Mitsuhiko Yamada

National Center of Neurology and Psychiatry · Department of Neuropsychopharmacolog

Early-life social isolation is associated with social and emotional problems in adulthood. However, neural mechanisms underlying how social deprivation impairs social and emotional development are poorly understood. Recently, the orbitofrontal cortex (OFC) and basolateral amygdala (BLA) have been highlighted as key nodes for social and emotional fu...

Duchenne muscular dystrophy (DMD) is a muscle disorder caused by DMD mutations and is characterized by neurobehavioural comorbidities due to dystrophin deficiency in the brain. The lack of Dp140, a dystrophin short isoform, is clinically associated with intellectual disability and autism spectrum disorders (ASDs), but its postnatal functional role...

The neuropeptide oxytocin (Oxt) plays important roles in modulating social behaviors. Oxytocin receptor (Oxtr) is abundantly expressed in the brain and its relationship to socio-behavioral controls has been extensively studied using mouse brains. Several genetic tools to visualize and/or manipulate Oxtr-expressing cells, such as fluorescent reporte...

Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the central nervous system, synthesized by two isoforms of glutamate decarboxylase (GAD): GAD65 and GAD67. GABA may act as a trophic factor during brain development, but its contribution to the development and maturation of cerebellar neural circuits is not known. To understan...

The immature brain is highly sensitive to disturbances in the functioning of N-methyl-D-aspartate (NMDA) receptor in rodents, and blockade of the receptor during postnatal brain development period causes schizophrenia-like behavior in adulthood. During the postnatal period, NR2A- and NR2B-containing NMDA receptors are highly expressed, and these tw...

We have previously established a novel stress model in which mice were exposed to emotional stress by witnessing socially defeated conspecifics in the social defeat stress (SDS) paradigm. In the present study, we attempted to establish a simpler and more standardized stress model by exposing male C57BL/6J mice to a video-recorded scene of the SDS....

We have previously reported that both methamphetamine (an indirect dopamine agonist) and phencyclidine (an antagonist of the NMDA receptor) enhanced mRNA expression of WD repeat domain 3 (WDR3) gene in the rat brain. However, the physiological function of WDR3 in the brain is still unclear. In the present study, we developed a novel polyclonal anti...

Early social experience is critical for development of social and emotional functions, and social adversity in early life induces social and emotional dysfunctions in rodents and human. However, its underlying neural mechanisms are poorly understood. Recently, the orbitofrontal cortex (OFC) and amygdala have been highlighted as key nods for social...

Exposure to stress induces alterations in synaptic functions, and increases the risk of stress-related psychiatric disorders, such as major depression and PTSD. To develop new treatments for stress-related psychiatric disorders, it is important to understand the effect of stress on the emotional circuits, such as prefrontal cortex (PFC), amygdala a...

Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the central nervous system, synthesized by two isoforms of glutamate decarboxylase (GAD): GAD65 and GAD67. GABA may act as a trophic factor during brain development, but its contribution to the development and maturation of cerebellar neural circuits is not known. To understan...

Rodents perceive the emotional states of conspecifics using vision. In the present study, we demonstrated that exposure to the video-recorded distress of conspecifics induces stress responses in male C57BL/6J mice. A single exposure to a video-recorded scene of the social defeat stress (SDS) increased plasma corticosterone levels in these mice. Thi...

Allergic dermatitis (AD), associated with pruritus and itchiness, is one of the major stressful conditions early in life. AD also influences the incidence of neuropsychiatric disorders and developmental disorders through neuro-immune interactions. To the best of our knowledge, there is no report that assesses the effects of early childhood dermatit...

Objective: The contribution of components in cognitive behavior therapy (CBT) to the total reduction of depression symptoms has not been well elucidated, and previous studies couldn't exclude the human factors in the therapy. Design: This is a secondary analysis of a randomized, controlled trial comparing automated smartphone CBT without human fact...

Stress increases the risk of neuropsychiatric disorders, such as major depression. Exposure to stress has been reported to induce various neuronal changes, such as alterations in synaptic transmission and structure. However, a causal link between stress-induced neural circuit alterations and changes in emotional behaviours is not well understood. I...

Impairments in synapse development are thought to cause numerous psychiatric disorders. Autism susceptibility candidate 2 (AUTS2) gene has been associated with various psychiatric disorders, such as autism and intellectual disabilities. Although roles for AUTS2 in neuronal migration and neuritogenesis have been reported, its involvement in synapse...

Background : Clinical trials have traditionally been analysed at the aggregate level, assuming that the group average would be applicable to all eligible and similar patients. We re-analyzed a mega-trial of antidepressant therapy for major depression to explore whether a multivariable prediction model may lead to different treatment recommendations...

