Neuroreceptor Inhibition by Clozapine Triggers Mitohormesis and Metabolic Reprogramming in Human Blood Cells.

The antipsychotic drug clozapine demonstrates superior efficacy in treatment-resistant schizophrenia, but its intracellular mode of action is not completely understood. Here, we analysed the effects of clozapine (2.5-20 µM) on metabolic fluxes, cell respiration, and intracellular ATP in human HL60 cells. Some results were confirmed in leukocytes of clozapine-treated patients. Neuroreceptor inhibition under clozapine reduced Akt activation with decreased glucose uptake, thereby inducing ER stress and the unfolded protein response (UPR). Metabolic profiling by liquid-chromatography/mass-spectrometry revealed downregulation of glycolysis and the pentose phosphate pathway, thereby saving glucose to keep the electron transport chain working. Mitochondrial respiration was dampened by upregulation of the F0F1-ATPase inhibitory factor 1 (IF1) leading to 30-40% lower oxygen consumption in HL60 cells. Blocking IF1 expression by cotreatment with epigallocatechin-3-gallate (EGCG) increased apoptosis of HL60 cells. Upregulation of the mitochondrial citrate carrier shifted excess citrate to the cytosol for use in lipogenesis and for storage as triacylglycerol in lipid droplets (LDs). Accordingly, clozapine-treated HL60 cells and leukocytes from clozapine-treated patients contain more LDs than untreated cells. Since mitochondrial disturbances are described in the pathophysiology of schizophrenia, clozapine-induced mitohormesis is an excellent way to escape energy deficits and improve cell survival.

Long-term persistence of the risk of agranulocytosis with clozapine compared with other antipsychotics: a nationwide cohort and case-control study in Finland.

BACKGROUND: Agranulocytosis is a life-threatening side-effect of clozapine, the only approved drug for treatment-resistant schizophrenia. The long-term profile of this complication has not yet been well established. Here we aim to describe the risk of clozapine-induced agranulocytosis over the long term. METHODS: We used the entire population of Finland to identify people diagnosed with schizophrenia or schizoaffective disorder between 1972 and 2014 and developed a Kaplan-Meier model of time to diagnosis of agranulocytosis during clozapine versus non-clozapine treatment over a 22-year observation period (1996 to 2017). Next, we developed a nested case-control model for agranulocytosis matching by sex, age, time since diagnosis, and being in the incident cohort on a 1 to 5 ratio. Various durations of use for clozapine and non-clozapine antipsychotic treatment were compared to the modal antipsychotic use duration, deriving adjusted odds ratios (aORs) in a multivariable regression model. Recurrence and lethality rates for clozapine-induced agranulocytosis were described. These data reflect on all individuals with lived experience of schizophrenia in Finland during the study time, although individuals with lived experience were not included in the design of the study. FINDINGS: We identified 61 769 people with schizophrenia or schizoaffective disorder (14 037 individuals treated with clozapine and 47 732 individuals treated with non-clozapine antipsychotics), with a mean age of 46·67 years (IQR 34·44-57·61), of whom 30 721 (49·7%) were female and 31 048 (50·3%) were male (data on ethnicity not available). Among those, 398 individuals were diagnosed with agranulocytosis (231 individuals treated with clozapine and 167 individuals treated with non-clozapine antipsychotics), representing a cumulative incidence of agranulocytosis for 1·37% (95% CI 0·58-3·16) on clozapine and 0·13% (0·04-0·23) on non-clozapine antipsychotics. In the case (n=398) versus control (n=1987) model, the risk of clozapine-induced agranulocytosis decreased steeply over time from an aOR of 36·01 (95% CI 16·79-77·22) for less than 6 months on clozapine to 4·38 (1·86-10·34) for clozapine use of 54 months or more. Only one of 3559 individuals starting clozapine died because of clozapine-induced agranulocytosis. INTERPRETATION: The risk of clozapine-induced agranulocytosis decreases steeply over time but might be persistently greater than that of non-clozapine antipsychotics. This long-term risk excess seems small in absolute terms compared with the known magnitude of the advantages of clozapine in relevant outcomes, including life expectancy. Given the widespread underuse of clozapine, relaxing the long-term neutrophil monitoring could favour the advantages of long-term clozapine use, including greater life expectancy, without incurring the intolerable risk of clozapine-induced agranulocytosis. FUNDING: Northwell Health and Sigrid Jusèlius Foundation.

