This article is a response to 'Hypnotic discontinuation is not synonymous with successful deprescribing: A Taiwan perspective'.
Tajika and colleagues found that, among Japanese respondents willing to consider lecanemab, the median smallest worthwhile difference exceeded the absolute benefit used in their study scenario. This commentary argues that this expectation-efficacy gap should be translated into concrete clinical tasks across the anti-amyloid care pathway, including expectation assessment, biomarker and eligibility counseling, shared decision-making, treatment monitoring, support for non-initiation or discontinuation, and continuing psychosocial care.
AIM:There is a critical need for objective biomarkers that can link peripheral assays to central neural network dysfunction. We investigated blood neurofilament light chain (NfL), a marker of axonal injury, and C-reactive protein (CRP), a marker of systemic inflammation, in relation to the brain network topology and microstructural integrity in methamphetamine use disorder (MUD), a paradigm of acquired neurotoxicity. METHODS:Forty-two male MUD patients and 44 male controls received diffusion and resting-state functional magnetic resonance imaging and underwent analysis of blood NfL and CRP levels. RESULTS:Compared to controls, MUD patients exhibited significantly elevated blood NfL and CRP levels, as well as salience-network dysfunction and microstructural abnormality. Furthermore, higher NfL levels were associated with lower local efficiency (segregation) in the right anterior insula and higher mean diffusivity in the right insula and supramarginal gyrus, supporting a link with axonal injury. By contrast, higher CRP levels were associated with integration-related graph measures in the bilateral supramarginal gyrus, suggesting that systemic inflammation may also be relevant to salience-network dysfunction in MUD. Crucially, the correlation involving NfL levels remained significant after controlling for the duration of methamphetamine use, and higher baseline NfL levels were significantly correlated with greater urine positivity rates during one-year follow-up. CONCLUSIONS:Blood NfL was associated with both functional and microstructural abnormalities of the salience network and potentially associated with relapse vulnerability in MUD.
AIM:Pathological dissociation is a complex clinical symptom widely observed across various psychiatric disorders. Dissociative symptoms prolong the duration of hospitalization and are associated with a poor clinical prognosis. Although several pathological models (e.g., the frontal-limbic overmodulation model and the defense cascade model) have been proposed to interpret dissociative symptoms, heterogeneous regional-level imaging findings impede our comprehension of the neural changes underlying dissociative symptoms across diagnoses. METHODS:Using the functional connectivity network mapping method, this study systematically screened 45 cross-diagnostic reports of dissociation-related structural and functional brain changes. By integrating resting-state imaging data from healthy individuals (n = 872), we constructed dissociative task-induced activation, gray matter volume (GMV), and resting-state activity impairment networks. Additionally, we performed spatial correlation analyses between the damage networks and 19 neurotransmitter distribution maps. RESULTS:The task-induced damage network showed the largest proportional overlap with the anterior salience network (SN, 12.25%), basal ganglia network (BGN, 13.57%), and dorsal default mode network (DMN, 17.74%). For the GMV damage network, the main overlap proportions were observed with the dorsal DMN (12.33%) and the anterior SN (7.67%). The resting-state activity damage network showed the greatest overlap with the anterior SN (5.17%), posterior SN (5.73%), auditory (5.47%), and sensorimotor network (4.50%). Spatial correlation analyses found associations between network changes and the distribution of N-methyl-D-aspartate receptors, vesicular acetylcholine transporter, cannabinoid receptor CB1, serotonin transporter, and mu-opioid receptor. CONCLUSION:This study further elucidated the neuroimaging changes underlying across-diagnostic dissociation and provided new insights for identifying network intervention targets to improve dissociative symptoms.
Addiction is a chronic relapsing condition characterized by compulsive reward seeking and impaired behavioral control, associated with major individual and societal burden. Mechanistic investigation in humans remains constrained by ethical limitations, uncontrolled exposure histories, and ecological confounds. Parkinson's disease treated with dopamine replacement therapy provides a human framework for investigating addiction-relevant mechanisms under controlled dopaminergic modulation. We performed a narrative synthesis of clinical, neuropsychological, pharmacological, neuroimaging, and electrophysiological evidence linking impulse control disorders and dopamine dysregulation syndrome in Parkinson's disease to dimensional and circuit-based models of addiction. We examined phenotypic and neurobiological convergences, experimental opportunities, and translational relevance while outlining its boundary conditions. A subset of Parkinson's disease patients exposed to dopamine replacement treatment develops impulse control disorders and dopamine dysregulation syndrome. Impulse control disorders comprise heterogeneous behavioral phenotypes that share selected dimensions with behavioral addictions, whereas dopamine dysregulation syndrome most closely approximates pharmacological substance use disorders. These phenotypes share selected addiction-related dimensions, including craving, impaired control, compulsive reward-seeking, and persistence despite harm, while showing partial clinical and neurobiological convergence with behavioral addictions and substance use disorders. Parkinson's disease patients with neuropsychiatric fluctuations may represent a sensitized vulnerability state in which dopaminergic modulation dynamically influences reward processing, motivation, and compulsive behaviors. Parkinson's disease under dopamine replacement therapy enables within-subject dopaminergic manipulation, longitudinal observation, prospective assessment of vulnerability traits, multimodal neurobiological investigation, and reduced environmental confounding. It therefore provides a unique human window for investigating addiction-relevant mechanisms under controlled dopaminergic modulation, complementing animal models while remaining constrained by disease-specific boundary conditions.
