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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: Identifying stable and consistent resting-state functional connectivity patterns across illness trajectories has the potential to be considered fundamental to the pathophysiology of schizophrenia. We aimed to identify consistent resting-state functional connectivity patterns across heterogeneous schizophrenia groups defined based on treatment response., Methods: In phase 1, we used a cross-sectional case-control design to characterize and compare stable independent component networks from resting-state functional magnetic resonance imaging scans of antipsychotic-naïve participants with first-episode schizophrenia (n = 54) and healthy participants (n = 43); we also examined associations with symptoms, cognition, and disability. In phase 2, we examined the stability (and replicability) of our phase 1 results in 4 groups (N = 105) representing a cross-sequential gradation of schizophrenia based on treatment response: risperidone responders, clozapine responders, clozapine nonresponders, and clozapine nonresponders following electroconvulsive therapy. Hypothesis-free whole-brain within- and between-network connectivity were examined., Results: Phase 1 identified posterior and anterior cerebellar hypoconnectivity and limbic hyperconnectivity in schizophrenia at a familywise error rate-corrected cluster significance threshold of p < .01. These network aberrations had unique associations with positive symptoms, cognition, and disability. During phase 2, we replicated the phase 1 results while comparing each of the 4 schizophrenia groups to the healthy participants. The participants in 2 longitudinal subdatasets did not demonstrate a significant change in these network aberrations following risperidone or electroconvulsive therapy. Posterior cerebellar hypoconnectivity (with thalamus and cingulate) emerged as the most consistent finding; it was replicated across different stages of treatment response (Cohen's d range -0.95 to -1.44), reproduced using different preprocessing techniques, and not confounded by educational attainment., Conclusions: Posterior cerebellar-thalamo-cingulate hypoconnectivity is a consistent and stable state-independent neural marker of schizophrenia., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: This case explores the challenges encountered in managing treatment-resistant paranoid schizophrenia, focusing on the limitations of using clozapine due to the risk of neutropenia. The United Kingdom Clozapine Patient Monitoring Service (UK CPMS) and its eligibility criteria are discussed, highlighting the potential benefits of expanding access to clozapine for patients who could potentially benefit from this medication. The integration of clozapine genetic testing as a personalized approach is explored, emphasizing the importance of identifying patients with a favorable genetic profile for clozapine response. Methods: Case report. Results: The case presentation of Mr. X exemplifies the difficulties faced in managing treatment-resistant schizophrenia when access to clozapine is restricted, leading to persistent negative symptoms. Conclusion: The article underscores the importance of innovative solutions and personalized care to enhance the treatment outcomes for patients with treatment-resistant paranoid schizophrenia. It acknowledges that certain restrictions of clozapine use may limit the effective management of patients with this condition., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Chemogenetics is a newly developed set of tools that allow for selective manipulation of cell activity. They consist of a receptor mutated irresponsive to endogenous ligands and a synthetic ligand that does not interact with the wild-type receptors. Many different types of these receptors and their respective ligands for inhibiting or excitating neuronal subpopulations were designed in the past few decades. It has been mainly the G-protein coupled receptors (GPCRs) selectively responding to clozapine-N-oxide (CNO), namely Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), that have been employed in research. Chemogenetics offers great possibilities since the activity of the receptors is reversible, inducible on demand by the ligand, and non-invasive. Also, specific groups or types of neurons can be selectively manipulated thanks to the delivery by viral vectors. The effect of the chemogenetic receptors on neurons lasts longer, and even chronic activation can be achieved. That can be useful for behavioral testing. The great advantage of chemogenetic tools is especially apparent in research on brain diseases since they can manipulate whole neuronal circuits and connections between different brain areas. Many psychiatric or other brain diseases revolve around the dysfunction of specific brain networks. Therefore, chemogenetics presents a powerful tool for investigating the underlying mechanisms causing the disease and revealing the link between the circuit dysfunction and the behavioral or cognitive symptoms observed in patients. It could also contribute to the development of more effective treatments.

Background: Clozapine is the only recommended antipsychotic medication for individuals diagnosed with treatment-resistant schizophrenia. Unfortunately, its wider use is hindered by several possible adverse effects, some of which are rare but potentially life threatening. As such, there is a growing interest in studying clozapine use and safety in routinely collected healthcare data. However, previous attempts to characterise clozapine treatment have had low accuracy., Aim: To develop a methodology for identifying clozapine treatment dates by combining several data sources and implement this on a large clinical database., Methods: Non-identifiable electronic health records from a large mental health provider in London and a linked database from a national clozapine blood monitoring service were used to obtain information regarding patients' clozapine treatment status, blood tests and pharmacy dispensing records. A rule-based algorithm was developed to determine the dates of starting and stopping treatment based on these data, and more than 10% of the outcomes were validated by manual review of de-identified case note text., Results: A total of 3,212 possible clozapine treatment periods were identified, of which 425 (13.2%) were excluded due to insufficient data to verify clozapine administration. Of the 2,787 treatments remaining, 1,902 (68.2%) had an identified start-date. On evaluation, the algorithm identified treatments with 96.4% accuracy; start dates were 96.2% accurate within 15 days, and end dates were 85.1% accurate within 30 days., Conclusions: The algorithm produced a reliable database of clozapine treatment periods. Beyond underpinning future observational clozapine studies, we envisage it will facilitate similar implementations on additional large clinical databases worldwide., (© 2024. The Author(s).)

We investigated the effectiveness of a decision support alert to improve prophylactic laxative use with clozapine in hospital. Prescribing data for first clozapine and laxative prescriptions were extracted and linked. Proportions of first clozapine prescriptions for which a laxative was co-prescribed within 24 hours was compared before and after alert implementation. The alert was associated with increased and earlier laxative co-prescribing.

