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Objective To determine if the cardiac function and "endocrinium" of Chinese patients are associated with dopamine D2 (DRD2) (rs6276) and DRD3 (rs6280, rs963468) genetic polymorphisms when treated with amisulpride. Methods This study enrolled 148 patients with schizophrenia who took amisulpride orally for 8 weeks. DRD2 (rs6276) and DRD3 (rs6280, rs963468) genetic polymorphisms were detected with TaqMan-MGB allelic discrimination. Results Analysis by multivariate covariance analysis (MANCOVA) showed that after adjusting for age, gender, and the baseline level, the increase in the level of aspartate aminotransferase (AST) and creatine kinase (CK) in the rs6276 AG group was higher than that in the AA and GG groups. Similarly, the changed estradiol (E2) level in rs6276 GG and rs963468 GG groups was higher than that in the other two groups. Adjusting for covariates, the increased triglyceride (TG) level in rs6276 GG and rs963468 GG groups was the highest among their different genotype groups. The increase in the level of "AST" in the rs6280 TT group was higher than that in the CC and CT groups upon adjusting for covariates. Similarly, MANCOVA showed that the increase in the level of "CK" in the rs6280 CT group was higher than that in the CC and CT groups. Besides, the increased level of "PRL" in the rs6280 CC group and rs963468 GG group was higher than that in their other two genotypes groups. ConclusionDRD2 (rs6276) and DRD3 (rs6280, rs963468) polymorphisms can affect amisulpride tolerability since they are associated with the observed adverse reactions, including cardiac dysfunction and endocrine disorders in Chinese patients with schizophrenia. [ABSTRACT FROM AUTHOR]

Schizophrenia is a serious mental disorder, and monitoring remission is a widely used measure of effectiveness of the treatment provided. It is very important to identify possible factors correlating with remission. In our substudy of BeSt InTro, a randomized controlled trial of three antipsychotic drugs, 126 patients with ICD-10 diagnoses F20–29 (F23 excluded) were randomized to one of the second-generation antipsychotic drugs amisulpride, aripiprazole or olanzapine. Remission rate was calculated at seven assessment points, with and without using the time criterion of six months included in the consensus remission criteria. Because of drop-out (n = 77), we had data for 49 patients at one-year follow-up. These data were used to calculate the one-year remission rate to 55 % (27/49), without taking into consideration the 6-month time criterion. When we applied the consensus remission criteria with the 6-month time criterion included, the one-year remission rate was calculated for 59 patients: 29 % (17/59). Antipsychotic drug naivety and low negative symptom load at baseline correlated highly with belonging to the remission group. Use of amisulpride was more probable to lead to remission than that of aripiprazole, but it was not more probable than the use of olanzapine (in per-protocol analyses). Negative symptoms showed the largest resistance to treatment. The lack of remission for the majority of the participants in this closely monitored antipsychotic drug trial is alarming and could act as a reminder that novel treatment principles are needed, especially targeted towards the negative symptoms in schizophrenia. [ABSTRACT FROM AUTHOR]

Identifying stable and consistent resting-state functional connectivity patterns across illness trajectories has the potential to be considered fundamental to the pathophysiology of schizophrenia. We aimed to identify consistent resting-state functional connectivity patterns across heterogeneous schizophrenia groups defined based on treatment response. In phase 1, we used a cross-sectional case-control design to characterize and compare stable independent component networks from resting-state functional magnetic resonance imaging scans of antipsychotic-naïve participants with first-episode schizophrenia (n = 54) and healthy participants (n = 43); we also examined associations with symptoms, cognition, and disability. In phase 2, we examined the stability (and replicability) of our phase 1 results in 4 groups (N = 105) representing a cross-sequential gradation of schizophrenia based on treatment response: risperidone responders, clozapine responders, clozapine nonresponders, and clozapine nonresponders following electroconvulsive therapy. Hypothesis-free whole-brain within- and between-network connectivity were examined. Phase 1 identified posterior and anterior cerebellar hypoconnectivity and limbic hyperconnectivity in schizophrenia at a familywise error rate–corrected cluster significance threshold of p <.01. These network aberrations had unique associations with positive symptoms, cognition, and disability. During phase 2, we replicated the phase 1 results while comparing each of the 4 schizophrenia groups to the healthy participants. The participants in 2 longitudinal subdatasets did not demonstrate a significant change in these network aberrations following risperidone or electroconvulsive therapy. Posterior cerebellar hypoconnectivity (with thalamus and cingulate) emerged as the most consistent finding; it was replicated across different stages of treatment response (Cohen's d range −0.95 to −1.44), reproduced using different preprocessing techniques, and not confounded by educational attainment. Posterior cerebellar-thalamo-cingulate hypoconnectivity is a consistent and stable state-independent neural marker of schizophrenia. [ABSTRACT FROM AUTHOR]

Background: Among psychiatric illnesses, schizophrenia remains a chronic debilitating disorder. Although newer atypical antipsychotics have shown better improvement in schizophrenia patients, they are still lacking conclusive evidence-based studies. Aims and Objectives: The comparative evaluation of amisulpride versus olanzapine in terms of therapeutic efficacy and their cost in schizophrenia patients. Materials and Methods: This was a prospective, randomized, open-label comparative study. Patients diagnosed with schizophrenia were randomly allocated into two treatment arms. One group (n = 50) was treated with olanzapine, and another group (n = 50) was treated with amisulpride. Patients were followed up for 12 weeks. Positive and negative syndrome scale score assessments were done to evaluate the efficacy parameter. Antipsychotic drug costs were also studied. Results: In the treatment duration, it was observed that the positive and negative syndrome scores were 42.7% in the olanzapine-administered group, whereas the score was 33.8% in patients treated with amisulpride. The reduction in clinical global impression (CGI) score was 57% in the olanzapine group and 37% in the amisulpride group. The cost range for amisulpride was (Rs) 52.5-115.9 and for olanzapine was (Rs) 6.7-13.1 per positive and negative syndrome score improvement. Conclusion: A significant decrease in positive and negative syndrome scores and CGI scores was evident in both groups treated with amisulpride and olanzapine, but olanzapine is more efficacious and cost-effective than amisulpride. [ABSTRACT FROM AUTHOR]

