.04, Armitage test]. A dose effect of the S allele was also
observed, as there is a correlation between the degree of
lethality of suicide attempts and the number of the S allele
(0, 1, or 2;
r 5
.185, p
5
.05).
Comorbid depression might explain increased suicide
attempts in samples of alcohol-dependent subjects. In our
sample, the two variables “existence of at least one major
depression episode” and “at least one suicide attempt”
were significantly interacting with the number of the S
allele (Table 2). Taking into account this interaction, we
found a significant impact of 5-HTTLPR polymorphisms
on suicide attempts alone, but not on major depression
alone. For example, in this sample 76.2% of
alcohol-dependent patients with the S allele and with lifetime
comorbid major depressive disorder (N
5
21) made at
least one suicide attempt. On the other hand, only 44.4%
of patients with no S allele and no comorbid lifetime major
depression disorder (N
5
27) made a suicide attempt
[
x
2(1)
5
5.46, p
5
.02].
Discussion
For the sample studied, no association could be found with
5-HTTPR polymorphisms and alcohol dependence per se, in
agreement with most recent studies (Edenberg et al 1998;
Jorm et al 1998). Accordingly, it can be inferred that the
changes in 5-HT reuptake capacity in alcoholic patients that
were noted in previous studies (Ernouf et al 1993; Heinz et al
1998) do not probably reflect changes in expression of the
5-HTT– encoding gene that would depend on the presence of
the S or L allele promoter. Indeed, opposite changes in 5-HT
reuptake—that is, an increase in platelets (Ernouf et al 1993)
versus a decrease in brain (Heinz et al 1998)— have been
reported in alcoholic patients, strongly suggesting that these
changes are independent of the 5-HTT gene promoter but are
related to local environmental conditions, affecting 5-HTT
functioning differently in the periphery versus in the central
nervous system. Furthermore, postmortem studies showed
that the density of 5-HTT binding sites in the midbrain of
alcoholic subjects was significantly higher than that in
con-Table 1. Genotype Counts of Polymorphism within the Serotonin Transporter (5-HTT) Promoter in Alcoholic Patients (with or without Suicide Attempts) and Unaffected Matched Control Subjects
5-HTTLPR genotypes
Control subjects
Alcohol-dependent subjects
Without suicide attempt
With suicide attempt
N (%) N (%) N (%)
LL 24 39.3% 21 38.2% 12 21.8%
LS 26 42.6% 26 47.3% 30 54.5%
SS 11 18.0% 8 14.5% 13 23.6%
Genotype counts are not significantly different in alcohol-dependent patients and control subjects [x2(2)
51.61, p5.45]. Genotypes with the “short” (s) allele (LS and SS) are more frequent in alcohol-dependent patients with suicide attempt (78.1%) than in alcohol-dependent patients without suicide attempt [61.8%;x2(1)
53.51, p5.06] and control subjects [60.6%;x2(1)
54.15, p5.04].
Table 2. Number of “Short” (S) Allele (Serotonin Transporter Gene Polymorphism) According to the Existence of Suicide Attempts and Lifetime Diagnosis of Depressive Disorder in 110 Alcohol-Dependent Patients
Suicide attempt
Lifetime major depressive (MD) disorder
With MD (no. of S allele)
Without MD (no. of S allele)
0 1 2 0 1 2
With 0 11 5 12 19 8
Without 6 4 1 15 22 7
trol subjects with the same SS or SL genotypes, in line with
the hypothesis that alcohol consumption per se can affect the
5-HTT at postranscriptional level(s) (Little et al 1998).
Interestingly, further phenotypic definition of alcoholic
patients led to the distinction of alcohol-dependent
sub-jects with dissocial personality disorder for whom a
significant association was found between the presence of
the S allele of the 5-HTT gene promoter and a
tempera-mental profile of high novelty seeking and low harm
avoidance (Edenberg et al 1998). In the present sample,
analysis of various phenotypic parameters revealed that
other subgroups could be identified within the alcoholic
population, depending on both a history of suicide
at-tempts and the presence of mood disorders.