The beneficial effects of omega (ω)-3 polyunsaturated fatty acid (PUFA) supplementation on major depressive disorder have been actively studied, but the underlying mechanism remains unknown. The present study examined the involvement of the nucleus accumbens (NAc) dopaminergic systems in behavioral changes in mice fed a diet high in ω-3 PUFAs. Mice...

[Introduction] Early postnatal period is sensitive window for the development of neural circuits and brain functions. Thus, stressful experience in early life increases risks of various psychiatric symptoms including social dysfunction. However, mechanisms how early life stress disrupt the development of social circuits in brain were less understoo...

The orbitofrontal cortex (OFC) has important roles for processing of negative emotion and has recently been highlighted as a critical region in stress-related psychiatric disorders such as depression. However, mechanisms how stress affect OFC circuit and induce psychiatric symptoms were less understood. OFC sends dense projection to the amygdala, w...

Aim: Suicide attempters have a high risk of repeated suicide attempts and completed suicide. There is evidence that assertive case management can reduce the incidence of recurrent suicidal behavior among suicide attempters. This study evaluated the effect of an assertive case management training program. Methods: This multicenter, before-and-aft...

We investigated whether benzothiazepines could produce anxiolytic effects via allopregnanolone (ALLO) biosynthesis in mice. We compared the behavioral effects caused by benzothiazepines to those caused by carbamazepine and sodium valproate. We found that a pretreatment with finasteride (a 5 alpha-reductase inhibitor) suppressed carbamazepine-induce...

Researchers increasingly use meta-analysis to synthesize the results of several studies in order to estimate a common effect. When the outcome variable is continuous, standard meta-analytic approaches assume that the primary studies report the sample mean and standard deviation of the outcome. However, when the outcome is skewed, authors sometimes...

Background Methamphetamine (METH) is one of the most widely distributed psychostimulants in worldwide. Despite active Countermeasures taken by different countries, neither the overall usage of METH nor the frequency of repeat users has reduced over the past decade. METH induces abuse and dependence as it acts on the central nervous system and tempo...

Background: Screening for major depression with the Patient Health Questionnaire-9 (PHQ-9) can be done using a cutoff or the PHQ-9 diagnostic algorithm. Many primary studies publish results for only one approach, and previous meta-analyses of the algorithm approach included only a subset of primary studies that collected data and could have publish...

In this study, we investigated the effects of emotional stress and physical stress using the social defeat stress (SDS) model in mice. Male C57BL/6 J mice were attacked by male non-retired ICR mice for 10 min daily for 10 days (physical stress; PS), while the other cohort of mice witnessed the defeat (emotional stress; ES). As a result, both PS and...

Equivalency of the diagnostic accuracy of the PHQ-8 and PHQ-9: a systematic review and individual participant data meta-analysis – ERRATUM - Yin Wu, Brooke Levis, Kira E. Riehm, Nazanin Saadat, Alexander W. Levis, Marleine Azar, Danielle B. Rice, Jill Boruff, Pim Cuijpers, Simon Gilbody, John P.A. Ioannidis, Lorie A. Kloda, Dean McMillan, Scott B....

Background Item 9 of the Patient Health Questionnaire-9 (PHQ-9) queries about thoughts of death and self-harm, but not suicidality. Although it is sometimes used to assess suicide risk, most positive responses are not associated with suicidality. The PHQ-8, which omits Item 9, is thus increasingly used in research. We assessed equivalency of total...

Objective: This study aimed to summarize interventions for suicide prevention in patients with cancer and highlight any methodological issues. Methods: We searched PubMed, PsycINFO, CINAHL, and the Cochrane database from their inception until July 2018. Additionally, we manually searched the references of included studies and recent systematic r...

Major depressive disorder (MDD) is the most common psychiatric disorders. However, a biochemical marker has yet to be established for clinical purposes. It is proposed that lysophosphatidic acid (LPA, 1-acyl-2-sn-glycerol-3-phosphoate) plays some important roles in emotional regulation of experimental animals. Therefore, in this study, we measured...

It is suggested that lysophosphatidic acid (LPA) plays a key role in the pathophysiology of schizophrenia. In this study, we measured LPA levels by enzyme-linked immunosorbent assay in cerebrospinal fluid (CSF) and plasma samples. The participants were 49 patients with schizophrenia and 49 normal healthy controls for CSF study, and 42 patients and...

Strategies to facilitate extinction of fear memory have attracted increasing attention for enhancing the effectiveness of exposure therapy for anxiety disorders. Previously, we demonstrated that systemic administration of a delta opioid receptor agonist, KNT-127, has clear anxiolytic-like effects in rats, without impairing memory. These observation...

Background Identifying the predictors of relapse could help to develop more individualized treatment strategies for major depression. The study aim was to explore predictors of depression relapse after remission using data from our previous multicenter randomized practical trial of patients with major depression. Methods Our cohort comprised subje...

