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Cognitive deficits are long-lasting consequences of drug use, yet the convergent mechanism by which classes of drugs with different pharmacological properties cause similar deficits is unclear. We find that both phencyclidine and methamphetamine, despite differing in their targets in the brain, cause the same glutamatergic neurons in the medial prefrontal cortex of male mice to gain a GABAergic phenotype and decrease expression of their glutamatergic phenotype. Suppressing drug-induced gain of GABA with RNA-interference prevents appearance of memory deficits. Stimulation of dopaminergic neurons in the ventral tegmental area is necessary and sufficient to produce this gain of GABA. Drug-induced prefrontal hyperactivity drives this change in transmitter identity. Returning prefrontal activity to baseline, chemogenetically or with clozapine, reverses the change in transmitter phenotype and rescues the associated memory deficits. This work reveals a shared and reversible mechanism that regulates the appearance of cognitive deficits upon exposure to different drugs.

Background: Although the number of studies on treatment-resistant schizophrenia (TRS) has been increasing, the global research hotspots and future research trends have not yet been established. Objective: This study identify the hotspots of TRS research and predict future research trends using a bibliometric analysis. Methods: The Web of Science Core Collection was searched using the keyword "TRS", econometric and co-occurrence analyses were conducted using CiteSpace and VOSviewer software, and the results were visualised. PRISMA reporting guidelines were used for this study. Results: In total, 912 publications were included in the analysis. The number of publications on TRS has shown an increasing trend over the past 20 years. The United States and University of London were the countries and institutions with the highest total number of publications, respectively. Schizophrenia Research was the journal with the highest number of articles. American Journal of Psychiatry was the most cited journal. Based on the results of this analysis, cognitive impairment, clozapine-resistant schizophrenia, early-onset schizophrenia, and early recognition of TRS will be hotspots for future research in this field. Conclusion: There has been an upward trend in the number of publications on TRS each year. However, issues such as how to use antipsychotics more efficiently to treat TRS and how to predict the emergence of TRS as early as possible are still in urgent need of research and are current challenges for clinicians. The results of this study not only predict and analyse future research hotspots but also help researchers identify appropriate research directions and partners. [ABSTRACT FROM AUTHOR]

Understanding the relationship between the concentration of a drug and its therapeutic efficacy or side effects is crucial in drug development, especially to understand therapeutic efficacy in central nervous system drug, quantifying drug-induced site-specific changes in the levels of endogenous metabolites, such as neurotransmitters. In recent times, evaluation of quantitative distribution of drugs and endogenous metabolites using matrix-assisted laser desorption/ionization (MALDI)-mass spectrometry imaging (MSI) has attracted much attention in drug discovery research. However, MALDI-MSI quantification (quantitative mass spectrometry imaging, QMSI) is an emerging technique, and needs to be further developed for practicable and convenient use in drug discovery research. In this study, we developed a reliable QMSI method for quantification of clozapine (antipsychotic drug) and dopamine and its metabolites in the rat brain using MALDI-MSI. An improved mimetic tissue model using powdered frozen tissue for QMSI was established as an alternative method, enabling the accurate quantification of clozapine levels in the rat brain. Furthermore, we used the improved method to evaluate drug-induced fluctuations in the concentrations of dopamine and its metabolites. This method can quantitatively evaluate drug localization in the brain and drug-induced changes in the concentration of endogenous metabolites, demonstrating the usefulness of QMSI. [ABSTRACT FROM AUTHOR]

While there is extensive literature examining the effectiveness of antipsychotic prescribing to patients with schizophrenia spectrum or other psychotic disorders in general psychiatric services, there is a dearth of studies examining antipsychotic prescribing practices and their effectiveness in forensic psychiatric services. Forensic psychiatric patients have unique challenges often due to their high-profile offences, public scrutiny, and legal requirements. This longitudinal, retrospective study aimed to examine antipsychotic prescribing and rehospitalization rates in a forensic psychiatric sample, along with relevant socio-demographic, clinical, and forensic characteristics. All patients had a psychotic illness and were prescribed antipsychotic medication. The sample included 153 patients, of which the majority were male (85.6%), Caucasian (71.2%), middle aged (30s to 50s), had schizophrenia or schizoaffective disorder (76.5%), had a substance use disorder (62.1%), and had a most serious index offence against the person (80.4%). Atypical antipsychotics accounted for the majority of antipsychotic prescriptions (75.9%) and the sample had an antipsychotic polypharmacy rate of 39.9%. The sample was divided into four primary antipsychotic formulation types, which were oral (34.0%), injection (39.2%), clozapine (19.0%), and subtherapeutic (7.8%). Regarding rehospitalization, 52.9% of the sample was rehospitalized, with the average number of rehospitalizations being 1.2 (SD = 1.7) and proportion of the follow up period rehospitalized being 16.4% (SD = 27.7%). Patients prescribed clozapine had numerically lower rates of rehospitalization than those prescribed oral and injection formulation types, but it was not statistically significant. With a 19.0% prescription rate, clozapine may be underutilized in this sample. Further research is needed to demonstrate the potential benefits of clozapine regarding rehospitalization in forensic psychiatric patients, as has already been done in general psychiatry. Advancing treatment of the high-profile forensic population can reduce stigma toward people with mental illness and criminal justice involvement. [ABSTRACT FROM AUTHOR]

