Distinct epigenetic signatures between adult-onset and late-onset depression.

The heterogeneity of major depressive disorder (MDD) is attributed to the fact that diagnostic criteria (e.g., DSM-5) are only based on clinical symptoms. The discovery of blood biomarkers has the potential to change the diagnosis of MDD. The purpose of this study was to identify blood biomarkers of DNA methylation by strategically subtyping patients with MDD by onset age. We analyzed genome-wide DNA methylation of patients with adult-onset depression (AOD; age ≥ 50 years, age at depression onset < 50 years; N = 10) and late-onset depression (LOD; age ≥ 50 years, age at depression onset ≥ 50 years; N = 25) in comparison to that of 30 healthy subjects. The methylation profile of the AOD group was not only different from that of the LOD group but also more homogenous. Six identified methylation CpG sites were validated by pyrosequencing and amplicon bisulfite sequencing as potential markers for AOD in a second set of independent patients with AOD and healthy control subjects (N = 11). The combination of three specific methylation markers achieved the highest accuracy (sensitivity, 64%; specificity, 91%; accuracy, 77%). Taken together, our findings suggest that DNA methylation markers are more suitable for AOD than for LOD patients.

Similar activation patterns in the prefrontal cortex for Chinese and Japanese verbal fluency tests with syllable cues as revealed by near-infrared spectroscopy.

The verbal fluency test (VFT) is utilized in neuropsychology to evaluate the cognitive function of the prefrontal cortex (PFC) in the human brain. We present a novel Chinese VFT similar to the established Japanese VFT; both tests prompt a syllable to the subject. However, it was uncertain whether the Chinese VFT can activate the PFC and whether PFC activation patterns are similar between the two tests. Here we administered the Chinese VFT to 30 native Chinese speakers and the Japanese VFT to 30 native Japanese speakers. We used near-infrared spectroscopy (NIRS) to observe PFC activation. Then we compared the similarities between the Chinese VFT and the Japanese VFT. The subjects generated an average of 12.8 ± 4.7 words during the Chinese VFT. NIRS indicates that the concentration of oxygenated hemoglobin during the test was significantly higher than those before and after the test. It exhibited similar PFC activation patterns with the Japanese VFT. The novel Chinese VFT can activate the PFC in the human brain effectively in Chinese speakers. Our work thus provides the first validated phonetically cued Chinese VFT, unique from other not strictly phonemic Chinese VFTs, and facilitates the diagnosis of various PFC-related cognitive impairments.

Characterization of the signature of peripheral innate immunity in women with later-life major depressive disorder.

The prevalence of depression in later life is higher in women than in men. However, the sex difference in the pathophysiology of depression in elderly patients is not fully understood. Here, we performed gene expression profiling in leukocytes of middle-aged and elderly patients with major depressive disorder, termed later-life depression (LLD) in this context, and we characterized the sex-dependent pathophysiology of LLD. A microarray dataset obtained from leukocytes of patients (aged ≥50 years) with LLD (32 males and 39 females) and age-matched healthy individuals (20 males and 24 females) was used. Differentially expressed probes were determined by comparing the expression levels between patients and healthy individuals, and then functional annotation analyses (Ingenuity Pathway Analysis, Reactome pathway analysis, and cell-type enrichment analysis) were performed. A total of 1656 probes were differentially expressed in LLD females, but only 3 genes were differentially expressed in LLD males. The differentially expressed genes in LLD females were relevant to leukocyte extravasation signaling, Tec kinase signaling and the innate immune response. The upregulated genes were relevant to myeloid lineage cells such as CD14+ monocytes. In contrast, the downregulated genes were relevant to CD4+ and CD8+ T cells. Remarkable innate immune signatures are present in the leukocytes of LLD females but not males. Because inflammation is involved in the pathophysiology of depression, the altered inflammatory activity may be involved in the pathophysiology of LLD in women. In contrast, abnormal inflammation may be an uncommon feature in LLD males.

Identification of commonly altered genes between in major depressive disorder and a mouse model of depression.

