Yeon Ho Joo

Association of the Glutamate Transporter Gene SLC1A1 With Atypical Antipsychotics-Induced Obsessive-compulsive Symptoms

CONTEXT Several studies have indicated that atypical antipsychotics (AAP) induce obsessive-compulsive (OC) symptoms. Research exploring the mechanism of this phenomenon, however, has been extremely limited. Considering the indirect evidence of genetic control and difficulties in developing animal models and performing gene expression studies, genetic association studies could be an important approach to understanding the molecular mechanism of AAP-induced OC symptoms. The glutamate transporter gene SLC1A1, which was recently reported to be associated with obsessive-compulsive disorder (OCD), is a promising candidate gene for susceptibility to AAP-induced OC symptoms. OBJECTIVE To determine whether polymorphisms in SLC1A1 are associated with AAP-induced OC symptoms in patients with schizophrenia. DESIGN A pharmacogenetic case-control association study. SETTING Outpatient schizophrenia clinics. PATIENTS Clinically stable patients with schizophrenia who were receiving AAP treatment (n = 94; OC group). The OC group consisted of 40 patients with AAP-induced OC symptoms, and the non-OC group consisted of 54 patients who had received AAP for more than 24 months without developing OC symptoms. MAIN OUTCOME MEASURES Allele, genotype, and haplotype frequencies. The association was tested with a logistic regression model using age, sex, and medication type as covariates. RESULTS Trends of association were observed in rs2228622 and rs3780412 (nominal P = .01; adjusted permutation P = .07) for the dominant model that was the inheritance model that best fit our data. In the haplotype -based analysis, the A/C/G haplotype at rs2228622-rs3780413-rs3780412 showed a significant association with AAP-induced OC symptoms; this association withstood multiple test correction (nominal P = .01; adjusted permutation P = .04; odds ratio, 3.955; 95% confidence interval, 1.366-11.452, for dominant model). CONCLUSIONS These results suggest that sequence variations in SLC1A1 are associated with susceptibility to AAP-induced OC symptoms. This is the first published pharmacogenetic study on this phenomenon and provides preliminary evidence of the involvement of glutamatergic neurotransmission in the pathogenesis of AAP-induced OC symptoms.

Brain-derived neurotrophic factor Val/Met polymorphism and bipolar disorder. Association of the Met allele with suicidal behavior of bipolar patients.

Background/Aims: The substitution of valine by methionine in the brain-derived neurotrophic factor (BDNF Val/Met) gene alters the intracellular trafficking and regulated secretion of BDNF. This study tested whether the BDNF Val/Met polymorphism is associated with bipolar disorder in Korean subjects, and whether clinical features vary according to genotype. Methods: The allelic and genotypic distributions of BDNF Val/Met were determined in a population of 169 bipolar patients and 251 normal controls. Between-genotype comparisons of clinical features were performed without a priori knowledge of the genotype of individual patients. Results: Allelic distributions did not differ significantly between bipolar patients and controls (χ2 = 0.400, p = 0.821). However, the rate of suicide attempts among the Val/Val (11.3%), Val/Met (28.8%) and Met/Met (38.9%) genotype groups were significantly different (χ2 = 9.879, p = 0.007). Relative to patients with the Val/Val genotype, those with the Met/Met genotype had a 4.9-fold higher risk of suicide attempts (95% CI, 1.7–14.7). Conclusions: These findings suggest that BDNF Val/Met is related to the suicidal behavior of bipolar patients, and may have clinical relevance as a biological indicator of bipolar patients at risk of suicide.

Bipolarity in depressive patients without histories of diagnosis of bipolar disorder and the use of the Mood Disorder Questionnaire for detecting bipolarity

OBJECTIVES The present study was performed to evaluate the frequency of bipolar disorders among patients (a) presenting with depressive episodes but (b) who have never been diagnosed with bipolar disorder (c) in routine clinical practice in Korean subjects and to identify which clinical features were helpful in discriminating bipolar patients from unipolar patients. In addition, authors assessed the practical use of the Mood Disorder Questionnaire (MDQ) to distinguish bipolar from unipolar disorder in these subjects and tested whether modifications of the MDQ scoring could improve its performance. METHODS We evaluated consecutive patients who satisfied the inclusion criteria of a current depressive episode, plus at least one previous depressive episode. Subjects were interviewed for diagnosis using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders IV after completing the MDQ. To improve assessment of hypomania history, the interviewer made strenuous efforts to explore a possible history of hypomania, and patient-derived data were supplemented by information from family members or close relatives. RESULTS Fifty-nine patients (53.2%) were classified as having bipolar disorder, leaving a group of 52 (46.8%) with unipolar depression. Among bipolar disorders, 1.8% (n = 2) had bipolar I disorder; 29.7% (n = 33), bipolar II disorder; 6.3% (n = 7), bipolar III disorder (history of antidepressant-induced hypomania without spontaneous hypomanic episode); and 15.3% (n = 17), bipolar disorder not otherwise specified (1-3 days brief hypomania). Postpartum depression (relative risk [RR] [95% confidence interval {CI}], 2.00 [1.23-3.24]), early age of onset (RR [95% CI], 1.85 [1.30-2.64]), mood lability (RR [95% CI], 1.85 [1.30-2.64]), brief depressive episode (RR [95% CI], 1.66 (1.16-2.37]), bipolar family history (RR [95% CI], 1.62 [1.08-2.43]), history of suicide attempt (RR [95% CI], 1.47 (1.05-2.04]), and alcohol problem (RR [95% CI], 1.45 (1.04-2.02]) were found to have higher risks for bipolar disorder among depressive subjects. We found that a modified scoring of the MDQ (ignoring question on functional impairment and co-occurrence of symptoms) yielded a sensitivity of 0.68 and a specificity of 0.63 for bipolar diagnosis, whereas the figures were 0.29 and 0.77, respectively, with the standard MDQ scoring. CONCLUSIONS The results of this study clearly indicate that a high frequency of bipolar disorders in depressive patients who have never been diagnosed with bipolar disorders and clinical features indicating bipolarity could help to differentiate bipolar subjects from unipolar subjects. Adapting the standard scoring, the MDQ showed limited use for detecting bipolar disorder; however, if the scoring modification is adapted, the MDQ can offer tolerable sensitivity.

