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Significant research and clinical efforts have improved the safety of clozapine since FDA approval. In the US, the Clozapine Risk Evaluation and Mitigation Strategy (REMS), implemented to ensure completion of hematologic monitoring, remains a major barrier to clozapine use. The FDA has the authority to modify the Clozapine REMS, the largest perceived barrier to increasing clozapine utilization. [Extracted from the article]

Introduction Amisulpride is an atypical antipsychotic. Rabbit syndrome(RS) may be seen after antipsychotics use a few days or long‐term application. RS occurs after more frequent typical antipsychotics and also in rare cases atypical antipsychotics.Its characterized by the involuntary rhythmic movements of the lips however involves no tongue movements. Objectives Case report and reflection on its etiology Methods Case report and literature review Results A 28-year-old female with a diagnosis of schizophrenia applied with the complaints and symptoms of withdrawal, do not want to leave the house, physical anergy and avolition that started after stopped taking her medications. She was admitted to the psychiatry service and amisulpride treatment was started and was gradually increased to 800 mg/day. After 30 days of hospitalization, the patient was discharged with mild recovery. 14 days after the discharge, because of the abnormal involuntary movements in mouth, the patient applied. In clinical examination without tounge involvement, rhythmic motions were observed in the lips and jaw.Neurological examination, labrotory tests and cranial screening were all normal. She was evaluated by a private psychiatrist and was diagnosed with RS. Amisulpride treatment changed to olanzapine treatment with 15 mg/day. After two months, RS spontaneously regressed. Conclusions The resolution of the involuntary movements following discontinuation of amisulpride in our case, supported the diagnosis of RS. Although the mechanism by which RS emerges as a side‐effect of amisulpride is not fully understood, the drug’s high affinity for and selective binding to dopaminergic D2 and D3 receptors are thought to be responsible for this involuntary motion disorder. Disclosure No significant relationships.

Introduction: Antipsychotics are psyschotropic medications that are indicated for the treatment of physchosis and mood disorders. Due to minimal side effects and their efficacy (affecting many receptors) compared to standard antipsychotics, today atypical antipsychotics are being used more and more as first-line treatment. The aim of this study is to show the efficacy of asenapine and its tolerability as opposed to other atypical antipsychotics. Objectives: 1. What are the side effects identified? 2. Side effects and efficacy of asenapine vs other atypical antipsychotics? Methods: It is a comparative, regular, clinical study, an examination case of a 53-year old female diagnosed with Schizoaffective Disorder 27 years ago and treated outside of hospital with atypical antipsychotics, such as: risperidone, olanzapine, quetiapine, aripiprazole, amisulpride. The study covers the timespan of 2010-2022. Results: The results showed that asenapine sublingual 15 mg had fewer side effects than other atypical antipsychotics. They were mouth dryness, headache, fatigue. The other atypical antipsychotics caused: metabolic disorders, like considerable weight gain, cholesterol and glycaemia increase, extrapyramidal side effects, hyperprolactinemia. Asenapine sublingual 15 mg was not as effective in treating Schyzoaffective Disorder as risperdal 5mg, olanzapine 15 mg, aripiprazole 20 mg, amisulpride 600 mg. The efficacy of asenapine sublingual 15mg was the same as quetiapine 400 mg. Conclusions: This study showed that asenapine has minimal side effects but its efficacy in treating Schyzoaffective Disorder as monotherapy is lower than other atypical antipsychotics. Key words: antipsychotics, schyzoaffective disorder, side effects, efficacy Disclosure of Interest: None Declared [ABSTRACT FROM AUTHOR]

Introduction: Antipsychotics are associated with increased serum prolactin. It depends on the type of the antipsychotics and gender. There are previous studies, but it is necessary to compare them including new drugs. Objectives: Antipsychotic drugs are known as the major cause of non-neoplastic hyperprolactinemia. This study aimed to investigate the levels of serum prolactin elevation depending on the use of antipsychotic drugs in patients through the Clinical Data Warehouse Methods: Our study included 118 subjects who were all diagnosed according to ICD-10 for schizophrenia, schizotypal and delusional disorders, manic episodes, and bipolar affective disorders. All the subjects were taking one of risperidone, blonanserin, amisulpride, and olanzapine. They had prolactin blood tests collected retrospectively through CDW. Results: Among the 118 subjects included in the analysis, the mean serum prolactin level was 65.1± 54.7ng/ml. Serum prolactin levels were significantly higher in subjects taking risperidone or amisulpride compared to blonanserin and olanzapine. The female subjects who took amisulpride or olanzapine had significantly higher prolactin levels, but there was no difference in prolactin levels between the sex in the subjects who took risperidone or blonanserin. Conclusions: This study suggests the need for regular monitoring of serum prolactin levels in patients who are taking antipsychotics, especially in female patients. Further studies on the subjects with controlled confounding variables and larger sample groups are needed. Disclosure of Interest: None Declared [ABSTRACT FROM AUTHOR]

