Clinical considerations and pitfalls in the use of depot antipsychotics.

Long-acting injectable antipsychotics (LAI) is a frequently used treatment modality which has advantages over oral antipsychotics regarding hospitalization or relapse prevention. However, the pharmacokinetic properties of LAI greatly differ from oral antipsychotics. This necessitates an increased knowledge about LAI among clinicians, especially when commencing treatment, changing doses and discontinuing treatment. In this review, we summarize an array of clinically important characteristics of LAI and give a conceptual framework for understanding the pharmacokinetics of LAI.

Metabolic Syndrome in people treated with Antipsychotics (RISKMet): A multimethod study protocol investigating genetic, behavioural, and environmental risk factors.

INTRODUCTION: The RISKMet project aims to: (1) identify risk factors for metabolic syndrome (MetS) by comparing patients with and without MetS; (2) characterise patients treated with second-generation antipsychotics (SGAs) about MetS diagnosis; (3) study behavioural patterns, including physical activity (PA) and dietary habits, in patients and healthy individuals using a prospective cohort design. METHOD: The RISKMet project investigates MetS in individuals treated with SGAs, focusing on both adult and paediatric populations. The study utilizes a case-control design to examine potential risk factors for MetS, categorizing participants as MetS+ considered as "Cases" and MetS- considered as "Controls" matched by sex and age. The evaluation of factors such as MetS, lifestyle habits, and environmental influences is conducted at two time points, T0 and T3, after 3 months. Subsequently, the project aims to assess body parameters, including physical examinations, and blood, and stool sample collection, to evaluate metabolic markers and the impact of SGAs. The analysis includes pharmacological treatment data and genetic variability. Behavioural markers related to lifestyle, eating behaviour, PA, and mood are assessed at both T0 and T3 using interviews, accelerometers, and a mobile app. The study aims to improve mental and physical well-being in SGA-treated individuals, establish a biobank for MetS research, build an evidence base for physical health programs, and develop preventive strategies for SGA-related comorbidities. CONCLUSIONS: This project innovates MetS monitoring in psychiatry by using intensive digital phenotyping, identifying biochemical markers, assessing familial risks, and including genetically similar healthy controls. STUDY REGISTRATION NUMBER: ISRCTN18419418 at www.isrctn.com.

Long-term persistence of the risk of agranulocytosis with clozapine compared with other antipsychotics: a nationwide cohort and case-control study in Finland.

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.

Olanzapine-induced cardiomyopathy: A mimicker of obesity cardiomyopathy?

Olanzapine, an atypical antipsychotic medication, has gained prominence in the treatment of schizophrenia and related psychotic disorders due to its effectiveness and perceived safety profile. However, emerging evidence suggests a potential link between olanzapine use and adverse cardiovascular effects, including cardiomyopathy. This narrative review explores the mechanisms, clinical implications, and management strategies associated with olanzapine-induced cardiomyopathy. A comprehensive review of the literature was conducted to investigate the relationship between olanzapine and cardiomyopathy. The search included epidemiological studies, clinical case reports, and mechanistic research focusing on the pathophysiology of olanzapine-induced cardiomyopathy. The review also examined treatment strategies for managing this potential complication. Olanzapine-induced cardiomyopathy is hypothesized to be associated with metabolic disturbances and receptor antagonism. The metabolic effects of olanzapine, such as weight gain, insulin resistance, and dyslipidemia, share similarities with obesity-related cardiomyopathy. Additionally, olanzapine's antagonism of certain receptors may contribute to cardiovascular stress. The review highlighted that patients with new-onset heart failure and significant weight gain while on olanzapine should be closely monitored for signs of cardiomyopathy. Early detection and prompt withdrawal of olanzapine, along with initiation of goal-directed medical therapy, are crucial for mitigating this potentially life-threatening condition. The relationship between olanzapine and cardiomyopathy is complex and not yet fully understood. However, the potential for significant cardiovascular risk necessitates vigilance among healthcare providers. Early identification and management of olanzapine-induced cardiomyopathy can improve patient outcomes. Further research is needed to elucidate the precise mechanisms behind this adverse effect and to develop optimized treatment strategies for patients requiring antipsychotic therapy.

Brexpiprazole toxicity in a paediatric patient.

Brexpiprazole is a relatively new drug that has no published research or applications within the paediatric population. Brexpiprazole targets multiple receptors and can manifest as multisystem symptoms when ingested in supratherapeutic quantities. In this report, we discuss the case of a child in early childhood who presented with delayed neurological and cardiac symptoms 24 hours after accidental ingestion of brexpiprazole. Due to delayed onset, this case highlights that a high index of suspicion and prolonged observation are necessary to appropriately manage brexpiprazole overdose or accidental ingestion.

