Drugs In Schizophrenia Research Articles

B-258 Rapid clozapine blood levels on the Beckman Coulter DxC 500 AU

Abstract Background Clozapine is the most effective drug for treatment-resistant schizophrenia. Multiple guidelines strongly recommend clozapine therapeutic drug monitoring (TDM). Measuring clozapine blood levels provides essential information when there are questions of medication adherence, efficacy, toxicity, medication interactions, or concern over other factors that may influence clozapine levels. Turnaround time is essential for effective clinical decisions. However, with liquid-chromatography/mass spectrometry, clozapine levels can take days to report results. To address the medical need for a faster turnaround time, a rapid clozapine immunoassay was developed for automated clinical chemistry analyzers. The immunoassay measuring range is based on established APA Practice Guidelines and ASCP/AGNP Consensus Statement. We developed an analyzer application for the DxC 500 AU (time to first result < 9 minutes) to expand the availability of rapid clozapine blood level testing. Methods The performance of the FDA-cleared clozapine assay was evaluated on the DxC 500 AU according to CLSI guidelines. Precision testing was performed with three clozapine spiked pools over five days with five replicates per sample. Precision sample recovery was assessed to their theoretical spike concentration. Linearity was verified with five spiked serum samples covering the measuring range. Method comparison was performed with 40 remnant patient samples vs. the Beckman Coulter AU480. Results Repeatability CV was ≤5.5% and within-laboratory precision CV was ≤6.1%. Individual deviation was ±20% and mean deviation was ±2% for all samples. Deviation from linearity was <3%. Deming regression statistics for the method comparison were a slope of 0.987, an intercept of 5.7, and an R of 0.9948. The methods are statistically equivalent: the 99% confidence limits contained 1 and 0 for the slope and intercept respectively. Conclusions The precision, recovery, linearity, and method comparison results for clozapine on the DxC 500 AU demonstrate that the analyzer can be used to generate robust results for clozapine.

Leveraging the Genetics of Psychiatric Disorders to Prioritize Potential Drug Targets and Compounds.

Genetics has the potential to inform biologically relevant drug treatment and repurposing which may ultimately improve patient care. In this study, we combine methods which leverage the genetics of psychiatric disorders to prioritize potential drug targets and compounds. We used the largest available genome-wide association studies, in European ancestry, of four psychiatric disorders [i.e., attention deficit hyperactivity disorder (ADHD), bipolar disorder, depression, and schizophrenia] along with genes encoding drug targets. With this data, we conducted drug enrichment analyses incorporating the novel and biologically specific GSA-MiXeR tool. We then conducted a series of molecular trait analyses using large-scale transcriptomic and proteomic datasets sampled from brain and blood tissue. This included the novel use of the UK Biobank proteomic data for a proteome-wide association study of psychiatric disorders. With the accumulated evidence, we prioritize potential drug targets and compounds for each disorder. We reveal candidate drug targets shared across multiple disorders as well as disorder-specific targets. Drug prioritization indicated genetic support for several currently used psychotropic medications including the antipsychotic paliperidone as the top ranked drug for schizophrenia. We also observed genetic support for other commonly used psychotropics (e.g., clozapine, risperidone, duloxetine, lithium, and valproic acid). Opportunities for drug repurposing were revealed such as cholinergic drugs for ADHD, estrogens for depression, and gabapentin enacarbil for schizophrenia. Our findings also indicate the genetic liability to schizophrenia is associated with reduced brain and blood expression of CYP2D6, a gene encoding a metabolizer of drugs and neurotransmitters, suggesting a genetic risk for poor drug response and altered neurotransmission. Here we present a series of complimentary and comprehensive analyses that highlight the utility of genetics for informing drug development and repurposing for psychiatric disorders. Our findings present novel opportunities for refining psychiatric treatment.