Introduction: Abnormalities in the hippocampus have been extensively reported in schizophrenia research. However, inconsistent findings exist, and how structural and functional abnormalities of the hippocampus are associated with clinical symptoms in schizophrenia, especially concerning clozapine treatment, remains uncertain. Methods: We recruited 52 patients with schizophrenia, each with an illness duration of at least 5 years, and categorized them based on clozapine treatment. T1-weighted images and resting-state functional magnetic resonance imaging scans were obtained and analyzed to perform group comparisons of the structural and functional changes in the hippocampus. Volumes of the hippocampal subregions, as well as resting-state functional connectivity maps from these areas were compared between the groups. Associations with clinical symptoms, including the severity of psychiatric symptoms and cognitive functions, were investigated. Results: The clozapine group (n=23) exhibited smaller volumes in several hippocampal subregions, including the CA1, CA4, granule cell and molecular layers of the dentate gyrus, compared to the non-clozapine group (n=29). Seven clusters with significant group differences in functional connectivity with these hippocampal subregions were identified, with six of these clusters showing increased functional connectivity in the clozapine group. The reduced volumes of the hippocampal subregions were moderately associated with the severity of negative symptoms, general intelligence, and executive function. Discussion: Patients with schizophrenia undergoing clozapine treatment exhibited smaller volumes in the hippocampal subregions, which were moderately associated with negative symptoms and cognitive functions, compared to those without clozapine treatment. [ABSTRACT FROM AUTHOR]

Clozapine and its metabolites require close therapeutic monitoring (TDM) in patients due to poor correlation between the administrated doses and resulting plasma concentrations, the narrow therapeutic interval, high inter-individual variability, and the risk of serious side effects once toxic levels are exceeded. The aim of the study was to develop a simple (relatively cheap) LC-UV method for the quantification of clozapine and its metabolites in plasma and urine samples. For sample preparation, liquid-liquid extraction (LLE) in n-octanol was more efficient and less limiting in injection volumes compared to the in-situ formation of SUPRAS. When analyzing urine, an alkalinization step before extraction was required. The proposed method produced linear concentration responses with/without internal standard (IS) for the target analytes, with LLOQs within the targeted range of 50 ppb and %RSD within the acceptable 15% range. Furthermore, sample stability studies proved that pre-extracted samples were stable for the short term at room temperature and long-term when frozen. [ABSTRACT FROM AUTHOR]

Background and Hypothesis There is a paucity of research on treatment outcomes of patients with psychosis and cannabis use disorder (CUD). We aimed to compare the effectiveness of antipsychotics in reducing the risk of hospitalization in patients with first-episode psychosis (FEP) and co-occurring CUD. Study Design We utilized a nationwide Swedish cohort of patients with longitudinal register data from the year 2006 to 2021. Participants were patients with FEP and co-occurring CUD (n  = 1820, 84.73% men, mean age 26.80 years, SD 8.25 years). The main outcome was hospitalization due to psychotic relapse. Hospitalization due to any psychiatric disorder or substance use disorder (SUD) were examined as secondary outcomes. Within-individual Cox regression models were used to study these associations. Study Results Use of any antipsychotic was associated with a 33% risk reduction of psychotic relapse (aHR = 0.67; 95% CI 0.60–0.75). Clozapine (0.43; 0.29–0.64), long-acting injectable (LAI) formulations of risperidone (0.40; 0.22–0.71), aripiprazole (0.42; 0.27–0.65), and paliperidone (0.46; 0.30–0.69) were associated with the lowest risk of relapse. The association between the LAI formulation of olanzapine and hospitalization due to psychosis was statistically non-significant (0.61; 0.35–1.05). Clozapine was associated with an 86% risk reduction of hospitalization due to SUD (0.14; 0.05–0.44). Of oral non-clozapine antipsychotics, aripiprazole was associated with the lowest risk of hospitalization due to psychotic relapse (0.61; 0.45–0.83). Conclusions These findings support the use of clozapine, LAI formulations of second-generation antipsychotics other than olanzapine, or oral aripiprazole to prevent hospitalization in FEP and co-occurring CUD. [ABSTRACT FROM AUTHOR]

Introduction: Abnormalities in the hippocampus have been extensively reported in schizophrenia research. However, inconsistent findings exist, and how structural and functional abnormalities of the hippocampus are associated with clinical symptoms in schizophrenia, especially concerning clozapine treatment, remains uncertain. Methods: We recruited 52 patientswith schizophrenia, eachwith an illness duration of at least 5 years, and categorized them based on clozapine treatment. T1- weighted images and resting-state functional magnetic resonance imaging scans were obtained and analyzed to perform group comparisons of the structural and functional changes in the hippocampus. Volumes of the hippocampal subregions, as well as resting-state functional connectivity maps from these areas were compared between the groups. Associations with clinical symptoms, including the severity of psychiatric symptoms and cognitive functions, were investigated. Results: The clozapine group (n=23) exhibited smaller volumes in several hippocampal subregions, including the CA1, CA4, granule cell and molecular layers of the dentate gyrus, compared to the non-clozapine group (n=29). Seven clusters with significant group differences in functional connectivity with these hippocampal subregions were identified, with six of these clusters showing increased functional connectivity in the clozapine group. The reduced volumes of the hippocampal subregions were moderately associated with the severity of negative symptoms, general intelligence, and executive function. Discussion: Patients with schizophrenia undergoing clozapine treatment exhibited smaller volumes in the hippocampal subregions, which were moderately associated with negative symptoms and cognitive functions, compared to those without clozapine treatment. [ABSTRACT FROM AUTHOR]