Clozapine is the most effective medication for the management of treatment-resistant schizophrenia and schizoaffective disorder, and its discontinuation can pose significant challenges in treatment. We present a patient with a diagnosis of schizoaffective disorder who was stable on clozapine for a decade until discontinuation due to thrombocytopenia. She experienced a relapse of her illness, presenting with psychotic and catatonic features with poor oral intake and physical health complications requiring a lengthy admission to the hospital. There was a poor response to alternative antipsychotics and a full course of electroconvulsive therapy. Intramuscular (IM) clozapine was initiated due to catatonia and refusal to accept oral medications. After receiving 10 doses of IM clozapine, she started accepting oral clozapine and made a full recovery within a few weeks. The low platelet count was persistent, and a bone marrow biopsy showed results consistent with immune thrombocytopenia being the cause of that low platelet count., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Clozapine is the effective therapy for treatment-refractory schizophrenia. However, the use of clozapine is limited by its adverse effects. As propranolol is frequently used for the prevention and treatment of clozapine-induced tachycardia, we performed a meta-analysis to evaluate the effects of propranolol on steady state pharmacokinetics of clozapine in schizophrenic patients., Methods: We included 16 retrospective studies on the effects of propranolol on steady state pharmacokinetics of clozapine in schizophrenic patients, with data from both generic and brand name treatment phases in eight clozapine bioequivalence studies conducted in a single center in China from 2018 to 2022. Review Manager 5.4 was used for meta-analysis of the included studies., Results: The SMDs with 95% CIs of AUC 0-12 , C max,ss , C, and C were calculated to be 0.44 (0.23, 0.64), 0.40 (0.20, 0.61), 0.43 (0.22, 0.63), and 0.44 (0.23, 0.64), respectively. These findings proved that combination with propranolol would increase the systemic exposure of clozapine. T 1/2 of clozapine was significantly longer in the presence of propranolol than in the absence of propranolol (SMD = 0.32, 95% CI [0.12, 0.52], p = 0.002). There was no statistically significant difference for T of clozapine in the presence or absence of propranolol (SMD =  - 0.05, 95% CI [- 0.25, 0.15], p = 0.63)., Conclusion: The combination with propranolol could significantly increase systemic exposure and extended T 1/2 of clozapine, and thus need to be considered in prescribing decisions., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: Previous research has suggested that demographic factors affect the likelihood of a patient with schizophrenia receiving a clozapine prescription. The authors aimed to determine the impact of race, social determinants of health, gender, rurality, and care patterns on clozapine prescription rates., Methods: This cross-sectional observational study used structured electronic health records data from 3,160 adult patients diagnosed as having schizophrenia between October 1, 2015, and November 30, 2021, in a multifacility health system. The social vulnerability index (SVI) was used to quantify social determinants of health. Descriptive data analysis, logistic regression, and sensitivity analysis were conducted to identify differences between patients with schizophrenia who received a clozapine prescription and those who received antipsychotic medications other than clozapine., Results: Overall, 401 patients with schizophrenia were given a clozapine prescription during the study period, and 2,456 received antipsychotics other than clozapine. Results of the logistic regression indicated that White race (OR=1.71, compared with Black race), community minority status and language SVI score (OR=2.97), and increased treatment duration (OR=1.36) were significantly associated with a higher likelihood of clozapine prescription; gender, rurality, age at first diagnosis, and ethnicity did not influence the likelihood of receiving clozapine., Conclusions: Black patients with schizophrenia had a lower likelihood of receiving a clozapine prescription compared with White patients, even after analyses accounted for demographic variables, social determinants of health, and care access patterns. Given the effectiveness of clozapine in managing treatment-resistant schizophrenia, it is crucial for future research to better understand the factors contributing to this treatment disparity., Competing Interests: Dr. Jarskog reports receiving research grant funding from Boehringer-Ingelheim, Corcept Therapeutics, and Otsuka and serving as a consultant to UpToDate and Signant Health. The other authors report no financial relationships with commercial interests.

Introduction: The aim of the study was to evaluate interaction effect of various augmentation strategies with clozapine in patients with Treatment-resistant schizophrenia., Methods: Data was extracted for change in positive and negative syndrome scale (PANSS) or brief psychiatric rating scale (BPRS) scores for monotherapy with various antipsychotic agents alone and their combination with clozapine. Individual patient data was generated using simulation of data (factorial trial framework) from published clinical trials for sample sizes from eight to 400 to evaluate interaction effect through linear modeling. Dose equivalents were calculated, and best fit models were determined for simulated data., Results: The polynomial model was found to be the best fit for the simulated data to determine interaction effect of combination. The clozapine augmentation with risperidone and ziprasidone was found to be antagonistic, whereas it was additive for haloperidol, aripiprazole, and quetiapine. A synergistic effect was observed for ECT combined with clozapine (Interaction effect: -7.62; p <0.001). A sample size of 250-300 may be sufficient to demonstrate a clinically significant interaction in future trials., Conclusion: Clozapine may be augmented with electroconvulsive therapy, leading to the enhancement of antipsychotic effect. Though some antipsychotics like aripiprazole demonstrate additive effects, they may also add to the adverse effects., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The Psychiatric Consultation Service at Massachusetts General Hospital sees medical and surgical inpatients with comorbid psychiatric symptoms and conditions. During their twice-weekly rounds, Dr Stern and other members of the Consultation Service discuss diagnosis and management of hospitalized patients with complex medical or surgical problems who also demonstrate psychiatric symptoms or conditions. These discussions have given rise to rounds reports that will prove useful for clinicians practicing at the interface of medicine and psychiatry., Prim Care Companion CNS Disord 2024;26(4):23f03702 ., Author affiliations are listed at the end of this article., (© Copyright 2024 Physicians Postgraduate Press, Inc.)

Aunque se utiliza comúnmente en la práctica clínica, la literatura científica sobre los patrones de prescripción de clozapina en Colombia es escasa. Se realizó un estudio observacional transversal en el servicio ambulatorio de una clínica de referencia en Bogotá, Colombia. Entre 2016 y 2018, se recetó clozapina a 2603 pacientes, principalmente para esquizofrenia y trastornos relacionados, trastorno afectivo bipolar y trastornos depresivos, a una dosis media de 100 mg/día. Después de controlar otras variables, la edad avanzada fue la única variable que explicó el uso de dosis inferiores a 100 mg/día. La clozapina no se utilizó sólo para la esquizofrenia resistente al tratamiento, y se necesitan estudios adicionales para explicar estas diferencias.

