Published papers

Early diagnosis of dementia including Alzheimer’s disease (AD) is an urgent medical and welfare issue. However, to date, no simple biometrics have been available. We reported that blood DNA methylation levels of the COASY gene, which encodes coenzyme A synthase, were increased in individuals with AD and amnestic mild cognitive impairment (aMCI). The present study sought to replicate these findings with larger numbers of samples. Another objective was to clarify whether COASY methylation is associated with neurodegeneration through a comparison of AD, AD with cardiovascular disease (CVD), and vascular dementia (VaD). We measured blood COASY methylation levels in normal controls (NCs) (n = 200), and individuals with aMCI (n = 22), AD (n = 151), and VaD (n = 21). Compared with NCs, they were significantly higher in individuals with aMCI and AD. Further, they were significantly higher in AD patients without cardiovascular diseases compared to AD patients with them. These findings suggest that COASY methylation levels may be related to neurodegeneration in AD.

Adherence to antipsychotic medication is critical for the treatment of patients with schizophrenia. Impaired insight into illness is one of the principal drivers of medication nonadherence, which contributes to negative clinical outcomes. The aims of this study were to examine the relationships between impaired insight and (1) rates of antipsychotic medication nonadherence, and (2) time to medication nonadherence using data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study. Insight was assessed using the Positive and Negative Syndrome Scale (PANSS) item G12 (lack of judgment and insight). Patients were divided into 3 groups based on their degree of insight impairment, i.e. no impairment (PANSS G12 = 1), minimal impairment (PANSS G12 = 2–3), and moderate-to-severe insight impairment (PANSS G12 ≥ 4). Medication nonadherence was defined as taking less than 80% of monthly pill counts. Kaplan-Meier survival and Cox regression analyses were performed to examine differences in time to medication nonadherence between insight groups. There were significant differences between insight groups in the percentage of nonadherent patients at 6 months (χ (2) = 8.80, p = 0.012) and 18 months (χ (2) = 10.04, p = 0.007) after study initiation. Moderate-to-severe insight impairment was associated with earlier nonadherence compared to minimal (χ = 4.70, p = 0.030) or no impairment (χ = 11.92, p = 0.001). The association remained significant after adjustment for illness severity, substance use, attitudes toward medication, cognition, level of hostility, and depression. The results of this study indicate a strong link between impaired insight and antipsychotic medication nonadherence. Interventions to enhance insight early during treatment may help improve medication adherence, and in turn, long-term clinical and functional outcomes in patients with schizophrenia. This article is part of the issue entitled ‘Special Issue on Antipsychotics’. 2 2 2 2

Abnormalities of the kynurenine (KYN) pathway may be implicated in the pathophysiology of depression. However, the relationships between depression and each metabolite of the KYN pathway remain uncertain. Therefore, we conducted a meta-analysis about the levels of the metabolites of KYN pathway between patients with depression and controls. Out of 899 initial records, we identified 22 articles to form the empirical basis. Seventeen, 10, and 18 studies examined levels of kynurenic acid (KYNA), quinolinic acid (QUIN), and KYN, respectively. KYNA and KYN levels were lower in patients with depression in comparison to controls, while QUIN levels did not differ between the two groups. Antidepressant-free patients showed decreased KYNA levels and increased QUIN levels compared with controls. Male ratios of the samples were negatively associated with study SMDs for KYNA. In conclusion, this meta-analysis revealed that patients with depression had decreased level of KYNA and KYN, whereas antidepressant-free patients showed increased level of QUIN. Nevertheless, given the heterogeneity among their sample characteristics, further research is clearly needed.

Approximately 30% of patients with schizophrenia do not respond to antipsychotics and are thus considered to have treatment-resistant schizophrenia (TRS). To date, only four studies have examined glutamatergic neurometabolite levels using proton magnetic resonance spectroscopy ( H-MRS) in patients with TRS, collectively suggesting that glutamatergic dysfunction may be implicated in the pathophysiology of TRS. Notably, the TRS patient population in these studies had mild-to-moderate illness severity, which is not entirely reflective of what is observed in clinical practice. In this present work, we compared glutamate + glutamine (Glx) levels in the dorsal anterior cingulate cortex (dACC) and caudate among patients with TRS, patients with non-TRS, and healthy controls (HCs), using 3T H-MRS (PRESS, TE = 35 ms). TRS criteria were defined by severe positive symptoms (i.e., ≥5 on 2 Positive and Negative Syndrome Scale (PANSS)-positive symptom items or ≥4 on 3 PANSS-positive symptom items), despite standard antipsychotic treatment. A total of 95 participants were included (29 TRS patients [PANSS = 111.2 ± 20.4], 33 non-TRS patients [PANSS = 49.8 ± 13.7], and 33 HCs). dACC Glx levels were higher in the TRS group vs. HCs (group effect: F[2,75] = 4.74, p = 0.011; TRS vs. HCs: p = 0.012). No group differences were identified in the caudate. There were no associations between Glx levels and clinical severity in either patient group. Our results are suggestive of greater heterogeneity in TRS relative to non-TRS with respect to dACC Glx levels, necessitating further research to determine biological subtypes of TRS. 1 1