Background/Objectives: Patients with schizophrenia have significant challenges in adhering to and complying with oral medicines, resulting in adverse consequences such as symptom worsening and psychotic relapse. Methods: This study aimed to develop clove oil-based bilosomes using definitive screening design (DSD) to maximize the anti-schizophrenic action of clozapine and promote its nose-to-brain delivery. The target was to optimize the physicochemical properties of bilosomes and incorporate them into mucoadhesive intranasal in situ gels, searching for augmented ex vivo and in vivo clozapine delivery. Results: The bilosomes' particle size was decreased by increasing the span, SDC, and clove oil amounts. In addition to using a high lipid amount, the aforementioned components also helped increase the entrapment efficiency values. Increased zeta potential was only observed by increasing surfactant amount and reducing clozapine concentration. After incorporation of optimized liquid clove oil-based bilosomes, which had a spherical nano-sized vesicular shape, into P 407-dependent gels, an HPMC (2% w/w)/P 407 (20% w/w)-containing formulation (G6) was selected as an optimized gel owing to its acceptable gelation time (13.28 s), gel strength (27.72 s), viscosity (12,766.67 cP), and mucoadhesive strength (4273.93 dyne/cm2). The optimized G6 exhibited higher Jss (50.86 μg/cm2·h−1) through the nasal mucosa compared to the control gel (23.03 μg/cm2·h−1). Compared to the control gel, G6 displayed higher relative bioavailability (491.37%) than a commercial tablet (264.46%). Following ELISA analysis, dopamine and serotonin were significantly reduced, while BDNF was remarkably increased after administration of optimized G6 into schizophrenic rats. Conclusion: Our study indicates the potential of intranasal bilosomal gels in upgrading the anti-schizophrenic and neuroprotective activity of clozapine. [ABSTRACT FROM AUTHOR]

Clozapine is the only approved antipsychotic for refractory schizophrenia to date. It can cause a range of serious and fatal adverse effects, including Clozapine-Induced Gastrointestinal Hypomotility (CIGH). While guidance is readily available to help manage CIGH effectively in hospital inpatients, practical recommendations applicable to the community (outpatient) setting are lacking. This project set out to improve the prevention, detection and management of CIGH in psychiatric outpatients. An initial baseline audit followed by quality improvement work was undertaken in a busy support worker-run community clozapine clinic focusing on, education and training, risk assessments and clinical documentation. The project was registered and managed using the Life QI web-based platform, where a set of primary and secondary drivers were defined and change ideas were executed. Qualitative and quantitative data were collected over a three-month period, demonstrating a significant improvement in clinical documentation (up from 36% to 99%). 23% of enhanced risk assessments resulted in treatment recommendations, modifiable risk factors were proactively discussed in 53% of clinic appointments and 65% of patients were provided with additional written information on CIGH. It was evident from staff and our patient feedback that further efforts would be required to continue to raise awareness about harms of unmanaged constipation among this client group. Future approaches may include enhanced collaborative efforts with primary care, and improving the skill mix in existing clozapine clinics, which could include the utilisation of mental health pharmacists. [ABSTRACT FROM AUTHOR]

Objectives: Parkinson's disease psychosis (PDP) is a prevalent non-motor symptom associated with Parkinson's disease. The treatment options for PDP are limited, and its pharmacological management remains ambiguous. This study aimed to evaluate the existing evidence in relation to clinical practice. Methods: This multi-methods study consisted of a systematic review of reviews, adhering to the PRISMA guidelines. The review was registered with PROSPERO. Following data extraction and assessment using the AMSTAR 2 tool, a narrative synthesis was performed. In the second phase of the study, a questionnaire was developed, validated, piloted, and distributed to the heads of specialized PD clinics in Germany and Austria. Results: The search resulted in the inclusion of eleven reviews. The quality of eight of these reviews was rated as high (n = 7) or moderate (n = 1). The reviews indicated that clozapine and pimavanserin demonstrated the highest efficacy and tolerability. Other antipsychotic medications either failed to alleviate PDP symptoms or resulted in distinct motor complications. The survey findings also favored clozapine for its efficacy in managing PDP and improving quality of life, although quetiapine was regarded as effective and pimavanserin was not available. Clinicians reported initiating antipsychotic treatment at various stages of PDP, with a tendency to reduce the dosage or discontinue D2 agonists or anticholinergics. Conclusions: The reviewed literature and the survey results consistently favored clozapine for its efficacy and tolerability in treating PDP. It may be considered the first-line treatment, with pimavanserin as an alternative option. [ABSTRACT FROM AUTHOR]

The current literature on the effects of clozapine on pregnancy is limited, and no cases of pregnant Japanese women have been reported. Decreased variability in the fetal heart rate due to clozapine exposure has been reported in countries other than Japan, but its association with serum concentrations of clozapine has not been documented. In this case, a 29‐year‐old Japanese primipara with treatment‐resistant schizophrenia taking clozapine 250 mg/day experienced pregnancy. The pregnancy progressed without complications. At 40 weeks and 2 days of gestation, the patient developed premature rupture of membranes, and decreased variability in the fetal heart rate and variable deceleration were observed, leading to an emergency cesarean section. The neonate had no congenital malformations, metabolic disorders, seizures, floppy infant syndrome, leukopenia, or neutropenia. Serum concentrations of clozapine and norclozapine (N‐desmethylclozapine), measured in the mother and in the neonate immediately after birth, suggested that clozapine and norclozapine were transported to the fetus during pregnancy. Based on these observations, the present case suggests that high fetal serum concentrations of clozapine and norclozapine may affect fetal heart rate. This case report concludes that, with careful monitoring, Japanese women taking clozapine can deliver successfully and emphasizes the importance of monitoring serum clozapine concentrations and fetal cardiac function throughout pregnancy, with particular attention to the later stages. [ABSTRACT FROM AUTHOR]

The task of a psychiatrist is to select the most appropriate medication or combination of drugs to treat the symptoms of schizophrenia while minimizing the risk of side effects and ensuring the patient achieves the highest level of functioning possible. This is a challenging task as the action of each drug or group of drugs is different. The efficacy of cariprazine, which affects D3 receptors as a D3/D2 receptor partial agonist, has been extensively studied and is one of the first medication choices by practicing psychiatrists when treating patients with negative symptomatology. In this clinical case, we demonstrate the effective and safe treatment of a patient's positive and affective symptoms using a combination of cariprazine, clozapine, and venlafaxine. [ABSTRACT FROM AUTHOR]

