Hsin Chun Tsai

Interaction of serotonin-related genes affects short-term antidepressant response in major depressive disorder

BACKGROUND Four serotonin-related genes including guanine nucleotide binding protein beta polypeptide 3 (GNB3), 5-hydroxytryptamine receptor 1A (HTR1A; serotonin receptor 1A), 5-hydroxytryptamine receptor 2A (HTR2A; serotonin receptor 2A), and solute carrier family 6 member 4 (SLC6A4; serotonin neurotransmitter transporter) have been suggested to be candidate genes for influencing antidepressant treatment outcome. The aim of this study was to explore whether interaction among these genes could contribute to the pharmacogenomics of short-term antidepressant response in a Taiwanese population with major depressive disorder (MDD). METHODS Included in this study were 101 MDD patients who were treated with antidepressants, 35 of whom were rapid responders and 66 non-responders after 2weeks of treatment. We genotyped four single nucleotide polymorphisms (SNPs), including GNB3 rs5443 (C825T), HTR1A rs6295 (C-1019G), HTR2A rs6311 (T102C), and SLC6A4 rs25533, and employed the generalized multifactor dimensionality reduction (GMDR) method to investigate gene-gene interactions. RESULTS Single-locus analyses showed the GNB3 rs5443 polymorphism to be associated with short-term antidepressant treatment outcome (P-value=0.029). We did not correct for multiple testing in these multiple exploratory analyses. Finally, the GMDR approach identified a significant gene-gene interaction (P-value=0.025) involving GNB3 and HTR2A, as well as a significant 3-locus model (P-value=0.015) among GNB3, HTR2A, and SLC6A4. CONCLUSIONS These results support the hypothesis that GNB3, HTR2A, and SLC6A4 may play a role in the outcome of short-term antidepressant treatment for MDD in an interactive manner. Future research with independent replication using large sample sizes is needed to confirm the functions of the candidate genes identified in this study as being involved in short-term antidepressant treatment response.

Effects of C825T polymorphism of the GNB3 gene on availability of dopamine transporter in healthy volunteers - A SPECT study

Striatal dopaminergic activity is significantly correlated with various cognitive activities, mood regulation, and even metabolic homeostasis, and is modulated by the dopamine transporter (DAT). The availability of DAT could be regulated by presynaptic autoreceptors, which are G-protein coupled receptors; however, whether functional variations in the common downstream signaling molecule, G-protein, could cause individual differences in presynaptic transporter availability remains unclear. To investigate this relationship, the DAT availability in seventy-eight healthy subjects was approximated using single photon emission computed tomography (SPECT) with [(99m)Tc] TRODAT-1, a radio-labeled form of tropan derivative for the selective labeling of DAT. The C825T single nucleotide polymorphism (SNP) (rs5443) of the beta subunit of the G-protein second messenger (GNβ3) gene was genotyped, and analysis of variance showed a significant difference in striatal DAT when referenced to the entire occipital lobe among the three genotypes. Post hoc independent t tests were also performed, and showed that the striatal DAT availability of the CC genotype was higher than that of the other two genotypes. These results indicated that genetic variation in the common downstream signaling molecule of the dopamine autoreceptor could affect the functional status of the striatal dopamine system. These results together with the known role of the GNβ3 gene might provide further evidence to support the common effect of the striatal dopamine system on mood and metabolic regulation.

C825T polymorphism of the GNB3 gene on valproate-related metabolic abnormalities in bipolar disorder patients.

Background: Valproate (VPA) is a mood stabilizer for treating patients with bipolar disorder (BD). It may cause metabolic abnormalities in certain bipolar patients. However, the genetic factors that influence the susceptibility remain unclear. Genetic polymorphism of the G-protein &bgr;3 subunit (GNB3) is reported to be associated with metabolic phenotypes. In the current study, we investigated the possible associations between the GNB3 variation and VPA-induced metabolic abnormalities. Methods: Subjects (n = 96) who met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for BD were recruited from the National Cheng Kung University Hospital. Their metabolic indices were measured. Results: The variation of GNB3 C825T showed an association with higher plasma total cholesterol (P = 0.037), triglyceride (P = 0.014), and leptin (P < 0.001) levels in BD patients treated with VPA. After adjusting for age, sex, types of BDs, and serum concentration of VPA, the variation of GNB3 C825T remained significantly associated with the levels of serum leptin and body mass index (BMI; P < 0.001 and P = 0.030, respectively). In addition, the GNB3 C825T showed significant drug-single-nucleotide polymorphism interactions with insulin levels (P = 0.033), triglyceride levels (P = 0.013), leptin levels (P = 0.013), and BMI (P = 0.018). These results indicated that the T allele may be associated with lower serum leptin levels and BMI in BD patients treated with VPA. Conclusions: The current study provides evidence that BD patients who are T allele carriers of the GNB3 C825T polymorphism have a lower risk for VPA-induced metabolic abnormalities. Further studies about the underlying mechanisms of G protein in VPA-induced metabolic abnormalities are warranted.