Background: Clozapine is the recommended treatment for managing treatment-resistant schizophrenia (TRS), and immunological mechanisms may be involved in its unique antipsychotic efficacy. This study investigated whether baseline immune abnormalities measured with blood cell count ratios can predict the clinical response after initiating treatment with clozapine in patients with clozapine naïve TRS., Methods: A longitudinal design was developed, involving 32 patients diagnosed with treatment-resistant, clozapine-naïve schizophrenia-spectrum disorder. Patients were evaluated at baseline before clozapine starting and 8 weeks of follow-up. Psychopathological status and immune abnormalities (blood cell count ratios: neutrophil-lymphocyte ratio [NLR], monocyte-lymphocyte ratio [MLR], platelet-lymphocyte ratio [PLR] and basophil-lymphocyte ratio [BLR]) were evaluated in each visit., Results: Baseline NLR (b=- 0.364; p=0.041) and MLR (b =- 0.400; p=0.023) predicted the change in positive symptoms over the 8-week period. Patients who exhibited a clinical response showed higher baseline NLR (2.38±0.96 vs. 1.75±0.83; p=0.040) and MLR (0.21±0.06 vs. 0.17±0.02; p=0.044) compared to non-responders. In the ROC analysis, the threshold points to distinguish between responders and non-responders were approximately 1.62 for NLR and 0.144 for MLR, yielding AUC values of 0.714 and 0.712, respectively. No statistically significant differences were observed in the blood cell count ratios from baseline to the 8-week follow-up., Conclusion: Our study emphasizes the potential clinical significance of baseline NLR and MLR levels as predictors of initial clozapine treatment response in patients with TRS. Future studies with larger sample sizes and longer follow-up periods should replicate our findings., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

We report the case of a 49-year-old male treatment-resistant schizophrenia patient, whose treatment with clozapine and sertraline was supplemented with cariprazine 1.5 mg/day while regularly presenting for electroconvulsive therapy. After 3 weeks of adjunctive treatment with cariprazine, blood tests revealed pronounced signs of rhabdomyolysis, including a creatine kinase serum level of 20 386 U/L and an AST serum level of 696 U/L. Clinically, the patient did not report somatic symptoms other than mild back pain. After discontinuation of cariprazine and normal saline infusion, the above-mentioned findings resolved rapidly. Although very rare, rhabdomyolysis can be a potentially dangerous side effect of cariprazine and clinicians should be aware of its possible occurrence., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Clozapine is the only approved antipsychotic for treatment-resistant schizophrenia (TRS). Although a large body of evidence supports its efficacy and favorable risk-benefit ratio in individuals who have failed two or more antipsychotics, clozapine remains underused. However, variations in clozapine utilization across geographic and clinical settings suggest that it could be possible to improve its use. In this narrative review and expert opinion, we summarized information available in the literature on the mechanisms of action, effectiveness, and potential adverse events of clozapine. We identified barriers leading to discouragement in clozapine prescription internationally, and we proposed practical solutions to overcome each barrier. One of the main obstacles identified to the use of clozapine is the lack of appropriate training for physicians: we highlighted the need to develop specific professional programs to train clinicians, both practicing and in residency, on the relevance and efficacy of clozapine in TRS treatment, initiation, maintenance, and management of potential adverse events. This approach would facilitate physicians to identify eligible patients and offer clozapine as a treatment option in the early stage of the disease. We also noted that increasing awareness of the benefits of clozapine among healthcare professionals, people with TRS, and their caregivers can help promote the use of clozapine. Educational material, such as leaflets or videos, could be developed and distributed to achieve this goal. The information provided in this article may be useful to improve disease burden and support healthcare professionals, patients, and caregivers navigating the complex pathways to TRS management., Competing Interests: Declaration of competing interest BCF declares that has received speaking honoraria (advisory board and educational lectures) and travel expenses from Rovi, Takeda, Menarini, Angelini, Teva, Otsuka, Lundbeck, Boehringer-Ingelheim and Johnson and Johnson. BC-F has also received fundings to support independent research initiatives (i.e., investigator initiated trials) from Lundbeck and also declares that has received funds from Viatris to conduct this study. CUC has been a consultant and/or advisor to or has received honoraria from: AbbVie, Acadia, Adock Ingram, Alkermes, Allergan, Angelini, Aristo, Biogen, Boehringer-Ingelheim, Bristol-Meyers Squibb, Car dio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Delpor, 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, Tabuk, 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. ODH has received investigator-initiated research funding from and/or participated in advisory/ speaker meetings organised by Angellini, Autifony, Biogen, Boehringer-Ingelheim, Eli Lilly, Elysium, Heptares, Global Medical Education, Invicro, Jansenn, Karuna, Lundbeck, Merck, Neurocrine, Ontrack/ Pangea, Otsuka, Sunovion, Recordati, Roche, Rovi and Viatris/ Mylan. He was previously a part-time employee of Lundbeck A/v. Dr Howes has a patent for the use of dopaminergic imaging. NS is a part time medical consultant for Viatris, Finland. He is also a Medical Advisor for Janssen-Cilag, Finland and Recordati, Sweden, and received lecture fees from Viatris, Finland; Otsuka, Finland. ADB has received unrestricted research support from Janssen, Lundbeck, and Otsuka and lecture honoraria for unrestricted educational meeting from Janssen, Chiesi, Lundbeck, Roche, Sunovion, Mylan, Viatris, Recordati, Angelini and Takeda; he has served on advisory boards for Eli Lilly, Jansen, Lundbeck, Otsuka, Roche, and Takeda, Chiesi, Recordati, Angelini, Viatris, Iqvia, Idorsia. OA acts as advisor and consultant for Janssen-Ortho (Johnson & Johnson); Otsuka; Lundbeck; Allergan/Abbvie; Mylan/Viatris; Teva; he is involved in speaking engagements for Janssen-Ortho (Johnson & Johnson); Lundbeck, Otsuka, Mylan/Viatris; HLS Therapeutics; Allergan/Abbvie; he holds research contracts with Janssen-Ortho (Johnson & Johnson); Lundbeck; Otsuka; Boehringer Ingelheim. AF is a consultant and/or speaker and/or has received research grants from Angelini, Apsen, Biogen, Boheringer Ingelheim, Idorsia Italfarmaco, Lundbeck, Janssen, Medicamenta, Mylan, Otsuka, Pfizer, Recordati, Sunovion, Viatris., (Copyright © 2024. Published by Elsevier B.V.)

Purpose: To evaluate and compare the prevalence and severity of dry eye disease (DED) among patients on atypical antipsychotics with controls., Methods: This cross-sectional study was conducted on patients who were on atypical antipsychotic therapy (study group) and matched controls (control group). Prevalence of DED was assessed using tear break up time. Statistical analysis was done using SPSS. Chi-square test and t -test were used. p < 0.05 was taken as the level of statistical significance., Results: Prevalence of DED was significantly more in study group. Polytherapy group has significantly high DED compared with monotherapy. Among monotherapy, clozapine had highest prevalence of DED ( p -0.013) and among the polytherapy, clozapine-quetiapine had highest prevalence of dry eye., Conclusion: Prevalence of DED was higher among antipsychotics than the normal population, and in polytherapy than monotherapy group. The patients on clozapine (monotherapy) and clozapine with quetiapine (polytherapy) had highest prevalence of DED.