Sexual side effects of antipsychotic drugs in schizophrenia: Protocol for a systematic review with single-arm, pairwise and network meta-analysis of randomized controlled trials and non-randomized studies

Introduction Sexual dysfunctions are common yet underreported side effects of antipsychotics for schizophrenia, affecting 30-80% of treated individuals. These side effects can severely impact social interactions and treatment adherence for individuals with schizophrenia, but comprehensive comparative evidence assessing the risk profiles of different antipsychotics is lacking. This study aims to address this gap using network meta-analysis that integrates data from both randomized-controlled trials (RCTs) and non-randomized studies (NRS). Protocol This systematic review will include both RCTs and NRS focusing on participants with schizophrenia or schizophrenia-like psychoses, without restrictions on symptoms, gender, ethnicity, age, or setting. For interventions, all second-generation antipsychotics will be included. The primary outcome will be the occurrence of at least one sexual adverse event of any kind. Secondary outcomes will be the occurrence of any sexual adverse event evaluated in men and women separately, and any adverse event related to the three phases of sexual response cycle separately: desire (e.g. libido, sexual thoughts), arousal (e.g. erection, lubrication) and orgasm (e.g. ejaculation, anorgasmia), and any adverse effect related to breast dysfunction and menstruation irregularities. Study selection and data extraction will be performed independently by two reviewers. The Cochrane Risk of Bias tool 1 and ROBINS-I will be employed to evaluate the risk of bias for RCTs and NRS, respectively. Single-arm meta-analysis of proportions will synthesize the average frequency of sexual adverse events in treated participants. Pairwise and network meta-analysis of RCTs and NRS will be used to evaluate comparative tolerability. Subgroup and sensitivity analyses will explore possible heterogeneity in results and validate the findings’ robustness. The quality of the evidence will be evaluated using GRADE. Discussion This study will provide vital insights into the sexual side effects of antipsychotics by combining evidence from clinical trials and real-world practice, facilitating better decision-making in choosing the optimal antipsychotic for individuals.

What Remains to Be Discovered in Schizophrenia Therapeutics: Contributions by Advancing the Molecular Mechanisms of Drugs for Psychosis and Schizophrenia.

Schizophrenia is a frequently debilitating and complex mental disorder affecting approximately 1% of the global population, characterized by symptoms such as hallucinations, delusions, disorganized thoughts and behaviors, cognitive dysfunction, and negative symptoms. Traditional treatment has centered on postsynaptic dopamine antagonists, commonly known as antipsychotic drugs, which aim to alleviate symptoms and improve functioning and the quality of life. Despite the availability of these medications, significant challenges remain in schizophrenia therapeutics, including incomplete symptom relief, treatment resistance, and medication side effects. This opinion article explores advancements in schizophrenia treatment, emphasizing molecular mechanisms, novel drug targets, and innovative delivery methods. One promising approach is novel strategies that target neural networks and circuits rather than single neurotransmitters, acknowledging the complexity of brain region interconnections involved in schizophrenia. Another promising approach is the development of biased agonists, which selectively activate specific signaling pathways downstream of receptors, offering potential for more precise pharmacological interventions with fewer side effects. The concept of molecular polypharmacy, where a single drug targets multiple molecular pathways, is exemplified by KarXT, a novel drug combining xanomeline and trospium to address both psychosis and cognitive dysfunction. This approach represents a comprehensive strategy for schizophrenia treatment, potentially improving outcomes for patients. In conclusion, advancing the molecular understanding of schizophrenia and exploring innovative therapeutic strategies hold promise for addressing the unmet needs in schizophrenia treatment, aiming for more effective and tailored interventions. Future research should focus on these novel approaches to achieve better clinical outcomes and improve the functional level and quality of life for individuals with schizophrenia.

Application of GWAS summary data and drug-induced gene expression profiles of neural progenitor cells in psychiatric drug prioritization analysis.

Common psychiatric disorders constitute one of the most substantial healthcare burdens worldwide. However, drug development in psychiatry remains hampered partiallydue to the lack of approaches to estimating drugs that can simultaneously modulate the expression of a nontrivial fraction of disease susceptibility genes. We proposed a new drug prioritization strategy under the framework of our previously proposed phenotype-associated tissues estimation approach (DESE) by investigating the drugs' selective perturbation effect on disease susceptibility genes. Based on the genome-wide association study summary data and drug-induced gene expression profiles of neural progenitor cells, we applied this strategy to prioritize candidate drugs for schizophrenia, depression and bipolar I disorder and identified several known therapeutic drugs among the top-ranked drug candidates. Also, our results revealed that the disease susceptibility genes involved in the selective gene perturbation analysis were enriched with many biologically sensible function terms and interacted with known therapeutic drugs. Our results suggested that selective gene perturbation analysis could be a promising starting point to prioritize biologically sensible drug candidates under the "one drug, multiple targets" paradigm for the drug development of common psychiatric disorders.

