 |
|
Association Between Serotonin Transporter Gene Promoter Polymorphism (5HTTLPR) and Behavioral Responses to Tryptophan Depletion in Healthy Women With and Without Family History of Depression
Alexander Neumeister, MD;
Anastasios Konstantinidis, MD;
Juergen Stastny, MD;
Markus J. Schwarz, MD;
Oliver Vitouch, PhD;
Matthaus Willeit, MD;
Nicole Praschak-Rieder, MD;
Johanna Zach, CTA;
Martina de Zwaan, MD;
Brigitta Bondy, MD;
Manfred Ackenheil, MD;
Siegfried Kasper, MD
Arch Gen Psychiatry. 2002;59:613-620.
ABSTRACT
| |
Background Evidence suggests that serotonin transporter gene promoter polymorphism
(5HTTLPR)–dependent low transcriptional activity
of the human serotonin transporter gene may be a genetic susceptibility factor
for depression. We studied the behavioral responses to tryptophan depletion
(TD) in healthy women with and without a first-degree family history of depression
and examined the relationship to 5HTTLPR alleles.
Methods Twenty-four healthy women with a negative family history of depression
and 21 women with a positive family history of depression were genotyped for
the polymorphism of the 5HTTLPR and then entered
a double-blind, placebo-controlled, randomized crossover TD study. The effects
of these interventions were assessed with measures of depression and plasma
tryptophan levels.
Results The TD induced a robust decrease of plasma tryptophan levels in all
women irrespective of family history of depression or 5HTTLPR genotypes. The s/s genotype of the 5HTTLPR was associated with an increased risk of developing
depressive symptoms during TD irrespective of family history. In contrast,
individuals with the l/l genotype did not develop
depressive symptoms, irrespective of family history. Finally, s/l subjects without family history showed a mood response that was
intermediate between the s/s and l/l subjects, while s/l subjects with a family
history of depression showed the same depressiogenic effect of TD as seen
in the s/s subjects.
Conclusions The results of the present study suggest that the s-allele of the 5HTTLPR and a positive family
history of depression are additive risk factors for the development of depression
during TD.
INTRODUCTION
THE INVOLVEMENT of serotonergic pathways in the pathogenesis of unipolar
depression has been the subject of intensive research for many years. There
is now substantial evidence suggesting that altered brain serotonergic transmission
plays a key role in the development of depression.1
Altered serotonin system indexes, including lower plasma tryptophan levels,2-3 reduced cerebrospinal fluid 5-hydroxyindoleacetic
acid levels,4 decreased platelet serotonin
uptake,5 and blunted neuroendocrine responses
in challenge studies of different serotonin receptors suggesting decreased
brain serotonin responsiveness,6-9
have been reported in depressed patients relative to healthy control subjects.
Moreover, brain imaging studies suggest widespread impairment of serotonergic
function in depression.10-11
The most widely reported serotonergic abnormality in major depression
involves the serotonin transporter (5-HTT).12
This is of particular interest because serotonin reuptake inhibitors, which
are the mainstay of pharmacologic treatment of depression,13
target the 5-HTT.14 The human 5-HTT gene has
been cloned and maps to chromosome 17q11.1-q12,15-16
and 2 common polymorphisms have been described: a variable-number tandem repeat
(VNTR) located in intron 2 (5-HTT-VNTR),16
and a deletion-insertion in the transcriptional control region approximately
1 kilobase upstream of the transcription initiation site (5HTTLPR).17 The promoter polymorphism
has been shown to influence transcription activity and 5-HTT function. The
short form of this variant, designated s, is associated
with lower basal and induced transcriptional efficiency of the 5-HTT gene
promoter, resulting in lower serotonin uptake activity, when compared with
the long form, designated l.17-21
The l/l genotype yielded higher levels of 5-HTT function
and expression than did the s/l and s/s genotypes, which did not differ significantly from each other.
Altogether, both in vitro and in vivo studies showed that the s-allele leads to reduced transcription and expression.