The heterogeneity of depression (due to factors such as varying age of onset) may explain why biological markers of major depressive disorder (MDD) remain uncertain. We aimed to identify gene expression markers of MDD in leukocytes using microarray analysis. We analyzed gene expression profiles of patients with MDD (age ≥50, age of depression onset <50) (N = 10, depressed state; N = 13, remitted state). Seven-hundred and ninety-seven genes (558 upregulated, 239 downregulated when compared to those of 30 healthy subjects) were identified as potential markers for MDD. These genes were then cross-matched to microarray data obtained from a mouse model of depression (676 genes, 148 upregulated, 528 downregulated). Of the six common genes identified between patients and mice, five genes (SLC35A3, HIST1H2AL, YEATS4, ERLIN2, and PLPP5) were confirmed to be downregulated in patients with MDD by quantitative real-time polymerase chain reaction. Of these genes, HIST1H2AL was significantly decreased in a second set of independent subjects (age ≥20, age of onset <50) (N = 18, subjects with MDD in a depressed state; N = 19, healthy control participants). Taken together, our findings suggest that HIST1H2AL may be a biological marker of MDD.

Extracellular Vesicles from Vascular Endothelial Cells Promote Survival, Proliferation and Motility of Oligodendrocyte Precursor Cells.

We previously examined the effect of brain microvascular endothelial cell (MVEC) transplantation on rat white matter infarction, and found that MVEC transplantation promoted remyelination of demyelinated axons in the infarct region and reduced apoptotic death of oligodendrocyte precursor cells (OPCs). We also found that the conditioned medium (CM) from cultured MVECs inhibited apoptosis of cultured OPCs. In this study, we examined contribution of extracellular vesicles (EVs) contained in the CM to its inhibitory effect on OPC apoptosis. Removal of EVs from the CM by ultracentrifugation reduced its inhibitory effect on OPC apoptosis. To confirm whether EVs derived from MVECs are taken up by cultured OPCs, we labeled EVs with PKH67, a fluorescent dye, and added them to OPC cultures. Many vesicular structures labeled with PKH67 were found within OPCs immediately after their addition. Next we examined the effect of MVEC-derived EVs on OPC behaviors. After 2 days in culture with EVs, there was significantly less pyknotic and more BrdU-positive OPCs when compared to control. We also examined the effect of EVs on motility of OPCs. OPCs migrated longer in the presence of EVs when compared to control. To examine whether these effects on cultured OPCs are shared by EVs from endothelial cells, we prepared EVs from conditioned media of several types of endothelial cells, and tested their effects on cultured OPCs. EVs from all types of endothelial cells we examined reduced apoptosis of OPCs and promoted their motility. Identification of the molecules contained in EVs from endothelial cells may prove helpful for establishment of effective therapies for demyelinating diseases.

Blood Transcriptomic Markers in Patients with Late-Onset Major Depressive Disorder.

We investigated transcriptomic markers of late-onset major depressive disorder (LOD; onset age of first depressive episode ≥ 50 years) from the genes expressed in blood cells and identified state-dependent transcriptomic markers in these patients. We assessed the genes expressed in blood cells by microarray and found that the expression levels of 3,066 probes were state-dependently changed in the blood cells of patients with LOD. To select potential candidates from those probes, we assessed the genes expressed in the blood of an animal model of depression, ovariectomized female mice exposed to chronic ultra-mild stress, by microarray and cross-matched the differentially expressed genes between the patients and the model mice. We identified 14 differentially expressed genes that were similarly changed in both patients and the model mice. By assessing statistical significance using real-time quantitative PCR (RT-qPCR), the following 4 genes were selected as candidates: cell death-inducing DFFA-like effector c (CIDEC), ribonuclease 1 (RNASE1), solute carrier family 36 member-1 (SLC36A1), and serine/threonine/tyrosine interacting-like 1 (STYXL1). The discriminating ability of these 4 candidate genes was evaluated in an independent cohort that was validated. Among them, CIDEC showed the greatest discriminant validity (sensitivity 91.3% and specificity 87.5%). Thus, these 4 biomarkers should be helpful for properly diagnosing LOD.

Gene expression alterations in the medial prefrontal cortex and blood cells in a mouse model of depression during menopause.

AIMS: The prevalence of major depressive disorder (MDD) is higher in women than in men, and this may be due to the decline in estrogen levels that occurs during the menopausal transition. We studied the biological alterations in the medial prefrontal cortex (mPFC), which is a region that is highly implicated in the neurobiology of MDD, and the blood cells (BCs) of ovariectomized (OVX) mice subjected to chronic mild stress (CMS), which represents a mouse model of depression during menopause. MAIN METHODS: The mPFC and the BCs were obtained from the same individuals. Gene expression levels were analyzed by microarray. The data were used for the Ingenuity Pathway Analysis and the Gene Ontology analysis. KEY FINDINGS: The gene expression alterations (GEAs) induced by OVX were mainly associated with ribosomal and mitochondrial functions in both the mPFC and the BCs. Rapamycin-insensitive companion of mTOR (RICTOR) was identified as a possible upstream regulator of the OVX-induced GEAs in both tissues. The CMS-induced GEAs were associated with retinoic acid receptor signaling, inflammatory cytokines and post-synaptic density in the mPFC, but not in the BCs. SIGNIFICANCE: OVX and CMS independently affect biological pathways in the mPFC, which is involved in the development of the depression-like phenotype. Because a subset of the OVX-induced GEAs in the mPFC also occurred in the BCs, the GEAs in the BCs might be a useful probe to predict biological pathways in the corresponding brain tissue under specific conditions such as OVX in females.