Impact of institutional quality improvement initiatives on metabolic monitoring in mental disorder in patients treated with antipsychotics: A meta-analysis of intervention studies.

Background: Compliance with guidelines regarding monitoring of metabolic adverse effects induced by antipsychotics has been consistently low. We characterised and evaluated the quality of institutional quality improvement (QI) interventions designed to address disparities between guidelines and real-world practices. Furthermore, we assessed the impact of these interventions on the screening and management of metabolic risks for inpatients receiving treatment with antipsychotic medications. Methods: We conducted a meta-analysis of institutional QI intervention studies aimed at improving antipsychotic-associated metabolic risk monitoring in hospitalised mental disease patients. Relevant studies were identified through searches conducted in the Embase and PubMed databases, as well as by reviewing previous reviews and meta-analyses. Quantitative analyses were performed, calculating odds ratios (ORs) and 95% confidence intervals (CIs) to assess the impact of QI programmes on guideline adherence in clinical practice. Results: We identified 12 intervention studies (n = 10 128 and n = 2667 patients in the pre-and post-intervention groups, respectively) and included them in our meta-analysis. QI interventions demonstrated effectiveness in bridging the guideline-practice gap in monitoring antipsychotic-induced metabolic adverse effects, as supported by the ORs and 95% CIs for post-intervention monitoring of plasma glucose, lipids, and blood pressure (BP) vs the pre-intervention period being OR = 6.90 (95% CI = 1.51-31.48), OR = 5.39 (95% CI = 4.01-7.24), and OR = 4.81 (95% CI = 1.23-18.79), respectively. Only 33.3% (4/12) of studies reported screening rates for all four metabolic parameters (plasma glucose, lipids, weight/body mass index (BMI), and BP). The median rates for metabolic screening of plasma glucose, lipids, and BP increased from 51.0-80.0%, 28.7-66.7%, and 91.7-95.8%, respectively. Up to 66.7% (8/12) of intervention studies lacked follow-up measures to treat or manage identified risks in hospitalised psychiatric patients, such as patient referrals, prescription of medications, and switching of antipsychotics. The odds of monitoring weight/BMI and glucose were greatest when QI programmes involved the participation of multidisciplinary health care professionals and patients, yielding OR = 3.35 (95% CI = 2.45-4.59) and OR = 57.51 (95% CI = 24.11-137.21), respectively. Conclusions: Institutional QI interventions were effective in enhancing monitoring practices in alignment with established guidelines for metabolic risk screening among hospitalised patients with mental disorders maintained on antipsychotic medications. Future institutional QI programmes should incorporate multidisciplinary strategies involving patient engagement and extend their focus beyond screening to incorporate follow-up risk management strategies once risks have been identified. Registration: PROSPERO CRD42023452138.

High circulating MIF levels indicate the association with atypical antipsychotic-induced adverse metabolic effects.

Atypical antipsychotics (AAPs) are primary medications for schizophrenia (SZ). However, their use is frequently associated with the development of adverse metabolic effects, and the mechanisms behind these negative effects remain inadequately elucidated. To investigate the role of macrophage migration inhibitory factor (MIF) in regulating antipsychotic-induced metabolic abnormalities, between 2017 and 2020, a cross-sectional study was conducted, involving 142 healthy individuals and 388 SZ patients undergoing treatment with either typical antipsychotic (TAP) or AAP medications. Symptoms of SZ patients were evaluated using the Positive and Negative Syndrome Scale (PANSS), and measurements of metabolic indices and plasma MIF levels were performed on all individuals. A significant increase in plasma MIF levels was observed in groups receiving five major AAP monotherapies in comparison to healthy controls (all p < 0.0001). There was no such increase shown in the group receiving TAP treatment (p > 0.05). Elevated plasma MIF levels displayed a notable correlation with insulin resistance (ß = 0.024, p = 0.020), as well as with the levels of triglycerides (ß = 0.019, p = 0.001) and total cholesterol (ß = 0.012, p = 0.038) in the groups receiving AAPs. However, while the TAP group also displayed certain metabolic dysfunction compared to healthy controls, no significant association was evident with plasma MIF levels (all p > 0.05). In conclusion, plasma MIF levels exhibit a distinctive correlation with metabolic abnormalities triggered by AAPs. Hence, there is potential for further development of MIF as a distinctive marker for monitoring adverse metabolic effects induced by AAPs in clinical settings.