In the initial study22 linking 5HTTLPR genotypes and behavioral variants, the authors
report that individuals with either 1 or 2 copies of the s-promoter region variant exhibit significantly greater levels of neuroticism,
defined as increased levels of anxiety, hostility, and depression, than subjects
homozygous for the long genotype in the sample as a whole and also within
sibships. Also, the subjects exhibited increased scores for Harm Avoidance
on the Tridimensional Personality Questionnaire.23
Subsequent attempts to replicate associations between 5HTTLPR and personality traits agreed with these initial findings,24-25 but others disagreed.26-28
Ongoing research explores possible associations between the 5HTTLPR variants and categorically defined neuropsychiatric disorders,
including affective illness,20, 29-30
panic disorder,31 autism,32
obsessive-compulsive disorder,33 schizophrenia,34 alcoholism,35 and
Alzheimer disease.36-37 Results
of studies disagree about the potential role of 5HTTLPR in the pathogenesis of depression.29, 38-40
Tryptophan depletion (TD) is a widely used research paradigm to study
the behavioral effects of transient reduced synthesis of brain serotonin41-42 by depletion of its precursor tryptophan.43-44 The literature on the behavioral
effects of TD in healthy control subjects is somewhat controversial. Taken
together, all studies report a high variability in the mood responses to TD,
and depressed mood occurred in only a subset of the subjects.
The variability in the reported mood-lowering effects of TD in healthy
subjects may result from a differing susceptibility to the behavioral effects
of TD. The present study was designed to explore the relationship between
family history (FH) of depression, 5HTTLPR genotypes,
and behavioral and biological responses to TD. We recruited healthy women
with and without a positive first-degree FH of depression. We hypothesized
that women with a positive first-degree FH of depression will experience a
transient lowering of their mood during TD, in contrast to women without a
positive first-degree FH of depression. On the basis of the evidence that
the s-allele of the 5HTTLPR
is associated with reduced 5-HTT functions, we tested the hypothesis that
women carrying the s/s and s/l genotypes are more vulnerable to the mood-lowering effects of TD and
thus will show more pronounced behavioral responses.
SUBJECTS AND METHODS
SUBJECTS
Forty-five white women, aged 19 to 53 years (mean ± SD age, 26.3
± 4.9 years), were recruited for this study through advertisements
between October 1997 and February 2000 (Table 1). All subjects were screened for present or past psychiatric
Axis I diagnoses by means of the Structured Clinical Interview for DSM-IV, nonpatient version.45 In addition,
the Structured Clinical Interview for DSM-IV for
Axis II Personality Disorders was administered.46
Inclusion criteria for all subjects included willingness to participate in
a TD study, good physical health, and the absence of any Axis I and II DSM-IV diagnoses. Physical examinations, including electrocardiogram
and blood and urine tests, ensured that all participants were medically healthy.
All subjects underwent urine pregnancy tests at the time of screening and
on the morning of the day before initiation of the depletion procedures. Smokers
were ineligible to participate.
|
|
|
|
Table 1. Demographic Characteristics of Healthy Female Subjects With
(FH+) and Without (FH-) a Family History of Depression
|
|
|
The FH data were collected by means of the Structured Clinical Interview
for DSM-IV for Axis I diagnoses. Interviews with
first-degree relatives (n = 150) were conducted by telephone, which has been
shown to provide results comparable with those of interviews done face-to-face.47-48 Moreover, relatives were asked to
provide us with information regarding their treatment for depression and potential
comorbid disorder. In case we were unable to obtain a personal interview with
the relative (n = 12; 7 men and 5 women) we used medical records and information
provided by the study subject to determine his or her psychiatric diagnosis.
Three relatives refused participation in the interview, 2 relatives had died
of suicide, and 7 relatives had died of disorders primarily unrelated to their
psychiatric disorder.
Inclusion criteria for positive FH of depression (FH+) were the presence
of at least 1 first-degree relative with major depression according to DSM-IV criteria and the documentation of at least 2 episodes
of depression that did require treatment, and/or an attempted or successful
suicide during a depressive episode. Families who did not meet these criteria
were considered as having a negative FH of depression (FH-).
All subjects were informed about the study design, which was approved
by the Ethics Committee of the University of Vienna, Vienna, Austria, and
written informed consent was obtained from all participants at the time of
initial screening. The informed consent included information about the potential
risk of transient mood alterations during the depletion sessions.
