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Alexandre González-Rodríguez,1 Rosa Catalán,1–4 Rafael Penadés,1–4 Clemente Garcia-Rizo,1,3,4 Miquel Bioque,1,4 Eduard Parellada,1,3–5 Miquel Bernardo1–4 1Barcelona Clinic Schizophrenia Unit (BCSU), Neuroscience Institute, Hospital Clinic of Barcelona, 2Department of Psychiatry and Clinical Psychobiology, University of Barcelona, 3Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain; 4Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain; 5Department of Pharmacology, University of Barcelona, Barcelona, Spain Background and objectives: Short-term studies focused on once-monthly paliperidone palmitate (PP) at doses of 25 mg eq, 50 mg eq, 75 mg eq, 100 mg eq, or 150 mg eq have shown its efficacy and tolerability in the treatment of schizophrenia patients. However, few open-label and long-term studies are available regarding this new pharmacological formulation. Thus, our main aim was to review the scientific evidence on efficacy, safety, tolerability, and preference of PP in these populations. Method: Electronic searches were conducted by using PubMed and ISI Web of Knowledge databases. All relevant studies published from 2009 until January 2015 were included without any language restriction if patients met diagnostic criteria for schizophrenia, and adequate information on efficacy, safety, and tolerability of once-monthly PP was available. Results: Nineteen studies were identified irrespective of the study design and duration of the follow-up period. Randomized, double-blind, placebo-controlled trials found that schizophrenia patients receiving PP showed a significant improvement in psychotic symptoms and similar adverse events compared to placebo and suggested that all doses of PP were efficacious and well tolerated. Other studies demonstrated noninferiority of PP compared to risperidone long-acting injectable in recently diagnosed schizophrenia patients, chronically ill patients, as well as in acute and nonacute symptomatic schizophrenia patients, and a similar proportion of treatment-emergent adverse events between both groups were also noted. Conclusion: Several studies have demonstrated that schizophrenia patients treated with PP show higher rates of improvement of psychotic symptoms compared to placebo, and similar efficacy and tolerability outcomes were noted when comparing PP to risperidone long-acting injectable or oral, paliperidone extended release. Keywords: once-monthly paliperidone palmitate, long-acting antipsychotics, psychosis, schizophrenia, safety, efficacy, relapses

Introduction: Psychotic patients often require pharmacological treatment, which may prove ineffective, leading to treatment-resistant psychosis necessitating the use of clozapine. However, the emergence of side effects can result in discontinuation, potentially triggering a relapse of psychotic symptoms. One significant side effect is antipsychotic-induced weight gain which, over time, can lead to adverse metabolic events. Recent translational research is evaluating the impact of prenatal factors on the metabolic outcomes of psychotic patients, using a surrogate marker of the intrauterine milieu such as birth weight (BW). Objectives: We aim to evaluate the changes in leptin, adiponectin, and insulin levels in patients with treatment-resistant psychosis who initiate clozapine treatment due to persistent psychotic symptoms. Methods: Subjects older than 18 years with a diagnostic of a major mental disorder and initiating clozapine were enrolled in this 18-months longitudinal study. Neurohormones levels, including leptin, adiponeptin, and insulin were measured at baseline, 8 and 18 months during follow-up. Statistical analysis were conducted by using a fixed-effects model. Results: A total of 23 subjects initiating clozapine were evaluated during the initial mandatory 18-week period. Neurohormones, specifically leptin and adiponectin, were measured at three time points: baseline, 8 weeks, and 18 weeks. The changes in leptin levels were significantly associated with birth BW with sex differences, being inversely correlated only in females. Adiponectin was significantly associated with BW, being inversely correlated in males. Conversely, there was no observed association between insulin levels and BW. Conclusions: Our findings highlight the significance of prenatal factors in influencing the subsequent evolution of neurohormones in individuals initiating clozapine treatment. This suggests that subjects with lower BW tend to exhibit elevated neurohormone values, emphasizing the role of prenatal events in this context. Disclosure of Interest: None Declared [ABSTRACT FROM AUTHOR]