Background: Impaired illness awareness or insight into illness (IIA) is a common feature of schizophrenia that contributes to medication nonadherence and poor clinical outcomes. Neuroimaging studies suggest IIA may arise from interhemispheric imbalance in frontoparietal regions, particularly in the posterior parietal area (PPA) and the dorsolateral prefrontal cortex (dlPFC). In this pilot study, we examined the effects of transcranial direct current stimulation (tDCS) on brain regions implicated in IIA. Methods: Eleven patients with schizophrenia with IIA (≥3 PANSS G12) and 10 healthy controls were included. A crossover design was employed where all participants received single-session bi-frontal, bi-parietal, and sham stimulation in random order. For each condition, we measured (i) blood oxygen level-dependent (BOLD) response to an illness awareness task pre- and post-stimulation, (ii) regional cerebral blood-flow (rCBF) prior to and during stimulation, and (iii) changes in illness awareness. Results: At baseline, patients with schizophrenia showed higher BOLD-response to an illness awareness task in the left-PPA compared to healthy controls. Bi-parietal stimulation reduced the interhemispheric imbalance in the PPA compared to sham stimulation. Relatedly, bi-parietal stimulation increased rCBF beneath the anode (21% increase in the right-PPA), but not beneath the cathode (5.6% increase in the left-PPA). Bi-frontal stimulation did not induce changes in rCBF. We found no changes in illness awareness. Conclusion: Although single-session tDCS did not improve illness awareness, this pilot study provides mechanistic justification for future investigations to determine if multi-session bi-parietal tDCS can induce sustained changes in brain activity in the PPA in association with improved illness awareness.

Cortical excitation/inhibition (E/I) imbalances contribute to various clinical symptoms observed in autism spectrum disorder (ASD). However, the detailed pathophysiologic underpinning of E/I imbalance remains uncertain. Transcranial magnetic stimulation (TMS) motor-evoked potentials (MEP) are a non-invasive tool for examining cortical inhibition in ASD. Here, we conducted a systematic review on TMS neurophysiology in motor cortex (M1) such as MEPs and short-interval intracortical inhibition (SICI) between individuals with ASD and controls. Out of 538 initial records, we identified six articles. Five studies measured MEP, where four studies measured SICI. There were no differences in MEP amplitudes between the two groups, whereas SICI was likely to be reduced in individuals with ASD compared with controls. Notably, SICI largely reflects GABA(A) receptor-mediated function. Conversely, other magnetic resonance spectroscopy and postmortem methodologies assess GABA levels. The present review demonstrated that there may be neurophysiological deficits in GABA receptor-mediated function in ASD. In conclusion, reduced GABAergic function in the neural circuits could underlie the E/I imbalance in ASD, which may be related to the pathophysiology of clinical symptoms of ASD. Therefore, a novel treatment that targets the neural circuits related to GABA(A) receptor-mediated function in regions involved in the pathophysiology of ASD may be promising.

Delay discounting (DD) represents decreased subjective value for delayed reward relative to the same reward at present. The concept of DD has been applied for pathophysiology of addiction and psychiatric disorders. However, the detailed neuroimaging correlates of DD underlying pathophysiology still remain unclear. Thus, we conducted a systematic review to investigate neural correlates of DD on magnetic resonance imaging studies among addiction and psychiatric disorders. Specific search terms were set on PubMed to identify relevant articles. Initial search identified 551 records and 31 studies met the inclusion criteria. The present review revealed that greater DD was correlated with increased activity in areas related to reward evaluation and prediction as well as decreased activity in areas related to cognitive control. Healthy controls showed smaller changes in activities of these areas associated with DD when compared to patient groups. As the neural basis related to DD, three neural networks have been proposed that are associated with the actions of short-term interests and long-term benefits. Among the three potential neural networks on DD, the first one included the ventromedial prefrontal cortex and ventral striatum and implicated in evaluating reward values, the second network included the anterior cingulate cortex and linked to cognitive control, and the third network included the middle temporal gyrus and was involved in predictions and affection. This review generated consistent findings on the neural basis of DD among patients with addiction and psychiatric disorders, which may represent the pathophysiology related to DD and impulsivity of mental illness.

