Serotonin systems appear to play a key role in the pathogenesis of major depression and the therapeutic mechanisms of antidepressants. The firing rate of dorsal raphe serotonergic neurons is controlled by somatodendritic 5-hydroxytryptamine 1A (HTR1A) autoreceptors, and desensitization of these receptors is implicated in the antidepressant mechanism of selective serotonin reuptake inhibitors. We tested whether a functional polymorphism (C-1019G) in the promoter region of the HTR1A gene and serotonin-related genetic variants are related to fluoxetine antidepressant effect. We genotyped the HTR1A C-1019G polymorphism as well as polymorphisms in the serotonin transporter gene-linked polymorphic region (SERTPR), variable-number tandem-repeat polymorphisms in intron 2 (STin2) of the serotonin transporter gene, serotonin 2A receptor (T102C), tryptophan hydroxylase (A218C), and G-protein beta3 subunit (C825T) in 224 Chinese patients from southern Taiwan with major depression, who accepted 4-week fluoxetine treatment and therapeutic evaluation. Our results demonstrated that the HTR1A −1019C/C carriers (P=0.009) and SERTPR l/l carriers (P<0.001) showed a better response to fluoxetine, while other polymorphisms were not associated with fluoxetine therapeutic response. The major limitation of this study is the lack of a placebo control. Future prospective study with placebo control may help to predict and individualize antidepressant treatment.
Several lines of evidence indicate that abnormalities in the functioning of the central serotonergic system are involved in the pathogenesis of depressive illness. Consequently, genes that code for proteins involved in regulating serotonergic neurotransmission have thus been major candidate genes for association studies of major depression. Serotonin type 1A (HTR1A) receptors and the serotonin transporters are decreased in depression, and recent genetic research in animals and humans has implicated both in depression (for a review, see Neumeister et al.1).
Selective serotonin reuptake inhibitors (SSRIs) are currently the first-line medication for treatment of major depression. As with all antidepressant therapies, there is variability among patients in terms of response to SSRI treatment, including demonstration of partial or zero response for 29–46% of patients with major depression.2 Of the possible factors causing interindividual variability in SSRI response, genetic factors may play an important role.3, 4 The identification of genetic factors underlying response to SSRI therapy may help to predict therapeutic response and facilitate determination of optimal drug selection.5
Recent pharmacogenetic SSRI research has focused on the possible associations between polymorphisms in candidate genes related to SSRI therapeutic effect and clinical response. The primary target for SSRI action is the serotonin transporter, and it has been determined that, in terms of transcriptional activity, the long (l) variant in the serotonin transporter gene-linked polymorphic region (SERTPR or 5-HTTLPR) is more than twice as active as the short (s) analog.6 In the study by Nakamura et al.,7 the SERTPR alleles reported as s and l were further divided into four and six kinds of allelic variants, respectively, and they also demonstrated some rare SERTPR variants. In 1998, Smeraldi et al.8 first demonstrated an association between therapeutic fluvoxamine response and the SERTPR polymorphism, with a better response to fluvoxamine demonstrated for l-allele carriers compared with s-variant homozygotes; six subsequent studies have shown either better response or more rapid response with the SERTPR l-allele (for reviews, see Tsai and Hong9 and Smits et al.10), although two Asian studies had contrasting findings.11, 12 In addition to SERTPR, several genetic polymorphisms have been reported to be associated with therapeutic response to SSRIs. Study has shown a less favorable response to SSRI in patients with the 10/12 genotype of a variable-number tandem-repeat polymorphism located in intron 2 of the serotonin transporter (STin2 or 5-HTTVNTR) in Asian population.11 HTR2A may play a role in the mechanism of antidepressant treatment and could be a candidate gene for the prediction of antidepressant response. Study by Minov et al.13 found a better response to antidepressants in patients with one or two C alleles of the HTR2A T102C polymorphism compared to T/T homozygotes. Tryptophan hydroxylase (TPH), the rate-limiting enzyme in the biosynthesis of serotonin, plays a vital role in serotonin metabolism. Recent studies have shown that there are two genes, TPH1 and TPH2, that encode TPH in mammals, and TPH2, rather than TPH1, is preferentially expressed in the brain.14 It was found that TPH1 A218C variants might be involved in the outcome of antidepressant treatment.15 Furthermore, a G-protein beta3 subunit (GNB3) C825T polymorphism, which has been shown to be associated with increased signal transduction and ion transport activity, was investigated in the response to antidepressant treatment in mood disorder patients, and the result showed a statistically significant association between T/T homozygosity and better response to 4-week antidepressant treatment.16 However, study by Joyce et al. demonstrated that for depressed patients under the age of 25 years the T allele of the GNB3 was associated with a markedly poorer response to antidepressants, while in patients 25 years or older, the GNB3 polymorphisms did not predict antidepressant response.17
