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The increasing demand in healthcare for accessible and cost-effective analytical tools is driving the development of reliable platforms to the customization of therapy according to individual patient drug serum levels, e.g. of anti-psychotics in schizophrenia. A modifier-free microfluidic paper-based electroanalytical device (μPED) holds promise as a portable, sensitive, and affordable solution. While many studies focus on the working electrode catalysts, improvements by engineering aspects e.g. of the electrode arrangement are less reported. In our study, we demonstrate the enhanced capabilities of the 3D electrode layout of μPED compared to 2D μPED arrangements. We especially show that screen printing can be employed to prepare 3D μPEDs. We conducted a comparison of different 2D and 3D electrode arrangements utilizing cyclic voltammetry in [Fe(CN) 6 ] 3-/4- , along with square-wave voltammetry for clozapine (CLZ) sensing. Our findings reveal that the utilization of the 3D μPED leads to an increase in both the electrochemically active surface area and the electron transfer rate. Consequently, this enhancement contributes to improve sensitivity in the CLZ sensing. The 3D μPED clearly outperforms the 2D μPED arrangement in terms of signal strength. With the 3D μPED under the optimized conditions, a linear dose-response for a concentration range from 7.0 to 100 μM was achieved. The limit of detection and sensitivity was determined to be 1.47 μM and 1.69 μA μM -1 cm -2 , respectively. This evaluation is conducted in the context of detection and determination of CLZ in a human blood serum sample. These findings underscore the potential of the 3D μPED for future applications in pharmacokinetic analyses and clinical tests to personalize the management of schizophrenia.

Clozapine-induced myocarditis (CIM) is among the most important adverse events limiting the use of clozapine as the most effective treatment for schizophrenia. CIM necessitates the immediate termination of clozapine, often resulting in its permanent discontinuation with considerable detrimental effects on patients' psychopathology and long-term outcome. Consequently, a clozapine re-challenge after CIM is increasingly regarded as a viable alternative, with published reports indicating a success rate of approximately 60%. However, published cases of re-challenges after CIM remain limited. Here, we provide a narrative review of the current state of research regarding the epidemiology, pathophysiology, risk factors, diagnosis and clinical management of CIM as well as a synthesis of current recommendations for re-challenging patients after CIM. This includes a step-by-step guide for this crucial procedure based on the current evidence regarding the pathophysiology and risk factors for CIM. Slow dose titration regimes and addressing risk factors including concomitant valproate and olanzapine are crucial both to prevent CIM and to ensure a safe and successful re-challenge. Furthermore, we discuss the utility of C-reactive protein, troponin, N-terminal-pro hormone and brain natriuretic peptide, therapeutic drug-monitoring and cardiac magnetic resonance imaging for CIM screening and diagnosis as well as for post-CIM re-challenges., (© 2024. The Author(s).)

Aim: This study evaluates the research output on Clozapine included in Scopus database during 1970-2021. Materials and Methods: The quantitative and qualitative analysis of publications on "Clozapine" covered in Scopus database during 1970-2021 was undertaken. The results obtained were further analysed using additional features in Scopus database. Results: 7399 publications on "Clozapine" were obtained from Scopus international database and these publications received 189068 citations, averaging 25.55 citations per paper (CPP). There was initial rise in the number of publications per year from 1988 to 1995, after that the number of publications has remained relatively stable. Authors from USA, U.K. and Germany contributed to the largest number of publications (2136, 709 and 457 publications respectively), and publications with authors from USA, Canada and Germany registered the highest CPP and relative citation index (RCI). The authors from King's College London, U.K, The Zucker Hillside Hospital, USA and University of Toronto, Canada published the highest number of publications. The organization that registered the highest CPP and RCI was Sandoz International GmbH, Switzerland, Long Island Jewish Medical Centre, USA and Vanderbilt University, School of Medicine, USA. The authors who published the highest number of publications were H.Y. Meltzer (USA), J.A. Lieberman (USA) and A. Weizman (Israel). The authors who registered the highest CPP and RCI were R. W. Kerwin (U.K.) and J.P. Lindermayer. The journals that published the highest number of publications were Journal of Clinical Psychopharmacology (351 papers), Journal of Clinical Psychiatry (282 papers), and American Journal of Psychiatry (255 papers). The most impactful publications were published in Archives of General Psychiatry, Schizophrenia Bulletin, Journal of Pharmacology and Experimental Therapeutics, and American Journal of Psychiatry. Conclusion: This study suggests that the numbers of publications on clozapine have remained stable over the years and maximum research has emerged from the developed countries. [ABSTRACT FROM AUTHOR]

