Chul Hyun Cho

Oxidative stress and tardive dyskinesia: pharmacogenetic evidence.

Tardive dyskinesia (TD) is a serious adverse effect of long-term antipsychotic use. Because of genetic susceptibility for developing TD and because it is difficult to predict and prevent its development prior to or during the early stages of medication, pharmacogenetic research of TD is important. Additionally, these studies enhance our knowledge of the genetic mechanisms underlying abnormal dyskinetic movements, such as Parkinsons disease. However, the pathophysiology of TD remains unclear. The oxidative stress hypothesis of TD is one of the possible pathophysiologic models for TD. Preclinical and clinical studies of the oxidative stress hypothesis of TD indicate that neurotoxic free radical production is likely a consequence of antipsychotic medication and is related to the occurrence of TD. Several studies on TD have focused on examining the genes involved in oxidative stress. Among them, manganese superoxide dismutase gene Ala-9Val polymorphisms show a relatively consistent association with TD susceptibility, although not all studies support this. Numerous pharmacogenetic studies have found a positive relationship between TD and oxidative stress based on genes involved in the antioxidant defense mechanism, dopamine turnover and metabolism, and other antioxidants such as estrogen and melatonin. However, many of the positive findings have not been replicated. We expect that more research will be needed to address these issues.

Exposure to dim artificial light at night increases REM sleep and awakenings in humans

ABSTRACT Exposure to artificial light at night (ALAN) has become increasing common, especially in developed countries. We investigated the effect of dALAN exposure during sleep in healthy young male subjects. A total of 30 healthy young male volunteers from 21 to 29 years old were recruited for the study. They were randomly divided into two groups depending on light intensity (Group A: 5 lux and Group B: 10 lux). After a quality control process, 23 healthy subjects were included in the study (Group A: 11 subjects, Group B: 12 subjects). Subjects underwent an NPSG session with no light (Night 1) followed by an NPSG session randomly assigned to two different dim light conditions (5 or 10 lux, dom λ: 501.4 nm) for a whole night (Night 2). We found significant sleep structural differences between Nights 1 and 2, but no difference between Groups A and B. Exposure to dALAN during sleep was significantly associated with increased wake time after sleep onset (WASO; F = 7.273, p = 0.014), increased Stage N1 (F = 4.524, p = 0.045), decreased Stage N2 (F = 9.49, p = 0.006), increased Stage R (F = 6.698, p = 0.017) and non-significantly decreased REM density (F = 4.102, p = 0.056). We found that dALAN during sleep affects sleep structure. Exposure to dALAN during sleep increases the frequency of arousals, amount of shallow sleep and amount of REM sleep. This suggests adverse effects of dALAN during sleep on sleep quality and suggests the need to avoid exposure to dALAN during sleep.

Association between restless legs syndrome and CLOCK and NPAS2 gene polymorphisms in schizophrenia

Previous studies have suggested that there is a genetic basis to restless legs syndrome (RLS) development. Occurrence of antipsychotic-induced RLS could also be due to differences in genetic susceptibility. We investigated whether CLOCK and NPAS2 gene polymorphisms are associated with RLS in schizophrenic patients on antipsychotics because RLS symptoms usually manifest during the evening and night. We assessed symptoms of RLS in 190 Korean schizophrenic patients on antipsychotics and divided the subjects into two groups according to the International Restless Legs Syndrome Study Group diagnostic criteria: (i) subjects who met all the criteria and (ii) the remaining subjects who did not meet all the criteria. We found a significant difference in the number of subjects with different genotype and allele carrier frequencies for the CLOCK gene (rs2412646) between the two groups (p = 0.031 and 0.010, respectively). Distribution of CLOCK haplotypes (rs2412646–rs1801260) was significantly different between schizophrenic patients with and without RLS (p = 0.021). However, the distributions of allelic, genotypic, and haplotypic variants of NPAS2 (rs2305160 and rs6725296) were not significantly different between the two groups. Our results suggest that CLOCK polymorphisms are associated with increased susceptibility of schizophrenic patients to RLS. We hypothesize that RLS in schizophrenia patients treated with antipsychotics may be a very mild akathisia that manifests during the night and is under control of circadian oscillation.

Advanced Circadian Phase in Mania and Delayed Circadian Phase in Mixed Mania and Depression Returned to Normal after Treatment of Bipolar Disorder.