Serotonin 5-HT7 receptors (5-HT7R) are attracting increasing attention as important participants in the mechanisms of Alzheimer’s disease and as a possible target for the treatment of various tau pathologies. In this study, we investigated the effects of amisulpride (5-HT7R inverse agonist) in C57BL/6J mice with experimentally induced expression of the gene encoding the aggregation-prone human Tau[R406W] protein in the prefrontal cortex. In these animals we examined short-term memory and the expression of genes involved in the development of tauopathy (Htr7 and Cdk5), as well as biomarkers of neurodegenerative processes – the Bdnf gene and its receptors TrkB (the Ntrk2 gene) and p75NTR (the Ngfr gene). In a short-term memory test, there was no difference in the discrimination index between mice treated with AAV-Tau[R406W] and mice treated with AAV-EGFP. Amisulpride did not affect this parameter. Administration of AAV-Tau[R406W] resulted in increased expression of the Htr7, Htr1a, and Cdk5 genes in the prefrontal cortex compared to AAV-EGFP animals. At the same time, amisulpride at the dose of 10 mg/kg in animals from the AAV-Tau[R406W] group caused a decrease in the Htr7, Htr1a genes mRNA levels compared to animals from the AAV-Tau[R406W] group treated with saline. A decrease in the expression of the Bdnf and Ntrk2 genes in the prefrontal cortex was revealed after administration of AAV-Tau[R406W]. Moreover, amisulpride at various doses (3 and 10 mg/kg) caused the same decrease in the transcription of these genes in mice without tauopathy. It is also interesting that in mice of the AAV-EGFP group, administration of amisulpride at the dose of 10 mg/kg increased the Ngfr gene mRNA level. The data obtained allow us to propose the use of amisulpride in restoring normal tau protein function. However, it should be noted that prolonged administration may result in adverse effects such as an increase in Ngfr expression and a decrease in Bdnf and Ntrk2 expression, which is probably indicative of an increase in neurodegenerative processes.

Background: Recent studies have shown that liver enzyme abnormalities were not only seen with typical antipsychotics (APs) but also with atypical antipsychotics (AAPs). During the last 20 years, the hepatotoxicity of various antipsychotics received much attention. However, systematic evaluations of hepatotoxicity associated with APs are limited. Methods: All drug related hepatic disorders cases were retrieved from the FDA Adverse Event Reporting System (FAERS) database using standardized MedDRA queries (SMQ) from the first quarter of 2017 to the first quarter of 2022. Patient characteristics and prognosis were assessed. In this study, a case/non-case approach was used to calculate reporting odds ratio (RORs) and 95% confidence intervals (CIs). We calculated the drug-induced liver injury (DILI) RORs for each AAPs. Results: A total of 408 DILI cases were attributed to AAPs during the study period. 18.6% of these were designated as serious adverse event (SAE), which include death (19.74%), hospitalization (68.42%), disability (2.63%), and life-threatening (9.21%) outcomes. The RORs values in descending order were: quetiapine (ROR = 0.782), clozapine (ROR = 0.665), aripiprazole (ROR = 0.507), amisulpride (ROR = 0.308), paliperidone (ROR = 0.212), risperidone (ROR = 0.198), ziprasidone (0.131). Conclusion: The result found in our study was that all AAPs didn't have a significant correlation with increased hepatotoxicity. Future analysis of the FAERS database in conjunction with other data sources will be essential for continuous monitoring of DILI. [ABSTRACT FROM AUTHOR]

Background Method Results Conclusion Facial expressions are a core aspect of non‐verbal communication. Reduced emotional expressiveness of the face is a common negative symptom of schizophrenia, however, quantifying negative symptoms can be clinically challenging and involves a considerable element of rater subjectivity. We used computer vision to investigate if (i) automated assessment of facial expressions captures negative as well as positive and general symptom domains, and (ii) if automated assessments are associated with treatment response in initially antipsychotic‐naïve patients with first‐episode psychosis.We included 46 patients (mean age 25.4 (6.1); 65.2% males). Psychopathology was assessed at baseline and after 6 weeks of monotherapy with amisulpride using the Positive and Negative Syndrome Scale (PANSS). Baseline interview videos were recorded. Seventeen facial action units (AUs), that is, activation of muscles, from the Facial Action Coding System were extracted using OpenFace 2.0. A correlation matrix was calculated for each patient. Facial expressions were identified using spectral clustering at group‐level. Associations between facial expressions and psychopathology were investigated using multiple linear regression.Three clusters of facial expressions were identified related to different locations of the face. Cluster 1 was associated with positive and general symptoms at baseline, Cluster 2 was associated with all symptom domains, showing the strongest association with the negative domain, and Cluster 3 was only associated with general symptoms. Cluster 1 was significantly associated with the clinically rated improvement in positive and general symptoms after treatment, and Cluster 2 was significantly associated with clinical improvement in all domains.Using automated computer vision of facial expressions during PANSS interviews did not only capture negative symptoms but also combinations of the three overall domains of psychopathology. Moreover, automated assessments of facial expressions at baseline were associated with initial antipsychotic treatment response. The findings underscore the clinical relevance of facial expressions and motivate further investigations of computer vision in clinical psychiatry. [ABSTRACT FROM AUTHOR]

