Search Results (149)

Therapeutic inertia has been extensively examined in chronic medical conditions but remains insufficiently conceptualized and empirically studied in psychiatry. This structured narrative review examines therapeutic inertia as a multilevel and potentially bidirectional phenomenon arising when clinically relevant care is not reconsidered or modified despite unmet therapeutic goals and the availability of a reasonable and feasible alternative. A targeted PubMed search was supplemented by backward and forward citation searching, prioritizing psychiatric evidence and foundational literature on clinical decision-making under uncertainty. The review distinguishes therapeutic inertia from appropriate caution, watchful waiting, informed refusal, structural non-access, therapeutic nihilism, medical futility, therapeutic obstinacy, and evidence-based deprescribing. Potential determinants include cognitive and emotional mechanisms, diagnostic and prognostic uncertainty, adverse-effect concerns, patient preferences and previous experiences, therapeutic relationships, resource constraints, fragmented care, guideline structures, workload, and medicolegal culture. Clozapine underutilization in treatment-resistant schizophrenia represents the most compelling psychiatric example, while direct but more limited evidence is available in major depressive and bipolar disorders; applications to anxiety, obsessive-compulsive, substance-use, and non-pharmacological care remain largely hypothesis-generating. Strategies include explicit therapeutic goals, planned reassessment, measurement-based and guideline-informed care, shared decision-making, multidisciplinary review, improved access, clinical decision support, and audit and feedback. Future research should use operational definitions, experimental and observational designs, patient-centered outcomes, and real-world data to determine when treatment non-modification is inappropriate and whether corrective interventions improve care without promoting indiscriminate escalation, coercion, polypharmacy, or premature discontinuation. Full article

Cancer is a leading health issue worldwide, affecting approximately 20 million people annually. Developing efficient chemotherapy agents for cancer treatment is a challenging, costly, and time-consuming process. Drug repurposing for cancer treatment provides an optimal alternative, as the pharmacokinetic properties and the safety of these drugs have been previously tested. It also offers a faster and more cost-effective path to novel cancer therapies, which is especially valuable when conventional treatments face resistance or toxicity limitations. Antipsychotic drugs, which are primarily used for treating psychiatric disorders, including schizophrenia and bipolar disorder, have recently been investigated for their potential anticancer effects through drug repurposing strategies. While covering preliminary data and providing an overview of their mechanisms of action, this review highlights the latest research on antipsychotic medications’ emerging potential in oncology in experimental models, emphasizing their observed anticancer effects in preclinical studies, safety profile and capacity to enhance the effectiveness of conventional therapies. Despite growing interest, a research gap remains in translating these findings to clinical oncology, an issue this review addresses by proposing future investigative directions. Full article

Background: Available data indicate that the development of refractory schizophrenia may result from neuroinflammation, dysregulation of neurotrophins and metalloproteinases (MMPs), oxidative stress (OS), and hormonal imbalance. Electroconvulsive therapy (ECT) is an effective therapeutic option for drug resistance, but its impact on brain-derived neurotrophic factor (BDNF) and MMPs remains underinvestigated. This study evaluates the influence of ECT on serum BDNF, MMPs (MMP-7, MMP-9, MMP-14), and tissue inhibitors of metalloproteinases (TIMP-1, TIMP-2, TIMP-3) in patients with treatment-resistant schizophrenia (TRS). Another goal of this study is an assessment of the relationships between these biomarkers and the intensity of schizophrenia symptoms. Methods: Serum concentrations of the aforementioned biomarkers were measured prior to and after ECT in eight patients and 13 healthy controls. The severity of schizophrenia symptoms was evaluated with the Positive and Negative Syndrome Scale (PANSS). Results: Bayesian analysis comparing pre-ECT serum concentrations of BDNF, MMPs, and their inhibitors in TRS patients with a control group showed a significant difference only for MMP-9. Furthermore, convincing evidence of a correlation between MMP-9 and MMP-14 was found in TRS patients. Although the ECT therapy did not result in changes in the serum concentrations of the studied biomarkers, substantial improvement in schizophrenia symptoms on the PANSS was observed. Conclusions: No significant biomarker changes (post- versus pre-treatment) were detected in this small exploratory cohort. Whether these biomarkers are involved in neuroinflammation (as possible contributors to the development of TRS) remains an open question, and therefore, further research on biomarkers in cerebrospinal fluid (CSF) may be suggested. Full article