Acute manipulation of Drd1 neurons in the prefrontal cortex bidirectionally regulates anxiety and depression-like behaviors.

BACKGROUND CONTEXT: The medial prefrontal cortex (mPFC) has been implicated in modulating anxiety and depression. Manipulation of Drd1 neurons in the mPFC resulted in variable neuronal activity and, consequently, strikingly different behaviors. The acute regulation of anxiety- and depression-like behaviors by Drd1 neurons, a major neuronal subtype in the mPFC, has not yet been investigated. PURPOSE: The purpose of this study was to investigate whether acute manipulation of Drd1 neurons in the mPFC affects anxiety- and depression-like behaviors. STUDY DESIGN: Male Drd1-Cre mice were injected with an adeno-associated virus (AAV) expressing hM3DGq or hM4DGi. Clozapine-n-oxide (CNO, 1 mg/kg, i.p.) was injected 30 min before the behavioral tests. METHODS: Male Drd1-Cre mice were injected with AAV-Ef1α-DIO-hM4DGi-mCherry-WPRE-pA, AAV-Ef1α-DIO-hM3DGq-mCherry-WPRE-pA or AAV-Ef1α-DIO-mCherry-WPRE-pA. Three weeks later, whole-cell recordings after CNO (5 µM) were applied to the bath were used to validate the functional expression of hM4DGi and hM3DGq. Four groups of mice underwent all the behavioral tests, and after each of the tests, the mice were allowed to rest for 3-4 days. CNO (1 mg/kg) was injected intraperitoneally 30 min before the behavior test. Anxiety-like behaviors were evaluated by the open field test (OFT), the elevated plus maze test (EPMT), and the novelty-suppressed feeding test (NSFT). Depression-like behaviors were evaluated by the sucrose preference test (SPT) and force swimming test (FST). For all experiments, coronal sections of the targeted brain area were used to confirm virus expression. RESULTS: Whole-cell recordings from brain slices demonstrated that infusions of CNO (5 µM) into mPFC slices dramatically increased the firing activity of hM3DGq-mCherry+ neurons and abolished the firing activity of hM4DGi-mCherry+ neurons. Acute chemogenetic activation of Drd1 neurons in the mPFC increased the time spent in the central area in the OFT, increased the time spent in the open arms in the EMPT, decreased the latency to bite the food in the NSFT, increased the sucrose preference in the SPT, and decreased the immobility time in the FST. Acute chemogenetic inhibition of Drd1 neurons in the mPFC decreased the time spent in the central area in the OFT, decreased the time spent in the open arms in the EMPT, increased the latency to bite the food in the NSFT, decreased the sucrose preference in the SPT, and increased the immobility time in the FST. CONCLUSIONS: The present study showed that acute activation of Drd1 neurons in the mPFC produced rapid anxiolytic- and antidepressant-like effects, and acute inhibition had the opposite effect, revealing that Drd1 neurons in the mPFC bidirectionally regulate anxiety- and depression-like behaviors. CLINICAL SIGNIFICANCE: The findings of the present study regarding the acute effects of stimulating Drd1 neurons in the mPFC on anxiety and depression suggest that Drd1 neurons in the mPFC are a focus for the treatment of anxiety disorders and depression.

Beneficial Effects of Concomitant Long-Acting Injectable Antipsychotics on Time to Rehospitalization in Patients With Treatment-Resistant Schizophrenia Receiving Clozapine: A Retrospective Cohort Study.