In the present study, the photocatalytic degradation of amisulpride using g-C3N4 catalyst under UV-A irradiation was investigated. The photocatalytic process was evaluated in terms of its effectiveness to remove amisulpride from ultrapure and real municipal wastewater. High removal percentages were achieved in both aqueous matrices. However, a slower degradation rate was observed using wastewater as matrix that could be attributed to its complex chemical composition. The transformation products (TPs) were identified with liquid chromatography–mass spectrometry (LC–MS) in both ultrapure and real municipal wastewater. Based on the identified TPs, the photocatalytic degradation pathways of amisulpride are proposed which include mainly oxidation, dealkylation, and cleavage of the methoxy group. Moreover, the contribution of reactive species to the degradation mechanism was studied using well-documented scavengers, and the significant role of h+ and O2•− in the reaction mechanism was proved. The evolution of ecotoxicity was also estimated using microalgae Chlorococcum sp. and Dunaliella tertiolecta. Low toxicity was observed during the overall process without the formation of toxic TPs when ultrapure water was used as matrix. In the case of real municipal wastewater, an increased toxicity was observed at the beginning of the process which is attributed to the composition of the matrix. The application of heterogeneous photocatalysis reduced the toxicity, and almost complete detoxification was achieved at the end of the process. Our results are in accordance with literature data that reported that heterogeneous photocatalysis is effective for the removal of amisulpride from aqueous matrices.

Introduction: Aripiprazole is hypothesized to have an effect on negative and cognitive symptoms in schizophrenia. Likewise, amisulpride is one of the only second-generation antipsychotics with which an effect on negative symptoms is reported. In the present study, we compare the effect of aripiprazole and amisulpride in initially antipsychotic-naïve patients with first-episode psychoses. Methods: Psychopathology and cognitive measures from two consecutive cohorts of antipsychotic-naïve first episode psychotic patients were obtained before and after 6 weeks of antipsychotic monotherapy with either aripiprazole or amisulpride. Matched healthy controls were included to account for retest effects on the cognitive measures. Analyses of variance (repeated-measures ANOVA) were performed to detect effect of time and possible cohort*time interactions. Results: Longitudinal data was obtained from 47 and 48 patients treated for 6 weeks with amisulpride or aripiprazole, respectively. For the Wallwork negative symptom dimension, there was a cohort*time interaction [ F (1, 93) = 4.29, p = 0.041] and a significant effect of time [ F (1, 93) = 6.03, p = 0.016], which was driven by an improvement in patients treated with aripiprazole [ t (47) = 4.1, p < 0.001] and not observed in patients treated with amisulpride (p > 0.5). For the eight cognitive measures, no cohort*time interaction was found and neither was cognitive improvement in any of the cohorts when accounting for retest effect. Conclusion: Patients treated with aripiprazole improved on negative symptoms, which was not the case for patients treated with amisulpride. This may point to a general effect of a partial D2 receptor agonist on negative symptoms in patients with first-episode psychoses. There was, however, no improvement in cognitive functions. [ABSTRACT FROM AUTHOR]

Evidence is mounting that the gut microbiome is related to the underlying pathogenesis of schizophrenia. However, effects of amisulpride on gut microbiota are poorly defined. This study was aimed at analyzing cytokines and fecal microbiota in patients with exacerbated symptoms of schizophrenia treated with amisulpride during four weeks of their hospital stay. In the present study, feces collected from patients with schizophrenia were analyzed using 16S rRNA pyrosequencing and bioinformatic analyses to ascertain gut microbiome composition and fasting peripheral blood cytokines. We found that patients undergoing treatment of schizophrenia with amisulpride had distinct changes in gut microbial composition at the genus level, increased levels of short-chain fatty acid-producing bacteria (Dorea and Butyricicoccus), and reduced levels of pathogenic bacteria (Actinomyces and Porphyromonas), but the level of Desulfovibrio was still high. We also found a significant downregulation of butanoate metabolism based on functional analysis of the microbiome. After treatment, elevated levels of interleukin- (IL-) 4 and decreased levels of IL-6 were found. Our findings extend prior work and suggest a possible pharmacological mechanism of amisulpride treatment for schizophrenia, which acts via mediation of the gut microbiome. [ABSTRACT FROM AUTHOR]