Current Findings and Potential Mechanisms of KarXT (Xanomeline-Trospium) in Schizophrenia Treatment.

Standard schizophrenia treatment involves antipsychotic medications that target D2 dopamine receptors. However, these drugs have limitations in addressing all symptoms and can lead to adverse effects such as motor impairments, metabolic effects, sedation, sexual dysfunction, cognitive impairment, and tardive dyskinesia. Recently, KarXT has emerged as a novel drug for schizophrenia. KarXT combines xanomeline, a muscarinic receptor M1 and M4 agonist, with trospium, a nonselective antimuscarinic agent. Of note, xanomeline can readily cross blood-brain barrier (BBB) and, thus, enter into the brain, thereby stimulating muscarinic receptors (M1 and M4). By doing so, xanomeline has been shown to target negative symptoms and potentially improve positive symptoms. Trospium, on the other hand, is not able to cross BBB, thereby not affecting M1 and M4 receptors; instead, it acts as an antimuscarinic agent and, hence, diminishes peripheral activity of muscarinic receptors to minimize side effects probably stemming from xanomeline in other organs. Accordingly, ongoing clinical trials investigating KarXT's efficacy in schizophrenia have demonstrated positive outcomes, including significant improvements in the Positive and Negative Syndrome Scale (PANSS) total score and cognitive function compared with placebo. These findings emphasize the potential of KarXT as a promising treatment for schizophrenia, providing symptom relief while minimizing side effects associated with xanomeline monotherapy. Despite such promising evidence, further research is needed to confirm the efficacy, safety, and tolerability of KarXT in managing schizophrenia. This review article explores the current findings and potential mechanisms of KarXT in the treatment of schizophrenia.

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

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. 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. 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. 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. Northwell Health and Sigrid Jusèlius Foundation.

Neurosterix launches with schizophrenia drug

Neurosterix launches with schizophrenia drug

Comparative Study of the Efficacy and Side Effects of Brand-Name and Generic Clozapine for Long-Term Maintenance Treatment Among Korean Patients With Schizophrenia: A Retrospective Naturalistic Mirror-Image Study.

Clozapine is considered the most reliable drug for treatment-resistant schizophrenia. In 2014, a generic formulation of clozapine (Clzapine) was introduced in Korea. This study was performed to provide clinical information regarding the use of clozapine and to compare efficacy and tolerability when converting from the brand-name formulation (Clozaril) to the generic formulation during longterm maintenance treatment among Korean patients with schizophrenia. This mirror-image study retrospectively investigated the electronic medical records of patients who had switched from Clozaril to Clzapine with a ≥1-year duration for each formulation. Clinical data were collected, including information regarding clozapine use, psychiatric hospitalization, co-medications, and blood test findings. Data before and after the switch were compared using paired t-tests. Among 332 patients, the mean 1-year dosages were 233.32±149.35 mg/day for Clozaril and 217.36±136.66 mg/day for Clzapine. The mean clozapine concentration-to-dose ratios were similar before and after the switch (Clozaril, 1.33±0.68; Clzapine, 1.26±0.80). Switching from Clozaril to Clzapine resulted in no significant differences in the hospitalization rate, hospitalization duration, or laboratory findings (liver function parameters, serum cholesterol level, and serum glucose level). Equivalent doses of co-prescribed antidepressants were decreased, but concomitant medications otherwise showed no significant differences. Clinical efficacy and tolerability appear comparable when switching to Clzapine during clozapine maintenance treatment. This study offers descriptive real-world clinical insights into clozapine maintenance treatment in Korea, thereby providing patients with more treatment options and contributing to the development of maintenance guidelines tailored to the Korean population.

The Natural Protoalkaloid Methyl-2-Amino-3-Methoxybenzoate (MAM) Alleviates Positive as well as Cognitive Symptoms in Rat and Mouse Schizophrenia Models.