Magnetoencephalography study of the effect of attention modulation on somatosensory processing in patients with major depressive disorder.

AIMS: Although affective and/or attention modulation of somatosensory processing has been well studied, the biological bases of somatic symptoms in patients with major depressive disorder (MDD) have rarely been examined. To elucidate changes in somatosensory processing underlying somatic symptoms in patients with MDD, we conducted a magnetoencephalography study of patients with MDD and healthy controls. METHODS: After median nerve stimulation, somatosensory evoked fields (SEF) were recorded in 10 patients with MDD and 10 sex-, age-, and height-matched healthy volunteers under somatosensory attending, visually attending, and non-attending conditions. The latencies and magnitudes of N20m and P60m SEF were examined. RESULTS: In the MDD group, P60m latency was significantly prolonged, irrespective of attention modulation, whereas N20m latency and root mean squares N20m and P60m amplitudes remained unchanged. Prolonged P60m latency negatively correlated with the somatosensory threshold, which was relatively high in the MDD group. Prolonged P60m latency also negatively correlated with a state of anxiety during the examination, but not with depressive symptoms or psychotropic medication. CONCLUSIONS: These results suggested that patients with MDD experience dysfunction in somatosensory information processing, approximately 60 ms after stimuli, irrespective of attentional conditions.

[The Report of the Survey to the Members of the Society about the Functional Dissociation of the Psychiatric Hospital beds].

In 2014, Japanese Ministry of Health, Labour and Welfare published the guideline on the policy of the psychiatric hospitals. We executed a survey to the members of "The Japanese Society of Psychiatry and Neurology" about the impression of this guideline, especially about "The functional differentiation of psychiatric hospital beds". Nine questions were notified on the home page of the society. 862 answers (5.3% of the members) were corrected by website from 1st to 30th of May in 2015. Attribution of the answers : doctors working at the psychiatric hospitals (70.9%), the psychiatric clinics (20%), the others (9.1%). The questions which more than 80% of the answers agreed were "The reduction of the psychiatric beds should be stepwise under the rule of check & balance in the improvement of the psychiatric community treatment", "Improve the function of the recovery phase treatment" and "The adequate treat- ment for the patients of the severe and chronic phases". The questions more than 55% of the answers agreed were "The reduction of the chronic phase beds for the improvement of the function of the acute phase beds". The questions which opposites exceeded (almost 47%) were "The assessment of the psychiatric symptoms in the patients of the chronic phase should be done by the third party" and "The facility for social skill treatment should be placed in the community". We could know the mind of the members about the revolution of the psychiatric.

[Toward the Introduction of Repetitive Transcranial Magnetic Stimulation in Japan to Treat Antidepressant-resistant Depression].

Treatment of major depressive disorder (MDD) can include a variety of biopsychosocial approaches. In medical practice, antidepressant drugs are the most common treatment for moderate to severe depressive episodes; however, their efficacy is limited. Many depressed patients are considered treatment-resistant, with 33% failing to achieve remission after ≥ 3 treatment trials. A systemic review and meta-analysis revealed that repetitive transcranial magnetic stimulation (rTMS) may be reasonably considered for patients with MDD and ≥ 2 prior failures of antidepressant treatment. No rTMS devices have been approved by the Japanese Pharmaceuticals and Medical Devices Agency, which has resulted in its off-label use; therefore, to offer better care for cases of treatment-resistant MDD, we should continue efforts to seek the introduction of rTMS to Japan.

Transplanted microvascular endothelial cells promote oligodendrocyte precursor cell survival in ischemic demyelinating lesions.