Widespread structrual abnormalities in subcortical brain regions have been identified in patients with schizophrenia. However, only a few studies have examined the neuroanatomical profiles of patients with treatment-resistant schizophrenia. The aim of this study was to compare differences in subcortical and hippocampal volumes between: (i) treatment-resistant patients who are non-responders to both first-line antipsychotics and clozapine (URS), (ii) treatment-resistant patients who are non-responders to first-line antipsychotics but are responders to clozapine (CLZ-Resp), (iii) responders to first-line antipsychotics (FL-Resp), and (iv) healthy controls. T1-weighted images of 103 participants (27 URS, 29 CLZ-Resp, 21 FL-Resp, and 26 healthy controls) were obtained. Group differences in striatal, thalamic, globus pallidus, amygdala, and hippocampus volumes were examined. Multiple regression analyses were performed to examine the associations between subcortical and hippocampal volumes and participant characteristics. The FL-Resp group showed larger striatal and globus pallidus volumes compared to the URS group and larger post-commissural putamen and globus pallidus volumes compared to healthy controls. The URS group showed smaller thalamic volume compared to healthy controls. There were no subcortical or hippocampal volume differences between the URS and CLZ-Resp groups. Differences in subcortical and hippocampal structural volumes were not related to symptom severity or chlorpromazine antipsychotic dose equivalents. Our findings suggest different structural volume alterations in subcortical brain regions between treatment-resistant schizophrenia and responders to first-line antipsychotics. Whether subcortical structure compromise is a distinct pathophysiological marker of treatment-resistant schizophrenia, or a result of antipsychotic exposure, remains to be explored.

Recent developments in neuroimaging techniques have advanced our understanding of biological mechanisms underpinning narcolepsy. We used MEDLINE to retrieve neuroimaging studies to compare patients with narcolepsy and healthy controls. Thirty-seven studies were identified and demonstrated several replicated abnormalities: (1) gray matter reductions in superior frontal, superior and inferior temporal, and middle occipital gyri, hypothalamus, amygdala, insula, hippocampus, cingulate cortex, thalamus, and nucleus accumbens, (2) decreased fractional anisotropy in white matter of fronto-orbital and cingulate area, (3) reduced brain metabolism or cerebral blood flow in middle and superior frontal, and cingulate cortex (4) increased activity in inferior frontal gyri, insula, amygdala, and nucleus accumbens, and (5) N-acetylaspartate/creatine-phosphocreatine level reduction in hypothalamus. In conclusion, all the replicated findings are still controversial due to the limitations such as heterogeneity or size of the samples and lack of multimodal imaging or follow-up. Thus, future neuroimaging studies should employ multimodal imaging methods in a large sample size of patients with narcolepsy and consider age, duration of disease, age at onset, severity, human leukocyte antigen type, cerebrospinal fluid hypocretin levels, and medication intake in order to elucidate possible neuroimaging characteristic of narcolepsy and identify therapeutic targets.

Background: Studies using proton magnetic resonance spectroscopy ( H-MRS) have reported altered neurometabolite levels in patients with schizophrenia. However, results are possibly confounded by the influence of antipsychotic (AP). Thus, this meta-analysis aimed to examine neurometabolite levels in AP-naïve/free patients with schizophrenia. Methods: A literature search was conducted using Embase, Medline, and PsycINFO to identify studies that compared neurometabolite levels in AP-naïve/free patients with schizophrenia to healthy controls (HCs). Eight neurometabolites (glutamate, glutamine, glutamate + glutamine, N-acetylaspartate [NAA], choline, creatine, myo-inositol, and γ-Aminobutyric acid [GABA]) and seven regions of interest (ROI; medial prefrontal cortex, dorsolateral prefrontal cortex, frontal white matter, occipital lobe, basal ganglia, hippocampus/medial temporal lobe, and thalamus) were examined. Results: Twenty-one studies (N = 1281) were included in the analysis. The results showed lower thalamic NAA levels (3 studies, n = 174, effect size = −0.56, P = 0.0005) in the patient group. No group differences were identified for other neurometabolites. Conclusions: Our findings suggest that impaired neuronal integrity in the thalamus may be a potential trait maker in the early stages of schizophrenia. 1