The development of new antipsychotics with pro-cognitive properties and less side effects represents a priority in schizophrenia drug research. In this study, we present for the first time a preclinical exploration of the effects of the promising natural atypical antipsychotic Methyl-2-Amino-3- Methoxybenzoate (MAM), a brain-penetrable protoalkaloid from the seed of the plant Nigella damascena. Using animal models related to hyperdopaminergic activity, namely the pharmacogenetic apomorphine (D2/D1 receptor agonist)-susceptible (APO-SUS) rat model and pharmacologically induced mouse and rat models of schizophrenia, we found that MAM reduced gnawing stereotypy and climbing behaviours induced by dopaminergic agents. This predicts antipsychotic activity. In line, MAM antagonized apomorphine-induced c-Fos and NPAS4 mRNA levels in post-mortem brain nucleus accumbens and dorsolateral striatum of APO-SUS rats. Furthermore, phencyclidine (PCP, an NMDA receptor antagonist) and 2,5-Dimethoxy-4-iodoamphetamine (DOI, a 5HT2A/2C receptor agonist) induced prepulse inhibition deficits, reflecting the positive symptoms of schizophrenia, which were rescued by treatment with MAM and atypical antipsychotics alike. Post-mortem brain immunostaining revealed that MAM blocked the strong activation of both PCP- and DOI-induced c-Fos immunoreactivity in a number of cortical areas. Finally, during a 28-day subchronic treatment regime, MAM did not induce weight gain, hyperglycemia, hyperlipidemia or hepato- and nephrotoxic effects, side effects known to be induced by atypical antipsychotics. MAM also did not show any cataleptic effects. In conclusion, its brain penetrability, the apparent absence of preclinical side effects, and its ability to antagonize positive and cognitive symptoms associated with schizophrenia make MAM an exciting new antipsychotic drug that deserves clinical testing.

Temporal trends in antipsychotic prescriptions for pediatric patients using an administrative hospital database in Japan: a retrospective study

BackgroundSchizophrenia is a psychiatric disorder characterized by hallucinations, delusions, and other symptoms. Although treatment guidelines for schizophrenia have been established in Japan, drugs are not recommended for pediatric schizophrenia. Additionally, the temporal trends in prescribing antipsychotics for pediatric patients with schizophrenia are unclear. Therefore, we aimed to clarify the trends in antipsychotic prescriptions for Japanese pediatric outpatients from 2015 to 2022.MethodsAdministrative data (as of November 2023) of Japanese pediatric outpatients with schizophrenia aged 0–18 years who visited acute-care diagnosis procedure combination hospitals between January 1, 2015, and December 31, 2022, were included in this study. The target drugs for schizophrenia were all indicated for treating schizophrenia and marketed in Japan as of December 2022. Annual prescription trends for antipsychotics during this period were calculated based on their proportions. The Cochran–Armitage trend test was used to evaluate the proportion of prescriptions for each antipsychotic.ResultsThe main drugs prescribed for these patients were aripiprazole and risperidone. Among male patients, the proportion of prescriptions for aripiprazole increased significantly from 21.2% in 2015 to 35.9% in 2022, whereas that for risperidone decreased significantly from 47.9% in 2015 to 36.7% in 2022 (both P < 0.001). Among female patients, the proportion of prescriptions for aripiprazole increased significantly from 21.6% in 2015 to 35.6% in 2022, whereas that for risperidone decreased significantly from 38.6% in 2015 to 24.8% in 2022 (both P < 0.001).ConclusionsAripiprazole and risperidone were primarily prescribed for pediatric schizophrenia in Japan during the study period. Additionally, the proportion of aripiprazole prescriptions increased over time.

Risperidone Associated With Acute Pulmonary Thromboembolism: A Case Report

Antipsychotic drugs (APs) are widely used drugs for schizophrenia. For decades, these agents are frequently associated with some side-effects, including increased the risk of Venous Thromboembolism (VTE). A case of a man (53 years old) with schizophrenia was reported in this study. The man with no identified risk factor for thromboembolism, and developed Pulmonary Embolism (PE) and Deep Vein Thrombosis (DVT) after treatment with risperidone 2 years. The current case indicates that use of risperidone for long time can be associated with the risk of PTE and DVT. Risperidone is a Second-Generation Antipsychotic medication (SGA), as a mixed serotonin 5HT2 and dopamine D2 receptor antagonist possibly implicated in this adverse event. As suggested by this observation, VTE and PTE risk not just appears to new users, so they should be vigilant monitored to ensure early detection and prompt treatment of VET and PTE during medication.