The mechanisms underlying the antidepressant effects of SSRIs are still unclear. However, data from both animal and human studies suggest that therapeutic effects seem to be related to desensitization of somatodendritic HTR1A autoreceptors in the raphe nuclei (for reviews, see Newman et al.18 and Stahl19). The increase in serotonin neurotransmission due to HTR1A autoreceptor desensitization associated with SSRI treatment to normo-sensitive HTR1A postsynaptic receptors in certain brain regions (e.g. hippocampus or cortex) may underlie the therapeutic efficacy of these drugs. From this finding, therefore, the HTR1A gene may be considered a candidate gene for the SSRI pharmacogenetic study. Recently, a study in Japanese depressed patients was published indicating that one nonsynonymous HTR1A Gly272Asp polymorphism was associated with antidepressant response to fluvoxamine (another SSRI).20 The HTR1A gene, mapped to chromosome 15q11, is intronless and codes a 422-amino-acid protein.21 Recently, a common promoter polymorphism (C-1019G; rs6295 (http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?rs=6295)) of HTR1A has been reported to be associated with panic disorder,22 major depression and suicide,23 and anxiety-related and depression-related personality traits.24 This promoter polymorphism is functional in that the −1019C allele was part of a 26-base pair (bp) imperfect palindrome that bound nuclear DEAF-1-related (NUDR) protein to repress HTR1A or heterologous promoters, whereas the −1019G allele abolished repression by NUDR.23 During the submission of this manuscript, Serretti et al.25 reported that this HTR1A C-1019G polymorphism is associated with 6-week fluvoxamine therapeutic response in bipolar depression, but not in major depression. Considering the close relationship between the HTR1A receptors and SSRI antidepressant effect, in the current study we investigated the possible association of this HTR1A C-1019G polymorphism and therapeutic response to fluoxetine (as an example of a SSRI) in patients with major depression. As therapeutic antidepressant effect may involve the interaction of many different genes, a single gene may play a relatively minor role in such a complicated mechanism and, thus, not be strongly associated with antidepressant response. Thus, we also conducted association studies with other candidate genetic polymorphisms to find the combination that gives the best predictive value for fluoxetine response, including polymorphisms that have been previously related to SSRI antidepressant response: SERTPR, STin2, HTR2A (T102C), TPH1 (A218C), and GNB3 (C825T).
Methods and samples
Within a two-year recruitment period, the study population consisted of 224 patients from southern Taiwan with major depression (male/female: 93/131; mean age: 44.0 years (s.d.: 16.7)), who met DSM-IV criteria and completed a 4-week therapeutic evaluation of fluoxetine. A senior psychiatrist (YWY) made the diagnosis by interviewing patients, family members and obtaining records where possible. Other inclusion criteria were a minimum baseline score of 18 on the 21-item Hamilton Depression Rating Scale (HAM-D)26 and the presence of depressive symptoms for at least 2 weeks before entry into the study without antidepressant treatment during that period (patients were drug-naive patients or had quit antidepressants for more than 2 weeks). Exclusion criteria were additional current DSM-IV Axis I diagnoses (including schizophrenia, bipolar disorder, substance abuse, generalized anxiety disorders, panic disorders, or obsessive compulsive disorders), personality disorders, pregnancy, recent suicide attempt, and major medical and/or neurological disorders. Of the 224 total patients, 119 had been enrolled in our previous study.27The sample consisted entirely of psychiatric outpatients and ethnic Chinese adults, with informed consents obtained from all participants prior to enrollment. The study approval was obtained from the local ethics committee, and the study was carried out in accordance with the principles of the Declaration of Helsinki.