Introduction: This study aimed to assess the association between long-acting injectable (LAI) antipsychotic prescription and the risk of psychiatric hospitalization in patients with treatment-resistant schizophrenia (TRS) receiving clozapine.Methods: In this retrospective cohort study at a single tertiary psychiatric center, we analyzed rehospitalization hazard ratios (HRs) in refractory schizophrenia patients, classified by DSM-IV-TR and DSM-5 criteria. We examined various psychotropic regimens-clozapine with or without other oral antipsychotics (OAPs) or LAI antipsychotics. Subgroups were stratified by daily clozapine dosage and previous admissions.Results: A total of 719 patients were included in the study. Analyses were conducted on all the patients over 3- month, 6-month, and 1-year periods. Patients treated with a combination of clozapine and LAI antipsychotics (CLO + LAI) had a significantly higher number of previous hospitalizations (P = .003), and a higher daily dose of clozapine (P < .001) was found in the CLO + OAP group than in the CLO (monotherapy) group and the CLO + LAI group. Patients treated with LAI antipsychotic comedication had significantly lower HRs for rehospitalization in 1 year among 3 studied groups. Moreover, the protective effects of LAI antipsychotics were observed in all the subgroups stratified by daily clozapine dosage and number of previous admissions to represent disease severity.Conclusion: The combination of clozapine and LAI antipsychotics was associated with a significantly lower risk of rehospitalization compared to both the combination of clozapine and OAPs and clozapine monotherapy. The use of LAI antipsychotics should be considered to prevent rehospitalization in patients with TRS who are already being treated with clozapine.

Clozapine Use Among People With Psychotic Disorders Who Experience Specific Indications for Clozapine.

Objective: To examine rates of clozapine use among people with psychotic disorders who experience specific indications for clozapine.Methods: Records data from 11 integrated health systems identified patients aged 18 years or older with recorded International Classification of Diseases, Tenth Revision, Clinical Modification, diagnoses of schizophrenia, schizoaffective disorder, or other psychotic disorder who experienced any of the 3 events between January 1, 2019, and December 31, 2019, suggesting indications for clozapine: a diagnosis of self-harm injury or poisoning, suicidal ideation diagnosed or in response to standardized assessments, and hospitalization or emergency department (ED) care for psychotic disorder despite treatment with 2 or more antipsychotic medications. Prescription dispensing data identified all clozapine use prior to or in the 12 months following each indication event. Analyses were conducted with aggregate data from each health system; no individual data were shared.Results: A total of 7,648 patients with psychotic disorder diagnoses experienced at least 1 indication event. Among 1,097 experiencing a self-harm event, 32 (2.9%) had any prior clozapine use, and 10 (0.9%) initiated clozapine during the following 12 months. Among 6,396 with significant suicidal ideation, 238 (3.7%) had any prior clozapine use, and 70 (1.1%) initiated clozapine over 12 months. Among 881 with hospitalization or ED visit despite pharmacotherapy, 77 (8.7%) had any prior clozapine treatment, and 41 (4.7%) initiated clozapine over 12 months. Among those with significant suicidal ideation, rates of both prior clozapine treatment and subsequent initiation varied significantly by race and ethnicity, with rates among Hispanic and non-Hispanic Black patients lower than among non Hispanic White patients.Conclusions: Initiating clozapine treatment is uncommon among people with psychotic disorders who experience events suggesting clozapine is indicated, with even lower rates among Black and Hispanic patients.

Chemogenetic inhibition of the lateral hypothalamus effectively reduces food intake in rats in a translational proof-of-concept study.

Despite the therapeutic potential of chemogenetics, the method lacks comprehensive preclinical validation, hindering its progression to human clinical trials. We aimed to validate a robust but simple in vivo efficacy assay in rats which could support chemogenetic drug discovery by providing a quick, simple and reliable animal model. Key methodological parameters such as adeno-associated virus (AAV) serotype, actuator drug, dose, and application routes were investigated by measuring the food-intake-reducing effect of chemogenetic inhibition of the lateral hypothalamus (LH) by hM4D(Gi) designer receptor stimulation. Subcutaneous deschloroclozapine in rats transfected with AAV9 resulted in a substantial reduction of food-intake, comparable to the efficacy of exenatide. We estimated that the effect of deschloroclozapine lasts 1-3 h post-administration. AAV5, oral administration of deschloroclozapine, and clozapine-N-oxide were also effective but with slightly less potency. The strongest effect on food-intake occurred within the first 30 min after re-feeding, suggesting this as the optimal experimental endpoint. This study demonstrates that general chemogenetic silencing of the LH can be utilized as an optimal, fast and reliable in vivo experimental model for conducting preclinical proof-of-concept studies in order to validate the in vivo effectiveness of novel chemogenetic treatments. We also hypothesize based on our results that universal LH silencing with existing and human translatable genetic neuroengineering techniques might be a viable strategy to affect food intake and influence obesity.