Introduction: 25-year-old woman originary from China. Moved to Barcelona 2 years ago for her master studies. Not known personal or familiar psychiatric record. Admitted to the psychiatric ward due to a 3-month psychotic episode with delusional features including transportation delusions "people can travel into other dimensions"; megalomaniac delusions, "I communicate with a Buddhist divinity called Guan Yin", "I have the mission of rejuvenating the population"; nihilistic and Cotard-like delusions "people around is old and dead"; denial of lineage syndrome, intermetamorphosis syndrome and doppelgänger syndrome. Nohallucinatory featureswere present. Severe emotional and behavioural implications were associated. Objectives: To analyse the transcultural component of bizarre delusions in a Chinese patient. Methods: Somatic causes for psychosis were ruled out. Risperidone up to 6 mg was started and afterwards intramuscular paliperidone palmitate 150+100 mg was administered, suspending risperidone. Results: Psychotic symptoms remitted progressively during hospitalization, so that the patient was discharged after 1-month. Conclusions: 1. This patient presented polymorphous bizarre delusions, some of them related to the Chinese culture. 2. Psychotic contents are influenced by the cultural beliefs. In this case, Guan Yin divinity (from Chinese religion) acquires psychotic implications being part of the cultural background of the patient. 3. The denial of lineage syndrome, which can be misinterpreted as a Capgras syndrome, is one of the most common delusions in China. 4. Due to the one-child policy, Chinese population aging will be a forecasted problem. The patient expressed this concert in a megalomaniac delusional manner. [ABSTRACT FROM AUTHOR]

Introduction: Clinical lycanthropy is an uncommon delusion of turning into a wolf. A systematic review in 2016 found only 13 case descriptions, only one not secondary to a psychiatric disorder. Objectives: To identify and describe an unusual symptom based on a clinical case. Methods: The present study is a case report of a patient admitted for clinical lycanthropy to our hospital. Wealso searched previously case reports, series and systematic reviews of clinical lycanthropy using a pubmed query ("lycanthropy", "cerebellum", "hydrocephalus", "psychosis"). Results: Mr. CJ. is a 38-year-old Mexican male, with no prior psychiatric history or substance use. He was admitted for bizarre behaviors and delusions. He had been living in the forest for the last weeks with the belief that he was a werewolf, and on full moon he behaved like a wolf (naked and howling). He also presented multimodal hallucinations, headache, ataxia and visual blur. The mental evaluation did not suggest a delirium. A CT scan revealed a left cerebellar lesion and hydrocephalus (Image 1,2,3). He experienced full remission of psychotic symptoms after external ventricular drain and antipsychotic treatment (risperidone, olanzapine). After surgical r emoval the histology revealed a cerebellar hemangioblastoma. Conclusions: The clinical presentation suggested the diagnosis of a psychotic disorder due to cerebellar hemangioblastoma with consequent hydrocephalus. Cerebellum abnormalities and hydrocephalus have been associated to psychotic symptoms. Furthermore, other case reports showed rapid recovery of psychosis due to hydrocephalus after neurosurgical intervention. To our knowledge, this is the first report about clinical lycanthropy due to a tumor of the central nervous system. [ABSTRACT FROM AUTHOR]

Introduction: 50-years-old man, originary from Germany, living in Spain since he had 26 years old. Not known personal psychiatric record; first grade relative with alcohol use disorder. As somatic medical record he presented paroxysmal atrial fibrillation treated with bisoprolol and amiodarone. He is brought to the Emergency room with disorganized behaviour and delusional ideas of prejudice, surveillance and complot. He also presents organic symptoms: fluctuating disorientation, dysarthria, tremors, fever, heat intolerance, weight loss, swallowing pain, decreased need for sleep and an antecedent of a recent phototoxic reaction. Objectives: To report an exceptional case of organic psychosis and to remark the need to screen somatic ethiologies for psychoses. Methods: A lumbar puncture, EEG and brain MRI with normal results ruled out neurological causes. The blood test showed neutrophilic leucocytosis and elevated T3 with supressed TSH. Olanzapine 20 mg was started. The Endocrinology Service started treatment with prednisone 40 mg and Methimazole 25 mg was started. Bisoprolol was maintained and amiodarone was stopped. A thyroid ultrasound was performed and concluded type 2 thyroiditis diagnosis. Results: Psychotic symptoms remitted in 1 week. Neurological and infectious causes were ruled out. Psychosis was related to a hyperthyroidism state. Amiodarone was established as the trigger of thyroxicosis. Conclusions: 1. Thyroxicosis, though atypical, can present with psychiatric symptoms. 2. It is always required to screen somatic ethiologies for psychoses, especially when somatic features (as in the case) are present. 3. Amiodarone overuse can cause endocrine and dermatological symptoms, as well as secondary psychiatric symptoms. [ABSTRACT FROM AUTHOR]