Neuropsychiatric disorders are common manifestations in 22q11.2 deletion syndrome (22q11.2DS-DiGeorge Syndrome). Although many patients with 22q11.2DS receive antipsychotic treatment for psychotic disorders, little is known about the safety and tolerability of antipsychotics in 22q11.2DS and resistant psychosis. The aim of this case series is to describe the effectiveness as well as safety and tolerability profile coming from the real-world observation of three clinical cases affected by 22q11.2DS and treatment-resistant psychosis. We administered the following tests: the Columbia Suicide Severity Rating Scale, the Hamilton Rating Scale for Anxiety, the Positive and Negative Severity Scale, the Clinical Global Impression-Severity Scale, the Yale-Brown Obsessive-Compulsive Scale, the Beck Depression Inventory and the Beck Hopelessness Scale. All these questionnaires were administered at the first visit (T0), and then 3 (T1) 6 (T2) and 12 months after (T3). We observed a clinical improvement that remained stable at 12 months. Furthermore, in our patients, the clinical effectiveness was achieved with a very low dose of clozapine (<150 mg/day) concerning the standard dose used in idiopathic schizophrenia (>300 mg/day to 600 mg/day)., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: The Mental Welfare Commission for Scotland published a report into the death of a young person, with recommendations for the Royal College of Psychiatry in Scotland Child and Adolescent Faculty; to explore if there were barriers to the use of Clozapine in young people in Scotland., Methods: A mixed-methods study was performed using a cross-sectional survey of clinicians working in child and adolescent psychiatry across Scotland, to determine attitudes towards clozapine use and the perceived barriers and facilitators to clozapine treatment., Results: Results suggest that there may be a lack of clearly defined pathways within and between services, as well as a lack of resources provided for the necessary monitoring of a young person started on clozapine. Multiple respondents felt unskilled in clozapine initiation and had not accessed formal training. The most frequently mentioned themes for improving facilitation of clozapine prescription were that of increased resources and training., Discussion: National policymakers including the Mental Welfare Commission, NHS Education for Scotland, and NHS Scotland should consider these findings to address the potential underutilisation of clozapine for people aged under 18 in services across Scotland. A review of current service provision should take place, with consideration of whether the facilitators to clozapine prescription which our study has highlighted could be implemented more effectively. This may help reduce identified barriers and increase clozapine prescription to those who would benefit from it, potentially improving outcomes for young people with treatment-resistant psychosis., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Walker et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Clozapine is an off-label drug used in most countries to prevent suicide in individuals with schizophrenia. However, few studies have reported real-world prescription practices. This study aimed to explore the association between a history of suicidal behavior and clozapine prescribing during eight weeks of hospitalization for individuals with early-stage schizophrenia., Methods: This observational cohort study used routine health data collected from a mental health hospital in Beijing, China. The study included 1057 inpatients who had schizophrenia onset within 3 years. History of suicidal behavior was coded from reviewing medical notes according to the Columbia Suicide Severity Rating Scale. Information on antipsychotic use during hospitalization was extracted from the prescription records. Time to clozapine use was analyzed using Cox regression models adjusted for sociodemographic and clinical covariates., Results: The prevalence rates of self-harm, suicidal behavior, and suicide attempt were 12.3%, 7.5%, and 5.4%, respectively. A history of self-harm history was positively associated with clozapine uses upon admission (4.1% vs. 0.8%, exact p = 0.009). Among those who had not used clozapine and had no clozapine contraindication, A history of suicidal behavior increased the possibility of switch to clozapine within 56 days after admission (Hazard Ratio[95% CI], 6.09[2.08-17.83]) or during hospitalization (4.18[1.62-10.78])., Conclusion: The use of clozapine for early-stage schizophrenia was more frequent among those with suicidal behavior than among those without suicidal behavior in China, although the drug instructions do not label its use for suicide risk., (© 2024. The Author(s).)

Competing Interests: BRL is the vice chair of the Psychopharmacology Committee of the Royal College of Psychiatrists. JBF declares no competing interests.

Psychopharmacotherapy for patients with schizophrenia in Japan has a long history of polypharmacy, which is rare worldwide but remains a critical problem. One reason for this is that clozapine was not available in Japan until 2009. We aimed to investigate the changes in psychopharmacotherapy in patients with schizophrenia over 12 years pre- and post-introduction of clozapine to clarify how psychopharmacotherapy for patients with schizophrenia has changed with the introduction of clozapine. We retrospectively collected data from the medical records of inpatients diagnosed with schizophrenia at the Okayama Psychiatric Medical Center. Chlorpromazine equivalent (CP-eq) decreased from 1276.6 mg/day in 2009 to 613.9 mg/day in 2020. The prescribed daily dose/defined daily dose (PDD/DDD) decreased from 3.0 in 2009 to 1.2 in 2020. The monotherapy rate increased from 24.4 % in 2009 to 74.6 % in 2020. Our institution began using clozapine in 2010, and the prescription rate for clozapine increased to 37.3 % in 2020. The prescription rate for more than three antipsychotics decreased from 27.8 % in 2009 to 0.8 % in 2020. The increase in clozapine prescription has contributed to an increased rate of antipsychotic monotherapy and a decreased rate of polypharmacy, promoting the optimization of schizophrenia medication. Clozapine therapy should be further promoted in Japan to reduce treatment-resistant schizophrenia due to polypharmacy as much as possible., Competing Interests: Declaration of Competing Interest Mr. Kitagawa has received research grants from the Policy-Based Medical Services Foundation, Japan Society for the Promotion of Science; speaker’s honoraria from Novartis Pharma and Otsuka; and manuscript fees from the Japanese Society of Psychiatric Pharmacy, the Pharmaceutical Society of Japan, Jiho, and Nanzando., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: We aimed at exploring the relationship between functional outcomes in patients on clozapine augmented with antipsychotics in treatment-resistant schizophrenia using standard outcome measures Health of Nation Outcome Scales (HoNOS) and Life Skills Profile (LSP-16)., Method: In a cross-sectional study of 83 patients on clozapine treated in a psychiatric rehabilitation hospital, the association between the primary outcome measure, LSP-16 including its subscales, and treatment with antipsychotic augmentation (AA) were analysed using linear regression., Result: The presence of moderate-to-severe positive symptoms on the HoNOS 6 dichotomised item measure was the only statistically significant predictor of functional impairment as determined by total LSP-16 score.The group of patients with ongoing positive symptoms (partial responders) were characterised by higher total LSP-16 scores, higher numbers of AA agents, and higher chlorpromazine equivalence. There was an inverse linear relationship between chlorpromazine equivalence of AA and total score of LSP-16 scale in the group of partial responders., Conclusion: Augmentation with other antipsychotic agents was associated with higher functioning in a cross-sectional study of patients with schizophrenia with poor response of positive symptoms to clozapine. This might be an important clinical factor to consider when prescribing antipsychotics to patients with clozapine-resistant schizophrenia., Competing Interests: DisclosureThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Treatment-resistant schizophrenia (TRS) is a challenging condition to treat for the correctional psychiatrist. Guidelines from the American Psychiatric Association indicate that the first-line pharmacotherapy for TRS is the use of the atypical antipsychotic clozapine. The use of clozapine is unique in that it requires patient adherence with weekly blood draws as a prophylactic measure against agranulocytosis and leukopenia. In the correctional setting, patients with severe and persistent schizophrenia are frequently nonadherent due to lack of insight and anemic access to health care resources, specifically as these pertain to clozapine. Therefore, an alternative treatment option would be a welcome solution for this demographic. Our literature review demonstrates a limited number of studies documenting the successful use of clozapine alternatives or combination antipsychotic therapy for treatment of TRS. In this article, we present a putative case where we believe that a combination regimen of paliperidone palmitate, oral aripiprazole, and escitalopram led to a notable mitigation of both positive and negative symptoms of psychosis in the case of an incarcerated patient with TRS, as well as an improvement in functional stability, which was conducive to housing in a less restrictive setting. A brief review of the published literature follows the report.

