Ming-Chao Chen

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.

Evidence for an Association between Polymorphism in the Serotonin-2A Receptor Variant (102T/C) and Increment of N100Am plitude in Schizophrenics Treated with Clozapine

Using event-related potentials (ERPs), a reduction in the auditory N100, N200 and P300 amplitude has been found in schizophrenic patients and may represent some pathophysiological deficit. Therefore, we investigated whether the genetic variant of the serotonin-2A receptor is associated with ERP change after clozapine treatment in schizophrenic patients. Ninety-nine schizophrenic patients were included in the study. The results demonstrated that patients with 102C/C genotype have higher N100 amplitude than other patients after clozapine treatment. Our findings suggested that serotonin-2A receptor polymorphism may relate to clozapine response in schizophrenic patients. An objective and reliable tool like ERPs to assess patients’ treatment response may afford more consistent results in pharmacogenetic studies.

Serotonin Dysfunction and Suicide Attempts in Major Depressives: An Auditory Event-Related Potential Study

Background: Serotonergic dysfunction is believed to be involved in suicide attempts. The loudness-dependent auditory evoked potential (LDAEP) is one of the validated indicators of the activity of the central serotonin system in humans. Objectives: This study was designed to investigate possible differences in the LDAEP and P300 between those depressed patients who attempted suicide and those who did not. Methods: The LDAEP and P300 levels were recorded for 66 depressive patients (among which 16 had attempted suicide). Results: Those who had attempted suicide showed a sharper slope of the LDAEP and increased frontal P300 amplitude. A high correlation between the LDAEP and P300, and a gender difference were also noted. Conclusions: Our results are concordant with previous assumptions about serotonin dysfunction in depressives who attempt suicide.

Predictive factors for QTc prolongation in schizophrenic patients taking antipsychotics.

BACKGROUND AND PURPOSE The rate-corrected electrocardiographic QT (QTc) interval may significantly increase in schizophrenic patients taking antipsychotics. QTc prolongation is a risk factor for development of arrhythmia. The objective of this study was to assess the predictors of QTc prolongation in schizophrenic patients taking antipsychotic medication. METHODS Electrocardiograms were obtained from 138 controls and 412 schizophrenic inpatients taking antipsychotics. QTc prolongation was defined as a mean value of 2 standard deviations above the controls. Predictors were analyzed with a logistic regression model. RESULTS Based on data obtained from controls, QTc prolongation was defined as a QTc greater than 421 ms. Logistic regression analysis showed that significant predictors for QTc prolongation were: female gender (odds ratio, 3.355 [95% CI, 1.767-6.371]); increased age (1.040 [1.011-1.069]); and increased doses of some antipsychotics, including clozapine (1.006 [1.003-1.008]), chlorpromazine (1.003 [1.002-1.005]), thioridazine (1.007 [1.003-1.011]), and sulpiride (1.001 [1.001-1.002]). CONCLUSIONS Predictors of the QTc prolongation in schizophrenic patients taking antipsychotic medications were female gender, old age, and treatment with clozapine, chlorpromazine, thiroridazine, or sulpiride.

The implication of functional connectivity strength in predicting treatment response of major depressive disorder: a resting EEG study.

Predicting treatment response in major depressive disorder (MDD) has been an important clinical issue given that the initial intent-to-treat response rate is only 50 to 60%. This study was designed to examine whether functional connectivity strengths of resting EEG could be potential biomarkers in predicting treatment response at 8 weeks of treatment. Resting state 3-min eyes-closed EEG activity was recorded at baseline and compared in 108 depressed patients. All patients were being treated with selective serotonin-reuptake inhibitors. Baseline coherence and power series correlation were compared between responders and non-responders evaluated at the 8th week by Hamilton Depression Rating Scale. Pearson correlation and receiver operating characteristic (ROC) analyses were applied to evaluate the performance of connectivity strengths in predicting/classifying treatment responses. The connectivity strengths of right fronto-temporal network at delta/theta frequencies differentiated responders and non-responders at the 8th week of treatment, such that the stronger the connectivity strengths, the poorer the treatment response. ROC analyses supported the value of these measures in classifying responders/non-responders. Our results suggest that fronto-temporal connectivity strengths could be potential biomarkers to differentiate responders and slow responders or non-responders in MDD.

