Association between HLA-DRB1*0405, -DQB1*0401 and -DQA1*0303 alleles and lamotrigine-induced cutaneous adverse drug reactions. A pilot case-control study from Japan.

BACKGROUND: Human leukocyte antigen (HLA) genotypes in lamotrigine -induced (LTG-induced) cutaneous adverse drug reactions (cADRs) have been described in several reports but controversy remains even for a given ethnic group. We attempted to clarify a possible association between LTG-induced cADRs and HLA alleles in Japanese patients. METHOD: Sixteen subjects, including eight patients with LTG-induced cADRs and eight LTG-tolerant controls were included in this study. All eight patients with LTG-induced cADRs gave positive results in a drug-induced lymphocyte stimulation test (DLST) with LTG. We performed HLA-typing for HLA-A, -B, -C, -DRB1, -DQA1, -DQB1, -DPA1 and -DPB1, using PCR with sequence-specific oligonucleotide probes and multiple analyte profiling (xMAP) technology (Luminex System; Luminex Corporation, Austin, TX). We examined differences between allele frequencies in our two groups of subjects and the allele frequencies in the general Japanese population. RESULTS: The frequencies of HLA-DRB1*0405, and HLA-DQB1*0401 alleles were higher in our LTG-cADRs patients than the reference frequencies in the general Japanese population. We also detected HLA-DQA1*0303 frequently in our LTG-cADRs patients, but data for this allele in the Japanese population was not available. Our observation was presumably due to the linkage disequilibrium among the three alleles. The haplotype frequency of HLA-DRB1*0405, DQB1*0401 and DQA1*0303 in our LTG-cADRs subjects was also different from the corresponding haplotype frequency in the database for the Japanese population and the difference was statistically significant. One patient with the HLA-DRB1*0405, -DQB1*0401 and DQA1*0303 haplotype was safely re-treated with LTG after results of a DLST with LTG ceased to be positive about 4 months after discontinuation of LTG. LIMITATIONS: Our analysis included only 16 patients. Associations between LTG-induced cADRs and specific HLA loci will have to be confirmed in larger studies. CONCLUSIONS: LTG-induced cADRs are associated with HLA-DRB1*0405, -DQB1*0401 and -DQA1*0303.

Low risk of male suicide and lithium in drinking water.

OBJECTIVE: Recently, several epidemiologic studies reported that lithium in drinking water may be associated with lower rates of suicide mortality at the population level, but other studies failed to confirm the association. The objective of the present study is to determine whether lithium in drinking water is associated with lower suicide rate after adjustment of potential confounding factors. METHOD: From 2010 to 2013, 274 mean lithium levels of 434 lithium samples in drinking water were examined in relation to suicide standardized mortality ratios (SMRs) in 274 municipalities of Kyushu Island in Japan. Weighted least squares regression analysis adjusted for the size of each population was used to investigate the association of lithium levels with suicide SMRs. The associations of lithium levels in drinking water with suicide SMRs (total, male, and female) were investigated adjusting for proportion of elderly people, proportion of 1-person households, proportion of people with college education or more, and proportion of people engaging in primary industry (adjusted model 1), and further adjustment was performed with overall unemployment rate, annual marriage rate, annual mean temperature, and annual postal savings per person (adjusted model 2). RESULTS: Lithium levels in drinking water were significantly (ß = -.169, P = .019) and inversely associated with male suicide SMRs but not total or female SMRs in the adjusted model 2. CONCLUSIONS: The present findings suggest that lithium in drinking water may be associated with the low risk of male suicide in the general population. Further studies are required to confirm these findings and investigate gender differences.

Identification of the neural correlates of cyclothymic temperament using an esthetic judgment for paintings task in fMRI.

