Anguelova M, Benkelfat C, Turecki G.
review of association studies investigating genes coding for serotonin receptors
and the serotonin transporter: I. Affective disorders.
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]
KM, Smits LJ, Schouten JS, Stelma FF, Nelemans P, Prins MH.
of SERTPR and STin2 in the serotonin transporter gene on the effect of selective
serotonin reuptake inhibitors in depression: a systematic review.
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."
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]
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.
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]
B, Pintor L, Gasto C, Rosa A, Bertranpetit J, Vieta E, Fananas L.
in the serotonin transporter gene and increased risk for major depression with
Hum Genet 1998 Sep;103(3):319-22
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]
RA, Ho L, Walsh C, Rubinsztein JS, Jain S, Paykel ES, Easton DF, Rubinsztein DC.
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
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]
AD, Battersby S, Bubb VJ, Fink G, Harmar AJ, Goodwim GM, Smith CA.
in serotonin transporter gene associated with susceptibility to major depression.
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."
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.
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]
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.
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]
AF, Henderson AS, Jacomb PA, Christensen H, Korten AE, Rodgers B, Tan X, Easteal
An association study of a functional polymorphism of the serotonin
transporter gene with personality and psychiatric symptoms.
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.
"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]
S, Ogilvie AD, Smith CA, Blackwood DH, Muir WJ, Quinn JP, Fink G, Goodwin GM,
Structure of a variable number tandem repeat of the serotonin
transporter gene and association with affective disorder.
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.
transporter gene not associated with psychotic symptomatology of mood disorders.
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
"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.
association between serotonin transporter gene polymorphism and violent suicidal
behavior in mood disorders.
Biol Psychiatry 2000 Aug 15;48(4):319-22
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]
JJ, Huang YY, Underwood MD, Kassir SA, Oppenheim S, Kelly TM, Dwork AJ, Arango
A serotonin transporter gene promoter polymorphism (5-HTTLPR)
and prefrontal cortical binding in major depression and suicide.
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]
L, Faludi G, Palkovits M, Demeter E, Bakish D, Lapierre YD, Sotonyi P, Hrdina
Frequency of long allele in serotonin transporter gene is increased
in depressed suicide victims.
Biol Psychiatry 1999 Jul 15;46(2):196-201
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."
F, Pollock B, Ferrell R.
Serotonin transporter promoter polymorphism
in african americans : allele frequencies and implications for treatment.
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]
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.
oxidase: A gene polymorphism, tryptophan hydroxylase gene polymorphism and antidepressant
response to fluvoxamine in Japanese patients with major depressive disorder.
Neuropsychopharmacol Biol Psychiatry 2002 Dec;26(7-8):1279-83
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]
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.
"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]
A, Zanardi R, Rossini D, Cusin C, Lilli R, Smeraldi E.
of tryptophan hydroxylase and serotonin transporter genes on fluvoxamine antidepressant
Mol Psychiatry 2001 Sep;6(5):586-92
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."
A, Zanardi R, Cusin C, Rossini D, Lorenzi C, Smeraldi E.
hydroxylase gene associated with paroxetine antidepressant activity.
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]
EJ, Slager SL, McGrath PJ, Knowles JA, Hamilton SP.
of serotonin-related genes in antidepressant response.
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."
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.
between -1438G/A promoter polymorphism in the 5-HT(2A) receptor gene and fluvoxamine
response in Japanese patients with major depressive disorder.
"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.
polymorphism and response to SSRIs in major depression and relevance to anxiety
disorders and substance abuse.
Pharmacogenomics 2000 Aug;1(3):335-41
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."
B, Catalan R, Gasto C, Gutierrez B, Fananas L.
of the serotonin transporter gene predicts non-remission in major depression patients
treated with citalopram in a 12-weeks follow up study.
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]
E, Zanardi R, Benedetti F, Di Bella D, Perez J, Catalano M.
within the promoter of the serotonin transporter gene and antidepressant efficacy
Mol Psychiatry 1998 Nov;3(6):508-11
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."
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.
(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]
DK, Lim SW, Lee S, Sohn SE, Kim S, Hahn CG, Carroll BJ.
transporter gene polymorphism and antidepressant response.
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.
study of the serotonin transporter promoter polymorphism and symptomatology and
antidepressant response in major depressive disorders.
"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]
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.
number of tandem repeats in the serotonin transporter gene does not affect the
antidepressant response to fluvoxamine.
Psychiatry Res 2002
"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."
JL, Johnson ME, Fei YJ, Li JQ, Shendarkar N, Hobby HM, Ganapathy V, Leibach FH.
conditions of serotonin transporter kinetics and genotype: influence on SSRI treatment
Biol Psychiatry 2002 May 1;51(9):723-32
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]
BG, Ferrell RE, Mulsant BH, Mazumdar S, Miller M, Sweet RA, Davis S, Kirshner
MA, Houck PR, Stack JA, Reynolds CF, Kupfer DJ.
in the serotonin transporter promoter affects onset of paroxetine treatment response
in late-life depression.
Neuropsychopharmacology 2000 Nov;23(5):587-90
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."
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.
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]
Serretti A, Artioli P, Lorenzi C, Pirovano A, Tubazio V, Zanardi R
The C(-1019)G polymorphism of the 5-HT1A gene promoter and antidepressant response in mood disorders: preliminary findings.
Int J Neuropsychopharmacol. 2004 Dec;7(4):453-60.
Several studies have demonstrated the involvement of 5-HT1A receptors in the pathogenesis of depression and in the antidepressant response to SSRIs. A functional new variant in the promoter region of the 5-HT1A gene was recently reported (-1019 C>G). The aim of this study is to investigate a possible association between this 5-HT1A receptor variant and antidepressant response to fluvoxamine in a sample of 262 mood-disorder subjects (151 major depressed and 111 bipolars) treated with fluvoxamine for 6 wk. The severity of depressive symptoms was assessed weekly with the Hamilton Rating Scale for Depression (HAMD). 5-HT1A variants did not influence antidepressant response in the whole sample and in unipolar subjects. In bipolars, 5-HT1A*C/C genotype carriers showed a better response to fluvoxamine (p=0.036), independently from clinical variables. The 5-HT1A polymorphism effect on antidepressant response was independent from the previously reported effect of the 5-HTTLPR polymorphism. In conclusion, 5-HT1A variants could influence the antidepressant efficacy in bipolar subjects, even if results must be verified on larger samples. [Abstract]
Lemonde S, Du L, Bakish D, Hrdina P, Albert PR
Association of the C(-1019)G 5-HT1A functional promoter polymorphism with antidepressant response.
Int J Neuropsychopharmacol. 2004 Dec;7(4):501-6.