Schizophrenia is characterized by delusions, hallucinations, anhedonia and apathy, and is a chronic mental illness, which still has no cure. It is diagnosed in three main groups, namely positive symptoms, negative symptoms, and cognitive symptoms, and affects the patient in major areas of life, such as work, interpersonal relationships, or self-care. The usual treatment is carried out with the help of antipsychotic medications, which mainly target the positive symptoms of the illness, but have little effect on the negative symptoms of schizophrenia. It is a disease that affects 1% of the population, and while it is not the most common of other mental disorders, it can be the most disabling. Virtual reality (VR) is increasingly used as a powerful auxiliary tool in rehabilitation. It allows an immersive audiovisual environment with high clinical relevance and robust validity, modernizing rehabilitation interventions, leading to improved motor function and biomechanical or diagnostic ability better than traditional methods used to treat patients under cognitive health. In this context, this paper addresses the design of virtual environments and computer simulations, providing the patient with an experience close to the real world, and allowing intensive repetition of essential tasks during the mental health rehabilitation process, with real-time feedback in a controlled and safe environment. Virtual reality (VR) is increasingly used as a powerful auxiliary tool in rehabilitation. [ABSTRACT FROM AUTHOR]

Objective: To investigate macroprolactinemia caused by antipsychotics and its clinical significance. Methods: A total of 133 patients with schizophrenia were selected, all of whom were treated with either risperidone or amisulpride alone. The levels of total prolactin (T‐PRL) and macroprolactin (MPRL) were measured before treatment as well as the second, fourth, and sixth weeks of treatment. Results: After 2 weeks of treatment, 75.09% (100/133) of the patients met the diagnostic criteria for hyperprolactinemia, the incidence of macroprolactinemia was 43% (43/100), and MPRL levels were positively correlated T‐PRL levels. Conclusion: Risperidone and amisulpride caused hyperprolactinemia and macroprolactinemia; thus, detection of MPRL in the clinical setting should be performed as this phenomenon appears early in treatment (the second week) and continues, that can avoid unnecessary examination and treatment for asymptomatic patients with macroprolactinemia. [ABSTRACT FROM AUTHOR]

Striatal dopamine dysfunction is associated with the altered top-down modulation of pain processing. The dopamine D2-like receptor family is a potential substrate for such effects due to its primary expression in the striatum, but evidence for this is currently lacking. Here, we investigated the effect of pharmacologically manipulating striatal dopamine D2 receptor activity on the anticipation and perception of acute pain stimuli in humans. Participants received visual cues that induced either certain or uncertain anticipation of two pain intensity levels delivered via a CO2 laser. Rating of the pain intensity and unpleasantness was recorded. Brain activity was recorded with EEG and analysed via source localisation to investigate neural activity during the anticipation and receipt of pain. Participants completed the experiment under three conditions, control (Sodium Chloride), D2 receptor agonist (Cabergoline), and D2 receptor antagonist (Amisulpride), in a repeated-measures, triple-crossover, double-blind study. The antagonist reduced an individuals' ability to distinguish between low and high pain following uncertain anticipation. The EEG source localisation showed that the agonist and antagonist reduced neural activations in specific brain regions associated with the sensory integration of salient stimuli during the anticipation and receipt of pain. During anticipation, the agonist reduced activity in the right mid-temporal region and the right angular gyrus, whilst the antagonist reduced activity within the right postcentral, right mid-temporal, and right inferior parietal regions. In comparison to control, the antagonist reduced activity within the insula during the receipt of pain, a key structure involved in the integration of the sensory and affective aspects of pain. Pain sensitivity and unpleasantness were not changed by D2R modulation. Our results support the notion that D2 receptor neurotransmission has a role in the top-down modulation of pain. [ABSTRACT FROM AUTHOR]

Background: The decision to initiate clozapine treatment should be made on an individual basis and may be closely related to the early detection of treatment‐resistant schizophrenia (TRS), although there is evidence that the early use of clozapine results in a better response to treatment. Therefore, we investigated the relationship between the examination rate of TRS and the prescription rate of clozapine. Methods: After attending a 1‐day educational program on schizophrenia based on the "Guidelines for the Pharmacological Treatment of Schizophrenia," we asked the participating facilities to submit records of whether or not TRS was evaluated for each patient. We calculated the clozapine prescription rate from the schizophrenic patients prescribed clozapine and all of the schizophrenic patients. Forty‐nine facilities in 2017 were included in the study. Results: There were dichotomous distributions in the examination rate of TRS and a non‐normal distribution in the prescription rate of clozapine. There was a significant correlation between the prescription rate of clozapine and the examination rate of TRS (rs = 0.531, P = 1.032 × 10−4). A significant difference was found in the prescription rate of clozapine between the three groups of facilities according to the examination rate of TRS. Conclusion: As a preliminary problem for the use of clozapine, in Japan, the examination rate of TRS varies, and there are many facilities that typically do not consider the possibility of TRS; this trend leads to a low rate of clozapine use. Clearly, further clinician training is needed for the early detection and appropriate management of TRS that includes an explanation of TRS and how to introduce clozapine therapy to patients and their families. [ABSTRACT FROM AUTHOR]