Purpose: Although clozapine was Food and Drug Administration (FDA) approved more than 3 decades ago, major barriers and gaps in knowledge continue to prevent its effective and safe use. We review modern-day problems encountered with clozapine in the United States (US)., Methods: Information surrounding current administrative, clinical, research, and technological gaps or barriers related to clozapine use in the US was reviewed., Findings: The history of how clozapine became FDA approved likely contributes to gaps in knowledge. The frequency of safety warnings added to the FDA prescribing information may add to fears about clozapine, as evidence by numerous published survey studies. The clozapine Risk Evaluation and Mitigation Strategy (REMS) program has been modified several times in the last decade, causing access and safety issues for patients, which are discussed. Evidence may suggest that the FDA REMS requirements for hematologic monitoring are too cumbersome, and there may be ability to safely loosen requirements. The COVID-19 pandemic brought forth the ability for extended interval monitoring but also greater awareness of the clozapine-inflammation interaction. Newer guidelines published describe considerations in personalizing clozapine titration based on principles of ethnopsychopharmacology. Emerging technologies to support the use of clozapine are not widely available., Implications: Clozapine is a unique life-saving drug but it is underused in the US, despite its established efficacy. The 2021 REMS changes led to significant difficulties for providers and patients. We highlight the importance of the clozapine-inflammation interaction, therapeutic drug monitoring, and the ability for individual care based on patient-specific factors. There is an urgent need for advancing technology used for clozapine monitoring, evaluating barriers created by REMS, and establishing consistent practices throughout the US., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Long-term institutionalization of the forensic psychiatry patient population places a psychological burden on patients and family members as well as a financial burden on the health care system at large. Although electroconvulsive therapy is a well-established tool for patients with treatment-resistant schizophrenia, it is infrequently used in the forensic setting. This review serves to demonstrate an example of electroconvulsive therapy in combination with clozapine as a means of reducing length of hospitalization in a forensic psychiatric patient. Furthermore, this review will discuss factors limiting the prescribing of electroconvulsive therapy to this patient population including ethical considerations and availability., Competing Interests: The authors have no conflicts of interest or financial disclosures to report., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

MiRNAs are small, non-coding RNAs that can silence the expression of various target genes by binding their mRNAs and thus regulate a wide range of crucial bodily functions. However, the miRNA expression profile of schizophrenia after antipsychotic mediation is largely unknown. Non-competitive N-methyl-D-aspartic acid (NMDA) receptor antagonists such as MK-801 have provided useful animal models to investigate the effects of schizophrenia-like symptoms in rodent animals. Herein, the hippocampal miRNA expression profiles of Sprague-Dawley rats pretreated with MK-801 were examined after antipsychotic clozapine (CLO) treatment. Total hippocampal RNAs from three groups were subjected to next-generation sequencing (NGS), and bioinformatics analyses, including differential expression and enrichment analyses, were performed. Eight miRNAs were differentially expressed between the MK-801 and vehicle (VEH) control groups. Interestingly, 14 miRNAs were significantly differentially expressed between the CLO + MK-801 and MK-801 groups, among which rno-miR-184 was the most upregulated. Further analyses suggested that these miRNAs modulate target genes that are involved in endocytosis regulation, ubiquitin-mediated proteolysis, and actin cytoskeleton regulation and thus might play important roles in the pathogenesis of schizophrenia. Our results suggest that differentially expressed miRNAs play important roles in the complex pathophysiology of schizophrenia and subsequently impact brain functions., (© 2021 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). Published by John Wiley & Sons Ltd.)