Clozapine-induced hypersalivation (CIH) affects 30–80% of patients on clozapine and is a major contributor of non-adherence. Current managements, largely based on systemic anticholinergics, can worsen other clozapine-related side effects. Here sublingual tropicamide 1% eye drops can be a low-cost alternative worth evaluating. We report a case series of seven patients with schizophrenia treated with sublingual tropicamide 1% ophthalmic solution (4–8 drops/day) for CIH. Treatment response was assessed by patient-reported percentage reduction in salivation. All seven patients reported improvement (25–80%). One patient reported a transient bitter taste; no systemic anticholinergic effects occurred. Sublingual tropicamide was associated with patient-reported improvement in CIH and was well tolerated in this small, uncontrolled series. Its short duration of action and local administration may offer practical advantages over systemic anticholinergics, though the mechanism remains unproven. Randomised trials with validated outcome measures are needed to establish its efficacy and safety. Full article

Background: Treatment-resistant schizophrenia (TRS) affects approximately 20–30% of patients and is associated with significant disability. EEG abnormalities, particularly background slowing and disorganized alpha activity, have been reported in TRS, but the role of alpha rhythm instability—here termed alpha dysrhythmia—remains poorly understood. Objective: To compare the individual alpha frequency (IAF) between patients with TRS and those in clinical remission, to examine associations between alpha dysrhythmia and specific symptom domains (especially disorganization), and to investigate its relationship with EEG background changes. Methods: Eighty-nine patients with schizophrenia were included. Alpha dysrhythmia was defined as intraindividual variability of dominant alpha frequency exceeding 1 Hz across consecutive EEG epochs. Quantitative spectral analysis was performed using FFT on artifact-free 4–9 s epochs. Clinical assessment included PANSS (positive, negative, and disorganized subscales), the Dissociation scale, BPRS, Hamilton D/A, and the OCD scale. Group comparisons used the Mann–Whitney U test; correlations used Pearson and Spearman coefficients; and stepwise regression identified independent predictors. Results: Alpha dysrhythmia was present in 46.1% of patients. Significant negative correlations were found between dysrhythmia and therapeutic response. Significant positive correlations were found with PANSS disorganized symptoms and the Dissociation scale. The Mann–Whitney U test showed that the dysrhythmia group had higher mean ranks for EEG background factor (EEG BA), the Dissociation scale, and PANSS disorganized symptoms. Stepwise regression identified EEG BA and the Dissociation scale as independent predictors. Conclusions: Alpha dysrhythmia is frequent in TRS patients and is specifically associated with poorer therapeutic response, disorganized symptoms, and dissociation. EEG BA (reflecting background changes) may serve as a neurophysiological biomarker for identifying patients at risk for treatment resistance. Full article

