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Anguelova M, Benkelfat C, Turecki G.
A systematic
review of association studies investigating genes coding for serotonin receptors
and the serotonin transporter: I. Affective disorders.
Mol
Psychiatry. 2003 Jun;8(6):574-91.
"The different 5-HT (serotonin) receptors
including the serotonin transporter (5-HTT) are candidate genes for affective
disorders such as major depressive disorder (MDD) and bipolar disorder (BD). They
have been investigated in a number of allelic association studies where the individual
results have been inconsistent, and therefore, definite conclusions are difficult
to make. Systematic reviews using meta-analytical techniques are a reliable method
for objectively and reproducibly assessing individual studies and generating combined
result. This study aimed at reviewing published studies investigating the association
between affective disorders (MDD and BD) and variation at genes coding for serotonin
receptors and the serotonin transporter. We performed National Library of Medicine
database searches to identify potential studies. More than 430 articles were reviewed
and 86 studies met the inclusion criteria for participation in our review. Of
these, 41 studies investigated 45 different 5-HT receptor variants and 45 studies
investigated at least one of two commonly studied 5-HTT polymorphisms in MDD.
Many studies investigated the association between MDD and BD with the 5-HT2A 102
T/C, the 5-HTT promoter 44 bp insertion/deletion and the intron 2 VNTR polymorphisms,
and thus, these could be pooled using meta-analytic techniques. The overall odds
ratio (OR) for the combined individual results was significant for BD and the
two 5-HTT polymorphisms: Mantel-Haenszel weighted OR=1.14, CI: 1.03-1.26, P=0.015
for the promoter locus (N=3467) and Mantel-Haenszel Weighted odds ratio OR=1.18,
CI: 1.05-1.32, P=0.004 for the VNTR locus (N=3620). However, sensitivity analysis
indicated that, in each case, the overall positive association could be mostly
attributed to the large effect of one individual study. Therefore, these results
suggest that, although promising, further studies are required to assess appropriately
the evidence suggesting an association between BD and 5-HTT." [Abstract] Smits
KM, Smits LJ, Schouten JS, Stelma FF, Nelemans P, Prins MH.
Influence
of SERTPR and STin2 in the serotonin transporter gene on the effect of selective
serotonin reuptake inhibitors in depression: a systematic review.
Mol
Psychiatry. 2004 May;9(5):433-441.
"Large differences in clinical response
to selective serotonin reuptake inhibitors (SSRIs) are observed in depressive
patients with different genotypes. Quantification of these differences is needed
to decide if genetic testing prior to antidepressant treatment is useful. We conducted
a systematic review of the literature on the influence of polymorphisms in the
serotonin transporter gene (SERTPR (or 5-HTTLPR) and STin2) on SSRI response.
Studies were identified by the use of MEDLINE, EmBase and PsycINFO, references
of articles, reviews and information from pharmaceutical companies. Nine studies
assessing the influence of SERTPR or STin2 on treatment response were included.
Outcome was expressed as the percentage of decrease in depression score (HAM-D
or MADRS) or as the percentage of responders (>/=50% reduction on the depression
scale). Both study methodologies and study outcomes showed large heterogeneity.
Weighted mean decreases in depression score for patients with the s/s, s/l and
l/l genotypes were 35.4, 46.3 and 48.0% at week 4, respectively, and 53.9, 54.6
and 48.3% at week 6. Among Caucasian patients, both mean decrease in depression
score and response rate were lowest in the s/s group, while among Asian patients,
results were inconsistent. Weighted response rates were 36.1% for the 10/12 genotype
of the STin2 polymorphism and 80.7% for the 12/12 genotype (chi(2)=27.8, P<0.001)
(only Asians). The available evidence points to a less favourable response to
SSRI treatment among Caucasian patients with the SERTPR s/s genotype and among
(Asian) patients with the STin2 10/12 genotype. In view of the scarcity and heterogeneity
of the studies, however, current information is insufficiently reliable as a basis
for implementing genetic testing in the diagnostic work-up of the depressive patient."
[Abstract]
Lotrich FE, Pollock BG
Meta-analysis of serotonin transporter polymorphisms and affective disorders.
Psychiatr Genet. 2004 Sep;14(3):121-9.
Polymorphisms in the promoter region (5-HTTLPR) of the serotonin transporter and a variable number of tandem repeats polymorphism in the second intron have been widely studied. However, the results of association studies examining unipolar depression (MDD) or bipolar disorder depression (BPD) have been mixed. To precisely ascertain small associations with both polymorphisms, a meta-analysis was performed involving several thousand subjects, using random-effects modeling. For MDD, the effect of the 5-HTTLPR genotype was significant (chi2=6.1, P<0.05), with 21% of MDD subjects and 17% of controls homozygous for the short (S) allele (odds ratio, 1.16). Similar findings were noted in BPD, with a higher frequency of S/S genotypes in affected patients, although the results did not reach statistical significance. Results of transmission disequilibrium tests trended in a similar direction but also did not reach statistical significance. No consistent effect of the variable number of tandem repeats polymorphism was revealed for either MDD or BPD. The results suggest that the S allele, or a neighboring allele in linkage disequilibrium, is recessive for MDD and possibly BPD. Notably, the association is very small. With these small associations, confounding issues such as population stratification require addressing. Significant heterogeneity between studies was also evident, possibly reflecting differences in diagnosis, different control populations, and different ethnic populations. These factors should Influence the interpretation of the association found in this analysis. [Abstract]
Arango
V, Huang Y, Underwood MD, Mann JJ.
Genetics of the serotonergic system
in suicidal behavior.
J Psychiatr Res. 2003 Sep-Oct;37(5):375-86.
"Genetic
factors contribute to the risk of psychopathology in many psychiatric conditions,
but the specific genes are yet to be identified. Neurotransmitter alterations
are implicated in the etiology of psychopathology based, in part, on studies of
neurotransmitter receptors and their biosynthetic or degradative enzymes in postmortem
tissue. Identification of the altered receptors and enzymes serves to identify
candidate genes of potential etiological significance. Polymorphisms in these
genes can contribute to alterations in protein function in vivo that are part
of the neurochemical underpinnings of psychopathologies such as major depressive
disorder, psychoses, alcoholism, personality disorders, aggressive-impulsive traits,
or suicidal behavior. Altered serotonergic function is implicated in the etiology
and pathogenesis of several major psychiatric conditions. In particular, there
is much evidence for an association of lower serotonergic function and suicidal
behavior. Thus genes related to the serotonergic system are candidate genes worthy
of study as part of the genetic diathesis for suicidal behavior. This review examines
the following polymorphisms in the serotonin biosynthetic enzyme tryptophan hydroxylase
(TPH; A779C substitution), the serotonin transporter (5-HTT, 5-HTTLPR allele),
the 5-HT(1B) receptor (G861C, C129T substitution) and the 5-HT(2A) receptor (T102C)
for their relationship to suicidal behavior. For the TPH gene, we found the less
common U or A allele variant of the A779C polymorphism was associated with suicide
attempt. Other studies have found the U allele to be associated with aggression
and lower serotonergic function in vivo. A 44 base pair insertion/deletion in
the 5' flanking promoter region of the 5-HTT gene may result in less 5-HTT expression
and 5-HTT binding. We examined 220 cases postmortem and found no association between
the promoter genotype and 5-HTT binding. We also found no association with major
depressive disorder (MDD), suicide or pathological aggression, despite finding
significantly fewer 5-HTT sites in the prefrontal cortex of depressed and/or suicide
cases. In genomic DNA samples from 178 unrelated subjects, we detected two polymorphisms
for the 5-HT(1B) receptor at nucleotides 861 and 129. However, no association
between either polymorphism and depression, suicide, aggression, or alcoholism
was observed. There are two common polymorphisms for the 5-HT(2A) receptor gene
in humans. The results of studies of 5-HT(2A) receptor gene polymorphisms do not
indicate significant major associations with suicidal behavior. In contrast, the
5-HT(2A) receptor itself is reported to be increased in suicide. Functional polymorphisms
involving the promoter region that affect gene expression may explain this finding.