Disturbances in circadian rhythms have been suggested as a possible cause of bipolar disorder (BD). Included in this study were 31 mood episodes of 26 BD patients, and 18 controls. Circadian rhythms of BD were evaluated at admission, at 2-week intervals during hospitalization, and at discharge. All participants wore wrist actigraphs during the studies. Saliva and buccal cells were obtained at 8:00, 11:00, 15:00, 19:00, and 23:00 for two consecutive days. Collected saliva and buccal cells were used for analysis of the cortisol and gene circadian rhythm, respectively. Circadian rhythms had different phases during acute mood episodes of BD compared to recovered states. In 23 acute manic episodes, circadian phases were ~ 7 hour advanced (equivalent to ~ 17 hour delayed). Phases of 21 out of these 23 cases returned to normal by ~ 7 hour delay along with treatment, but two out of 23 cases returned to normal by ~ 17 hour advance. In three cases of mixed manic episodes, the phases were ~ 6–7 hour delayed. For five cases of depressive episodes, circadian rhythms phases were ~ 4–5 hour delayed. After treatment, circadian phases resembled those of healthy controls. Circadian misalignment due to circadian rhythm phase shifts might be a pathophysiological mechanism of BD.

Association between Antipsychotics-Induced Restless Legs Syndrome and Tyrosine Hydroxylase Gene Polymorphism

Objective Restless legs syndrome (RLS) has been reported to be more prevalent in schizophrenic patients who take antipsychotics. The cause of RLS is unknown but associated with dopaminergic deficiency. Tyrosine hydroxylase (TH) is the enzyme responsible for catalyzing the conversion of L-tyrosine to DOPA. The purpose of this study is to determine whether the TH gene Val81Met polymorphism is associated with antipsychotic-induced RLS. Methods One hundred ninety Korean schizophrenic patients were evaluated by the diagnostic criteria of the International RLS Study Group (IRLSSG). The genotyping was performed by PCR-based methods. Results Of the one hundred ninety schizophrenic patients, 44 (23.2%) were found to have RLS. Although there were no significant associations between TH genotypes or allele frequencies and RLS, when separate analyses were performed by sex (male or female), we detected significant differences in the frequencies of the genotype (χ2=6.15, p=0.046) and allele (χ2=4.67, p=0.031) of the TH gene Val81Met polymorphism between those with and without RLS in the female patients. Conclusion These findings suggest that the TH gene Val81Met SNP might be associated with antipsychotic-induced RLS in female schizophrenic patients.

Association of CLOCK, ARNTL, and NPAS2 gene polymorphisms and seasonal variations in mood and behavior

Seasonal affective disorder (SAD) is a condition of seasonal mood changes characterized by recurrent depression in autumn or winter that spontaneously remits in spring or summer. Evidence has suggested that circadian gene variants contribute to the pathogenesis of SAD. In this study, we investigated polymorphisms in the CLOCK, ARNTL, and NPAS2 genes in relation to seasonal variation in 507 healthy young adults. Seasonal variations were assessed with the Seasonality Pattern Assessment Questionnaire. The prevalence of SAD was 12.0% (winter-type 9.3%, summer-type 2.8%). No significant difference was found between the groups in the genotype distribution of ARNTL rs2278749 and NPAS2 rs2305160. The T allele of CLOCK rs1801260 was significantly more frequent in seasonals (SAD + subsyndromal SAD) compared with non-seasonals (p = 0.020, odds ratio = 1.89, 95% confidence interval = 1.09–3.27). Global seasonality score was significantly different among genotypes of CLOCK rs1801260, but not among genotypes of ARNTL rs2278749 and NPAS2 rs2305160. However, statistical difference was observed in the body weight and appetite subscales among genotypes of ARNTL rs2278749 and in the body weight subscale among genotypes of NPAS2 rs2305160. There was synergistic interaction between CLOCK rs1801260 and ARNTL rs2278749 on seasonality. To our knowledge, this study is the first to reveal an association between the CLOCK gene and seasonal variations in mood and behavior in the Korean population. Although we cannot confirm previous findings of an association between SAD and the ARNTL and NPAS2 genes, these genes may influence seasonal variations through metabolic factors such as body weight and appetite. The interaction of the CLOCK and ARNTL genes contributes to susceptibility for SAD.