This international guideline proposes improving clozapine package inserts worldwide by using ancestry-based dosing and titration. Adverse drug reaction (ADR) databases suggest that clozapine is the third most toxic drug in the United States (US), and it produces four times higher worldwide pneumonia mortality than that by agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers, the lowest dose; male smokers, the highest dose). Poor metabolizer status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity, or inflammation with C-reactive protein (CRP) elevations. The Asian population (Pakistan to Japan) or the Americas' original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/mL. In the US, daily doses of 300–600 mg/day are recommended. Slow personalized titration may prevent early ADRs (including syncope, myocarditis, and pneumonia). This guideline defines six personalized titration schedules for inpatients: 1) ancestry from Asia or the original people from the Americas with lower metabolism (obesity or valproate) needing minimum therapeutic dosages of 75–150 mg/day, 2) ancestry from Asia or the original people from the Americas with average metabolism needing 175–300 mg/day, 3) European/Western Asian ancestry with lower metabolism (obesity or valproate) needing 100–200 mg/day, 4) European/Western Asian ancestry with average metabolism needing 250–400 mg/day, 5) in the US with ancestries other than from Asia or the original people from the Americas with lower clozapine metabolism (obesity or valproate) needing 150–300 mg/day, and 6) in the US with ancestries other than from Asia or the original people from the Americas with average clozapine metabolism needing 300–600 mg/day. Baseline and weekly CRP monitoring for at least four weeks is required to identify any inflammation, including inflammation secondary to clozapine rapid titration. [ABSTRACT FROM AUTHOR]

Ankyrin repeat and kinase domain containing 1 (ANKK1) is a member of the receptor-interacting protein serine/threonine kinase family, known to be involved in cell proliferation, differentiation and activation of transcription factors. Genetic variation within the ANKK1 locus is suggested to play a role in vulnerability to addictions. However, ANKK1 mechanism of action is still poorly understood. It has been suggested that ANKK1 may affect the development and/or functioning of dopaminergic pathways. To test this hypothesis, we generated a CRISPR-Cas9 loss of function ankk1 zebrafish line causing a 27 bp insertion that disrupts the ankk1 sequence introducing an early stop codon. We found that ankk1 transcript levels were significantly lower in ankk1 mutant (ankk127 ins ) fish compared to their wild type (ankk1 +/+) siblings. In ankk1 +/+ adult zebrafish brain, ankk1 protein was detected in isocortex, hippocampus, basolateral amygdala, mesencephalon, and cerebellum, resembling the mammalian distribution pattern. In contrast, ankk1 protein was reduced in the brain of ankk127 ins/ 27 ins fish. Quantitative polymerase chain reaction analysis revealed an increase in expression of drd2b mRNA in ankk127 ins at both larval and adult stages. In ankk1 +/+ adult zebrafish brain, drd2 protein was detected in cerebral cortex, cerebellum, hippocampus, and caudate homolog regions, resembling the pattern in humans. In contrast, drd2 expression was reduced in cortical regions of ankk127 ins/ 27 ins being predominantly found in the hindbrain. No differences in the number of cell bodies or axonal projections detected by anti-tyrosine hydroxylase immunostaining on 3 days post fertilization (dpf) larvae were found. Behavioral analysis revealed altered sensitivity to effects of both amisulpride and apomorphine on locomotion and startle habituation, consistent with a broad loss of both pre and post synaptic receptors. Ankk127 ins mutants showed reduced sensitivity to the effect of the selective dopamine receptor antagonist amisulpride on locomotor responses to acoustic startle and were differentially sensitive to the effects of the non-selective dopamine agonist apomorphine on both locomotion and habituation. Taken together, our findings strengthen the hypothesis of a functional relationship between ANKK1 and DRD2 , supporting a role for ANKK1 in the maintenance and/or functioning of dopaminergic pathways. Further work is needed to disentangle ANKK1 's role at different developmental stages. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to investigate the characteristics and spectrum of cardiotoxicity induced by various antipsychotics based on the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database. Methods: Data of the FAERS database from the first quarter of 2015 to the fourth quarter of 2020 were downloaded for disproportionality analysis. The significant signal was evaluated by reporting odds ratios and information components with statistical shrinkage transformation. Results: A total of 2,361,487 records were extracted for disproportionality analysis. Among the 10 antipsychotics, clozapine and amisulpride performed strong cardiotoxicity. Cardiomyopathy, cardiac arrhythmia, and Torsade de pointes/QT prolongation were the common cardiac adverse event induced by antipsychotics. Different characteristics of the spectrum of cardiotoxicity in various APs were discovered after further data mining. Moreover, evidence of the association between antipsychotics and eosinophilic myocarditis, peripartum cardiomyopathy was provided in this study. Conclusion: Antipsychotics presented cardiotoxicity in different degrees, and more cardiac examinations should be monitored in patients with antipsychotics. [ABSTRACT FROM AUTHOR]