Studies of candidate genes related to serotonergic function in brain are increasingly
used to establish genetic alterations contributing to psychiatric illness. The
most meaningful studies combine the study of candidate genes with direct measures
of related proteins as well as psychopathology." [Abstract]
Hoefgen B, Schulze TG, Ohlraun S, von Widdern O, Höfels S, Gross M, Heidmann V, Kovalenko S, Eckermann A, Kölsch H, Metten M, Zobel A, Becker T, Nöthen MM, Propping P, Heun R, Maier W, Rietschel M
The power of sample size and homogenous sampling: Association between the 5-HTTLPR serotonin transporter polymorphism and major depressive disorder.
Biol Psychiatry. 2005 Feb 1;57(3):247-51.
BACKGROUND: Several lines of evidence indicate that abnormalities in the functioning of the central serotonergic system are involved in the pathogenesis of affective illness. A 44-base-pair insertion/deletion polymorphism in the 5' regulatory region of the serotonin transporter gene (5-HTTLPR), which influences expression of the serotonin transporter, has been the focus of intensive research since an initial report on an association between 5-HTTLPR and depression-related personality traits. Consistently replicated evidence for an involvement of this polymorphism in the etiology of mood disorders, particularly in major depressive disorder (MDD), remains scant. METHODS: We assessed a potential association between 5-HTTLPR and MDD, using the largest reported sample to date (466 patients, 836 control subjects). Individuals were all of German descent. Patients were systematically recruited from consecutive inpatient admissions. Control subjects were drawn from random lists of the local Census Bureau and screened for psychiatric disorders. RESULTS: The short allele of 5-HTTLPR was significantly more frequent in patients than in control subjects (45.5% vs. 39.9%; p = .006; odds ratio = 1.26). CONCLUSIONS: These results support an involvement of 5-HTTLPR in the etiology of MDD. They also demonstrate that the detection of small genetic effects requires very large and homogenous samples. [Abstract]
Gutierrez
B, Pintor L, Gasto C, Rosa A, Bertranpetit J, Vieta E, Fananas L.
Variability
in the serotonin transporter gene and increased risk for major depression with
melancholia.
Hum Genet 1998 Sep;103(3):319-22
"The
serotonin transporter (SERT) gene is a particularly interesting candidate for
genetic involvement in affective disorders owing to its role in both the regulation
of serotonergic neurotransmission and the mechanism of action of many antidepressant
drugs. In this study, variability in the SERT gene was analyzed for the first
time in a sample of patients with major depression with melancholia (MDDM) in
the context of a genetic association study. Two different polymorphisms of the
SERT gene (17q11.1-17q12) were analyzed: a variable number of tandem repeats (VNTR)
polymorphism in intron 2, and a deletion/insertion polymorphism (5-HTTLPR) in
the promoter region of the gene, the short variant of which (allele 484) reduces
the transcriptional efficiency of the SERT gene. Our sample consisted of 74 unrelated
subjects who strictly met DSM-IV criteria for MDDM and 84 healthy controls, all
of Spanish origin. The analysis of haplotype distribution for both polymorphisms
showed significant differences between cases and controls (log-likelihood ratio
chi2=11.15, df=4, P=0.025). Moreover, when the frequencies of the 484-STin2.10
haplotype were considered in comparison with any other haplotype combination,
a significant increase in this haplotype was found in patients with MDDM [z=2.53
(95% CI, 1.21-5.34), P=0.007]. According to these results, variability in the
SERT gene has a small effect on liability to MDDM. Our findings are compatible
with an additive effect of both the 484 low-activity allele and a mutation elsewhere
within the transporter gene or a susceptibility locus nearby in linkage disequilibrium
with the VNTR marker." [Abstract] Furlong
RA, Ho L, Walsh C, Rubinsztein JS, Jain S, Paykel ES, Easton DF, Rubinsztein DC.
Analysis
and meta-analysis of two serotonin transporter gene polymorphisms in bipolar and
unipolar affective disorders.
Am J Med Genet 1998 Feb 7;81(1):58-63
"The
serotonin transporter is a compelling candidate gene to examine in bipolar and
unipolar affective disorder, since drugs that specifically inhibit the serotonin
transporter can successfully treat depression. Previous association studies of
a VNTR polymorphism in intron 2 and a functional insertion/deletion polymorphism
in the promoter of this gene have produced conflicting results. The present study
examined allele and genotype frequencies for both of these polymorphisms and resulting
haplotypes in 87 English Caucasian bipolar patients, 125 English Caucasian unipolar
affective disorder patients, and 174 controls. No significant associations were
detected when these unipolar or bipolar cases were compared either separately
or as a pooled "affective disorder" group to the controls. A meta-analysis
of over 1,400 individuals of European Caucasian origin was then performed, comprising
772 controls, 375 bipolar and 299 unipolar patients for the VNTR polymorphism,
and 739 controls, 392 bipolar and 275 unipolar patients for the promoter polymorphism.
A significant association of promoter allele 2 was shown with bipolar (estimated
odds ratio 1.21; 95% confidence interval 1.00-1.45), unipolar (OR 1.23; 95% CI
1.01-1.42), and combined bipolar + unipolar groups (OR 1.22; 95% CI 1.04-1.42).
There was no demonstrable allelic association of the VNTR polymorphism with affective
disorder: for the combined bipolar + unipolar group the odds ratios for VNTR alleles
9 and 10, compared with the common allele 12 were 1.05 (95% CI 0.56-1.95) and
0.90 (95% CI 0.77-1.05). These results suggest that the promoter allele 2, which
has previously been shown to result in lower levels of serotonin transporter transcription,
may be associated with affective disorder risk." [Abstract] Ogilvie
AD, Battersby S, Bubb VJ, Fink G, Harmar AJ, Goodwim GM, Smith CA.
Polymorphism
in serotonin transporter gene associated with susceptibility to major depression.
Lancet
1996 Mar 16;347(9003):731-3
"BACKGROUND; The serotonin transporter of
the brain provides the primary target for the action of selective antidepressant
drugs. We set out to identify polymorphisms of the serotonin transporter gene
and to find out whether there was a relation between any such polymorphisms and
the occurrence of affective disorder. METHODS: A comparison of a polymorphic region
of the human serotonin transporter gene was carried out between two groups. The
study group comprised 83 patients (39 unipolar depressive disorder, 44 bipolar
disorder) with major affective disorder. The control group comprised 122 anonymous
blood donors, and 71 volunteers who had been screened for psychiatric disorders.
FINDINGS: We detected three novel alleles of the variable-number-tandem-repeat
(VNTR) region (STin2.9, STin2.10) and Stin2.12) containing nine, ten and 12 copies
of the VNTR element, respectively. The frequencies of the different forms of the
allele in the control group were compared with those in the affective disorder
group. There was a significant difference between the control and affective disorder
groups, largely explained by the excess of the STin2.9 allele in the unipolar
group (chi2=10.05, p<0.004 [Bonferroni corrected]). The presence of the allele
with nine copies of the repeat was significantly associated with risk of unipolar
disorder (odds ratio=6.95 [95% CI 1.8-27.2]). INTERPRETATION: This association,
for an obvious candidate gene, may provide a critical starting point for an understanding
of the likely polygenic contributions towards susceptibility to affective disorder."
[Abstract] Hoehe
MR, Wendel B, Grunewald I, Chiaroni P, Levy N, Morris-Rosendahl D, Macher JP,
Sander T, Crocq MA.
Serotonin transporter (5-HTT) gene polymorphisms
are not associated with susceptibility to mood disorders.