Background: Clozapine is the only medication with Food and Drug Administration approval for treatment-resistant schizophrenia. However, it is underutilized in the United States because of several life-threatening adverse effects, including clozapine-associated myocarditis (CAM), and a limited understanding of how to manage these complications. To date, recommendations for rechallenging patients with CAM that incorporate the cardiac literature or cardioprotective medications have not been developed., Findings: In this article, we outline a protocol developed with cardiologists and guided by the cardiac literature that provides direction on how to monitor for the initial development of CAM and how to rechallenge patients with CAM. Furthermore, we present 2 successful cases of clozapine rechallenge that were managed using this protocol., Conclusions: In both cases, the patients showed marked improvement in their psychiatric symptoms and functioning, demonstrating the importance of considering rechallenge in patients after CAM., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Aim: Improving access to clozapine is a recognized priority nationally across Early Intervention in Psychosis Services (EIPS) in the UK. Treatment resistance (TR) may be identifiable from early episode psychosis and appears to be characterized by negative symptoms and younger age of onset. This mixed method cross-sectional snapshot analysis of antipsychotic (AP) prescribing in an EIPS, explored clozapine eligibility (CE) and prioritization of AP prescribing based on choice, selectivity and appropriateness., Method: We screened 150 service users and 79% (n = 119) were retained after inclusion criteria were applied. We explored CE in all service users who were indicated clozapine based on the product licence (n = 78), and whether there was association between CE and number of hospital admissions, AP trials, age at first episode and duration of untreated psychosis., Results: Following multidisciplinary clinical discussions, we found that 23 service users were CE; 8 were offered and declined clozapine. When compared to non-CE service users, significant factors associated with CE were history of two or more hospital admissions (Mann-Whitney U = 269, P = .008), more than two trials of two different APs (Mann-Whitney U = 517, P ≤ .01), and younger age first episode (independent-samples t-test, P = .047). A total of 47.5% of all service users had been started on olanzapine as their first AP, despite high risk of cardiometabolic syndrome., Conclusion: We propose that EIP services adopt a proactive approach in screening for TR, taking into account negative symptoms and young age at onset, prioritizing service users with two or more hospital admissions and AP trials., (© 2020 John Wiley & Sons Australia, Ltd.)

The continuous monitoring of antipsychotic drug release in the patient undergoing treatment is significant for dose monitoring. Hence, as a part of treatment, frequent blood tests are required to detect the drug level. In this context, the development of a miniaturized POC (Point-of-Care) Electrochemical sensing platform plays a significant role. The present work demonstrates the realization of a paper-based electrochemical sensing device for sensing of antipsychotic drug Clozapine (CLZ). A commercial Toray paper was used as a base electrode that showed high conductivity, mechanical strength, and gas permeability, hence appropriate for electrochemical sensing. Toray fibrous carbon electrodes were used for the sensing of CLZ. The CO 2 laser system with optimized speed (6.5 %) and power (4.5 %) was efficiently used to fabricate a simple, low-cost, and miniaturized Toray paper electrochemical device (TPED). The electrode surface was characterized using scanning electron microscopy, which showed a high porous gas diffusion layer with denser carbon. Cyclic Voltammetry (CV) and Chronoamperometry (CA) techniques were used to study the electrochemical characterization of the CLZ. The analytical performance of TPED was validated by sensing various concentrations of CLZ in a linear range from 0.5 µM to 5 µM with a Limit of detection (LoD) of 0.5 µM and a Limit of Quantification (LoQ) of 1.69 µM using cyclic voltammetry and the linear from 0.5 µM to 5 µM with a limit of detection (LoD) of 0.01 µM and Limit of Quantification (LoQ) of 0.05 µM using chronoamperometry techniques. Furthermore, the interference mitigation of TPED was examined with other biomolecules. Finally, the practicability of TPED was tested by performing a real sample analysis in blood serum. Based on the analytical performance, it was confirmed that the fabricated device has the ability to be applied in biomedical applications for drug sensing in point-of-care testing. [Display omitted] • Novel Miniaturized Toray paper-based device for clozapine detection is presented. • The device was characterized by various electrochemical techniques. • A Linear concentration range of 0.5 µM to 5 µM was achieved. • LOD and LOQ of 0.5 µM and 0.69 µM, respectively were obtained. • Serum sample was used for real sample analysis and upto 98 % efficacy obtained. [ABSTRACT FROM AUTHOR]