For the fluoxetine treatment, the daily doses were 20 mg/day in the beginning, and based on the clinical response after 2-week treatment the investigator could increase the dosage to 40 mg/day. No other psychotropic medications were permitted; however, anxiolytics were allowed for insomnia. Treatment efficacy was evaluated by one investigator (YWY), blind to patient genotype, who administered the HAM-D Scale before and after the 4-week fluoxetine treatment. Responders were defined as patients with at least 50% decrease in HAM-D total score after 4-week fluoxetine treatment. This definition is commonly used in short-term antidepressant treatment response evaluation (e.g., Yoshid et al.,12 Minov et al.13 and Zill et al.16).
For HTR1A C-1019G genotyping, genomic DNA was extracted from EDTA-anticoagulated venous blood samples. The DNA fragment of interest was amplified using polymerase chain reaction (PCR). In order to create an HpyCH4 IV restriction site to distinguish the polymorphism, mismatched forward primer 5′ IndexTermTGG AAG AAG ACC GAG TGT GTC TAC 3′ (underlined A is mismatched) and backward primer 5′ IndexTermTTC TCC CTG AGG GAG TAA GGC TGG 3′ were designed according to the sequence of GenBank Accession Number AC122707. The 182-bp PCR products were digested with Hpy CH4IV and then separated on 3% agarose gels. Under ultraviolet illumination an uncut 182 bp band indicates −1019C allele, while two bands of 158 and 24 bp indicate −1019G allele. Incomplete digestion was ruled out by the presence of homozygous G type in each batch of the restriction reaction, while contaminated PCR amplification was always monitored by a tube of reaction mixture without genomic DNA. SERTPR, STin2, HTR2A T102C, TPH1 A218C, and GNB3 C825T polymorphism genotyping methods were detailed in our previous reports.28, 29, 30, 31
Comparisons of genotype frequencies between responders and nonresponders were carried out for each polymorphism using χ2 or Fisher's tests. Differences in continuous variables (e.g. age, HAM-D score) were evaluated by Student's t-test or one-way analysis of variance, followed by the LSD multiple-range tests for comparison among groups. A logistic-regression analysis was performed using fluoxetine antidepressant response as the dependent variable, and age, sex, fluoxetine dose, and genotypes as the predictor variables. The probability of a type one error was set at a maximum level of 0.05. With six comparisons of the genotype frequencies between responders and nonresponders, using the Bonferroni procedure, a P-value less than 0.0083 was considered significant. Data are presented as the mean (standard deviation (s.d.)).
The mean fluoxetine dose for the 224 patients was 25.8 mg/day (s.d.: 19.1) at week 4 and 81 (36.2%) of the 224 patients had at least 50% decrease in HAM-D total score after 4-week medication. There were no significant differences in gender or baseline HAM-D score between the responder and the nonresponder groups (Table 1); however, the nonresponder group had an older mean age compared with the responder group.
Genotype distributions for all of the genetic polymorphisms were in Hardy–Weinberg equilibrium. There were no significant associations between fluoxetine response and STin2, HTR2A (T102C), TPH1 (A218C), and GNB3 (C825T) genotype groups; however, the HTR1A C-1019G genotype (P=0.009) and SERTPR genotype (P<0.001) frequencies were associated with response to fluoxetine treatment (Table 2). For the SERTPR genotypes, patients with the l/l genotype had a significantly better response to fluoxetine than patients carrying the s-allele. Using s-allele carriers as baseline, the odds ratio for l/l carriers was 8.6 (95% CI, 2.8–26.6). If we excluded the 119 patients studied in our previous report,21 l/l homozygotes still had a significantly better response to fluoxetine than patients who were s-allele carriers (n=105; P=0.009). For the HTR1A genotypes, patients with the C/C genotype had a significantly better response to fluoxetine than patients who were G-allele carriers. Using G-allele carriers as baseline, the odds ratio for the C/C carriers was 4.4 (95% CI, 1.1–17.6).