Am
J Med Genet 1998 Feb 7;81(1):1-3
"In a population-based association study,
we tested the hypothesis that allelic variants of the human serotonin transporter
(5-HTT) gene confer susceptibility to mood disorders. Both a biallelic repeat
polymorphism in the 5' promotor region that differentially modulates gene expression
and a second intron variable-number-tandem-repeat (VNTR) marker were genotyped
in 294 controls and 115 patients with mood disorders. Subjects were of West European
descent and included 36 patients with major depressive disorder (MDD) and 79 patients
with bipolar I disorder (BD). No significant differences in genotype or allele
frequencies were found at either locus between controls and combined patients,
nor between controls and MDD or BD patients separately. Thus, our data do not
support the association between depressive disorder and a nine-repeat allelic
variant of the 5-HTT VNTR marker recently reported by Ogilvie et al. (Lancet 347:731-733,
1996). More importantly, no association between alleles conveying functional differences
in 5-HTT gene expression and MDD or BD could be found. Taken together, our data
suggest that the 5-HTT gene is not commonly involved in the susceptibility to
mood disorders." [Abstract]
Nobile M, Cataldo MG, Giorda R, Battaglia M, Baschirotto C, Bellina M, Marino C, Molteni M
A case-control and family-based association study of the 5-HTTLPR in pediatric-onset depressive disorders.
Biol Psychiatry. 2004 Aug 15;56(4):292-5.
BACKGROUND: Pediatric depression can be particularly informative for clarification of the causes of mood disorders. The aim of this work was to explore the possible association between childhood- and early-adolescent-onset DSM-IV depressive disorders (DD; including major depression and dysthymia) and the serotonin transporter-linked promoter polymorphism (5-HTTLPR) locus. METHODS: The case-control sample consisted of 68 unrelated patients with DD, and 68 unrelated age- and gender-matched healthy control subjects. The same patients were included in the family-based study, which consisted of 41 triads and 11 dyads. RESULTS: An excess of the SS-genotype (p =.025) and of the S-allele (p =.021) was found among DD children (odds ratio = 1.81; 95% confidence interval = 1.12-2.94). The family-based results suggested that the S-allele was preferentially transmitted to depressed children (haplotype-based haplotype relative risk: chi(2) = 7.231 df = 1, p =.007; transmission disequilibrium test: chi(2) = 5.233, df = 1, p =.022). CONCLUSIONS: A role for the 5-HTTLPR locus that needs replication in larger samples is suggested in childhood DD. [Abstract]
Yen
FC, Hong CJ, Hou SJ, Wang JK, Tsai SJ.
Association study of serotonin
transporter gene VNTR polymorphism and mood disorders, onset age and suicide attempts
in a Chinese sample.
Neuropsychobiology. 2003;48(1):5-9.
"The
human serotonin transporter (5-HTT) gene is an important candidate for the pathogenesis
of mood disorders. Associations have been reported between a variable-number tandem-repeat
polymorphism in intron 2 of the serotonin transporter gene (5-HTTVNTR) and mood
disorders in a number of studies of Western and Chinese populations. However,
no such relationships have been determined in other analogous research. To replicate
these positive findings in a Chinese population and to determine the association
between onset age of bipolar disorder and 5-HTTVNTR, we investigated the prevalence
of this polymorphism in an independent Chinese population (83 bipolar disorder
patients, 77 major depressive disorder patients and 169 controls), demonstrating
no significant association between the 5-HTTVNTR polymorphism and mood disorders
or age at onset. Further, no association was demonstrated between this polymorphism
and suicidal history in mood disorder patients. These negative findings suggest
that 5-HTTVNTR does not play a major role in the pathogenesis of mood disorder
in Chinese populations." [Abstract] 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 Sep;3(5):449-51
"A functional polymorphism in the regulatory
region of the serotonin transporter gene has been reported to be associated with
anxiety-related personality traits. We attempted to replicate this finding in
an association study involving 759 Caucasians selected from the general Australian
population. We found no associations with personality traits (including neuroticism,
negative affect and behavioral inhibition), anxiety and depressive symptoms, or
alcohol misuse." [Abstract]
Seretti A, Cusin C, Lattuada E, Di Bella D, Catalano
M, Smeraldi E.
Serotonin transporter gene (5-HTTLPR) is not associated
with depressive symptomatology in mood disorders.
Mol Psychiatry
1999 May;4(3):280-3
"Disturbances of the serotoninergic neutrotransmitter
system have been implicated in the pathogenesis of mood disorders. A functional
polymorphism in the upstream regulatory region of the serotonin transporter gene
(5-HTTLPR) has been recently reported to be associated with both unipolar and
bipolar disorder. In this study, we investigated the possibility that the 5-HTTLPR
might be associated with depressive symptomatology in a sample of mood disorder
subjects. One hundred and thirty-two psychiatric inpatients affected by major
depressive (n = 67) and bipolar (n = 65) disorder (DSM-IV) were assessed at admission
by the Hamilton Depression Rating Scale (HAMD-21, divided into Core, Sleep, Activity,
Psychic anxiety, Somatic anxiety and Delusion clusters) and were typed using PCR
techniques. The only prior treatment permitted was low dose benzodiazepines (<5
mg diazepam or equivalent); no prior (<2 weeks) antidepressant or neuroleptic
treatment was allowed. 5-HTTLPR variants were not associated with total depressive
symptomatology as measured by HAMD. The short 5-HTTLPR variant was marginally
associated with higher psychic anxiety scores (F = 7.11, d.f. = 1,262, P = 0.008).
The association was stronger among bipolars and early onset subjects. 5-HTTLPR
variants were not associated with the remaining symptom clusters. The upstream
regulatory region of the serotonin transporter gene has not, therefore, a major
influence on the depressive symptomatology in mood disorder subjects." [Abstract] Battersby
S, Ogilvie AD, Smith CA, Blackwood DH, Muir WJ, Quinn JP, Fink G, Goodwin GM,
Harmar AJ.
Structure of a variable number tandem repeat of the serotonin
transporter gene and association with affective disorder.
Psychiatr
Genet 1996 Winter;6(4):177-81
"We have recently reported an association
between a polymorphism of a variable number tandem repeat (VNTR) region of the
serotonin transporter gene and susceptibility to major depressive disorder. We
identified three alleles containing respectively 9 (STin2.9), 10 (STin2.10) and
12 (STin2.12) copies of a repetitive element. We report here the sequences of
the three alleles. The repetitive element conformed to the consensus sequence,
GGCTGYGACCY(R)GRRTG, where Y = T/C, R = G/A, with loss of the 12th base pair in
one of the repeating elements. We have also extended the numbers of cases and
controls in the study. The frequencies of the three alleles in 119 individuals
with single or recurrent major depressive episodes, 128 individuals with bipolar
disorder and a group of 346 controls were compared. There was a significant difference
between patients with affective disorder and controls in the proportion of individuals
carrying the STin2.9 allele. For the risk of unipolar disorder given a single
STin2.9 allele, the odds ratio was 4.44 (95% Cl, 1.65-11.95) and for bipolar disorder
3.22 (95% Cl, 1.15-9.09). The findings support the hypothesis that allelic variation
in the serotonin transporter gene may contribute to susceptibility for both major
depression and bipolar disorder." [Abstract]
Serretti A, Lattuada E, Catalano M, Smeraldi E.
Serotonin
transporter gene not associated with psychotic symptomatology of mood disorders.
Psychiatry
Res 1999 Apr 19;86(1):59-65
"A functional polymorphism in the upstream
regulatory region of the serotonin transporter gene (5-HTTLPR) has been recently
reported to be associated with mood disorders. In the present study we investigated
the possible influence of 5-HTTLPR on the symptomatology of mood disorders. Two
hundred and thirty inpatients affected by mood disorders (160 bipolar and 70 major
depressive disorder) were assessed by the Operational Criteria checklist for psychotic
illness (OPCRIT) and were also typed for the 5-HTTLPR variants using PCR techniques.