Schizophrenia (SZ) is a deleterious brain disorder characterised by its heterogeneity and complex symptomatology consisting of positive, negative and cognitive deficits. Current antipsychotic drugs ameliorate the positive symptomatology, but are inefficient in treating the negative symptomatology and cognitive deficits. The neurodevelopmental glutamate hypothesis of SZ has opened new avenues in the development of drugs targeting the glutamatergic system. One of these new therapies involves the positive allosteric modulators (PAMs) of metabotropic glutamate receptors, mainly types 2/3 (mGluR2/3). mGluR2/3 PAMs are selective for the receptor, present high tolerability and can modulate the activity of the receptor for long periods. There is not much research in clinical trials regarding mGluR2/3 PAMs. However, several lines of evidence from animal models have indicated the efficiency of mGluR2/3 PAMs. In this review, focusing on in vivo animal studies, we will specifically discuss the utilization of SZ animal models and the various methods employed to assess animal behaviour before summarising the evidence obtained to date in the field of mGluR2/3 PAMs. By doing so, we aim to deepen our understanding of the underlying mechanisms and the potential efficiency of mGluR2/3 PAMs in treating SZ. Overall, mGluR2/3 PAMs have demonstrated efficiency in attenuating SZ-like behavioural and molecular deficits in animal models and could be useful for the early management of the disorder or to treat specific subsets of patients., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Current antipsychotics (APs) effectively control positive psychotic symptoms, mainly by blocking dopamine (DA) D2 receptors, but have little effect on negative and cognitive symptoms. Increased glutamate (GLU) release would trigger neurotoxicity, leading to apoptosis and synaptic pruning, which is involved in the pathophysiology of schizophrenia. New pharmacological strategies are being developed such as positive allosteric modulators (PAMs) of the metabotropic GLU receptor 2 (mGluR2) that inhibit the presynaptic release of GLU. We previously reported that treatment of adult mice with JNJ-46356479 (JNJ), a recently developed mGluR2 PAM, partially improved neuropathological deficits and schizophrenia-like behavior in a postnatal ketamine mouse model. In the present study, we evaluated, for the first time, the putative neuroprotective and antiapoptotic activity of JNJ in a human neuroblastoma cell line and compared it with the effect of clozapine (CLZ) as a clinical AP with the highest efficacy and with apparent utility in managing negative symptoms. Specifically, we measured changes in cell viability, caspase 3 activity and apoptosis, as well as in the expression of key genes involved in survival and cell death, produced by CLZ and JNJ alone and in combination with a high DA or GLU concentration as apoptosis inducers. Our results suggest that JNJ is not neurotoxic and attenuates apoptosis, particularly by decreasing the caspase 3 activation induced by DA and GLU, as well as increasing and decreasing the number of viable and apoptotic cells, respectively, only when cultures were exposed to GLU. Its effects seem to be less neurotoxic and more neuroprotective than those observed with CLZ. Moreover, JNJ partially normalized altered expression levels of glycolytic genes, which could act as a protective factor and be related to its putative neuroprotective effect. More studies are needed to define the mechanisms of action of this GLU modulator and its potential to become a novel therapeutic agent for schizophrenia.