Association between serotonin transporter availability and overall rating scores of quality of life in healthy volunteers.

Depression and impaired quality of life (QOL) are frequently observed in patients suffering from a variety of diseases. In addition, it has been reported that an enhanced degradation of the serotonin precursor tryptophan may contribute to QOL deterioration in some diseases. However, it is unclear whether the correlation between the QOL scores and the central serotonergic tone is only mediated by the severity of either the depression symptoms or the physical illness itself. The present study examined the relationship between serotonin transporter (SERT) availability and life quality as measured by the World Health Organization Quality of Life brief version questionnaire (WHO-QOL) in healthy participants in order to exclude the influence of depressive mood and disease. The SERT availability in the midbrain was approximated using SPECT with [(123)I] ADAM ligand in fifty-eight healthy volunteers. The overall rating sub scores of the WHO-QOL correlated positively with serotonin transporter availability in the males. Central serotoninergic activity may play a role in the overall rating scores of the WHO-QOL.

The prevalence of metabolic syndrome in drug-naive bipolar II disorder patients before and after twelve week pharmacological intervention

BACKGROUND Accumulating evidence indicates a high prevalence rate of metabolic disturbance in bipolar disorder (BP) patients. However, the prevalence across BP subtypes has been investigated to a lesser degree. In the current study, we surveyed the prevalence of metabolic syndrome among drug-naïve bipolar II patients. Moreover, the effects of pharmacological treatment on metabolic indexes were also evaluated. METHODS This study recruited fifty-six drug-naïve BP II patients diagnosed according to the DSM-IV criteria. Among them, forty-four patients completed a 12-week pharmacological intervention with valproic acid, fluoxetine and lorazepam. Metabolic profiles and body mass index (BMI) were measured at baseline and 2 weeks, 8 weeks, and 12 weeks after receiving medication. RESULTS The mean age of the 56 patients was 30.3±11.1. Before receiving medication, 6.5% of the patients met the ATP III criterion for metabolic syndrome. Among the 44 patients who completed the 12-week pharmacological intervention, the prevalence of metabolic syndrome increased from 7% to 10%. Repeated measurements showed that the changes in metabolic indexes were not significant, with the exceptions of BMI, waist circumference, and buttock circumference. In addition, the interaction between the improvement of hypomanic symptoms and BMI change was significant. LIMITATIONS The study was limited by the follow-up duration and sample size. CONCLUSIONS In drug-naïve BP II patients, the prevalence of metabolic syndrome was significantly lower than that observed before in BP I patients. However, medications use was also associated with an increased risk of metabolic disturbance, although the impact was lesser. Clinical evidence suggests that metabolism and emotion homeostasis might share common mechanisms.

The change of insulin levels after six weeks antidepressant use in drug-naïve major depressive patients.

BACKGROUND A reciprocal relationship between diabetes risk and depression has been reported. There are few studies investigating glucose-insulin homeostasis before and after short-term antidepressant treatment in drug-naïve major depressive disorder (MDD) patients. METHODS This study included 104 healthy controls and 50 drug-naïve MDD patients diagnosed according to the DSM-IV criteria. These MDD patients were randomly assigned to receive fluoxetine or venlafaxine for six weeks. Depressive symptoms, body mass index, fasting plasma levels of glucose and insulin were measured. RESULTS Compared to the healthy controls, the fasting plasma insulin and the homeostasis model of assessment for pancreatic β-cell secretory function (HOMA-β) was significantly lower in the MDD patients before antidepressant treatment (7.7±4.8 μIU/mL vs. 5.1±4.2 μIU/mL, p=0.006; 114.2±72.3% vs. 74.8±52.0%, p=0.005, respectively). However, these indices were not correlated with depression severity. After 6 weeks of fluoxetine or venlafaxine treatment, the level of HOMA-β borderline significantly increased (108.1±75.5%, p=0.059). LIMITATIONS The study was limited by the follow-up duration and lack of a placebo group. CONCLUSIONS Antidepressants might affect insulin secretion independently of the therapeutic effects on MDD. Further studies are needed to investigate the long-term effects of antidepressants on insulin regulation in MDD patients.