Objectives: This paper critiques the haematological monitoring guidelines for clozapine. It describes the history of clozapine, as well as the pathophysiology and epidemiology of clozapine-induced neutropenia (CIN) and agranulocytosis (CIA). The paper appraises the extant literature on mandatory clozapine haematological monitoring. Conclusion: Contemporary Australian protocols for clozapine haematological monitoring are not consistent with the current evidence base. CIN and CIA are rare occurrences, and the associated risk of death is low. Potential modifications to existing guidelines include changing neutrophil thresholds for patients with benign ethnic neutropenia and reducing the frequency or removing haematological monitoring after two years of clozapine treatment. [ABSTRACT FROM AUTHOR]

Without a functioning prefrontal cortex, humans and other animals are impaired in measures of cognitive control and behavioral flexibility, including attentional set-shifting. However, the reason for this is unclear with evidence suggesting both impaired and enhanced attentional shifting. We inhibited the medial prefrontal cortex (mPFC) of rats while they performed a modified version of an attentional set-shifting task to explore the nature of this apparent contradiction. Twelve adult male Lister hooded rats received AAV5-CaMKIIa-hM4D(Gi)-mCherry viral vector bilaterally into mPFC to express inhibitory 'Designer Receptors Exclusively Activated by Designer Drugs' (iDREADDs). The receptors were activated by systemic clozapine N-oxide (CNO) to inhibit mPFC function. The rats were tested in the standard attentional set-shifting task four times: twice after i.p. administration and twice after oral administration of vehicle or CNO (10 mg/kg). They were then tested twice in a modified task, with or without oral CNO. The modified task had an extra stage before the extradimensional shift, in which the relevant exemplars remained relevant and new exemplars that were fully predictive but redundant replaced the previous irrelevant exemplars. These exemplars then became relevant at the subsequent ED stage. In the standard task, mPFC inactivation impaired attentional set-shifting, consistent with previous findings. However, in the modified task, mPFC inactivation abolished ED shift-costs. The results support the suggestion that the mPFC is needed for the downregulation of attention that prevents learning about redundant and irrelevant stimuli. With mPFC inactivated, the rat learns more rapidly when previously redundant exemplars become the only relevant information., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Clozapine remains the only pharmacological treatment option for treatment-resistant schizophrenia. Therapeutic drug monitoring (TDM) of clozapine is recommended, although evidence for the therapeutic range of 350-600 ng/ml is limited. In various countries including Serbia, TDM of clozapine is not routinely performed. This study evaluated the distribution of clozapine levels and their relationship with clinical outcomes in Serbian patients who had not undergone prior TDM. 140 Patients with treatment-resistant schizophrenia and schizo-affective disorder were enrolled. Clozapine levels were measured by dried blood spot (DBS) analysis. Side effects were evaluated by GASS-c, severity of symptoms and functional impairment with WHODAS, CGI-S and GAF. Of the patients, 51.2% had subtherapeutic levels, 24.8% were in the therapeutic window, and 24% had supratherapeutic levels. Clozapine levels showed no association with side effects and a weak positive association with symptom severity and functional impairment. No serious side effects were observed in patients with clozapine levels surpassing 1000 ng/ml (n = 8). Based on these findings, we propose that the upper limit of the therapeutic range should not be regarded as an absolute barrier, and guidelines should allow for a personalized approach when prescribing clozapine., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Ongoing psychiatric follow-up and medication adherence improve outcomes for patients with psychotic disorders. Due to COVID-19, outpatient care may have been disrupted, impacting healthcare utilization., Methods: A retrospective population-wide study was conducted for adults in Manitoba, Canada. Medication adherence and healthcare utilization were examined from 2019 to 2021. The presence of a diagnosed psychotic disorder was identified in the five years before the index date in each year. The LAI and clozapine cohorts consisted of those who received at least two prescriptions in each year 180 days before the March 20th index date. The change in adherence was measured using the average Medication Possession Ratio. Healthcare utilization rates were compared using Generalized Estimating Equation models., Results: There were no significant differences between LAI and clozapine discontinuation rates before and during the pandemic. In the LAI cohort, general practitioner visits decreased significantly (-3.5 %, p = 0.039) across four quarters of 2021 versus 2019. All-cause hospitalizations decreased by 16.8 % in 2020 versus 2019 (p = 0.0055), while psychiatric hospitalizations decreased by 18.7 % across four quarters in 2020 (p = 0.0052) and 13.7 % in 2021 (p = 0.0425), versus 2019 in the LAI cohort. There was a significant transition to virtual care during the first wave of COVID-19 (71 % in clozapine, 51 % in LAI cohorts). Trends in total outpatient visits and non-psychiatric hospitalizations remained stable., Conclusion: COVID-19 had no substantial impact on LAI and clozapine discontinuation rates for patients previously adherent. Outpatient care remained stable, with a significant proportion of visits being done virtually at the outset of the pandemic., Competing Interests: Declaration of