First, we found that in the recruited alcohol-dependent
patients the risk for suicidal behavior and, particularly, for
repeated suicide attempts and attempts with high lethality
is partly dependent on 5-HTTLPR polymorphisms. In our
sample, the S allele is qualitatively distinguishing patients
with or without suicide attempts and is quantitatively
correlated to number and severity of suicide attempts.
The second result of our study is that comorbid mood
disorder is significantly interacting with 5-HTTLPR
poly-morphisms to “explain” suicide attempts in
alcohol-depen-dent patients. It is the interaction that is involved and not
mood disorder per se, as 5-HTTLPR polymorphisms are
not associated with depression in our sample. These results
are consistent with those of Bellivier et al (2000) showing
no direct impact of 5-HTTLPR on recurrent mood
disor-der, but a significant impact of the S allele on suicide
attempts, especially for those with high lethality.
Long-term, prospective studies of psychiatric patients
have shown that affective disorder and alcoholism are
most frequently found in suicidal cases. Thus, Robins
(1981) reported that of 134 subjects who committed
suicide, 47% were suffering from depression and 25%
from alcoholism. Similarly, in their study Barraclough et
al (1974) noted that most patients among 100 suicide cases
were suffering from either depression (70%) or alcoholism
(15%). Furthermore, the most prevalent psychopathology
among alcoholics who commit suicide is affective disorder
(Berglund 1984; Cornelius et al 1995; Murphy et al 1979;
Whitters et al 1985).
Acute alcohol intake transiently increases central 5-HT
functioning, whereas chronic intake decreases it
(LeMar-quand et al 1994a). Chronic alcohol intake may lead to a state
of lowered central 5-HT functioning characterized by a
propensity toward disinhibited behavior, thus increasing the
potential for aggressive behavior (Pihl and LeMarquand
1998). When expressed towards the self (suicide), aggressive
behavior has been associated with low CSF levels of the
5-HT metabolite 5-HIAA regardless of diagnosis
(Traskman-Bendz et al 1986; Tuinier et al 1995; van Praag 1983), this
relationship being particularly significant for violent suicide
(Asberg et al 1976). It is the severity and impulsivity of
suicide that may thus be related to low 5-HT functioning. On
the other hand, depression per se is also associated with
reduced 5-HT neurotransmission, as evidenced by low CSF
5-HIAA levels (Meltzer and Lowy 1987) and plasma free
tryptophan levels (Coppen and Wood 1978; DeMeyer et al
1981) in depressed patients. The existence of a causal
relationship between depression and reduced 5-HT
neuro-transmission is strongly supported by the observation that
tryptophan depletion (which efficiently decreases central
5-HT synthesis [Nishizawa et al 1997]) can produce a
lowering of mood both in normal subjects and in recovered
depressed patients (Benkelfat et al 1994; Salomon et al 1993;
Smith et al 1997).
In our sample, the S allele, leading to lower 5-HT
transport capacity than the L allele (Heils et al 1996), is
associated with an increased risk of suicide attempts, this
association being stronger for numerous suicide attempts
with high lethality. Variation of the S allele frequency
according to number and severity of suicide attemps could
be interpreted in two ways. First, the impact of the S allele
could be associated with the aggressive/impulsive
dimen-sion, which is probably (quantitatively) increased in severe
suicide attempts. Another explanation is that the
(qualita-tive) presence of nonviolent, nonimpulsive suicide
at-tempts (e.g., pill ingestion) is probably reduced in more
severe suicide attempts.
The impact of the S allele is also especially significant
when lifetime comorbid depression is present, and when
suicide attempts are characterized by frequent antecedents
and severe lethality. Mood disorders and alcohol
depen-dence may interact with a genetic (relative) deficiency in
5-HT reuptake, thereby increasing the risk for aggressive/
impulsive behaviors such as suicide attempts.
Some limitations have to be raised in this study,
however, notably regarding the limited size of our sample.