Antidepressants, such as serotonin or noradrenaline reuptake inhibitors (e.g. fluoxetine, nefadozone) or 5-HT1A agonists (flibanserin), desensitize the 5-HT1A autoreceptor, which may contribute to their clinical efficacy. The 5-HT1A receptor gene is repressed by NUDR/DEAF-1 in raphe cells at the C-, but not at the G-allele of the C(-1019)G polymorphism that is associated with major depression and suicide. Depressed patients (n=118) were treated with antidepressants including fluoxetine or nefadozone combined with pindolol or flibanserin alone. The severity of depression was assesssed using the Hamilton Rating Scale for Depression. Although patients had similar severity initially, those with the homozygous G(-1019) genotype responded significantly less to flibanserin (p=0.039) and in pooled antidepressant treatment groups (p=0.0497) and were approximately twice as likely to be non-responders as those with the C(-1019)C genotype. These results implicate the C(-1019)G 5-HT1A gene polymorphism as a potential marker for antidepressant response, suggesting a role for repression of the 5-HT1A gene. [Abstract]
Putzhammer A, Schoeler A, Rohrmeier T, Sand P, Hajak G, Eichhammer P
Evidence of a role for the 5-HTTLPR genotype in the modulation of motor response to antidepressant treatment.
Psychopharmacology (Berl). 2004 Aug 18;
RATIONALE. Serotonergic mechanisms are thought to play an important role in the
regulation of mood, motor activity and sleep patterns. Serotonin reuptake is
controlled by the serotonin transporter (5-HTT) and by a common functional
insertion/deletion polymorphism in the corresponding gene's promoter region
(5-HTTLPR). Homozygosity for the long variant may confer a favourable response
to treatment with serotonin reuptake inhibitors (SSRIs), and to sleep
deprivation. OBJECTIVES. The study assessed the role of the 5-HTTLPR genotype in
determining motor side effects of antidepressant medication. METHODS. Motor
activity patterns of 62 patients with major depression who were being treated
with either SSRIs or tricyclic antidepressants (TCAs) were monitored over a 24-h
period using a wrist-actograph. Additionally, motor activity was rated in a
semi-structured interview using the motor agitation and retardation scale
(MARS). RESULTS. Night-time motor activity was significantly increased in
homozygous carriers of the long 5-HTTLPR allele (LL-genotype) who were being
treated with SSRIs in comparison to short allele carriers (LS-genotype and
SS-genotype), regardless of the type of antidepressant treatment ( P<0.001). It was also significantly increased in comparison to patients with the LL-genotype who were being treated with TCAs ( P<0.01). Differences in actographic motor activity were most prominent between 11 p.m. and 4 a.m. Clinical ratings of motor activity also showed a trend toward higher agitation scores in patients with the LL-genotype who received SSRI treatment. CONCLUSIONS. Homozygosity for the long variant of the 5-HTTLPR may cause a predisposition to increased night-time motor activity in conjunction with SSRI treatment.
Steimer W, Zöpf K, von Amelunxen S, Pfeiffer H, Bachofer J, Popp J, Messner B, Kissling W, Leucht S
Amitriptyline or Not, That Is the Question: Pharmacogenetic Testing of CYP2D6 and CYP2C19 Identifies Patients with Low or High Risk for Side Effects in Amitriptyline Therapy.
Clin Chem. 2005 Feb;51(2):376-85.
BACKGROUND: Amitriptyline has been replaced in many countries by alternative and more expensive drugs based on claims of improved tolerability and toxicity and despite slightly reduced efficacy. Preliminary studies indicate that adverse effects could be linked to polymorphisms of drug-metabolizing enzymes, but information on their clinical impact remains scanty and includes mainly case reports. We conducted a prospective blinded two-center study seeking correlations between CYP2C19 and CYP2D6 genotypes, drug concentrations, adverse events, and therapy response. METHODS: Fifty Caucasian inpatients with at least medium-grade depressive disorder received amitriptyline at a fixed dose of 75 mg twice a day. Blood samples for concentration monitoring of amitriptyline and nortriptyline were taken weekly until discharge along with evaluations of depression (Hamilton Depression Scale and Clinical Global Impression Scale) and side effect (Dosage Record and Treatment Emergent Symptoms Scale; DOTES) scores. RESULTS: In a ROC analysis, nortriptyline but not amitriptyline concentrations correlated with side effects (DOTES sum score >/=5; area under the curve, 0.733; P = 0.008). Carriers of two functional CYP2D6 alleles had a significantly lower risk of side effects than carriers of only one functional allele (12.1% vs 76.5%; P = 0.00001). The lowest risk was observed for carriers of two functional CYP2D6 alleles combined with only one functional CYP2C19 allele [0 of 13 (0%) vs 9 of 11 (81.8%) for the high-risk group; P = 0.00004]. We found no correlations between drug concentrations or genotypes and therapeutic response. CONCLUSIONS: Combined pharmacogenetic testing for CYP2D6 and CYP2C19 identifies patients with low risk for side effects in amitriptyline therapy and could possibly be used to individualize antidepressive regimens and reduce treatment cost. Identification of genotypes associated with slightly reduced intermediate metabolism may be more important than currently anticipated. It could also be the key to demonstrating cost-effectiveness for CYP2D6 genotyping in critical dose drugs. [Abstract]
Zill P, Baghai TC, Zwanzger P, Schule C, Eser D,
Rupprecht R, Moller HJ, Bondy B, Ackenheil M.
SNP and haplotype analysis
of a novel tryptophan hydroxylase isoform (TPH2) gene provide evidence for association
with major depression.
Mol Psychiatry. 2004 May 4 [Epub
ahead of print]
"Tryptophan hydroxylase (TPH), being the rate-limiting
enzyme in the biosynthesis of serotonin plays a major role as candidate gene in
several psychiatric disorders. Recently, a second TPH isoform (TPH2) was identified
in mice, which was exclusively present in the brain. In a previous post-mortem
study of our own group, we could demonstrate that TPH2 is also expressed in the
human brain, but not in peripheral tissues. This is the first report of an association
study between polymorphisms in the TPH2 gene and major depression (MD). We performed
single-nucleotide polymorphism (SNP), haplotype and linkage disequlibrium studies
on 300 depressed patients and 265 healthy controls with 10 SNPs in the TPH2 gene.
Significant association was detected between one SNP (P=0.0012, global P=0.0051)
and MD. Haplotype analysis produced additional support for association (P<0.0001,
global P=0.0001). Our findings provide evidence for an involvement of genetic
variants of the TPH2 gene in the pathogenesis of MD and might be a hint on the
repeatedly discussed duality of the serotonergic system. These results may open
up new research strategies for the analysis of the observed disturbances in the
serotonergic system in patients suffering from several other psychiatric disorders."
Zhang X, Gainetdinov RR, Beaulieu JM, Sotnikova TD, Burch LH, Williams RB, Schwartz DA, Krishnan KR, Caron MG
Loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression.
Neuron. 2005 Jan 6;45(1):11-6.
Dysregulation of central serotonin neurotransmission has been widely suspected as an important contributor to major depression. Here, we identify a (G1463A) single nucleotide polymorphism (SNP) in the rate-limiting enzyme of neuronal serotonin synthesis, human tryptophan hydroxylase-2 (hTPH2). The functional SNP in hTPH2 replaces the highly conserved Arg441 with His, which results in approximately 80% loss of function in serotonin production when hTPH2 is expressed in PC12 cells. Strikingly, SNP analysis in a cohort of 87 patients with unipolar major depression revealed that nine patients carried the mutant (1463A) allele, while among 219 controls, three subjects carried this mutation. In addition, this functional SNP was not found in a cohort of 60 bipolar disorder patients. Identification of a loss-of-function mutation in hTPH2 suggests that defect in brain serotonin synthesis may represent an important risk factor for unipolar major depression. [Abstract]
DJ, Bader M.