Background: In patients with schizophrenia, violent behavior is a clinically important factor that prevents their discharge. Clozapine is an effective antipsychotic medication for treatment‐resistant schizophrenia, and its usefulness for aggressive behavior has also been suggested. Case Presentation: We present the case of a 38‐year‐old male patient diagnosed with schizophrenia who was successfully treated with clozapine after recurrent violent behavior. He was diagnosed with schizophrenia during his adolescence. He was hospitalized for treatment in his teens, but his hallucinations and delusions persisted even after discharge. In his 30s, he became noticeably emotionally unstable, and despite being treated for an adequate period with sufficient doses of several antipsychotics, his symptoms did not improve. This led to repeated hospitalizations triggered by violent behavior toward his parents and siblings within the home. During his fourth hospitalization, clozapine was initiated due to multiple incidents of violence toward nursing staff secondary to hallucinations and delusions. As the dose of clozapine was gradually increased with therapeutic drug monitoring, the patient's hostility, uncooperativeness, and suspiciousness markedly improved, and his aggressive behavior disappeared. He was discharged to a facility on day 194 after starting clozapine and has continued outpatient visits. Conclusion: Clozapine was suggested to be effective for aggressive behavior in patients with treatment‐resistant schizophrenia and should be actively considered. In such cases, regular measurement of blood concentration is useful for adjusting the dosage of clozapine. [ABSTRACT FROM AUTHOR]

For several decades, the dopamine hypothesis contributed to the discovery of numerous typical and atypical antipsychotics and was the sole hypothesis for the pathophysiology of schizophrenia. However, neither typical nor atypical antipsychotics, other than clozapine, have been effective in addressing negative symptoms and cognitive impairments, which are indices for the prognostic and disability outcomes of schizophrenia. Following the development of atypical antipsychotics, the therapeutic targets for antipsychotics expanded beyond the blockade of dopamine D2 and serotonin 5-HT2A receptors to explore the partial agonism of the D2 receptor and the modulation of new targets, such as D3, 5-HT1A, 5-HT7, and metabotropic glutamate receptors. Despite these efforts, to date, psychiatry has not successfully developed antipsychotics with antipsychotic properties proven to be superior to those of clozapine. The glutamate hypothesis, another hypothesis regarding the pathophysiology/pathomechanism of schizophrenia, was proposed based on clinical findings that N-methyl-D-aspartate glutamate receptor (NMDAR) antagonists, such as phencyclidine and ketamine, induce schizophrenia-like psychotic episodes. Large-scale genome-wide association studies (GWASs) revealed that approximately 30% of the risk genes for schizophrenia (the total number was over one hundred) encode proteins associated with glutamatergic transmission. These findings supported the validation of the glutamate hypothesis, which was inspired by the clinical findings regarding NMDAR antagonists. Additionally, these clinical and genetic findings suggest that schizophrenia is possibly a syndrome with complicated pathomechanisms that are affected by multiple biological and genetic vulnerabilities. The glutamate hypothesis has been the most extensively investigated pathophysiology/pathomechanism hypothesis, other than the dopamine hypothesis. Studies have revealed the possibility that functional abnormalities of the NMDAR play important roles in the pathophysiology/pathomechanism of schizophrenia. However, no antipsychotics derived from the glutamatergic hypothesis have yet been approved for the treatment of schizophrenia or treatment-resistant schizophrenia. Considering the increasing evidence supporting the potential pro-cognitive effects of glutamatergic agents and the lack of sufficient medications to treat the cognitive impairments associated with schizophrenia, these previous setbacks cannot preclude research into potential novel glutamate modulators. Given this background, to emphasize the importance of the dysfunction of the NMDAR in the pathomechanism and/or pathophysiology of schizophrenia, this review introduces the increasing findings on the functional abnormalities in glutamatergic transmission associated with the NMDAR. [ABSTRACT FROM AUTHOR]

Schizophrenia (SCH) is a mental disorder that requires long-term antipsychotic treatment. SCH patients are thought to have an increased sensitivity to stress. The dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, observed in SCH, could include altered levels of glucocorticoids, glucocorticoid receptors (GRs), and associated proteins. The perinatal administration of phencyclidine (PCP) to rodents represents an animal model of SCH. This study investigated the effects of perinatal PCP exposure and subsequent haloperidol/clozapine treatment on corticosterone levels measured by ELISA and the expression of GR-related proteins (GR, pGR, HSP70, HSP90, FKBP51, and 11β-Hydroxysteroid dehydrogenase-11β-HSD) determined by Western blot, in different brain regions of adult rats. Six groups of male rats were treated on the 2nd, 6th, 9th, and 12th postnatal days (PN), with either PCP or saline. Subsequently, one saline and one PCP group received haloperidol/clozapine from PN day 35 to PN day 100. The results showed altered GR sensitivity in the rat brain after PCP exposure, which decreased after haloperidol/clozapine treatment. These findings highlight disturbances in the HPA axis in a PCP-induced model of SCH and the potential protective effects of antipsychotics. To the best of our knowledge, this is the first study to investigate the effects of antipsychotic drugs on the HPA axis in a PCP animal model of SCH. [ABSTRACT FROM AUTHOR]

BackgroundClozapine belongs to atypical antipsychotic drugs that has shown significant efficacy in treating schizophrenia. However， clozapine can induce arrhythmias in patients. Currently， there is a lack of systematic research on the types and incidence of clozapine-induced arrhythmias.ObjectiveTo explore the types and incidence of arrhythmias in patients with schizophrenia induced by clozapine through Meta-analysis， so as to provide references for clinical treatment.MethodsOn October 31， 2022， a search was conducted through PubMed， Embase， Cochrane Library and China National Knowledge Infrastructure （CNKI） to collect relevant literature on clozapine-induced arrhythmia in patients with schizophrenia. Joanna Briggs Institute （JBI） was used to evaluate the quality of the included literature. Meta-analysis was conducted using Review Manager 5.4.ResultsA total of 12 studies were included， involving 42 490 schizophrenia patients taking clozapine. The incidence of arrhythmias caused by clozapine was 23% （95% CI： 0.16~0.29）. Among them， the incidence of tachycardia was 25% （95% CI： 0.15~0.35）， atrial arrhythmia was 6% （95% CI： -0.02~0.14）， ventricular arrhythmia was 7% （95% CI： -0.02~0.16）， conduction block was 2% （95% CI： 0~0.04）， QTc prolongation was 4% （95% CI： -0.04~0.12） and T-wave changes was 23% （95% CI： 0.16~0.30）.ConclusionSchizophrenia patients taking clozapine may increase their risk of developing arrhythmia， with tachycardia being the most prevalent. ［Funded by Graduate Innovation Fund of Kunming Medical University （number， 2023S302）］