The main analyses are based on the comparison of two
groups of 55 subjects each, but some subsamples, such as
those with severe suicide attempts (N
5
15), are of limited
size, especially as interaction between different variables
has been tested. Although very similar results have been
found in Bellivier and colleagues’ study (2000)—namely,
the S allele is not increasing the risk for any specific
psychiatric disorder, but instead is associated with suicide
behavior— other replications have to be made on larger
samples of alcohol-dependent subjects.
References
Armitage P (1955): Test for linear trends in proportions and frequencies. Biometrics 11:375–386.
Asberg M, Tra¨skman L, Thore´n P (1976): 5-HIAA in the cerebrospinal fluid—a biochemical suicide predictor? Arch
Gen Psychiatry 33:1193–1197.
Ball D, Hill L, Freeman B, Eley TC, Strelau J, Riemann R (1997): The serotonin transporter gene and peer-rated neurot-icism. Neuroreport 8:1301–1304.
Balldin J, Berggren U, Bokstro¨m K, Eriksson M, Gottfries CG, Karlsson I, et al (1994a): Six-month open trial with zimeli-dine in alcohol-dependent patients: Reduction in days of alcohol intake. Drug Alcohol Depend 35:245–248.
Balldin J, Berggren U, Engel J, Eriksson M, Hård E, So¨derpalm B (1994b): Effect of citalopram on alcohol intake in heavy drinkers. Alcohol Clin Exp Res 18:1133–1136.
Barraclough B, Bunch J, Nelson B, Sainsbury P (1974): A hundred cases of suicide: Clinical aspects. Br J Psychiatry 125:355–373.
Bellivier F, Laplanche JL, Leboyer M, Feingold J, Bottos C, Allilaire JF, et al (1997): Serotonin transporter gene and manic depressive illness: An association study. Biol
Psychi-atry 41:750 –752.
Bellivier F, Szo¨ke A, Henry C, Lacoste J, Bottos C, Nosten-Bertrand M, et al (2000): Possible association between serotonin transporter gene polymorphism and violent suicidal behavior in mood disorders. Biol Psychiatry 48:319 –322. Benkelfat C, Ellenbogen MA, Dean P, Palmour RM, Young SN
(1994): Mood-lowering effect of tryptophan depletion. En-hanced susceptibility in young men at genetic risk for major affective disorders. Arch Gen Psychiatry 51:687– 697. Berglund M (1984): Suicide in alcoholism: A prospective study
of 88 suicides. I. The multidimensional diagnosis at first admission. Arch Gen Psychiatry 41:888 – 891.
Collier DA, Sto¨ber G, Li T, Heils A, Catalano M, Di Bella D (1996):A novel functional polymorphism within the promoter of the serotonin transporter gene: Possible role in suscepti-bility to affective disorders. Mol Psychiatry 1:453– 460. Coppen A, Wood K (1978): Tryptophan and depressive illness.
Psychol Med 8:49.
Cornelius J, Salloum I, Mezzich J, Cornelius M, Fabrega H, Ehler J, et al (1995): Disproportionate suicidality in patients with comorbid major depression and alcoholism. Am J
Psychiatry 152:358 –364.
DeMeyer M, Shea P, Hendrie H, Yoshimura N (1981): Plasma tryptophan and five other amino acids in depressed and normal subjects. Arch Gen Psychiatry 38:642– 646. Edenberg HJ, Reynolds J, Koller DL, Begleiter H, Bucholz KK,
Conneally MP, et al (1998): A family-based analysis of whether the functional promoter alleles of the serotonin transporter gene 5-HTT affect the risk for alcohol depen-dence. Alcohol Clin Exp Res 22:1080 –1085.
Ellis PM, Salmond C (1994): Is platelet imipramine binding reduced in depression: A meta-analysis. Biol Psychiatry 36:292–299.
Ernouf D, Compagnon P, Lothion P, Narcisse G, Be´nard JY, Daoust M (1993): Platelets 3H 5-HT uptake in descendants from alcoholic patients: A potential risk factor for alcohol dependence. Life Sci 52:989 –995.