Extensive research has been undertaken to predict treatment response (TR) to antipsychotics. Most studies address TR to antipsychotics in general and as monotherapy, however, it is unknown whether patients might respond favourably to a combination of antipsychotics. This study aimed to identify differential predictors for TR to monotherapy with amisulpride or olanzapine compared to a combination of antipsychotics. Post-hoc analysis was conducted of data collected from the COMBINE-study, a double-blind, randomized, controlled trial. Demographic and disease-related measures were gathered at baseline to predict TR after eight weeks defined by the Positive and Negative Syndrome Scale. Missing values were accounted for by a random replacement procedure. Attrition effects and multicollinearity were analysed and sets of logistic regression models were calculated for different treatment groups. Of the 321 randomized patients, 201 completed procedures until week eight and 197 were included in the analyses. For all treatment groups, early TR after two weeks and high subjective well-being under antipsychotics at baseline were robust predictors for TR. The propensity for early side effects also indicated a higher risk of later non-response. Specific parameter estimates were rather similar between treatment groups. Early TR, drug-related subjective well-being, and early side effect propensity evolved as predictors for later TR whether to monotherapy or combination strategy. Accordingly, due to a lack of differential predictors, early and close monitoring of targeted and unwanted effects is indicated to guide respective treatment decisions. [ABSTRACT FROM AUTHOR]

Despite the high prevalence of anxiety in schizophrenia, no established guideline exists for the management of these symptoms. We aimed to synthesize evidence on the effect of second-generation antipsychotics (SGAs) on anxiety in patients with schizophrenia. We systematically searched Medline, Embase, PsycInfo, Web of Science, PubMed, and Cochrane library to identify randomized controlled trials of SGAs that reporting anxiety measures in schizophrenia. The search was limited to English-language articles published before February 2024. Data were pooled using a random-effects model. Among 48 eligible studies, 29 (n = 7712) were included in the meta-analyses comparing SGAs to placebo, haloperidol, or another SGAs for their effect on anxiety/depression. SGAs had a small effect on anxiety/depression versus placebo (SMD = −0.28 (95 % CI [−0.34, −0.21], p <.00001, I2 = 47 %, n = 5576)) associated with efficacy for positive (z = 5.679, p <.001) and negative symptoms (z = 4.490, p <.001). Furthermore, SGAs were superior to haloperidol (SMD = −0.44, 95 % CI [−0.75, −0.13], p =.005, n = 1068) with substantial study-level heterogeneity (I2 = 85 %). Excluding one study of quetiapine in first-episode patients (SMD = −3.05, n = 73), SGAs showed a small effect on anxiety/depression versus haloperidol without heterogeneity (SMD = −0.23, 95 % CI [−0.35, −0.12], p = 01; I2 = %0). Risperidone's effect on anxiety/depression was comparable to olanzapine (SMD = −0.02, 95 % CI [−0.24,0.20], p =.87, I2 = 45 %, n = 753) and amisulpride (SMD = 0.27, 95 % CI [−1.08,0.61], p =.13, I2 = 50 %, n = 315). While SGAs showed a small effect on anxiety/depression, the findings are inconclusive due to scarcity of research on comorbid anxiety in schizophrenia, heterogeneity of anxiety symptoms, and the scales used to measure anxiety. Further studies employing specific anxiety scales are required to explore antipsychotics, considering their receptor affinity and augmentation with serotonin/norepinephrine reuptake inhibitors or benzodiazepines for managing anxiety in schizophrenia. [ABSTRACT FROM AUTHOR]

Nonracemic amisulpride (SEP‐4199) is an investigational 85:15 ratio of aramisulpride to esamisulpride and currently in clinical trials for the treatment of bipolar depression. During testing of SEP‐4199, a pharmacokinetic/pharmacodynamic (PK/PD) disconnect was discovered that prompted the development of a controlled‐release (CR) formulation with improved therapeutic index for QT prolongation. Observations that supported the development of a CR formulation included (i) plasma concentrations of amisulpride enantiomers were cleared within 24‐hours, but brain dopamine D2 receptor (D2R) occupancies, although achieving stable levels during this time, required 5 days to return to baseline; (ii) nonracemic amisulpride administered to non‐human primates produced significantly greater D2R occupancies during a gradual 6‐hour administration compared with a single bolus; (iii) concentration–occupancy curves were left‐shifted in humans when nonracemic amisulpride was gradually administered over 3 and 6 hours compared with immediate delivery; (iv) CR solid oral dose formulations of nonracemic amisulpride were able to slow drug dissolution in vitro and reduce peak plasma exposures in vivo in human subjects. By mathematically solving for a drug distribution step into an effect compartment, and for binding to target receptors, the discovery of a novel PK/PD model (termed here as Distribution Model) accounted for hysteresis between plasma and brain, a lack of receptor saturation, and an absence of accumulation of drug occupancy with daily doses. The PK/PD disconnect solved by the Distribution Model provided model‐informed drug development to continue in Phase III using the non‐bioequivalent CR formulation with diminished QT prolongation as dose‐equivalent to the immediate release (IR) formulation utilized in Phase II. [ABSTRACT FROM AUTHOR]

Background: Shared decision-making (SDM) has yet to be successfully adopted into routine use in psychiatric settings amongst people living with severe mental illnesses. Suboptimal rates of SDM are particularly prominent amongst patients with psychotic illnesses during antipsychotic treatment choices. Many interventions have been assessed for their efficacy in improving SDM within this context, although results have been variable and inconsistent. Aims: To generate an in-depth understanding of how, why, for whom, and to what extent interventions facilitating the application of SDM during antipsychotic treatment choices work and the impact of contextual factors on intervention effectiveness. Methods: This review will use realist review methodology to provide a causal understanding of how and why interventions work when implementing SDM during antipsychotic treatment choices. The cohort of interest will be those experiencing psychosis where ongoing treatment with an antipsychotic is clinically indicated. The review will take place over five stages; (1) Locating existing theories, (2) Searching for evidence, (3) Selecting articles, (4) Extracting and organising data and (5) Synthesizing evidence and drawing conclusions. An understanding of how and why interventions work will be achieved by developing realist programme theories on intervention effectiveness through iterative literature reviews and engaging with various stakeholder groups, including patient, clinician and carer representatives. Discussion: This is the first realist review aiming to identify generative mechanisms explaining how and why successful interventions aimed at improving SDM within the parameters outlined work and in which contexts desired outcomes are most likely to be achieved. Review findings will include suggestions for clinicians, policy and decision-makers about the most promising interventions to pursue and their ideal attributes. [ABSTRACT FROM AUTHOR]

