Tai-Jui Chen

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.

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.

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.

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.

Association Study of a Brain-Derived Neurotrophic Factor (BDNF) Val66Met Polymorphism and Personality Trait and Intelligence in Healthy Young Females

Brain-derived neurotrophic factor (BDNF), a member of the nerve-growth-factor family, plays an important role in neuronal survival and development, and it can modulate serotonergic activity. Further, BDNF has been implicated in the expression of personality traits and in cognitive function. We tested the associations between functional BDNF Val66Met genetic variants, and personality trait and intelligence in a cohort of 114 healthy young Chinese females. Subjects with the Val/Val genotype had a significantly higher mean performance IQ than Val/Met carriers, especially for the Object Assembly subtest. No significant association was demonstrated for the BDNF polymorphism and any of the Tridimensional Personality Questionnaire personality-factor scores, including harm avoidance. These results suggest that genetic variants of the BDNF gene may play a role in specific cognitive functions, but not in overall intelligence. In contrast to a recent report, however, this polymorphism does not appear to be associated with the neuroticism-related personality trait.

Tryptophan hydroxylase 2 gene is associated with major depression and antidepressant treatment response.

Tryptophan hydroxylase-2 (TPH2) is the rate-limiting biosynthetic isoenzyme for serotonin that is preferentially expressed in the brain and has been implicated in the pathogenesis of major depressive disorder (MDD) and in the mechanism of antidepressant action. This study aimed to investigate whether common genetic variation in the TPH2 gene is associated with MDD and therapeutic response to antidepressants in a Chinese population. A total of 508 MDD patients and 463 unrelated controls were recruited. Among the MDD patients, 187 accepted selective serotonin reuptake inhibitor (fluoxetine or citalopram) antidepressant treatment for 8 weeks with therapeutic evaluation before and after treatment. Five TPH2 polymorphisms were genotyped and their association with MDD or treatment response was assessed by haplotype and single-marker analysis. In single-marker-based analysis, the rs17110747-G homozygote polymorphism was found to be more frequent in the MDD patients than in the controls (P=0.002). Genotype analysis in responders (defined as those with a 50% reduction in baseline Hamilton score) and non-responders after 8 weeks of antidepressant treatment showed that the proportion of rs2171363 heterozygote carriers was higher in the responders than the non-responders (P=0.009). No significant association with MDD or antidepressant therapeutic response was discovered in haplotype analyses. Our findings show that TPH2 genetic variants may play a role in MDD susceptibility and in acute therapeutic response to selective serotonin reuptake inhibitors.

Sexually dimorphic effect of catechol-O-methyltransferase val158met polymorphism on clinical response to fluoxetine in major depressive patients

BACKGROUND Essential in dopamine degradation, it was suggested that catechol-O-methyltransferase (COMT) might be involved in the action of antidepressants and may therefore be a promising candidate for antidepressant pharmacogenetic studies. METHODS COMT Val158met polymorphism was genotyped in 334 Chinese major depressive disorder (MDD) patients who were treated with fluoxetine for at least 4 weeks. Clinical response was evaluated using the 21-item Hamilton Rating Scale for Depression (HAM-D(21)). In the analysis of association, response was defined as >or=50% decrease in HAM-D(21) score after treatment and then further clarified by intra-individual changes in HAM-D(21) score. RESULTS We found that the COMT val158met polymorphism was not associated with 4-week fluoxetine therapeutic response; however, association analysis showed that patients with the COMT(Val/Val) genotype had poorer responses in the eighth week (CLUMP T1 P=0.020) and consistently showed significantly smaller reductions in HAM-D(21) scores in the eighth week (P=0.027). Further stratification based on gender revealed an isolated effect of the COMT genotype in males (P=0.035) but not in females (P=0.650) in percent reduction in HAM-D(21) scores in the eighth week. LIMITATIONS There was a lack of placebo control and the serum fluoxetine concentration was not taken into account. CONCLUSIONS This identified association between the COMT genetic variation and antidepressant response may be useful either as a clinical predictor in the future.

Reduced physiologic complexity is associated with poor sleep in patients with major depression and primary insomnia

BACKGROUND Depression is known to be associated with altered cardiovascular variability and increased cardiovascular comorbidity, yet it is unknown whether altered cardiac autonomic function in depression is associated with insomnia, a common symptom comorbid with depression. This study aimed to investigate the long-term diurnal profile of autonomic function as measured by heart rate variability (HRV) in both major depression and primary insomnia patients. METHOD A total of 52 non-medicated patients with major depression, 47 non-medicated patients with primary insomnia, and 88 matched controls without insomnia were recruited. Each subject was assessed by means of sleep and mood questionnaires and underwent twenty-four-hour ambulatory electrocardiogram monitoring. Standard HRV analysis and a well-validated complexity measure, multiscale entropy, were applied to comprehensively assess the diurnal profiles of autonomic function and physiologic complexity in our study sample. RESULTS Compared with the controls, the patients with major depression and those with primary insomnia exhibited significant reductions in parasympathetic-related HRV indices, and this association was mainly driven by the presence of poor sleep. Both groups of patients also exhibited significant reductions in physiologic complexity during the sleep period as compared with the healthy controls. Alterations in HRV indices were correlated with perceived sleep questionnaire scores but not with depression scales. CONCLUSIONS Our findings suggest a pivotal role of sleep disturbance in regulating cardiovascular variability in major depression and primary insomnia patients. These findings could highlight the importance of treating insomnia as an independent disease rather than a symptom.