Clozapine is the only approved medication for treatment-resistant schizophrenia which is equally prevalent on male and female patients. However, studies showed that clozapine is less frequently prescribed to women compared to men.

This study aims to investigate the role of sex in clozapine prescription, taking into account potential sociodemographic and clinical confounding factors.

Patients aged 18-65, with a diagnosis of schizophrenia spectrum disorders were selected from the 46,222 individuals who had access to outpatient psychiatric services of Ferrara, Italy, from 1991 to 2021. Sociodemographic and clinical information including clozapine prescription timing and dosage were analyzed.

Among 3901 patients with a schizophrenia spectrum disorders, those who had been prescribed clozapine (189, 4.8%) were significantly more likely to be male (57%), younger at admission to care (30 vs 39.7 years old) and with a schizophrenia diagnosis (77% vs. 49%) compared to those without clozapine prescription. Within patients with a diagnosis of schizophrenia (n = 145), women (n = 60, 41%), compared to men, experienced twice the delay to be prescribed clozapine, both from the prescription of the first antipsychotic to clozapine (mean 1265.7 vs 746.6 days in men, p = 0.03) and from the prescription of the third antipsychotic to clozapine (mean 1214.5 vs 725.8 days in men, p = 0.03). Also, within those diagnosed with schizophrenia, women with a diagnosis of schizophrenia were less likely than men to be prescribed clozapine after the first and third antipsychotic considering both crude (HR = 0.66, p = 0.07; HR = 0.53, p = 0.025) and adjusted hazard ratios (HR = 0.65, p = 0.07; HR = 0.51, p = 0.021).

This study showed disparities based on sex in both the use and timing of clozapine, which disadvantages women diagnosed with schizophrenia. Further interventions are needed to increase awareness of possible sex-based barriers to clozapine use in clinical practice, measurement of sources of gender specific bias, and quality improvement initiatives to continuously address challenges in providing adequate treatment to this vulnerable population.

Croatia has implemented anti-suicide measures due to its high suicide rates. Clozapine has anti-suicidal effects. Using the international database (VigiBase), we explored Croatia's unusual clozapine pharmacovigilance. First, we compared the United Kingdom (UK) with Croatia for clozapine adverse drug reactions (ADRs) and fatal outcomes from clozapine's introduction through January 15, 2023. If the UK is considered 1, and after adjusting for population, Croatia had much lower rates (1 vs. 0.08 for clozapine ADR reports, 1 vs. 0.02 for fatal outcomes and 1 vs. 0.14 for percentage of clozapine reports out of all drug reports). Through 2023, the UK had 52,252 ADR reports and 6,567 fatal outcomes from clozapine-treated patients vs. Croatia with 395 reports and 6 fatal outcomes. The Croatian pharmacovigilance agency (and most national agencies) needs to learn from the UK's agency to better report clozapine ADRs. Second, we analyze suicide behaviors in Croatian clozapine-treated patients reported to VigiBase. Through 2023 the UK reported 537 clozapine-treated patients with at least 1 suicidal behavior versus 95 from Croatia. After adjusting for population, the UK reported a much smaller number of reports of suicidal behavior than Croatia (1 vs. 2.73). This overreporting by Croatian physicians may be a sign of the success of Croatia's anti-suicide measures. The percentage of fatal outcomes in 77 Croatian patients with an intentional overdose was 1.3 % (1/77) vs. 16.8 % in 411 non-Croatian patients, but this is possibly contaminated by early reporting (patients might die after the report). Longitudinal studies of clozapine overdoses in Croatia are needed.

This study explored a new method for nursing staff's work with collaborative violence risk management, to be used in forensic psychiatric inpatient settings. The components of the method, the background to, and the rationale for collaborative risk management in forensic mental health settings were outlined. An inductive content analysis of 50 of these collaborative violence risk management plans was conducted. The focus of the analysis was the types and frequencies of early warning signs for aggression, risk factors/scenarios for aggression, risk management strategies, and responsibilities devised to address that risk as well as goals agreed upon between patients and staff concerning that risk. The results showed that patients and staff could generate collaborative violence risk management plans which displayed a content with a high degree of face validity and content validity when comparing the content of the plans to previous literature on violence risk assessment and management in forensic mental health settings. Although collaborative work on violence risk and violence risk management poses several challenges within forensic psychiatric contexts, the results showed that these approaches hold some promise in such settings - focusing on risk reduction through goal-oriented collaboration between patient and staff - and are worthy of further development and investigation.

This is the second part of a 2-part article that proposes improving the United States (US) clozapine package insert. Part II focuses on fatal outcomes and the 5 boxed warnings, 4 specifically for clozapine: severe neutropenia, seizure, orthostatic hypotension and myocarditis, and 1 for all antipsychotics (elderly with dementia).

US reports to the World Health Organization's global pharmacovigilance database were analyzed from clozapine's introduction to January 15, 2023.