Neuropsychiatric symptoms (NPS) inevitably occur during the course of Alzheimer’s disease (AD) including psychosis, aggression, and depression. The effectiveness of pharmacological treatments for NPS has been limited because of their lack of efficacy, discontinuation due to undesirable adverse events, or poor adherence. In recent consensus guidelines, non-pharmacological treatments for NPS have been prioritized as first-line management strategies. Pharmacological treatments for severe NPS should be administrated as a second-line approach, and have been suggested to be started at a lower dosage followed by titration to a minimum effective dosage and for a limited time period. However, recent studies have shown that some patients receiving pharmacological treatments do not exhibit treatment efficacy in comparison with placebo. The concurrence of several sub-symptoms in NPS makes it difficult to target one symptom exclusively. Therefore, the current review focuses on a strategy for such refractory NPS in patients with AD. Recent randomized controlled trials have shown that the severity of NPS gradually reduces in a time-dependent manner regardless of active treatments. Therefore, clinicians should consider potential causes of NPS sub-symptoms from multifactorial aspects and select alternative treatments (e.g. neuromodulation or relocation into specialized care units) during the long-term disease course.

Backgrounds and aims: While the Internet became an indispensable component of our contemporary life, public and academic attention is also gathered to its negative impact, namely Internet addiction (IA). Although clinicodemographic and behavioral factors are hypothetically implicated in the mechanism of IA, it still remains largely unknown how such factors are linked to IA severity. Thus, this study sought to examine relationships among IA severity and factors potentially associated with IA in Japanese students in different educational stages. Methods: We conducted a questionnaire-based survey, which included questions about types of online activities and clinicodemographic information, the IA test for IA severity, and the K6 scale for psychological distress in 3,224 students at elementary, junior, and senior high schools, and universities. A multiple regression analysis was performed to predict IA severity with clinicodemographic and behavioral factors. Results: IA severity was significantly positively related to the following factors: e-messaging, social networking services (SNS), games, holiday Internet usage, and K6 scores, while IA severity had negative correlation with using Internet for educational purposes, age of first exposure to the Internet, and sleep duration. Age was not related to IA severity among participants using both SNS and e-messaging. Conclusions: IA was linked to various online activities and the degree of psychological distress. This indicates the importance of comprehensive assessment of online behavior and psychological factors for further understanding of IA.

Background: Despite a steady increase in life expectancy, a few studies have investigated cross-sectional correlates and longitudinal predictors of cognitive function, a core domain of the successful aging, among socio-clinico-demographic factors in the oldest-old exclusively. Objectives: The aims of this study were to examine socio-clinico-demographic characteristics associated with global cognition and its changes in the oldest-old. Methods: We reanalyzed a dataset of cognitively preserved community-dwelling subjects aged 85 years and older in the Tokyo Oldest Old Survey on Total Health, a 6-year longitudinal observational study. This study consisted of (1) baseline cross-sectional analyses examining correlates of global cognition (n = 248) among socio-clinico-demographic factors and (2) longitudinal analyses examining baseline predictors for changes of global cognition in 3-year follow-up (n = 195). The Mini-Mental State Examination was used as a screening test to assess global cognition. Results: At baseline, higher weights were related to higher cognitive function in the oldest-old. The baseline predictors of global cognitive decline in 3-year follow-up were higher global cognition, shorter education period, and lower sociocultural activities and lower instrumental activity of daily living, in this order. Conclusions: The present study suggests that it is crucial to attain higher education during early life and avoid leanness or obesity, participate in sociocultural cognitive activities during late life, and maintain instrumental activity of daily living to preserve optimal cognitive function in the oldest-old, which will facilitate developing prevention strategies for cognitive decline and promoting successful aging in this increasing population.