The role of glial cells in schizophrenic brain

Schizophrenia, as a complex neurological disorder, has many distressing symptoms such as hallucinations and some of the common mood or cognitive disorders commonly associated with mental illness. Once suffering from schizophrenia, peoples work and life will be greatly troubled. It is also often associated with other psychiatric disorders, which makes it extremely difficult to treat clinically. However, a diverse of different studies have been able to identify a clear link with neurotransmitter signaling pathways and some brain activity, such as dopamine projection pathways and a significant reduction in gray matter in patients. This research will focus on another dimension, namely the reduction of gray matter volume, to investigate the relationship between oligodendrocyte and astrocyte function and schizophrenia, in an attempt to provide a new vision for the clinical treatment system. In addition, it is expected that this research can also provide a new idea for the development of new drugs for schizophrenia.

Augmentation Strategies for Partial or Non-responders to Clozapine in Patients with Schizophrenia: A Bayesian Network Meta-analysis of Randomized Controlled Trials.

Clozapine is the only approved drug for treatment-resistant schizophrenia, but the response to the drug is often inadequate. Augmentation with other antipsychotics, anticonvulsants, and antidepressants is recommended for such patients, but there is a lack of evidence regarding the most effective therapy. This network meta-analysis was conducted to evaluate the efficacy of pharmacological agents used in the augmentation strategies in patients who were partial/ non-responders to clozapine. Relevant data were extracted from 30 randomized controlled trials through searches of electronic databases (MEDLINE/PubMed, Embase, Cochrane, clinical trial registries). PRISMA guidelines were followed for the extraction, management, analysis, and reporting of the data. The outcome measure in this study was a reduction in symptom severity according to total PANSS/BPRS and was reported as the standardized mean difference with a 95% credible interval. Bayesian network meta-analysis with random effects model and uninformative priors was conducted, and the ranking probability of each intervention was done. Meta-regression was done to assess the effect of duration on the reduction in symptom severity scores. Mirtazapine (-5.2 [95%CrI: -7.7, -2.7]) and memantine (-2.1 [95%CrI: -4.0, -0.19]] were more efficacious than placebo for augmentation of clozapine in partial/non-responders and were the most effective adjunctive agents as per SUCRA scores. Both drugs did not cause a significant increase in frequency of adverse events compared to placebo. There was a significant effect of duration on the reduction in symptom severity. There was no evident publication bias. Mirtazapine and memantine may prove beneficial for augmentation of clozapine in non/partial responders to monotherapy.

Therapeutic Dosage of Antipsychotic Drug Aripiprazole Induces Persistent Mitochondrial Hyperpolarisation, Moderate Oxidative Stress in Liver Cells, and Haemolysis.

Aripiprazole has fewer metabolic side effects than other antipsychotics; however, there are some severe ones in the liver, leading to drug-induced liver injury. Repeated treatment with aripiprazole affects cell division. Since this process requires a lot of energy, we decided to investigate the impact of aripiprazole on rat liver cells and mitochondria as the main source of cellular energy production by measuring the mitochondrial membrane potential, respiration, adenosine triphosphate (ATP) production, oxidative stress, antioxidative response, and human blood haemolysis. Here, we report that mitochondrial hyperpolarisation from aripiprazole treatment is accompanied by higher reactive oxygen species (ROS) production and increased antioxidative response. Lower mitochondrial and increased glycolytic ATP synthesis demand more glucose through glycolysis for equal ATP production and may change the partition between the glycolysis and pentose phosphate pathway in the liver. The uniform low amounts of the haemolysis of erythrocytes in the presence of aripiprazole in 25 individuals indicate lower quantities of the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH+H+), which is in accordance with a decreased activity of glucose 6-phosphate dehydrogenase and the lower dehydrogenase activity upon aripiprazole treatment. The lower activity of glucose 6-phosphate dehydrogenase supports a shift to glycolysis, thus rescuing the decreased mitochondrial ATP synthesis. The putative reduction in NADPH+H+ did not seem to affect the oxidised-to-reduced glutathione ratio, as it remained equal to that in the untreated cells. The effect of aripiprazole on glutathione reduction is likely through direct binding, thus reducing its total amount. As a consequence, the low haemolysis of human erythrocytes was observed. Aripiprazole causes moderate perturbations in metabolism, possibly with one defect rescuing the other. The result of the increased antioxidant enzyme activity upon treatment with aripiprazole is increased resilience to oxidative stress, which makes it an effective drug for schizophrenia in which oxidative stress is constantly present because of disease and treatment.

