Younger W.-Y. Yu

Association 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.

Association study of a brain‐derived neurotrophic‐factor genetic polymorphism and major depressive disorders, symptomatology, and antidepressant response

Preclinical studies have shown that brain‐derived neurotrophic factor (BDNF) may be involved in both antidepressant action and the pathophysiology of major depressive disorder (MDD). The present study tested the hypothesis that the BDNF‐gene Val66Met polymorphism is associated with MDD, its clinical manifestations, and antidepressant response. To elucidate a genetic predisposition of MDD, we studied BDNF‐gene Val66Met polymorphism in 152 MDD patients in 255 normal controls. We also examined the association of this polymorphism and fluoxetine therapeutic response in 110 MDD patients who received a 4‐week fluoxetine treatment. No significant differences were demonstrated for the genotype or allele frequency of the BDNF polymorphism comparing the MDD and control groups. Further, no significant differences were noted comparing the three‐genotype groups for depressive‐cluster symptoms. However, a trend (P = 0.086) to improved 4‐week‐fluoxetine antidepressant response was demonstrated for heterozygous patients in comparison to homozygous analogs. This finding suggests the BDNF polymorphism investigated plays no major role in the pathogenesis of MDD.

ASSOCIATION STUDY OF A MONOAMINE OXIDASE A GENE PROMOTER POLYMORPHISM WITH MAJOR DEPRESSIVE DISORDER AND ANTIDEPRESSANT RESPONSE

Monoamine oxidase A (MAOA), a mitochondrial enzyme involved in the degradation of biogenic amines, may be implicated in the pathogenesis of major depressive disorder (MDD) and be related to the therapeutic effects of antidepressants. To elucidate a genetic predisposition of MDD, we studied a variable-number-tandem-repeat (VNTR) polymorphism in the promoter region of the MAOA gene in a Chinese population of 230 MDD patients and 217 controls. We also examined the association of this polymorphism and antidepressant therapeutic response in the MDD patients who underwent a 4-week fluoxetine treatment. Our results showed a significantly increased frequency of 4-repeat (4R) allele in MDD patients, especially in the female population. Furthermore, MDD female patients who were 3R homozygotes had a significantly better response to 4-week fluoxetine treatment when compared to 4R carriers (p=0.024), but there was a nonsignificant difference found in male patients (p=0.081). Since the 4R allele transcribed 2–10 times more efficiently than those with 3R allele, our findings suggest that the MAOA-uVNTR may be involved in the pathogenesis of MDD and the antidepressant therapeutic mechanisms in Chinese population, and that there may be a gender effect in this association.

Association study of a functional catechol-O-methyltransferase-gene polymorphism and cognitive function in healthy females

Using the Wisconsin Card Sorting Test, it has been determined, that the catechol-O-methyltransferase (COMT) Val158Met genetic polymorphism, a functional polymorphism that may affect dopamine metabolism, is associated with prefrontal cognitive function. This study of a cohort of 120 healthy young Chinese females attempted to utilize P300 event-related potentials to replicate this finding and to test the relationship between this COMT polymorphism and cortical physiology. The results demonstrate that subjects bearing the Met/Met homozygote have significantly lower mean P300 latencies than do analogs bearing the Val allele. A significant association between this COMT polymorphism and perseverative errors was not demonstrated in the Wisconsin Card Sorting Test, however. We suggest that, although the COMT Val158Met genetic polymorphism may play a role in cognitive function, ethnicity and testing method may affect the association. Since statistical relationships between P300 components and both the COMT genetic polymorphism and schizophrenic disorders have been demonstrated, it seems reasonable to suggest that this COMT genetic variant may affect the P300 abnormality in schizophrenia.

An association study of a brain-derived neurotrophic factor Val66Met polymorphism and clozapine response of schizophrenic patients

A growing body of evidence suggests the involvement of brain-derived neurotrophic factor (BDNF) in both antipsychotic action and schizophrenia pathogenesis. The present study tested the hypothesis that the BDNF-gene Val66Met polymorphism is associated with schizophrenia and clozapines therapeutic response. To identify any genetic predisposition to schizophrenia, we studied the BDNF-gene Val66Met polymorphism in 93 schizophrenic patients and 198 normal controls. Statistical analysis was used to test the association between this polymorphism and clozapine response the schizophrenic group. A trend (P=0.055) was demonstrated between genetic predisposition and Val66Met genotypes in 93 schizophrenic patients, especially for those with good response to clozapine (P=0.023). No significant difference in clozapine therapeutic response was demonstrated comparing the three Val66Met-genotype subgroups. Our finding suggests that this BDNF-gene Val66Met polymorphism may be related to schizophrenia pathogenesis in patients responsive to clozapine treatment.

Association study of the interleukin-1 beta (C-511T) genetic polymorphism with major depressive disorder, associated symptomatology, and antidepressant response.