Clozapine is the only approved antipsychotic for treatment-resistant schizophrenia (TRS). Although a large body of evidence supports its efficacy and favorable risk-benefit ratio in individuals who have failed two or more antipsychotics, clozapine remains underused. However, variations in clozapine utilization across geographic and clinical settings suggest that it could be possible to improve its use. In this narrative review and expert opinion, we summarized information available in the literature on the mechanisms of action, effectiveness, and potential adverse events of clozapine. We identified barriers leading to discouragement in clozapine prescription internationally, and we proposed practical solutions to overcome each barrier. One of the main obstacles identified to the use of clozapine is the lack of appropriate training for physicians: we highlighted the need to develop specific professional programs to train clinicians, both practicing and in residency, on the relevance and efficacy of clozapine in TRS treatment, initiation, maintenance, and management of potential adverse events. This approach would facilitate physicians to identify eligible patients and offer clozapine as a treatment option in the early stage of the disease. We also noted that increasing awareness of the benefits of clozapine among healthcare professionals, people with TRS, and their caregivers can help promote the use of clozapine. Educational material, such as leaflets or videos, could be developed and distributed to achieve this goal. The information provided in this article may be useful to improve disease burden and support healthcare professionals, patients, and caregivers navigating the complex pathways to TRS management. [ABSTRACT FROM AUTHOR]

Aims: This study aimed to assess the frequency of dosing inconsistencies in prescription data and the effect of four dosing assumption strategies on adherence estimates for antipsychotic treatment. Methods: A retrospective cohort, which linked prescription and dispensing data of adult patients with ≥1 antipsychotic prescription between 2015‐2016 and followed up until 2019, in Catalonia (Spain). Four strategies were proposed for selecting the recommended dosing in overlapping prescription periods for the same patient and antipsychotic drug: (i) the minimum dosing prescribed; (ii) the dose corresponding to the latest prescription issued; (iii) the highest dosing prescribed; and (iv) all doses included in the overlapped period. For each strategy, one treatment episode per patient was selected, and the Continuous Medication Availability measure was used to assess adherence. Descriptive statistics were used to describe results by strategy. Results: Of the 277 324 prescriptions included, 76% overlapped with other prescriptions (40% with different recommended dosing instructions). The number and characteristics of patients and treatment episodes (18 292, 18 303, 18 339 and 18 536, respectively per strategy) were similar across strategies. Mean adherence was similar between strategies, ranging from 57 to 60%. However, the proportion of patients with adherence ≥90% was lower when selecting all doses (28%) compared with the other strategies (35%). Conclusion: Despite the high prevalence of overlapping prescriptions, the strategies proposed did not show a major effect on the adherence estimates for antipsychotic treatment. Taking into consideration the particularities of antipsychotic prescription practices, selecting the highest dose in the overlapped period seemed to provide a more accurate adherence estimate. [ABSTRACT FROM AUTHOR]

A major effort of the pharmaceutical industry has been to identify and market drug treatments that are effective in ameliorating the symptoms of psychotic illness but without the limitations of the current treatments acting at dopamine D2 receptors. These limitations include the induction of a range of adverse effects, the inadequate treatment response of a substantial proportion of people with schizophrenia, and the generally poor response to negative and cognitive features of the disease. Recently introduced drug treatments have gone some way to avoiding the first of these, with a reduced propensity for weight gain, cardiovascular risk and extrapyramidal motor effects. Despite claims of some small improvements in negative symptoms, these drugs have not demonstrated substantial increases in efficacy. Of the drugs currently in development as antipsychotic agents, several are misleadingly described as having novel 'non-dopaminergic' mechanisms that may offer improvements in addressing the limitations of adverse effects and efficacy. It will be argued, using the trace amine-associated receptor 1 agonist as an example, that several of these new drugs still act primarily through modulation of dopaminergic neurotransmission and, in not addressing the primary pathology of schizophrenia, are therefore unlikely to have the much-needed improvements in efficacy required to address the unmet need associated with resistance to current treatments. [ABSTRACT FROM AUTHOR]

To investigate the efficacy and tolerability of medications, such as mouthwash use of 1 % atropine sulfate and tropicamide drops, oral amitriptyline and amisulpride used for clozapine-induced hypersalivation (CIH). The medical charts of inpatients with psychotic disorders between 2010 and 2022 were reviewed retrospectively. We detected 161 patients with eligible data who received or commenced clozapine. Primary outcome was defined as the percentage change in the diameter of a wet patch on the pillow (DWP) for improvements in CIH. The frequency of CIH was 42 % (n = 68). The first step medications for CIH were tropicamide drops (49 %), atropine drops (43 %) and amitriptyline (3 %). After the first step, the median DWP significantly decreased by −33 %. During the index hospitalization, in 18 patients with persistent CIH, the median DWP significantly decreased by −42 % with the second step medications which also included amisulpride. There were no reported serious adverse events. The change in DWP was significantly correlated with the duration of clozapine treatment (r = 306) and clozapine serum level at discharge (r = 0.294). A linear regression model showed a link between the change in DWP and reduced Positive and Negative Syndrome Scale scores. Our findings emphasize that mouthwash use of atropine or tropicamide drops has a satisfying and tolerable effect in treating CIH. Switching medications for CIH seems to be effective when CIH persists despite a first step agent. Controlled follow-up studies are needed to understand the relationship between CIH, clozapine serum levels, illness severity, and functioning. [ABSTRACT FROM AUTHOR]