Association Between Clozapine Exposure and Risk of Hematologic Malignancies in Veterans With Schizophrenia.

Objective: The objective of this study was to examine the relationship between clozapine use and hematologic malignancies, using national administrative data from the United States Veterans Health Administration (VHA).Methods: This case-control study of veterans with schizophrenia matched cases with incident hematologic malignancy to 10 controls without hematologic malignancy by gender, age, and time since first schizophrenia diagnosis from October 1999, the beginning of VHA data archives, to June 2022. Schizophrenia diagnoses were identified using International Classification of Diseases, Ninth Revision, code 295.x and International Statistical Classification of Diseases, Tenth Revision, codes F20.x and F25.x from inpatient hospitalization and outpatient encounter data. Additional inclusion criteria were age 18-85 years, no prior history of malignancy, and at least 1 year of antipsychotic exposure. Clozapine exposure was assessed using 3 metrics: any exposure, years of exposure, and cumulative defined daily doses (DDD). Conditional multivariable logistic regression was used to adjust for nonmatched confounding variables.Results: A total of 2,306 veterans with schizophrenia were identified with an incident diagnosis of hematologic malignancy and matched to 23,043 controls. Any prior clozapine exposure was more commonly observed among cases (5.3%) than controls (4.1%) and was significantly different after adjustment (odds ratio [OR], 1.31; 95% CI, 1.08-1.60). Risk was dose-dependent, where cumulative clozapine exposures from 3,000 to 4,999 DDD (OR, 1.78; 95% CI, 1.13-2.79) and ≥5,000 DDD (OR, 1.81; 95% CI, 1.24-2.64) were significantly associated with malignancy risk. Similarly, clozapine exposure of 5 or more years was associated with malignancy risk (OR, 1.88; 95% CI, 1.43-2.47).Conclusion: Consistent with prior report, this study observed an increased risk of hematologic malignancy associated with clozapine exposure. These findings suggest patients receiving clozapine use, particularly those with long-term use, should be closely monitored for hematologic malignancy.

Can Slow Personalized Titration Using C-Reactive Protein Monitoring Decrease the High Rates and Mortality of Clozapine-Associated Myocarditis Seen in Some Countries? A Call for Research.

PURPOSE/BACKGROUND: The hypothesis that slower personalized titration may prevent clozapine-associated myocarditis and decrease the disproportion incidence of 3% found in Australia was not described in a recent Australian article in this journal. METHODS: Six countries in addition to Australia have published information suggesting a similar incidence of clozapine-associated myocarditis. On September 19, 2023, PubMed searches were updated for articles from the United States, Korea, Japan, Canada, New Zealand, and Turkey. FINDINGS/RESULTS: An incidence of 3.5% (4/76) was found in a US hospital, but US experts were the first to propose that clozapine-associated myocarditis may be a hypersensitivity reaction associated with rapid titration and possibly preventable. Koreans and Japanese are of Asian ancestry and need lower minimum therapeutic doses for clozapine than patients of European ancestry. A 0.1% (2/1408) incidence of myocarditis during clozapine titration was found in a Korean hospital, but pneumonia incidence was 3.7% (52/1408). In 7 Japanese hospitals, 34% (37/110) of cases of clozapine-associated inflammation were found during faster titrations (based on the official Japanese titration) versus 13% (17/131) during slower titrations (based on the international titration guideline for average Asian patients). Recent limited studies from Canada, New Zealand, and Turkey suggest that slower personalized titration considering ancestry may help prevent clozapine-associated myocarditis. IMPLICATIONS/CONCLUSIONS: Other countries have very limited published data on clozapine-associated myocarditis. Based on a recent Australian case series and these non-Australian studies, the author proposes that Australia (and other countries) should use slow personalized titration for clozapine based on ancestry and c-reactive protein monitoring.