Background: Glioblastoma is currently an incurable cancer. Genome-wide association studies have demonstrated that 41 genetic variants are associated with glioblastoma and may provide an option for drug development.Methods: We investigated FDA-approved antipsychotics for their potential treatment of glioblastoma based on genome-wide association studies data using a 'pathway/gene-set analysis' approach.Results: The in-silico screening led to the discovery of 12 candidate drugs. DepMap portal revealed that 42 glioma cell lines show higher sensitivities to 12 candidate drugs than to Temozolomide, the current standard treatment for glioblastoma.Conclusion: In particular, cell lines showed significantly higher sensitivities to Norcyclobenzaprine and Protriptyline which were predicted to bind targets to disrupt a certain molecular function such as DNA repair, response to hormones, or DNA-templated transcription, and may lead to an effect on survival-related pathways including cell cycle arrest, response to ER stress, glucose transport, and regulation of autophagy. However, it is recommended that their mechanism of action and efficacy are further determined. [ABSTRACT FROM AUTHOR]

Clozapine is the only antipsychotic with proven effectiveness in treatment-resistant schizophrenia. It is usually administered using commercially available oral tablets, but not all patients are willing or able to take medicines in this way. Orodispersible clozapine tablets are available from several manufacturers and may be useful where swallowing solid dosage forms is difficult, or as an aid to observe compliance. Liquid formulations of clozapine can be prepared extemporaneously or purchased commercially, but most preparations are suspensions (clozapine is poorly soluble) and patients may find them unpalatable. The administration of clozapine (suspension or crushed tablets) via enteral feeding tubes (predominantly nasogastric) has been reported both in medically unwell patients and in patients refusing clozapine. Enteral administration is likely to be superseded by intramuscular clozapine, which has recently been re-introduced and is being widely used in some countries. Successful use of this formulation in enforced treatment strategies has been described by several authors with good long-term outcomes when switched to oral treatment. Intramuscular clozapine has also been used in physically ill patients who are unable to take any form of enteral medication. Other methods of delivery (transdermal, nasal) are not yet commercially available, but offer promise of further treatment options for this group of seriously ill patients. [ABSTRACT FROM AUTHOR]

Although relapse is an important outcome to measure the effectiveness of schizophrenia treatment, no standard definition exists. This review aimed at identifying definitions and measurements of schizophrenia relapse in observational studies of long‐acting injectables (LAIs) versus oral antipsychotics (OAPs) and at determining their impact on heterogeneity of comparative effectiveness estimates. A systematic review was conducted using MEDLINE and Embase (01 January 2010–11 November 2019 [date last searched]). Pragmatic searches of gray literature and snowballing were also conducted. Search outputs were screened independently by two assessors at first stage, and full‐text of potentially eligible sources at second stage. For each retained source, definition and measurement of relapse, study methods, and comparative effectiveness estimates were extracted. Heterogeneity of estimates was assessed using I2 statistic with a threshold of 50% for substantial heterogeneity. Literature search yielded 543 sources and pragmatic searches, 21, of which 35 were eligible. Twelve definitions of relapse were found based on hospitalization/emergency department (ED) data (28 studies) or clinical assessment (5 studies). No definition was provided in five studies. According to quantitative analyses, in studies defining relapse as schizophrenia‐related hospitalization and/or ED visits over 1‐year follow‐up, LAIs were significantly more effective than OAPs. For studies measuring relapse based on all‐cause hospitalization, heterogeneity was too high for pooling; yet this definition is the most frequently found in pooled estimates published in the literature. Schizophrenia relapse definitions led to substantial heterogeneity of comparative effectiveness estimates of LAIs versus OAPs. Creating study subgroups based on relapse definition effectively reduces statistical heterogeneity. [ABSTRACT FROM AUTHOR]