Abstract Psychiatric drugs do not vanish after being carried to wastewater treatment plants by the urine or feces of patients and, a variable portion of their dose and also unused or expired drugs are lost to the environment. This is because the technology of plants is not intended to eradicate pharmaceuticals and their metabolites. Above all, psychotropics can change population dynamics and behavior at lower doses. We believe that antipsychotics have not gotten enough attention when it comes to drug pollution and that their importance as environmental pollutants has been underestimated. An innovative approach to eliminating pharmaceutical pollutants from water is the application of advanced oxidation methods. Among these oxidation methods are photocatalysis, ozonation, UV/hydrogen peroxide oxidation, and photo-Fenton oxidation. Photocatalytic degradation of pharmaceuticals is now the most widely used method since it is affordable and ecologically beneficial due to the reusable nature of the photocatalyst. When light is absorbed during photocatalytic degradation, electrons in the valence band (VB) get excited and migrate into the conduction band (CB). Consequently, hydroxyl radicals (•OH) are produced by VB’s holes carrying out oxidation processes on photocatalyst surfaces. The charge difference between the two bands encourages reduction reactions by CB electrons at the surface. To perform successfully, a photocatalyst has to have enough surface-active sites, a favorable band edge location, modest bandgap energy, increased charge separation, and charge transfer. Due to the above-mentioned concerns, the investigation and analysis of the photocatalytic degradation of six psychiatric drugs—carbamazepine, sertraline, amisulpride, amitriptyline, diazepam, and alprazolam—are the main objectives of this review.

[Display omitted] Synaptic dysfunction is a core component of the pathophysiology of schizophrenia. However, the genetic risk factors and molecular mechanisms related to synaptic dysfunction are still not fully understood. The Stonin 2 (STON2) gene encodes a major adaptor for clathrin-mediated endocytosis (CME) of synaptic vesicles. In this study, we showed that the C–C (307Pro-851Ala) haplotype of STON2 increases the susceptibility to schizophrenia and examined whether STON2 variations cause schizophrenia-like behaviors through the regulation of CME. We found that schizophrenia-related STON2 variations led to protein dephosphorylation, which affected its interaction with synaptotagmin 1 (Syt1), a calcium sensor protein located in the presynaptic membrane that is critical for CME. STON2307Pro851Ala knockin mice exhibited deficits in synaptic transmission, short-term plasticity, and schizophrenia-like behaviors. Moreover, among seven antipsychotic drugs, patients with the C-C (307Pro-851Ala) haplotype responded better to haloperidol than did the T-A (307Ser-851Ser) carriers. The recovery of deficits in Syt1 sorting and synaptic transmission by acute administration of haloperidol effectively improved schizophrenia-like behaviors in STON2307Pro851Ala knockin mice. Our findings demonstrated the effect of schizophrenia-related STON2 variations on synaptic dysfunction through the regulation of CME, which might be attractive therapeutic targets for treating schizophrenia-like phenotypes. [ABSTRACT FROM AUTHOR]

Psychiatric drugs do not vanish after being carried to wastewater treatment plants by the urine or feces of patients and, a variable portion of their dose and also unused or expired drugs are lost to the environment. This is because the technology of plants is not intended to eradicate pharmaceuticals and their metabolites. Above all, psychotropics can change population dynamics and behavior at lower doses. We believe that antipsychotics have not gotten enough attention when it comes to drug pollution and that their importance as environmental pollutants has been underestimated. An innovative approach to eliminating pharmaceutical pollutants from water is the application of advanced oxidation methods. Among these oxidation methods are photocatalysis, ozonation, UV/hydrogen peroxide oxidation, and photo-Fenton oxidation. Photocatalytic degradation of pharmaceuticals is now the most widely used method since it is affordable and ecologically beneficial due to the reusable nature of the photocatalyst. When light is absorbed during photocatalytic degradation, electrons in the valence band (VB) get excited and migrate into the conduction band (CB). Consequently, hydroxyl radicals (•OH) are produced by VB's holes carrying out oxidation processes on photocatalyst surfaces. The charge difference between the two bands encourages reduction reactions by CB electrons at the surface. To perform successfully, a photocatalyst has to have enough surface-active sites, a favorable band edge location, modest bandgap energy, increased charge separation, and charge transfer. Due to the above-mentioned concerns, the investigation and analysis of the photocatalytic degradation of six psychiatric drugs—carbamazepine, sertraline, amisulpride, amitriptyline, diazepam, and alprazolam—are the main objectives of this review. [ABSTRACT FROM AUTHOR]

Approximately 8 % of patients with schizophrenia are diagnosed before age 18, and 18 % experience their first symptoms before age 18. This narrative review explores the management of patients with early-onset schizophrenia (EOS) and childhood-onset schizophrenia (COS) from diagnosis to their transition to adult care settings. Early diagnosis of schizophrenia in children and adolescents is essential for improving outcomes, but delays are common due to overlapping of symptoms with developmental phenomena and other psychiatric conditions, including substance use, and lack of clinicians' awareness. Once diagnosed, antipsychotic treatment is key, with specific second-generation agents generally being preferred due to better tolerability and their broader efficacy evidence-base in youth. Dosing should be carefully individualized, considering age-related differences in drug metabolism and side effect liability. Clinicians must be vigilant in detecting early non-response and consider switching or dose escalation when appropriate. Since early age of illness onset is a consistent risk factor for treatment-resistant schizophrenia (TRS), clinicians need to be competent in diagnosing TRS and using clozapine. Since COS and EOS are associated with cognitive deficits and impaired functioning, psychosocial interventions should be considered to improve overall functioning and quality of life. Good long-term outcomes depend on continuous treatment engagement, and successful transitioning from pediatric to adult care requires careful planning, early preparation, and collaboration between pediatric and adult clinicians. Targeting functional outcomes and quality of life in addition to symptom remission can improve overall patient well-being. Comprehensive evaluations, age-specific assessments, and targeted interventions are needed to address the unique challenges of EOS and COS. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Post-schizophrenic depression (PSD) increases the morbidity, mortality, and health burden in patients with schizophrenia. However, treatment of PSD is challenging due to the lack of substantial evidence of standard clinical practice. This study was aimed at comparing the efficacy and safety of low-dose amisulpride versus olanzapine-fluoxetine combination (OFC) in PSD. This was a randomized controlled trial conducted in sixty patients with PSD fulfilling the eligibility criteria. Recruited patients were randomized to receive either amisulpride at low dose (i.e., 100–300 mg/day) or OFC (5/10 mg + 20 mg) for eight weeks. The Calgary Depression Scale for Schizophrenia (CDSS), the Clinical Global Impression-Severity (CGI-S) and serum BDNF levels were assessed at baseline and after eight weeks of treatment. The change in the CDSS scores from baseline over eight weeks was significant in both the amisulpride and OFC groups. However, the changes were not significant when compared between the groups. Similarly, the changes in CGI-S scores and serum BDNF levels were significant in each group; but non-significant between the groups. A significant negative correlation was found between the changes in the CDSS scores and the serum BDNF levels in each group. No significant adverse events were noted in either group. Thus, to conclude, low-dose amisulpride can be a potential monotherapy in PSD with a favourable clinical outcome and safety profile (ClinicalTrials.gov ID: NCT04876521). [ABSTRACT FROM AUTHOR]