Background: The neural basis of treatment-resistant schizophrenia (TRS) remains unclear. Previous neuroimaging studies suggest that aberrant connectivity between the anterior cingulate cortex (ACC) and default mode network (DMN) may play a key role in the pathophysiology of TRS. Thus, we aimed to examine the connectivity between the ACC and posterior cingulate cortex (PCC), a hub of the DMN, computing isolated effective coherence (iCoh), which represents causal effective connectivity. Methods: Resting-state electroencephalogram with 19 channels was acquired from seventeen patients with TRS and thirty patients with non-TRS (nTRS). The iCoh values between the PCC and ACC were calculated using sLORETA software. We conducted four-way analyses of variance (ANOVAs) for iCoh values with group as a between-subject factor and frequency, directionality, and laterality as within-subject factors and post-hoc independent t-tests. Results: The ANOVA and post-hoc t-tests for the iCoh ratio of directionality from PCC to ACC showed significant findings in delta (t = 7.659, p = 0.008) and theta (t = 8.066, p = 0.007) bands in the left side (TRS < nTRS). Conclusion: Left delta and theta PCC and ACC iCoh ratio may represent a neurophysiological basis of TRS. Given the preliminary nature of this study, these results warrant further study to confirm the importance of iCoh as a clinical indicator for treatment-resistance. 45 45

Previous proton magnetic resonance spectroscopy ( H-MRS) studies have reported disrupted levels of various neurometabolites in patients with schizophrenia. An area of particular interest within this patient population is the striatum, which is highly implicated in the pathophysiology of schizophrenia. The present study examined neurometabolite levels in the striatum of 12 patients with schizophrenia receiving antipsychotic treatment for at least 1 year and 11 healthy controls using 3-Tesla H-MRS (PRESS, TE = 35 ms). Glutamate, glutamate+glutamine (Glx), myo-inositol, choline, N-acetylaspartate, and creatine levels were estimated using LCModel, and corrected for fraction of cerebrospinal fluid in the H-MRS voxel. Striatal neurometabolite levels were compared between groups. Multiple study visits permitted a reliability assessment for neurometabolite levels (days between paired H-MRS acquisitions: average = 90.33; range = 7–306). Striatal neurometabolite levels did not differ between groups. Within the whole sample, intraclass correlation coefficients for glutamate, Glx, myo-inositol, choline, and N-acetylaspartate were fair to excellent (0.576–0.847). The similarity in striatal neurometabolite levels between groups implies a marked difference from the antipsychotic-naïve first-episode state, especially in terms of glutamatergic neurometabolites, and might provide insight regarding illness progression and the influence of antipsychotic medication. 1 1 1 1

Aim: Few cohort studies targeting the oldest-old individuals have been carried out. The subiculum in the hippocampus is thought to be related to memory function, and atrophy of this structure might result in the conversion from amnestic mild cognitive impairment to Alzheimer's disease. Thus, we sought to examine the relationship between subiculum volumes and memory function in individuals aged ≥95 years, using a novel cognitive examination called the Addenbrooke's Cognitive Examination III (ACE-III) and an advanced magnetic resonance imaging analytical method, Multiple Automatically Generated Templates Brain Segmentation Algorithm (MAGeTbrain), to measure hippocampal subfield volumes. Methods: A part of the cohort data of the Arakawa 95+ study for the oldest-old aged ≥95 years was used. A total of 10 individuals completed all of the examinations. The MAGeT brain was applied to estimate the subfield volumes of the hippocampus. Correlation analyses and multiple regression analyses were carried out to examine a relationship among ACE-III memory scores and the subfield volumes in the hippocampus, including the subiculum. Results: There was a significant relationship between ACE-III memory scores and subdivision volumes. Regression analyses showed that subiculum volumes were associated with ACE-III memory scores in the oldest-old individuals (β = 0.721, P = 0.019; F = 8.67, adjusted R = 0.46). Conclusions: The subiculum might play a pivotal role in memory function in the oldest-old individuals aged ≥95 years. The present finding warrants further research including larger sample sizes. Geriatr Gerontol Int 2019; 19: 347–351. 1, 8 2

Despite previous neuroimaging studies demonstrating morphological abnormalities of the thalamus and other subcortical structures in patients with schizophrenia, the potential role of the thalamus and its subdivisions in the pathophysiology of this illness remains elusive. It is also unclear whether similar changes of these structures occur in individuals at high risk for psychosis. In this study, magnetic resonance imaging was employed with the Multiple Automatically Generated Templates (MAGeT) brain segmentation algorithm to determine volumes of the thalamic subdivisions, the striatum (caudate, putamen, and nucleus accumbens), and the globus pallidus in 62 patients with schizophrenia, 38 individuals with an at-risk mental state (ARMS) [4 of whom (10.5%) subsequently developed schizophrenia], and 61 healthy subjects. Cognitive function of the patients was assessed by using the Brief Assessment of Cognition in Schizophrenia (BACS) and the Schizophrenia Cognition Rating Scale (SCoRS). Thalamic volume (particularly the medial dorsal and ventral lateral nuclei) was smaller in the schizophrenia group than the ARMS and control groups, while there were no differences for the striatum and globus pallidus. In the schizophrenia group, the reduction of thalamic ventral lateral nucleus volume was significantly associated with lower BACS score. The pallidal volume was positively correlated with the dose of antipsychotic treatment in the schizophrenia group. These results suggest that patients with schizophrenia, but not those with ARMS, exhibit volume reduction in specific thalamic subdivisions, which may underlie core clinical features of this illness.