Ewald H, Flint T, Degn B, Mors O, Kruse TA (1998): A functional variant of the serotonin transporter gene in families with bipolar affective disorder. J Affect Disord 48:135–144. Ferreira L, Soares-Da-Silva P (1991): 5-Hydroxytryptamine and
alcoholism. Hum Psychopharmacol 6:S21–S24.
Gutie´rrez B, Arranz MJ, Collier DA, Valle`s V, Guillamat R, Bertranpetit J (1998): Serotonin transporter gene and risk for bipolar affective disorder: An association study in a Spanish population. Biol Psychiatry 43:843– 847.
Heils A, Teufel A, Petri S, Stober G, Riederer P, Bengel D, et al (1996): Allelic variation of human serotonin transporter gene expression. J Neurochem 66:2621–2624.
Heinz A, Ragan P, Jones DW, Homner D, Williams W, Knable MB, et al (1998): Reduced central serotonin transporters in alcoholism. Am J Psychiatry 155:1544 –1549.
Higley J, Hasert M, Suomi S, Linnoila M (1998): The serotonin reuptake inhibitor sertraline reduces excessive alcohol con-sumption in nonhuman primates: Effect of stress.
Neuropsy-chopharmacology 18:431– 443.
Jorm AF, Henderson AS, Jacomb PA, Christensen H, Korten AE, Rodgers B (1998): An association study of a functional polymorphism of the serotonin transporter gene with person-ality and psychiatric symptoms. Mol Psychiatry 3:449 – 451. Kessler R, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S, et al (1994): Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. Arch Gen
Psychiatry 51:8 –19
Kunugi H, Hattori M, Kato T, Tatsumi M, Sakai T, Sasaki T (1997) Serotonin transporter gene polymorphisms: Ethnic difference and possible association with bipolar affective disorder. Mol Psychiatry 2:457– 462.
Lejoyeux M (1996): Use of serotonin (5-hydroxytryptamine) reuptake inhibitors in the treatment of alcoholism. Alcohol
Alcohol 31(suppl 1):69 –75.
LeMarquand D, Pihl R, Benkelfat C (1994a): Serotonin and alcohol intake, abuse and dependence: Findings of animal studies. Biol Psychiatry 36:395– 421.
LeMarquand D, Pihl RO, Benkelfat C (1994b): Serotonin and alcohol intake, abuse, and dependence: Clinical evidence.
Biol Psychiatry 36:326 –337.
Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, et al (1996): Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274:1527–1531.
Little KY, McLaughlin DP, Zhang L, Livermore CS, Dalack GW, McFinton PR, et al (1998): Cocaine, ethanol, and genotype effects on human midbrain serotonin transporter binding sites and mRNA levels. Am J Psychiatry 155:207– 213.
Loparev VN, Cartas MA, Monken C, Velpandi A, Srinivajan A (1991): An efficient and simple method of DNA extraction from whole blood and cell lines to identify infectious agents.
J Virol Methods 34:105–112.
Lu MR, Wagner GC, Fisher H (1994): Ethanol consumption following acute treatment with methysergide, fluoxetine, fenfluramine, and their combination. Alcohol Clin Exp Res 18:60 – 63.
Nakai T (1997) Serotonin transporter gene regulatory region polymorphism and panic disorder. Mol Psychiatry 2:390 – 392.
McBride WJ, Murphy JM, Yoshimoto K, Lumeng L, Li TK (1993): Serotonin mechanisms in alcohol drinking behavior.
Drug Dev Res 30:170 –177.
McDougle CJ, Epperson CN, Price LH, Gelernter J (1998): Evidence for linkage disequilibrium between serotonin trans-porter protein gene (SLC6A4) and obsessive compulsive disorder. Mol Psychiatry 3:270 –273.
Meltzer H, Lowy M (1987): The serotonin hypothesis of depres-sion. In: Meltzer H, editor. Psychopharmacology, the Third
Generation of Progress. New York: Raven, 513–526.
Meltzer HY, Arora RC, Baber R, Tricou BJ (1981): Serotonin uptake in blood platelets of psychiatric patients. Arch Gen
Psychiatry 38:1322–1326.