AIM:The COVID-19 pandemic had substantial effects on youth mental health. Most previous studies focused on the initial pandemic years, leaving the post-restriction period underexplored. We examined trajectories of newly recorded psychiatric diagnoses among Japanese youths across two policy shifts: March 2020 school closures and May 2023 reclassification of COVID-19 as an influenza-equivalent Category V disease. METHODS:We conducted an interrupted time-series analysis using the National Database of Health Insurance Claims, covering over 99% of the Japanese population. The study included 21 million individuals aged under 19 years to analyze monthly trends in first recorded psychiatric diagnoses from January 2018 to March 2024. Segmented negative binomial regression was used to estimate shifts in levels and trends following both policy interventions. RESULTS:Following the 2020 closures, eating disorders showed sex-specific patterns: males showed an immediate 28.8% decrease (IRR 0.712, 95% CI 0.619-0.819), whereas females showed a 28.4% increase (IRR 1.284, 95% CI 1.045-1.576). Newly recorded ADHD diagnoses showed an 8.1% immediate decrease (IRR 0.919, 95% CI 0.847-0.997). During the restriction period, anxiety/stress-related and mood disorders showed apparent surge patterns following infection waves. After restrictions were lifted in 2023, eating disorders among males showed an upward level shift (IRR 1.214, 95% CI 1.076-1.370). Neurodevelopmental disorders showed preliminary downward trends in the post-restriction period. CONCLUSION:This nationwide study of 21 million youths suggested differential diagnostic patterns across pandemic phases. These contrasting trajectories highlight the need for subgroup-level post-pandemic diagnostic surveillance.
AIM:Neuroinflammation has been implicated in the pathogenesis of major depressive disorder (MDD), with interferon regulatory factor 1 (IRF1) playing a potential role. MicroRNAs (miRs) are also involved in MDD through posttranscriptional regulation of gene expression. This study investigated whether miR-20a-5p regulates IRF1 in MDD. METHODS:IRF1 mRNA and miR-20a-5p expression levels were measured by qPCR in postmortem hippocampi from 14 MDD subjects and 14 controls, and in chronic social defeat stress (CSDS) mice. Their regulatory relationship was examined in HEK293 cells using miR-20a-5p overexpression and a dual-luciferase assay. Neuro2a cells treated with DMSO were used to evaluate the effects of cellular stress on Irf1 and miR-20a-5p expression. RESULTS:IRF1 mRNA and miR-20a-5p expression levels were significantly increased in both MDD hippocampi and CSDS mice. Luciferase assays showed that miR-20a-5p directly targeted the conserved seed sequence within the IRF1 3'-UTR and suppressed IRF1 expression. During the early phase of cellular stress, Irf1 mRNA was upregulated, whereas miR-20a-5p was downregulated, suggesting that stress initially induces Irf1 expression, followed by secondary regulation of miR-20a-5p. CONCLUSION:IRF1 mRNA expression was increased in the hippocampus of both MDD subjects and CSDS mice. Moreover, miR-20a-5p directly targeted the IRF1 3'-UTR, supporting a potential miR-20a-5p-IRF1 regulatory axis involved in inflammatory signaling in MDD. However, its functional significance in vivo remains to be determined.
