Purpose/Background: 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). Methods: US reports to the World Health Organization's global pharmacovigilance database were analyzed from clozapine's introduction to January 15, 2023. Findings/Results: 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. Implications/Conclusions: 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.

Purpose/Background: Clozapine was approved in the United States (US) using 1989 regulations and knowledge. After 30 years, many sections of the US package insert (PI) are outdated. Methods: We comprehensively reviewed the literature to propose PI updates. We present the information in 2 articles. In Part I, we focus on basic pharmacology based on 407 relevant articles. Part II focuses on clinical aspects and pharmacovigilance. Findings/Results: Based on more recent expectations of Food and Drug Administration regulations, we reviewed clozapine basic pharmacology including the following: 1) clearance, 2) pharmacokinetics and pharmacodynamics, and 3) monitoring tools. We identified 9 major problems in the basic pharmacological sections of the PI including the following: 1) in vivo studies indicate that clozapine is dependent on CYP1A2 for its metabolism, 2) the minor role of CYP2D6 in clozapine metabolism requires removing the PI recommendation to lower clozapine doses in CYP2D6 poor metabolizers, 3) in nontoxic concentrations CYP3A4 has a minor role in clozapine metabolism and potent CYP3A4 inhibitors lack clinically relevant effects, 4) several drug-drug interactions need to be updated based on recent literature, 5) systemic inflammation may decrease clozapine metabolism and increase the risk of clozapine intoxication, 6) obesity may decrease clozapine metabolism, 7) patients of Asian and Indigenous American ancestry need lower clozapine doses, 8) personalized titration and c-reactive protein monitoring should be considered until prospective studies are available, and 9) the half-life section needs to be modified to acknowledge that single dosing at night is frequent in the US. Implications/Conclusions: An improvement in the US clozapine PI may lead to improvement in PIs worldwide.

Since the mid-1950s discovery of the first effective antipsychotic medications (APM), we have only been able to improve the tolerability but not the overall efficacy of currently available APMs, as reflected by effectiveness trials in Europe and the United States. This inability to develop more effective APMs is attributable to multiple factors, including failure to create and use assessment tools to assess core symptom domains in schizophrenia, move beyond the dopaminergic hypothesis and to develop “me too” drugs, imposing ill-defined research domain criteria, and lacking federal funding for clinical trials. The classification of APMs is also confusing, including second-generation, partial agonists, and multimodal APMs in the same class of APMs, despite significant differences in their mechanisms of action. Other factors stagnating drug development include inadequate sample sizes to address heterogeneity, lack of statistical measures correlating with clinical significance, using the atheoretical basis of psychiatric diagnoses, failure to control placebo response, and high cost of newer and perhaps more tolerable APMs. Furthermore, there has been a failure to develop early predictors of antipsychotic response and various tools to optimize an APM response. Finally, some mental health providers are also responsible for the suboptimal use of APMs, by using excessive maintenance doses, often with irrational polypharmacy, further compromising effectiveness and medication adherence. However, some bright spots in antipsychotic development include improved tolerability of APMs and long-acting injectables to address the high prevalence of medication nonadherence. This review critically reviews 70 years of antipsychotic development, the reasons behind the failure to develop more effective APMs, and suggestions for future direction.

Reports of COVID-related psychosis in young patients are scarce. Here, the authors compare 2 published cases of adolescents who developed psychosis in the context of COVID complications with a new case of an adolescent who developed post-COVID psychosis.

There is growing research interest in learning the genetic basis of response and adverse effects with psychotropic medications, including antipsychotic drugs. However, the clinical utility of information from genetic studies is compromised by their controversial results, primarily due to relatively small effect and sample sizes. Clinical, demographic, and environmental differences in patient cohorts further explain the lack of consistent results from these genetic studies. Furthermore, the availability of psychopharmacological expertise in interpreting clinically meaningful results from genetic assays has been a challenge, one that often results in suboptimal use of genetic testing in clinical practice. These limitations explain the difficulties in the translation of psychopharmacological research in pharmacogenetics and pharmacogenomics from bench to bedside to manage increasingly treatment-refractory psychiatric disorders, especially schizophrenia. Although these shortcomings question the utility of genetic testing in the general population, the commercially available genetic assays are being increasingly utilized to optimize the effectiveness of psychotropic medications in the treatment-refractory patient population, including schizophrenia. In this context, patients with treatment-refractory schizophrenia are among of the most vulnerable patients to be exposed to the debilitating adverse effects from often irrational and high-dose antipsychotic polypharmacy without clinically meaningful benefits. The primary objective of this comprehensive review is to analyze and interpret replicated findings from the genetic studies to identify specific genetic biomarkers that could be utilized to enhance antipsychotic efficacy and tolerability in the treatment-refractory schizophrenia population.

Although valproic acid (VPA) induces the metabolism of multiple other drugs, the clinical reports of VPA autoinduction are rare. A comprehensive literature search yielded only one published case series, which provided the rationale to conduct a review of the published cases along with a new case of VPA autoinduction. Although there may be myriad of reasons for lack of published cases of VPA autoinduction, potential underreporting may be one of the core reasons. Lack of understanding into the highly complex metabolism of VPA may also make it difficult to recognize and report VPA autoinduction. However, it is important to mention that in addition to autoinduction increased elimination of VPA may be mediated by several pharmacokinetic (PK) factors, such as drug interactions, genetic polymorphisms of metabolic enzymes, and protein displacement reactions. As VPA is metabolized by multiple metabolic pathways, the risk for drug interactions is relatively high. There is also a growing evidence for high genetic inducibility of some enzymes involved in VPA metabolism. Protein displacement reactions with VPA increase the biologically active and readily metabolizable free fraction and pose a diagnostic challenge as they are usually not requested by most clinicians. Thus, monitoring of free fraction with total VPA levels may prevent clinically serious outcomes and optimize VPA treatment in clinically challenging patients. This case-based review compares the clinical data from three published cases and a new case of VPA autoinduction to enhance clinicians' awareness of this relatively rare but clinically relevant phenomenon along with a discussion of potential underlying mechanisms.