Schizophrenia (SZ) is a heterogeneous mental disorder, affecting ~1% of the worldwide population. One of the main pathophysiological theories of SZ is the imbalance of excitatory glutamatergic pyramidal neurons and inhibitory GABAergic interneurons, involving N-methyl-D-aspartate receptors (NMDAr). This may lead to local glutamate storms coupled with excessive dendritic pruning and subsequent cellular stress, including nitrosative stress, during a critical period of neurodevelopment, such as adolescence. Nitrosative stress is mediated by nitric oxide (NO), which is released by NO synthases (NOS) and has emerged as a key signaling molecule implicated in SZ. Regarding glutamatergic models of SZ, the administration of NMDAr antagonists has been found to increase NOS levels in the prefrontal cortex (PFC) and ventral hippocampus (HPC). We hypothesized that suboptimal NOS function in adolescence could be a target for early treatments, including clozapine (CLZ) and the novel metabotropic glutamate receptor modulator JNJ-46356479 (JNJ). We analyzed the protein levels of NOS isoforms in adult PFC and HPC of a postnatal ketamine induced murine model of SZ receiving CLZ or JNJ during adolescence by western blot. Endothelial NOS and neuronal NOS increased under ketamine administration in PFC and decreased in CLZ or JNJ treatments. The same trends were found in the HPC in neuronal NOS. In contrast, inducible NOS was increased under JNJ treatment with respect to ketamine induction in the HPC, and the same trends were found in the PFC. Taken together, our findings suggest a misbalance of the NOS system following NMDAr antagonist administration, which was then modulated under early CLZ and JNJ treatments.

Schizophrenia (SZ) is a deleterious brain disorder affecting cognition, emotion and reality perception. The most widely accepted neurochemical-hypothesis is the imbalance of neurotransmitter-systems. Depleted GABAergic-inhibitory function might produce a regionally-located dopaminergic and glutamatergic-storm in the brain. The dopaminergic-release may underlie the positive psychotic-symptoms while the glutamatergic-release could prompt the primary negative symptoms/cognitive deficits. This may occur due to excessive synaptic-pruning during the neurodevelopmental stages of adolescence/early adulthood. Thus, although SZ is not a neurodegenerative disease, it has been suggested that exaggerated dendritic-apoptosis could explain the limited neuroprogression around its onset. This apoptotic nature of SZ highlights the potential therapeutic action of anti-apoptotic drugs, especially at prodromal stages. If dysregulation of apoptotic mechanisms underlies the molecular basis of SZ, then anti-apoptotic molecules could be a prodromal therapeutic option to halt or prevent SZ. In fact, risk alleles related in apoptotic genes have been recently associated to SZ and shared molecular apoptotic changes are common in the main neurodegenerative disorders and SZ. PRISMA-guidelines were considered. Anti-apoptotic drugs are commonly applied in classic neurodegenerative disorders with promising results. Despite both the apoptotic-hallmarks of SZ and the widespread use of anti-apoptotic targets in neurodegeneration, there is a strikingly scarce number of studies investigating anti-apoptotic approaches in SZ. We analyzed the anti-apoptotic approaches conducted in neurodegeneration and the potential applications of such anti-apoptotic therapies as a promising novel therapeutic strategy, especially during early stages.

Schizophrenia disorder remains an unsolved puzzle. However, the integration of recent findings from genetics, molecular biology, neuroimaging, animal models and translational clinical research offers evidence that the synaptic overpruning hypothesis of schizophrenia needs to be reassessed. During a critical period of neurodevelopment and owing to an imbalance of excitatory glutamatergic pyramidal neurons and inhibitory GABAergic interneurons, a regionally-located glutamate storm might occur, triggering excessive dendritic pruning with the activation of local dendritic apoptosis machinery. The apoptotic loss of dendritic spines would be aggravated by microglia activation through a recently described signaling system from complement abnormalities and proteins of the MHC, thus implicating the immune system in schizophrenia. Overpruning of dendritic spines coupled with aberrant synaptic plasticity, an essential function for learning and memory, would lead to brain misconnections and synaptic inefficiency underlying the primary negative symptoms and cognitive deficits of schizophrenia. This driving hypothesis has relevant therapeutic implications, including the importance of pharmacological interventions during the prodromal phase or the transition to psychosis, targeting apoptosis, microglia cells or the glutamate storm. Future research on apoptosis and brain integrity should combine brain imaging, CSF biomarkers, animal models and cell biology.