competing interest The authors of the paper do not have any conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The nucleus reuniens (RE) of the ventral midline thalamus is a critical node in the communication between the orbitomedial prefrontal cortex (OFC) and the hippocampus (HF). While RE has been shown to directly participate in memory-associated functions through its connections with the medial prefrontal cortex and HF, less is known regarding the role of RE in executive functioning. Here, we examined the involvement of RE and its projections to the orbital cortex (ORB) in attention and behavioral flexibility in male rats using the attentional set shifting task (AST). Rats expressing the hM4Di DREADD receptor in RE were implanted with indwelling cannulas in either RE or the ventromedial ORB to pharmacologically inhibit RE or its projections to the ORB with intracranial infusions of clozapine-N-oxide hydrochloride (CNO). Chemogenetic-induced suppression of RE resulted in impairments in reversal learning and set-shifting. This supports a vital role for RE in behavioral flexibility - or the ability to adapt behavior to changing reward or rule contingencies. Interestingly, CNO suppression of RE projections to the ventromedial ORB produced impairments in rule abstraction - or dissociable effects elicited with direct RE suppression. In summary, the present findings indicate that RE, mediated in part by actions on the ORB, serves a critical role in the flexible use of rules to drive goal directed behavior. The cognitive deficits of various neurological disorders with impaired communication between the HF and OFC, may be partly attributed to alterations of RE -- as an established intermediary between these cortical structures., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: Access to literature on clozapine in Russian language remains strikingly limited. We aimed to identify and translate clinical evidence on clozapine-based treatment outcomes., Methods: We performed a systematic review in PubMed, Embase and scientific indexes from former USSR states searching for articles published in Russian from the database inception till January 2023 and summarized the data in a scoping review (PROSPERO Reg. Number CRD42023386737)., Results: A total of 60 papers were included comprising eight main topic categories: 1) clozapine-related intoxications (n = 20), 2) effectiveness/efficacy and safety of clozapine treatment (n = 14), 3) adverse drug-induced reactions (ADRs) related to clozapine treatment (n = 9), 4) therapeutic drug monitoring for clozapine (n = 5), 5) combination of clozapine and non-pharmacological treatments (n = 4), 6) pharmacoepidemiology of clozapine (n = 3), 7) effects of clozapine on the brain electrical activity (n = 3), and 8) novel clozapine formulations (n = 2). Among clozapine-related intoxications there were reports of criminal poisoning, which was associated with low lethality. Worse outcomes were accompanied by systemic reactions to intoxications. Clinical benefits of hemoadsorption were reported in the management of clozapine-related intoxications. Only half of studies reporting clozapine effectiveness used standardized scales to assess outcomes. Clozapine superiority in treatment-resistant schizophrenia (TRS) was replicated in one trial. No reports of clozapine-related agranulocytosis were identified. Clozapine ranked among most prescribed antipsychotics for TRS and non-TRS., Conclusions: As clinical research in former USSR states is advancing to adopt western clinical research standards, comparability and extrapolation of findings is expected to increase, with transfer of older findings to clinical practice being particularly challenging., Competing Interests: Declaration of competing interest Georgios Schoretsanitis has served as a consultant for HLS Therapeutics and Thermo Fisher and has received speaker's fees from HLS Therapeutics. All other authors report no conflicts of interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: As access to an essential part of clozapine research from the former Union of Soviet Socialist Republics (USSR) states is very limited, quality aspects have not gained attention so far, and harmonization with modern research standards remains unclear., Methods: We performed a systematic search in PubMed, Embase and scientific indexes from former USSR states for articles published in Russian language till January 2023 (PROSPERO Reg. Number CRD42023386737) and assessed their quality using the modified Strengthening the reporting of observational studies in epidemiology (STROBE)-Checklist. We compared quality aspects for papers published before and after 2000., Results: A total of 60 papers were considered. Conflicts of interests and funding sources were reported in 5 and 3 (8 % and 5 %) studies respectively; ethical approval was warranted in two studies (3 %). Statistical analysis was performed in 57 (95 %) studies, but statistical methods were described in 21 (35 %) studies. When comparing studies before and after 2000, there was a trend towards improvement for several aspects, with the only significant differences being the objectives' specification (43 vs 83 %, p < 0.003) and the reporting of statistical methodology (0.0 vs 46 %, p < 0.001), which were more frequently available in papers after 2000., Conclusions: Clozapine papers in Russian language suffered from severe methodological drawbacks limiting generalizability. Changes regarding