DESIGN OF THE STUDY
At the time of the initial screening, blood was drawn from all subjects
for genotyping. After their relatives had been screened, subjects were assigned
to either the FH+ or FH- group. According to their genotype (s/s, s/l, or l/l)
and FH, subjects were enrolled into a double-blind, placebo-controlled crossover
TD study and were randomly assigned to undergo either TD first and sham depletion
second or sham depletion first and TD second. To avoid carryover effects,
a period of at least 6 days between each depletion procedure was established.
All women were studied during the follicular phase of their menstrual cycle.
We used a modified methodology for TD and sham depletion as described
previously.49 The TD was induced on day 1,
at 8:30 AM, by administration of 50 white capsules containing an amino acid
mixture consisting of L-isoleucine (4.2 g), L-leucine (6.6 g), L-lysine (4.8
g), L-methionine (1.5 g), L-phenylalanine (6.6 g), L-threonine (3.0 g), and
L-valine (4.8 g). During sham depletion, subjects received on day 1, at 8:30
AM, 50 white capsules containing 31.5 g of lactose.
The effects of TD and sham depletion were evaluated with measures of
depression and measures of plasma total and free tryptophan concentrations
within each depletion procedure on day 1, at 8:30 AM, 2:00 PM, and 4:30 PM,
and on day 2, at 8:30 AM. Patients did not eat on day 1 of the study until
about 5:00 PM. Thereafter, patients returned to unrestricted food intake.
Four raters, blind to the FH and genotype of the subjects and to the
depletion condition, used an 18-item version of the Hamilton Depression Rating
Scale (HDRS) modified from a standard version to assess mood.50
The items assessing sleep, diurnal variation, eating, and weight change were
omitted. The intraclass correlation coefficient51
among raters was 0.95.
All subjects were contacted by one of us (A.N.) about 1 month after
completion of the study to obtain information about their mood. Subjects were
encouraged to contact a clinician of the research team also in the future
if persistent mood alterations occur.
BIOCHEMICAL ASSAYS
Genotyping
DNA was extracted from whole blood by means of a kit (QIAamp Blood Isolation
Kit; QIAGEN GmbH, Hilden, Germany). Primers flanking the 5-HTT promoter polymorphic
region (5HTTP-F 5'-TGA ATG CCA GCA CCT AAC CC-3'; 5-HTTP-R 5'-TTC
TGG 'TGC CAC CTA GAC GC-3') were used to generate a 406–base
pair (deletion)/450–base pair (insertion) fragment.32
Polymerase chain reaction was performed in a final volume of 25 µL consisting
of 50-ng DNA, l µmol/L of each primer, 200-µM deoxynucleotide
triphosphate, 100-µM 7-deaza–guanosine triphosphate, 5% dimethyl
sulfoxide, 10-mM Tris hydrochloride (pH 8.3), 50-mM potassium chloride, 1.5-mM
magnesium chloride, and 2.5 U of DNA polymerase (AmpliTaq Gold; PerkinElmer,
Langen, Germany). Annealing was carried out at 61°C for 30 seconds, extension
at 72°C for 1 minute, and denaturation at 95°C for 30 seconds for
40 cycles. Polymerase chain reaction products were separated on a 3% agarose
gel (FMC NuSieve 3:1; Biozym Diagnostic GmbH, Oldendorf, Germany) and visualized
by ethidium bromide staining.
Assessments of Plasma Total and Free Tryptophan Concentrations
Patients were asked to rest for 30 minutes before each blood draw. Collected
blood was immediately centrifuged for 17 minutes at 4°C and 3000 rpm.
Serum was frozen at -70°C until analyzed. Proteins were precipitated
by adding 20 mL of 70% perchloric acid to 400 mL of serum. Centrifugation
Centrifugation (Hettich Mikro 22 R centrifuge; Hettich Zentrifugen, Tuttlingen,
Germany) for 30 minutes at 14 000 rpm (at 4°C) gave a colorless liquid
above a yellowish white precipitate. Of this liquid, 100 mL was injected into
the high-performance liquid chromatography, leaving another 100 mL for a second
injection. Plasma total tryptophan concentrations were assessed by means of
high-performance liquid chromatography with fluorometric detection. For detection
of free tryptophan, samples were filtered through a 10-kd filter (Chemicon;
Millipore Corporation, Bedford, Mass). Tryptophan in the ultrafiltrate was
measured by high-performance liquid chromatography with fluorometric detection.52
DATA ANALYSIS
All behavioral and biochemical data were analyzed with a 4-way analysis
of variance (ANOVA) with repeated measures using genotype (l/l, s/l, and s/s),
and FH (FH+ vs FH-) as between-subject factors, and condition (TD vs
sham depletion) and time as within-subject factors. Potential order effects
were assessed with a 5-way ANOVA including order of depletion sessions. With
all Huynh-Feldt correction coefficients equal to 1, sphericity of the repeated-measures
design was assumed, and thus uncorrected P values
are reported. Significant interactions found in the ANOVAs were further examined
with paired t tests, comparing baseline scores with
peak values during the depletion session. Between-group differences were assessed
by means of unpaired t tests. Since all t tests were hypothesis driven, no multiple-comparison correction was
made in the individual t test. Pearson correlation
coefficients were calculated to evaluate the relationship between plasma tryptophan
levels and behavioral changes. Results are reported as means ± SDs.