Mortality risk and mood stabilizers in bipolar disorder: a propensity-score-weighted population-based cohort study in 2002-2018.

AIMS: Accumulating studies have assessed mortality risk associated with mood-stabilizers, the mainstay treatment for bipolar disorder (BD). However, existing data were mostly restricted to suicide risk, focused on lithium and valproate and rarely adequately adjusted for potential confounders. This study aimed to assess comparative mortality risk with all, natural and unnatural causes between lithium, valproate and three frequently prescribed second-generation antipsychotics (SGA), with adjustment for important confounders. METHODS: This population-based cohort study identified 8137 patients with first-diagnosed BD, who had exposed to lithium (n = 1028), valproate (n = 3580), olanzapine (n = 797), quetiapine (n = 1975) or risperidone (n = 757) between 2002 and 2018. Data were retrieved from territory-wide medical-record database of public healthcare services in Hong Kong. Propensity-score (PS)-weighting method was applied to optimize control for potential confounders including pre-existing chronic physical diseases, substance/alcohol use disorders and other psychotropic medications. PS-weighted Cox proportional-hazards regression was conducted to assess risk of all-, natural- and unnatural-cause mortality related to each mood-stabilizer, compared to lithium. Three sets of sensitivity analyses were conducted by restricting to patients with (i) length of cumulative exposure to specified mood-stabilizer ≥90 days and its medication possession ratio (MPR) ≥90%, (ii) MPR of specified mood-stabilizer ≥80% and MPR of other studied mood-stabilizers <20% and (iii) monotherapy. RESULTS: Incidence rates of all-cause mortality per 1000 person-years were 5.9 (95% confidence interval [CI]: 4.5-7.6), 8.4 (7.4-9.5), 11.1 (8.3-14.9), 7.4 (6.0-9.2) and 12.0 (9.3-15.6) for lithium-, valproate-, olanzapine-, quetiapine- and risperidone-treated groups, respectively. BD patients treated with olanzapine (PS-weighted hazard ratio = 2.07 [95% CI: 1.33-3.22]) and risperidone (1.66 [1.08-2.55]) had significantly higher all-cause mortality rate than lithium-treated group. Olanzapine was associated with increased risk of natural-cause mortality (3.04 [1.54-6.00]) and risperidone was related to elevated risk of unnatural-cause mortality (3.33 [1.62-6.86]), relative to lithium. The association between olanzapine and increased natural-cause mortality rate was consistently affirmed in sensitivity analyses. Relationship between risperidone and elevated unnatural-cause mortality became non-significant in sensitivity analyses restricted to low MPR in other mood-stabilizers and monotherapy. Valproate- and lithium-treated groups did not show significant differences in all-, natural- or unnatural-cause mortality risk. CONCLUSION: Our data showed that olanzapine and risperidone were associated with higher mortality risk than lithium, and further supported the clinical guidelines recommending lithium as the first-line mood-stabilizer for BD. Future research is required to further clarify comparative mortality risk associated with individual SGA agents to facilitate risk-benefit evaluation of alternative mood-stabilizers to minimize avoidable premature mortality in BD.

Antipsychotic Medication Continuation vs Taper and Discontinuation in Patients With Schizophrenia and Other Nonaffective Psychotic Disorders.

Schizophrenia is a major mental illness that is managed with long-term antipsychotic medication as a standard of care. Antipsychotic medications, however, are associated with many subjective and objective adverse effects. These adverse effects have driven the study of risk-mitigation strategies such as targeted intermittent therapy and dose reduction and drug discontinuation. Randomized controlled trials (RCTs) of these strategies have been synthesized in meta-analysis; both strategies have been associated with no functional benefits and with an increased risk of relapse. The RCTs, however, have been criticized because, in many, patients were abruptly switched to the target dose or too rapidly tapered, thereby predisposing the RCT to failure of the intervention. Two important RCTs examined gradual individualized dose reduction and discontinuation. One, conducted in first-episode psychosis patients who were free from positive symptoms for 6 months, found that, at 18-month follow-up, dose reduction was associated with a higher risk of relapse (number needed to harm [NNH] = 5) and with no functional benefits. However, after return to routine clinical care, at a 7-year follow-up, the dose reduction group had better functional outcomes and similar clinical outcomes relative to the maintenance treatment group. The other RCT, conducted in patients with relapsing psychosis, found that, at a 2-year follow-up, dose reduction was associated with a higher risk of relapse (NNH = 5) and with no improvements in social, cognitive, quality of life, satisfaction, and other domains. Many large nationwide observational studies have found that antipsychotic discontinuation by patients with first-episode psychosis and schizophrenia is associated with increased relapse, rehospitalization, suicide mortality, cardiovascular mortality, and all-cause mortality. There is also the ethical matter that attempts to identify the few who may benefit from antipsychotic dose reduction and discontinuation may compromise the health and stability of the many who require long-term maintenance treatment.