Background: Treatment effects of conventional approaches with antipsychotics or psychosocial interventions are limited when it comes to reducing negative and cognitive symptoms in schizophrenia. While there is emerging clinical evidence that new, augmented protocols based on theta-burst stimulation can increase rTMS efficacy dramatically in depression, data on similar augmented therapies are limited in schizophrenia. The different patterns of network impairments in subjects may underlie that some but not all patients responded to given stimulation locations. Methods: Therefore, we propose an augmented theta-burst stimulation protocol in schizophrenia by stimulating both locations connected to negative symptoms: (1) the left dorsolateral prefrontal cortex (DLPFC), and (2) the vermis of the cerebellum. Ninety subjects with schizophrenia presenting negative symptoms and aging between 18 and 55 years will be randomized to active and sham stimulation in a 1:1 ratio. The TBS parameters we adopted follow the standard TBS protocols, with 3-pulse 50-Hz bursts given every 200 ms (at 5 Hz) and an intensity of 100% active motor threshold. We plan to deliver 1800 stimuli to the left DLPFC and 1800 stimuli to the vermis daily in two 9.5-min blocks for 4 weeks. The primary endpoint is the change in negative symptom severity measured by the Positive and Negative Syndrome Scale (PANSS). Secondary efficacy endpoints are changes in cognitive flexibility, executive functioning, short-term memory, social cognition, and facial emotion recognition. The difference between study groups will be analyzed by a linear mixed model analysis with the difference relative to baseline in efficacy variables as the dependent variable and treatment group, visit, and treatment-by-visit interaction as independent variables. The safety outcome is the number of serious adverse events. Discussion: This is a double-blind, sham-controlled, randomized medical device study to assess the efficacy and safety of an augmented theta-burst rTMS treatment in schizophrenia. We hypothesize that social cognition and negative symptoms of patients on active therapy will improve significantly compared to patients on sham treatment. Trial registration: The study protocol is registered at "ClinicalTrials.gov" with the following ID: NCT05100888. All items from the World Health Organization Trial Registration Data Set are registered. Initial release: 10/19/2021. [ABSTRACT FROM AUTHOR]

Clozapine (CZ) is a prescribed benzodiazepine psychiatric drug that is often possessed as an illicit drug and is associated with drug-facilitated sexual assaults (DFSA) due to its strong sedative capabilities. Hence, we propose an electrified liquid–liquid interface (eLLI) based transducing element as an alternative electroanalytical platform for rapid screening of CZ in soft and hard drinks which is habitually associated with DFSA crimes. First, molecular partitioning and the effect of chemical composition, pH, and the presence of ethanol in the biphasic configuration of the aqueous phase on the interfacial behaviour and analytical performance of the CZ at the eLLI have been investigated with voltammetry. Next, the electrochemical profiles of various soft and hard drinks were studied at the eLLI. The eLLI-based CZ sensor has shown a broad dynamic range (15–150 μM), lower detection limits (1μM), and adequate reliability towards rapid CZ screening in spiked soft and hard drink samples with reference to the standard chromatographic analysis. [ABSTRACT FROM AUTHOR]

Background: Patients with autism spectrum disorder (ASD) may experience severe psychiatric symptoms, often unresponsive to conventional pharmacological therapies, highlighting the need for more effective alternatives. Aims: This study aims to map and synthesize evidence on the use of clozapine as a therapeutic option for managing severe psychiatric symptomatology co-occurring with ASD. Methods: We conducted a scoping review on multiple sources following the JBI guidelines. The search strategy was inclusive, targeting both peer-reviewed publications and gray literature presenting empirical data on the use of clozapine therapy for patients with ASD accompanied by comorbid psychiatric symptoms. Two independent evaluators performed the selection of studies, data extraction, and critical appraisal. Results: The review included 46 studies, encompassing 122 ASD individuals who received clozapine therapy. The sources of evidence comprise 31 case reports, 8 case series, 6 retrospective observational studies, and 1 quasi-experimental prospective study. The tables present the findings along with a narrative summary. Clozapine treatment demonstrated benefits in four groups of severe and treatment-resistant psychiatric symptoms in ASD patients: disruptive behaviors, psychotic symptoms, catatonia, and mood symptoms. Although side effects were common, tolerability was generally satisfactory. However, severe adverse events, such as seizures, moderate neutropenia, and myocarditis, underscore the need for intensive clinical monitoring. Conclusions: While clozapine shows promise as a pharmacological intervention for severe psychopathologies in ASD, more rigorous clinical studies are required to elucidate its efficacy and safety in this population. The limited robustness of the evidence calls for caution, signaling an early research stage into this topic. [ABSTRACT FROM AUTHOR]