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., Competing Interests: Declaration of interests JMR has received honoraria from Teva, Karuna, and Janssen; royalties from UpToDate; and grant support from Saladax and Alkermes. JMK has received consulting fees or honoraria for lectures from Alkermes, Allergan, Boehringer Ingelheim, Cerevel, Click Therapeutics, Dainippon Sumitomo, H Lundbeck, Health Rhythms, HLS Therapeutics, Indivior, Intracellular Therapies, Janssen, Johnson and Johnson, Karuna, LB Pharmaceuticals, Merck, Minerva, Newron, Novartis, NW PharmaTech, Otsuka, Roche, Saladax, Sunovion, and Teva; grant support from Click Therapeutics, H Lundbeck, Janssen, Otsuka, Saladax, Sunovion, and Valera; and is a stockholder for Cerevel, Health Rhythms, Karuna, LB Pharmaceuticals, North Shore Therapies, and the Vanguard Research Group. JT, HT, and AT have participated in research projects funded by grants from Janssen-Cilag and Eli Lilly paid to their institution. JT has been a consultant or advisor to or has received honoraria from Eli Lilly, Evidera, Janssen-Cilag, Lundbeck, Orion, Otsuka, Mediuutiset, Sidera, and Sunovion. HT has received personal fees from Janssen-Cilag and Otsuka., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Clozapine was first manufactured in China in 1976. Clozapine is currently used not only for treatment-refractory schizophrenia (TRS), but also continues to be used in the treatment of patients with non-TRS and other mental disorders; moreover, low-dose clozapine is also used in sedative-hypnotic therapy and in combination with other drugs. There is need for studies in China using various titrations and assessing their risk for myocarditis and aspiration pneumonia. The Chinese clozapine package insert will also greatly benefit from these changes., Competing Interests: Declaration of competing interest In the last 3 years, the authors report no conflicts of interest., (Copyright © 2023. Published by Elsevier B.V.)