Differences were considered significant at P<.05
(2-tailed).
RESULTS
BIOCHEMICAL EFFECTS
The administration of the tryptophan-deficient amino acid mixture resulted
in a profound decline in plasma total and free tryptophan concentrations (Table 2), whereas only modest decreases
were observed during sham depletion. The repeated-measures ANOVA of plasma
tryptophan was significant for both total tryptophan (condition x time
interaction: F3,117 = 149.42, P<.001)
and free tryptophan (condition x time interaction: F3,117
= 68.30, P<.001). There was no effect of 5HTTLPR genotype (genotype x condition x time
interaction: F6,117 = 0.20, P = .98) and
FH of depression (FH x condition x time interaction: F3,117 = 1.20, P = .31) for free tryptophan. The
order of depletion sessions (tryptophan-deficient amino acid mixture or lactose
first) did not affect the outcome.
|
|
|
|
Table 2. Changes in Plasma Total and Free Tryptophan Concentrations
During Tryptophan Depletion and Sham Depletion*
|
|
|
BEHAVIORAL EFFECTS
The 4-way ANOVA assessing the effects of TD in the sample as a whole
determined a significant genotype x FH x condition x time
interaction (F6,117 = 3.13, P = .007).
The evaluation of to what extent FH influenced the behavioral responses to
TD showed a significant FH x condition x time interaction (F3,117 = 2.99, P = .03). This indicates that
FH+ subjects had more prominent responses to the depressiogenic effects of
TD than did FH- subjects.
The evaluation of whether the mood-lowering effects of TD may be explained
by 5HTTLPR genotypes exhibited profound effects.
We found a significant main effect of genotype (F2,39 = 9.43, P<.001) and a highly significant genotype x condition
x time interaction (F6,117 = 12.54, P<.001).
Post hoc comparisons showed significant increases of HDRS total scores from
baseline in s/s carriers irrespective of their FH
of depression (Figure 1, A and B).
Most prominent effects of TD were found 5 hours after ingestion of the tryptophan-deficient
amino acid mixture (FH+: 0.8 ± 0.5 vs 9.2 ± 2.1, t4 = -10.3, P<.001; FH-:
0.3 ± 0.5 vs 8.5 ± 2.9, t3
= -6.6, P = .007). Similarly, s/l carriers showed significant increases of HDRS total scores 5 hours
after ingestion of the tryptophan-depleting amino acid mixture (FH+: 0.1 ±
0.4 vs 10.0 ± 4.5, t6 = -5.7, P<.001; FH-: 0.5 ± 0.9 vs 4.6 ±
2.9, t9 = -4.22, P = .002) in both the FH+ and FH- groups
(Figure 1, C and D). Notably, the mood-lowering effects of TD were
significantly more pronounced in the FH+ group than in the FH- group
(unpaired t test: t15 = -3.00, P = .009). In contrast, no
significant behavioral changes were found in l/l
carriers in both the FH+ (t8 = -2.0, P = .08) and FH- (t9 = 0.0, P = 1.0) groups
(Figure 1, E and F).
|
|
|
|
Scores (means ± SDs) on a modified version of the Hamilton
Depression Rating Scale (HDRS, 21-item version) of healthy female subjects
(n = 45) with positive and negative first-degree family histories of depression
and differing serotonin transporter gene promoter polymorphism (5HTTLPR) genotypes.
|
|
|
Six subjects developed HDRS total scores greater than 10 during TD.
