Association between the Arylalkylamine N-Acetyltransferase (AANAT) Gene and Seasonality in Patients with Bipolar Disorder

Objective@#Bipolar disorder (BD) is complex genetic disorder. Therefore, approaches using clinical phenotypes such as biological rhythm disruption could be an alternative. In this study, we explored the relationship between melatonin pathway genes with circadian and seasonal rhythms of BD. @*Methods@#We recruited clinically stable patients with BD (n=324). We measured the seasonal variation of mood and behavior (seasonality), and circadian preference, on a lifetime basis. We analyzed 34 variants in four genes (MTNR1a, MTNR1b, AANAT, ASMT) involved in the melatonin pathway. @*Results@#Four variants were nominally associated with seasonality and circadian preference. After multiple test corrections, the rs116879618 in AANAT remained significantly associated with seasonality (corrected p=0.0151). When analyzing additional variants of AANAT through imputation, the rs117849139, rs77121614 and rs28936679 (corrected p=0.0086, 0.0154, and 0.0092) also showed a significant association with seasonality. @*Conclusion@#This is the first study reporting the relationship between variants of AANAT and seasonality in patients with BD. Since AANAT controls the level of melatonin production in accordance with light and darkness, this study suggests that melatonin may be involved in the pathogenesis of BD, which frequently shows a seasonality of behaviors and symptom manifestations.

Association between the Arylalkylamine N-Acetyltransferase (AANAT) Gene and Seasonality in Patients with Bipolar Disorder

Objective@#Bipolar disorder (BD) is complex genetic disorder. Therefore, approaches using clinical phenotypes such as biological rhythm disruption could be an alternative. In this study, we explored the relationship between melatonin pathway genes with circadian and seasonal rhythms of BD. @*Methods@#We recruited clinically stable patients with BD (n=324). We measured the seasonal variation of mood and behavior (seasonality), and circadian preference, on a lifetime basis. We analyzed 34 variants in four genes (MTNR1a, MTNR1b, AANAT, ASMT) involved in the melatonin pathway. @*Results@#Four variants were nominally associated with seasonality and circadian preference. After multiple test corrections, the rs116879618 in AANAT remained significantly associated with seasonality (corrected p=0.0151). When analyzing additional variants of AANAT through imputation, the rs117849139, rs77121614 and rs28936679 (corrected p=0.0086, 0.0154, and 0.0092) also showed a significant association with seasonality. @*Conclusion@#This is the first study reporting the relationship between variants of AANAT and seasonality in patients with BD. Since AANAT controls the level of melatonin production in accordance with light and darkness, this study suggests that melatonin may be involved in the pathogenesis of BD, which frequently shows a seasonality of behaviors and symptom manifestations.

Effect of Delayed Clozapine Initiation on Acute Treatment Response in Treatment-Resistant Schizophrenia / 대한정신분열병학회지

Objectives@#Recent studies have reported that delayed initiation of clozapine can affect clinical response in patients with treatment-resistant schizophrenia (TRS). This study aimed to explore the relationship between delayed initiation of clozapine and acute treatment response. @*Methods@#Sixty-five inpatients with TRS who started clozapine for the first time were included through a retrospective chart review. Acute treatment response was defined as a 30% reduction in the Positive and Negative Syndrome Scale score or a Clinical Global Impression of Improvement score of 1 (very much improved) or 2 (much improved) at 4 weeks after initiating clozapine. @*Results@#After meeting the TRS criteria, the mean delay for initiating clozapine was approximately 13.8 months. The delay was shorter in patients who showed a better response to clozapine in logistic regression analysis (p=0.037). @*Conclusion@#Our findings suggest that reducing the delay in initiating clozapine increases the effectiveness of clozapine in patients with TRS.