Abstract Background In patients with schizophrenia, violent behavior is a clinically important factor that prevents their discharge. Clozapine is an effective antipsychotic medication for treatment‐resistant schizophrenia, and its usefulness for aggressive behavior has also been suggested. Case Presentation We present the case of a 38‐year‐old male patient diagnosed with schizophrenia who was successfully treated with clozapine after recurrent violent behavior. He was diagnosed with schizophrenia during his adolescence. He was hospitalized for treatment in his teens, but his hallucinations and delusions persisted even after discharge. In his 30s, he became noticeably emotionally unstable, and despite being treated for an adequate period with sufficient doses of several antipsychotics, his symptoms did not improve. This led to repeated hospitalizations triggered by violent behavior toward his parents and siblings within the home. During his fourth hospitalization, clozapine was initiated due to multiple incidents of violence toward nursing staff secondary to hallucinations and delusions. As the dose of clozapine was gradually increased with therapeutic drug monitoring, the patient's hostility, uncooperativeness, and suspiciousness markedly improved, and his aggressive behavior disappeared. He was discharged to a facility on day 194 after starting clozapine and has continued outpatient visits. Conclusion Clozapine was suggested to be effective for aggressive behavior in patients with treatment‐resistant schizophrenia and should be actively considered. In such cases, regular measurement of blood concentration is useful for adjusting the dosage of clozapine.

Existing data suggest that clozapine has lesser propensity of developing akathisia as compared to first general antipsychotics. Clozapine is mostly used in patients with treatment-resistant schizophrenia, which is a second-generation antipsychotic. Akathisia is one of the rare side effects of clozapine. A 34-year-old woman with a 7-year history of schizophrenia exhibited positive and negative symptoms, initially treated with haloperidol and clonazepam. Despite relief in positive symptoms, she experienced recurring cycles of symptom exacerbation upon discontinuing medication. Because of poor compliance, she was admitted and started on clozapine, reaching 150 mg/day. Although showing symptom improvement, she developed clozapine-induced akathisia, characterized by restlessness and limb movements. Propranolol and a gradual reduction in clozapine alleviated akathisia, supplemented by lorazepam. The Barnes Akathisia Rating Scale dropped to 0 after three weeks. This case highlights the challenges of managing schizophrenia and the importance of tailored medication strategies. The use of clozapine should be customized based on each patient’s needs to prevent clozapine-induced akathisia.

RationaleDesigner receptors exclusively activated by designer drugs (DREADDs) are a tool for "remote control" of defined neuronal populations during behavior. These receptors are inert unless bound by an experimenter-administered designer drug, commonly clozapine-n-oxide (CNO). However, questions have emerged about the suitability of CNO as a systemically administered DREADD agonist.ObjectivesSecond-generation agonists such as JHU37160 (J60) have been developed, which may have more favorable properties than CNO. Here we sought to directly compare effects of CNO (0, 1, 5, & 10 mg/kg, i.p.) and J60 (0, 0.03, 0.3, & 3 mg/kg, i.p.) on operant food pursuit.MethodsMale and female TH:Cre + rats and their wildtype (WT) littermates received cre-dependent hM4Di-mCherry vector injections into ventral tegmental area (VTA), causing inhibitory DREADD expression in VTA dopamine neurons of TH:Cre + rats. All rats were trained to stably lever press for palatable food on a fixed ratio 10 schedule, and doses of both agonists were tested on separate days in counterbalanced order.ResultsAll three CNO doses reduced operant rewards earned in rats with DREADDs, and no CNO dose had behavioral effects in WT controls. The highest J60 dose tested significantly reduced responding in DREADD rats, but this dose also increased responding in WTs, indicating non-specific effects. The magnitude of CNO and J60 effects in TH:Cre + rats were correlated and were present in both sexes.ConclusionsFindings demonstrate the usefulness of directly comparing DREADD agonists when optimizing behavioral chemogenetics, and highlight the importance of proper controls, regardless of the DREADD agonist employed.

Clozapine remains the only effective medication for treatment-resistant schizophrenia (TRS), with response rates [greater than or equal to] 40% in controlled trials, compared with < 5% for other antipsychotics, and [...]

Disorders manifested by both neurological and mental disorders belong to the neuropsychiatric diseases. This category includes Alzheimer's disease, Parkinson's disease, Wernicke–Korsakoff syndrome, delirium tremens, catatonia and anti-NMDA receptor encephalitis. The etiology of psychotic disorders in neuropsychiatric diseases probably differs from that in schizophrenia and other psychoses, which causes both inefficiency and adverse events when using antipsychotics in neuropsychiatry. In the absence of a therapeutic alternative, antipsychotics can be prescribed with caution for neurodegenerative disorders, whereas catatonia is a relative, and anti-NMDA receptor encephalitis is an absolute contraindication to their use.

Abstract 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.