Association Between Clozapine Exposure and Risk of Hematologic Malignancies in Veterans With Schizophrenia.

Objective: The objective of this study was to examine the relationship between clozapine use and hematologic malignancies, using national administrative data from the United States Veterans Health Administration (VHA).Methods: This case-control study of veterans with schizophrenia matched cases with incident hematologic malignancy to 10 controls without hematologic malignancy by gender, age, and time since first schizophrenia diagnosis from October 1999, the beginning of VHA data archives, to June 2022. Schizophrenia diagnoses were identified using International Classification of Diseases, Ninth Revision, code 295.x and International Statistical Classification of Diseases, Tenth Revision, codes F20.x and F25.x from inpatient hospitalization and outpatient encounter data. Additional inclusion criteria were age 18-85 years, no prior history of malignancy, and at least 1 year of antipsychotic exposure. Clozapine exposure was assessed using 3 metrics: any exposure, years of exposure, and cumulative defined daily doses (DDD). Conditional multivariable logistic regression was used to adjust for nonmatched confounding variables.Results: A total of 2,306 veterans with schizophrenia were identified with an incident diagnosis of hematologic malignancy and matched to 23,043 controls. Any prior clozapine exposure was more commonly observed among cases (5.3%) than controls (4.1%) and was significantly different after adjustment (odds ratio [OR], 1.31; 95% CI, 1.08-1.60). Risk was dose-dependent, where cumulative clozapine exposures from 3,000 to 4,999 DDD (OR, 1.78; 95% CI, 1.13-2.79) and ≥5,000 DDD (OR, 1.81; 95% CI, 1.24-2.64) were significantly associated with malignancy risk. Similarly, clozapine exposure of 5 or more years was associated with malignancy risk (OR, 1.88; 95% CI, 1.43-2.47).Conclusion: Consistent with prior report, this study observed an increased risk of hematologic malignancy associated with clozapine exposure. These findings suggest patients receiving clozapine use, particularly those with long-term use, should be closely monitored for hematologic malignancy.

A review on side effect management of second-generation antipsychotics to treat schizophrenia: a drug safety perspective.

INTRODUCTION: Effective side effects management present a challenge in antipsychotic treatment with second-generation antipsychotics (SGAs). In recent years, most of the commonly used SGAs, except for clozapine, have been shown to differ only slightly in their effectiveness, but considerably regarding perceived side effects, safety profiles, and compatibility to preexisting medical conditions. AREAS COVERED: The current state of available evidence on side-effect management in SGA treatment of patients with schizophrenia spectrum disorders (SSD) is reviewed. In addition, current guideline recommendations are summarized, highlighting evidence gaps. EXPERT OPINION: SGA safety and side effects needs to be considered in treatment planning. Shared decision-making assistants (SDMA) can support patients, practitioners and relatives to orient their decisions toward avoiding side effects relevant to patients' adherence. Alongside general measures like psychosocial and psychotherapeutic care, switching to better tolerated SGAs can be considered a relatively safe strategy. By contrast, novel meta-analytical evidence emphasizes that dose reduction of SGAs can statistically increase the risk of relapse and other unfavorable outcomes. Further, depending on the type and severity of SGA-related side effects, specific treatments can be used to alleviate induced side effects (e.g. add-on metformin to reduce weight-gain). Finally, discontinuation should be reserved for acute emergencies.

The role of psychosis and clozapine load in excessive checking in treatment-resistant schizophrenia: longitudinal observational study.

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.

Influence of CYP2C19 and CYP2D6 on side effects of aripiprazole and risperidone: A systematic review.