Proinflammatory cytokines, including interleukin (IL)-1beta, are suggested to have a role in the pathogenesis of major depressive disorder (MDD) and be related to the therapeutic effects of antidepressants. To elucidate a genetic predisposition of MDD, we studied biallelic polymorphism in the promoter region (position -511) of the IL-1beta gene in 157 patients with MDD and in 112 controls. We also examined the association of this polymorphism and fluoxetine therapeutic response in 119 MDD patients who received a 4-week fluoxetine treatment. No significant difference was found in the genetic polymorphism between MDD patients and controls. However, MDD patients who were homozygous for the -511T allele of the IL-1beta gene had a trend of less severity of depressive symptoms and more favorable fluoxetine therapeutic response than -511C carriers. Further study with a larger sample is needed to clarify the role of the IL-1beta genetic polymorphisms in the symptoms and treatment effects in MDD.

Serotonin-6 receptor variant (C267T) and clinical response to clozapine.

Clozapine is an effective atypical antipsychotic that has high affinity for serotonin type 6 receptors (5HT6). We tested the hypothesis that clinical response to clozapine in patients refractory to typical antipsychotic treatment is related to the genetic variant (C267T) of the 5HT6 receptors. Ninety-nine schizophrenic patients with a history of non-response to typical antipsychotics were included in the study. The results demonstrated a modest but significant relationship between presence of the variant of the 5HT6 receptors and the response to clozapine in these patients. Patients with homogenous 267T/T genotype had a better response than other patients. Although replication is required, these results suggest that the 5HT6 receptor C267T polymorphism may be involved in clozapine response, especially in patients with anxious or depressed symptoms.

Association study of two serotonin 1A receptor gene polymorphisms and fluoxetine treatment response in Chinese major depressive disorders

The firing rate of dorsal raphe serotonergic neurons is modulated by somatodendritic 5-hydroxytryptamine 1A (HTR1A) autoreceptors. Evidence from animal and clinical studies has suggested that desensitization of HTR1A is implicated in the antidepressant therapeutic mechanism of selective serotonin reuptake inhibitors (SSRIs). Recent studies, including our recent findings, have reported that a functional HTR1A C-1019G polymorphism in the promoter region, as well as a nonsynonymous polymorphism, Gly272Asp, may be associated with SSRI pharmacogenetics. In this study, we tested whether Gly272Asp genetic variants are related to a 4-week fluoxetine antidepressant effect in 222 Chinese major depressive patients. We also tested the linkage disequilibrium (LD) measurement between HTR1A Gly272Asp and C-1019G polymorphisms, and haplotype analysis was conducted to assess the association between the two markers within the HTR1A gene and fluoxetine antidepressant response. The results show that the HTR1A Gly272Asp polymorphism was not associated with fluoxetine therapeutic response. The two markers are in strong LD and the HTR1A haplotype of the two polymorphisms is associated with fluoxetine therapeutic response. This association is gender-specific and mostly arises from the effect of HTR1A C-1019G polymorphism: female patients with -1019C/C genotype showed a better response than -1019G carriers. These findings need to be confirmed in other ethnic populations.

No evidence for association of serotonin-2A receptor variant (102T/C) with schizophrenia or clozapine response in a Chinese population

The serotonin hypothesis in schizophrenia had regained interest with the superior efficacy of clozapine in the refractory schizophrenic patients. Among the serotonin receptors, the serotonin 2A (5HT2A) receptor subtype is the most widely studied. Previous studies on the association between a silent mutation polymorphism of the 5HT2A gene (102T/C) and schizophrenia or clozapine response have yielded conflicting findings. Therefore, we investigated whether these genetic variants of the 5HT2A receptor are associated with schizophrenia or with response to clozapine treatment in a Chinese population. Ninety-seven schizophrenic patients and 101 control subjects were included in the study. The receptor variants were found at similar frequencies in schizophrenic patients and healthy control subjects. Also, we did not find the variants to influence the response to clozapine in schizophrenic patients. We suggest that the assessment method of clozapine response and the ethnicity may influence the result.

Association study of catechol-O-methyltransferase gene and dopamine D4 receptor gene polymorphisms and personality traits in healthy young chinese females.

Human personality traits, which are substantially heritable, may be modulated by monoamine neurotransmitters. It has been demonstrated that the catechol-O-methyltransferase (COMT) Val158Met genetic polymorphism, a functional polymorphism that may affect monoamine metabolism, is possibly associated with specific personality traits. In addition, a polymorphism in the dopamine D4 receptor (DRD4) gene exon 3 has been associated in some, but not all, studies with the novelty seeking personality trait, as evaluated by the Tridimensional Personality Questionnaire (TPQ). In this study, associations between these two polymorphisms and TPQ personality traits were investigated in a sample population of 120 healthy young Chinese females. The results of this analysis reveal that the COMT Val158Met polymorphism was significantly associated with novelty seeking (p = 0.017) and reward dependence scores (p = 0.015) in our sample. However, no significant differences were demonstrated comparing TPQ-specific scores for subjects bearing different DRD4 genotypes. The present study suggests that the functional COMT Val158Met genetic polymorphism contributes to individual differences in the personality traits novelty seeking and reward dependence. Similar to the results of a recent meta-analytic review, however, no association was demonstrated between this DRD4 polymorphism and novelty seeking in our young Chinese female sample population.