A unique central tryptophan hydroxylase isoform.
Pharmacol. 2003 Nov 1;66(9):1673-80.
5-HT) is a neurotransmitter synthesized in the raphe nuclei of the brain stem
and involved in the central control of food intake, sleep, and mood. Accordingly,
dysfunction of the serotonin system has been implicated in the pathogenesis of
psychiatric diseases. At the same time, serotonin is a peripheral hormone produced
mainly by enterochromaffin cells in the intestine and stored in platelets, where
it is involved in vasoconstriction, haemostasis, and the control of immune responses.
Moreover, serotonin is a precursor for melatonin and is therefore synthesized
in high amounts in the pineal gland. Tryptophan hydroxylase (TPH) catalyzes the
rate limiting step in 5-HT synthesis. Until recently, only one gene encoding TPH
was described for vertebrates. By gene targeting, we functionally ablated this
gene in mice. To our surprise, the resulting animals, although being deficient
for serotonin in the periphery and in the pineal gland, exhibited close to normal
levels of 5-HT in the brain stem. This led us to the detection of a second TPH
gene in the genome of humans, mice, and rats, called TPH2. This gene is predominantly
expressed in the brain stem, while the classical TPH gene, now called TPH1, is
expressed in the gut, pineal gland, spleen, and thymus. These findings clarify
puzzling data, which have been collected over the last decades about partially
purified TPH proteins with different characteristics and justify a new concept
of the serotonin system. In fact, there are two serotonin systems in vertebrates,
independently regulated and with distinct functions." [Abstract]
A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, McClay J, Mill J, Martin
J, Braithwaite A, Poulton R.
Influence of life stress on depression:
moderation by a polymorphism in the 5-HTT gene.
2003 Jul 18;301(5631):386-9.
"In a prospective-longitudinal study of a
representative birth cohort, we tested why stressful experiences lead to depression
in some people but not in others. A functional polymorphism in the promoter region
of the serotonin transporter (5-HT T) gene was found to moderate the influence
of stressful life events on depression. Individuals with one or two copies of
the short allele of the 5-HT T promoter polymorphism exhibited more depressive
symptoms, diagnosable depression, and suicidality in relation to stressful life
events than individuals homozygous for the long allele. This epidemiological study
thus provides evidence of a gene-by-environment interaction, in which an individual's
response to environmental insults is moderated by his or her genetic makeup."
L, Faludi G, Palkovits M, Bakish D, Hrdina PD.
lines of evidence indicate that abnormalities in the functioning of the central
serotonergic system are involved in the pathogenesis of depressive illness and
suicidal behavior. Studies have shown that the number of brain and platelet serotonin
transporter binding sites are reduced in patients with depression and in suicide
victims, and that the density of 5-HT2A receptors is increased in brain regions
of depressed in suicide victims and in platelets of depressed suicidal patients.
Genes that code for proteins, such as tryptophan hydroxylase, 5-HT transporter,
and 5-HT2A receptor, involved in regulating serotonergic neurotransmission, have
thus been major candidate genes for association studies of suicide and suicidal
behavior. Recent studies by our group and by others have shown that genetic variations
in the serotonin-system-related genes might be associated with suicidal ideation
and completed suicide. We have shown that the 102 C allele in 5-HT2A receptor
gene was significantly associated with suicidal ideation (chi2 = 8.5. p < .005)
in depressed patients. Patients with a 102 C/C genotype had a significantly higher
mean HAMD item #3 score (indication of suicidal ideation) than T/C or T/7 genotype
patients. Our results suggest that the 102T/C polymorphism in 5-HT2A receptor
gene is primarily associated with suicidal ideation in patients with major depression
and not with depression itself. We also found that the 5-HT transporter gene S/L
polymorphism was significantly associated with completed suicide. The frequency
of the L/L genotype in depressed suicide victims was almost double of that found
in control group (48.6% vs. 26.2%). The odds ratio for the L allele was 2.1 (95%
CI 1.2-3.7). The association between polymorphism in serotonergic genes and suicidality
supports the hypothesis that genetic factors can modulate suicide risk by influencing
serotonergic activity." [Abstract]
D, Van Gestel S, Massat I, Blairy S, Adolfsson R, Blackwood D, Del-Favero J, Dikeos
D, Jakovljevic M, Kaneva R, Lattuada E, Lerer B, Lilli R, Milanova V, Muir W,
Nothen M, Oruc L, Papadimitriou G, Propping P, Schulze T, Serretti A, Shapira
B, Smeraldi E, Stefanis C, Thomson M, Van Broeckhoven C, Mendlewicz J.
hydroxylase polymorphism and suicidality in unipolar and bipolar affective disorders:
a multicenter association study.
Biol Psychiatry 2001 Mar
"BACKGROUND: Being the rate-limiting enzyme in the biosynthesis
of serotonin, the tryptophan hydroxylase gene (TPH) has been considered a possible
candidate gene in bipolar and unipolar affective disorders (BPAD and UPAD). Several
studies have investigated the possible role of TPH polymorphisms in affective
disorders and suicidal behavior. METHODS: The TPH A218C polymorphism has been
investigated in 927 patients (527 BPAD and 400 UPAD) and their matched healthy
control subjects collected within the European Collaborative Project on Affective
Disorders. RESULTS: No difference of genotype distribution or allele distribution
was found in BPAD or UPAD. No statistically significant difference was observed
for allele frequency and genotypes counts. In a genotype per genotype analysis
in UPAD patients with a personal history of suicide attempt, the frequency of
the C-C genotype (homozygosity for the short allele) was lower in UPAD patients
(24%) than in control subjects (43%) (chi(2) = 4.67, p =.03). There was no difference
in allele or genotype frequency between patients presenting violent suicidal behavior
(n = 48) and their matched control subjects. CONCLUSIONS: We failed to detect
an association between the A218C polymorphism of the TPH gene and BPAD and UPAD
in a large European sample. Homozygosity for the short allele is significantly
less frequent in a subgroup of UPAD patients with a history of suicide attempt
than in control subjects." [Abstract]
M, Courtet P, Bellivier F, Leboyer M, Boulenger JP, Castelhau D, Ferreira M, Lambercy
C, Mouthon D, Paoloni-Giacobino A, Vessaz M, Malafosse A, Buresi C.
attempts and the tryptophan hydroxylase gene.
"Tryptophan hydroxylase (TPH) is the rate-limiting
enzyme of serotonin synthesis. In this case-control study, we investigated whether
the TPH gene was a susceptibility factor for suicidal behavior. Seven polymorphisms
spanning the entire gene were studied in a case-control study including 231 individuals
who had attempted suicide and 281 controls. Significant associations were found
between variants in introns 7, 8 and 9 (chi(2) = 11.2, df = 1, P< 0.0008 for
the allele distribution; these loci are in complete linkage disequilibrium) and
in the 3' noncoding region (chi(2) = 30.94, P = 0.0014) and suicide attempt. The
association was strongest for subjects who had attempted suicide by violent means
and who had a history of major depression. No significant association was observed
between suicide attempts and polymorphisms in the promoter, intron 1 and intron
3. The results presented here, and those of previous studies, suggest that a genetic
variant of the 3' part of the TPH gene may be a susceptibility factor for a phenotype
combining suicidal behavior, mood disorder and impulsive aggression." [Abstract]
H, Ishida S, Kato T, Sakai T, Tatsumi M, Hirose T, Nanko S.
for an association of polymorphisms of the tryptophan hydroxylase gene with affective
disorders or attempted suicide among Japanese patients.