Background/Objectives: Electroconvulsive therapy (ECT) is among the most effective treatments for severe major depression, treatment-resistant depression, psychotic and bipolar depression, catatonia, and selected psychotic disorders. Yet response, remission, seizure adequacy, and cognitive tolerability remain difficult to predict for an individual patient. This review examines whether oral and gut microbial signatures can inform precision ECT as contextual biological markers, rather than as standalone explanations of ECT efficacy. Methods: A structured narrative PubMed/MEDLINE search was conducted on 1 May 2026 and supplemented by targeted manual searches of Crossref, Google Scholar, journal websites, and reference lists updated through 17 May 2026. Evidence was grouped as direct human ECT–microbiome studies, indirect human ECT biomarker studies, preclinical electroconvulsive shock (ECS) studies, and mechanistic microbiome–gut–brain literature. Results: Direct human ECT–microbiome evidence remains very limited and currently consists of two small prospective cohorts with sufficient microbiome data, totaling approximately 25 patients across studies, plus one single-patient case report. In severe or treatment-resistant depression, a pilot oral microbiome study with sufficient microbiological data from 14 patients reported higher pre-treatment oral alpha diversity in responders than in non-responders, without a consistent global oral microbiome shift after ECT. In schizophrenia, a small stool microbiome cohort of 11 patients suggested that baseline Bifidobacterium and Lactobacillus proportions may relate to symptom improvement, although sample size and confounding preclude firm inference. Conclusions: Microbiome-informed precision ECT remains a biologically plausible research direction, but current human evidence supports only cautious evaluation of baseline microbial context as a candidate predictor, not clinical microbiome-guided ECT, mediation, or microbiome-modifying intervention. The strongest current biological bridge comes from inflammatory markers, particularly baseline CRP and IL-6. Preclinical ECS studies support gut inflammatory, motility and vagal mechanisms, but they cannot substitute for human validation. Full article

Fear is a transdiagnostic construct implicated in multiple psychiatric disorders, reflecting a partial dissociation between clinical phenotypes and underlying neurobiological mechanisms. Converging evidence suggests that aberrant fear processing plays a central role in cognitive and psychopathological models of psychosis. In this narrative review, we synthesize evidence on the neurobiological mechanisms of aberrant fear modulation in schizophrenia from a translational perspective, integrating findings from neuroimaging, preclinical models, pharmacological interventions, and psychotherapy. Schizophrenia is characterized by aberrant emotional processing and inappropriate neural responses to stimuli with reduced or absent objective salience, reflecting impaired discrimination of relevant environmental information. At the system level, evidence implicates dysregulation of cortico-limbic and salience-processing networks in altered fear learning, threat appraisal, and emotional prediction. Neurochemical findings indicate that dopamine–glutamate dysregulation and associated intracellular signaling pathways act as upstream modulatory mechanisms contributing to these network-level abnormalities. Therapeutic interventions, including antipsychotic drugs and psychotherapeutic approaches, partially modulate these systems, although effects remain heterogeneous. Overall, the evidence supports a hierarchical model in which aberrant fear processing in schizophrenia arises from disrupted salience attribution and impaired integration across cognitive, affective, and neurobiological levels. This intermediate dysfunction links molecular alterations to large-scale network disturbances and clinical symptom expression, providing a framework for more mechanism-based therapeutic strategies. Full article

Background: Immune mechanisms are increasingly implicated in the heterogeneity of schizophrenia spectrum disorders. Cytomegalovirus (CMV), a latent immunomodulatory herpesvirus, is linked to cognitive and immunological alterations, but its electrophysiological correlates remain largely unexplored. This study investigates the relationships among CMV serostatus, EEG features, inflammatory markers, and clinical–cognitive variables. Methods: In this prospective cross-sectional study, 123 patients with schizophrenia spectrum disorders underwent integrated clinical, cognitive, laboratory, and qualitative visual EEG assessments. CMV exposure was determined via IgG serology. Results: Global electroencephalographic EEG organization did not differ by CMV serostatus. However, a descriptive increase in resting-state sharp-wave discharges was observed in CMV-seronegative patients, independent of baseline cortical rhythms. Immunologically, CMV-seropositive individuals exhibited significantly higher total leukocyte counts, consistent with latent viral immune remodeling rather than overt systemic inflammation. Clinically, CMV-seropositive patients demonstrated descriptively higher scores on the disorganization dimension derived from the PANSS (Positive and Negative Syndrome Scale) five-factor consensus model. While these variations did not retain statistical significance after multiple testing correction, separate dimensional analyses revealed that patients exhibiting sharp waves demonstrated better overall cognitive functioning and superior performance within a memory-related item grouping. Notably, the presence of sharp-wave activity was independent of both peripheral inflammatory profiles and treatment-resistant status, underscoring a distinct electrophysiological phenotype. Conclusions: CMV exposure represents a modulating biological background associated with corrected leukocyte elevations and subtle electrophysiological variability, rather than a direct determinant of global clinical severity. The nominal EEG variations and their independent link to better-preserved memory performance highlight non-linear neuroimmune interactions. Given the cross-sectional design, these exploratory patterns warrant a non-causal interpretation but outline a foundation for future longitudinal investigations. Full article