We previously showed that transplantation of brain microvascular endothelial cells (MVECs) greatly stimulated remyelination in the white matter infarct of the internal capsule (IC) induced by endothelin-1 injection and improved the behavioral outcome. In the present study, we examined the effect of MVEC transplantation on the infarct volume using intermittent magnetic resonance image and on the behavior of oligodendrocyte lineage cells histochemically. Our results in vivo show that MVEC transplantation reduced the infarct volume in IC and apoptotic death of oligodendrocyte precursor cells (OPCs). These results indicate that MVECs have a survival effect on OPCs, and this effect might contribute to the recovery of the white matter infarct. The conditioned-medium from cultured MVECs reduced apoptosis of cultured OPCs, while the conditioned medium from cultured fibroblasts did not show such effect. These results suggest a possibility that transplanted MVECs increased the number of OPCs through the release of humoral factors that prevent their apoptotic death. Identification of such humoral factors may lead to the new therapeutic strategy against ischemic demyelinating diseases.

Glutamate Decarboxylase 67 Deficiency in a Subset of GABAergic Neurons Induces Schizophrenia-Related Phenotypes.

Decreased expression of the GABA synthetic enzyme glutamate decarboxylase 67 (GAD67) in a subset of GABAergic neurons, including parvalbumin (PV)-expressing neurons, has been observed in postmortem brain studies of schizophrenics and in animal models of schizophrenia. However, it is unclear whether and how the perturbations of GAD67-mediated GABA synthesis and signaling contribute to the pathogenesis of schizophrenia. To address this issue, we generated the mice lacking GAD67 primarily in PV neurons and characterized them with focus on schizophrenia-related parameters. We found that heterozygous mutant mice exhibited schizophrenia-related behavioral abnormalities such as deficits in prepulse inhibition, MK-801 sensitivity, and social memory. Furthermore, we observed reduced inhibitory synaptic transmission, altered properties of NMDA receptor-mediated synaptic responses in pyramidal neurons, and increased spine density in hippocampal CA1 apical dendrites, suggesting a possible link between GAD67 deficiency and disturbed glutamatergic excitatory synaptic functions in schizophrenia. Thus, our results indicate that the mice heterozygous for GAD67 deficiency primarily in PV neurons share several neurochemical and behavioral abnormalities with schizophrenia, offering a novel tool for addressing the underlying pathophysiology of schizophrenia.

Histone deacetylase mediates the decrease in drebrin cluster density induced by amyloid beta oligomers.

Dendritic spine defects are found in a number of cognitive disorders, including Alzheimer's disease (AD). Amyloid beta (Aß) toxicity is mediated not only by the fibrillar form of the protein, but also by the soluble oligomers (Aß-derived diffusible ligands, ADDLs). Drebrin is an actin-binding protein that is located at mature dendritic spines. Because drebrin expression is decreased in AD brains and in cultured neurons exposed to Aß, it is thought that drebrin is closely associated with cognitive functions. Recent studies show that histone deacetylase (HDAC) activity is elevated in the AD mouse model, and that memory impairments in these animals can be ameliorated by HDAC inhibitors. In addition, spine loss and memory impairment in HDAC2 over-expressing mice are ameliorated by chronic HDAC inhibitor treatment. Therefore, we hypothesized that the regulation of histone acetylation/deacetylation is critical to synaptic functioning. In this study, we examined the relationship between HDAC activity and synaptic defects induced by ADDLs using an HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA). We show that ADDLs reduce the cluster density of drebrin along dendrites without reducing drebrin expression. SAHA markedly increased the acetylation of histone proteins, and it simultaneously attenuated the ADDL-induced decrease in drebrin cluster density. In comparison, SAHA treatment did not affect the density of drebrin clusters or dendritic protrusions in control neurons. Therefore, SAHA likely inhibits ADDL-induced drebrin loss from dendritic spines by stabilizing drebrin in these structures, rather than by increasing drebrin clusters or dendritic protrusions. Taken together, our findings suggest that HDAC is involved in ADDL-induced synaptic defects, and that the regulation of histone acetylation plays an important role in modulating actin cytoskeletal dynamics in dendritic spines under cellular stress conditions, such as ADDL exposure.

[Implementation of Guidelines on Conflict of Interest in Clinical Research of the Japanese Society of Psychiatry and Neurology: actual status and future perspectives].

In May 2011, the Japanese Society of Psychiatry and Neurology released their Guidelines on Conflict of Interest (COI) in Clinical Research and detailed regulations. These guidelines cover clinical research, although each committee of the society may have a policy to cover basic research as well as clinical research. The COI Committee implemented the guidelines, including a one-year trial period. According to the guidelines, members of the society have to disclose their COIs at the time of presentations, manuscript submissions, and publications; the board and committees members have to submit their COIs to the president of the society. During the trial period, the latter was limited to the four committees involved in the development of the guidelines: Conflict of Interest; Pharmaceutical Affairs; Research Ethics; and Editorial Committees. The COI Committee reviewed the COIs submitted by the board and committee members. The COI Committee found that, among the 382 board and committee members, 298 were without COI; 31 COIs were regarded by one committee member as not necessary to be circulated to all the attending members (total of these 2 categories: 329, 87%); 31 COIs (8%) were regarded as necessary to be circulated; and 18 cases (4.7%) were problematic: not submitted or explicit rejection of submission. Considering the seriousness of scientific misconduct by a researcher in another disease area who resigned his professorship and is now under investigation, we should further discuss the implementation of our COI guidelines.