Yin Cao,1– 4 Qingrong Xia,1– 4 Jun Liang,1– 4 Jiequan Wang,1– 4 Feng Shan,1– 4 Biao Dai1– 4 1Department of Pharmacy, Affiliated Psychological Hospital of Anhui Medical University, Hefei, People’s Republic of China; 2Department of Pharmacy, Hefei Fourth People’s Hospital, Hefei, People’s Republic of China; 3Psychopharmacology Research Laboratory, Anhui Mental Health Center, Hefei, People’s Republic of China; 4Department of Clinical Pharmacy, Anhui Clinical Research Center for Mental Disorders, Hefei, People’s Republic of ChinaCorrespondence: Jun Liang, Department of Pharmacy, Hefei Fourth People’s Hospital, 316 Huangshan Road, Hefei, 230000, People’s Republic of China, Email amhcliangj@163.comObjective: The present study aims to investigate the effect of common cold on the serum clozapine concentrations in hospitalized patients with schizophrenia.Methods: A total of 65 schizophrenic patients with common cold receiving clozapine treatment were retrospectively enrolled. The demographic data, medication situation, clozapine concentration, and parameters of routine haematological and biochemical laboratory tests were obtained from the medical record system. The serum clozapine concentration and clozapine concentration/dose (C/D) ratios between the baseline period and cold period were compared by paired-sample t tests. Association between the changes in serum concentration and C/D ratios of clozapine and changes in white blood cell (WBC) and neutrophil (NE) counts was evaluated using Pearson correlation analysis.Results: The serum clozapine concentration (t = − 9.856, P < 0.001) and clozapine C/D ratios (t = − 10.071, P < 0.001) were found to be significantly elevated in the cold period compared to the baseline period. Moreover, the changes in the serum clozapine concentration were found to be significantly elevated in female patients compared to male patients (t = − 2.483, P = 0.017). Furthermore, changes in the serum clozapine concentration were positively correlated to the changes in WBC (r = 0.303, P = 0.014) and NE (r = 0.315, P = 0.011) counts. Similarly, changes in clozapine C/D ratios were positively correlated to the changes in WBC (r = 0.275, P = 0.027) and NE (r = 0.328, P = 0.008) counts.Conclusion: The serum clozapine concentrations in patients with schizophrenia during the common cold period were increased, which might by related to the elevated WBC and NE counts.Keywords: clozapine, blood drug concentration, schizophrenia, white blood cell count, neutrophil count, common cold

Background: Catatonia has been reported with withdrawal of medications. Among the various psychotropics, clozapine has been implicated to cause catatonia when abruptly withdrawn. The data regarding clozapine withdrawal catatonia are scarce and are mostly available in the form of case reports and series. Aim: In this case series, we present three cases of clozapine withdrawal catatonia and review the available literature on clozapine withdrawal clozapine. Results: All the three patients developed catatonia within 48 h to 14 days of stoppage of clozapine in the doses of 100–350 mg/day. Two of the patients experiencing clozapine withdrawal improved with reinstitution of clozapine in the previous doses along with benzodiazepines. However, one patient additionally required electroconvulsive therapy (ECT) for the management of withdrawal catatonia. A review of literature showed that clozapine withdrawal catatonia has male preponderance and has been reported with withdrawal of clozapine doses of 50–550 mg/day. The catatonia usually starts in 48 h to 2 weeks of stopping clozapine. Available literature suggests that most of the patients have been managed with restarting of clozapine, along with lorazepam and occasional patients require ECT. Conclusions: To conclude our case series and the available review of literature suggests that sudden discontinuation of clozapine can lead to withdrawal catatonia. Our cases also highlight the importance of reviewing treatment history, especially of abrupt discontinuation of clozapine when a patient on clozapine present with catatonia. This can be very helpful in deciding about further management.

Abstract 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.

Clozapine is primarily metabolized via cytochrome P450(CYP)1A2 and to a lesser extent CYP3A4, CYP2C19, and CYP2D6. Metabolic inhibitors of clozapine, such as fluvoxamine and ciprofloxacin, are important to recognize to avoid adverse drug events. Estrogen-containing oral contraceptives (eOCPs) are weaker CYP1A2 and CYP2C19 inhibitors but are associated with a 2-fold increase of clozapine concentrations. The potential for phenoconversion due to a CYP genetic polymorphism can add additional complexities when considering drug interactions. A case report is presented of a suspected interaction between newly initiated clozapine and a prescribed eOCP for which the patient’s pharmacogenomic status was known. A 17-year-old, nonsmoking, White female with a history of schizophrenia was initiated on clozapine 12.5 mg at bedtime with a plan to increase by 25 mg every 4 days in the outpatient setting. The patient was a known rapid CYP1A2 metabolizer without identified sources of CYP1A2 induction and a CYP2C19 rapid metabolizer. Based on pharmacogenomic testing, there was no suspicion for significant gene-drug interactions. Yet, as the patient was prescribed an eOCP, a clozapine concentration was obtained after reaching 150 mg at bedtime. This steady-state clozapine concentration was found to be 560 ng/mL, correlating with worsening sedation and constipation. Given ongoing side effects, clozapine was lowered to 100 mg at bedtime; however, ongoing intolerance ultimately led to clozapine discontinuation. This case highlights the potential interaction between clozapine and eOCP in a CYP1A2 and CYP2C19 rapid metabolizer, leading to clozapine intolerance and discontinuation. The concomitant use of clozapine and eOCPs should be undertaken judiciously.

Introduction Clozapine is the only antipsychotic approved for treatment-resistant schizophrenia, but without appropriate monitoring, it can be associated with potentially fatal outcomes. An International Adult Clozapine Titration Guideline categorizes patients into normal or slow metabolizers. Categorization provides clozapine titration schedules and recommends regular c-reactive protein (CRP) and clozapine concentration monitoring to reduce the risk of adverse drug reactions (ADRs). The impact of the guideline on clozapine ADRs has not been evaluated. Methods A retrospective chart review assessed clozapine titrations, laboratory monitoring, ADRs, and discontinuations for clozapine-naive adult inpatients at a single center from January 1, 2013, to June 1, 2022. Each patient’s cumulative weekly clozapine dosage was compared with their guideline recommended dosage to create a percent accordance. Linear logistic regression evaluated the relationship between titration speed and the presence of an ADR, while descriptive statistics analyzed laboratory monitoring. Results Forty-three patients were included, with the majority being White males with schizophrenia. An inverse relationship existed between the last inpatient week clozapine dose percent accordance and the probability of an ADR. Nonobese patients were less likely than obese patients to experience an ADR (odds ratio = 0.17; 95% CI, 0.03-0.99). CRP and clozapine concentration monitoring was suboptimal. Discussion Based on our small retrospective review of primarily White males, more aggressive clozapine titrations did not increase ADRs. Future studies with more diverse samples are needed and should focus on specific ADRs, which may have increased occurrence with rapid titrations. Obese patients were at higher risk of ADRs, correlating with the guideline-recommended slower titrations for these patients.