Background/Objectives: Clozapine is the sole antipsychotic approved for treatment-resistant schizophrenia, but it is a double-edged therapeutic option due to various lethal adverse reactions. This study aimed to assess the risk of long-term clozapine medication-induced cardiotoxicity, which has not yet been fully elucidated. Methods: This study is a multicenter retrospective cohort study of patients with schizophrenia in Japan and China who received clozapine monotherapy. Cases for which serum NT-proBNP concentration and LVEF derived from echocardiography were available in 2025 were included. In addition, blood examinations, including those administered by the Japanese Clozaril Patient Monitoring Service, were statistically analyzed as independent variables. Results: Among a total of 315 cases, including 99 Japanese (clozapine exposure duration: 57.5 ± 4.0 months) and 216 Chinese (208.1 ± 11.0 months) cases, were enrolled. In both Japan and China, age-standardized prevalence of heart failure among patients with prescribed clozapine were higher compared to general population, with odds ratios of 3.2 (95%CI: 1.4–6.4) and 6.9 (95%CI: 3.6–12.0), respectively. The risk factors for stage-B heart failure associated with clozapine were prolonged exposure duration, higher plasma levels of clozapine, and increasing monocytes. Unexpectedly, over 70% of cases with stage-B heart failure associated with clozapine identified in this study did not have metabolic complications. Other than those with cardiomyopathy, myocardial infarction, ileus, or chronic renal failure, no cases with ejection fraction < 50% were observed, suggesting that stage-B heart failure associated with clozapine is speculated to be likely suggestive of HFpEF. Conclusions: Traditionally, psychiatry has focused on myocarditis and cardiomyopathy developing several weeks and months after initiation of clozapine medication; however, this study revealed asymptomatic heart failure as a third cardiac adverse reaction of clozapine that develops years later. Therefore, regular monitoring of NT-proBNP contributes to improving long-term prognosis of treatment-resistant schizophrenia with prescribed clozapine. Full article

Introduction: Growing evidence indicates that diet quality significantly influences metabolic parameters and cognitive functioning. In healthy individuals, higher consumption of minimally processed foods and products rich in omega-3 fatty acids is associated with a more favorable lipid profile and better cognitive performance. Patients with schizophrenia present an increased risk of metabolic disturbances and reduced cognitive functioning. This suggests that this group may be particularly sensitive to nutritional factors. However, relatively few studies have simultaneously examined the relationships between diet, metabolism, and cognitive profile in patients with schizophrenia and healthy individuals. Aim: The aim of the study was to compare the relationships between the frequency of consumption of selected food categories and metabolic parameters (glycemia, lipid profile, and insulin resistance), as well as cognitive functions (Stroop Test, Trail Making Test, and verbal fluency), in patients with schizophrenia and healthy men. Methods: The study included 21 patients with schizophrenia and 20 healthy men. All participants completed a questionnaire assessing the frequency of food consumption. Blood samples were collected to determine glucose, insulin, HDL, LDL, and triglyceride levels, and the HOMA-IR index was calculated. Cognitive functioning was assessed using the Stroop Test (RCNb, NCWd) and the Trail Making Test (TMT-A and TMT-B), which measure psychomotor speed and visuospatial working memory, respectively, and the verbal fluency test (semantic and phonological). Correlation analyses were performed separately in both groups. Due to the small sample size, all correlations are treated as exploratory and are analyzed with correction for multiple comparisons. Results: Exploratory analyses identified several patterns of associations between the frequency of consumption of selected food categories, metabolic parameters, and cognitive performance in both healthy men and patients with schizophrenia. The observed patterns differed between groups, suggesting that clinical status and treatment-related factors may modify diet–metabolism–cognition relationships. These findings highlight potential pathways linking dietary habits with metabolic and cognitive outcomes and provide a basis for further hypothesis-driven research. Conclusions: Diet quality may be related to metabolic status and cognitive functioning. However, the pattern of these associations differs between patients with schizophrenia and healthy individuals. The findings suggest that diet may play a role in metabolic health and cognitive functioning, particularly in clinical populations. Full article