J Psychiatry 1999 May;156(5):774-6
"OBJECTIVE: Tryptophan hydroxylase
is the rate-limiting enzyme in the biosynthesis of serotonin. The authors examined
whether polymorphisms A218C and A779C in intron 7 of the tryptophan hydroxylase
gene are associated with a risk for affective disorders or suicidal behavior.
METHOD: Subjects were 141 patients with bipolar disorder and 73 patients with
unipolar affective disorder, 46 of whom had a history of attempted suicide, and
208 healthy volunteers. All subjects were unrelated to each other, and all were
Japanese. Genotyping was performed by polymerase chain reaction amplification
followed by digestion by a restriction enzyme and single-strand conformational
polymorphism analysis. RESULTS: There was no significant genotypic or allelic
association of the A218C polymorphism with bipolar disorder, unipolar depression,
or history of attempted suicide. In nearly 100% of the subjects, genotypes for
the A779C were identical to those for the A218C. CONCLUSIONS: The authors conclude
that the examined polymorphisms are unlikely to have major relevance to the pathogenesis
of affective disorders or suicidal behavior." [Abstract]
SJ, Hong CJ, Wang YC.
Tryptophan hydroxylase gene polymorphism (A218C)
and suicidal behaviors.
Neuroreport 1999 Dec 16;10(18):3773-5
dysfunction is implicated in mood disorders and suicidal behaviors. Genetic variants
of tryptophan hydroxylase (TPH), a rate-limiting enzyme in the biosynthesis of
serotonin, were associated with suicidal behaviors in three reports, but were
not found in other studies. We investigated the TPH A218C polymorphism in 151
subjects with mood disorders and 200 control subjects. The results demonstrated
a significant difference in genotypic distribution between controls and depressed
patients, but not bipolar patients. A positive association between TPH polymorphism
and suicidal behaviors was found in depressed patients and not in bipolar patients.
We suggest that the association of TPH variants and suicide might depend on the
diagnosis, and TPH mutation plays no major role in the pathogenesis of bipolar
T, Frisch A, Persson ML, Wasserman D, Rockah R, Michaelovsky E, Apter A, Jonsson
EG, Nothen MM, Weizman A.
Search for association between suicide
attempt and serotonergic polymorphisms.
"Serotonergic neurotransmission has been implicated
in suicidal behavior. Polymorphisms in the genes coding for tryptophan hydroxylase,
serotonin receptor 2A and serotonin transporter were investigated in a sample
of suicide attempters (n = 165) and healthy control subjects (n = 99). No significant
differences were found for any of the investigated polymorphisms. Neither did
any significant differences emerge in comparison with control subjects when the
suicide attempters were grouped into different diagnostic categories: unipolar
disorder (n = 45), adjustment disorder (n = 37), substance use disorder (n = 37)
and personality disorder, cluster B (n = 36). The results suggest that alleles
defined by the investigated polymorphisms do not represent a major determinant
in suicide attempt. However, a highly significant (P = 0.001; odds ratio, 1.47;
99% confidence interval, 1.42-1.53) allelic association between tryptophan hydroxylase
and suicide attempt is indicated after pooling our data with literature data.
In light of previous data, a possible association between the tryptophan hydroxylase
polymorphism and a phenotype that may become differently stratified within differently
selected samples of suicide attempters is discussed."
L, Bakish D, Hrdina PD.
Tryptophan hydroxylase gene 218A/C polymorphism
is associated with somatic anxiety in major depressive disorder.
Affect Disord 2001 Jun;65(1):37-44
"BACKGROUND: Abnormalities in functioning
of the central serotonergic system have been implicated in the pathogenesis of
depressive illness and suicidal behavior. Tryptophan hydroxylase (TPH) is the
rate-limiting enzyme in the biosynthesis of serotonin, therefore, it may play
an important role in regulation or control of serotonin functions. The aim of
the present investigation was to determine whether there is an association between
TPH gene polymorphism and major depression. particularly in patients with suicidal
ideation. METHODS: A total of 135 unrelated patients suffering from major depressive
disorder and 196 normal unrelated controls were included in the study. All controls
and patients were Caucasian. A biallelic polymorphism at the tryptophan hydroxylase
locus was genotyped. RESULTS: No significant difference between controls and depressed
subjects in TPH gene polymorphism was detected. There was no association between
TPH gene polymorphism and suicidal ideation. Total HAMD scores were not different
between the genotypes or alleles in patients. However, among the HAMD clusters,
somatic anxiety was significantly associated with TPH genotypes and alleles in
that patients with 218A/A genotype had a significantly higher somatic anxiety
scores compared to other genotypes. LIMITATION: Potential confounding effect of
population stratification can not be excluded. The functional relevance of the
TPH gene 218A/C polymorphism is, at present, uncertain. CONCLUSION: The polymorphism
in serotonergic system related genes may be associated with depressive symptoms
in major depressive disorder. The results suggest that analysis of clusters that
narrow down the phenotype may be more suitable in genetic studies of major depressive
Sun HS, Tsai HW, Ko HC, Chang FM, Yeh TL
Association of tryptophan hydroxylase gene polymorphism with depression, anxiety and comorbid depression and anxiety in a population-based sample of postpartum Taiwanese women.
Genes Brain Behav. 2004 Dec;3(6):328-36.
Depression and anxiety disorders often coexist clinically and both are known to have a genetic basis, but the mode of inheritance is too complicated to be determined so far. Serotonin is the biogenic amine neurotransmitter most commonly associated with depression and anxiety. Since tryptophan hydroxylase (TPH1) is the rate-limiting enzyme in serotonin biosynthesis, its role in the pathophysiology of these psychiatric diseases has been intensively studied. In this study, we examined whether polymorphism of the TPH1 gene is related to the etiology of major depression, anxiety and comorbid depression and anxiety. Five single nucleoside polymorphisms of the TPH1 gene were studied in a population-based sample of postpartum Taiwanese women consisting of 120 subjects with depression or/and anxiety and 86 matched normal controls. A significant difference (P = 0.0107) in genotype frequency for the T27224C polymorphism was found between the comorbid and normal groups, and risk analysis showed that the C allele conferred a strong protective effect (odds ratio = 0.27; 95% confident interval = 0.11-0.7). Three-allele haplotypes involving T27224C polymorphism were constructed and haplotype associations between particular haplotype combinations and various diseases identified. However, the associations were weak and the overall haplotype frequency profiles in all groups were similar. The results suggest that depression, anxiety, and comorbid depression and anxiety disorders may have related etiologies. In addition, this study suggests that the TPH1 gene might play a role in the pathogenesis of these closely related disorders. [Abstract]
EC, Chan AO, Tan CH, Mahendran R, Wang A, Chua HC.
linkage disequilibrium studies of the tryptophan hydroxylase gene polymorphisms
and major depressive disorder.
Psychiatr Genet. 2003 Sep;13(3):151-4.