Background: Around 30% of patients with schizophrenia are considered treatment resistant (TRS). Only around 40% of TRS patients respond to clozapine. Long acting injectable antipsychotics could be a useful augmentation strategy for nonresponders., Methods: We conducted a multicenter, observational, naturalistic, retrospective, 6-month mirror-image study to evaluate the efficacy and tolerability of clozapine and paliperidone palmitate association in 50 patients with TRS and other psychotic disorders. Clinical outcomes and side effects were systematically assessed., Results: Six months after starting the combined treatment, participants showed a significant relief of symptoms, decreasing the Brief Psychiatric Rating Scale total score from 18.32 ± 7.71 to 7.84 ± 5.16 (p < 0.001). The number of hospitalizations, the length of hospital stays and the number of visits to emergency services also decreased, while an increase of the functionality was observed (Personal and Social Performance total score increased from 46.06 ± 118.7 to 60.86 ± 18.68, p < 0.001). There was also a significant decrease in the number and severity of side effects with the combination therapy, decreasing the Udvalg for Kliniske Undersogelser total score from 10.76 ± 8.04 to 8.82 ± 6.63 (p = 0.004)., Conclusions: This study provides the first evidence that combining clozapine with paliperidone palmitate in patients with TRS and other psychotic disorders could be effective and safe, suggesting further research with randomized controlled trials of augmentation strategies for clozapine nonresponder patients., Policy Significance Statement: Patients with psychotic disorders such as schizophrenia show a variable response to antipsychotic treatments. Around 30% of patients are considered treatment resistant, indicated by insufficient symptom control to at least two different drugs. In these resistant cases, clozapine should be indicated, as it has shown to be superior to other options. However, only 40% of patients respond to clozapine, being necessary to establish which treatments could best potentiate clozapine action. Combining clozapine with long acting injectable antipsychotics, and particularly paliperidone palmitate, could be a useful strategy. We conducted a multicenter study of 50 patients with treatment-resistant schizophrenia and other psychotic disorders comparing the efficacy and tolerability in the 6 month-period prior and after starting the clozapine and paliperidone palmitate association. Our study suggests that this combination could be effective and safer, laying the groundwork for future clinical trials with this combination.

(1) Background: The cognitive reserve (CR) concept has not been precisely defined in severe mental disorders and has been estimated using heterogeneous methods. This study aims to investigate and develop the psychometric properties of the Cognitive Reserve Assessment Scale in Health (CRASH), an instrument designed to measure CR in people with severe mental illness; (2) Methods: 100 patients with severe mental illness (non-affective psychoses and affective disorders) and 66 healthy controls were included. The internal consistency and convergent validity of CRASH were assessed. Spearman's correlations coefficients were also performed to examine the relationship between CRASH and neuropsychological tests, psychosocial functioning, and clinical course; (3) Results: The internal consistency was high (Cronbach's alpha coefficient = 0.903). The CRASH global score had a large positive correlation with the Cognitive reserve questionnaire total score ( r = 0.838, p < 0.001), demonstrating good convergent validity. The correlation coefficients between the CRASH total scores and clinical, functional, and neuropsychological performance were different between groups. In order to provide clinical interpretation, severity classification based on diagnosis (non-affective psychotic disorders, affective disorders, and healthy controls) have been created; (4) Conclusions: CRASH is the first CR measure developed specifically for patients with severe mental illness, facilitating reliable and valid measurement of this construct. The scale may aid in the stratification of patients and the implementation of personalized interventions.

Auditory verbal hallucinations (AVH) in schizophrenia are typically characterized by rich emotional content. Despite the prominent role of emotion in regulating normal perception, the neural interface between emotion-processing regions such as the amygdala and auditory regions involved in perception remains relatively unexplored in AVH. Here, we studied brain metabolism using FDG-PET in 9 remitted patients with schizophrenia that previously reported severe AVH during an acute psychotic episode and 8 matched healthy controls. Participants were scanned twice: (1) at rest and (2) during the perception of aversive auditory stimuli mimicking the content of AVH. Compared to controls, remitted patients showed an exaggerated response to the AVH-like stimuli in limbic and paralimbic regions, including the left amygdala. Furthermore, patients displayed abnormally strong connections between the amygdala and auditory regions of the cortex and thalamus, along with abnormally weak connections between the amygdala and medial prefrontal cortex. These results suggest that abnormal modulation of the auditory cortex by limbic-thalamic structures might be involved in the pathophysiology of AVH and may potentially account for the emotional features that characterize hallucinatory percepts in schizophrenia.