Interaction between genetic variants of DLGAP3 and SLC1A1 affecting the risk of atypical antipsychotics-induced obsessive-compulsive symptoms.

Adverse effects of atypical antipsychotics (AAP) can include obsessive–compulsive (OC) symptoms. Based on biological evidence of the relationship between the glutamatergic system and both OC disorder and AAP, this study aimed to determine whether DLGAP3, coding a post‐synaptic scaffolding protein of glutamatergic synapses, is associated with AAP‐induced OC symptoms. Furthermore, we explored the interactions between DLGAP3 and a previously reported susceptibility gene, the glutamate transporter gene SLC1A1, regarding this phenotype. Subjects were clinically stable schizophrenia patients receiving AAP treatment (n = 94), and they comprised an OC group (n = 40) and a non‐OC group (n = 54) (patients with and without AAP‐induced OC symptoms, respectively). We performed allelic/genotypic/haplotype association analyses for seven tag single‐nucleotide polymorphisms of DLGAP3 and gene–gene interaction analyses with rs2228622 of SLC1A1, observing a nominally significant association between AAP‐induced OC symptoms and rs7525948 in both simple chi‐square tests and the regression analyses (nominal P < 0.05). In the logistic regression analysis of gene–gene interaction, we found a significant interaction effect of rs7525948 of DLGAP3 and rs2228622 of SLC1A1 (permutation P = 0.036) on AAP‐induced OC symptoms, with a 30.2 times higher odds for individuals carrying risk genotypes at both loci in comparison with the reference group, which had no risk genotypes. This study provides suggestive evidence that DLGAP3 and its interactive effect with SLC1A1 might be involved in susceptibility to developing OC symptoms in schizophrenia patients receiving AAP treatment.

Correlates of metabolic abnormalities in bipolar I disorder at initiation of acute phase treatment.

Objective Treatment of bipolar patients is often complicated by metabolic abnormalities such as obesity, diabetes, and dyslipidemia. We therefore evaluated the prevalence of these abnormalities and their correlates, in bipolar I patients, at the time of commencement of pharmacological treatment for acute mood episodes. Methods The study cohort consisted of 184 bipolar I patients hospitalized for treatment of acute mood episodes. Socio-demographic and clinical variables were noted and metabolic parameters, including body mass index, fasting plasma glucose, fasting total cholesterol, and current treatment(s) for diabetes and/or dyslipidemia were measured before initiating medication(s). Results Fifty-six (30.4%) subjects met our criteria for obesity; 80 (43.5%) had hyperglycemia, with 8 (4.3%) receiving anti-diabetic medication; and 38 (20.7%) had hypercholesterolemia, with 2 (1.1%) receiving cholesterol-lowering agents. We found that male sex (χ2=5.359, p=0.021), depressed or mixed state versus manic state (χ2=4.302, p=0.038), and duration of illness (t=2.756, p=0.006) were significantly associated with obesity. Older age (t=3.668, p<0.001), later age of disease onset (t=2.271, p=0.024), and lower level of educational attainment (β=-0.531, p=0.001) were associated with hyperglycemia. Conclusion Our finding that metabolic abnormalities are prevalent when initiating acute pharmacological treatment in bipolar I patients indicates that these factors should be integrated into treatment plans at the onset of disease management.

Heart rate variability in the subsyndromal depressive phase of bipolar disorder

Aims:  To compare the heart rate variability of bipolar patients in the subsyndromal depressive phase with healthy controls and to evaluate the relationship between severity of subsyndromal depressive symptoms and heart rate variability.