Objective Cognitive improvement after antipsychotic agents in patients with schizophrenia (SCZ) appears to involve redox regulation through neurotrophins such as brain derived neurotropic factor (BDNF). This study examined whether cognitive improvement was associated with the increase in superoxide dismutase (SOD) and whether higher levels of BDNF could have a permissive role in allowing SOD to improve cognition. Methods We examined this hypothesis in 183 drug-naïve first-episode SCZ patients taking risperidone monotherapy for 12 weeks. We measured total copper-zinc SOD (CuZn-SOD), manganese SOD (Mn-SOD), and SOD activities and BDNF levels in these patients and compared their levels with 152 healthy controls. We assessed cognitive functioning and clinical symptoms at baseline and 12-week follow-up. Results After treatment with risperidone, CuZn-SOD activity was significantly increased, and BDNF levels were slightly increased. Increased CuZn-SOD activity was associated with the cognitive effectiveness of risperidone monotherapy. The BDNF levels and SOD activities were correlated at baseline but not after 12-week treatment. Furthermore, baseline CuZn-SOD activity positively correlated with improvement on the delayed memory subscale of the Repeatable Battery for the Assessment of Neuropsychological Status only in the high BDNF subgroup. Conclusions Our longitudinal study suggests that risperidone can enhance SOD activity and that, in combination with higher baseline BDNF levels acting in a permissive role, can improve cognitive impairments in SCZ. Greater baseline CuZn-SOD activity also may have predictive value for cognitive improvement of delayed memory in SCZ patients receiving risperidone treatment. [ABSTRACT FROM AUTHOR]

Background: Akathisia tends to develop as an early complication of antipsychotic treatment in a dose-dependent manner. Although withdrawal akathisia has been reported after the discontinuation or dose reduction of typical antipsychotic drugs, akathisia following atypical antipsychotic drug withdrawal remains a rare phenomenon. Case presentation: A 24-year-old woman with an acute psychotic episode was admitted and initially treated with aripiprazole. The aripiprazole dose was titrated up to 30 mg/day over 9 days and maintained for the next 3 days; however, her psychotic symptoms persisted without change. She was switched to amisulpride, with the dose increased over 2 weeks to 1000 mg/day. Subsequently, although the patient's psychotic episode subsided, her serum prolactin levels increased markedly. After discharge, the amisulpride dose was increased to 1200 mg/day owing to auditory hallucinations and was maintained with quetiapine (100–200 mg/day) and benztropine (1 mg/day) for 13 weeks. Given the potential for hyperprolactinemia as a side effect, the amisulpride dose was reduced to 800 mg/day concurrently with the discontinuation of benztropine; however, these changes resulted in severe restlessness without other extrapyramidal symptoms. The withdrawal akathisia disappeared over 2 weeks after switching to aripiprazole (10 mg/day) with propranolol (40 mg/day) and the patient's prolactin levels had normalized after 6 months of aripiprazole monotherapy. Conclusions: The present case highlights the potential for the development of withdrawal akathisia when the dose of amisulpride is tapered abruptly. Thus, a slow tapering and careful monitoring are recommended when switching from amisulpride to other antipsychotic drugs. Furthermore, this case suggests that changing the regimen to aripiprazole with propranolol may be a potential option for amisulpride withdrawal akathisia superimposed on pre-existing hyperprolactinemia. [ABSTRACT FROM AUTHOR]

Backgrounds: This meta‐analysis aimed to assess antipsychotic and placebo effects in patients with schizophrenia at the level of symptom factors. Methods: A systematic literature search up to June 2020 was undertaken and 62 studies were included, with 23,478 patients with schizophrenia at the study baseline point. We calculated mean differences with 95% confidence intervals. The comparison was made according to the study content using a continuous method with a random‐effects model. Results: Patients with schizophrenia treated by antipsychotic drugs had a significantly lower psychiatric rating scale total score; lower clinical global impression of severity; lower positive and negative syndrome scale; and lower assessment of negative symptoms total score, when compared to placebo treated patients. Conclusions: Patients with schizophrenia treated with an antipsychotic drug show a much greater improvement and lower inconsistency in the level of symptom factors when compared to the effects of placebo. Our findings evidence for a comparatively homogeneous outcome of the antipsychotic‐treatment in improving schizophrenia symptoms. This opposes the notion of the presence of patient sub‐groups with treatment non‐responsive schizophrenia. [ABSTRACT FROM AUTHOR]