Murphy G, Armstrong J, Hermele S, Fischer J, Clendenin W (1979): Suicide and alcoholism: Interpersonal loss confirmed as a predictor. Arch Gen Psychiatry 36:65– 69.
Nakamura T, Muramatsu T, Ono Y, Matsushita S, Higuchi S, Mizushima H, et al (1997): Serotonin transporter gene regu-latory region polymorphism and anxiety-related traits in the Japanese. Am J Med Genet 74:544 –545.
Naranjo CA, Poulos CX, Bremner KE, Lanctot KL (1994): Fluoxetine attenuates alcohol intake and desire to drink. Int
Clin Psychopharmacol 9:163–172.
Nishizawa S, Benkelfat C, Young SN, Leyton M, Mzengeza S, De Montigny C, et al (1997): Differences between males and females in rates of serotonin synthesis in human brain. Proc
Natl Acad Sci U S A 94:5308 –5313.
Nurnberger JI, Blehar MC, Kaufmann CA, York-Cooler C, Simpson SG, Harkavy-Friedman J, et al (1994): Diagnostic Interview for Genetic Studies: Rationale, unique features, and training. Arch Gen Psychiatry 51:849 – 862.
Pihl R, LeMarquand D (1998): Serotonin and aggression and the alcohol-aggression relationship. Alcohol Alcohol 33:55– 65. Rees M, Norton N, Jones I, McCandless F, Scourfield J,
Holmans P, et al (1997): Association studies of bipolar disorder at the human serotonin transporter gene (hSERT; 5-HTT). Mol Psychiatry 2:398 – 402.
Robins E (1981): The Final Months: A Study of the Lives of 134
Persons Who Committed Suicide. New York: Oxford
Univer-sity Press.
Rossow I, Amundsen A (1995): Alcohol abuse and suicide: A 40-year prospective study of Norwegian conscripts. Addiction 90:685– 691.
Salomon R, Miller H, Delgado P, Charney D (1993): The use of tryptophan depletion to evaluate central serotonin function in depression and other neuropsychiatric disorders. Int Clin
Psychopharmacol 8:41– 46.
Sander T, Harms H, Dufeu P, Kuhn S, Hoehe M, Lesch KP, et al (1998): Serotonin transporter gene variants in alcohol-depen-dent subjects with dissocial personality disorder. Biol
Psychi-atry 43:908 –912.
Schmidt L, Rommelspacher H, Lesch KP, Sander T (1997): Variants of the dopamine and serotonin transporter genes and alcohol withdrawal vulnerability. Am J Med Genet 6:621– 622.
Sellers EM, Higgins GA, Sobell MB (1992): 5-HT and alcohol abuse. Trends Pharmacol Sci 13:69 –75.
Selzer M (1971): The Michigan Alcoholism Screening Test: The quest for a new diagnostic instrument. Am J Psychiatry 127:89 –94.
Smith KA, Fairburn CG, Cowen PJ (1997): Relapse of depres-sion after rapid depletion of tryptophan. Lancet 349:915–919. Traskman-Bendz L, Asberg M, Schalling D (1986): Serotonin-ergic function and suicidal behavior in personality disorders.
Ann N Y Acad Sci 487:168 –174.
Tuinier S, Verhoeven W, van Praag HM (1995): Cerebrospinal fluid 5-hydroxyindoleacetic acid and aggression: A critial reappraisal of the clinical data. Int Clin Psychopharmacol 10:147–156.
Tu¨rker T, Sodmann R, Goebel U, Jatzke S, Knapp M, Lesch KP, et al (1998): High ethanol tolerance in young adults is associated with the low-activity variant of the promoter of the human serotonin transporter gene. Neurosci Lett 248:147– 150.
van Praag HM (1983): CSF5-HIAA and suicide in non-depressed schizophrenics. Lancet ii:977–978.
Whitters A, Cadoret R, Widmir R (1985): Factors associated with suicide attempts in alcohol abusers? J Affect Disord 9:19 –23.