There is no established treatment for patients with clozapine-resistant schizophrenia (CRS). Clozapine augmentation strategies with antipsychotics or others substances are effective in comparison with placebo while and Electroconvulsive therapy (ECT) showed to be effective in comparison with treatment as usual (TAU) but not with placebo (sham-ECT). In the present double- blind randomized controlled trial, we compared 40 outpatients who received 20 sessions of ECT (n = 21) or sham-ECT (n = 19) (age = 37.40 ± 9.62, males = 77.5 %, illness duration = 14.95 ± 8.32 years, mean total Positive and Negative Syndrome Scale (PANSS) = 101.10 ± 24.91) who fulfilled well-defined CRS criteria including baseline clozapine plasma levels ≥350 ng/mL. The primary outcome was the ≥50 % PANSS Total Score reduction; secondary outcomes were the scores of the PANSS subscales, PANSS five-factor dimensions, PANSS-6 and the Calgary Depression Rating Scale (CDRS). Treatment response was analyzed by percentage reduction, Linear Mixed Models and effect sizes. At baseline both groups showed no differences except for years of school education (included as a covariate). At endpoint, only 1/19 of the completers (5.26 %) in the ECT group and 0/17 in the sham-ECT group showed a ≥50 % total PANSS score reduction. Both groups showed no significant differences of the total PANSS score (F = 0.12; p = 0.73), Positive (F = 0.27, p = 0.61), Negative (F = 0.25, p = 0.62), and General Psychopathology scores (F = 0.01, p = 0.94) as well for all PANSS five factors, the PANSS-6 and CDRS. Thus, the present study found no evidence that ECT is better than Sham-ECT in patients with CRS. Future sham-ECT controlled studies with larger sample sizes are warranted to test the efficacy of ECT for patients with CRS., Competing Interests: Declaration of competing interest During the period of the study (2018–2022), Helio Elkis received a research grant from FAPESP and honoraria for participation as a member of advisory boards, speaker, or travel support from the following pharmaceutical companies: Aché, Cristália, Daiichi- Sankyo, Janssen, Mantecorp- Hypera and Teva. Samuel Araujo Leite received an MSc scholarship from the CAPES, a Brazilian Educational Funding Agency from June 2019 to May 2021. C Correll 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, 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, Seqirus, SK Life Science, Sunovion, Sun Pharma, Supernus, Takeda, Teva, 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, Sage, Supernus, Tolmar 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, Mindpax, LB Pharma, PsiloSterics and Quantic. The other participants have no conflict of interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Although uncommon, the risk of aggression and violence is greater in people with schizophrenia than in the general population. Clozapine is the "gold standard" pharmacologic treatment for the management of persistent agitation and aggression in people with schizophrenia and is consistently recommended by guidelines and reviews for this purpose. Although clozapine is indicated for treatment-resistant schizophrenia based on its superior efficacy, studies have proposed that clozapine may have specific properties that ameliorate aggression and hostility that are distinct from its antipsychotic effects. A literature review was conducted on June 3, 2023, using the US National Library of Medicine's PubMed resource to identify articles focusing on clozapine for the treatment of aggression, violence, and/or hostility in patients with schizophrenia or schizoaffective disorder. The majority of evidence, including from randomized control trials, supports the utilization of clozapine as maintenance treatment for persistent aggressive behavior in patients with schizophrenia, and supports that its anti-aggressive effects may be independent from its antipsychotic properties (e.g. - treatment of hallucinations and delusions). Future randomized control studies evaluating clozapine and clozapine serum levels with aggression as the primary outcome would be of benefit., Competing Interests: Declaration of competing interest J. Faden has, in the past 5 years, served as a consultant to BioXcel and Noven and received grant funding from BioXcel. L. Citrome has, in the past 5 years, served as a Consultant: AbbVie/Allergan, Acadia, Adamas, Alkermes, Angelini, Astellas, Avanir, Axsome, Biogen, BioXcel, Boehringer Ingelheim, Cadent Therapeutics, Cerevel, Clinilabs, COMPASS, Delpor, Eisai, Enteris BioPharma, HLS Therapeutics, Idorsia, INmune Bio, Impel, Intra-Cellular Therapies, Janssen, Karuna, Lundbeck, Luye, Lyndra, Maplight, Marvin, Medavante-ProPhase, Merck, Mitsubishi-Tanabe Pharma, Neumora, Neurocrine, Neurelis, Noema, Novartis, Noven, Otsuka, Ovid, Praxis, Recordati, Relmada, Reviva, Sage, Sumitomo/Sunovion, Supernus, Teva, University of Arizona, Vanda, Wells Fargo, and one-off ad hoc consulting for individuals/entities conducting marketing, commercial, or scientific scoping research. Speaker: AbbVie/Allergan, Acadia, Alkermes, Angelini, Axsome, BioXcel, Eisai, Idorsia, Intra-Cellular Therapies, Janssen, Lundbeck, Neurocrine, Noven, Otsuka, Recordati, Sage, Sunovion, Takeda, Teva, and CME activities organized by medical education companies such as Medscape, NACCME, NEI, Vindico, and Universities and Professional Organizations/Societies. Stocks (small number of shares of common stock): Bristol-Myers Squibb, Eli Lilly, J & J, Merck, Pfizer purchased >10 years ago, stock options: Reviva. Royalties/Publishing Income: Taylor & Francis (Editor-in-Chief, Current Medical Research and Opinion, 2022-date), Wiley (Editor-in-Chief, International Journal of Clinical Practice, through end 2019), UpToDate (reviewer), Springer Healthcare (book), Elsevier (Topic Editor, Psychiatry, Clinical Therapeutics)., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Clozapine is an important drug in the treatment of Parkinson's disease (PD). It has proven efficacy in treating PD psychosis without worsening motor function, as well as in treating tremor refractory to L-Dopa, yet it is severely underused in the United States. Unlike the situation of treatment resistant schizophrenia, this underuse is underrecognized., Competing Interests: Declaration of competing interest Consulting: EPI Q. Royalties: Karger Press; Cambridge University Press; Medlink. Travel: Intl Parkinson's and Related Disorders Association., (Copyright © 2023. Published by Elsevier B.V.)

Aim: Clozapine is indicated as the last-line agent for the treatment of refractory schizophrenia due to its side effects. This study included an Asian schizophrenia population and investigated the effect of clozapine on the risks of all-cause, natural, and suicide mortality., Methods: This study included a large-scale schizophrenia inpatient cohort derived from the National Health Insurance Research Database from January 1, 2001, to December 31, 2019 (n = 43,025). Of them, we selected those who received clozapine (clozapine cohort, n = 5800). From those who never used clozapine, we selected two individuals for each patient in the clozapine cohort by matching by age, sex, and the year of the index date (ratio: 1:2, control cohort, n = 11,583). The clozapine and nonclozapine control cohorts together were defined as the study cohort (n = 17,383). Multivariate Cox proportional-hazards regression with a time-dependent model was performed to investigate the effect of individual antipsychotic agents on mortality., Results: All individual first-generation antipsychotics were not associated with mortality risk. However, most individual second-generation antipsychotics exerted protective effects against all-cause and natural mortality. Furthermore, only clozapine and risperidone were significantly associated with a low risk of suicide mortality. Only clozapine exhibited a dose-dependent relationship with all-cause, natural, and suicide mortality., Conclusions: This study provides robust evidence supporting the strong protective effect of clozapine on all-cause, suicide, and natural mortality risks in an Asian population. Under close monitoring, clozapine use can be advantageous in patients with schizophrenia who are at a high risk of suicide., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2023. Published by Elsevier B.V.)

Competing Interests: Declaration of competing interest Dr. Kane has been a consultant for or received honoraria from Alkermes, Dainippon Sumitomo, Eli Lilly, Forum, Allergan, Genentech, H. Lundbeck, Intracellular Therapies, Janssen Pharmaceutica, Johnson and Johnson, LB Pharmaceuticals, Merck, Minerva, Neurocrine, Otsuka, Pierre Fabre, Reviva, Roche, Sunovion, Takeda and Teva. He has received grant support from Otsuka, Lundbeck and Janssen. He has participated in advisory boards for Alkermes, Dainippon Sumitomo, Intracellular Therapies, Lundbeck, Neurocrine, Otsuka, Pierre Fabre, Takeda, and Teva. He is a Shareholder in Vanguard Research Group and LB Pharmaceuticals, Inc. Dr. Schoretsanitis has received consulting/speaker's fees from Dexcel Pharma, HLS Therapeutics, Saladax and Thermo Fisher Scientific. Dr. Rubio has received consulting fees/honoraria for lectures from Janssen, Karuna and Teva. He has also received grant support from Alkermes. Dr. Correll has been a consultant and/or advisor to or has received honoraria from: AbbVie, Acadia, Adock Ingram, Alkermes, Allergan, Angelini, Aristo, Biogen, Boehringer-Ingelheim, Bristol-Meyers Squibb, Car dio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Delpor, 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, Tabuk, 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.