Aims: Clozapine is licensed for treatment-resistant psychosis and remains underutilised. This may berelated to the stringent haematological monitoring requirements that are mandatory in most countries. We aimed to compare guidelines internationally and develop a novel Stringency Index. We hypothesised that the most stringent countries would have increased healthcare costs and reduced prescription rates. Method: We conducted a literature review and survey of guidelines internationally. Guideline identification involved a literature review and consultation with clinical academics. We focused on the haematological monitoring parameters, frequency and thresholds for discontinuation and rechallenge after suspected clozapine-induced neutropenia. In addition, indicators reflecting monitoring guideline stringency were scored and visualised using a choropleth map. We developed a Stringency Index with an international panel of clozapine experts, through a modified-Delphi-survey. The Stringency Index was compared to health expenditure per-capita and clozapine prescription per 100 000 persons. Results: One hundred twocountries were included, from Europe (n = 35), Asia (n = 24), Africa (n = 20), South America (n = 11), North America (n = 7) and Oceania and Australia (n = 5). Guidelines differed in frequency of haematological monitoring and discontinuation thresholds. Overall, 5% of included countries had explicit guidelines for clozapine-rechallenge and 40% explicitly prohibited clozapine-rechallenge. Furthermore, 7% of included countries had modified discontinuation thresholds for benign ethnic neutropenia. None of the guidelines specified how long haematological monitoring should continue. The most stringent guidelines were in Europe, and the least stringent were in Africa and South America. There was a positive association (r = 0.43, p < 0.001) between a country's Stringency Index and healthcare expenditure per capita. Conclusions: Recommendations on how haematological function should be monitored in patients treated with clozapine vary considerably between countries. It would be useful to standardise guidelines on haematological monitoring worldwide. [ABSTRACT FROM AUTHOR]

Aims: To evaluate the quality of mental health care delivered to patients with schizophrenia and related disorders taken-in-care by mental health services in four Italian regions (Lombardy, Emilia-Romagna, Lazio, Sicily). Methods: Thirty-one clinical indicators concerning accessibility, appropriateness, continuity and safety were defined and estimated using healthcare utilisation (HCU) databases, containing data on mental health treatments, hospital admissions, outpatient interventions, lab tests and drug prescriptions. Results: A total of 70 586 prevalent patients with schizophrenia and related disorders treated in 2015 were identified, of whom 1752 were newly taken-in-care by the facilities of regional mental health services. For most patients community care was accessible and moderately intensive. However, care pathways were not implemented based on a structured assessment and only half of the patients received psychosocial treatments. One patient out of ten had access to psychological interventions and psychoeducation. Activities specifically addressed to families involved a third of prevalent patients and less than half of new patients. One patient out of six was admitted to a community residential facility, and one out of ten to a General Hospital Psychiatric Ward (GHPW); higher values were identified in new cases. In general hospitals, few patients had a length of stay (LoS) of more than 30 days, while one-fifth of the admissions were followed by readmission within 30 days of discharge. For two-thirds of patients, continuity of community care was met, and six times out of ten a discharge from a GHPW was followed by an outpatient contact within 2 weeks. For cases newly taken-in-care, the continuity of community care was uncommon, while the readiness of outpatient contacts after discharge was slightly more frequent. Most of the patients received antipsychotic medication, but their adherence to long-term treatment was low. Antipsychotic polytherapy was frequent and the control of metabolic side effects was poor. The variability between regions was high and consistent in all the quality domains. Conclusions: The Italian mental health system could be improved by increasing the accessibility to psychosocial interventions, improving the quality of care for newly taken-in-care patients, focusing on somatic health and mortality, and reducing regional variability. Clinical indicators demonstrate the strengths and weaknesses of the mental health system in these regions, and, as HCU databases, they could be useful tools in the routine assessment of mental healthcare quality at regional and national levels. [ABSTRACT FROM AUTHOR]

The Dutch Clozapine Collaboration Group is frequently asked for advice about the management of clozapine-treated patients when infected with or vaccinated against SARS-CoV-2. We provide state of the art information about the risks of SARS-CoV-2 infection for patients on clozapine and we give advice on measures to be taken, especially in regard to the monitoring of clozapine plasma levels, WBC count and differentiation during COVID-19 and after vaccination. We present an overview of relevant editorials, observational studies, and case studies, in which COVID-19 was reported in patients on clozapine. Patients using clozapine may have a higher risk of infection than patients with schizophrenia spectrum disorders (SSD) using other antipsychotics. SARS-CoV-2 infection can result in a dangerous increase of clozapine plasma levels, and granulocytopenia and lymphocytopenia (generally mild and short-term) may also occur, usually not as a result of clozapine treatment. Clozapine intoxication, pneumonia and delirium are the main complications of COVID-19 in patients on clozapine. In order to prevent clozapine intoxication, reduction of the original dose by half is generally recommended in clozapine users who contract COVID-19. When a cytokine storm is suspected in an advanced stage of COVID-19, reduction by three quarters seems more appropriate. If COVID-19 patients on clozapine develop granulocytopenia, SARS-CoV-2, rather than clozapine, should be considered as the cause. Schizophrenia patients in general and clozapine users in particular belong to a high-risk group that warrants early vaccination on a medical indication. [ABSTRACT FROM AUTHOR]