The US was the top reporter worldwide for clozapine with 56,003 reports and 9587 associated fatal outcomes. The 4 clozapine boxed warnings were associated with 534 fatal outcomes (218 with severe neutropenia, 131 with seizures, 125 with orthostasis, 36 with myocarditis, 24 with cardiomyopathy, and 0 with mitral valve prolapse). With no boxed warnings, pneumonia was associated with 674 fatal outcomes and increased white blood cell count (a sign of infection) with 596 fatal outcomes. After considering overlaps, pneumonia and increases in white blood cell count explained 900 fatalities, or 9.4% of 9587 fatal outcomes. The Food and Drug Administration continues to focus on severe neutropenia which was associated with only 218 or 2.3% of fatal outcomes, whereas 97.7% of fatal outcomes reported in US clozapine-treated patients had another cause.

To help prevent future deaths in clozapine-treated patients, the clozapine package insert should focus on fatal outcomes during infections. Part II offers detailed solutions regarding current boxed warnings and lack of a warning for pneumonia and other infections. The Supplementary Material includes letters of support from 124 non-US clozapine experts from 44 countries/regions who support Parts I and II.

Psychopharmacotherapy plays an important role in the treatment of mentally disordered offenders (MDOs) with schizophrenia spectrum disorders. However, there have been few large-scale reports from multiple forensic psychiatric wards. This study aimed to clarify the current state of antipsychotic medications for MDOs with schizophrenia spectrum disorders in Japanese forensic psychiatric wards.

Medical information, including age, sex, psychiatric diagnosis, index offense, seclusion or restraint experience during hospitalization, and medication for patients discharged from 32 forensic wards nationwide between September 1, 2019 and December 31, 2021 was provided by the Database Scientific Utilization Project of Japanese forensic psychiatric wards. We analyzed the data of MDOs with schizophrenia spectrum disorders who were prescribed psychotropic medications at the time of discharge, especially focusing on comparing differences between the three groups (clozapine, long-acting injection (LAI), and other medications).

A total of 362 MDOs with schizophrenia spectrum disorders were prescribed psychotropic medications at discharge. The prescription rates of clozapine and LAI were 23.2% and 24.9%, respectively. Additionally, the rate of antipsychotic polypharmacy was 37.8%. Among the three groups, the clozapine group had the highest rate of seclusion experience (46.4%), a long mean length of hospitalization (1758 days), and the lowest rate of antipsychotic polypharmacy (4.8%). Olanzapine was the most commonly prescribed antipsychotic medication.

This study revealed the current state of antipsychotic medications for MDOs admitted to forensic psychiatric wards in Japan. Future studies are needed to clarify the relevance of antipsychotic medications in the prognosis of MDOs.

From schoolyard fights to international conflicts, aggression is an enigmatic force that has shaped human behaviour and social dynamics throughout human history. It is a phenomenon as old as humanity itself, but its complexity continues to confuse and fascinate us alike. Whether it is the tension that boils in a heated argument or the explosive violence of warfare, aggression permeates our lives in subtle and overt ways. This paper analyses forms of aggression, some theories that explain aggression in humans, especially in youth, but the most emphasis is placed on neurobiological changes in brain structures associated with aggressiveness. Special attention has been paid to parenting as a factor in the occurrence/overcoming of aggression in children. Finally, some therapeutic guidelines for overcoming this negative phenomenon are enumerated.

The use of network pharmacology and blood metabolomics to study the pathogenesis of violent aggression in patients with schizophrenia and the related drug mechanisms of action provides new directions for reducing the risk of violent aggression and optimizing treatment plans.

To explore the metabolic regulatory mechanism of olanzapine in treating patients with schizophrenia with a moderate to high risk of violent aggression.

Metabolomic technology was used to screen differentially abundant metabolites in patients with schizophrenia with a moderate to high risk of violent aggression before and after olanzapine treatment, and the related metabolic pathways were identified. Network pharmacology was used to establish protein-protein interaction networks of the core targets of olanzapine. Gene Ontology functional analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were subsequently performed.

Compared with the healthy group, the patients with schizophrenia group presented significant changes in the levels of 24 metabolites related to the disruption of 9 metabolic pathways, among which the key pathways were the alanine, aspartate and glutamate metabolism and arginine biosynthesis pathways. After treatment with olanzapine, the levels of 10 differentially abundant metabolites were significantly reversed in patients with schizophrenia. Olanzapine effectively regulated six metabolic pathways, among which the key pathways were alanine, aspartate and glutamate metabolism and arginine biosynthesis pathways. Ten core targets of olanzapine were involved in several key pathways.

The metabolic pathways of alanine, aspartate, and glutamate metabolism and arginine biosynthesis are the key pathways involved in olanzapine treatment for aggressive schizophrenia.