Mania, Depression, Delusion and Disorganization were the four symptomatologic
factors used as phenotype definition. 5-HTTLPR variants were not associated with
these symptomatologic factors, and consideration of possible stratification effects,
such as sex, age of onset and polarity, did not reveal any association either.
The serotonin transporter gene does not, therefore, appear to be associated with
the symptomatology of mood disorders." [Abstract]
Nobile M, Begni B, Giorda R, Frigerio A, Marino
C, Molteni M, Ferrarese C, Battaglia M.
Effects of serotonin transporter
promoter genotype on platelet serotonin transporter functionality in depressed
children and adolescents.
J Am Acad Child Adolesc Psychiatry
1999 Nov;38(11):1396-402
"OBJECTIVE: To investigate possible associations
between serotonin transporter (5-HTT) promoter genotypic variants (l/l, l/s, and
s/s) and differential regulation of platelet 5-HTT functionality parameters in
a group of drug-naive depressed children and adolescents and healthy controls.
METHOD: Children and adolescents with major depression (n = 18) defined by DSM-III-R
criteria and normal controls (n = 21) were assessed both for platelet serotonin
functionality and for genotypic variants on 5-HTT promoter region. Four parameters
were considered: (1) serotonin uptake rate (Vmax); (2) serotonin dissociation
constant (K(m)); (3) paroxetine binding and density of site (Bmax); and (4) paroxetine
dissociation constant (Kd). RESULTS: Depressed children had lower Vmax and K(m).
Control subjects with l/l genotype had significantly higher Vmax than control
subjects with l/s and s/s genotype. Control subjects with l/l genotype also had
significantly higher Vmax than their depressed homologs. In contrast, Vmax was
not significantly different between depressed and nondepressed subjects who carried
the other 2 genotypes. The 5-HTT promoter genotype, diagnoses, or their interaction
had no effect on the other serotonin parameters. CONCLUSIONS: While showing a
significant decrease of Vmax and K(m) in a group of drug-naive depressed children
and adolescents, these data suggest that l/l genotype has a substantial effect
on the decrease of Vmax during a depressive episode." [Abstract]
Bellivier F, Szoke A, Henry C, Lacoste J, Bottos C, Nosten-Bertrand
M, Hardy P, Rouillon F, Launay JM, Laplanche JL, Leboyer M.
Possible
association between serotonin transporter gene polymorphism and violent suicidal
behavior in mood disorders.
Biol Psychiatry 2000 Aug 15;48(4):319-22
"BACKGROUND:
Genes involved in the serotonin system are major candidates in association studies
of suicidal behavior. In this case-control study we investigated whether the serotonin
transporter (5-HTT) gene encoding the protein responsible for the reuptake of
serotonin from the synapse after its release from serotonergic neurons is a susceptibility
factor for suicidal behavior. METHODS: A functional polymorphism of the 5-HTT
gene (a 44-base pair insertion/deletion in the 5-HTT-linked polymorphic region
[5-HTTLPR]) was studied in a population of 237 consecutive patients with affective
disorder (unipolar or bipolar) and 187 control subjects. Ninety-nine patients
had attempted suicide at least once, of whom 26 made a violent attempt. RESULTS:
No association was found between the "s" allele of the 5-HTTLPR and
suicide attempt; however, there was a significant difference in allele distributions
between patients who had made violent suicide attempts and control subjects. CONCLUSIONS:
A genetic variant of the 5-HTT gene may predispose individuals to violent suicidal
behavior. The precise phenotype associated with the 5-HTT gene is unclear, and
therefore further studies are required to replicate these findings." [Abstract] Mann
JJ, Huang YY, Underwood MD, Kassir SA, Oppenheim S, Kelly TM, Dwork AJ, Arango
V.
A serotonin transporter gene promoter polymorphism (5-HTTLPR)
and prefrontal cortical binding in major depression and suicide.
Arch
Gen Psychiatry 2000 Aug;57(8):729-38
"BACKGROUND: Major depression and
suicide are associated with fewer serotonin transporter (5-HTT) sites. The 5'-flanking
promoter region of the 5-HTT gene has a biallelic insertion/deletion (5-HTTLPR).
We assayed prefrontal cortical (PFC) 5-HTT binding in major depression and suicide
and examine the relationship to the 5-HTTLPR allele. METHODS: Postmortem brain
samples from 220 individuals were genotyped for the 5-HTTLPR polymorphism. Binding
of 5-HTT was assayed by quantitative autoradiography in the PFC of a subset of
subjects (n = 159). Clinical information, including DSM-III-R Axis I diagnoses,
was obtained by psychological autopsy and medical chart review. RESULTS: Binding
to 5-HTT was lower in the ventral PFC of suicides compared with nonsuicides and
was lower throughout the PFC of subjects with a history of major depression. The
5-HTTLPR genotype was associated with major depression but not with suicide or
5-HTT binding. CONCLUSIONS: A diffuse reduction of 5-HTT binding in the PFC of
individuals with major depression may reflect a widespread impairment of serotonergic
function consistent with the range of psychopathologic features in major depression.
The localized reduction in 5-HTT binding in the ventral PFC of suicides may reflect
reduced serotonin input to that brain region, underlying the predisposition to
act on suicidal thoughts. The 5-HTTLPR genotype was not related to the level of
5-HTT binding and does not explain why 5-HTT binding is lower in major depression
or suicide." [Abstract] Du
L, Faludi G, Palkovits M, Demeter E, Bakish D, Lapierre YD, Sotonyi P, Hrdina
PD.
Frequency of long allele in serotonin transporter gene is increased
in depressed suicide victims.
Biol Psychiatry 1999 Jul 15;46(2):196-201
"BACKGROUND:
There is evidence indicating that serotonin uptake and density of 5-HT2A receptors
are altered in brain regions of depressed suicide victims and in platelets of
depressed suicidal subjects. The present investigation tested the hypothesis that
these changes in the serotonergic system in depressed suicide victims are trait
rather than state markers and associated with a polymorphism in respective candidate
genes. METHODS: Two polymorphic variants (102T/C polymorphism and His452Tyr functional
polymorphism) of the 5-HT2A receptor gene and a functional polymorphism in the
5' regulatory region of the 5-HT transporter gene, have been determined in genomic
DNA obtained from postmortem brain samples of 24 depressed suicide victims and
31 control subjects of the same ethnic background. In a subset of subjects, density
(Bmax) of 5-HT uptake sites (labeled with 3H-paroxetine) and of 5-HT2A receptors
(labeled with 3H-ketanserin) was also determined in prefrontal cortex samples.
RESULTS: The major finding of this study was a significantly higher frequency
of the 5-HT transporter gene long (L) allele (chi 2 = 3.9, df = 1; p = .048) in
depressed suicides. No significant differences between suicides and controls were
observed for the 102T/C polymorphism and His452Tyr polymorphism of 5-HT2A receptor
gene. The density of 3H-paroxetine binding sites tended to be higher in subjects
expressing the short (S) allele of 5-HT transporter gene. Furthermore, there was
a significant difference in serotonin transporter binding sites between the genotype
S/S and combined genotypes S/L and L/L. CONCLUSIONS: Our finding provides the
first evidence suggesting that a functional polymorphism in the regulatory region
of serotonin transporter gene may be associated with suicide in depressed subjects."
[Abstract] Lotrich
F, Pollock B, Ferrell R.
Serotonin transporter promoter polymorphism
in african americans : allele frequencies and implications for treatment.