A simple, cost-effective, and stability-indicating first-derivative spectrophotometric technique for quantifying Paliperidone in different pharmaceutical formulations is developed. In this method, the drug shows a maximum dA/dλ at 245 nm. The drug follows Beer–Lambert's law in the concentration range 2.5–70 μg/mL. Various degradation studies for the drug, such as acid hydrolysis, base hydrolysis, thermal, oxidative, and photolytic degradation are performed, and the results thereof are within the acceptable limit. The analytical method validation parameters like linearity, LOD, LOQ, precision, accuracy, etc. are conducted for the method as per the ICH Q2R(1) guideline, and the values are within the allowable range. Hence, for the determination of the Paliperidone quantity in pharmaceutical dosage forms, the developed process is a feasible one. [ABSTRACT FROM AUTHOR]

Ankyrin repeat and kinase domain containing 1 (ANKK1) is a member of the receptor-interacting protein serine/threonine kinase family, known to be involved in cell proliferation, differentiation and activation of transcription factors. Genetic variation within the ANKK1 locus is suggested to play a role in vulnerability to addictions. However, ANKK1 mechanism of action is still poorly understood. It has been suggested that ANKK1 may affect the development and/or functioning of dopaminergic pathways. To test this hypothesis, we generated a CRISPR-Cas9 loss of function ankk1 zebrafish line causing a 27 bp insertion that disrupts the ankk1 sequence introducing an early stop codon. We found that ankk1 transcript levels were significantly lower in ankk1 mutant (ankk127ins) fish compared to their wild type (ankk1+/+) siblings. In ankk1+/+ adult zebrafish brain, ankk1 protein was detected in isocortex, hippocampus, basolateral amygdala, mesencephalon, and cerebellum, resembling the mammalian distribution pattern. In contrast, ankk1 protein was reduced in the brain of ankk127ins/27ins fish. Quantitative polymerase chain reaction analysis revealed an increase in expression of drd2b mRNA in ankk127ins at both larval and adult stages. In ankk1+/+ adult zebrafish brain, drd2 protein was detected in cerebral cortex, cerebellum, hippocampus, and caudate homolog regions, resembling the pattern in humans. In contrast, drd2 expression was reduced in cortical regions of ankk127ins/27ins being predominantly found in the hindbrain. No differences in the number of cell bodies or axonal projections detected by anti-tyrosine hydroxylase immunostaining on 3 days post fertilization (dpf) larvae were found. Behavioral analysis revealed altered sensitivity to effects of both amisulpride and apomorphine on locomotion and startle habituation, consistent with a broad loss of both pre and post synaptic receptors. Ankk127ins mutants showed reduced sensitivity to the effect of the selective dopamine receptor antagonist amisulpride on locomotor responses to acoustic startle and were differentially sensitive to the effects of the non-selective dopamine agonist apomorphine on both locomotion and habituation. Taken together, our findings strengthen the hypothesis of a functional relationship between ANKK1 and DRD2, supporting a role for ANKK1 in the maintenance and/or functioning of dopaminergic pathways. Further work is needed to disentangle ANKK1’s role at different developmental stages.

Clinical drug development in psychiatry is challenging due to heterogeneous patient populations and the uncertainty of measuring neuropsychiatric constructs with symptom rating scales. Here we describe the development and implementation of an enrichment algorithm that identifies canonical versus anomalous symptom presentations, at the individual subject level, based on MADRS ratings obtained at screening and baseline. Data from 5 randomized, placebo-controlled, phase 3 trials in bipolar I disorder was used (N = 2026 subjects and 15,239 MADRS assessments). A variance-covariance difference (VCD) vector was developed to encode individual symptom structure using the 10 items of MADRS from the two sequential assessments. An anomaly score, calculated from each subject's VCD vector was derived by isolation forest to quantify the degree of disparity from the hypothesized canonical item structure. A retrospective application of the algorithm reliably identified a threshold anomaly score above which the psychometric properties of MADRS deteriorate. Consistent with increasing the certainty of MADRS ratings, subjects with a canonical symptom structure at baseline demonstrated greater effect sizes post-baseline in a phase 2 placebo-controlled trial of non-racemic amisulpride (SEP-4199) for bipolar depression, analyzed retrospectively. Our analyses show that the developed algorithm can reduce the symptom structure heterogeneity at baseline and thus improve the measurement certainty of psychiatric symptoms in clinical trials. This novel enrichment method has been prospectively implemented in a Phase 3 clinical study of SEP-4199 and is consistent with regulatory guidelines aimed at increasing the statistical power and lowering patient-burden in clinical trials. Clinical Trials Registry: NCT00868452, NCT00868699, NCT01284517, NCT01986101, NCT03543410, NCT05169710., Competing Interests: Declaration of competing interest SCH, ST, STS and KSK are employees of Sumitomo Pharma America, Inc. (formerly Sunovion Pharmaceuticals)., (Copyright © 2024 Elsevier Inc. All rights reserved.)