standardization, transparency, ethics, and good scientific practice are urgently required. Using reporting checklists and predefining protocols are the first steps towards quality upgrade and accelerate the integration of science from the former USSR states into the world scientific system., Competing Interests: Declaration of competing interest Dr. Kuzo has received educational grants from Lundbeck. Dr. Seifritz has received educational grants, consulting fees and lecture honoraria from Janssen Cilag, Lundbeck, Angelini, Otsuka, Servier, Ricordati, Vifor, Sunovion, Schwabe and Mepha. Dr. Schoretsanitis has served as a consultant for Dexcel Pharma, HLS Therapeutics, and Thermo Fisher and has received speaker's fees from HLS Therapeutics. All other authors report no conflicts of interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: The literature has paid very little attention to pericarditis, pericardial effusion and pancreatitis during clozapine treatment in children and adolescents., Methods: Cases of clozapine-associated pericarditis and pancreatitis in children were studied using searches in: 1) PubMed (June 16, 2023), and 2) the World Health Organization's pharmacovigilance database (June 1, 2022), VigiBase. VigiBase uses a logarithmic measure of disproportionality called the information component (IC)., Results: The PubMed search yielded 3 clozapine-associated pericarditis cases, 1 pancreatitis case and 1 with both. VigiBase provided a significant clozapine-associated pericarditis IC = 3.6 with an IC 025  = 2.9 (only 3 cases were expected while 22 were observed). VigiBase provided a significant clozapine-associated pancreatitis IC = 2.2 with an IC 025  = 1.4 (only 3 cases were expected while 16 were observed). In VigiBase clozapine-associated pericarditis and pericardial effusion in youth looked similar and on a continuum with myocarditis, as myocarditis, pericarditis and pancreatitis appeared to occur mainly during clozapine titration. Combining PubMed and VigiBase we identified: 1) 29 cases of at least possible clozapine-associated pericarditis/pericardial effusion (6 probable and 23 possible) including 7 cases with and 22 without myocarditis, and 2) 17 cases of clozapine-associated pancreatitis (1 definite and 16 possible). Two of the pancreatitis cases occurred during overdoses. No fatal outcomes were found in any clozapine-associated pericarditis and pancreatitis cases., Conclusions: Despite the lack of attention in the literature to clozapine-associated pericarditis and pancreatitis, results demonstrate that they can happen in youth, particularly during titration. Pericarditis and pancreatitis appear to be forms of clozapine-associated inflammation during dose titration., Competing Interests: Declaration of competing interest No commercial organizations had any role in the writing of this paper for publication. In the last 3 years, RdF has received speaker fee from Janssen Pharmaceutica and travel support from Janssen Pharmaceutica and ROVI; CUC has been a consultant and/or advisor to or has received honoraria from: AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Biogen, Boehringer-Ingelheim, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Denovo, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Jamjoom Pharma, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Neurelis, Newron, Noven, Novo Nordisk, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Sage, Seqirus, SK Life Science, Sumitomo Pharma America, Sunovion, Sun Pharma, Supernus, Takeda, Teva, Tolmar, Vertex, and Viatris. He provided expert testimony for Janssen and Otsuka. He served on a Data Safety Monitoring Board for Compass Pathways, Denovo, Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva. He has received grant support from Janssen and Takeda. He received royalties from UpToDate and is also a stock option holder of Cardio Diagnostics, Kuleon Biosciences, LB Pharma, Mindpax, and Quantic; GS has received speaker/consultation fees from Dexcel Pharma, HLS Therapeutics and Thermo Fisher. In the last 3 years, the remaining authors report no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Antipsychotic drugs (APDs) are the primary pharmacological treatment for schizophrenia, a complex disorder characterized by altered neuronal connectivity. Atypical or second-generation antipsychotics, such as Risperidone (RSP) and Clozapine (CZP) predominantly block dopaminergic D 2 and serotonin receptor 2A (5-HT2A) neurotransmission. Both compounds also exhibit affinity for the 5-HT7R, with RSP acting as an antagonist and CZP as an inverse agonist. Our study aimed to determine whether RSP and CZP can influence neuronal morphology through a 5-HT7R-mediated mechanism. Here, we demonstrated that CZP promotes neurite outgrowth of early postnatal cortical neurons, and the 5-HT7R mediates its effect. Conversely, RSP leads to a reduction of neurite length of early postnatal cortical neurons, in a 5-HT7R-independent way. Furthermore, we found that the effects of CZP, mediated by 5-HT7R activation, require the participation of ERK and Cdk5 kinase pathways. At the same time, the modulation of neurite length by RSP does not involve these pathways. In conclusion, our findings provide valuable insights into the morphological changes induced by these two APDs in neurons and elucidate some of the associated molecular pathways. Investigating the 5-HT7R-dependent signaling pathways underlying the neuronal morphogenic effects of APDs may contribute to the identification