BACKGROUND: There is a well-known association between artistic creativity and cyclothymic temperament but the neural correlates of cyclothymic temperament have not yet been fully identified. Recently, we showed that the left lingual gyrus and bilateral cuneus may be associated with esthetic judgment of representational paintings, we therefore sought to investigate brain activity during esthetic judgment of paintings in relation to measures of cyclothymic temperament. METHODS: Regions of interest (ROI) were set at the left lingual gyrus and bilateral cuneus using automated anatomical labeling, and percent signal changes of the ROIs were measured by marsbar toolbox. The associations between percent signal changes of the ROIs during esthetic judgments of paintings and cyclothymic temperament scores were investigated by Pearson׳s coefficient. Moreover, the associations were further analyzed using multiple regression analysis whereby cyclothymic temperament scores were a dependent factor and percent signal changes of the 3 ROIs and the other 4 temperament scores were independent factors. RESULTS: There was a significantly negative association of cyclothymic temperament scores with the percent signal changes of the left lingual gyrus during esthetic judgments of paintings, but not with those of bilateral cuneus. Even after adjustment using multiple regression analysis, this finding remained unchanged. LIMITATIONS: The number of subjects was relatively small and the task was limited to appreciation of paintings. CONCLUSIONS: The present findings suggest that cyclothymic temperament may be associated with the left lingual gyrus.

Difference in brain activations during appreciating paintings and photographic analogs.

Several studies have investigated neural correlates of aesthetic appreciation for paintings but to date the findings have been heterogeneous. This heterogeneity may be attributed to previous studies' measurement of aesthetic appreciation of not only the beauty of paintings but also the beauty of motifs of the paintings. In order to better elucidate the beauty of paintings, it seems necessary to compare aesthetic appreciation of paintings and photographic analogs which included corresponding real images. We prepared for famous painters' pictures and their photographic analogs which were set up to resemble each painting in order to investigate the hypothesis that there exist specific neural correlates associated with the aesthetic appreciation for paintings. Forty-four subjects participated in functional magnetic resonance study which required comparisons of aesthetic appreciation of paintings of still life and landscape versus photographic analogs including corresponding real images of still life and landscape. Bilateral cuneus and the left lingual gyrus were activated in the comparison of aesthetic appreciation of paintings versus photographic analogs. In conclusion, the present findings suggest a possibility of the existence of specific neural correlates associated with the aesthetic appreciation for paintings and that bilateral cuneus and the left lingual gyrus may be involved.

Association between affective temperaments and regional gray matter volume in healthy subjects.

BACKGROUND: Affective temperaments such as cyclothymic and hyperthymic temperaments have been regarded as potential antecedents of bipolar disorder but the neural substrates underlying these temperaments have not been identified. The aim of this study is to determine whether these temperaments are associated with specific neural substrates in regional brain morphology in healthy subjects. METHODS: We conducted a cross-sectional neuroimaging study of 60 healthy subjects (30 males and 30 females) with affective temperaments. All participants underwent the Mini-International Neuropsychiatric Interview (MINI) to screen for the past and present psychiatric disorder. The scores of cyclothymic and hyperthymic temperaments were measured by the Temperament Scale of Memphis, Pisa, Paris and San Diego-Autoquestionnaire. We analyzed the association between voxel-based morphometry of the brain and these affective temperaments. RESULTS: Subjects classified as having high cyclothymic scores had a significantly larger gray matter volume of the left medial frontal gyrus (MFG) than low cyclothymic subjects. High hyperthymic males also had significantly larger gray matter volume of the left MFG than low hyperthymic males, but there was no difference in females. Subjects with both high cyclothymic and high hyperthymic temperaments demonstrated significantly larger gray matter volume of the left MFG than their counterparts. Region of interest analysis revealed that peaks of these clusters showed a significant positive correlation of the regional volume with temperament scores. LIMITATIONS: The subjects were relatively young and the number was relatively small. Due to the nature of a cross-sectional research design, we could not determine the causal relationship between temperament and the volume changes. CONCLUSIONS: These findings suggest that cyclothymic and hyperthymic temperaments in healthy subjects may have their morphological basis in the left MFG.

Repeated seizures in an elderly patient with alcohol dependence and mild cognitive impairment.

A 69-year-old man with alcohol dependence and mild cognitive impairment (MCI) suffered from repeated tonic-clonic seizures. The seizures typically occurred several hours after his last alcohol intake at home (early withdrawal seizure) and 22 days after his last intake of alcohol (14 days after the last dose of diazepam substituting for alcohol: late withdrawal seizure) on the ward. Psychiatrists in charge of this patient found it difficult to attribute his seizures to alcohol withdrawal syndrome (AWS) because of the atypical onset. The patient responded to diazepam resumption and valproate combination. This case highlights the need to always consider AWS as a possible cause of seizures and to gradually decrease diazepam as a substitute for alcohol. Moreover, in this patient, MCI may have induced vulnerability in the brain for AWS and the patients' older age might have decreased liver function leading to delayed onset of the seizures after diazepam withdrawal.