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. [ABSTRACT FROM AUTHOR]

Objective: This pharmacovigilance study evaluated the profile of clozapine-related adverse events by region using the Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: We categorized each case into five regions (America, Europe/West Asia, Oceania, Asia, and Africa) based on the reporting country information in the FAERS database. The number of clozapine-related adverse events reported in each region was aggregated according to the preferred term (PT) and the Standardized Medical Dictionary for Regulatory Activities (MedDRA) Query (SMQ). Results: A total of 101,872 clozapine-related adverse events were registered in the FAERS database. In America and Europe, leukocyte or neutrophil count abnormalities accounted for half of the top 10 PTs by relative reporting rate. However, Asia had higher relative reporting rates of pyrexia and salivary hypersecretion (13.91% and 10.85%, respectively). Regarding the SMQ, the relative reporting rates of infective pneumonia, convulsions, extrapyramidal syndrome, gastrointestinal obstruction, and hyperglycaemia/new onset diabetes mellitus were higher in Asia than in other regions (5.26%, 9.72%, 12.65%, 5.13%, and 8.26%, respectively), with significant differences even after adjusting for confounding factors using multivariate logistic regression analysis. Conclusion: Spontaneous reports of adverse events associated with clozapine show regional disparities, particularly in Asia, where concentration-dependent adverse events are more frequently reported. However, the spontaneous reporting system has several limitations, requiring further research for validation. [ABSTRACT FROM AUTHOR]

Accurately measuring drug and its release kinetics in both in vitro and in vivo environments is crucial for enhancing therapeutic effectiveness while minimizing potential side effects. Nevertheless, the real-time visualization of drug release from microspheres to monitor potential overdoses remains a challenge. The primary objective of this investigation was to employ fluorescence imaging for the real-time monitoring of drug release from microspheres in vitro, thereby simplifying the laborious analysis associated with the detection of drug release. Two distinct varieties of microspheres were fabricated, each encapsulating different drugs within PLGA polymers. Cy5 was selected as the donor, and Cy7 was selected as the acceptor for visualization and quantification of the facilitated microsphere drug release through the application of the fluorescence resonance energy transfer (FRET) principle. The findings from the in vitro experiments indicate a correlation between the FRET fluorescence alterations and the drug release profiles of the microspheres. [ABSTRACT FROM AUTHOR]

Purpose: Examine the alterations in antipsychotic concentrations following coronavirus disease-2019 (COVID-19) infection among hospitalized patients with mental disorders and conduct an analysis of the factors influencing these changes. Methods: Data were collected from inpatients at Beijing Huilongguan Hospital between December 12, 2022, and January 11, 2023, pre- and post-COVID-19. Based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, 329 inpatients with mental disorders were included (3 with incomplete data excluded). Primary outcomes assessed changes in antipsychotic concentrations pre- and post-COVID-19, while secondary outcomes examined factors linked to concentration increases and antipsychotic dose adjustments. Results: Clozapine (P < 0.001), aripiprazole (P < 0.001), quetiapine (P = 0.005), olanzapine (P < 0.001), risperidone (P < 0.001), and paliperidone (P < 0.001) concentrations increased post-COVID-19 in patients with mental disorders. Notably, clozapine concentration surpassing pre-infection levels was highest. Clozapine users were more likely to adjust their dose (50.4%) compared to olanzapine (17.5%) and other antipsychotics. Moreover, traditional Chinese patent medicines and antibiotics during COVID-19 infection were associated with antipsychotic reduction or withdrawal (OR = 2.06, P = 0.0247; OR = 7.53, P = 0.0024, respectively). Conclusion: Antipsychotic concentrations in hospitalized patients with mental disorders increased after COVID-19 infection, that may be related not only to COVID-19, but also to the use of Chinese patent medicines during infection. The pre-infection concentration and types of antipsychotics, patient's gender, and combination of traditional Chinese medicine or antibiotics, were factors found to correlate with increased drug concentrations and necessitate dose adjustments. [ABSTRACT FROM AUTHOR]

Smoking cessation in patients treated with clozapine might lead to elevated plasma concentrations and severe side effects. This case report investigated the trajectory of clozapine plasma concentrations over time after smoking cessation in a Chinese inpatient with schizophrenia. This case report delineates the temporal response of plasma clozapine concentrations and dose-corrected clozapine plasma concentrations in a 33-year-old inpatient with schizophrenia who had a substantial smoking history and ceased smoking abruptly during dose titration. This case report presents a sudden increase in plasma clozapine concentrations and dose-corrected plasma clozapine concentrations after smoking cessation, followed by a rapid decline in dose-corrected plasma clozapine concentrations during the initial 2 weeks and a return to precessation levels approximately 1 month later. The findings suggest that clinicians and pharmacists should adjust clozapine dosage in accordance with changes in smoking status, taking into consideration the temporal effects. Postsmoking cessation adjustments to clozapine dosage should be coupled with therapeutic drug monitoring, especially for patients with heavy smoking habits. Moreover, the advice of the clinical pharmacist should be considered in complex cases to ensure safe use of clozapine. [ABSTRACT FROM AUTHOR]

The article presents questions and answers related to adjunctive agents for suboptimal response to clozapine, combination of clozapine and a first-generation antipsychotic for treatment of neuroleptic malignant syndrome, management of the adverse effects of clozapine, and changes in the frequency of complete blood count monitoring and absolute neutrophil count.