Background: Auditory verbal hallucinations (AVHs) are a core symptom of schizophrenia. Previous reports on neural activity patterns associated with AVHs are inconsistent, arguably owing to the lack of an adequate control group (i.e., patients with similar characteristics but without AVHs) and neglect of the potential confounding effects of medication., Methods: The current study was conducted in a homogeneous group of patients with schizophrenia to assess whether the presence or absence of AVHs was associated with differential regional cerebral glucose metabolic patterns. We investigated differences between patients with commenting AVHs and patients without AVHs among a group of dextral antipsychotic-naive inpatients with acute first-episode schizophrenia examined with [(18)F]fluoro-deoxyglucose positron emission tomography (FDG-PET) at rest. Univariate and multivariate approaches were used to establish between-group differences., Results: We included 9 patients with AVHs and 7 patients without AVHs in this study. Patients experiencing AVHs during FDG uptake had significantly higher metabolic rates in the left superior and middle temporal cortices, bilateral superior medial frontal cortex and left caudate nucleus (cluster level p < 0.005, family wise error-corrected, and bootstrap ratio > 3.3, respectively). Additionally, the multivariate method identified hippocampal-parahippocampal, cerebellar and parietal relative hypoactivity during AVHs in both hemispheres (bootstrap ratio < -3.3)., Limitations: The FDG-PET imaging technique does not provide information regarding the temporal course of neural activity. The limited sample size may have increased the risk of false-negative findings., Conclusion: Our results indicate that AVHs in patients with schizophrenia may be mediated by an alteration of neural pathways responsible for normal language function. Our findings also point to the potential role of the dominant caudate nucleus and the parahippocampal gyri in the pathophysiology of AVHs. We discuss the relevance of phenomenology-based grouping in the study of AVHs.

Background: Some studies suggest individuals with schizophrenia have an increased risk of diabetes prior to antipsychotic use. Small sample sizes and the potential for confounding by hypercortisolaemia have decreased confidence in those results., Aims: To examine diabetes-related factors in newly diagnosed, antipsychotic-naive people with non-affective psychosis., Method: Participants with psychosis (the psychosis group; n = 50) and matched controls (the control group; n = 50) were given a 2 h oral glucose tolerance test. Fasting concentrations were also determined for adiponectin, interleukin-6 and C-reactive protein., Results: Compared with the control group, the psychosis group had significant increases in 2 h glucose and interleukin-6 concentrations, and in the prevalence of abnormal glucose tolerance (16% of psychosis group v. 0% of control group). Adiponectin and C-reactive protein concentrations did not differ significantly between the two groups. These findings could not be attributed to differences in cortisol concentrations, smoking, gender, neighbourhood of residence, body mass index, aerobic conditioning, ethnicity, socioeconomic status or age., Conclusions: Individuals with non-affective psychosis appear to have an increased prevalence of abnormal glucose tolerance prior to antipsychotic treatment, as well as abnormalities in a related inflammatory molecule. These underlying problems may contribute to the metabolic side-effects of antipsychotic medications.

Unlabelled: This study assesses prefrontal and temporal regional cerebral blood flow (rCBF) changes in young, neuroleptic-naive schizophrenic patients with acute disease., Methods: A selected population of 10 young, never-treated schizophrenic women with acute disease was studied by two hexamethylpropyleneamine oxime (HMPAO) brain SPECT sessions, performed 48 hr apart, both at rest and during a prefrontal activation task using the Wisconsin Card Sort Test (WCST). All patients met Diagnostic and Statistical Manual of Mental Disorders, 3rd edition-revised criteria for schizophrenia or schizophreniform disorder, were neuroleptic-naive and had acute symptoms., Results: Under resting conditions, the schizophrenic group had significantly higher rCBF in the prefrontal regions, mainly in the left side and including the anterior cingulate, than did the controls. In addition, schizophrenic patients showed significant interhemispheric differences in prefrontal and posterior temporal index values at rest (left hyperfrontality and left hypotemporality). During WCST activation, the control group showed significant increases in prefrontal blood flow, whereas the schizophrenic group did not., Conclusion: These results support a physiologic dysfunction of the prefrontal cortex in schizophrenia that is present at the onset of the illness prior to neuroleptic treatment. Furthermore, both left hyperfrontality and left hypotemporality may indicate a brain lateralization defect in schizophrenia.