Clozapine monitoring at a specialised psychiatric hospital: A retrospective chart review

Background: Clozapine is the only Food and Drug Administration (FDA) and National Institute for Care and Excellence (NICE) approved drug for treatment-resistant schizophrenia (TRS). Its potentially life-threatening haematological side effects of neutropaenia and agranulocytosis mandate rigorous monitoring of neutrophil counts, presenting unique, Third-World population challenges.Aim: To describe the Clozapine white blood cell monitoring practice and outcomes in a local psychiatric hospital.Setting: At a specialist Psychiatry unit in Durban, KwaZulu-Natal, which follows a modified algorithm of the South African Standard Treatment Guidelines for Clozapine monitoring.Methods: A retrospective chart review composed of 120 patients on Clozapine treatment from 01 July 2018–31 December 2020. Demographic and clinical information was captured in a Redcap database. Descriptive statistics using categorical variables were used.Results: The study population was from a low socioeconomic background, with low levels of education and employment. A baseline neutrophil count was recorded in 58 files (48.3%). Clozapine was stopped in 6 out of the 120 patients due to ‘neutropaenia’ (absolute neutrophil counts ranging from 1.18 to 1.6); none developed agranulocytosis. Their duration of Clozapine treatment ranged from 2 weeks–15 years.Conclusion: Haematological monitoring frequency and documentation of patients receiving Clozapine were not in compliance with the hospital’s adapted guidelines and may have resulted in the termination of treatment before true neutropaenia developed. Patients developed neutropaenia at low doses of Clozapine and after many years of treatment.Contribution: These results suggest local Clozapine monitoring guidelines should be more strictly adhered to.

Study on the daily dose and serum concentration of clozapine in psychiatric patients and possible influencing factors of serum concentration

BackgroundClozapine is the most effective drug for treatment-resistant schizophrenia, and the dosage and concentration of clozapine in the treatment of mental illness vary greatly in different populations and are affected by many factors.MethodsThe serum clozapine concentration of 3734 psychiatric patients was detected, and data on daily dose, sex, age and other medical records were collected for statistical analysis.ResultsThe mean daily dose, mean serum concentration and mean C/D (concentration/dose) ratio of clozapine were 191.02 ± 113.47 mg/day, 326.15 ± 235.66 ng/mL and 1.94 ± 1.25 ng/mL per mg/day, respectively. There was difference in daily dose between sexes, and females had higher daily dose (p <0.01), higher serum clozapine concentrations (p < 0.01) and higher C/D ratios (p < 0.01). There were significant differences in daily dose (p < 0.001), serum drug concentration (p < 0.001) and C/D ratio (p < 0.001) among different age groups. The daily dose decreased with age (p for trend < 0.001), and the C/D ratio increased with age (p for trend < 0.001). Inpatients and outpatients had no difference in daily dose, but inpatients had higher serum concentration (p < 0.001) and C/D ratio (p < 0.001). There was no difference in daily dose among different occupations, but there were significant differences in serum concentration (p < 0.001) and C/D ratio (p < 0.001), and unemployed patients may have higher serum concentration and C/D ratio. Duration of disease, comorbidity, marital status, and psychotic type may influence the daily dose and serum concentration.ConclusionsThe effective daily dose and serum concentration of clozapine in the study area may be lower than recommended levels, and women have higher serum concentrations and slower metabolic rates. With increasing age, the daily dose decreases, and the metabolic rate slows. Inpatient status and occupation of patients may influence the serum concentration and metabolic rate of clozapine.

Novel Compounds in the Treatment of Schizophrenia-A Selective Review.