Hyperthymic temperament and rapid reaction time in brightness preference.

BACKGROUND: It is well-known that Type A behavior pattern is characterized by hard-driving, competitive behavior and time urgency. Also, people with hyperthymic temperament are known to have high energy levels and are full of plans. It is therefore hypothesized that hyperthymic temperament is associated with rapid processing and fast reaction time in making decisions. METHODS: Using data from our previous experimental studies (N=58) examining brightness judgment and brightness preference, reaction time (RT) was investigated in relation to hyperthymic temperament scores and fMRI signal changes of the left inferior orbitofrontal cortex during brightness judgment. RESULTS: RT for brightness judgment was significantly shorter than RT for brightness preference. Significant associations were found between RT for brightness preference and hyperthymic temperament scores, and RT for brightness preference and fMRI signal changes of the left inferior orbitofrontal cortex whilst performing brightness preference task. Multiple regression analysis revealed that RT for brightness preference task was significantly and negatively associated with hyperthymic temperament scores, and significantly and positively associated with fMRI signal changes of the left inferior orbitofrontal cortex. LIMITATIONS: It is uncertain whether the findings of RT (around 1s) can be extrapolated to routine life (around 24h) and whether RT for brightness preference can be generalized to a variety of daily activities. CONCLUSIONS: The present findings suggest that hyperthymic temperament is associated with rapid processing. Further studies are required to overcome the above limitations.

Hyperthymic temperament and brightness preference in healthy subjects: further evidence for involvement of left inferior orbitofrontal cortex in hyperthymic temperament.

BACKGROUND: Hyperthymic temperament has been generally accepted as one of premorbid temperament of bipolar disorders. Although several studies indicate that subjects with hyperthymic temperament receive more illuminance, our recent study suggests that the threshold of brightness and darkness judgment is not different between more and less hyperthymic subjects, and that hyperthymic temperament may be associated with left inferior orbitofrontal cortex, which has been reported to be associated with bipolar disorder. Therefore, at the next stage, it can be hypothesized that hyperthymic subjects may prefer brightness (i.e., heliotropism) and thereby seek illuminance, and that percent signal changes of left inferior orbitofrontal cortex during the preference task may be associated with hyperthymic temperament scores. METHODS: We compared brightness preference and un-preference between more and less hyperthymic subjects, and investigated percent signal changes of left inferior orbitofrontal cortex during brightness preference judgment, brightness un-preference judgment, and control task by using functional Magnetic Resonance Imaging (fMRI). RESULTS: There were significant differences in brightness preference judgment and un-preference judgment, showing that more hyperthymic subjects preferred brighter illuminace levels and un-preferred darker illuminance levels than less hyperthymic subjects. Moreover, fMRI signal changes of left inferior orbitofrontal cortex was significantly and negatively associated with hyperthymic temperament scores. LIMITATIONS: It is unknown why left but not right inferior orbitofrontal cortex was associated with hyperthymic temperament scores. CONCLUSIONS: The present findings suggest that more hyperthymic subjects may prefer brightness and un-prefer darkness than less hyperthymic subjects (i.e., heliotropism), and reconfirm that hyperthymic temperament may be associated with left inferior orbitofrontal cortex, which have been reported to be associated with bipolar disorders.

Hyperthymic temperament and brightness judgment in healthy subjects: involvement of left inferior orbitofrontal cortex.

BACKGROUND: Hyperthymic temperament has been generally accepted as one of premorbid temperament of bipolar disorders. Since recent several studies indicate an association between illuminance and hyperthymic temperament, it can be hypothesized that more hyperthymic temperament subjects have a different threshold of brightness or darkness perception in comparison with less hyperthymic temperament subjects. METHODS: We compared the threshold of brightness and darkness judgment between more and less hyperthymic subjects, and by simultaneously using fMRI we compared activations of whole brain between these subjects by two sample t-test. Furthermore, the association between the activations and hyperthymic temperament scores was analyzed. RESULTS: Although there was no significant difference in the threshold of brightness or darkness judgment between more and less hyperthymic subjects, there was a significant difference in activations of the regions including left superior temporal gyrus, left inferior orbitofrontal cortex, left triangular inferior frontal gyrus and left insula between these subjects. Moreover, there was a significantly positive association between a cluster containing left inferior orbitofrontal cortex and hyperthymic temperament scores. The common activated region of these two analyses (categorical and continuous ones) was determined as left inferior orbitofrontal cortex. LIMITATIONS: Limitation of the present study is a lack of brightness and darkness preference experiment between more and less hyperthymic subjects. CONCLUSIONS: The present findings suggest that the threshold of brightness and darkness judgment is not different between more and less hyperthymic subjects, and that hyperthymic temperament may be associated with left inferior orbitofrontal cortex, which has been reported to be associated with bipolar disorder.