Background: Dual disorders (DDs) involve the coexistence of a substance use disorder (SUD) with another mental illness, often from the psychotic and affective categories. They are quite common in clinical practice and present significant challenges for both diagnosis and treatment. This study explores the effectiveness of brexpiprazole, a third-generation antipsychotic, in an Italian sample of individuals diagnosed with schizophrenia spectrum disorder and a comorbid SUD. Methods: Twenty-four patients, diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) and enrolled in several Italian hospitals, underwent a psychometric assessment at baseline (T0) and one month (T1) after starting brexpiprazole treatment administered at a mean dosage of 2 mg/day. Results: Brexpiprazole demonstrated significant reductions in psychopathological burden (Positive and Negative Syndrome Scale/PANSS total score: p < 0.001). Positive (p = 0.003) and negative (p = 0.028) symptoms, substance cravings (VAS craving: p = 0.039), and aggression (MOAS scale: p = 0.003) were notably reduced. Quality of life improved according to the 36-item Short Form Health Survey (SF-36) subscales (p < 0.005). Conclusions: This study provides initial evidence supporting brexpiprazole's efficacy and safety in this complex patient population, with positive effects not only on psychopathology and quality of life, but also on cravings. Further studies involving larger cohorts of subjects and extended follow-up periods are needed. [ABSTRACT FROM AUTHOR]

Rationale: The precise diagnosis and treatment of cognitive impairment remains a major challenge in the field of schizophrenia (SCZ) research. Synaptic dysfunction and loss are thought to be closely related to the occurrence and development of SCZ and may be involved in cognitive dysfunction. Objectives: The purpose of this study was to investigate whether neuronal pentraxins (NPTXs) plays a role in the etiology of SCZ and provide evidence of its possible therapeutic value a new target for drug development. Methods: We recruited 275 participants, of whom 148 were SCZ from psychiatric hospital and 127 healthy control (HC) subjects from communities. Plasma concentrations of NPTXs were measured in HC and SCZ at baseline and after 8 weeks of antipsychotic treatment. The MATRICS Cognitive Consensus Battery was used to evaluate cognitive function. Furthermore, the brain is parcellated into 246 subregions using the Brainnetome atlas, and we extracted regional white matter volumes from magnetic resonance images of the SCZ groups. Results: Plasma NPTX2 levels were significantly lower in SCZ compared with HC subjects, but were significantly raised in SCZ after 8 weeks of antipsychotic treatment compared to baseline. In addition, baseline plasma NPTX2 levels were positively correlated with cognitive performance. Conclusions: These findings indicate that NPTX2 may reveal novel aspects of disease etiology and act as a promising target for new drug development. [ABSTRACT FROM AUTHOR]

The rapid fabrication is described of binary electrocatalyst based on a highly porous metal–organic framework with zirconium metal core (Zr-MOF) decorated over the graphitic carbon nitride (g-C3N4) nanosheets via facile ultrasonication method. It is used for the robust determination of antipsychotic drug chlorpromazine (CLP) from environmental samples. The electrochemical behaviour of 2D Zr-MOF@g-C3N4 was characterized by cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) studies. The crystalline and porous nature of the composite was characterized by XRD and SEM analysis. The functional groups and surface characteristics were investigated by FT-IR, Raman and XPS. The major electrochemical properties of the Zr-MOF@g-C3N4 composite towards CLP detection were analyzed by CV, chronocoulometric (CC), chronoamperometric (CA) and differential pulse voltammetry (DPV) techniques. The composite exhibits a low detection limit (LOD) of 2.45 nM with a linear range of 0.02 to 2.99 µM and attractive sensitivity for CLP. The sensor system shows higher selectivity towards the possible interferences of CLP drug and exhibits better repeatability and stability. Finally, the fabricated sensor system shows a high recovery range varying from 96.2 to 98.9% towards the real samples. The proposed electrochemical probe might be a promising alternative to the prevailing diagnostic tools for the detection of CLP. [ABSTRACT FROM AUTHOR]

Background Acute antipsychotic poisoning is correlated to a high prevalence of qt interval prolongation. Aim This study aimed to evaluate early qt interval prolongation predictors in acute antipsychotic-poisoned patients. Methodology This prospective cohort study enrolled 70 symptomatic patients with acute antipsychotic poisoning. Sociodemographic data, toxicological, clinical, investigation, and outcomes were collected and analyzed. The estimation of the corrected qt interval (QTc) was performed using Bazett's method. Primary outcome was normal or abnormal length of QTc interval. Secondary outcomes included duration of hospital stay, complete recovery and mortality. The corrected qt interval was analyzed by univariate and multivariate logistic regression analysis. Results Patients were divided into groups A (normal QTc interval up to 440 msec; 58.6% of cases) and B (prolonged QTc interval ≥ 440 msec; 41.4% of cases). Patients in group B had significantly high incidences of quetiapine intake, bradycardia, hypotension, hypokalemia, and long duration of hospital stay. By multivariate analysis, quetiapine [Odd's ratio (OR): 39.674; Confidence Interval (C.I:3.426–459.476)], bradycardia [OR: 22.664; C.I (2.534–202.690)], and hypotension [OR: 16.263; (C.I: 2.168–122.009)] were significantly correlated with prolonged QTc interval. Conclusion In acute antipsychotic poisoning, quetiapine, bradycardia, and hypotension are early clinical predictors for prolonged QTc interval. [ABSTRACT FROM AUTHOR]

Introduction The complex nature of neurocognitive impairment in schizophrenia has been discussed in light of the mixed effects of antipsychotic drugs, psychotic symptoms, dopamine D2 receptor blockade, and intelligence quotient (IQ). These factors have not been thoroughly examined before. Methods This study conducted a comprehensive re-analysis of the CATIE data using machine learning techniques, in particular Conditional Inference Tree (CTREE) analysis, to investigate associations between neurocognitive functions and moderating factors such as estimated trough dopamine D2 receptor blockade with risperidone, olanzapine, or ziprasidone, Positive and Negative Syndrome Scale (PANSS), and baseline IQ in 573 patients with schizophrenia. Results The study reveals that IQ, age, and education consistently emerge as significant predictors across all neurocognitive domains. Furthermore, higher severity of PANSS-negative symptoms was associated with lower cognitive performance scores in several domains. CTREE analysis, in combination with a genetic algorithm approach, has been identified as particularly insightful for illustrating complex interactions between variables. Lower neurocognitive function was associated with factors such as age>52 years, IQ<94/95,<12/13 education years, and more pronounced negative symptoms (score<26). Conclusions These findings emphasize the multifaceted nature of neurocognitive functioning in patients with schizophrenia, with the PANSS-negative score being an important predictor. This gives rise to a role in addressing negative symptoms as a therapeutic objective for enhancing cognitive impairments in these patients. Further research must examine nonlinear relationships among various moderating factors identified in this work, especially the role of D2 occupancy. [ABSTRACT FROM AUTHOR]

