Kentaro Kohno

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 (β = -.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.

Serum Ghrelin Levels and the Effects of Antidepressants in Major Depressive Disorder and Panic Disorder

Background: Two opposing models for the action of ghrelin in the behavioral responses to stress were recently proposed. Some studies suggest that an increase in ghrelin contributes to the mechanisms responsible for the development of stress-induced depression and anxiety, while others suggest that it helps minimize what otherwise would be more severe manifestations of depression and anxiety following stress. Methods: We measured serum ghrelin levels, Profile of Mood States (POMS) scores and State-Trait Anxiety Inventory scores in nonresponders (treatment-resistant patients; 30) and responders (38) with major depressive disorder (MDD), nonresponders (29) and responders (51) with panic disorder and 97 healthy controls. Results: The ghrelin concentration in nonresponders with MDD was higher than that of responders with MDD and normal controls. The ghrelin concentration in nonresponders with panic disorder was higher than that of normal controls. POMS vigor scores in patients with MDD and panic disorder were significantly decreased compared with those in healthy controls. Other POMS scores in patients with MDD and panic disorder were significantly increased compared with those of healthy controls. Trait and state anxiety of the State-Trait Anxiety Inventory in MDD and panic disorder patients were higher than those in healthy controls. Conclusions: These results indicate that decreased serum ghrelin levels might be associated with antidepressant treatment to confer the maximum therapeutic effect in patients with MDD and panic disorder.

Elevated salivary α-amylase and cortisol levels in unremitted and remitted depressed patients.

Abstract Objective. Major depressive disorder (MDD) is often associated with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis via chronic stress. Psychosocial stress-induced activation of salivary α-amylase (sAA) represents sympathoadrenal medullary system (SAM) activity, and sAA has become an emerging biomarker for sympathetic nervous system activity. In contrast to salivary cortisol, sAA has been less extensively studied in depressed patients. The present study sought to address this problem by measuring sAA and salivary cortisol levels in patients with major depressive disorder. Methods. The authors recorded Spielberger State-Trait Anxiety Inventory (STAI) scores along with, levels of sAA and salivary cortisol in 28 patients with unremitted major depressive disorder, 43 remitted patients and 103 healthy volunteers. Results. STAI (State or Trait) measurements in unremitted patients with MDD were significantly increased compared with healthy controls and remitted patients. SAA and cortisol levels in unremitted patients were also significantly elevated compared to controls and remitted patients. Finally, sAA levels were significantly correlated with HRSD in unremitted patients with MDD. Conclusion. These preliminary results suggest that sAA may be a state-dependent marker of major depressive disorder in addition to salivary cortisol.

Trace lithium is inversely associated with male suicide after adjustment of climatic factors.

BACKGROUND Previously, we showed the inverse association between lithium in drinking water and male suicide in Kyushu Island. The narrow variation in meteorological factors of Kyushu Island and a considerable amount of evidence regarding the role of the factors on suicide provoked the necessities of adjusting the association by the wide variation in sunshine, temperature, rain fall, and snow fall. METHODS To keep the wide variation in meteorological factors, we combined the data of Kyushu (the southernmost city is Itoman, 26°) and Hokkaido (the northernmost city is Wakkanai, 45°). Multiple regression analyses were used to predict suicide SMRs (total, male and female) by lithium levels in drinking water and meteorological factors. RESULTS After adjustment of meteorological factors, lithium levels were significantly and inversely associated with male suicide SMRs, but not with total or female suicide SMRs, across the 153 cities of Hokkaido and Kyushu Islands. Moreover, annual total sunshine and annual mean temperature were significantly and inversely associated with male suicide SMRs whereas annual total rainfall was significantly and directly associated with male suicide SMRs. LIMITATIONS The limitations of the present study include the lack of data relevant to lithium levels in food and the proportion of the population who drank tap water and their consumption habits. CONCLUSIONS The present findings suggest that trace lithium is inversely associated with male but not female suicide after adjustment of meteorological factors.

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.

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.

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.

Therapeutic Window of Lamotrigine for Mood Disorders: A Naturalistic Retrospective Study

INTRODUCTION Lamotrigine is widely used for mood disorders including bipolar disorder and major depression, but its therapeutic levels have yet to be determined. This study was conducted to investigate the hypothesis that lamotrigine may have a therapeutic window for mood disorders. METHODS 25 patients with mood disorders received lamotrigine for more than one year during which time plasma lamotrigine levels were measured at least once. Their mental state was retrospectively and regularly but blindly assessed using the Clinical Global Impression-Severity (CGI-S) scale. In order to investigate our hypothesis, we depicted the relationship between the last lamotrigine levels and the last CGI scores in 25 patients. If any, the potential therapeutic window was further investigated. RESULTS The relationship between the last lamotrigine levels and the last CGI scores in the 25 patients indicated the presence of a therapeutic window of lamotrigine from 5 to 11 μg/mL. The repeated measures of ANOVA reached a significant tendency of the effects of lamotrigine levels within 5-11 μg/mL on better CGI-S scores, and the CGI-S scores at the last observation of the 15 patients whose lamotrigine levels were within 5-11 μg/mL were significantly better than those of 10 patients whose lamotrigine levels were not within 5-11 μg/mL. CONCLUSION These findings suggest that lamotrigine may have a therapeutic window for patients with mood disorder from 5 to 11 μg/mL.

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.

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.