Am
J Pharmacogenomics 2003;3(2):145-7
"Background: Americans of African ancestry
are less likely to receive a selective serotonin reuptake inhibitor (SSRI) for
treatment of major depressive disorder than Americans of European ancestry. A
functional insertion/deletion polymorphism in the promoter of the serotonin transporter
(5-HTT) gene SLC6A4 has been shown to modulate SLC6A4 transcription, affecting
response to SSRIs. Several studies in populations of predominantly European ancestry
have consistently found that the SLC6A4 promoter polymorphism (referred to as
the 5-HTT-linked polymorphic region; 5-HTTLPR) long (L) allele is associated with
better response to SSRI treatment than the short (S) allele.Objective: The frequency
of SLC6A4 (5-HTTLPR) alleles in 865 black Americans and Afro-Caribbeans was examined
to assess possible implications for treatment.Study design and methods: SLC6A4
(5-HTTLPR) genotypes were determined in individuals with self-identified African
ancestry from South Carolina (n = 489), western Pennsylvania (n = 207), and Tobago
(n = 169). Frequencies were compared using chi-square analyses.Results: It was
verified that the L allele is highly prevalent in Americans of African ancestry,
ranging from 77% in western Pennsylvania to 87% in South Carolina. The frequency
of the SLC6A4-(L) allele is significantly higher in African-Americans than has
been reported for European-Americans (typically 56-60%). There are both statistically
significant geographic differences and slight deviations from Hardy-Weinberg equilibrium.Conclusions:
Given the potential influence on treatment response, these findings have implications
for the use of SSRIs in this population. The results suggest that additional studies
to examine the impact of these alleles on treatment response in African-Americans
are warranted." [Abstract] Yoshida
K, Naito S, Takahashi H, Sato K, Ito K, Kamata M, Higuchi H, Shimizu T, Itoh K,
Inoue K, Tezuka T, Suzuki T, Ohkubo T, Sugawara K, Otani K.
Monoamine
oxidase: A gene polymorphism, tryptophan hydroxylase gene polymorphism and antidepressant
response to fluvoxamine in Japanese patients with major depressive disorder.
Prog
Neuropsychopharmacol Biol Psychiatry 2002 Dec;26(7-8):1279-83
"Monoamine
oxidase A (MAOA) and tryptophan hydroxylase (TPH) are the staple enzymes in the
metabolism of serotonin (5-HT). The genetic polymorphisms of these two enzymes
might individually alter the production, release, reuptake or degradation of 5-HT
during the treatment of selective serotonin reuptake inhibitors (SSRIs), leading
to the individual differences in the antidepressant effects of SSRIs. The authors
investigated whether a functional polymorphism in the MAOA gene promoter (MAOA-VNTR)
and a TPH gene polymorphism in intron 7 (TPH-A218C) were associated with the antidepressant
response to fluvoxamine in 66 Japanese patients with major depressive disorder
during a 6-week study with a specific dosage plan. Fifty-four patients completed
the study. The present study fails to demonstrate that the genetic polymorphisms
of MAOA-VNTR and TPH-A218C affect the antidepressant effect of fluvoxamine in
Japanese patients with major depressive disorder." [Abstract] Yoshida
K, Naito S, Takahashi H, Sato K, Ito K, Kamata M, Higuchi H, Shimizu T, Itoh K,
Inoue K, Suzuki T, Ohkubo T.
Monoamine oxidase A gene polymorphism,
5-HT 2A receptor gene polymorphism and incidence of nausea induced by fluvoxamine.
Neuropsychobiology.
2003;48(1):10-3.
"Selective serotonin reuptake inhibitors cause a side
effect of nausea with high frequency, but there have been no accurate methods
to predict its incidence. The authors first investigated whether a functional
polymorphism in the monoamine oxidase A (MAOA-VNTR) and a -1438G/A polymorphism
in the promoter region of the 5-HT(2A) gene were associated with the incidence
of nausea induced by fluvoxamine. Fluvoxamine was administered for 6 weeks with
a specific dosage plan (50-200 mg/day) in 66 Japanese major depressive patients.
The frequency of MAOA-VNTR allele 1 was significantly higher in the patients without
nausea than in ones with nausea in the statistical analysis including the patients
whose plasma levels were below the average and who were considered to be pharmacodynamically
more sensitive to nausea. This study showed that the genetic polymorphism of MAOA-VNTR
might affect the incidence of nausea induced by SSRIs. If this finding is replicated
in other studies with more subjects, MAOA-VNTR polymorphism would be of great
clinical use to predict the incidence of nausea induced by SSRIs." [Abstract] Serretti
A, Zanardi R, Rossini D, Cusin C, Lilli R, Smeraldi E.
Influence
of tryptophan hydroxylase and serotonin transporter genes on fluvoxamine antidepressant
activity.
Mol Psychiatry 2001 Sep;6(5):586-92
"The
aim of the present study was to test a possible effect of the A218C tryptophan
hydroxylase (TPH) gene variant on the antidepressant activity of fluvoxamine in
a sample of major and bipolar depressives, with or without psychotic features.
Two hundred and seventeen inpatients were treated with fluvoxamine 300 mg and
either placebo or pindolol in a double blind design for 6 weeks. The severity
of depressive symptoms was weekly assessed with the Hamilton Rating Scale for
Depression. TPH allelic variants were determined in each subject by using a PCR-based
technique. No significant finding was observed in the overall sample as well as
in the pindolol group, while TPH*A/A was associated with a slower response to
fluvoxamine treatment in subjects not taking pindolol (P = 0.001). This effect
was independent from the previously reported influence of 5-HTTLPR polymorphism.
If confirmed, these results may shed further light on the genetically determined
component of the response to pharmacological treatments, thus helping the clinician
to individualize each patient's therapy according to their genetic pattern."
[Abstract] Serretti
A, Zanardi R, Cusin C, Rossini D, Lorenzi C, Smeraldi E.
Tryptophan
hydroxylase gene associated with paroxetine antidepressant activity.
Eur
Neuropsychopharmacol 2001 Oct;11(5):375-80
"The possible association of
the A218C tryptophan hydroxylase (TPH) gene variant with the antidepressant activity
of paroxetine was investigated in a sample of 121 inpatients affected by a major
depressive episode and treated with paroxetine 20-40 mg with either placebo or
pindolol in a double blind design for 4 weeks. The severity of depressive symptoms
was weekly assessed with the Hamilton Rating Scale for Depression. TPH allelic
variants were determined in each subject using a PCR-based technique. TPH*A/A
and TPH*A/C variants were associated with a poorer response to paroxetine treatment
when compared to TPH*C/C (P=0.005); this difference was not present in the pindolol
augmented group. Other variables, such as sex, diagnosis, presence of psychotic
features, severity of depressive symptomatology at baseline and paroxetine plasma
level, were not associated with the outcome. TPH gene variants are therefore a
possible modulator of paroxetine antidepressant activity." [Abstract] Peters
EJ, Slager SL, McGrath PJ, Knowles JA, Hamilton SP.
Investigation
of serotonin-related genes in antidepressant response.
Mol
Psychiatry. 2004 Mar 30 [Epub ahead of print]
"In this study, we sought
out to test the hypothesis that genetic factors may influence antidepressant response
to fluoxetine. The investigation focused on seven candidate genes in the serotonergic
pathway involved in the synthesis, transport, recognition, and degradation of
serotonin. Our clinical sample consisted of 96 subjects with unipolar major depression
treated with fluoxetine with response variables assessed after a 12-week trial.
Patient data were also collected to investigate the pattern of drug response.
Using a high-throughput single-nucleotide polymorphism (SNP) genotyping platform
and capillary electrophoresis, we genotyped patients at 110 SNPs and four repeat
polymorphisms located in seven candidate genes (HTR1A, HTR2A, HTR2C, MAOA, SLC6A4,
TPH1, and TPH2). Statistical tests performed included single-locus and haplotype
association tests, and linkage disequilibrium (LD) estimation. Little evidence
of population stratification was observed in the sample with 20 random SNPs using
a genomic control procedure. Our most intriguing result involved three SNPs in
the TPH1 gene and one SNP in the SLC6A4 gene, which show significant single-locus
association when response to fluoxetine is compared to nonresponse (P=0.02-0.04).
