Decelerated epigenetic aging associated with mood stabilizers in the blood of patients with bipolar disorder

There is high mortality among patients with bipolar disorder (BD). Studies have reported accelerated biological aging in patients with BD. Recently, Horvath and Hannum et al. independently developed DNA methylation (DNAm) profiles as “epigenetic clocks,” which are the most accurate biological age estimate. This led to the development of two accomplished measures of epigenetic age acceleration (EAA) using blood samples, namely, intrinsic and extrinsic EAA (IEAA and EEAA, respectively). IEAA, which is based on Horvath’s clock, is independent of blood cell counts and indicates cell-intrinsic aging. On the other hand, EEAA, which is based on Hannum’s clock, is associated with age-dependent changes in blood cell counts and indicates immune system aging. Further, Lu et al. developed the “GrimAge” clock, which can strongly predict the mortality risk, and DNAm-based telomere length (DNAmTL). We used a DNAm dataset from whole blood samples obtained from 30 patients with BD and 30 healthy controls. We investigated Horvath EAA, IEAA, Hannum EAA, EEAA, Grim EAA, DNAmTL, and DNAm-based blood cell composition. Compared with controls, there was a decrease in Horvath EAA and IEAA in patients with BD. Further, there was a significant decrease in Horvath EAA and IEAA in patients with BD taking medication combinations of mood stabilizers (including lithium carbonate, sodium valproate, and carbamazepine) than in those taking no medication/monotherapy. This study provides novel evidence indicating decelerated epigenetic aging associated with mood stabilizers in patients with BD

Epigenetic clock analysis of blood samples from Japanese schizophrenia patients

The accelerated aging hypothesis of schizophrenia (SCZ) has been proposed. DNA methylation profiles were developed for determining “epigenetic age.” Here, we assessed intrinsic and extrinsic epigenetic age acceleration (IEAA and EEAA, respectively) in SCZ. We examined two independent cohorts of Japanese ancestry. The first cohort consisted of 80 patients with SCZ under long-term or repeated hospitalization and 40 controls, with the economical DNA pooling technique. The second cohort consisted of 24 medication-free patients with SCZ and 23 controls. Blood of SCZ subjects exhibited decreased EEAA in the first cohort (p = 0.0162), but not in the second cohort. IEAA did not differ in either cohort. We performed replication analyses using publicly available datasets from European ancestry (three blood and one brain datasets). One blood dataset showed increased EEAA in SCZ (p = 0.0228). Overall, our results provide evidence for decreased EEAA in SCZ associated with hospitalization in the Japanese population

mtDNA and Hemodynamics in Mood Disorders

Background: Given a lack of markers, diagnoses of bipolar disorder (BD) and major depressive disorder (MDD) rely on clinical assessment of symptoms. However, the depressive mood states of BD and depressive symptoms of MDD are often difficult to distinguish, which leads to misdiagnoses, which in turn leads to inadequate treatment. Previous studies have shown that the hemodynamic responses of the left frontopolar cortex measured by near-infrared spectroscopy (NIRS) differ between BD and MDD; these hemodynamic responses are associated with altered mitochondrial metabolism; and mitochondrial DNA copy number (mtDNAcn), an index of mitochondrial dysfunction, tends to decrease in BD and increase in MDD patients. In this study, we confirmed that mtDNAcn trends in opposite directions in BD and MDD. We then determined whether mtDNAcn could enhance the utility of NIRS as a diagnostic marker to distinguish between BD and MDD. Methods: We determined mtDNAcn in peripheral blood samples from 58 healthy controls, 79 patients with BD, and 44 patients with MDD. Regional hemodynamic responses during a verbal fluency task (VFT) in 24 BD patients and 44 MDD patients, matched by age and depression severity, were monitored using NIRS. Results: Measurements of mtDNAcn were lower in BD patients and higher in MDD patients than in controls. The left frontopolar region exhibited the most significant differences in mean VFT-related oxy-Hb changes between the BD and MDD groups. Multivariate logistic regression analysis with variables including age, sex, hemodynamic response of the left frontopolar region, and mtDNAcn showed high accuracy for distinguishing BD from MDD (area under the curve = 0.917; 95% confidence interval = 0.849–0.985). For the BD group, we observed a positive correlation between hemodynamic responses in the left frontopolar region and mtDNAcn, while for the MDD group, we observed a negative correlation. Conclusions: Our findings suggest that the association between hemodynamic response and mitochondrial dysfunction in BD or MDD plays an important role in differentiating the pathophysiological mechanisms of BD from those of MDD