Risk factors for suicide in Japan: a model of predicting suicide in 2008 by risk factors of 2007.

BACKGROUND: This study aims to comprehensively investigate the causal relationship between suicide and its risk factors in a longitudinal design. METHODS: A model was derived in which suicide rate in 2008 was longitudinally and comprehensively predicted by potential risk factors recorded one year before (2007) which included personal and interpersonal factors, medical factors, economic factors, climate factors, alcoholic factors, and ω-3 fatty-acid factors. RESULTS: In males, elderly population rate and complete unemployment rate predicted SMR of suicide significantly and positively whereas marriage rate and annual postal savings per person predicted SMR of suicide significantly and negatively. Also in females, complete unemployment rate predicted SMR of suicide significantly and positively whereas annual mean temperature predicted SMR of suicide significantly and negatively. LIMITATIONS: The limitations of this study are that predictions are based on the data of only the recent two years, that these epidemiological data cannot be always extrapolated to individuals, and that other factors should be taken into consideration to female suicide. CONCLUSIONS: The present findings suggest that male suicide may be accounted for by older age, more complete employment rate, less marriage rate and less annual postal savings whereas female suicide may be accounted for by more complete employment rate and lower annual mean temperature.

Type A behavior pattern: Bortner scale vs. Japanese-original questionnaires.

BACKGROUND: Type A behavior pattern (TABP) has been regarded as a putative risk factor for coronary heart disease and recent studies from our group suggest that TABP individuals, identified via the Bortner scale whose validity had been confirmed by structured interviews, may have a greater tendency towards hyperthymic temperament, shorter sleep time and shorter snooze time. Since the Bortner scale was developed in USA and may reflect western culture, it is necessary to reconfirm our findings using a Japanese questionnaire such as Coronary-prone Type Scale for Japanese (CTS) and Kwansei Gakuin's daily life questionnaire (KG questionnaire). METHODS: Fifty healthy subjects were assessed for TABP using the Bortner scale, as well as the CTS and KG questionnaires. Hyperthymic temperament was assessed via the Japanese standardized version of the Temperament Evaluation of Memphis, Pisa, Paris and San Diego-auto questionnaire (TEMPS-A), while sleep time and snooze time were measured by actigraphy. RESULTS: Both CTS and KG questionnaire scores were significantly and positively associated with the Bortner scale scores. Although CTS and KG scores were significantly and positively associated with hyperthymic temperament scores, none were associated with sleep time or snooze time. LIMITATIONS: The number of subjects was relatively small. CONCLUSIONS: The findings suggest that Japanese questionnaires such as CTS and KG questionnaires are valid as measures of TABP. Moreover, the association between TABP and hyperthymic temperament was reconfirmed by both CTS and KG questionnaires, whereas the association between TABP and sleep pattern was not. As such, the present findings provide supportive evidence about the usefulness of CTS and KG questionnaires.

Latitude effect on bipolar temperaments.