All odds ratios indicated an increased risk of not responding to fluoxetine. In
the specific response vs nonspecific and nonresponse comparison, three SNPs in
the TPH2 gene (P=0.02-0.04) were positively associated and one SNP in the HTR2A
gene (P=0.02) was negatively associated. When comparing specific response to nonspecific
response, we found significant negative associations in three SNPs in the HTR2A
gene (P=0.001-0.03) and two SNPs in the MAOA gene (P=0.03-0.05). We observed variable,
although strong LD, in each gene and unexpectedly low numbers of estimated haplotypes,
formed from tagged SNPs. Significant haplotype associations were found in all
but the HTR1A and HTR2C genes. Although these data should be interpreted cautiously
due to the small sample size, these results implicate TPH1 and SLC6A4 in general
response, and HTR2A, TPH2, and MAOA in the specificity of response to fluoxetine.
Intriguingly, we observe that a number of the less frequent alleles of many of
the SNP markers were associated with the nonresponse and nonspecific phenotypes."
[Abstract] Sato
K, Yoshida K, Takahashi H, Ito K, Kamata M, Higuchi H, Shimizu T, Itoh K, Inoue
K, Tezuka T, Suzuki T, Ohkubo T, Sugawara K, Otani K.
Association
between -1438G/A promoter polymorphism in the 5-HT(2A) receptor gene and fluvoxamine
response in Japanese patients with major depressive disorder.
Neuropsychobiology
2002;46(3):136-40
"Genetic polymorphism of the serotonin 5-HT(2A) receptor
seems to be associated with therapeutic response to selective serotonin reuptake
inhibitors (SSRIs). The present study investigated whether a novel -1438G/A polymorphism
in the promoter region of the 5-HT(2A )receptor gene is associated with therapeutic
response to fluvoxamine (an SSRI) in 66 Japanese patients with major depressive
disorder. Fluvoxamine (50 to 200 mg) was administered twice daily for 6 weeks.
Fifty-four patients completed this study. The genotype distribution and the allele
frequencies showed no significant difference between responders and non-responders.
The time-course of the Montgomery-Asberg Depression Rating Scale scores showed
no significant difference among -1438G/G, -1438G/A, and -1438A/A genotype groups.
The results demonstrated that the -1438G/A promoter polymorphism in the 5-HT(2A)
receptor gene was unlikely to have a major role in therapeutic response to fluvoxamine
in Japanese patients with major depressive disorder." [Abstract]
Murphy GM, Kremer C, Rodrigues HE, Schatzberg AF
Pharmacogenetics of antidepressant medication intolerance.
Am J Psychiatry. 2003 Oct;160(10):1830-5.
OBJECTIVE: The authors sought to identify genetic markers for antidepressant medication intolerance. Genetic variation in drug metabolizing enzymes such as cytochrome P450 2D6 (CYP2D6) has been postulated to underlie antidepressant intolerance (pharmacokinetic effect). However, variation in genes encoding serotonin receptors could also explain antidepressant side effects (pharmacodynamic effect). METHOD: An 8-week, double-blind, randomized pharmacogenetic study compared the widely prescribed antidepressants paroxetine (a selective serotonin reuptake inhibitor [SSRI]) and mirtazapine (not an SSRI) in 246 elderly patients with major depression. Genotypes were determined for the 102 T/C single nucleotide polymorphism (SNP) in the serotonin 2A (5-HT(2A)) locus (HTR2A), previously associated with psychotropic medication treatment outcome. Oligonucleotide microarrays were used to extensively characterize variation in the CYP2D6 gene. Clinical outcomes included treatment discontinuations, adverse events, medication compliance, and change in mood. RESULTS: Survival analysis showed discontinuations due to paroxetine-induced side effects were strongly associated with the HTR2A C/C genotype. There was a significant linear relationship between the number of C alleles and the probability of discontinuation. Side effect severity in paroxetine-treated patients with the C/C genotype was also greater. In contrast, HTR2A 102 T/C genotype had no effect on mirtazapine side effects. CYP2D6 genotype did not predict treatment outcome for either medication. CONCLUSIONS: Pharmacodynamic differences among patients due to variant 5-HT(2A) receptors appear to be more important than pharmacokinetic variation in determining paroxetine intolerance. Pharmacogenetic markers may be useful in predicting antidepressant treatment outcome. [Abstract]
Murphy GM, Hollander SB, Rodrigues HE, Kremer C, Schatzberg AF
Effects of the serotonin transporter gene promoter polymorphism on mirtazapine and paroxetine efficacy and adverse events in geriatric major depression.
Arch Gen Psychiatry. 2004 Nov;61(11):1163-9.
BACKGROUND: The "long/short"polymorphism (5HTTLPR) in the promoter of the serotonin transporter gene (SLC6A4) has been proposed as a pharmacogenetic marker for antidepressant efficacy. Some but not all studies have found that the short form of 5HTTLPR (S allele) results in decreased efficacy of selective serotonin reuptake inhibitors. OBJECTIVE: To determine if the 5HTTLPR polymorphism influences the efficacy and tolerability of mirtazapine and paroxetine hydrochloride, 2 frequently prescribed antidepressants with differing pharmacologic profiles, in geriatric depression. DESIGN: Double-blind, randomized 8-week study. SETTING: Eighteen academic and private outpatient clinics. PATIENTS: We evaluated 246 cognitively intact patients 65 years or older with major depression. INTERVENTIONS: Antidepressant therapy with 15 to 45 mg/d of mirtazapine (n = 124) or 20 to 40 mg/d of paroxetine (n = 122). MAIN OUTCOME MEASURES: The Hamilton Depression Rating Scale-17 and Geriatric Depression Scale, severity of adverse events and dosing compliance indexes, and discontinuations due to adverse events. Outcome measures were stratified according to 5HTTLPR genotypes. RESULTS: Geriatric Depression Scale scores indicated that S allele carriers treated with paroxetine showed a small impairment in antidepressant response. Among mirtazapine-treated patients, there was little indication that the 5HTTLPR genotype affected antidepressant efficacy. However, the 5HTTLPR polymorphism had a dramatic effect on adverse events. Among paroxetine-treated subjects, S allele carriers experienced more severe adverse events during the course of the study, achieved significantly lower final daily doses, and had more discontinuations at days 14, 21, 28, 42, and 49. Surprisingly, among mirtazapine-treated subjects, S allele carriers had fewer discontinuations due to adverse events, experienced less severe adverse events, and achieved higher final daily doses. CONCLUSIONS: These results support the hypothesis that the S allele of 5HTTLPR at the SLC6A4 locus is associated with a poor outcome after treatment with selective serotonin reuptake inhibitors. However, the major effect was on the tolerability of these drugs rather than efficacy. Results from mirtazapine-treated patients indicate that the effect of this polymorphism on outcome may depend on the mechanism of antidepressant action. [Abstract]
Durham LK, Webb SM, Milos PM, Clary CM, Seymour AB
The serotonin transporter polymorphism, 5HTTLPR, is associated with a faster response time to sertraline in an elderly population with major depressive disorder.
Psychopharmacology (Berl). 2004 Aug;174(4):525-9.