Two subjects had HDRS total scores of 16 and 15. However, in none of our subjects
did the development of depressive symptoms, reflected by the increase of HDRS
scores, require treatment, and the effects were transient. In the morning
after TD, all subjects were fully recovered, and most symptoms had completely
disappeared.
The analysis of the mood item of the HDRS agreed with the results from
the HDRS total scores and indicated that in some individuals one of the core
symptoms of depression was affected. We found a trend toward significance
in the FH x condition x time interaction (F3,117 =
2.5, P = .06) and a highly significant genotype x
condition x time interaction (F6,117 = 4.4, P<.001).
COMMENT
In the present study, we examined the relationship between neurochemistry,
behavior, and genetics. This study is, to our knowledge, the first to assess
behavioral responses to TD in healthy female control subjects in relation
to their FH of depression and their individual 5HTTLPR
polymorphisms. The s/s genotype was associated with
an increased risk of developing depressive symptoms during TD, irrespective
of the FH for depression. In contrast, women with the l/l genotype did not develop depressive symptoms to TD, irrespective of
the FH for depression, implying that this genotype exerted a protective effect
on mood in the TD paradigm. Finally, healthy female FH- subjects with
the s/l genotype showed a mood response to TD that
was intermediate between those of the s/s and l/l subjects, while s/l FH+ subjects
showed the same depressiogenic effects of TD seen in the s/s subjects. Conclusively, the s-allele of
the 5HTTLPR and a positive FH of depression appear
to be additive risk factors for the development of depression during TD.
Previous TD studies in healthy control subjects have shown highly variable
mood responses to TD. This may be explained by differing susceptibilities
to the mood-lowering effects of TD. Subjects with no personal history of depression
but with a positive FH of affective disorders have been shown to be at risk
to develop depressive symptoms during TD,53-55
although one study disagrees.56 Although the
reasons for this discrepancy are unknown, the reported elevated dropout rate
in that study may explain the differing results. Eleven (34%) of 32 subjects
did not complete the study because of increased fatigue, loss of interest
to complete the study, and having started an antidepressant treatment during
the study. It can be speculated that, at least in some of these subjects,
depressive symptoms may have occurred. Studies assessing mood responses to
TD in healthy subjects without an FH of affective disorders suggest a greater
risk for women to develop depressive symptoms during TD.54, 57
However, these findings remain controversial and could not be replicated by
others.58-60 Altogether,
these studies and the present findings suggest that responses to lowered tryptophan
availability may reveal a genetic vulnerability to depression in some individuals.
The present study has a number of potential limitations that warrant
discussion. First, the sample size is large relative to previous TD studies,
but subsamples were relatively small. Replication of our findings is needed.
Second, we have to acknowledge that we have collected information about the
FH of psychiatric illnesses only among first-degree relatives of our study
subjects. This may be relevant, since evidence in the literature suggests
that families with single cases of affective illnesses may differ from families
with multiple affected individuals in different generations.61-62
However, a strength of the present study is the personal interviews of the
first-degree relatives, providing us with detailed information about psychiatric
and medical illness and treatment of each first-degree family member.
Moreover, we studied only women in the present study, and thus our findings
cannot be generalized to men. In view of the evidence on gender-related differences
in serotonin system functioning in animals63-65
and in humans,41, 66 we decided
to include only women in the present study. The importance of differential
modulation of serotonergic transmission between males and females is supported
by their differing responsivity and tolerance to selective serotonin reuptake
inhibitors and tricyclic antidepressants in the treatment of depression.67 Previous studies showed that TD induces lowering
of mood in FH+ males,53 but not in FH-
males.53, 68 However, 5HTTLPR genotypes have not been assessed in the noted studies. Thus,
it is of interest to extend our findings to a sample of healthy men with different 5HTTLPR genotypes.