The prediction levels were calculated by logistic regression analysis using fluoxetine antidepressant response as the dependent variable and age, gender, fluoxetine dose, and HTR1A (C/C vs G-allele carriers) and SERTPR genotypes (l/l vs s-allele carriers) as predictor variables. Patient age (P=0.045; 95% CI, 1.0–1.1), SERTPR genotype (P<0.001; 95% CI, 3.3–34.9), and HTR1A genotype (P=0.023; 95% CI, 1.2–20.4) were significant predictors of therapeutic response to fluoxetine (overall (age, SERTPR, and HTR1A genotypes) P<0.001; pseudo r2=0.132).
We further evaluated therapeutic response by the total HAMD score percentage reduction ((baseline score−four-week score) × 100/baseline score) with ANOVA test, with total HAMD score percentage reduction as the dependent variable, genotypic group as the independent variable, and age and fluoxetine dose as covariates in the analyses. There was significant difference comparing the three SERTPR genotypic groups (P<0.001), but not the other genotypic groups (data not shown), for the total HAMD score percentage reduction.
In this study, among 224 patients who completed a 4-week fluoxetine treatment, 81 (36.2%) patients were considered fluoxetine responders defined by a minimum 50% reduction in HAM-D total score from baseline. This response rate is low compared with the response rates of most short-term antidepressant studies.32 However, this response rate is similar to that of our previous double-blind, group-comparative study of the treatment response with mirtazapine or fluoxetine in depressed Chinese patients, which showed 39% response rate for fluoxetine group at week 4.33 Further, the low fluoxetine mean dose 25.8 mg/day (s.d.: 19.1) may also explain the low response rate observed. Whether the fluoxetine therapeutic response rate is ethnic-dependent may need further exploration.
The major finding of this pharmacogenetic study in fluoxetine therapeutic response is that the HTR1A C-1019G polymorphism, in addition to SERTPR polymorphism, is associated with antidepressant response to fluoxetine. In this study, 70% of HTR1A C/C homozygotes were responders, whereas only 34.6% of G-allele carriers were responders. Recently, Serretti et al.25 reported that this HTR1A C-1019G polymorphism is associated with 6-week fluvoxamine therapeutic response in bipolar depression but not in major depression. They found that C/C genotype carriers showed a better response to fluvoxamine (P=0.036), independently from clinical variables.
The association between the HTR1A polymorphism and therapeutic response to fluoxetine is supported by data from both animal and human studies showing that the therapeutic effects of SSRIs seem to be related to desensitization of somatodendritic HTR1A autoreceptors in the raphe nuclei and normo-sensitive HTR1A postsynaptic receptors in certain brain regions.18, 19 Furthermore, reports that several HTR1A agonists exert antidepressant activity or augment SSRI antidepressant effect further support the important role of HTR1A receptors in SSRI antidepressant action.34 It is unknown how the HTR1A C-1019G polymorphism affects fluoxetine antidepressant effect. In a recent report, it was demonstrated that the C-allele was part of a 26 bp imperfect palindrome that bound transcription factors NUDR to repress HTR1A promoters, whereas the G-allele abolished repression by NUDR protein.23 This effect would lead to elevated levels of HTR1A in G-allele homozygotes compared with the C-allele homozygotes.23 Since therapeutic mechanisms of SSRIs may be related to desensitization of somatodendritic HTR1A autoreceptors in the raphe nuclei,18 it is likely that this polymorphism may affect the fluoxetine effect on desensitization of somatodendritic HTR1A receptor, resulting in better therapeutic antidepressant response in patients carrying C/C genotype. It is also possible that the association of HTR1A C-1019G polymorphism and fluoxetine antidepressant response is due to linkage disequilibrium between this polymorphism and a nearby functional polymorphism. A recent study in Japanese patients found that a HTR1A Gly272Asp polymorphism was associated with fluvoxamine antidepressant response.20 As haplotype analysis combines information concerning two or more known polymorphisms in the same candidate gene by taking into account their dependence, examining these two polymorphisms together would have a greater power than studying the polymorphisms separately. Future study using these two HTR1A polymorphisms for antidepressant pharmacogenetic study may help to reveal the HTR1A genetic effect in antidepressant response.