Complex psychosis is a clinically relevant rehabilitation construct rather than a formal diagnostic category and refers to psychotic illness associated with treatment-resistant symptoms, functional impairment, and additional cognitive, psychiatric, neurodevelopmental, or physical health complexity. In this clinician-oriented narrative review, we synthesised current evidence on rehabilitation interventions for adults with complex psychosis, integrating direct evidence from specialist rehabilitation settings with indirect evidence from schizophrenia-spectrum studies when clinically informative. We searched major clinical databases, prioritised guidelines, systematic reviews, meta-analyses, and controlled studies, and organised the synthesis by functional domain and pathway relevance. Evidence was strongest for cognitive remediation, particularly when combined with broader psychiatric rehabilitation or vocational support, for family interventions in relapse prevention, and for individual placement and support in competitive employment. Social–cognitive and metacognitive interventions appear clinically valuable, although transfer to real-world functioning is more variable. Community-based rehabilitation, supported accommodation, illness self-management, and ecological adaptation strategies remain central to functional recovery when embedded within multidisciplinary pathways. Digital and virtual interventions are promising adjuncts, but their efficacy remains heterogeneous and implementation challenges include engagement, privacy, and service integration. Overall, rehabilitation in complex psychosis is most convincing when it is personalised, measurement-based, and delivered through integrated service models linking assessment, intervention selection, supported living, and recovery-oriented care. Full article

Treatment-resistant schizophrenia (TRS) remains a significant clinical challenge due to limited therapeutic options and a poor understanding of its underlying biology. Recent findings suggest that immune system dysregulation may play a critical role in the pathophysiology of TRS. This systematic review aimed to synthesize current evidence on immunological abnormalities associated with TRS, with a focus on inflammatory markers, immune cell profiles, and the role of autoantibodies, and to explore their potential utility in diagnosis and treatment. A systematic review of the literature was conducted in accordance with PRISMA guidelines, incorporating clinical, molecular, and translational studies on immunological markers in patients with TRS. Included studies assessed cytokine levels, immune cell phenotypes, autoantibodies, genetic factors, and the effects of immunomodulatory therapies. Emphasis was placed on findings differentiating TRS from treatment-responsive schizophrenia. TRS is associated with distinct immune profiles, including elevated IL-6, IL-8, TNF-α, and sCD25 levels, overexpression of CD33 on monocytes and expansion of CD123+ plasmacytoid dendritic cells. Autoantibodies, particularly those targeting glutamatergic receptors, are more prevalent in TRS and decrease with clozapine treatment. Predictive models using IgM autoantibodies and genetic variants show promise for early identification of at-risk individuals. Emerging immunomodulatory treatments such as rituximab, levamisole, and senolytics are under investigation, offering potential for personalized strategies. Immunological dysfunction represents a reproducible and biologically relevant feature of TRS. Integration of immune biomarkers into clinical practice may enhance diagnostic precision and inform personalized therapeutic approaches. Future research should prioritize standardized biomarker protocols and longitudinal studies to validate causal associations and optimize treatment algorithms. Full article