BACKGROUND: Growing evidence points to an association of daily light exposure and both mood and mood disorders. In recent studies, we demonstrated that higher illuminance of daytime may be positively associated with hyperthymic temperament while lower illuminance of daytime may be positively associated with cyclothymic temperament. However, it is not possible to determine whether hyperthymic or cyclothymic temperament induces higher or lower illuminance via heliotropism or non-heliotropism or whether higher or lower illuminance induces hyperthymic or cyclothymic temperament via light effects. METHODS: In order to elucidate these questions, we sought to compare bipolar temperaments between residents who live in regions with varying levels of sunshine. Japan has 4 large islands -Hokkaido, Honshu, Shikoku, and Kyushu. Sapporo in Hokkaido and Oita in Kyushu located at 43° and 33° of latitude differ significantly in mean yearly sunshine. We investigated the data of 189 subjects (94 from Sapporo and 95 from Oita) including their data of Temperament Evaluation of Memphis, Pisa, Paris and San Diego-auto questionnaire version (TEMPS-A). RESULTS: Multiple regression analyses revealed that latitude (Sapporo or Oita) effect predicted significant variance of hyperthymic temperament, but not of the other temperaments. LIMITATIONS: The limitation of the present study was that there was a small but significant difference in age between the subjects of Sapporo and those of Oita. Therefore, we included age in the multiple regression analysis. Second, there were several climate factors other than sunshine which were significantly different between Sapporo and Oita. We cannot exclude these effects completely. Finally, we did not consider other factors such as psychosocial factors which might have affected bipolar temperaments. CONCLUSIONS: The present findings suggest that relatively lower latitude (potentially via more sunshine) may induce hyperthymic temperament.

Is serotonergic function associated with the antidepressant effects of modified-electroconvulsive therapy?

BACKGROUND: The effect of modified-electroconvulsive therapy (m-ECT) on central serotonergic function has not been sufficiently investigated. The aim of the present study is to investigate this effect via the neuroendocrine challenge test. METHODS: Sixteen inpatients (9 men and 7 women) with major depressive disorder who were receiving m-ECT at our university hospital were recruited. A neuroendocrine challenge test to estimate central serotonergic function was performed both before and after m-ECT treatment. RESULTS: On the whole, depressive symptoms significantly improved, but the improvement was not associated with changes in serotonergic function. LIMITATIONS: The study was open-labeled and performed with a small number of subjects and no control group. CONCLUSION: Serotonergic function may not be associated with the antidepressant effects of ECT.

Bipolar temperaments and light.

BACKGROUND: Converging lines of evidence have established a relationship between exposure to ambient light and both mood state and mood disorders. In view of the association between mood disorder and affective disposition, in this study, the relationship between temperament (depressive, cyclothymic, hyperthymic, irritable and anxious) and daily light exposure was closely examined. METHODS: Fifty-six subjects completed the Japanese standardized version of the Temperament Evaluation of Memphis, Pisa, Paris and San Diego-auto questionnaire version (TEMPS-A) and illuminance of daytime using actigraphy. RESULTS: Cyclothymic temperament scores were significantly and negatively associated with illuminance of daytime whereas hyperthymic temperament scores were significantly and positively associated with illuminance of daytime. LIMITATIONS: Sample size was relatively small and they were only healthy subjects and no patients. CONCLUSIONS: The findings suggest that illuminance of daytime may be related to both cyclothymic and hyperthymic temperaments but that the associations lie in opposite directions. If this is the case, it seems important to consider individual patients' temperaments when light therapy is used to treat their depressive episode. Further studies are required to determine why and how these temperaments are associated with illuminance.

Effect of temperaments on quality of life and social adaptation in depressive patients with mood disorder.

AIMS: The aim of this study was to investigate the effects of temperament on quality of life and social adaptation in depressive patients with mood disorder. METHODS: Forty-six consecutive depressive outpatients were investigated by using the Temperament Evaluation of Memphis, Pisa, Paris and San Diego-Autoquestionnaire version, the Munich Personality Test, the World Health Organization Quality of Life 26 (WHO QOL 26), and the Social Adaptation Self-evaluation Scale (SASS). The unpaired t-test, Pearson's r and multiple regression analysis were used to assess three variables (age, the number of temperaments and/or personality types, and Hamilton Depression Rating Scale scores) as independent variables with the scores of WHO QOL 26 and SASS as the dependent variables. RESULTS: The number of temperaments and/or personalities and Hamilton Depression Rating Scale scores were significantly and negatively associated with WHO QOL 26 scores while only the number of temperaments and/or personalities was significantly and negatively associated with SASS scores. CONCLUSIONS: The findings suggest that the combination of temperaments and/or personality types assessed with the Temperament Evaluation of Memphis, Pisa, Paris and San Diego-Autoquestionnaire version and the Munich Personality Test may worsen both quality of life and social adaptation and that some temperaments and/or personality types in combination may be subclinical manifestations of mood disorders.