Previously, we reported that expression of Rho/Rho-associated kinase (Rho/ROCK) pathway related genes in the rat brain were decreased after chronic administration of antidepressants, imipramine and sertraline. Then, we hypothesized that inhibition of ROCK would serve as a medication to treat stress-related mental disorders. In this study, we invest...

Background There is evidence that several intervention types, including psychotherapy, reduce repeat suicide attempts. However, these interventions are less applicable to the heterogeneous patients admitted to emergency departments (EDs). The risk of a repeat suicide attempt is especially high in the first 6 months after the initial attempt. Theref...

Background Suicide is a critical global health issue. Japan has had a high suicide rate for the last 12 decades. In 2007, the Japanese Central Government Office issued the “General Principles of Suicide Prevention Policy”. An important component of this policy was the gatekeeper training (GKT) program. GKT is a widely recommended suicide prevention...

Background: Gatekeeper training (GKT) is a common intervention aiming to prevent suicidal behavior. We investigated updated evidence for the effectiveness of GKT in suicide prevention using data from randomized controlled trials (RCTs) and intervention studies, and we also describe variations in existing GKT programs. Methods: We performed a system...

Background Depression is increasingly recognized as a chronic and relapsing disorder. However, an important minority of patients who start treatment for their major depressive episode recover to euthymia. It is clinically important to be able to predict such individuals. Methods The study is a secondary analysis of a recently completed pragmatic m...

RationaleWe previously reported that systemic administration of a selective delta opioid receptor (DOP) agonist, KNT-127, produced potent anxiolytic-like effects in rats. Interestingly, DOPs are highly distributed in the basolateral region of the amygdala (BLA). Objectives In this study, we investigated the effect of intra-BLA administration of KNT...

We previously reported that systemic administration of a delta opioid receptor (DOP) agonist, KNT-127, produced a potent anxiolytic-like effect in rats. Interestingly, DOPs are highly distributed in the prelimbic medial prefrontal cortex (PL-PFC). In the present study, we investigated the effect of KNT-127 co-perfusion in the PL-PFC on anxiety-like...

Introduction: Suicide attempt is the most important risk factor for later suicide. A randomised-controlled, multicentre trial of postsuicide attempt case management for the prevention of further suicide attempts in Japan, named ACTION-J, has established effective interventions for prevention of suicide reattempts. The ACTION-J assertive case manag...

Background: For patients starting treatment for depression, current guidelines recommend titrating the antidepressant dosage to the maximum of the licenced range if tolerated. When patients do not achieve remission within several weeks, recommendations include adding or switching to another antidepressant. However, the relative merits of these gui...

Background: Different diagnostic interviews are used as reference standards for major depression classification in research. Semi-structured interviews involve clinical judgement, whereas fully structured interviews are completely scripted. The Mini International Neuropsychiatric Interview (MINI), a brief fully structured interview, is also someti...

Aims: To evaluate the association between interview method and odds of major depression classification, controlling for depressive symptom scores and participant characteristics.

Background: A strong and growing body of evidence has demonstrated the effectiveness of cognitive behavioral therapy (CBT), either face-to-face, in person, or as self-help via the Internet, for depression. However, CBT is a complex intervention consisting of several putatively effective components, and how each component may or may not contribute...

Recently, we demonstrated that riluzole, which has been shown to block the glutamatergic system, facilitates fear extinction in rats. Here, we undertook experiments on contextual fear conditioning to clarify the actions of riluzole on the reconsolidation of fear memory in rats. We used the fast-acting benzodiazepine midazolam as a reconsolidation-i...

Background We previously reported that the novel selective delta opioid receptor (DOP) agonist KNT-127 did not cause convulsions in mice, whereas the prototype DOP agonist SNC80 did. Previous studies have reported that SNC80 caused electroencephalographic (EEG) disturbances in rodents. However, whether KNT-127 affects EEG responses is unknown. Ther...

A general understanding exists that inhibition of glutamatergic neurotransmission in the basolateral amygdala (BLA) impairs fear extinction in rodents. Surprisingly, we recently found that systemic administration of riluzole, which has been shown to inhibit the glutamatergic system, facilitates extinction learning in rats with a preconditioned cont...

We previously reported that systemic administration of the selective delta opioid receptor (DOP) agonist KNT-127 produces potent anxiolytic-like effects in rats. Although a higher distribution pattern of DOPs was reported in the prelimbic medial prefrontal cortex (PL-PFC) of rodents, the role of DOPs in PL-PFC and in anxiolytic-like effects have no...

It is widely thought that inactivation of the glutamatergic system impairs recognition memory in rodents. However, we previously demonstrated that systemic administration of riluzole, which blocks the glutamatergic system, enhances recognition memory in the rat novel object recognition (NOR) test. The mechanisms underlying this paradoxical effect o...