In the study, our findings cannot support previous reports that STin2, HTR2A T102C, TPH1 A218C, and GNB3 C825T polymorphisms are related to SSRI therapeutic response.11, 13, 15, 16, 17 However, we have similar findings as previous reports that SERTPR is associated with SSRI antidepressant response in Western populations (for reviews, see Nakamura et al.7 and Smeraldi et al.8) and Asian populations (our earlier study27). We also confirmed a previous report that age is associated with SSRI therapeutic effect.35
A previous retrospective study has demonstrated that age may have diverse effects in the therapeutic response of various antidepressants.36 In our study, the nonresponder group had an older mean age compared with the responder group. The mechanism underlying age effect on fluoxetine response is unclear. In literature there is evidence that HTR1A receptor density might differ according to age.37, 38 Since HTR1A is important in antidepressant therapeutic mechanisms, age may affect fluoxetine response through the change in HTR1A receptor density.
Interindividual variation in SSRI antidepressant response is affected by genetic factors and other factors such as age; thus, a single polymorphism might well only explain some of the observed variation. For example, it was determined that the SERTPR polymorphism accounts for 5.1% of the variance in SSRI response in our previous report27 and 7% of the variance in the study by Serretti et al.15 HTR1A and serotonin transporter both influence serotonin availability in brain.39 Furthermore, animal study showed that inactivation of serotonin transporter gene in mice leads to selective desensitization and downregulation of HTR1A autoreceptors.1 These data suggested that both genes might interact to modulate serotonin transmission and possibly SSRI therapeutic effects. In the present study, the combination of two polymorphisms (SERTPR and HTR1A C-1019G polymorphism) and age accounts for 13.2% of the variance of response to fluoxetine. Further study with analyses of multiple genes possibly implicated in the antidepressant effects of SSRIs may give a better predictive value for response to treatment.
In this study, we found a moderate liability effect of HTR1A C-1019G polymorphism in short-term fluoxetine antidepressant response. However, there are several limitations of this study. First, the HAM-D scale was only administered before and after 4-week fluoxetine treatment. The fluoxetine response was quite low in our study, which probably reflects the fact that response was assessed at 4 weeks – rather than 8, as would be much more typical. Thus, the association between HTR1A C/C genotype and fluoxetine treatment effect may represent earlier rather than ‘better’ response. Furthermore, placebo-pattern response has an earlier onset of response and/or lack of persistence in improvement after onset. It should be better to monitor the treatment every week with the administration of the HAM-D, especially in the early stage of antidepressant treatment, since genotype might condition the antidepressant response over time. Second, a very significant limitation of the study is the lack of a placebo control. It is well known that placebo response plays a very important role as a notable component of therapeutic response to antidepressant agents (e.g. Rausch et al.40). In addition, it is considered that the placebo response is greater in patients with mild to moderate depression than more severe forms of depression, we cannot exclude some patients in the responder group were due to placebo effect. The lack of placebo control would limit whether and to what extent the findings in the present study can be attributed to a drug-related genetic or biological factor. Finally, some factors possibly influencing treatment effect, such as past psychiatric diagnosis, history of suicide, age of onset, drug side effects from treatment (e.g. Murphy et al.41), prior treatment, and dropout during treatment, were not included in this study.
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This work was supported by Grant 92-2314-B-075-087 from the National Science Council, Taiwan, and, Grant VGH92-161 from the Taipei Veterans General Hospital.
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Hong, CJ., Chen, TJ., Yu, YY. et al. Response to fluoxetine and serotonin 1A receptor (C-1019G) polymorphism in Taiwan Chinese major depressive disorder. Pharmacogenomics J 6, 27–33 (2006). https://doi.org/10.1038/sj.tpj.6500340
- serotonin 1A receptor
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