Another issue that raised our attention was the relatively young age
of the subjects in the present study. However, we do not believe that the
age of our subjects influenced the results of this study. Previous studies
have shown that most patients with recurrent unipolar depression with at least
1 affected family member had experienced a depressive episode before 25 years
of age.69 Furthermore, the modal age at onset
of depression is slightly lower in women than in men70
and is even earlier in the offspring of depressed parents.71-73
We acknowledge that the use of a modified procedure to deplete tryptophan
makes it difficult to compare results with those of other TD studies. This
study used a smaller amino acid load (32 g) than previous TD studies (100
g). Nevertheless, we found decreases in plasma total and free tryptophan levels
of 73% to 84% and 73% to 83%, respectively. This is comparable with other
TD studies using the original method of Young and colleagues.74
It must be considered that brain tryptophan concentrations depend not only
on plasma tryptophan concentrations, but also on the concentrations of the
other large neutral amino acids, competing with tryptophan for uptake at the
blood-brain barrier.75-77
Thus, one cannot conclude that the behavioral effects result from TD per se,
since behavioral changes resulting from higher levels of the other amino acids
cannot be excluded.
The question arises whether 5HTTLPR genotypes
may serve as genetic markers linked to different risks for developing depression
in healthy subjects. This would be of particular interest and relevance because
the proportions of 5HTTLPR genotypes in the general
population are as follows: s/s, 0.16; s/l, 0.48; and l/l, 0.36.22, 25
Thus, a substantial proportion of the general population are carriers of the s-allele. Preliminary evidence supports such an assumption.
Neonates carrying the s-allele of the 5HTTLPR show lowered alertness and visual and auditory behavior, perhaps
reflecting reduced adult novelty-seeking behavior.78
Follow-up studies of this sample showed most negative emotionality and most
distress to daily situations in infants with the s/s 5HTTLPR genotype.79 However, to answer the
question of whether the s-allele is associated with
an increased risk of developing depression, carefully designed, prospective
genetic epidemiologic studies are needed.
AUTHOR INFORMATION
Submitted for publication May 31, 2001; final revision received September
26, 2001; accepted October 1, 2001.
This study was presented in part in abstract form at the 56th Annual
Meeting of the Society of Biological Psychiatry, May 3-5, 2001, New Orleans,
La.
This study was supported in part by a Hirtl/Buss grant, Vienna, Austria
(Dr Neumeister). Dr Neumeister is supported by the Austrian Program for Advanced
Research and Technology, Vienna.
Corresponding author and reprints: Alexander Neumeister, MD, National
Institutes of Health, NIMH, Mood and Anxiety Disorders Research Program, North
Drive, Bldg 15K/Room 200, Bethesda, MD 20892-2670 (e-mail: neumeisa{at}intra.nimh.nih.gov).
From the National Institute of Mental Health, Mood and Anxiety Disorders
Program, Bethesda, Md (Dr Neumeister); Department of General Psychiatry, University
of Vienna, Vienna, Austria (Drs Neumeister, Konstantinidis, Stastny, Willeit,
Praschak-Rieder, de Zwaan, and Kasper); Department of Neurochemistry, University
Hospital of Psychiatry, Munich, Germany (Drs Schwarz, Bondy, and Ackenheil
and Ms Zach); and the Max Planck Institute for Human Development, Berlin,
Germany (Dr Vitouch).
REFERENCES
| |
1. Heninger GR, Charney DS, Sternberg DE. Serotonergic function in depression: prolactin response to intravenous
tryptophan in depressed patients and healthy subjects. Arch Gen Psychiatry. 1984;41:398-402.
ABSTRACT
2. Coppen A, Eccleston EG, Peet M. Total and free tryptophan concentration in the plasma of depressive
patients. Lancet. 1973;2:60-63.
ISI
| PUBMED
3. Cowen PJ, Parry-Billings M, Newsholme EA. Decreased plasma tryptophan levels in major depression. J Affect Disord. 1989;16:27-31.
FULL TEXT
|
ISI
| PUBMED
4. Asberg M, Thoren P, Traskman L, Bertilsson L, Ringberger V. "Serotonin depression"—a biochemical subgroup within the affective
disorders? Science. 1976;191:478-480.
FREE FULL TEXT
5. Healy D, Leonard BE. Monoamine transport in depression: kinetics and dynamics. J Affect Disord. 1987;12:91-103.
FULL TEXT
|
ISI
| PUBMED
6. Cowen PJ, Charig EM. Neuroendocrine responses to intravenous tryptophan in major depression. Arch Gen Psychiatry. 1987;44:958-966.
ABSTRACT
7. Mann JJ, McBride PA, Malone KM, DeMeo M, Keilp J. Blunted serotonergic responsivity in depressed inpatients. Neuropsychopharmacology. 1995;13:53-64.