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

Schizophrenia is a mental illness characterized by disturbances in the perception of reality, thinking, emotions, and social functioning. This significantly impacts the quality of life of patients and leads to long-term disability. Despite advances in understanding its pathogenesis and treatment, schizophrenia remains a clinical challenge, especially due to the diversity of its symptoms and the complexity of its mechanisms. Schizophrenia is associated with abnormal functioning of the dopaminergic system, disturbances in glutamatergic neurotransmission, and oxidative stress in the brain. In recent years, there has been increasing interest in optimizing the treatment of mental disorders. The potential use of ascorbic acid, or vitamin C, in the therapy of schizophrenia could bring substantial benefits to patients. Ascorbic acid exhibits antioxidant and neuroprotective properties, suggesting its potential efficacy in reducing brain oxidative stress and improving neurotransmission. Additionally, there have been reports of its positive effects on psychotic symptoms and its potential in reducing the side effects of antipsychotic drugs. In this review article, we present the current state of knowledge on the potential use of ascorbic acid in the treatment of schizophrenia as an adjunct to standard pharmacological therapy. We analyze existing clinical studies and the mechanisms of action of vitamin C, suggesting its promising role as an adjunctive therapy in the treatment of schizophrenia. These insights, though not yet widely disseminated, may be significant for the further development of therapeutic strategies for this mental illness. [ABSTRACT FROM AUTHOR]

Clozapine is an antipsychotic drug whose accumulation in white cells can sometimes prove toxic; understanding the transporters and alleles responsible is thus highly desirable. We used a strategy in which a yeast (Saccharomyces cerevisiae) CRISPR-Cas9 knock-out library was exposed to cytotoxic concentrations of clozapine to determine those transporters whose absence made it more resistant; we also recognised the structural similarity of the fluorescent dye safranin O (also known as safranin T) to clozapine, allowing it to be used as a surrogate marker. Strains lacking the mitochondrial ABC transporter MDL1 (encoded by YLR188W) showed substantial resistance to clozapine. MDL1 overexpression also conferred extra sensitivity to clozapine and admitted a massive increase in the cellular and mitochondrial uptake of safranin O, as determined using flow cytometry and microscopically. Yeast lacking mitochondria showed no such unusual accumulation. Mitochondrial MDL1 is thus the main means of accumulation of clozapine in S. cerevisiae. The closest human homologue of S. cerevisiae MDL1 is ABCB10. [ABSTRACT FROM AUTHOR]

Background: Catatonia has been reported with withdrawal of medications. Among the various psychotropics, clozapine has been implicated to cause catatonia when abruptly withdrawn. The data regarding clozapine withdrawal catatonia are scarce and are mostly available in the form of case reports and series. Aim: In this case series, we present three cases of clozapine withdrawal catatonia and review the available literature on clozapine withdrawal clozapine. Results: All the three patients developed catatonia within 48 h to 14 days of stoppage of clozapine in the doses of 100-350 mg/day. Two of the patients experiencing clozapine withdrawal improved with reinstitution of clozapine in the previous doses along with benzodiazepines. However, one patient additionally required electroconvulsive therapy (ECT) for the management of withdrawal catatonia. A review of literature showed that clozapine withdrawal catatonia has male preponderance and has been reported with withdrawal of clozapine doses of 50-550 mg/day. The catatonia usually starts in 48 h to 2 weeks of stopping clozapine. Available literature suggests that most of the patients have been managed with restarting of clozapine, along with lorazepam and occasional patients require ECT. Conclusions: To conclude our case series and the available review of literature suggests that sudden discontinuation of clozapine can lead to withdrawal catatonia. Our cases also highlight the importance of reviewing treatment history, especially of abrupt discontinuation of clozapine when a patient on clozapine present with catatonia. This can be very helpful in deciding about further management. [ABSTRACT FROM AUTHOR]

Introduction: Currently, 21 million people live with the disease, mostly in low to middle-income countries. We aimed to assess the survival of patients with schizophrenia using clozapine compared with non-clozapine atypical antipsychotics provided by the Brazilian National Health System using realworld data. Materials and methods: This is an open retrospective cohort study of patients diagnosed with schizophrenia to whom atypical antipsychotics were dispensed by the Brazilian National Health System between 2000 and 2015, based on deterministic-probabilistic pairing of administrative data records. The Kaplan-Meier method was used to estimate the cumulative probability of survival and the Cox proportional hazards model was adjusted to assess the risk factors for survival via the hazard ratio (HR). Result: Participants were 375,352 adults with schizophrenia, with an overall survival rate of 76.0% (95%CI 75.0-76.0) at the end of the cohort. Multivariate analysis indicated a greater risk of death for men (HR=1.30; 95%CI 1.27-1.32), older adults (HR=17.05; 95%CI 16.52-17.60), and in the Southeast region of Brazil (HR=1.20; 95%CI 1.17-1.23). Patients who used non-clozapine atypical antipsychotics had a 21% greater risk of death when compared to those taking clozapine (HR=1.21; 95%CI 1.14-1.29). Additionally, a history of hospitalization for pneumonia (HR=2.17; 95%CI 2.11-2.23) was the main clinical variable associated with increased risk of death, followed by hospitalization for lung cancer (HR=1.82; 95%CI 1.58-2.08), cardiovascular diseases (HR=1.44; 95%CI 1.40-1.49) and any type of neoplasia (HR=1.29; 95%CI 1.19-1.40). Discussion: This is the first published Brazilian cohort study that evaluated survival in people with schizophrenia, highlighting the impact of atypical antipsychotics. In this real-world analysis, the use of clozapine had a protective effect on survival when compared to olanzapine, risperidone, quetiapine, and ziprasidone. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]