Genome-wide association studies identify polygenic effects for completed suicide in the Japanese population

Suicide is a significant public health problem worldwide, and several Asian countries including Japan have relatively high suicide rates on a world scale. Twin, family, and adoption studies have suggested high heritability for suicide, but genetics lags behind due to difficulty in obtaining samples from individuals who died by suicide, especially in non-European populations. In this study, we carried out genome-wide association studies combining two independent datasets totaling 746 suicides and 14,049 non-suicide controls in the Japanese population. Although we identified no genome-wide significant single-nucleotide polymorphisms (SNPs), we demonstrated significant SNP-based heritability (35–48%; P < 0.001) for completed suicide by genomic restricted maximum-likelihood analysis and a shared genetic risk between two datasets (P best = 2.7 × 10−13) by polygenic risk score analysis. This study is the first genome-wide association study for suicidal behavior in an East Asian population, and our results provided the evidence of polygenic architecture underlying completed suicide

Association between the examination rate of treatment-resistant schizophrenia and the clozapine prescription rate in a nationwide dissemination and implementation study

Background: The decision to initiate clozapine treatment should be made on an individual basis and may be closely related to the early detection of treatment-resistant schizophrenia (TRS), although there is evidence that the early use of clozapine results in a better response to treatment. Therefore, we investigated the relationship between the examination rate of TRS and the prescription rate of clozapine. Methods: After attending a 1-day educational program on schizophrenia based on the "Guidelines for the Pharmacological Treatment of Schizophrenia," we asked the participating facilities to submit records of whether or not TRS was evaluated for each patient. We calculated the clozapine prescription rate from the schizophrenic patients prescribed clozapine and all of the schizophrenic patients. Forty-nine facilities in 2017 were included in the study. Results: There were dichotomous distributions in the examination rate of TRS and a non-normal distribution in the prescription rate of clozapine. There was a significant correlation between the prescription rate of clozapine and the examination rate of TRS (r s = 0.531, P = 1.032 × 10−4). A significant difference was found in the prescription rate of clozapine between the three groups of facilities according to the examination rate of TRS. Conclusion: As a preliminary problem for the use of clozapine, in Japan, the examination rate of TRS varies, and there are many facilities that typically do not consider the possibility of TRS; this trend leads to a low rate of clozapine use. Clearly, further clinician training is needed for the early detection and appropriate management of TRS that includes an explanation of TRS and how to introduce clozapine therapy to patients and their families

Improvements in the degree of understanding the treatment guidelines for schizophrenia and major depressive disorder in a nationwide dissemination and implementation study

Background: To implement clinical practice guidelines (CPGs), it is necessary for psychiatrists to deepen their understanding of the CPGs. The Effectiveness of Guidelines for Dissemination and Education in Psychiatric Treatment (EGUIDE) project is a nationwide dissemination and implementation study of two sets of CPGs for schizophrenia and major depressive disorder (MDD). Methods: A total of 413 psychiatrists (n = 212 in 2016; n = 201 in 2017) learned the two CPGs in the education program of the EGUIDE project, and clinical knowledge of these CPGs was evaluated at baseline and after the programs. To improve the correct answer rate for clinical knowledge after the programs, we revised the lecture materials associated with items that had a low correct answer rate in 2016 and used the revised lecture materials with the CPGs in 2017. The rates of correct answers after the programs between the 2016 and 2017 groups were compared. Results: The correct answer rate of one item on the schizophrenia CPG and one item on the MDD CPG tended to be improved (S-D5 and D-C6) and that of one on the MDD CPG was significantly improved (D-D3, P = 0.0008) in the 2017 group compared to those in the 2016 group. Conclusions: We reported improvements in clinical knowledge of CPGs after the EGUIDE program in the 2017 group following revision of the lecture materials based on results from the 2016 group. These attempts to improve the degree of understanding of CPGs may facilitate the successful dissemination and implementation of psychiatric guidelines in everyday practice