Association between a Genetic Variant of CACNA1C and the Risk of Schizophrenia and Bipolar I Disorder Across Diagnostic Boundaries / 대한정신분열병학회지

OBJECTIVES: Genome-wide association studies (GWASs) and meta-analyses indicate that single-nucleotide polymorphisms (SNPs) in the a-1C subunit of the L-type voltage-dependent calcium channel (CACNA1C) gene increase the risk for schizophrenia and bipolar disorders (BDs). We investigated the association between the genetic variants on CACNA1C and schizophrenia and/or BDs in the Korean population. METHODS: A total of 582 patients with schizophrenia, 336 patients with BDs consisting of 179 bipolar I disorder (BD-I) and 157 bipolar II disorder (BD-II), and 502 healthy controls were recruited. Based on previous results from other populations, three SNPs (rs10848635, rs1006737, and rs4765905) were selected and genotype-wise association was evaluated using logistic regression analysis under additive, dominant and recessive genetic models. RESULTS: rs10848635 showed a significant association with schizophrenia (p=0.010), the combined schizophrenia and BD group (p=0.018), and the combined schizophrenia and BD-I group (p=0.011). The best fit model was dominant model for all of these phenotypes. The association remained significant after correction for multiple testing in schizophrenia and the combined schizophrenia and BD-I group. CONCLUSION: We identified a possible role of CACNA1C in the common susceptibility of schizophrenia and BD-I. However no association trend was observed for BD-II. Further efforts are needed to identify a specific phenotype associated with this gene crossing the current diagnostic categories.

Long-Term Treatment Response to Lithium and Valproate in Patients with Bipolar 1 Disorder Treated More Than 2 Years : A Retrospective Study

OBJECTIVES: Treatment response of bipolar disorders (BDs) to long-term mood stabilizers maintenance has not been well explored because of complicated clinical and treatment courses. This study aims at investigating long-term clinical response of BDs to lithium and/or valproate in a naturalistic setting of a tertiary-care university-affiliated hospital. METHODS: Subjects were 65 patients with bipolar I (BD-I) disorders who had been treated with lithium and/or valproate for more than two years at single bipolar disorder clinic. Long-term response to the best treatment based on treatment algorithms and the current clinical standard of care was retrospectively evaluated using the Alda Scale and the Clinical Global Impression Scale for use in bipolar illness (CGI-BP). Patients were classified into full responder and partial/non responder groups based on the total score of the Alda Scale with the cut-off score generated from the frequentist mixture analysis of the authors' previous study. RESULTS: The mean duration of treatment with the index medication was 69.2 months. Baseline demographic and clinical characteristics were not different among three mood stabilizer groups (valproate, lithium, and combination groups). Twenty-one subjects were classified into full responder group (32.3%). Treatment response assessed by the Alda Scale and CGI-BP scores was not different between lithium and valproate groups. The Alda Scale scores were well correlated with the CGI-BP scores (p < 0.05). CONCLUSIONS: One third of the patients showed a full response to the long-term lithium and/or valproate treatment in BD-I. The degree of response was similar between lithium and valproate groups.

Association Study of ANK3 Polymorphism and Risk of Schizophrenia

OBJECTIVES: Previous genome-wide association studies have indicated the association between ankyrin 3 (ANK3) and the vulnerability of schizophrenia. We investigated the association between single nucleotide polymorphisms (SNPs) covering the whole ANK3 locus and schizophrenia in the Korean population. METHODS: The study subjects were 582 patients with schizophrenia and 502 healthy controls. Thirty-eight tag SNPs on ANK3 and five additional SNPs showing significant association with schizophrenia in previous studies were genotyped. RESULTS: Three (rs10994181, rs16914791, rs1938526) of 43 SNPs showed a nominally significant association (p < 0.05) with at least one genotype model. But none of these associations remained significant after adjusting for multiple testing errors with Bonferroni's correction. CONCLUSIONS: We could not identify a significant association between ANK3 and schizophrenia in the Korean population. However, three SNPs showing an association signal with nominal significance need to be investigated in future studies with higher statistical power and more specific phenotype crossing the current diagnostic categories.