Rapid Metabolism Underlying Subtherapeutic Serum Levels of Atypical Antipsychotics Preceding Clozapine Treatment: A Retrospective Analysis of Real-World Data.

INTRODUCTION: Adequate antipsychotic treatment intensity is required before diagnosing resistant schizophrenia and initiating clozapine treatment. We aimed to investigate potential rapid drug metabolism underlying low dose-adjusted serum concentration (CD) of non-clozapine atypical antipsychotics preceding clozapine treatment. METHODS: Patients using non-clozapine, atypical antipsychotics (aripiprazole, risperidone, olanzapine, or quetiapine) within 1 year before starting clozapine were included in this study from a therapeutic drug monitoring service in Oslo, Norway, between 2005 and 2023. Patients were assigned into low CD (LCD) and normal CD (NCD) subgroups. Using a reference sample with 147,964 antipsychotic measurements, LCD was defined as CDs below the 25th percentile, while patients with NCD exhibited CDs between the 25th and 75th percentile of the respective reference measurements. Metabolic ratios, doses, and frequency of subtherapeutic levels of non-clozapine antipsychotics were compared between LCD and NCD groups. RESULTS: Preceding clozapine treatment, 110 out of 272 included patients (40.4%) were identified with LCD. Compared with the NCD group, LCD patients exhibited higher metabolic ratios of olanzapine (1.5-fold; p < 0.001), quetiapine (3.0-fold; p < 0.001), and risperidone (6.0-fold; p < 0.001). Metabolic ratio differences were independent of smoking and CYP2D6 genotype for olanzapine (p = 0.008) and risperidone (p = 0.016), respectively. Despite higher doses of olanzapine (1.25-fold; p = 0.054) and quetiapine (1.6-fold; p = 0.001) in LCD versus NCD patients, faster metabolism among the former was accompanied by higher frequencies of subtherapeutic levels of olanzapine (3.3-fold; p = 0.044) and quetiapine (1.8-fold; p = 0.005). CONCLUSION: LCD and associated rapid metabolism of non-clozapine antipsychotics is frequent before starting clozapine treatment. For olanzapine and quetiapine, this is associated with significantly increased risk of having subtherapeutic concentrations.

Exploring clozapine pharmacokinetics in Tunisian schizophrenic patients: A population-based modelling approach investigating the impact of genetic and non-genetic variables.

Clozapine is characterized by a large within- and between-patient variability in its pharmacokinetics, attributed to non-genetic and genetic factors. A cross-sectional analysis of clozapine trough concentration (Clz C0) issued from Tunisian schizophrenic patients was collected and analysed using a nonparametric modelling approach. We assessed the impact of demographic covariates (age, weight and sex), patient's habits (smoking status, alcohol and caffeine intake) and the genetic factors (CYP1A2*1C, CYP1A2*1F and CYP2C19*2 polymorphisms) on each pharmacokinetic parameter. An external validation of this pharmacokinetic model using an independent data set was performed. Fit goodness between observed- and individual-predicted data was evaluated using the mean prediction error (% MPE), the mean absolute prediction error (% MAPE) as a measure of bias, and the root mean squared error (% RMSE) as a measure of precision. Sixty-three CLz C0 values issued from 51 schizophrenic patients were assessed in this study and divided into building and validation groups. CYP1A2*1F polymorphism and smoking status were the only covariates significantly associated with clozapine clearance. Precision parameters were as follows: 1.02%, 0.95% and 22.4%, respectively, for % MPE, % MAPE and % RMSE. We developed and validated an accurate pharmacokinetic model able to predict Clz C0 in Tunisian schizophrenic patients using the two parameters CYP1A2*1F polymorphism and smoking.

Clozapine Prescripers-Dogmatic or Pragmatic?