FULL TEXT
|
ISI
| PUBMED
8. Meltzer HY, Maes M. Effects of ipsapirone on plasma cortisol and body temperature in major
depression. Biol Psychiatry. 1995;38:450-457.
FULL TEXT
|
ISI
| PUBMED
9. Siever LJ, Murphy DL, Slater S, de la Vega E, Lipper S. Plasma prolactin changes following fenfluramine in depressed patients
compared to controls: an evaluation of central serotonergic responsivity in
depression. Life Sci. 1984;34:1029-1039.
FULL TEXT
|
ISI
| PUBMED
10. Malison RT, Price LH, Berman R, van Dyck CH, Pelton GH, Carpenter L, Sanacora G, Owens MJ, Nemeroff CB, Rajeevan N, Baldwin RM, Seibyl JP, Innis RB, Charney DS. Reduced brain serotonin transporter availability in major depression
as measured by [123I]-2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane
and single photon emission computed tomography. Biol Psychiatry. 1998;44:1090-1098.
FULL TEXT
|
ISI
| PUBMED
11. Mann JJ, Malone KM, Diehl DJ, Perel J, Cooper TB, Mintun MA. Demonstration in vivo of reduced serotonin responsivity in the brain
of untreated depressed patients. Am J Psychiatry. 1996;153:174-182.
FREE FULL TEXT
12. Owens MJ, Nemeroff CB. Role of serotonin in the pathophysiology of depression: focus on the
serotonin transporter. Clin Chem. 1994;40:288-295.
FREE FULL TEXT
13. Tylee A for the Depression Research in European Society. Depression in Europe: experience from the DEPRES II survey. Eur Neuropsychopharmacol. 2000;10(suppl 4):S445-S448.
14. Pirker W, Asenbaum S, Kasper S, Walter H, Angelberger P, Koch G, Pozzera A, Deecke L, Podreka I, Brucke T. Beta-CIT SPECT demonstrates blockade of 5HT-uptake sites by citalopram
in the human brain in vivo. J Neural Transm Gen Sect. 1995;100:247-256.
FULL TEXT
|
ISI
| PUBMED
15. Ramamoorthy S, Bauman AL, Moore KR, Han H, Yang-Feng T, Chang AS, Ganapathy V, Blakely RD. Antidepressant- and cocaine-sensitive human serotonin transporter:
molecular cloning, expression, and chromosomal localization. Proc Natl Acad Sci U S A. 1993;90:2542-2546.
FREE FULL TEXT
16. Lesch KP, Balling U, Gross J, Strauss K, Wolozin BL, Murphy DL, Riederer P. Organization of the human serotonin transporter gene. J Neural Transm Gen Sect. 1994;95:157-162.
FULL TEXT
|
ISI
| PUBMED
17. Heils A, Teufel A, Petri S, Stober G, Riederer P, Bengel D, Lesch KP. Allelic variation of human serotonin transporter gene expression. J Neurochem. 1996;66:2621-2624.
ISI
| PUBMED
18. Heils A, Mossner R, Lesch KP. The human serotonin transporter gene polymorphism: basic research and
clinical implications. J Neural Transm. 1997;104:1005-1014.
19. Little KY, McLaughlin DP, Zhang L, Livermore CS, Dalack GW, McFinton PR, DelProposto ZS, Hill E, Cassin BJ, Watson SJ, Cook EH. Cocaine, ethanol, and genotype effects on human midbrain serotonin
transporter binding sites and mRNA levels. Am J Psychiatry. 1998;155:207-213.
FREE FULL TEXT
20. Collier DA, Stober G, Li T, Heils A, Catalano M, Di Bella D, Arranz MJ, Murray RM, Vallada HP, Bengel D, Muller CR, Roberts GW, Smeraldi E, Kirov G, Sham P, Lesch KP. A novel functional polymorphism within the promoter of the serotonin
transporter gene: possible role in susceptibility to affective disorders. Mol Psychiatry. 1996;1:453-460.
ISI
| PUBMED
21. Greenberg BD, Tolliver TJ, Huang SJ, Li Q, Bengel D, Murphy DL. Genetic variation in the serotonin transporter promoter region affects
serotonin uptake in human blood platelets. Am J Med Genet. 1999;88:83-87.