Variability in hepatic cytochrome P450 (CYP) enzymes such as 2C19 and 2D6 may influence side-effect and efficacy outcomes for antipsychotics. Aripiprazole and risperidone are two commonly prescribed antipsychotics, metabolized primarily through CYP2D6. Here, we aimed to provide an overview of the effect of CYP2C19 and CYP2D6 on side-effects of aripiprazole and risperidone, and expand on existing literature by critically examining methodological issues associated with pharmacogenetic studies. A PRISMA compliant search of six electronic databases (Pubmed, PsychInfo, Embase, Central, Web of Science, and Google Scholar) identified pharmacogenetic studies on aripiprazole and risperidone. 2007 publications were first identified, of which 34 were included. Quality of literature was estimated using Newcastle-Ottowa Quality Assessment Scale (NOS) and revised Cochrane Risk of Bias tool. The average NOS score was 5.8 (range: 3-8) for risperidone literature and 5 for aripiprazole (range: 4-6). All RCTs on aripiprazole were rated as high risk of bias, and four out of six for risperidone literature. Study populations ranged from healthy volunteers to inpatient individuals in psychiatric units and included adult and pediatric samples. All n = 34 studies examined CYP2D6. Only one study genotyped for CYP2C19 and found a positive association with neurological side-effects of risperidone. Most studies did not report any relationship between CYP2D6 and any side-effect outcome. Heterogeneity between and within studies limited the ability to synthesize data and draw definitive conclusions. Studies lacked statistical power due to small sample size, selective genotyping methods, and study design. Large-scale randomized trials with multiple measurements, providing robust evidence on this topic, are suggested.

Antipsychotic medications and sleep problems in patients with schizophrenia.

BACKGROUND: Sleep problems are common and related to a worse quality of life in patients with schizophrenia. Almost all patients with schizophrenia use antipsychotic medications, which usually increase sleep. Still, the differences in subjective sleep outcomes between different antipsychotic medications are not entirely clear. METHODS: This study assessed 5466 patients with schizophrenia and is part of the nationwide Finnish SUPER study. We examined how the five most common antipsychotic medications (clozapine, olanzapine, quetiapine, aripiprazole, and risperidone) associate with questionnaire-based sleep problems in logistic regression analyses, including head-to-head analyses between different antipsychotic medications. The sleep problems were difficulties initiating sleep, early morning awakenings, fatigue, poor sleep quality, short (≤6 h) and long sleep duration (≥10 h). RESULTS: The average number of antipsychotic medications was 1.59 per patient. Clozapine was associated with long sleep duration (49.0 % of clozapine users vs 30.2 % of other patients, OR = 2.05, 95 % CI 1.83-2.30, p < .001). Olanzapine and risperidone were in head-to-head analyses associated with less sleep problems than patients using aripiprazole, quetiapine, or no antipsychotic medication. Aripiprazole and quetiapine were associated with more insomnia symptoms and poorer sleep quality. Patients without antipsychotic medications (N = 159) had poorer sleep quality than patients with antipsychotic use, and short sleep duration was common (21.5 % of patients not using antipsychotics vs 7.8 % of patients using antipsychotics, OR = 2.97, 95 % CI 1.98-4.44, p < .001). CONCLUSIONS: Prevalence of sleep problems is markedly related to the antipsychotic medication the patient uses. These findings underline the importance of considering and assessing sleep problems when treating schizophrenia patients with antipsychotics.

Clearing the Fog: A Review of Antipsychotics for Parkinson's-Related Hallucinations: A Focus on Pimavanserin, Quetiapine and Clozapine.

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.

Can Slow Personalized Titration Using C-Reactive Protein Monitoring Decrease the High Rates and Mortality of Clozapine-Associated Myocarditis Seen in Some Countries? A Call for Research.

PURPOSE/BACKGROUND: The hypothesis that slower personalized titration may prevent clozapine-associated myocarditis and decrease the disproportion incidence of 3% found in Australia was not described in a recent Australian article in this journal. METHODS: Six countries in addition to Australia have published information suggesting a similar incidence of clozapine-associated myocarditis. On September 19, 2023, PubMed searches were updated for articles from the United States, Korea, Japan, Canada, New Zealand, and Turkey. FINDINGS/RESULTS: An incidence of 3.5% (4/76) was found in a US hospital, but US experts were the first to propose that clozapine-associated myocarditis may be a hypersensitivity reaction associated with rapid titration and possibly preventable. Koreans and Japanese are of Asian ancestry and need lower minimum therapeutic doses for clozapine than patients of European ancestry. A 0.1% (2/1408) incidence of myocarditis during clozapine titration was found in a Korean hospital, but pneumonia incidence was 3.7% (52/1408). In 7 Japanese hospitals, 34% (37/110) of cases of clozapine-associated inflammation were found during faster titrations (based on the official Japanese titration) versus 13% (17/131) during slower titrations (based on the international titration guideline for average Asian patients). Recent limited studies from Canada, New Zealand, and Turkey suggest that slower personalized titration considering ancestry may help prevent clozapine-associated myocarditis. IMPLICATIONS/CONCLUSIONS: Other countries have very limited published data on clozapine-associated myocarditis. Based on a recent Australian case series and these non-Australian studies, the author proposes that Australia (and other countries) should use slow personalized titration for clozapine based on ancestry and c-reactive protein monitoring.