OBJECTIVES Alterations in the level of the serotonin, serotonin uptake and the
number of binding sites have been linked to affective illness. We investigated
the association of tryptophan hydroxylase gene polymorphisms and unipolar depression
in a case-control study design.METHODS Patients and ethnically matched controls
were genotyped for three polymorphisms of the tryptophan hydroxylase gene.RESULTS
Significant difference in genotype frequency between patient and control groups
was observed for the IVS7+218A>C polymorphism but not for the two promoter
polymorphisms -1067G>A and -347T>G. Strong linkage disequilibrium among
the three polymorphisms was also observed.CONCLUSIONS As the sample size was small,
the positive association would need to be replicated by family-based association
studies or in a larger set of samples. As our results did not indicate association
with either of the two promoter polymorphisms, there is a need to continue the
search for the causative variant directly involved in the susceptibility to unipolar
depression in Chinese as this polymorphism within the intron might not be the
true susceptibility variant." [Abstract]
NJ, Buckland PR, Hall H, Owen MJ, O'Donovan MC.
receptor gene locus does not contain common polymorphism affecting mRNA levels
in adult brain.
Mol Psychiatry. 2004 Jan;9(1):109-14.
serotonin-2A (HTR2A) receptor is a molecule of particular interest in biological
psychiatry, as it is an important target for psychotropic drugs, and altered HTR2A
expression has been found in several neuropsychiatric conditions, including depression
and schizophrenia. Genetic association has been reported between a synonymous
102T/C polymorphism in the gene encoding HTR2A and a number of clinical phenotypes,
including schizophrenia, clozapine response, psychotic symptoms in Alzheimer's
disease and certain features of depression. Given that there are no known effects
of the 102T/C polymorphism on the structure of the receptor, attention has switched
to the possibility that the observations of both altered expression and genetic
association point to functional sequence variants that alter expression of the
HTR2A gene. Moreover, data have been presented recently suggesting that mRNAs
containing the 102T- and C-alleles are differentially expressed. This suggests
a direct effect of the variant itself on mRNA levels, or the influence of a distinct
regulatory variant, such as the -1438A/G promoter polymorphism, with which it
is in perfect linkage disequilibrium. The present study tested this hypothesis
by employing a highly accurate quantitative allele- specific primer extension
assay to measure the relative expression of brain mRNAs carrying each allele in
23 individuals heterozygous for the 102T/C polymorphism. Comparison between allele
ratios derived from genomic DNA and mRNA from several cortical regions revealed
that the 102C- and T-alleles are expressed identically. Furthermore, the absence
of any interindividual variability in relative mRNA allele ratio suggests that
the HTR2A locus is unlikely to contain common polymorphisms or epigenetic modification
that alter HTR2A mRNA levels in adult brain, and essentially exclude such phenomena
as a potential explanation for the altered expression and genetic associations
that have been reported to date." [Abstract]
MJ, Lee HJ, Lee HJ, Ham BJ, Cha JH, Ryu SH, Lee MS.
major depressive disorder and the -1438A/G polymorphism of the serotonin 2A receptor
study investigated the possible effect of the -1438A/G single-nucleotide polymorphism
in the promoter region of the serotonin 2A receptor (5-HTR2A) gene on major depressive
disorder (MDD) in a Korean population. This polymorphism was analyzed in 189 patients
with MDD and in 148 unrelated healthy controls using a case-control design, which
revealed a significant difference in the genotype distributions (chi(2) = 10.78,
d.f. = 2, p = 0.005). The frequency of the -1438G allele was also much higher
in MDD patients than in normal controls (chi(2) = 7.20, p = 0.007; OR = 1.52,
95% CI 1.12-2.06). We also found significantly more carriers of the G allele (GG+AG
genotypes) in MDD patients than in normal controls (chi(2) = 10.18, p = 0.001;
OR = 2.46, 95% CI 1.40-4.32). Our results support the hypothesis that the -1438A/G
polymorphism of the promoter region of the 5-HTR2A gene is associated with MDD
patients in a Korean population." [Abstract]
B, Gasto C, Catalan R, Gutierrez B, Pintor L, Fananas L.
receptor gene 102T/C polymorphism is associated with suicidal behavior in depressed
Am J Med Genet 2001 Dec 8;105(8):801-4
lines of evidence suggest that genetic factors constitute an important determinant
of suicidal behavior. A significant association between the 5-HT(2A)-C allele
and suicidality has recently been reported. The aim of this study was to investigate
whether the proposed association between 5-HT(2A)-102T/C polymorphism and suicidality
could be replicated in a larger and independent sample of Spanish patients with
major depression. The 102T/C polymorphism of the 5-HT(2A) receptor gene was analyzed
in 159 patients with major depression (DSM-IV criteria) and 164 unrelated and
healthy controls using a case control design. All individuals were subjects of
Spanish origin. Significant differences in allele (chi-square = 4.13, df = 1,
P = 0.04) and genotype (chi-square = 6.19, df = 2, P = 0.04) distributions were
found between non-suicide attempters and suicide attempters. Moreover, those patients
carrying 5-HT(2A)-C allele had more than five times the risk for attempting suicide
than noncarriers (OR = 5.50, 95% CI = 1.18-35.20, P = 0.01). Our results replicate
the proposed association between 5HT(2A)-C allele and suicidality in major depression.
Moreover, no overall associations are detected when patients with major depression
and controls are compared for 102T/C frequencies, suggesting that the increased
risk for suicidality conferred by 5-HT(2A)-C allele is primarily associated with
suicidal behavior and not with the diagnosis of major depression itself."
B, Kuznik J, Baghai T, Schule C, Zwanzger P, Minov C, de Jonge S, Rupprecht R,
Meyer H, Engel RR, Eisenmenger W, Ackenheil M.
Lack of association
of serotonin-2A receptor gene polymorphism (T102C) with suicidal ideation and
Am J Med Genet 2000 Dec 4;96(6):831-5
dysfunction has been implicated in the pathophysiology of affective disorders
and suicidality. Especially the density of the 5-HT2A receptor was claimed as
being increased in suicidality, proposed as an adaptive upregulation due to reduced
serotonergic transmission. Recent studies have shown an association of allele
C of the 5-HT2A-T102C polymorphism with suicidal ideation in patients with major
depression. The purpose of this study was to test whether this proposed marker
indicates susceptibility not only to suicidal ideation in depressed patients but
also to suicidality as a syndrome. We investigated the 5-HT2A-T102C polymorphism
in 131 suicide victims with unknown underlying psychiatric diagnoses, 84 patients
with major depression with or without suicidal ideation, and 125 healthy controls.
We were unable to find any association of genotype or allele frequencies to major
depression, suicidal ideation, or suicide as a syndrome. Thus, our results suggest
that this polymorphism may not commonly be involved in the susceptibility to suicidality."
S, Turecki G, Bakish D, Du L, Hrdina PD, Bown CD, Sequeira A, Kushwaha N, Morris
SJ, Basak A, Ou XM, Albert PR.
Impaired repression at a 5-hydroxytryptamine
1A receptor gene polymorphism associated with major depression and suicide.
Neurosci. 2003 Sep 24;23(25):8788-99.