Clozapine, amongst antipsychotics, has a unique composite mode of action that might translate into an expanded therapeutic potential on clinical grounds. Sorely, clozapine remains underutilized.

Clozapine Treatment for Aggressive Behaviors in Youths with Neurodevelopmental Disorders.

Objectives: The aim of this study was to assess effectiveness and tolerability of Clozapine in the treatment of aggression in youth with Neurodevelopmental Disorders. Methods: Patients were consecutively admitted at our third-level university hospital with nationwide catchment from June 2018 to October 2022, and followed up to July 2023. Eligibility criteria were as follows: (1) Autism Spectrum Disorder (ASD) and/or Intellectual Disability/Borderline Cognitive Functioning, (2) behavioral dyscontrol with physical aggression; (3) age range between 8 and 18 years; (4) clinical indication for Clozapine treatment after at least two failed trials with other Second-Generation Antipsychotics (SGAs); (5) availability of an at least 6-month-long follow-up. To evaluate the response to Clozapine, we used the Clinical Global Impressions (CGI) rating scales (Clinical Global Impressions-Severity [CGI-S] and Clinical Global Impressions-Improvement [CGI-I]), the Children's Global Assessment Scale (CGAS), and the Aberrant Behavior Checklist (ABC). Results: Twenty-six children and adolescents (21 boys, age 13.47 ± 2.05 years, follow-up duration 9.77 ± 3.50 months) were included in the analysis. Clinical severity (CGI-S) and functional impairment (Clinical Global Assessment Scale) significantly improved, as well as the ABC Total Score and the scores in several subscales. Sixteen patients (61.54%) were responders (CGI-I ≤2), and 13 (50.00%) displayed remission of aberrant behaviors (ΔABC-Total >35), while response/remission condition was not affected by add-on medications and psychotherapy. Most frequent side effects were increased appetite (50.00%), sialorrhea (38.46%), and increased repetitive behaviors (26.92%). Two patients presented epileptic seizures, while no patients presented leucopoenia. Conclusions: Our results suggest that Clozapine may be helpful in ameliorating treatment-resistant aggression in youth with neurodevelopmental conditions. Possible pharmacological strategies for the management of most frequent side effects are also suggested.

The role of psychosis and clozapine load in excessive checking in treatment-resistant schizophrenia: longitudinal observational study.

BACKGROUND: A significant proportion of people with clozapine-treated schizophrenia develop 'checking' compulsions, a phenomenon yet to be understood. AIMS: To use habit formation models developed in cognitive neuroscience to investigate the dynamic interplay between psychosis, clozapine dose and obsessive-compulsive symptoms (OCS). METHOD: Using the anonymised electronic records of a cohort of clozapine-treated patients, including longitudinal assessments of OCS and psychosis, we performed longitudinal multi-level mediation and multi-level moderation analyses to explore associations of psychosis with obsessiveness and excessive checking. Classic bivariate correlation tests were used to assess clozapine load and checking compulsions. The influence of specific genetic variants was tested in a subsample. RESULTS: A total of 196 clozapine-treated individuals and 459 face-to-face assessments were included. We found significant OCS to be common (37.9%), with checking being the most prevalent symptom. In mediation models, psychosis severity mediated checking behaviour indirectly by inducing obsessions (r = 0.07, 95% CI 0.04-0.09; P < 0.001). No direct effect of psychosis on checking was identified (r = -0.28, 95% CI -0.09 to 0.03; P = 0.340). After psychosis remission (n = 65), checking compulsions correlated with both clozapine plasma levels (r = 0.35; P = 0.004) and dose (r = 0.38; P = 0.002). None of the glutamatergic and serotonergic genetic variants were found to moderate the effect of psychosis on obsession and compulsion (SLC6A4, SLC1A1 and HTR2C) survived the multiple comparisons correction. CONCLUSIONS: We elucidated different phases of the complex interplay of psychosis and compulsions, which may inform clinicians' therapeutic decisions.

Multiple serum anti-glutamate receptor antibody levels in clozapine-treated/naïve patients with treatment-resistant schizophrenia.