Sex-specific associations between plasma oxytocin levels and schizotypal personality features in healthy individuals

OBJECTIVES Oxytocin (OT) has been shown to play a crucial role in the biology of social interaction. Sex differences associated with this neuropeptide system have been reported. OT may serves as an indicator of interpersonal stress, especially in women. The aim of this study was to investigate the sex-specific associations between plasma OT levels and schizotypal personality features, especially in interpersonal dimension, in healthy individuals. METHODS Ninety six healthy participants, including 41 males and 55 females, were recruited. Fasting blood samples were analyzed by enzyme immunoassay of OT. The Schizotypal Personality Questionnaire (SPQ) was administered. Mann-Whitney U test was used to test the difference between male and female. Spearmans ρ correlation analysis (two-tailed) was carried out to examine the association between OT level and SPQ score. RESULTS The results showed that OT level was significantly positively correlated with total score and interpersonal dysfunction dimensional scores of the SPQ only in females. CONCLUSIONS Although the causal relationship remains unclear, our findings provide further evidence to support the sexual dimorphic role of OT in interpersonal biology. Moreover, the effect of sex difference also is taken into consideration.

Association between Blood Level of Plasma Oxytocin and Novelty Seeking among Methadone-Maintained Heroin Users

Background: Oxytocin interacts with the dopaminergic system, which plays a role in addiction behaviors. The association between oxytocin and addiction was confirmed in animal studies. Novelty seeking is one of the predictors and indicators of drug addiction. The aim of the present study was to probe the association between oxytocin and novelty seeking. Methods: The study was conducted in a methadone maintenance therapy clinic of a medical center in Taiwan; 77 patients with heroin dependency were enrolled. Plasma oxytocin was measured using an ELISA kit. Novelty seeking was measured using an established instrument (the novelty seeking subscale of the Tridimensional Personality Questionnaire). Results: A significant negative association (ρ = -0.27, p = 0.02; r = -0.34, p = 0.003) between the blood level of plasma oxytocin and novelty seeking was found. This association was significant after controlling the effects of perceived social support and the dosage of methadone (r = -0.32, p = 0.006). Conclusion: The negative association between oxytocin and novelty seeking may provide insight into future treatments for addiction.

The readmission rate and medical cost of patients with schizophrenia after first hospitalization - A 10-year follow-up population-based study

BACKGROUND Hospital readmissions caused by relapse in patients with schizophrenia are associated with prognosis. Identifying individuals at high risk of readmission and providing interventions to lower the readmission rate are important. METHODS Patients with schizophrenia who were hospitalized for the first time were recruited from the National Health Insurance Research Database from 2001 to 2010 (n=808, mean age 28.9years) and compared with matched controls. Data on the demographics, cost, and utilization of medical resources of patients who were readmitted were compared with non-readmitted patients. The readmission time curve was analyzed by the Kaplan-Meier method. RESULT 570 (70.5%) patients were readmitted within 10years; the median time between admissions was 1.9years, and 25% of subjects were readmitted within 4months of the first hospitalization. There were no significant differences in age, gender, or length of hospitalization between the readmission and non-readmission groups. Taking into account all psychiatric medical services, the readmission group had a significantly higher mean frequency of care and a greater medical cost than the non-readmission group and matched controls. However, there were no significant differences with regard to non-psychiatric medical services. CONCLUSION Schizophrenia has a high rate of readmission and high medical cost in naturalistic settings. In addition to the traditional hospital-based treatment model for patients with schizophrenia, the development of an effective intervention program is important, especially in the early years of the disease.

Lower availability of striatal dopamine transporter in generalized anxiety disorder: A preliminary two-ligand SPECT study

Dopamine and serotonin have been indirectly found to be associated with generalized anxiety disorder (GAD). The aims of this study were to examine the availabilities of the striatal dopamine transporter (DAT) and the midbrain serotonin transporter (SERT) in patients with GAD. 12 patients with GAD and 12 sex-matched, age-matched, and smoking status-matched healthy controls were recruited. The availabilities of DAT and SERT were approximated using single-photon emission computed tomography, with [99mTc]TRODAT-1 and [123I]ADAM as the ligands. There were several missing data for six participants with GAD in the ADAM study because of a lack of the radioligand at the time of the experiment. The DAT availability in the striatum was significantly lower in the patients with GAD than in the healthy controls. However, the SERT availability did not differ between the two groups. The results with respect to the striatal DAT level suggested a potential role in the pathophysiology of GAD.