"Inhibition of serotonergic raphe
neurons is mediated by somatodendritic 5-HT1A autoreceptors, which may be increased
in depressed patients. We report an association of the C(-1019)G 5-HT1A promoter
polymorphism with major depression and suicide in separate cohorts. In depressed
patients, the homozygous G(-1019) allele was enriched twofold versus controls
(p = 0.0017 and 0.0006 for G/G genotype and G allele distribution, respectively),
and in completed suicide cases the G(-1019) allele was enriched fourfold (p =
0.002 and 0.00008 for G/G genotype and G allele distribution, respectively). The
C(-1019) allele was part of a 26 bp imperfect palindrome that bound transcription
factors nuclear NUDR [nuclear deformed epidermal autoregulatory factor (DEAF-1)]/suppressin
and Hairy/Enhancer-of-split-5 (Drosophila) (Hes5) to repress 5-HT1A or heterologous
promoters, whereas the G(-1019) allele abolished repression by NUDR, but only
partially impaired Hes5-mediated repression. Recombinant NUDR bound specifically
to the 26 bp palindrome, and endogenous NUDR was present in the major protein-DNA
complex from raphe nuclear extracts. Stable expression of NUDR in raphe cells
reduced levels of endogenous 5-HT1A protein and binding. NUDR protein was colocalized
with 5-HT1A receptors in serotonergic raphe cells, hippocampal and cortical neurons,
and adult brain regions including raphe nuclei, indicating a role in regulating
5-HT1A autoreceptor expression. Our data indicate that NUDR is a repressor of
the 5-HT1A receptor in raphe cells the function of which is abrogated by a promoter
polymorphism. We suggest a novel transcriptional model in which the G(-1019) allele
derepresses 5-HT1A autoreceptor expression to reduce serotonergic neurotransmission,
predisposing to depression and suicide." [Abstract]
DW, Deng ZL, Ishigaki T, Nakamura Y, Suzuki Y, Miyasato K, Ohara K, Ohara K.
gene encoding the 5-HT1A receptor is intact in mood disorders.
"We studied the 5-HT1A receptor gene in 50 mood disorders
and 50 normal volunteers. The 5-HT1A receptor gene was amplified by polymerase
chain reaction and sequenced by the dideoxy method. The sequence of the 5-HT1A
receptor encodes a protein of 422 amino acids, that is, one amino acid longer
than the reported sequence (Kobilka et al. 1987). The DNA sequence at positions
454 to 459 is CGC GCC GCT, not CCG CGT, and the amino acids sequence at these
positions is changing from proline arginine to arginine alanine alanine. These
differences, however, were observed in both mood disorders and controls. One silent
polymorphism, CTG to GTA at position 294, was found. These results suggest that
the 5-HT1A receptor gene is intact in mood disorders." [Abstract]
Ohtani M, Shindo S, Yoshioka N.
of the tryptophan hydroxylase gene and serotonin 1A receptor gene in suicide victims
Tohoku J Exp Med. 2004 Feb;202(2):123-33.
Prefecture, Japan, has consistently recorded the highest level of suicide rates
in all of Japan. In this study, we attempted to determine whether genetic differences
between suicide victims and the normal population in Akita exist. We also researched
the geographical differences in polymorphisms of the genes between people living
in Akita Prefecture and those living in other prefectures with lower suicide rates
as recorded in previously-published studies. Specifically, we investigated two
serotonin-related genes including three substitutions connected to human emotional
states such as despondency and depression: the tryptophan hydroxylase (TPH) gene
(A779C and A218C in the intron) and the serotonin1A (5-HT1A) receptor gene (Pro
16Leu in the cording region). 134 suicide victims and 325 healthy volunteers were
examined. For this process, we used two analytical procedures: (1) polymerase
chain reaction (PCR) followed by single-strand conformational polymorphisms analysis
for the A779C of TPH and the 5-HT1A receptor genes and (2) PCR followed by restriction
fragment length polymorphism analysis for the A218C of TPH gene. No significant
differences of the genotypes and the allele frequencies between the suicide samples
and those of the healthy controls were discerned. Moreover, the genotype distributions
of the TPH and 5-HT1A receptor genes were compared between Akita Prefecture and
other prefectures, but no significant differences were found. In conclusion, no
significant relation could be established statistically concerning the serotonin
related genes between the suicide samples and control samples in Akita."
B, Gutierrez B, Pintor L, Gasto C, Fananas L.
Variability in the
5-HT(2A) receptor gene is associated with seasonal pattern in major depression.
Psychiatry 2001 Mar;6(2):239-42
"The 102-T/C polymorphism of the 5-HT(2A)
receptor gene was analysed in 159 patients with major depression and 164 unrelated
and healthy controls using a case-control design. Allele and genotype frequencies
did not differ between cases and controls. No differences according to sex, age
of onset, melancholia, suicidal behaviour or family history of psychiatric illness
were found. However, genotype distributions significantly differed between patients
with seasonal pattern in their episodes (MDS) and patients with no seasonal pattern
(N-MDS) (chi(2) = 10.63; P = 0.004). A seasonal pattern was 7.57 times more frequent
in 102C-allele carriers than in 102T homozygous (95.1% of patients MDS carried
102C-allele vs 72% of patients N-MDS (chi(2) = 9.45, df=1, P = 0.002; OR = 7.57
(95% CI: 1.65--48.08)). These results suggest that variation in the 5-HT2A receptor
gene may play a role in the development of major depression with seasonal pattern
and support the existence of a genetic and etiological heterogeneity underlying
the diagnosis of major depression." [Abstract]
L, Bakish D, Lapierre YD, Ravindran AV, Hrdina PD.
polymorphism of serotonin 2A receptor gene with suicidal ideation in major depressive
Am J Med Genet 2000 Feb 7;96(1):56-60
is evidence indicating that density of 5-HT2A receptors is altered in brain regions
of depressed suicide victims and in platelets of suicidal subjects with major
depression or schizophrenia. Recent studies have also shown an association between
the allele C of 102T/C polymorphism in the 5-HT2A receptor gene and schizophrenia.
The present investigation tested the hypothesis that the observed changes in 5-HT2A
receptor density in platelets of patients with major depression are a trait rather
than state phenomenon and are associated with the 102 C allele in 5-HT2A receptor
gene in a sample of 120 patients with major depression and a group of 131 control
subjects comparable with respect to age, sex, and ethnic background. The allele
and genotype frequencies of 102T/C polymorphism in 5-HT2A receptor gene were compared
between patients and control subjects and between suicidal and non-suicidal patient
groups. The major finding of this study was a significant association between
the 102 C allele in 5-HT2A receptor gene and major depression, chi(2) = 4.5, df
= 1, P = 0.03, particularly in patients with suicidal ideation, chi(2) = 8.5,
df = 1, P < 0.005. Furthermore, we found that patients with a 102 C/C genotype
had a significantly higher mean HAMD item 3 score (indication of suicidal ideation)
than T/C or T/T genotype patients. Our results suggest that the 102T/C polymorphism
in 5-HT2A receptor gene is primarily associated with suicidal ideation in patients
with major depression." [Abstract]
C, Baghai TC, Schule C, Zwanzger P, Schwarz MJ, Zill P, Rupprecht R, Bondy B.
and -transporter polymorphisms: lack of association in patients with major depression.
Lett 2001 May 4;303(2):119-22
"Disturbances in serotonergic neurotransmission
system have been implicated in the etiology of mood disorders. As the importance
of genetic factors is well established, genes encoding for proteins of the serotonergic
pathway are important candidates to unravel the underlying genetic contribution.