FULL TEXT
|
ISI
| PUBMED
22. Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, Benjamin J, Muller CR, Hamer DH, Murphy DL. Association of anxiety-related traits with a polymorphism in the serotonin
transporter gene regulatory region. Science. 1996;274:1527-1531.
FREE FULL TEXT
23. Cloninger CR, Przybeck TR, Svrakic DM. The Tridimensional Personality Questionnaire: U.S. normative data. Psychol Rep. 1991;69(3, pt 1):1047-1057.
24. Greenberg BD, Li Q, Lucas FR, Hu S, Sirota LA, Benjamin J, Lesch KP, Hamer D, Murphy DL. Association between the serotonin transporter promoter polymorphism
and personality traits in a primarily female population sample. Am J Med Genet. 2000;96:202-216.
FULL TEXT
|
ISI
| PUBMED
25. Mazzanti CM, Lappalainen J, Long JC, Bengel D, Naukkarinen H, Eggert M, Virkkunen M, Linnoila M, Goldman D. Role of the serotonin transporter promoter polymorphism in anxiety-related
traits. Arch Gen Psychiatry. 1998;55:936-940.
FREE FULL TEXT
26. Ebstein RP, Gritsenko I, Nemanov L, Frisch A, Osher Y, Belmaker RH. No association between the serotonin transporter gene regulatory region
polymorphism and the Tridimensional Personality Questionnaire (TPQ) temperament
of harm avoidance. Mol Psychiatry. 1997;2:224-226.
FULL TEXT
|
ISI
| PUBMED
27. Flory JD, Manuck SB, Ferrell RE, Dent KM, Peters DG, Muldoon MF. Neuroticism is not associated with the serotonin transporter (5-HTTLPR)
polymorphism. Mol Psychiatry. 1999;4:93-96.
FULL TEXT
|
ISI
| PUBMED
28. Jorm AF, Henderson AS, Jacomb PA, Christensen H, Korten AE, Rodgers B, Tan X, Easteal S. An association study of a functional polymorphism of the serotonin
transporter gene with personality and psychiatric symptoms. Mol Psychiatry. 1998;3:449-451.
FULL TEXT
|
ISI
| PUBMED
29. Bellivier F, Laplanche JL, Leboyer M, Feingold J, Bottos C, Allilaire JF, Launay JM. Serotonin transporter gene and manic depressive illness: an association
study. Biol Psychiatry. 1997;41:750-752.
FULL TEXT
|
ISI
| PUBMED
30. Rees M, Norton N, Jones I, McCandless F, Scourfield J, Holmans P, Moorhead S, Feldman E, Sadler S, Cole T, Redman K, Farmer A, McGuffin P, Owen MJ, Craddock N. Association studies of bipolar disorder at the human serotonin transporter
gene (hSERT; 5HTT). Mol Psychiatry. 1997;2:398-402.
FULL TEXT
|
ISI
| PUBMED
31. Deckert J, Catalano M, Heils A, Di Bella D, Friess F, Politi E, Franke P, Nothen MM, Maier W, Bellodi L, Lesch KP. Functional promoter polymorphism of the human serotonin transporter:
lack of association with panic disorder. Psychiatr Genet. 1997;7:45-47.
ISI
| PUBMED
32. Cook EH Jr, Courchesne R, Lord C, Cox NJ, Yan S, Lincoln A, Haas R, Courchesne E, Leventhal BL. Evidence of linkage between the serotonin transporter and autistic
disorder. Mol Psychiatry. 1997;2:247-250.
FULL TEXT
|
ISI
| PUBMED
33. McDougle CJ, Epperson CN, Price LH, Gelernter J. Evidence for linkage disequilibrium between serotonin transporter protein
gene (SLC6A4) and obsessive compulsive disorder. Mol Psychiatry. 1998;3:270-273.
FULL TEXT
|
ISI
| PUBMED
34. Malhotra AK, Goldman D, Mazzanti C, Clifton A, Breier A, Pickar D. A functional serotonin transporter (5-HTT) polymorphism is associated
with psychosis in neuroleptic-free schizophrenics. Mol Psychiatry. 1998;3:328-332.
FULL TEXT
|
ISI
| PUBMED
35. Sander T, Harms H, Lesch KP, Dufeu P, Kuhn S, Hoehe M, Rommelspacher H, Schmidt LG. Association analysis of a regulatory variation of the serotonin transporter
gene with sever |