Personality traits and affective morbidity in patients with bipolar I disorder: The five-factor model perspective

In this study, we aimed to extend the present knowledge regarding the relationship of personality traits, as specified by the five-factor model (FFM), with the affective morbidity of bipolar I disorder. The primary aim of this study is to investigate the association of personality traits with affective morbidity, particularly with hospitalization for depressive, manic, or mixed episodes, in patients with bipolar I disorder. The Revised NEO Personality Inventory was administered to 83 subjects who showed a euthymic mood state. Multivariate Poisson regression analysis was performed to identify associations between five domains of personality and the number of hospitalizations for affective episode(s) (manic, depressive, and mixed state). As a secondary research interest, we attempted to determine personality traits which would be significantly different between subjects with Affective Switch from mania into depression Without Euthymia (ASWE) and non-ASWE. The Neuroticism score was positively associated with the number of hospitalization for depression and the total number of hospitalizations Extraversion and Openness scores showed a negative relationship with the number of hospitalizations for depression and the total number of hospitalizations. We found that ASWE patients showed significantly higher Neuroticism scores than did the non-ASWE group. However, there was no significant association between the hospitalization for manic episode and any particular personality trait based on the FFM. This study reveals that personality traits based on the FFM may contribute to an increased likelihood of depressive morbidity and switch into depression.

Genetic Polymorphisms in the HTR2C and Peroxisome Proliferator-Activated Receptors Are Not Associated with Metabolic Syndrome in Patients with Schizophrenia Taking Clozapine

Objective Genetic variation in the serotonin-2C receptor encoded by the HTR2C gene is one of the genetic determinants of antipsychotic-induced weight gain. Peroxisome proliferator-activated receptors are nuclear receptors regulating the expression of genes involved in lipid and glucose metabolism. In this cross-sectional study, we investigated whether HTR2C-759C/T, HTR2C-697G/C, PPARα V227A, and PPARγ 161C/T genotypes were associated with metabolic syndrome (MetS) in patients with schizophrenia taking clozapine. Methods One hundred forty-six Korean patients using clozapine for more than one year were genotyped for the HTR2C-759C/T, HTR2C-697G/C, PPARα V227A, and PPARγ 161C/T polymorphisms, and their weight, waist circumference, blood pressure, triglycerides, high-density lipoprotein-cholesterol, total cholesterol, and glucose were measured. We used the criteria for MetS proposed by the National Cholesterol Education Program-adapted Adult Treatment Panel III. Results The prevalence of MetS was 47.3% and was similar among men (49%) and women (42.9%). We found no significant differences between patients with and without MetS in terms of genotypes or allele frequencies. Logistic regression analyses also revealed no association between MetS and each genotype. Conclusion We did not find significant associations between four polymorphisms (HTR2C-759C/T, HTR2C-697G/C, PPARα V227A, and PPARγ 161C/T) and MetS in patients with schizophrenia taking clozapine.

Partial evidence of an association between epidermal growth factor A61G polymorphism and age at onset in male schizophrenia

Epidermal growth factor (EGF) is a well-known neurotrophic factor regulating the development of various neuronal cells, including dopaminergic neurons, and dysfunction of EGF signals has been demonstrated as a risk factor for schizophrenia. Recently, several researchers have investigated associations including age at onset (AAO) with EGF A61G functional polymorphism, but the results of these studies have been controversial. Thus, we investigated whether A61G plays a role in predisposition to schizophrenia and its effects on AAO. Our subjects included 190 patients with schizophrenia and 347 controls. We assessed three different points of AAO: age at first occurrence of positive psychotic symptoms, medication, and hospitalization as a patient with schizophrenia. We found no differences in allele and genotype frequencies between patients and controls or associations between A61G and AAOs across stratified points in the entire sample and in each gender. However, we found significant gender differences in patients with the AA genotype in all stratified points of AAOs. Subset analyses of G allele distribution between clinical subsets with an AAO cutoff of 20 years revealed that male patients with early onset schizophrenia were more likely to exhibit the common AA homozygote than male patients with adulthood onset schizophrenia. In conclusion, although we were unable to support an association between EGF A61G and schizophrenia, the AA genotype might play a disease-modifying role differentially according to gender.

Comparative Study of Personality Traits in Patients with Bipolar I and II Disorder from the Five-Factor Model Perspective

Objective The distinguishing features of Bipolar I Disorder (BD I) from Bipolar II Disorder (BD II) may reflect a separation in enduring trait dimension between the two subtypes. We therefore assessed the similarities and differences in personality traits in patients with BD I and BD II from the perspective of the Five-Factor Model (FFM). Methods The revised NEO Personality Inventory (NEO-PI-R) was administered to 85 BD I (47 females, 38 males) and 43 BD II (23 females, 20 males) patients. All included patients were in remission from their most recent episode and in a euthymic state for at least 8 weeks prior to study entry. Results BDII patients scored higher than BD I patients on the Neuroticism dimension and its four corresponding facets (Anxiety, Depression, Self-consciousness, and Vulnerability). In contrast, BD II patients scored lower than BD I patients on the Extraversion dimension and its facet, Positive emotion. Competence and Achievement-striving facets within the Conscientiousness dimension were significantly lower for BD II than for BD I patients. There were no significant between-group differences in the Openness and Agreeableness dimensions. Conclusion Disparities in personality traits were observed between BD I and BD II patients from the FFM perspective. BD II patients had higher Neuroticism and lower Extraversion than BD I patients, which are differentiating natures between the two subtypes based on the FFM.