Schizophrenia is a chronic neuropsychiatric syndrome that significantly impacts daily function and quality of life. All of the available guidelines suggest a combined treatment approach with pharmacologic agents and psychological interventions. However, one in three patients is a non-responder, the effect on negative and cognitive symptoms is limited, and many drug-related adverse effects complicate clinical management. As a result, discovering novel drugs for schizophrenia presents a significant challenge for psychopharmacology. This selective review of the literature aims to outline the current knowledge on the aetiopathogenesis of schizophrenia and to present the recently approved and newly discovered pharmacological substances in treating schizophrenia. We discuss ten novel drugs, three of which have been approved by the FDA (Olanzapine/Samidorphan, Lumateperone, and Pimavanserin). The rest are under clinical trial investigation (Brilaroxazine, Xanomeline/Trospium, Emraclidine, Ulotaront, Sodium Benzoate, Luvadaxistat, and Iclepertin). However, additional basic and clinical research is required not only to improve our understanding of the neurobiology and the potential novel targets in the treatment of schizophrenia, but also to establish more effective therapeutical interventions for the syndrome, including the attenuation of negative and cognitive symptoms and avoiding dopamine blockade-related adverse effects.

A new era for schizophrenia drug development – Lessons for the future

For many patients and their treating clinicians, the pharmacological management of psychotic symptoms centres on trying to find a regime that balances efficacy and quality of life, impairing side effects associated with dopamine antagonism. Recent reports of a positive Phase III study from Karuna Therapeutics indicate that the first primarily non-dopamine-based treatment for schizophrenia may come to market soon with the potential for substantially reduced or differentiated side effects. Against a background of repeated failures, Karuna's success promises a desperately needed new treatment option for patients. It also reflects some hard-won lessons about the methodology for schizophrenia drug development. Teaser A positive Phase II study and positive media report from a Phase III study with xanomeline/trospium may herald the first truly new treatment option for schizophrenia patients in decades. This drug's journey to this point reflects some hard-won lessons about the methodology for schizophrenia drug development.

Brexpiprazole augmentation in a clozapine-resistant young schizophrenic patient: a successful case report.

IntroductionAlthough clozapine is considered the most effective drug for Treatment Resistant Schizophrenia (TRS), only 40% of patients treated will meet clinical response. Literature reviews and meta-analytic data offer no definite conclusions about the most effective clozapine augmentation strategies. Nevertheless, it has been suggested that the lack of evidence should not discourage clinicians from trying out new strategies in individual patients. Brexpiprazole is a novel 5-HT and DA modulator antipsychotic that exhibits partial agonism to D2/D3 and 5HT1A receptors, antagonism to 5HT2A and α-1B/2C receptors and represents a promising new drug in the pharmacotherapy of schizophrenia for both acute and maintenance treatment. In current literature there is no evidence of experiences in brexpiprazole augmentation for clozapine resistant patients.ObjectivesThis case report describes a successful clinical experience of brexpiprazole augmentation in a complicated case of clozapine resistant paranoid schizophrenia with consistent negative symptoms, the clinical evolution and metabolic improvement consequent to this therapy combination.MethodsIn a 27 male TRS patient, sequentially treated with adequate doses of risperidone, cariprazine, aripiprazole and olanzapine monotherapy, prescribed for adequate time, clozapine treatment was started, with a gradual titration from 25 to 300 mg/day, without significant clinical response on both positive and negative symptoms. Successively was introduced fluoxetine, from 10 to 30 mg/day, with no relevant clinical improvement. After 2 months of pharmacological stabilization with clozapine and fluoxetine described dosages, brexpiprazole was introduced starting from 1 mg/day and rapidly increasing till 4 mg/day.ResultsAfter 6 weeks of treatment, PANSS positive and negative subscales showed a significant decrease, respectively from 28 to 17 and from 42 to 20, while general psychopathology subscale decreased from 66 to 34. Negative sub-items with major improvement were those regarding blunted affect, emotional withdrawal, poor rapport, and passive/apathetic social withdrawal. Brexpiprazole augmentation also allowed to slowly decrease (in 6 months) clozapine dose till actual 150 mg/day, with a significant improvement in general tolerability and a slow decline in metabolic parameters (BMI from 36.5 to 30.3; fasting glucose from 112 to 92 mg/dL; total cholesterol from 248 to 182 mg/dL; total triglycerides from 392 to 198 mg/dL).ConclusionsIn this case report brexpiprazole augmentation in a clozapine resistant young schizophrenic patient was an effective strategy with significant symptoms improvement, in particular in PANSS general psychopathology and PANSS negative subscales. The consequent clozapine dose reduction contribute to the slow decrease in metabolic parameters considered.Disclosure of InterestNone Declared