Background: Schizophrenia is a heterogeneous disorder, and treatment-resistant schizophrenia (TRS) affects 20–30% of patients, yet objective biomarkers for its identification remain limited. Routine electroencephalography (EEG) offers a non-invasive window into cortical network dynamics, with previous studies reporting paroxysmal epileptiform activity and background slowing in a subset of patients. However, the biological significance of these findings—whether purely pathological or potentially compensatory—remains unclear. This study aimed to compare EEG abnormalities between TRS patients and those in clinical remission and to propose an integrative neurobiological interpretation. Methods: In a cross-sectional design, 89 patients with schizophrenia (39 TRS, 50 in remission) underwent routine EEG recordings using the international 10–20 system. TRS was defined according to TRRIP consensus criteria, requiring <20% symptom reduction after adequate antipsychotic trials. EEG analysis focused on the prevalence of interictal epileptiform discharges (IEDs) and the severity of background slowing, assessed on a 4-point ordinal scale. Results: IEDs were more than twice as prevalent in TRS patients compared to those in remission. Background slowing was significantly more severe in the TRS group, with the majority showing moderate-to-severe abnormalities versus predominantly normal-to-mild patterns in remission patients. Focal EEG abnormalities also followed this pattern. Multivariate analysis confirmed that both IEDs and background severity were independent predictors of TRS. Conclusions: EEG abnormalities, particularly IEDs and background slowing, are potential neurophysiological signatures associated with treatment resistance. We propose an integrative hypothesis suggesting that IEDs may originate as a failed compensatory mechanism—the brain’s attempt to restore network homeostasis. In chronic TRS these discharges become maladaptive, contributing to excitotoxicity and network dysfunction. This framework opens avenues for EEG-based stratification and novel therapeutic strategies targeting cortical excitability. Full article

Glutamate metabotropic receptors (mGluRs) and their molecular partners at the postsynaptic density (PSD) represent a highly dynamic molecular hub that integrates multiple neurotransmitter signals and regulates synaptic plasticity and metaplasticity, which are putatively involved in the pathophysiology of psychiatric illnesses, including schizophrenia. Group I mGluRs (mGluR1 and mGluR5) interact with PSD adaptor and scaffolding proteins, such as Homer, Shank, Norbin, and PICK1, as well as intracellular downstream effectors, creating a molecular network that resembles a Lego-like structure, where modular protein interactions fine-tune glutamatergic transmission. Evidence from preclinical research indicates that dysregulation of mGluR expression and function, along with disrupted PSD protein expression, may contribute to the pathophysiology of schizophrenia by altering glutamatergic neurotransmission and synaptic stability. Antipsychotic mechanisms of action may involve, at least in part, the modulation of mGluR activity mediated through PSD proteins. Notably, novel agents that enhance spinogenesis by acting at the level of PSD proteins, such as SPG302, may open promising avenues for therapeutics aimed at restoring synaptic integrity. While Group I mGluRs dominate postsynaptic regulation, Group II (mGluR2/3) and III (mGluR4/6/7/8) receptors -primarily presynaptic- inhibit neurotransmitter release and plasticity, offering complementary therapeutic avenues. Emerging strategies, such as allosteric modulators of mGluRs, aim to rebalance synaptic signaling in treatment-resistant schizophrenia. This review synthesizes how PSD proteins and mGluRs interact in schizophrenia, exploring their potential as druggable targets for novel therapies. Full article

Schizophrenia is a complex, chronic psychiatric disorder with significant global impact, characterized by persistent positive, negative, and cognitive symptoms that are not fully addressed by current treatments. This review aims to synthesize established theories and advancing mechanistic concepts and also critically compare the latest international treatment guidelines. Recent evidence expands beyond the traditional dopamine hypothesis to include glutamatergic, serotonergic, and cholinergic dysfunctions, as well as emerging mechanisms such as neuroinflammation, oxidative stress, iron dysregulation, and gut–brain interactions. A review of major international guidelines (APA, NICE, CINP, WFSBP, and others) confirms consensus on the use of second-generation antipsychotics as first-line therapy and the early introduction of clozapine for treatment-resistant cases. All guidelines emphasize the essential role of integrated psychosocial interventions, including cognitive behavioral therapy for psychosis, family psychoeducation, and supported employment. Differences remain regarding the prioritization of precision medicine, pharmacogenomics, and digital health innovations. Prognosis varies widely but improves with early intervention, sustained treatment adherence, and comprehensive physical health monitoring. Overall, schizophrenia care is evolving toward a precision-based, recovery-oriented model that integrates biological, psychological, and social strategies to improve long-term outcomes and quality of life. Full article