of novel targets for the treatment of schizophrenia., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Clozapine, which is widely used to treat schizophrenia, shows low bioavailability due to poor solubility and high first-pass metabolism. The study aimed to design clozapine-loaded carbon dots (CDs) to enhance availability of the clozapine to the brain via intranasal pathway. The CDs were synthesized by pyrolysis of citric acid and urea at 200 °C by hydrothermal technique and characterized by photoluminescence, transmission electron microscopy (TEM), X-ray Photoelectron Spectrometer (XPS), and Fourier transform infrared spectrum (FTIR). The optimized clozapine-loaded CDs (CLZ-CDs-1:3-200) showed a quasi-spherical shape (9-12 nm) with stable blue fluorescence. The CDs showed high drug solubilization capacity (1.5 mg drug in 1 mg/ml CDs) with strong electrostatic interaction with clozapine (drug loading efficiency = 94.74%). The ex vivo release study performed using nasal goat mucosa showed sustained release of clozapine (43.89%) from CLZ-CDs-1:3-200 for 30 h. The ciliotoxicity study (histopathology) confirmed no toxicity to the nasal mucosal tissues using CDs. In the rat model (in vivo pharmacokinetic study), when CDs were administrated by the intranasal route, a significantly higher concentration of clozapine in the brain tissue (C max = 58.07 ± 5.36 μg/g and AUC t (µg/h*g) = 105.76 ± 12.31) was noted within a short time (t max = 1 h) compared to clozapine suspension administered by intravenous route (C max = 20.99 ± 3.91 μg/g, AUC t (µg/h*g) = 56.89 ± 12.31, and t max = 4 h). The high value of drug targeting efficiency (DTE, 486%) index and direct transport percentage (DTP, 58%) indicates the direct entry of clozapine-CDs in the brain via the olfactory route. In conclusion, designed CDs demonstrated a promising dosage form for targeted nose-to-brain delivery of clozapine for the effective treatment of schizophrenia., Competing Interests: Declaration of Competing Interest The authors declare no known competing financial interests that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Determination of antiepileptic drugs and antipsychotics in human serum is significant in individualized drug administration and therapeutic drug monitoring (TDM). In this study, we developed a rapid label-free TDM method for the antiepileptic drug carbamazepine (CBZ) and the antipsychotic clozapine (CLO) in human serum. This detection strategy is based on the combination of surface-enhanced Raman scattering (SERS) and magnetic solid-phase extraction (MSPE). Initially, Fe 3 O 4 @SiO 2 @MIL-101(Fe) nanocomposites were synthesized by the layer-by-layer self-assembly method and characterized using scanning electron microscopy, transmission electron microscopy, X-ray diffraction, Brunauer-Emmett-Teller, ultraviolet-visible, and Fourier transform infrared analyses. Subsequently, CBZ and CLO were detected in human serum using Fe 3 O 4 @SiO 2 @MIL-101(Fe) as the solid-phase extraction adsorbent and Ag nanoparticles as SERS substrates. The potential of the MSPE-SERS method for the label-free TDM of CBZ and CLO was then investigated. Fe 3 O 4 @SiO 2 @MIL-101(Fe) prevents magnetic particle aggregation and demonstrates rapid magnetic separation capability that simplifies the pretreatment process and reduces interference from complex matrices. Its large surface area can effectively enrich targets in complex matrices, thereby improving the SERS detection sensitivity. The linearity between CBZ and CLO was excellent over the concentration range of 0.1-100 µg/mL (calculated as the intensity of the SERS characteristic peaks of CBZ and CLO at 728 cm and 1054 cm -1 , respectively), with correlation coefficients (R 2 ) of 0.9987 and 0.9957, and detection limits of 0.072 and 0.12 µg/mL, respectively. The recoveries of CBZ with CLO ranged from 94.0 % to 105.0 %, and their relative standard deviations were <6.8 %. Compared to other assays, the developed MSPE-SERS method has the advantages of simple sample pretreatment, rapid detection, and good reproducibility, which provides a novel approach for the TDM of other drugs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Antipsychotics are the foundation of pharmacologic treatment for schizophrenia. There are many oral antipsychotics available and given that these medications are generally considered comparably efficacious when titrated to an adequate dose, their varied tolerability, and safety profiles become critically important for medication selection., Areas Covered: This paper reviews tolerability and safety considerations for first-line second-generation oral antipsychotics currently approved for the treatment of schizophrenia in the USA. Excluded from consideration are clozapine and non-oral formulations., Expert Opinion: Among antipsychotics, there are many differences in adverse reactions observed in clinical trials, such as variable likelihood to cause sedation vs insomnia, weight gain and abnormalities in glucose/lipid metabolism, hyperprolactinemia, potential for impact on the QT interval, and motoric adverse effects. Additional safety data that can help with medication selection include safety in pregnancy and lactation, and potential for drug-drug interactions. Ultimately, working with patients to personalize treatment by focusing on safety and individual tolerability considerations for various adverse effects can help in building a therapeutic alliance and improving patients' outcomes.