OKCAM: an ontology-based, human-centered knowledgebase for cell adhesion molecules

‘Cell adhesion molecules’ (CAMs) are essential elements of cell/cell communication that are important for proper development and plasticity of a variety of organs and tissues. In the brain, appropriate assembly and tuning of neuronal connections is likely to require appropriate function of many cell adhesion processes. Genetic studies have linked and/or associated CAM variants with psychiatric, neurologic, neoplastic, immunologic and developmental phenotypes. However, despite increasing recognition of their functional and pathological significance, no systematic study has enumerated CAMs or documented their global features. We now report compilation of 496 human CAM genes in six gene families based on manual curation of protein domain structures, Gene Ontology annotations, and 1487 NCBI Entrez annotations. We map these genes onto a cell adhesion molecule ontology that contains 850 terms, up to seven levels of depth and provides a hierarchical description of these molecules and their functions. We develop OKCAM, a CAM knowledgebase that provides ready access to these data and ontologic system at http://okcam.cbi.pku.edu.cn. We identify global CAM properties that include: (i) functional enrichment, (ii) over-represented regulation modes and expression patterns and (iii) relationships to human Mendelian and complex diseases, and discuss the strengths and limitations of these data

Clozapine and Antipsychotic Monotherapy

Background: Although clozapine is effective for treatment-resistant schizophrenia (TRS), the rate of clozapine prescription is still low. Whereas antipsychotic monotherapy is recommended in clinical practice guidelines, the rate of antipsychotic polypharmacy is still high. There is little evidence on whether a clozapine prescription influences changes in the rate of monotherapy and polypharmacy, including antipsychotics and other psychotropics. We therefore hypothesized that the rate of antipsychotic monotherapy in patients with TRS who were prescribed clozapine would be higher than that in patients with schizophrenia who were not prescribed clozapine. Methods: We assessed 8306 patients with schizophrenia nationwide from 178 institutions in Japan from 2016 to 2019. We analyzed the psychotropic prescription data at discharge in patients diagnosed with TRS and with no description of TRS (ND-TRS) based on the diagnosis listed in the discharge summary. Results: The rate of antipsychotic monotherapy in the TRS with clozapine group (91.3%) was significantly higher than that in the TRS without clozapine group (45.9%; P < 2.0 × 10−16) and the ND-TRS without clozapine group (54.7%; P < 2.0 × 10−16). The rate of antipsychotic monotherapy without any other concomitant psychotropics in the TRS with clozapine group (26.5%) was significantly higher than that in the TRS without clozapine group (12.6%; P = 1.1 × 10−6) and the ND-TRS without clozapine group (17.0%; P = 5.9 × 10−6). Conclusions: Clozapine prescription could be associated with a high rate of antipsychotic monotherapy. Patients will benefit from the correct diagnosis of TRS and thus from proper clozapine prescription

A Genome-Wide Association Study on Obesity and Obesity-Related Traits

Large-scale genome-wide association studies (GWAS) have identified many loci associated with body mass index (BMI), but few studies focused on obesity as a binary trait. Here we report the results of a GWAS and candidate SNP genotyping study of obesity, including extremely obese cases and never overweight controls as well as families segregating extreme obesity and thinness. We first performed a GWAS on 520 cases (BMI>35 kg/m2) and 540 control subjects (BMI<25 kg/m2), on measures of obesity and obesity-related traits. We subsequently followed up obesity-associated signals by genotyping the top ∼500 SNPs from GWAS in the combined sample of cases, controls and family members totaling 2,256 individuals. For the binary trait of obesity, we found 16 genome-wide significant signals within the FTO gene (strongest signal at rs17817449, P = 2.5×10−12). We next examined obesity-related quantitative traits (such as total body weight, waist circumference and waist to hip ratio), and detected genome-wide significant signals between waist to hip ratio and NRXN3 (rs11624704, P = 2.67×10−9), previously associated with body weight and fat distribution. Our study demonstrated how a relatively small sample ascertained through extreme phenotypes can detect genuine associations in a GWAS