BACKGROUND:Major depressive disorder (MDD) aggregates in families. The neostriatum, key to reward and attachment circuits, has the highest density of serotonin 4 receptors (5-HT4R). Striatal 5-HT4R is low in MDD and linked to familial depression risk. Poor parental bonding increases depression risk, yet whether nature and nurture converge on 5-HT4R is unknown. We investigated whether parental bonding quality is associated with adult neostriatal 5-HT4R levels and could replicate prior findings on familial predisposition. METHODS:Familial predisposition, parental bonding instrument, and positron emission tomography data with [11C]SB207145 were available from 70 unmedicated MDD patients and 95 healthy controls (64% female; aged 18-57 years). 5-HT4R binding was quantified in the neostriatum and, secondarily, the amygdala, ACC, and neocortex. Linear regression models examined associations among 5-HT4R binding, familial predisposition to depression, and parental bonding, adjusting for sex, age, depression, and tracer mass. Sensitivity analyses were conducted with adjustments for hormonal contraceptives and within the healthy subsample only. RESULTS:Familial predisposition linked to neostriatal 5-HT4R differently by sex (sex interaction, P = 0.037): predisposed females had 6.8% higher binding than non-predisposed females (P = 0.024); males showed no significant difference in association. This was consistent across sensitivity analyses and secondary regions. Parental bonding was not associated with 5-HT4R in any region. CONCLUSION:Familial predisposition to depression is associated with neostriatal 5-HT4R in a sexually dimorphic manner, suggesting that inherited depression risk influences the serotonergic system through sex-specific mechanisms. The absence of parental bonding effects suggests that the impact on the serotonergic system may be subtle or compensated for.
Aim We aimed to examine the psychometric properties of the second version of the Brief Evaluation of Psychosis Symptom Domains (BE‐PSD‐V2.0) and its correspondence with the Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression–Severity scale (CGI‐S) scores. Methods This cross‐sectional study was conducted at 18 institutes in Japan. We performed correlational analyses to test the convergent and divergent validity of the BE‐PSD‐V2.0. Inter‐rater reliability was assessed using intraclass correlation coefficients (ICCs). The equipercentile equating method was employed to examine the linking of the BE‐PSD‐V2.0 with the PANSS and the CGI‐S. Results A total of 353 patients with schizophrenia spectrum disorders were included. Spearman's rank correlation coefficients between the BE‐PSD‐V2.0 item scores and their corresponding PANSS factor scores ranged from 0.64 to 0.86, indicating sufficient convergent validity. These specific correlation coefficients were consistently the highest among all item‐to‐factor comparisons, indicating sufficient divergent validity. In 34 patients, ICCs for the BE‐PSD‐V2.0 item and total scores ranged from 0.60 to 0.94, showing sufficient inter‐rater reliability. Conversion tables were established between the BE‐PSD‐V2.0 total score and the PANSS total score, between the BE‐PSD‐V2.0 total score and the CGI‐S score, and between the BE‐PSD‐V2.0 item scores and their corresponding PANSS factor scores. A correspondence between symptomatic remission criteria using the PANSS and BE‐PSD‐V2.0 was confirmed. Conclusions The BE‐PSD‐V2.0 possesses sufficient psychometric properties and corresponds to the PANSS and CGI‐S. It is a sound and reliable brief rating scale for assessing symptoms in schizophrenia spectrum disorders, and its established conversion correspondences facilitate score interpretation within existing clinical paradigms for both clinical practice and research.
AIM:In schizophrenia, disrupted perceptual processes contribute to positive symptoms. However, it remains unclear how top-down priors and bottom-up likelihoods are represented across the hierarchy of visual cortices. To identify these processes within cortical hierarchies, the circular inference model offers a framework to account for the biased integration of priors and likelihoods that may underlie hallucinations and delusions. METHODS:Twenty-one participants, including 10 schizophrenia patients and 11 healthy controls, conducted a perceptual decision-making task while undergoing functional MRI (fMRI) scanning. Participants first received probabilistic hints about forthcoming objects, then viewed a blurred image, and finally answered the object identity and confidence using a slider. Subjects' performances were analyzed based on Bayesian perception models, and the variables representing top-down prior and bottom-up likelihood were used for fMRI data analysis. RESULTS:Region of interest analysis revealed significantly enhanced top-down-related activity throughout the visual cortex in schizophrenia, compared with healthy controls (F(1,133) = 8.82, p = 0.003, η 2 $$ {\eta}^2 $$ = 0.059). In addition, exploratory ROI analyses found increased bottom-up-related activity in the early visual areas in individuals with higher delusion scores (V1: r = 0.41, p = 0.059, V2: r = 0.47, p = 0.030). CONCLUSIONS:Using model-based fMRI analysis, these findings provide evidence for enhanced top-down activity across the visual hierarchy in schizophrenia. Exploratory analyses also suggested a potential association between bottom-up hypersensitivity and delusional ideation; however, this association did not survive multiple-comparison correction. Our results are consistent with altered circular information flow in the visual cortex and highlight the value of model-based neuroimaging for uncovering latent abnormalities in perceptual processing.
This article relates to AI companions and synthetic intimacy: An emerging blind spot in psychiatric risk assessment.