Background: Up to 1/2 of outpatients prescribed clozapine may be partially/fully non-adherent, based on therapeutic drug monitoring (TDM). Three indices for measuring partial/full non-adherence are proposed a: 1) clozapine concentration/dose (C/D) ratio which drops to half or more of what is expected in the patient; 2) clozapine/norclozapine ratio that becomes inverted; and 3) clozapine concentration that becomes non-detectable., Methods: These 3 proposed indices are based on a literature review and 17 cases of possible non-adherence from 3 samples: 1) an inpatient study in a Chinese hospital, 2) an inpatient randomized clinical trial in a United States hospital, and 3) and a Uruguayan outpatient study., Results: The first index of non-adherence is a clozapine C/D ratio which is less than half the ratio corresponding to the patient's specific ancestry group and sex-smoking subgroup. Knowing the minimum therapeutic dose of the patient based on repeated TDM makes it much easier to establish non-adherence. The second index is inverted clozapine/norclozapine ratios in the absence of alternative explanations. The third index is undetectable concentrations. By using half-lives, the chronology of the 3 indices of non-adherence was modeled in two patients: 1) the clozapine C/D ratio dropped to ≥1/2 of what is expected from the patient (around day 2); 2) the clozapine/norclozapine ratio became inverted (around day 3); and 3) the clozapine concentration became undetectable by the laboratory (around days 9-11)., Conclusion: Prospective studies should further explore these proposed clozapine indices in average patients, poor metabolizers (3 presented) and ultrarapid metabolizers (2 presented)., Competing Interests: Declaration of competing interest GS has received speaker/consultation fees from HLS Therapeutics and Thermo Fisher. AEAY has received speaker/advisory board fees from Janssen, Abdi İbrahim Otsuka and Nobel, and has received investigator fees from Janssen. CBE received honoraria for conferences from Forum pour la formation médicale, Janssen-Cilag, Lundbeck, Otsuka, Sandoz, Servier, Sunovion, Sysmex Suisse AG, Takeda, Vifor-Pharma, and Zeller in the past 3 years. SRC received speaker/consultation fees from: Janssen-Cilag, Lundbeck, Otsuka and Servier and research funding from Janssen-Cilag, Lundbeck, Otsuka and Gilead. SHK has received research grants from Janssen and Dongwha. JGL has consulted/spoken on behalf of Saladax Biomedical. RMP has received speaker/consultation fees from Eisai, HLS Therapeutics, Jansen, Lundbeck, and Otsuka. HT has received grants from Daiichi Sankyo and Novartis Pharma; speaker's fees from EA. Pharma, Eisai, Kyowa, Janssen, Lundbeck, Meiji Seika Pharma, MSD, Otsuka, Sumitomo Pharma, Takeda, and Yoshitomiyakuhin; and consulting fees from Janssen, Mitsubishi Tanabe Pharma, Ono, and Sumitomo Pharma. CUC has been a consultant and/or advisor to or has received honoraria from: AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Boehringer-Ingelheim, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Denovo, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Newron, Noven, Novo Nordisk, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Seqirus, SK Life Science, Sunovion, Sun Pharma, Supernus, Takeda, Teva, 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, Mindpax, LB Pharma and Quantic. In the last 3 years, the remaining authors report no conflicts of interest., (Copyright © 2023. Published by Elsevier B.V.)

Competing Interests: Declaration of competing interest From the 1970s to the early 1990s, I was an employee of Sandoz Pharmaceuticals. Subsequent to my retirement, I served occasionally as a paid consultant to Sandoz. I have not served in that capacity for at least 15 years. I have no other competing interests to declare.

Competing Interests: Declaration of competing interest The authors declare no conflict of interest.

Background: This study investigates whether early clozapine use is associated with improved responses in different clinical domains, including positive and negative symptoms, functioning, and well-being., Methods: Data from 254 clozapine-treated patients at Cambridgeshire and Peterborough NHS Foundation Trust (CPFT) were analysed. Among them, 231 (90.9 %) had a diagnosis of schizophrenia, 21 (8.3 %) schizoaffective disorder, and 2 (0.8 %) had other diagnoses. The International Classification of Diseases-Mortality and Morbidity Statistics criteria (ICD-10) were employed (World Health Organization, 1992). The cohort was assessed using the positive and negative syndrome scale (PANSS), the Brief Negative Symptom Scale (BNSS), Global Assessment of Functioning Scale (GAF), and the short version of Warwick-Edinburgh Mental Well-being Scale (SWEMWBS). Logistic regression models (for positive and negative symptom remission) and linear regression (for functioning and well-being) were utilized to assess the influence of time to clozapine initiation (TCI), age at the first episode of psychosis (AFE), duration of clozapine treatment (DCT), and gender., Results: Early clozapine treatment (within the first three years after the first episode of psychosis) was associated with increased negative symptom remission (exp (B) = 0.38; p = 0.02) and higher functioning scores (β = -0.12, p = 0.046). However, no effect of time to clozapine initiation was found on positive symptom remission rates or well-being scores., Conclusions: Initiating clozapine treatment within the first 3 years of the first episode of psychosis may lead to reduced severity of negative symptoms and improved functioning in clozapine-treated patients. The time to clozapine initiation did not influence its effect on positive symptom remission rates., Competing Interests: Declaration of competing interest Dr. Muñoz-Manchado has received travel support from Adamed (2023), Otsuka and Neuraxpharm (2022). Pérez-Revuelta has received honoraria from Adamed (2023). Dr. Bernardo has received grant/research support and has been on the speakers/advisory board of ABBiotics, Adamed, Angelini, Casen Re-cordati, Janssen-Cilag, Menarini, Rovi and Takeda. Dr. Villagrán-Moreno has received consultancy honoraria from Rovi (2022) and speaker fees from Rovi (2022, 2023) Janssen (2022), and Adamed (2022 and 2023). Dr. Fernández-Egea has received consultancy honoraria from Boehringer-Ingelheim (2022), Atheneum (2022) and Rovi (2022), speaker fees by Adamed (2022) and Otsuka (2023) and training and research material from Merz (2020). The rest of the authors declare no conflict of interest for this study., (Copyright © 2023 Elsevier B.V. All rights reserved.)