This study addresses the challenging task of quantitatively investigating drug release from PLGA microspheres after in vivo administration. The objective is to employ Förster resonance energy transfer (FRET) to visualize drug-encapsulated microspheres in both in vitro and in vivo settings. The primary goal is to establish a quantitative correlation between FRET fluorescence changes and microsphere drug release. The study selects drugs with diverse structures and lipid solubility to explore release mechanisms, using PLGA as the matrix material. Clozapine and risperidone serve as model drugs. FRET molecules, Cy5 and Cy5.5, along with Cy7 derivatives, create FRET donor-acceptor pairs. In vitro results show that FRET fluorescence changes align closely with microsphere drug release, particularly for the Cy5.5-Cy7 pair. In vivo experiments involve subcutaneous administration of microspheres to rats, tracking FRET fluorescence changes while collecting blood samples. Pharmacokinetic studies on clozapine and risperidone reveal in vivo absorption fractions using the Loo-Riegelman method. Correlating FRET and in vivo absorption data establishes an in vitro-in vivo relationship (IVIVR). The study demonstrates that FRET-based fluorescence changes quantitatively link to microsphere drug release, offering an innovative method for visualizing and monitoring release in both in vitro and in vivo settings, potentially advancing clinical applications of such formulations., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ping Hu reports financial support was provided by National Natural Science Foundation of China. Ping Hu reports financial support was provided by Science and Technology Program of Guangzhou, China. Ping Hu reports financial support was provided by Natural Science Foundation of Guangdong Province of China. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Psychosis in Parkinson's disease is a common phenomenon associated with poor outcomes. To clarify the pathophysiology of this condition and the mechanisms of antipsychotic treatments, we have here characterized the neurophysiological brain states induced by clozapine, pimavanserin, and the novel prospective antipsychotic mesdopetam in a rodent model of Parkinson's disease psychosis, based on chronic dopaminergic denervation by 6-OHDA lesions, levodopa priming, and the acute administration of an NMDA antagonist. Parallel recordings of local field potentials from eleven cortical and sub-cortical regions revealed shared neurophysiological treatment effects for the three compounds, despite their different pharmacological profiles, involving reversal of features associated with the psychotomimetic state, such as a reduction of aberrant high-frequency oscillations in prefrontal structures together with a decrease of abnormal synchronization between different brain regions. Other drug-induced neurophysiological features were more specific to each treatment, affecting network oscillation frequencies and entropy, pointing to discrete differences in mechanisms of action. These findings indicate that neurophysiological characterization of brain states is particularly informative when evaluating therapeutic mechanisms in conditions involving symptoms that are difficult to assess in rodents such as psychosis, and that mesdopetam should be further explored as a potential novel antipsychotic treatment option for Parkinson psychosis., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Stephan Hjorth, Peder Svensson, Susanna Waters are employed by IRL AB and hold stock in IRL AB. Remaining authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The degenerative nature of Huntington's disease drastically reduces quality of life for sufferers while limiting life expectancy itself. Among other sequalae, psychosis and chorea remain persistently difficult disease manifestations to manage for patients. Clozapine is an atypical antipsychotic medication with a multineuroreceptor affinity, which gives it a broad range of action. Clozapine has been documented to have good remedial actions on chorea and psychosis in patients with Huntington's disease. Here the authors make the case for further research. [ABSTRACT FROM AUTHOR]