[Adverse drug reactions of psychotropic agents: adverse drug reactions and safety monitoring of psychotropic agents].

Pharmacological treatments of psychiatric illness have been developed and many psychotropic drugs are now on the market. The body of safety information regarding psychotropic agents is so large that it is difficult for clinicians to consider all the details of possible adverse drug reactions(ADRs) in daily clinical practice. Although it is impossible to predict and prevent all occurrences of ADRs, many of them may be preventable. In this context, there is a strong need for compact manuals of diagnosis and treatment for ADRs arising from psychotropic agents that are likely to be used in daily practice. Under the auspices of the Japanese Society of Psychiatry and Neurology, a task force was convened to answer this need. This review focuses on the general considerations of ADRs with psychotropic agents, based on discussions of the task force. We also discuss the guidelines for drug safety monitoring, targeted towards specific psychiatric disorders or patients taking specific classes of drugs. Finally, we introduce the Adverse Drug Reactions Relief System in Japan.

Temporal lobe and inferior frontal gyrus dysfunction in patients with schizophrenia during face-to-face conversation: a near-infrared spectroscopy study.

Schizophrenia (SC) is marked by poor social-role performance and social-skill deficits that are well reflected in daily conversation. Although the mechanism underlying these impairments has been investigated by functional neuroimaging, technical limitations have prevented the investigation of brain activation during conversation in typical clinical situations. To fill this research gap, this study investigated and compared frontal and temporal lobe activation in patients with SC during face-to-face conversation. Frontal and temporal lobe activation in 29 patients and 31 normal controls (NC) (n = 60) were measured during 180-s conversation periods by using near-infrared spectroscopy (NIRS). The grand average values of oxyhemoglobin concentration ([oxy-Hb]) changes during task performance were analyzed to determine their correlation with clinical variables and Positive and Negative Syndrome Scale (PANSS) subscores. Compared to NCs, patients with SC exhibited decreased performance in the conversation task and decreased activation in both the temporal lobes and the right inferior frontal gyrus (IFG) during task performance, as indicated by the grand average of [oxy-Hb] changes. The decreased activation in the left temporal lobe was negatively correlated with the PANSS disorganization and negative symptoms subscores and that in the right IFG was negatively correlated with illness duration, PANSS disorganization, and negative symptom subscores. These findings indicate that brain dysfunction in SC during conversation is related to functional deficits in both the temporal lobes and the right IFG and manifests primarily in the form of disorganized thinking and negative symptomatology.

[Clinical application of near-infrared spectroscopy (NIRS) in psychiatry: the advanced medical technology for differential diagnosis of depressive state].

Near-infrared spectroscopy (NIRS) is a functional neuroimaging technique that has been increasingly employed in psychology and psychiatry. Because NIRS can detect only cerebral cortex reactivities with low spatial resolution and may suffer from contaminating signals from skin and skull, its data should be interpreted as a global index of cerebral cortex reactivities. Within these limitations, the advantages of NIRS over fMRI such as complete non-invasiveness, small measurement apparatus, high time resolution, and natural examination setting makes it the preferred method in studies of brain substrates of subjective feeling of sleepiness and fatigue, personality, conversation, and psychiatric disorders. Two-thirds of the original articles on NIRS application in psychiatry have been published by Japanese researchers. NIRS examination of psychiatric disorders using a verbal fluency task of only three minutes demonstrated their characteristics of frontal lobe function: depression was characterized by smaller activation, bipolar depression by comparable but delayed activation, and schizophrenia by reduced activation followed by re-activation during the post-task period. These characteristics can also be identified in individual NIRS data using two automatically calculated parameters. Based on these results, NIRS application in psychiatry has been approved as one of the Advanced Medical Technologies in 2009 as an aid for differential diagnosis of depressive symptoms. A lack of clinical laboratory tests for diagnosis and treatment has been one of the major difficulties for reliable diagnosis, quantitative treatment assessment, and prevention of psychiatric disorders; NIRS may be the first step toward such clinical laboratory tests in psychiatry.