Fibromyalgia is a complex chronic pain condition associated with widespread symptoms and perceptual distortions beyond nociception. Alterations in body image, body representation, and interoception may contribute to symptom severity and reduced quality of life. This review synthesizes evidence related to body image in adults with fibromyalgia. A systematic review and meta-analysis were conducted following PRISMA 2020 guidelines. PubMed, Scopus, and Web of Science were searched. Eligible studies included quantitative and qualitative designs examining body image, body awareness, and body esteem in adults with fibromyalgia. Risk of bias was assessed using the Newcastle-Ottawa Scale and the CASP checklist. A random-effects meta-analysis was performed. Meta-regression and subgroup analyses explored sources of variance. Twenty-five studies were included. Patients with fibromyalgia showed significant impairments in body image, body awareness, and body esteem compared to healthy controls and other rheumatic conditions (pooled ES = 0.99; 95% CI [0.64-1.35]). These disturbances were positively associated with pain intensity and disease impact, and negatively with quality of life, anxiety, depression, and alexithymia. Qualitative findings described bodily alienation and transformation of bodily identity. Evidence was limited by cross-sectional designs and variability in outcome measures. Fibromyalgia involves multidimensional disturbances of the bodily self with perceptual, cognitive, and affective components, associated with greater symptom burden and poorer quality of life. Longitudinal and mixed-methods research integrating neurobiological and subjective measures is needed, alongside standardized tools and targeted interventions for body awareness and interoceptive regulation.
This article relates to Response to commentary "Hypnotic-associated falls across the diurnal cycle: pharmacokinetic signal or delirium rhythm?"
Aim The Treatment-Response-and-Resistance-in-Psychosis (TRRIP) criteria recognizes negative symptoms as defining features for treatment-resistant schizophrenia (TRS). Social motivation refers to the desire to pursue social reward (and to avoid social punishment). Impaired social motivation is related to negative symptoms but has seldom been studied in TRS patients. We aimed to characterize social motivation processing in TRS patients and examine the impacts of negative symptoms on social motivation processing.Methods We recruited 60 TRS patients, 60 remitted schizophrenia patients and 60 controls. In the Social Incentive Delay (SID) task, participants had to hit the targets within the response window to seek positive/neutral/negative social outcomes in emoji formats; and they also rated their emotions during the anticipation and receipt of social outcomes. Generalized-estimation-equation (GEE) models examined the impacts of TRS/remitted schizophrenia, negative symptoms, and the interaction between clinical-group-status and cue-valence on the SID performance, that is, hit-or-not, anticipatory pleasure, and consummatory pleasure.Results The interaction between TRS status and social reward/punishment significantly predicted anticipatory pleasure, implicating that TRS patients' anticipatory pleasure was less subject to social reward/punishment compared to controls. Moreover, the interaction between TRS and social reward significantly predicted consummatory pleasure, implicating that TRS patients' consummatory pleasure was less subject to social reward compared to controls. Negative symptoms significantly predicted the SID accuracy in clinical participants, supporting its relationship with social motivation processing.Conclusion TRS patients have altered social motivation processing, affecting anticipatory and consummatory pleasure. Social motivation deficit may be an intervention target for negative symptoms and social functioning impairments in TRS patients.
AIMS:Clozapine-induced agranulocytosis (CIA) is traditionally considered an idiosyncratic, dose-independent reaction. However, emerging evidence suggests that clozapine-related inflammatory events may exhibit dose-dependent characteristics, leading us to hypothesize that CIA risk may similarly relate to early cumulative exposure. METHODS:Using Japan's nationwide Clozaril Patient Monitoring Service database (2009-2024), the 30-day cumulative dose following initiation was calculated for all treated patients. Participants were stratified into quartiles (Q1-Q4). CIA was defined as two consecutive absolute neutrophil counts <500/mm3. The incidence of CIA was compared across quartiles using Kaplan-Meier survival curves and Cox proportional hazards models adjusted for age and sex. RESULTS:Among 18,189 patients (mean age 42.9 [SD 12.7]; 46.4% female), 138 (0.76%) developed CIA, with no cases occurring within the first 30 days. The incidence rates of CIA in Q1, Q2, Q3, and Q4 were 0.44%, 0.66%, 0.74%, and 1.20%, respectively. Compared with Q1, hazard ratios (HRs) over 180 days were 1.78 (95% confidence interval [CI] 0.96-3.30; P = 0.0659), 2.01 (95% CI 1.10-3.66; P = 0.0233), and 3.07 (95% CI 1.74-5.42; P < 0.001) for Q2, Q3, and Q4, respectively. Male sex and age >40 years were identified as independent risk factors. E-values for Q4 HR were 5.59 (point estimate) and 2.88 (95% CI), indicating high robustness against unmeasured confounders such as co-medications. CONCLUSIONS:Higher early cumulative clozapine exposure was associated with increased CIA risk. These findings suggest that early exposure may serve as a clinically relevant marker of CIA risk, although causal inference is limited and further research is needed.