BACKGROUND: Glutamatergic function abnormalities have been implicated in the etiology of treatment-resistant schizophrenia (TRS), and the efficacy of clozapine may be attributed to its impact on the glutamate system. Recently, evidence has emerged suggesting the involvement of immune processes and increased prevalence of antineuronal antibodies in TRS. This current study aimed to investigate the levels of multiple anti-glutamate receptor antibodies in TRS and explore the effects of clozapine on these antibody levels. METHODS: Enzyme linked immunosorbent assay (ELISA) was used to measure and compare the levels of anti-glutamate receptor antibodies (NMDAR, AMPAR, mGlur3, mGluR5) in clozapine-treated TRS patients (TRS-C, n = 37), clozapine-naïve TRS patients (TRS-NC, n = 39), and non-TRS patients (nTRS, n = 35). Clinical symptom severity was assessed using the Positive and Negative Symptom Scale (PANSS), while cognitive function was evaluated using the MATRICS Consensus Cognitive Battery (MCCB). RESULT: The levels of all four glutamate receptor antibodies in TRS-NC were significantly higher than those in nTRS (p < 0.001) and in TRS-C (p < 0.001), and the antibody levels in TRS-C were comparable to those in nTRS. However, no significant associations were observed between antibody levels and symptom severity or cognitive function across all three groups after FDR correction. CONCLUSION: Our findings suggest that TRS may related to increased anti-glutamate receptor antibody levels and provide further evidence that glutamatergic dysfunction and immune processes may contribute to the pathogenesis of TRS. The impact of clozapine on anti-glutamate receptor antibody levels may be a pharmacological mechanism underlying its therapeutic effects.

Antipsychotic drugs selectively decorrelate long-range interactions in deep cortical layers.

Psychosis is characterized by a diminished ability of the brain to distinguish externally driven activity patterns from self-generated activity patterns. Antipsychotic drugs are a class of small molecules with relatively broad binding affinity for a variety of neuromodulator receptors that, in humans, can prevent or ameliorate psychosis. How these drugs influence the function of cortical circuits, and in particular their ability to distinguish between externally and self-generated activity patterns, is still largely unclear. To have experimental control over self-generated sensory feedback, we used a virtual reality environment in which the coupling between movement and visual feedback can be altered. We then used widefield calcium imaging to determine the cell type-specific functional effects of antipsychotic drugs in mouse dorsal cortex under different conditions of visuomotor coupling. By comparing cell type-specific activation patterns between locomotion onsets that were experimentally coupled to self-generated visual feedback and locomotion onsets that were not coupled, we show that deep cortical layers were differentially activated in these two conditions. We then show that the antipsychotic drug clozapine disrupted visuomotor integration at locomotion onsets also primarily in deep cortical layers. Given that one of the key components of visuomotor integration in cortex is long-range cortico-cortical connections, we tested whether the effect of clozapine was detectable in the correlation structure of activity patterns across dorsal cortex. We found that clozapine as well as two other antipsychotic drugs, aripiprazole and haloperidol, resulted in a strong reduction in correlations of layer 5 activity between cortical areas and impaired the spread of visuomotor prediction errors generated in visual cortex. Our results are consistent with the interpretation that a major functional effect of antipsychotic drugs is a selective alteration of long-range layer 5-mediated communication.

Exploring clozapine use in severe psychiatric symptoms associated with autism spectrum disorder: A scoping review.