We examined two polymorphisms in the serotonin-2A-receptor gene (5-HT2A; T102C
and His452Tyr) and the insertion/deletion polymorphism in the promoter region
of the serotonin transporter (5-HTTLPR) in a sample of 173 patients with major
depression and 121 healthy controls. No statistical significant differences between
patients and controls were found for any of the three investigated polymorphisms,
neither in the distribution of the genotypes nor in allele frequencies. However,
concerning the 5-HTTLPR polymorphism, the frequency of S/S (short allele) homozygotes
was higher (23.1%) than in the control group (14.0%), but this failed to reach
significance. Moreover we observed a different treatment response in patients
with one or two C-alleles of the T102C polymorphism, with a significantly higher
decrease in HAMD-17 (ANOVA: d.f. = 1, F = 5,288, P = 0.023) after 4 weeks of antidepressant
treatment. Overall our results suggest that the investigated 5-HT2A and 5-HTTLPR
polymorphisms are not major susceptibility factors in the etiology of major depression.
However, subtypes might be identified at least on a basis of differential treatment
A, Lilli R, Lorenzi C, Smeraldi E.
No association between serotonin-2A
receptor gene polymorphism and psychotic symptomatology of mood disorders.
Res 1999 Jun 30;86(3):203-9
"Abnormalities of the serotonergic system
are involved in the pathophysiology of mood disorders. In the present study, we
investigated the possible influence of the T102C polymorphism of the serotonin-2A
receptor gene (5-HT2A, 13q14-21) on the symptomatology of mood disorders. Inpatients
affected by mood disorders (n = 246, 149 bipolar, 97 major depressive disorder)
were assessed with a checklist of operational criteria for psychotic illness (OPCRIT)
to score their lifetime psychotic symptomatology. The subjects were also typed
for 5-HT2A variants using polymerase chain reaction techniques. No association
was found between this polymorphism and psychopathology as defined by the four
symptomatologic factors used in phenotype definition (mania, depression, delusion
and disorganization). Genetic variation at the 5-HT2A receptor gene does not,
therefore, appear to play a major role in the pathogenesis of major mood disorders."
HY, Ishigaki T, Tani K, Chen K, Shih JC, Miyasato K, Ohara K, Ohara K.
receptor gene polymorphism in mood disorders.
1997 Apr 1;41(7):768-73
"Genes that regulate the serotonin (5-HT) system
including 5-HT receptors may be involved in mood disorders. We studied 5-HT2A
receptor exons and the adjacent intron regions in 102 patients with mood disorders
(71 depressive disorders and 31 bipolar disorders). In 34 mood disorder cases,
the gene encoding the 5-HT1A receptor had been sequenced, but no disease-specific
polymorphism was found. The substitution of C for T at position 102 in exon 1,
which had been reported by Warren et al., was confirmed. The corresponding amino
acid, serine, did not change. The allele frequency of C [corrected] at position
102 was significantly higher in patients with depressive disorders than in those
with bipolar disorders and healthy control subjects. Furthermore, the mean age
of onset in the patients heterozyous for the T and C alleles was lower than that
in those homozygous for the C allele. No other polymorphism in the gene was found."
B, Macciardi F, Segman RH, Adolfsson R, Blackwood D, Blairy S, Del Favero J, Dikeos
DG, Kaneva R, Lilli R, Massat I, Milanova V, Muir W, Noethen M, Oruc L, Petrova
T, Papadimitriou GN, Rietschel M, Serretti A, Souery D, Van Gestel S, Van Broeckhoven
C, Mendlewicz J.
Variability of 5-HT2C receptor cys23ser polymorphism
among European populations and vulnerability to affective disorder.
Psychiatry 2001 Sep;6(5):579-85
"We examined a structural variant of
the serotonin 2C (5-HT2C) receptor gene (HTR2C) that gives rise to a cysteine
to serine substitution in the N terminal extracellular domain of the receptor
protein (cys23ser),5 in 513 patients with recurrent major depression (MDD-R),
649 patients with bipolar (BP) affective disorder and 901 normal controls. The
subjects were drawn from nine European countries participating in the European
Collaborative Project on Affective Disorders. There was significant variation
in the frequency of the HT2CR ser23 allele among the 10 population groups included
in the sample (from 24.6% in Greek control subjects to 9.2% in Scots, 2 = 20.9,
df 9, P = 0.01). Logistic regression analysis demonstrated that over and above
this inter-population variability, there was a significant excess of HT2CR ser23
allele carriers in patients compared to normal controls that was demonstrable
for both the MDD (2 = 7.34, df 1, P = 0.006) and BP (2 = 5.45, df 1, P = 0.02)
patients. These findings support a possible role for genetically based structural
variation in 5-HT2C receptors in the pathogenesis of major affective disorder."
Huang YY, Oquendo MA, Friedman JM, Greenhill
LL, Brodsky B, Malone KM, Khait V, Mann JJ.
Substance abuse disorder
and major depression are associated with the human 5-HT1B receptor gene (HTR1B)
Neuropsychopharmacology 2003 Jan;28(1):163-9
5-HT(1B) receptor has been implicated in several psychopathologies, including
pathological aggression, alcoholism and suicide. To test these and related potential
genetic relationships in a single population, the human 5-HT(1B) receptor (h5-HTR(1B))
genotype for the G861C polymorphism was determined in 394 psychiatric patients
and 96 healthy volunteers. Structured clinical interviews generated DSM III-R
diagnoses. No significant association of the genotype or allele frequencies of
the h5-HTR(1B) G861C locus was observed with diagnoses of alcoholism, bipolar
disorder, schizophrenia or a history of a suicide attempt. Exploratory analyses
indicated an association of the genotype and allele frequencies of the h5-HTR(1B)
G861C locus with a history of substance abuse disorder (chi(2) = 9.51, df = 2,
p = 0.009; chi(2) = 7.31, df = 1, p = 0.007, respectively) and with a diagnosis
of a major depressive episode (chi(2) = 6.83, df = 2, p = 0.033; chi(2) = 5.81,
df = 1, p = 0.016, respectively). Significant gene dose effects on the risk for
substance abuse disorder and a major depressive episode were observed with the
861C allele (Armitage linearity tendency test: chi(2) = 7.20, df = 1, p = 0.008;
chi(2) = 6.80, df = 1, p = 0.009, respectively). Substance abuse disorder and
major depression appear to be associated with the h5-HTR(1B) G861C locus in the
patient population, but other psychopathologies such as bipolar disorder, schizophrenia,
alcoholism, and suicide attempts were not found to be associated with this polymorphism.
This preliminary result will need replication, given the limitations of association
JT, Arranz MJ, Munro J, Osbourn S, Kerwin RW, Collier DA.
analysis of the 5-HT5A gene in depression, psychosis and antipsychotic response.