RATIONALE: A common polymorphism (5HTTLPR) within the promoter region of the serotonin transporter gene (LSC6A4) has been shown to influence response time as well as overall response to selective serotonin reuptake inhibitors (SSRIs) in subjects with major depressive disorder. We hypothesized that a similar effect in response time to sertraline would be observed and that no effect on response time would be seen in a placebo arm. OBJECTIVES: We tested the hypothesis that subjects homozygous for the long allele at the 5HTTLPR polymorphism would respond more rapidly to sertraline than subjects carrying one or two copies of the short allele. METHODS: HAM-D and CGI-I responses to sertraline and placebo were measured weekly in the context of an 8-week, placebo-controlled study in elderly depressed subjects. Genotyping of the 5HTTLPR polymorphism was performed to test for correlations with response at each week in the sertraline and placebo groups ( n=206). RESULTS: Subjects homozygous for the long allele of 5HTTLPR showed a significant increase in response at week 1 and week 2, as assessed by the CGI-I scale compared with subjects carrying one or two copies of the short allele ( P=0.01 at both weeks). No significant difference was observed in the placebo group. CONCLUSIONS: These results suggest that genetic variation in the serotonin transporter gene effects the response time to sertraline and provides complementing evidence to previous reports that this polymorphism affects response time to other SSRIs. [Abstract]
Lee MS, Lee HY, Lee HJ, Ryu SH
Serotonin transporter promoter gene polymorphism and long-term outcome of antidepressant treatment.
Psychiatr Genet. 2004 Jun;14(2):111-5.
OBJECTIVE: This study investigates the relationship between the serotonin transporter linked polymorphic region (5-HTTLPR) and the long-term outcome of antidepressant treatment. METHODS: One hundred and twenty-eight patients with major depressive disorder were evaluated for long-term outcome (up to 3 years) of antidepressant treatment. The severity and improvement of depression were assessed with the Clinical Global Impression scale. The genotypes of 5-HTTLPR in the patients were determined using polymerase chain reaction. RESULTS: During the long-term treatment of antidepressants (1-3 years of treatment), clinical improvement of depressive symptoms was more significant for carriers of the long (l) allele [l/l and l/short (s) genotypes] than for those possessing the s/s genotype (P=0.025 at 1 year, P=0.005 at 2 years, P=0.005 at 3 years). A response to treatment was also significantly more frequent in carriers of the l allele than in those with the s/s genotype (P=0.015). CONCLUSION: These findings show that patients with major depressive disorder possessing the 5-HTTLPR l allele may exhibit a better long-term outcome when treated with antidepressants. [Abstract]
Weizman A, Weizman R.
Serotonin transporter
polymorphism and response to SSRIs in major depression and relevance to anxiety
disorders and substance abuse.
Pharmacogenomics 2000 Aug;1(3):335-41
"The
selective serotonin re-uptake inhibitors (SSRIs) which modulate serotonergic activity
are effective in the treatment of serotonin-related mental disorders, such as
depression and anxiety. These agents bind to the serotonin transporter (5-HTT)
and inhibit its capacity to transport serotonin (5-hydroxytryptamine; 5-HT). A
functional polymorphism in the promoter region of 5-HTT (5-HTTLPR) has been described.
The insertion variant of this polymorphism (long allele) is associated with higher
expression of brain 5-HTT compared to the deletion variant (short allele). An
association between the 5-HTTLPR polymorphism and mental disorders has been reported
by some, but not all, investigators. In addition, the 5-HTT gene polymorphisms
were found to be associated with a better and faster response to SSRIs with or
without pindolol augmentation in depressed patients. Further studies are needed
to clarify the relationship between the 5-HTT genotype, the susceptibility to
mental disorders, the response to serotonergic agents and the side effect profile."
[Abstract] Arias
B, Catalan R, Gasto C, Gutierrez B, Fananas L.
5-HTTLPR polymorphism
of the serotonin transporter gene predicts non-remission in major depression patients
treated with citalopram in a 12-weeks follow up study.
J
Clin Psychopharmacol. 2003 Dec;23(6):563-7.
"In the context of a long
term follow-up study, we analysed the possible implication of the 5-HTTLPR polymorphism
at the serotonin transporter gene in clinical response and remission of major
depressive patients treated with citalopram. The sample consisted of 131 patients,
all of Spanish origin, diagnosed according to DSM-IV criteria. A 21-item Hamilton
Depression Rating Scale (HDRS) was used to evaluate severity of the symptoms during
the follow-up and to determine clinical response and remission condition of the
patients at 4th and 12th week, respectively. Our results showed that S/S genotype
of the 5-HTTLPR polymorphism was associated with the non-Remission condition at
12th week (chi2 = 8.7, P = 0.013). Moreover, homozygous for the allele S presented
three times more risk for non reaching remission of depressive episode after citalopram
treatment than patients with any other 5-HTTLPR genotype combination (chi2: 7.29,
P = 0.006; OR = 3.23 [95%CI: 1.24-8.5]). In conclusion, our results show that
genetic variation of serotonin transporter is involved in clinical remission of
major depressive episodes after twelve weeks of citalopram treatment." [Abstract]
Smeraldi
E, Zanardi R, Benedetti F, Di Bella D, Perez J, Catalano M.
Polymorphism
within the promoter of the serotonin transporter gene and antidepressant efficacy
of fluvoxamine.
Mol Psychiatry 1998 Nov;3(6):508-11
"Depression
with psychotic features has been shown to respond to selective serotonin reuptake
inhibitors (SSRIs). The serotonin transporter (5-HTT) is a prime target for SSRIs.
A functional polymorphism within the promoter region of the 5-HTT gene, leading
to different transcriptional efficiency, was recently reported. We tested the
hypothesis that allelic variation of the 5-HTT promoter could be related to the
antidepressant response to fluvoxamine and/or augmentation with pindolol (a serotonin
autoreceptors antagonist) which has been suggested as an augmentation therapy
for nonresponders. One hundred and two inpatients with major depression with psychotic
features were randomly assigned to treatment with a fixed dose of fluvoxamine
and either placebo or pindolol for 6 weeks. Depression severity was assessed once
a week using the Hamilton Depression Rating Scale. Allelic variation in each subject
was determined using a PCR-based method. Data were analyzed with a three-way repeated
measures analysis of variance. Both homozygotes for the long variant (l/l) of
the 5-HTT promoter and heterozygotes (l/s) showed a better response to fluvoxamine
than homozygotes for the short variant (s/s). In the group treated with fluvoxamine
plus pindolol all the genotypes acted like l/l treated with fluvoxamine alone.
Fluvoxamine efficacy in delusional depression seems to be related to allelic variation
within the promoter of the 5-HTT gene. Even though other factors may be implicated,
genotyping at 5-HTT promoter may represent a promising tool to individualize the
pharmacological treatment of depression."
[Abstract] Durham
LK, Webb SM, Milos PM, Clary CM, Seymour AB.
The serotonin transporter
polymorphism, 5HTTLPR, is associated with a faster response time to sertraline
in an elderly population with major depressive disorder.
Psychopharmacology
(Berl). 2003 Sep 4 [Epub ahead of print].
"RATIONALE. A common polymorphism
(5HTTLPR) within the promoter region of the serotonin transporter gene (LSC6A4)
has been shown to influence response time as well as overall response to selective
serotonin reuptake inhibitors (SSRIs) in subjects with major depressive disorder.
We hypothesized that a similar effect in response time to sertraline would be
observed and that no effect on response time would be seen in a placebo arm. OBJECTIVES.
We tested the hypothesis that subjects homozygous for the long allele at the 5HTTLPR
polymorphism would respond more rapidly to sertraline than subjects carrying one
or two copies of the short allele. METHODS. HAM-D and CGI-I responses to sertraline
and placebo were measured weekly in the context of an 8-week, placebo-controlled
study in elderly depressed subjects. Genotyping of the 5HTTLPR polymorphism was
performed to test for correlations with response at each week in the sertraline
and placebo groups ( n=206). RESULTS. Subjects homozygous for the long allele
of 5HTTLPR showed a significant increase in response at week 1 and week 2, as
assessed by the CGI-I scale compared with subjects carrying one or two copies
of the short allele ( P=0.01 at both weeks). No significant difference was observed
in the placebo group. CONCLUSIONS. These results suggest that genetic variation
in the serotonin transporter gene effects the response time to sertraline and
provides complementing evidence to previous reports that this polymorphism affects
response time to other SSRIs." [Abstract] Kim
DK, Lim SW, Lee S, Sohn SE, Kim S, Hahn CG, Carroll BJ.