Schizophrenia is a highly heterogenous disorder with substantial interindividual variation in how the illness is experienced and how it presents clinically. The disorder is composed of primary symptom clusters-positive symptoms, negative symptoms, disorganization, neurocognitive deficits, and social cognitive impairments. These, along with duration, severity, and excluding other possible etiologies, comprise the diagnostic criteria for the disorder outlined in the two commonly used diagnostic classification systems-the Diagnostic Statistical Manual of Mental Disorders, Fifth Edition, Text Revision and the International Classification of Diseases, 11th Revision. These primary symptoms as well as accessory symptoms (mood disturbances, anxiety, violence) and comorbidities (substance use, suicidality) bear upon each other to varying degrees and impact functional outcomes. The following review presents two patient cases illustrating the clinical heterogeneity of schizophrenia, the natural history of the illness and diagnosis, followed by the current understanding of the primary symptom clusters, accessory symptoms, and comorbidities. In addition to noting symptom prevalence, onset, and change over time, attention is paid to the impact of symptoms on functional outcome.

Antipsychotics effective for schizophrenia approved prior to 2024 shared the common mechanism of postsynaptic dopamine D2 receptor antagonism or partial agonism. Positive psychosis symptoms correlate with excessive presynaptic dopamine turnover and release, yet this postsynaptic mechanism improved positive symptoms only in some patients, and with concomitant risk for off-target motor and endocrine adverse effects; moreover, these agents showed no benefit for negative symptoms and cognitive dysfunction. The sole exception was data supporting cariprazine's superiority to risperidone for negative symptoms. The muscarinic M1/M4 agonist xanomeline was approved in September 2024 and represents the first of a new antipsychotic class. This novel mechanism improves positive symptoms by reducing presynaptic dopamine release. Xanomeline also lacks any D2 receptor affinity and is not associated with motor or endocrine side effects. Of importance, xanomeline treated patients with higher baseline levels of cognitive dysfunction in clinical trials data saw cognitive improvement, a finding likely related to stimulation of muscarinic M1 receptors. Treatment resistance is seen in one-third of schizophrenia patients. These individuals do not have dopamine dysfunction underlying their positive symptoms, and therefore show limited response to antipsychotics that target dopamine neurotransmission. Clozapine remains the only medication with proven efficacy for resistant schizophrenia, and with unique benefits for persistent impulsive aggression and suicidality. New molecules are being studied to address the array of positive, negative and cognitive symptoms of schizophrenia; however, until their approval, clinicians must be familiar with currently available agents and be adept at prescribing clozapine.

We aimed to synthesize the information on the risks and benefits of clozapine prescription for resistant challenging behavior in persons with neurodevelopmental disorders.

Articles were identified with MEDLINE, Web of Sciences, and PsycINFO search from inception through January 2024. The review was restricted to persons with intellectual disability (ID) and/or autism spectrum disorder (ASD) without comorbid psychotic or affective disorder. Data were synthesized narratively.

We identified 24 articles (13 case reports, eight chart studies, two controlled studies, one pharmaco-epidemiological study) including 296 patients with ID (n = 222) or ASD (n = 74) (10% aged ≤ 18 years). After clozapine initiation, a decreased frequency of challenging behavior persisting over time was reported in most participants included in clinical studies, and a significant reduction in the number of admissions in the population-based two-year mirror-image study. Adverse drug reactions were those commonly observed with clozapine, i.e. constipation, sedation, and weight gain.

Since only four participants were included in the controlled studies, the benefits of clozapine in neurodevelopmental disorders are supported by a body of evidence exclusively drawn from observational studies. Further studies are required to clarify the indications of clozapine with respect to the unmet need induced by resistant challenging behavior.

PROSPERO database registration number CRD42024522343.

In the United States, clozapine was first approved for treatment-resistant schizophrenia and then for suicidality in schizophrenia psychoses. Systematic reviews support clozapine's anti-suicidal effect, but the forensic literature stresses its lethality during overdoses.

Clozapine reports to the international pharmacovigilance database (VigiBase) were analyzed for suicidal ideation, suicide attempts, intentional overdose, and completed suicides from introduction to 1 January 2024. VigiBase uses the information component (IC) as a disproportionality analysis.

The clozapine ICs (range: other antipsychotics) were: 1) suicidal ideation IC = 0.570 with IC025 = 0.454 to IC975 = 0.680 (IC = 3.568 for aripiprazole and 1.729 for risperidone), 2) suicide attempt IC = 1.428 with IC025 = 1.323 to IC975 = 1.529 (IC = 4.150 for quetiapine and 2.968 for risperidone), 3) intentional overdose: IC = 0.995 with IC025 = 0.864 to IC975 = 1.120 (IC = 4.080 for quetiapine and 1.957 for aripiprazole), and 4) completed suicide IC = 1.133 with IC025 = 1.026 to IC975 = 1.235 (IC = 4.648 for quetiapine and 2.160 for risperidone). In summary, all clozapine ICs were significantly lower. We found 2391 clozapine-treated patients on the suicidality spectrum (627 cases with suicidal ideation, 752 with suicide attempt, 488 with intentional overdose, and 731 with completed suicide) but many were taking other antipsychotics. The most frequent reporting countries were the United States, the United Kingdom, and Croatia.

This pharmacovigilance study, with all its inherent limitations, provides independent proof, not overlapping with prior literature, that clozapine may have specific strong anti-suicidal effects that do not appear to be present in other antipsychotics. Further VigiBase studies are needed to compare the lethality of an intentional overdose of clozapine (14.3%) with other antipsychotics.

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.