Association Study of a Functional MAOA-uVNTR Gene Polymorphism and Personality Traits in Chinese Young Females

Monoamine oxidase A (MAOA), a mitochondrial outer membrane enzyme, degrades biogenic amines including norepinephrine, dopamine and serotonin, which have been implicated in the expression ofpersonality traits. We tested the associations between functional MAOA-uVNTR genetic variants and personality traits in a cohort of 370 healthy young Chinese females. Subjects who were homozygous for the 4-repeat allele of the MAOA-uVNTR gene tended to have a higher total score on the Harm Avoidance (HA) dimension of the Tridimensional Personality Questionnaire (TPQ) (p = 0.056), and had a significantly higher score on subdimension 4 of HA (p = 0.020) compared with the 3-repeat carriers. No significant association was demonstrated for MAOA-uVNTR polymorphism and the other two dimensions (Novelty Seeking and Reward Dependence) of TPQ. These results suggest that genetic variants of the MAOA gene may play a role in HA, but not in Novelty Seeking or Reward Dependence.

Association Study of a Functional MAOA-uVNTR Gene Polymorphism and Cognitive Function in Healthy Females

Monoamine oxidase A (MAOA) is a mitochondrial enzyme involved in the degradation of dopamine, serotonin and norepinephrine and these neurotransmitters are hypothesized to be involved in the cognitive function of humans. This study of a cohort of 191 healthy young Chinese females attempts to utilize the intelligence quotient (IQ), Wisconsin Card Sorting Test (WCST) and P300 event-related potentials as cognitive assessments for testing the relationship between the polymorphism with a variable number of tandem repeats (VNTR) in the upstream regulatory region (MAOA-uVNTR) and cognition. The results demonstrate that subjects bearing the 4/4-repeat genotype have a significantly higher full IQ than subjects bearing the 3/3-repeat genotype. However, there is no significant association between this MAOA-uVNTR polymorphism and the WCST and P300. Our study shows that the MAOA-uVNTR genetic polymorphism plays a role in the IQ; however, this may be a chance finding as the result was negative after using the Bonferroni adjustment. Therefore, we suggest that our study should be replicated and that the testing method, sex, disease and ethnicity should also be considered in future studies.

Association analysis for serotonin transporter promoter polymorphism and auditory evoked potentials for major depression.

The serotonergic system has been implicated in the production of the N1 and P2 components of auditory evoked potentials (AEPs). Moreover, studies have indicated the influence of heritability in the genesis of these AEP components. The serotonin transporter is the major site of serotonin reuptake into the presynaptic neuron, and it has been determined that variants in the serotonin transporter gene-linked polymorphic region (5-HTTLPR) may affect gene transcription activity. The present study tested the hypothesis that the 5-HTTLPR genetic polymorphism is associated with the N1 and P2 components of AEPs in a sample of 127 Chinese patients (mean age: 41.6 years; male/female ratio: 58/69) diagnosed with major depression. Analysis of the results revealed a significantly shorter P2 latency for patients bearing the s/s genotype in comparison with l allele carriers, especially for the female patients (p = 0.004). The 5-HTTLPR polymorphism accounted for 3.4% of the variance in P2 latency. Our findings suggest a relationship between the 5-HTTLPR polymorphism and AEP P2 latency, and further studies of other genetic polymorphisms in the serotonergic system may help to predict this latency.

Association Analysis for the C-1019G Promoter Variant of the 5-HT1A Receptor Gene with Auditory Evoked Potentials in Major Depression

Involvement of the serotonergic system in N1 and P2 components of auditory evoked potentials (AEPs) has been implicated. Moreover, studies have indicated the presence of heritability in the genesis of AEP components. The serotonin 1A (5-HT1A) receptor gene is a strong candidate for N1 and P2 components of the AEPs because 5-HT1A receptor regulates the firing of serotonergic neurons. The present study tested the hypothesis that the 5-HT1A promoter genetic polymorphism (C-1019G) is associated with N1 and P2 components of AEPs in unmedicated major depression patients. The sample consisted of 221 Chinese patients (mean age: 44.3 years; male/female: 93/128) diagnosed with major depression. AEPs and 5-HT1A genotyping were done for each patient. Patients with the C/C genotype had a significantly shorter P2 latency when compared with C/G or G/G genotype patients (p = 0.049), and the difference in P2 latency was significant among the 5-HT1A genotype groups in male patients (p = 0.031) but not in female patients (p = 0.398). These findings suggest that this 5-HT1A polymorphism may affect AEP P2 latency in a gender-dependent manner. Further studies with other genetic polymorphisms in the serotonergic system may help to clarify the relation between serotonergic function and AEP components.