Background: The relationship between dopamine D receptor (D R) occupancy and impaired illness awareness (IIA) remains unclear. While IIA is associated with illness severity and cognitive dysfunction, antipsychotic medication, the principal treatment for schizophrenia, indirectly improves IIA, but may simultaneously contribute to cognitive dysfunction at supratherapeutic doses. Aim and methods: We investigated the influence of estimated D R (Est.D R) occupancy by antipsychotics on the relationships between IIA and illness severity, and IIA and cognition. IIA was assessed in 373 adult patients with schizophrenia (18−62 years) using data from CATIE. IIA was measured using the Positive and Negative Syndrome Scale (PANSS) item G12. D R occupancy levels were estimated from plasma concentrations for risperidone, olanzapine, and ziprasidone. Correlation, regression, and path analyses were performed to examine IIA's relationship to illness severity, cognition, and Est.D R. Results: Illness severity was predictive of IIA. However, premorbid IQ, cognition, and Est.D R did not predict IIA, and Est.D R did not serve either a moderating or mediating role in both regression and path analyses. Conclusions: Consistent with previous literature, our results suggest that IIA is a function of illness severity in adult patients with schizophrenia. Future studies should explore whether D R occupancy mediates the relationships between IIA and illness severity, and IIA and cognitive dysfunction, in late-life schizophrenia (i.e. ≥60 years) given the effects of aging on cognition, IIA, and antipsychotic sensitivity. 2 2 2 2 2 2 2 2 2

Approximately one-third of patients with schizophrenia have treatment-resistant schizophrenia (TR-SCZ), which is a condition characterized by suboptimal response to antipsychotics other than clozapine. Importantly, treatment with clozapine—the only antipsychotic with an indication for TR-SCZ—is often delayed, which could contribute to negative outcomes. Given that the specific impact of delay in clozapine initiation is not well understood, we aimed to conduct a systematic search of the Ovid Medline database to identify English language publications exploring the impact of delay in clozapine initiation on treatment outcomes in patients with TR-SCZ. Additionally, clinico-demographic factors associated with clozapine delay were examined. Our search identified four retrospective studies that showed an association between longer delay in clozapine initiation and poorer treatment outcomes, even after including covariates, such as age, sex, and duration of illness. In addition, we found six studies that showed an association between age and clozapine delay, but results with regard to other clinico-demographic variables were inconsistent. Overall, the available literature reveals a possible link between delay in clozapine use and poorer treatment outcomes in patients with TR-SCZ. However, given the relatively small number of studies on this clinically important topic, future research is warranted to draw more definitive conclusions. ®

Background: Neurophysiology including P300, that is a typical index of event-related potential, may be potential biomarkers for bipolar disorder (BD) and it can be useful towards elucidating the pathophysiology of BD. However, previous findings from P300 studies were inconsistent due to the heterogeneity of research methods, which make it difficult to understand the neurobiological significance of them. The aim of this study is to conduct a meta-analysis on P300 in patients with BD. Method: A literature search was conducted using PubMed to identify studies that compared P300 event-related potential between patients with BD and healthy controls (HCs). We analyzed P300 indices such as amplitude and latency of P3a and P3b in auditory or visual paradigms. Further, moderator analyses were conducted to investigate the influence of patient characteristics (i.e. history of psychosis, diagnostic subcategories [BD-I/BD-II], and phase of illness [euthymic, manic, or depressive]) on P300 indices. Result: Out of 124 initial records, we included 30 articles (BD: N = 1331; HCs: N = 1818). Patients with BD showed reduced P3a and P3b amplitude in both paradigms and delayed P3b latency in auditory paradigms compared to HCs. There was no influence on the history of psychosis, diagnostic subcategories, or phase of illness on P300 indices. Limitation: The difference in medication use was difficult to control and it may affect the results. Conclusion: This meta-analysis provides evidence for P300 abnormalities in patients with BD compared to HCs. Our results suggest that P300 may be trait markers rather than state markers in this illness.