2000 Jun 26;11(9):2017-20
"The serotonergic system is targeted by both
antidepressants and atypical antipsychotic drugs such as clozapine. Genetic variation
in the 5-HT5A gene might be involved in susceptibility to depression, the major
psychoses or in influencing clinical response to treatment. To examine this hypothesis
we genotyped two polymorphisms (-19G/C; 12A/T) in the human 5-HT5A receptor gene
in a sample of 269 unrelated schizophrenic patients treated with clozapine, 112
bipolar patients, 75 unipolar patients and 187 controls. After five-fold correction
for multiple testing, allelic association was found with the -19G/C polymorphism
and bipolar affective disorder, (p = 0.025; OR 0.56), unipolar depression (p =
0.004; OR 0.52) and schizophrenia (p = 0.036; OR 0.67) indicating a potential
protective effect of the G19 allele. For the 12A/T polymorphism allelic association
was observed with unipolar depression only (p = 0.004). We conclude that allelic
variation in the human 5-HT5A receptor gene may be involved in susceptibility
to schizophrenia and affective disorders but not in determining response to clozapine."
B, Collier DA, Gasto C, Pintor L, Gutierrez B, Valles V, Fananas L.
variation in the 5-HT5A receptor gene in patients with bipolar disorder and major
Neurosci Lett 2001 May 4;303(2):111-4
the present study, genetic variation of the 5-HT5A receptor was analyzed in patients
affected by affective disorders and healthy controls. The sample consisted of
181 patients with major depression, 88 patients with bipolar affective disorder
(BP) and 157 unrelated controls (C), all of Spanish origin. Two polymorphisms
(-19G/C and 12A/T) in the 5-HT5A receptor gene were analyzed by polymerase chain
reaction amplification and subsequent enzyme digestion. No genotype, allele or
haplotype differences were found when we compared patients and controls. When
clinical variables were considered as possible tools for detecting genetic heterogeneity,
no differences were found. Our results suggest that the polymorphisms analyzed
in the 5-HT5A receptor gene do not play a major role in the pathogenesis of affective
DC, Svenson I, Marchuk DA, Levy RM, Hays JC, Flint EP, Krishnan KR, Siegler IC.
differences in the serotonin transporter-linked polymorphic region in geriatric
Am J Geriatr Psychiatry 2002 Mar-Apr;10(2):185-91
studies have examined the role of genetic variations in the serotonin transporter-linked
polymorphic region (5HTTLPR) in affective disorders. The authors studied 182 older
depressed subjects and 107 elderly control subjects and obtained DNA for genotyping
at the 5HTTLPR. There were no significant differences in allele frequencies generally
or for number of short alleles for the group as a whole, but interesting gender
effects emerged. Among men, 23% of depressed men had two short alleles, compared
with only 5% of control subjects. Among women, 67% of depressed women with more
than one episode had at least one short allele, compared with 41% of single-episode
female patients. Also, 74% of women with a positive family history of psychiatric
illness in any female relative had at least one short allele, whereas 53% had
at least one short allele who did not have such a family history. Our results
add to the literature linking this gene to affective illness. The negative association
of allele frequency and depression may be related to the relatively small sample
size. The findings raise the possibility that this genetic locus may exert differential
effects based on gender, increasing risk in men, and increasing risk of recurrence
in women." [Abstract]
WH, Huo SJ, Cheng CY, Hong CJ, Tsai SJ.
Association study of the
5-HT(6) receptor polymorphism (C267T) and symptomatology and antidepressant response
in major depressive disorders.
serotonergic neurotransmitter system has been implicated in the pathogenesis of
major depressive disorder (MDD). Of the 14 human serotonin (5-HT) receptors, the
5-HT(6) receptor may be a candidate for the study of MDD because of its relative
abundance in certain limbic areas and its high affinity to several antidepressants.
The present study tested the hypothesis that a 5-HT(6) genetic polymorphism (C267T)
is associated with the clinical manifestations of, and/or antidepressant response
in, MDD. The Hamilton Depression Rating Scale was used to assess 57 MDD patients
before antidepressant treatment, with 34 patients completing the 4-week treatment
and evaluation. The results of the association study provide that the 5-HT(6)
C267T genetic variant does not play a major role in producing the clinical manifestations
or antidepressant response for MDD patients. Further study with a functional 5-HT(6)
polymorphism is needed to explore the role of 5-HT(6) in the pathogenesis of MDD."
Frisch A, Postilnick D, Rockah R, Michaelovsky E, Postilnick
S, Birman E, Laor N, Rauchverger B, Kreinin A, Poyurovsky M, Schneidman M, Modai
I, Weizman R.
Association of unipolar major depressive disorder with
genes of the serotonergic and dopaminergic pathways.
Psychiatry 1999 Jul;4(4):389-92
"Major depressive disorder (MDD) is a
severe psychiatric disorder with a lifetime prevalence of about 15%.1 The importance
of the genetic component is well accepted,2 but the mode of inheritance is complex
and non-Mendelian. A line of evidence suggests the involvement of serotonin and
dopamine neurotransmitters in the pathophysiology of depression. In the present
study, 102 unipolar MDD patients and 172 healthy controls were genotyped for polymorphisms
in four serotonergic and three dopaminergic candidate genes [tryptophan hydroxylase
(TPH), serotonin receptor 2A (HTR2A), serotonin receptor 2C (HTR2C), serotonin
transporter promoter region (5-HTTLPR), dopamine receptor D4 (DRD4), dopamine
transporter (DAT1) and catechol-O-methyl transferase (COMT)]. There were no statistical
differences between MDD patients and healthy controls in the genotypic and allelic
distribution of all polymorphisms investigated. Thus, our study does not support
a major role for these polymorphisms in contributing to susceptibility to MDD,
although it does not preclude minor effects." [Abstract]
Golimbet VE, Alfimova MV, Shchebatykh TV, Abramova LI, Kaleda
VG, Rogaev EI.
Serotonin transporter polymorphism and depressive-related
symptoms in schizophrenia.
Am J Med Genet. 2004 Apr 1;126B(1):1-7.
role for the serotonin transporter (5-HTT) gene polymorphism in mental illnesses
and anxiety-traits has been implicated. The contribution of genetic factors in
personality traits and the manifestation of specific symptoms in psychiatric illnesses
have yet to be elucidated. Anxious-depressive symptoms are a significant component
in a pattern of schizophrenic symptoms. This study focused on the relation between
5-HTT polymorphism and clinical presentations of schizophrenia, specifically those
related to the affective spectrum. Using clinical and psychological analyses,
we tested the genetic association between the 5-HTTLPR polymorphism (5-HTT gene-linked
polymorphic region) and anxiety- and depressive-related symptoms emerged in schizophrenia.
In 260 patients with an ICD-10 diagnosis of schizophrenia (broad definition),
we studied the 5-HTTLPR genotype (insertion-deletion polymorphism), the Positive
and Negative Syndrome Scale (PANSS), and self-rated inventories (EPI, MMPI, STAI)
scores. Patients with the "ss" genotype (deletion variant) scored significantly
higher on "Guilt feelings" and "Depression" items, as compared
with those of the "ll" genotype (insertion variant) (P = 0.016, 0.039,
respectively). The frequency of the "ss" genotype was reduced in patients
with no depression or guilt feelings, or in those patients exhibiting questionable
symptoms. In contrast, the "ss" genotype carriers prevailed among the
patients with mild, moderate, or severe ratings of the symptoms. The scores on
all anxiety- and depression-related traits, self-rated by the patients, did not
significantly differ by genotype. Our finding may contribute to understanding
of molecular genetic features underlying an appearance of psychopathological symptoms
emerged in schizophrenia." [Abstract]