A Comparison of Personality Characteristics and Psychiatric Symptomatology between Upper Airway Resistance Syndrome and Obstructive Sleep Apnea Syndrome

Objective To investigate the personality characteristics of patients with upper airway resistance syndrome (UARS) and those of patients with obstructive sleep apnea syndrome (OSAS). Methods Eighty-eight patients with UARS and 365 patients with OSAS participated. All patients had a diagnostic full-night attended polysomnography (PSG) and completed the Athens Insomnia Scale (AIS), Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), Symptom Checklist-90-Revision (SCL-90-R) and Eysenck Personality Questionnaire (EPQ). Results The UARS group scored significantly higher than the OSAS group on the ESS, AIS, and PSQI (p<0.001). The scores of all SCL-90-R subscales in the UARS group were significantly higher than those in the OSA group (all p<0.001, except for somatization, p=0.016). Patients with UARS scored lower on EPQ-E (extroversion/introversion) (p=0.006) and EPQ-L (lie) (p<0.001) than those with OSA. UARS patients also showed higher scores on EPQ-P (psychoticism) (p=0.002) and EPQ-N (neuroticism) (p<0.001) than OSAS patients. Conclusion Our results suggest that patients with UARS have worse subjective sleep quality than OSAS patients in spite of their better PSG findings. UARS patients tend to have more neurotic and sensitive personalities than patients with OSAS, which may be a cause of the clinical features of UARS.

Comparison of wearable activity tracker with actigraphy for sleep evaluation and circadian rest-activity rhythm measurement in healthy young adults

Objective The purpose of this study was to evaluate the applicability of data obtained from a wearable activity tracker (Fitbit Charge HR) to medical research. This was performed by comparing the wearable activity tracker (Fitbit Charge HR) with actigraphy (Actiwatch 2) for sleep evaluation and circadian rest-activity rhythm measurement. Methods Sixteen healthy young adults (female participants, 62.5%; mean age, 22.8 years) wore the Fitbit Charge HR and the Actiwatch 2 on the same wrist; a sleep log was recorded over a 14-day period. We compared the sleep variables and circadian rest-activity rhythm measures with Wilcoxon signed-rank tests and Spearmans correlations. Results The periods and acrophases of the circadian rest-activity rhythms and the sleep start times did not differ and correlated significantly between the Fitbit Charge HR and the Actiwatch 2. The Fitbit Charge HR tended to overestimate the sleep durations compared with the Actiwatch 2. However, the sleep durations showed high correlation between the two devices for all days. Conclusion We found that the Fitbit Charge HR showed high accuracy in sleep evaluation and circadian rest-activity rhythm measurement when compared with actigraphy for healthy young adults. The results suggest that the Fitbit Charge HR could be applicable on medical research as an alternative tool to actigraphy for sleep evaluation and measurement of the circadian rest-activity rhythm.

Solar radiation increases suicide rate after adjusting for other climate factors in South Korea.

Previous studies have indicated that suicide rates have significant seasonal variations. There is seasonal discordance between temperature and solar radiation due to the monsoon season in South Korea. We investigated the seasonality of suicide and assessed its association with climate variables in South Korea.

Molecular circadian rhythm shift due to bright light exposure before bedtime is related to subthreshold bipolarity

This study examined the link between circadian rhythm changes due to bright light exposure and subthreshold bipolarity. Molecular circadian rhythms, polysomnography, and actigraphy data were studied in 25 young, healthy male subjects, divided into high and low mood disorder questionnaire (MDQ) score groups. During the first 2 days of the study, the subjects were exposed to daily-living light (150 lux) for 4 hours before bedtime. Saliva and buccal cells were collected 5 times a day for 2 consecutive days. During the subsequent 5 days, the subjects were exposed to bright light (1,000 lux), and saliva and buccal cell samples were collected in the same way. Molecular circadian rhythms were analyzed using sine regression. Circadian rhythms of cortisol (F = 16.956, p < 0.001) and relative PER1/ARNTL gene expression (F = 122.1, p < 0.001) showed a delayed acrophase in both groups after bright light exposure. The high MDQ score group showed a significant delay in acrophase compared to the low MDQ score group only in salivary cortisol (F = 8.528, p = 0.008). The high MDQ score group showed hypersensitivity in cortisol rhythm shift after bright light exposure, suggesting characteristic molecular circadian rhythm changes in the high MDQ score group may be related to biological processes downstream from core circadian clock gene expression.