Serotonin
transporter gene polymorphism and antidepressant response.
Neuroreport
2000 Jan 17;11(1):215-9
"We examined allelic polymorphisms of the serotonin
transporter (5-HTT) gene and antidepressant response to 6 weeks' treatment with
the selective serotonin reuptake inhibitor (SSRI) drugs fluoxetine or paroxetine.
We genotyped 120 patients and 252 normal controls, using polymerase chain reaction
of genomic DNA with primers flanking the second intron and promoter regions of
the 5-HTT gene. Diagnosis of depression was not associated with 5-HTT polymorphisms.
Patients homozygous l/l in intron 2 or homozygous s/s in the promoter region showed
better responses than all others (p < 0.0001, p = 0.0074, respectively). Lack
of the l/l allele form in intron 2 most powerfully predicted non-response (83.3%).
Response to SSRI drugs is related to allelic variation in the 5-HTT gene in depressed
Korean patients." [Abstract]
Yu YW, Tsai SJ, Chen TJ, Lin CH, Hong CJ.
Association
study of the serotonin transporter promoter polymorphism and symptomatology and
antidepressant response in major depressive disorders.
Mol
Psychiatry 2002;7(10):1115-9
"The serotonin transporter (5-HTT) is the
site of primary action for the selective serotonin reuptake inhibitors (SSRIs).
Previous Western reports have demonstrated that the lallele of the 5-HTT gene-linked
polymorphic-region (5-HTTLPR) polymorphism is associated with better SSRI antidepressive
effects than the s allele, however, another study of a Korean population has produced
a contrasting finding. The present study tested the hypothesis that the 5-HTTLPR
genetic polymorphism is associated with SSRI antidepressant response by evaluating
total and cluster depressive symptoms for 121 Chinese patients diagnosed with
major depression. Analysis of the results reveals that patients with the l/l genotype
had a significantly better response to SSRI (fluoxetine) when compared with s
allele carriers, as evaluated on the basis of total (P = 0.013), core (P = 0.011),
and psychic-anxiety (P = 0.005) and somatic-anxiety (P = 0.002) Hamilton Depression
Rating Scale-score percentage change. Our findings confirm reports that the l
allele is associated with better SSRI response." [Abstract] Ito
K, Yoshida K, Sato K, Takahashi H, Kamata M, Higuchi H, Shimizu T, Itoh K, Inoue
K, Tezuka T, Suzuki T, Ohkubo T, Sugawara K, Otani K.
A variable
number of tandem repeats in the serotonin transporter gene does not affect the
antidepressant response to fluvoxamine.
Psychiatry Res 2002
Aug 30;111(2-3):235-9
"A variable number of tandem repeats (VNTR) in the
second intron of the serotonin transporter gene (STin2) has been studied in association
with the susceptibility to affective disorders. Recently, it was reported that
selective serotonin reuptake inhibitors were more effective in patients with major
depressive disorder having the homozygous allele pair (12-copy/12-copy) of VNTR
in the STin2 than in ones having other allele combinations. As the study had methodological
problems, further studies are needed to confirm the above finding. Therefore,
the authors investigated whether the allelic variation of VNTR in the STin2 was
associated with the antidepressant response to fluvoxamine in 66 patients with
major depressive disorder. Fluvoxamine was prescribed up to 200 mg/day in the
dosing protocol for 6 weeks. The present study showed no significant association
between the polymorphism of VNTR in the STin2 and the treatment response to fluvoxamine."
[Abstract] Rausch
JL, Johnson ME, Fei YJ, Li JQ, Shendarkar N, Hobby HM, Ganapathy V, Leibach FH.
Initial
conditions of serotonin transporter kinetics and genotype: influence on SSRI treatment
trial outcome.
Biol Psychiatry 2002 May 1;51(9):723-32
"BACKGROUND:
Fifty-one patients with major depression were classified for 5-HTT promoter region
polymorphism and platelet 5-HTT kinetics before treatment with fluoxetine, and
then examined for treatment outcome. METHODS: Dose was stratified from 1.25 mg
to 40 mg per day to allow for the possibility that one genotype could express
a lower-dose fluoxetine response. A repeated-measures analysis of variance of
24-item Hamilton depression change through baseline, 1-week placebo lead-in, and
6, 12, and 18 weeks treatment was done to test a genotype effect on outcome. RESULTS:
Genotype had a significant effect on outcome (F = 4.7, p <.02), with the initial
affinity constant (K(m)) (F = 11.9, p =.001), and dose (F = 6.0, p <.02) being
significant covariates on outcome as well. The gene effect, however, was complex
in that the 5-HTT promoter region insertion showed two effects: both a placebo
response effect (F = 4, p <.025), and a drug dose response effect (r =.40,
p <.01). The long allele group was more responsive to placebo, as well as more
responsive to drug dose than was the short allele group. CONCLUSIONS: This is
the first study to examine the antidepressant dose-response relationship to 5-HTT
kinetics and genetics. The findings indicate that both the initial affinity and
genotype of 5-HTT may contribute in unique ways to the variation in the outcome
of depression treatment trials." [Abstract] Pollock
BG, Ferrell RE, Mulsant BH, Mazumdar S, Miller M, Sweet RA, Davis S, Kirshner
MA, Houck PR, Stack JA, Reynolds CF, Kupfer DJ.
Allelic variation
in the serotonin transporter promoter affects onset of paroxetine treatment response
in late-life depression.
Neuropsychopharmacology 2000 Nov;23(5):587-90
"The
relationship of the serotonin transporter gene promoter region polymorphism (5-HTTLPR)
to antidepressant response was examined in 95 elderly patients receiving a protocolized
treatment for depression with paroxetine or nortriptyline. Patients were treated
for up to 12 weeks and assessed weekly with clinical ratings and measurements
of plasma drug concentrations. Twenty-one of the paroxetine-treated subjects were
found to have the ll genotype and 30 had at least one s allele. There were no
baseline differences between these groups in pretreatment Hamilton Rating Scale
for Depression (HRSD) scores or anxiety symptoms. During acute treatment with
paroxetine, mean reductions from baseline in HRSD were significantly more rapid
for patients with the ll genotype than for those possessing an s allele, despite
equivalent paroxetine concentrations. Onset of response to nortriptyline was not
affected. Allelic variation of 5-HTTLPR may contribute to the variable initial
response of patients treated with a selective serotonin reuptake inhibitor."
[Abstract]
Yoshida
K, Ito K, Sato K, Takahashi H, Kamata M, Higuchi H, Shimizu T, Itoh K, Inoue K,
Tezuka T, Suzuki T, Ohkubo T, Sugawara K, Otani K.
Influence of the
serotonin transporter gene-linked polymorphic region on the antidepressant response
to fluvoxamine in Japanese depressed patients.
Prog Neuropsychopharmacol
Biol Psychiatry 2002 Feb;26(2):383-6
"The presence of the long (l) variant
of the serotonin (5-hydroxytryptamine: 5-HT) transporter gene-linked polymorphic
region (5-HTTLPR) is reported to be associated with a more favorable and faster
antidepressant effect of selective serotonin reuptake inhibitors in Caucasians.
The frequency of the l allele is lower in Japanese than in Caucasians; therefore,
the antidepressant effect of fluvoxamine can be not as good in Japanese as in
Caucasians. The authors investigated whether 5-HTTLPR was associated with the
antidepressant response to fluvoxamine in 66 Japanese patients with major depressive
disorder in a protocolized-dosing 6-week study. The short (s) allele frequency
was significantly higher in the responsive individuals than in the nonresponsive
ones (P = .010). The present study suggests that fluvoxamine is not less effective
in depressive patients carrying the s allele than in the ones carrying the l allele
and it is not less effective in Japanese than in Caucasians." [Abstract]</ |