This issue focuses on the past, the present and the future of clozapine. Of the 43 clozapine articles, nine are historical articles dealing with the past, 29 deal with the present and five with laboratory assays which may influence its future use. These 43 articles include 219 different authors from 56 countries/regions and five continents., Competing Interests: Declaration of competing interest In the last 3 years the author reports no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Clozapine is a gold standard treatment for treatment-resistant schizophrenia. However, the patients' and caregivers' perception and their experience with clozapine has remained much less explored., Aim: To review the available literature on the patients' and caregivers' attitudes, perceptions, and experiences with clozapine., Methodology: 27 original research and review articles published in PubMed-indexed journals till March 2023 in the English language, exploring the patient and/or caregiver/family member's experience with using clozapine, were included., Results: 30-80 %of patients and 92-100 % of caregivers were found to have a positive attitude towards clozapine in terms of its impact on psychopathology, cognitive and social functioning of the patient, and caregiving needs. Most patients and caregivers also found that the positive effects of clozapine outweighed the side effects and distress related to repeated blood testing. However, a lack of satisfaction was noted among both patients and caregivers regarding the knowledge provided to them regarding clozapine, especially regarding its common adverse effects. Discontinuation of clozapine was found to be more commonly done by the patients' accord rather than clinicians, and the perceived side effects like hypersalivation and excessive sedation emerge as important factors that lead to discontinuation rather than the need for repeated blood testing., Conclusions: Overall, patients and their caregivers share a positive attitude towards clozapine and perceive it to be an effective and beneficial drug, but more effort needs to be directed by the clinical teams to educate the users of clozapine regarding its complete side effect profile and provide continuous guidance about dealing with the emerging side effects throughout treatment., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Laboratories commonly provide norclozapine concentrations when a plasma clozapine level is requested, but the appropriate use of this information for the treatment of individuals with schizophrenia is not always clear. Particularly vexing is the fact that norclozapine possesses pharmacological properties that are distinct from its parent compound and which contribute to clozapine's efficacy signal, yet the literature focuses primarily on the association of clozapine levels with symptomatic improvement. The purpose of this brief article is to highlight findings with respect to the need to track norclozapine levels, or the ratio of clozapine/norclozapine plasma levels, to optimize efficacy among inadequate responders to clozapine treatment. In addition, there will be a discussion of the specific type of information provided by the clozapine/norclozapine ratio on clozapine's clearance, and how this ratio is sometimes misinterpreted. There is clinical value from to be derived from norclozapine levels and the clozapine/norclozapine ratio for schizophrenia management, and the principles governing use of this information will be distilled into 3 succinct axioms to aid clinicians in managing their clozapine-treated patients with schizophrenia., Competing Interests: Declaration of competing interest Dr. Meyer reports having received speaking or advising fees in the past 24 months from: AbbVie, Alkermes, BioXcel, ITCI, Karuna, Neurocrine, Noven, Otsuka-USA, Sumitomo Pharma (formerly Sunovion) and Teva., (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.)

Competing Interests: Declaration of competing interest We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us. We confirm that we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, with respect to intellectual property. In so doing we confirm that we have followed the regulations of our institutions concerning intellectual property. We further confirm that any aspect of the work covered in this manuscript that has involved human participants has been conducted with the ethical approval of all relevant bodies and that such approvals are acknowledged within the manuscript. We understand that the Corresponding Author is the sole contact for the Editorial process (including Editorial Manager and direct communications with the office). She is responsible for communicating with the other authors about progress, submissions of revisions and final approval of proofs. We confirm that we have provided a current, correct email address which is accessible by the Corresponding Author and which has been configured to accept email from mzolezzi@qu.edu.qa.

Competing Interests: Declaration of competing interest All authors declare that they have no conflict of interest.

Competing Interests: Declaration of competing interest I have no competing interests to declare. I declare that I have not received any financial support for the preparation of the article.

While clozapine is the most effective antipsychotic treatment for treatment-resistant schizophrenia, it remains underutilized across the United States, warranting a more comprehensive understanding of variation in use at the county level, as well as characterization of existing prescribing patterns. Here, we examined both Medicaid and Medicare databases to (1) characterize temporal and geographic variation in clozapine prescribing and, (2) identify patient-level characteristics associated with clozapine use. We included Medicaid and Fee for Service Medicare data in the state of Pennsylvania from January 1, 2013, through December 31, 2019. We focused on individuals with continuous enrollment, schizophrenia diagnosis, and multiple antipsychotic trials. Geographic variation was examined across counties of Pennsylvania. Regression models were constructed to determine demographic and clinical characteristics associated with clozapine use. Out of 8,255 individuals who may benefit from clozapine, 642 received treatment. We observed high medication burden, overall, including multiple antipsychotic trials. We also identified variation in clozapine use across regions in Pennsylvania with a disproportionate number of prescribers in urban areas and several counties with no identified clozapine prescribers. Finally, demographic, and clinical determinants of clozapine use were observed including less use in people identified as non-Hispanic Black, Hispanic, or with a substance use disorder. In addition, greater medical comorbidity was associated with increased clozapine use. Our work leveraged both Medicaid and Medicare data to characterize and surveil clozapine prescribing. Our findings support efforts monitor disparities and opportunities for the optimization of clozapine within municipalities to enhance clinical outcomes., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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.

Objectives: Despite the importance of a satisfying sexual life, most patients with schizophrenia spectrum disorders do not discuss sexual issue with their clinicians. The current study seeks to determine the prevalence and socio-clinical correlates of sexual dysfunction among patients with schizophrenia spectrum disorders receiving typical and atypical antipsychotic medications. The second objective is to determine the frequency and correlates of specific sexual dysfunction (desire, arousal, erection/lubrication and orgasm) by gender and drug type using the Arizona Sexual Experience Scale., Methodology: This cross-sectional study used standardized structured interviewer based survey to assess sexual dysfunction among patients with schizophrenia that are both sexually active and inactive at a tertiary hospital in Maiduguri from December 2020 to April 2021. Participants were also assayed for prolactin using ELISA Kit for a possible association with sexual dysfunction., Results: The overall prevalence of sexual dysfunction among patients with schizophrenia spectrum disorder receiving antipsychotics was 34% with patients on typical and atypical antipsychotics reporting rates of 36.8% and 24.6%, respectively. Among the typical and atypical antipsychotics, patients receiving haloperidol (40.3%) and risperidone (37.5%) reported a relatively higher frequency of sexual dysfunction compared to those receiving clozapine (18.2%). Independent correlates of sexual dysfunction were: female gender (OR = 1.89, 95% CI = 1.17-3.06; P = .010), being unmarried (OR = 1.51, 95% CI = 1.17-1.96; P = .001), pseudoparkinsonism (OR = 1.66, 95% CI = 1.02-2.69; P = .008), prolactin (OR = 2.15, 95% CI = 1.34-3.43; P = .001) and severity of illness (OR = 1.34, 95% CI = 1.03-1.75; P = .030)., Conclusion: Sexual dysfunction is prevalent among patients with schizophrenia spectrum disorder receiving either typical or atypical antipsychotics., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.