Ching-Hua Lin

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.

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.

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 Analysis of Brain-Derived Neurotrophic Factor Val66Met Polymorphisms with Alzheimer’s Disease and Age of Onset

Because of a decrease in central brain-derived neurotrophic factor (BDNF) levels in Alzheimer’s disease (AD) and the important role of BDNF in neuronal survival, BDNF may represent a candidate gene conferring susceptibility to AD. Recently, a functional BDNF Val66Met polymorphism has been associated with AD in an Italian population. In the present study, we investigated a possible role of this BDNF polymorphism in the susceptibility of AD or AD onset in a Chinese population. Comparing AD patients and controls, the distribution of the BDNF genotypes and alleles did not differ significantly. The onset age was not significantly different comparing the three BDNF genotype groups. Our negative findings suggest that it is unlikely that the BDNF Val66Met polymorphism plays a major role in the pathogenesis of AD in the Chinese population and do not support previous findings that homozygosity for the 66Val allele confers an increased risk for AD. Further studies with genetic variations in BDNF relating either to AD-associated depression or to the AD treatment response are suggested.

Genetic variants of the serotonin system and weight change during clozapine treatment.

Clozapine-induced weight gain may impair health and affect patient compliance. The aim of this study is to investigate the relationship between the genetic variants of the serotonin system and clozapine-induced body weight change (BWC). Ninety-three treatment-resistant schizophrenic patients were weighed monthly for 4 months during clozapine treatment. At the conclusion of treatment, patients had gained an average of 2.4 kg body weight, with BWC ranging from -17.5 to +12.9 kg. The levels of the serotonin transporter variants, serotonin 2A, serotonin 2C and serotonin 6, demonstrated no statistically significant relationship to BWC. Patients with a lower initial body mass index demonstrated a greater weight gain associated with clozapine treatment. Further exploration of the neurotransmitters implicated in the antipsychotic-induced BWC is important in order to reduce the morbidity and noncompliance associated with weight gain.

Intelligence and event-related potentials for young female human volunteer apolipoprotein E ε4 and non-ε4 carriers

Abstract The apolipoprotein E (APOE) e4 allele is associated with late-onset Alzheimers disease and cognitive function in aging normal populations. To study the effect of the presence of the e4 allele on cognitive function, we compared intelligence-test scores and component values for event-related potentials for e4 and non-e4 carriers in a group of 134 young females. The results demonstrate modest increases in performance intelligence quotient (IQ) and N100 amplitude for e4 carriers ( P =0.038 and 0.068, respectively). Our findings suggest that cognitive impairment, associated with the presence of the e4 allele, is age-dependent and thus not probable for young women. The higher performance IQ scores demonstrated for e4 carriers require further exploration.

Association analysis for NMDA receptor subunit 2B (GRIN2B) genetic variants and psychopathology and clozapine response in schizophrenia.

It is known that a syndrome resembling schizophrenia is produced by the N-methyl-d-aspartate receptor antagonists. It has also been demonstrated that the level of an ionotropic N-methyl-d-aspartate 2B subunit (GRIN2B) of the glutamate receptor tends to increase after subchronic administration of clozapine, suggesting that GRIN2B may play an active role in the pathogenesis of schizophrenia and the function of clozapine medication. We studied 100 schizophrenic patients, investigating the associations for the GRIN2B genetic variants, and psychiatric symptoms and clozapine response. No significant differences were demonstrated comparing these three groups in terms of the baseline Brief Psychiatric Rating Scale (BPRS) score (P = 0.441). The percentage of patients scoring within 20% of baseline BPRS after clozapine treatment was similar for the three genotype groups (P = 0.132). A marginally higher mean clozapine dosage was revealed, however, for patients bearing the 2664C/C genotype (P = 0.013). Although replication of this research is required to confirm the results, an association for the GRIN2B C2664T polymorphism and clozapine treatment is suggested from our findings, which may assist in the prediction of optimal dosage for schizophrenic patients.

Association analysis of polymorphism in the promoter region of the α2a-adrenoceptor gene with schizophrenia and clozapine response

There exists considerable evidence implicating the alpha (alpha) adrenergic system in the superior therapeutic effects of clozapine for the treatment of schizophrenia, as also its associated adverse hypersalivation side effect. It would seem plausible for variants of the adrenoceptors to be associated with the clozapine response. The present study tested the hypothesis that a biallelic polymorphism in the promoter region of the alpha2a-adrenoceptor gene confers susceptibility to schizophrenia, and is associated with a clozapine-induced (favorable) therapeutic response and/or a clozapine-induced hypersalivation. Ninety-seven treatment-resistant schizophrenic patients were assessed using the Brief Psychiatric Rating Scale before and after clozapine treatment. The results of clozapine treatment demonstrated that the alpha2a-adrenoceptor gene variants did not play a major role in the susceptibility, hypersalivation adverse effect or clozapine response of patients with schizophrenia. The polymorphism of the alpha2a-adrenoceptor gene investigated is not likely to play a major role in the pathogenesis of schizophrenic disorders or clozapine response, although the hypothesis that these genes are implicated in the cognitive deficit and polydipsia associated with schizophrenic disorders may, however, still warrant further study.

Brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms in Parkinson's disease and age of onset

Given the implications with respect to neuronal survival and the decreased level of the protein in the striatal region in Parkinsons disease (PD), brain-derived neurotrophic factor (BDNF) may be a candidate gene conferring susceptibility to PD. In a recent study of a Japanese population, a functional BDNF Val66Met polymorphism was associated with PD, however, an analogous investigation of a western population did not replicate this finding. In the present study of a Chinese sample, we have investigated the associations between the BDNF polymorphism and susceptibility to PD and PD onset age. The distribution of the BDNF genotypes and alleles did not differ significantly comparing PD patients and controls. Further, the onset age was not significantly different comparing the three BDNF genotype groups. Thus, our negative findings suggest that it is unlikely that the BDNF Val66Met polymorphism plays a major role in the pathogenesis of PD in the Chinese population. Other BDNF genetic variants, and the association of these variants with PD symptomatology or treatment response, may merit further investigation.

Genetic variant of the histamine-1 receptor (glu349asp) and body weight change during clozapine treatment.

Clozapine treatment frequently causes body weight gain that may impair health and may affect patient compliance. While the histamine-1 (H1) receptor may play a major role in the mechanism of the clozapine-induced body weight change, we tested the relationship between the genetic variant (Glu349Asp) of the H1 receptor and the clozapine-induced body weight change. Eighty-eight schizophrenic patients treated with clozapine were included in this study. Analysis of body weight change after 4 months of clozapine treatment showed no relationship with the H1 genotype. Further exploration of the other H1 genotypes and the antipsychotic-induced body weight change may help in the understanding of the mechanisms of antipsychotic-induced body weight gain and in the choice of patients antipsychotic regimens.