BACKGROUND: Patients with autism spectrum disorder (ASD) may experience severe psychiatric symptoms, often unresponsive to conventional pharmacological therapies, highlighting the need for more effective alternatives. AIMS: This study aims to map and synthesize evidence on the use of clozapine as a therapeutic option for managing severe psychiatric symptomatology co-occurring with ASD. METHODS: We conducted a scoping review on multiple sources following the JBI guidelines. The search strategy was inclusive, targeting both peer-reviewed publications and gray literature presenting empirical data on the use of clozapine therapy for patients with ASD accompanied by comorbid psychiatric symptoms. Two independent evaluators performed the selection of studies, data extraction, and critical appraisal. RESULTS: The review included 46 studies, encompassing 122 ASD individuals who received clozapine therapy. The sources of evidence comprise 31 case reports, 8 case series, 6 retrospective observational studies, and 1 quasi-experimental prospective study. The tables present the findings along with a narrative summary. Clozapine treatment demonstrated benefits in four groups of severe and treatment-resistant psychiatric symptoms in ASD patients: disruptive behaviors, psychotic symptoms, catatonia, and mood symptoms. Although side effects were common, tolerability was generally satisfactory. However, severe adverse events, such as seizures, moderate neutropenia, and myocarditis, underscore the need for intensive clinical monitoring. CONCLUSIONS: While clozapine shows promise as a pharmacological intervention for severe psychopathologies in ASD, more rigorous clinical studies are required to elucidate its efficacy and safety in this population. The limited robustness of the evidence calls for caution, signaling an early research stage into this topic.

Chemogenetic Manipulation of Amygdala Kappa Opioid Receptor Neurons Modulates Amygdala Neuronal Activity and Neuropathic Pain Behaviors.

Neuroplasticity in the central nucleus of the amygdala (CeA) plays a key role in the modulation of pain and its aversive component. The dynorphin/kappa opioid receptor (KOR) system in the amygdala is critical for averse-affective behaviors in pain conditions, but its mechanisms are not well understood. Here, we used chemogenetic manipulations of amygdala KOR-expressing neurons to analyze the behavioral consequences in a chronic neuropathic pain model. For the chemogenetic inhibition or activation of KOR neurons in the CeA, a Cre-inducible viral vector encoding Gi-DREADD (hM4Di) or Gq-DREADD (hM3Dq) was injected stereotaxically into the right CeA of transgenic KOR-Cre mice. The chemogenetic inhibition of KOR neurons expressing hM4Di with a selective DREADD actuator (deschloroclozapine, DCZ) in sham control mice significantly decreased inhibitory transmission, resulting in a shift of inhibition/excitation balance to promote excitation and induced pain behaviors. The chemogenetic activation of KOR neurons expressing hM3Dq with DCZ in neuropathic mice significantly increased inhibitory transmission, decreased excitability, and decreased neuropathic pain behaviors. These data suggest that amygdala KOR neurons modulate pain behaviors by exerting an inhibitory tone on downstream CeA neurons. Therefore, activation of these interneurons or blockade of inhibitory KOR signaling in these neurons could restore control of amygdala output and mitigate pain.

Clearing the Fog: A Review of Antipsychotics for Parkinson's-Related Hallucinations: A Focus on Pimavanserin, Quetiapine and Clozapine.

Parkinson's disease is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms, including hallucinations. The use of antipsychotic medications is a common strategy to manage hallucinations associated with Parkinson's disease psychosis (PDP). However, careful consideration is necessary when selecting the most appropriate drug due to the potential risks associated with the available treatment options. Atypical antipsychotics (AAPs), such as Pimavanserin and Clozapine, have effectively controlled PDP symptoms. On the contrary, the support for utilizing quetiapine is not as substantial as other antipsychotics because research studies specifically investigating its application are still emerging and relatively recent. The broad mechanisms of action of AAPs, involving dopamine and serotonin receptors, provide improved outcomes and fewer side effects than typical antipsychotics. Conversely, other antipsychotics, including risperidone, olanzapine, aripiprazole, ziprasidone, and lurasidone, have been found to worsen motor symptoms and are generally not recommended for PDP. While AAPs offer favorable benefits, they are associated with specific adverse effects. Extrapyramidal symptoms, somnolence, hypotension, constipation, and cognitive impairment are commonly observed with AAP use. Clozapine, in particular, carries a risk of agranulocytosis, necessitating close monitoring of blood counts. Pimavanserin, a selective serotonin inverse agonist, avoids receptor-related side effects but has been linked to corrected QT (QTc) interval prolongation, while quetiapine has been reported to be associated with an increased risk of mortality. This review aims to analyze the benefits, risks, and mechanisms of action of antipsychotic medications to assist clinicians in making informed decisions and enhance patient care.