Model‐informed precision dosing using virtual twins (MIPD‐VTs) is an emerging strategy to predict target drug concentrations in clinical practice. Using a high virtualization MIPD‐VT approach (Simcyp version 21), we predicted the steady‐state clozapine concentration and clozapine dosage range to achieve a target concentration of 350 to 600 ng/mL in hospitalized patients with treatment‐resistant schizophrenia (N = 11). We confirmed that high virtualization MIPD‐VT can reasonably predict clozapine concentrations in individual patients with a coefficient of determination (R2) ranging between 0.29 and 0.60. Importantly, our approach predicted the final dosage range to achieve the desired target clozapine concentrations in 73% of patients. In two thirds of patients treated with fluvoxamine augmentation, steady‐state clozapine concentrations were overpredicted two to four‐fold. This work supports the application of a high virtualization MIPD‐VT approach to inform the titration of clozapine doses in clinical practice. However, refinement is required to improve the prediction of pharmacokinetic drug–drug interactions, particularly with fluvoxamine augmentation. [ABSTRACT FROM AUTHOR]

Background: Adherence to antipsychotic medication and care discontinuity remain a challenge to healthcare practitioners providing care to patients with schizophrenia. Objective: This study used real-world data from a US hospital-based, all-payer database to examine clinical quality measures among patients with schizophrenia initiated on a long-acting injectable (LAI) or switched to a new oral antipsychotic medication (OAP) following a hospitalization. Methods: A retrospective cohort study using the PINC AI™ Healthcare Database compared two cohorts of patients with schizophrenia on post-index hospitalization clinical quality and care continuity endpoints. Patients initiated on an LAI (n = 7292) or switched to a new OAP (n = 31,956) during an index hospitalization between April 2017 and April 2020 were included. Propensity score weighting addressed differences in patient, hospital, and clinical characteristics between the two cohorts. Results: Patients who initiated an LAI experienced significantly greater adjusted 30-day antipsychotic medication continuation to index therapy, higher rate of 30-day outpatient follow-up care, longer mean time to discontinuation of index therapy, and lower risk of discontinuing their index treatment compared to patients who switched to a new OAP (all p values < 0.001). Probability of 30-day antipsychotic medication continuation was significantly higher for LAI initiators than for patients who switched to a new OAP, even after controlling for patient, clinical, and hospital characteristics (adjusted odds ratio = 1.2, 95% CI 1.1–1.3, p < 0.001). Conclusion: Patients who initiated an LAI in a hospital setting experienced better clinical quality and care continuity outcomes compared to patients who were switched to a new OAP. These findings may be useful in identifying solutions to help improve the quality of medication management post-hospital discharge among patients with schizophrenia. [ABSTRACT FROM AUTHOR]

This is a rare side effect of amisulpride-induced phonic and motor tics that completely resolved within 2 weeks of stopping the drug. Naranjo adverse drug effect probability scale is eight, suggests that it's a probable causation of the tics.

Antipsychotics are the mainstay treatment for the majority of severe mental illnesses. Such patients are also more prone to develop medical comorbidities, which complicate the treatment decisions. It is estimated that up to 40% of individuals with schizophrenia have impaired glucose tolerance (IGT) or diabetes, which can be attributed to a combination of genetic, lifestyle, and medication-related factors. Some widely used antipsychotic medications like olanzapine, risperidone, and clozapine have been associated with an increased risk of weight gain, insulin resistance, and other metabolic abnormalities, which can worsen IGT and increase the risk of developing diabetes. Among second-generation antipsychotics (SGAs), amisulpride, aripirazole, and ziprasidone have a fairly low potency to cause obesity and hyperglycemia. In this context, clinicians must balance the benefits and risks of different antipsychotic medications and consider the individual's specific needs and preferences. Here, we shall discuss three cases, to ascertain how the use of amisulpride helped in glycemic control, and also reflect on probable etiologies leading to deranged glucose levels.

This article explores the use of stem cell models and postmortem studies to investigate the neurodevelopment of the striatum in schizophrenia. Stem cell-derived neurons have been found to exhibit similar cellular characteristics to those observed in postmortem analyses. The authors of this study developed a method to directly compare stem cell-derived neurons with postmortem brain tissue from the same individuals, focusing on the striatum. They found that the stem cell-derived neurons exhibited schizophrenia-associated signatures similar to those seen in adult brain tissue, suggesting an accelerated developmental trajectory in schizophrenia. The study also contributes to the ongoing debate about the accuracy of postmortem human neurons as representations of disease processes in the living brain. [Extracted from the article]

The aim of our study was to evaluate the efficacy of cariprazine augmentation of clozapine in treatment-resistant schizophrenia in a retrospective chart review. Among 916 medical records of schizophrenia patients, we identified 12 individuals treated with a combination of those drugs for a duration of 3–60 weeks [median 32 (10–40)]. Clinical Global Impression–Improvement (CGI-I) scores were used to measure the treatment response between the introduction of cariprazine augmentation of clozapine and the last point of observation. The majority of the patients presented treatment response (9/12 patients, 75%) after 4–16 weeks of therapy [median 6 (4–12)]. Treatment was associated with the decrease in positive, negative, affective, and anxiety symptom severity, as well as improvement of patient global functioning. One patient discontinued the treatment due to side effects (akathisia), and two patients halted the therapy due to the exacerbation of psychotic symptoms. Our study presents a thorough clinical description of the largest number of treatment-resistant schizophrenia patients medicated using cariprazine augmentation of clozapine in a “real-world” setting. Our results suggest that the use of this combination may lead to the improvement in a broad range of symptoms of patients with this condition. [ABSTRACT FROM AUTHOR]

Schizophrenia is a complex psychotic disorder with co-occurring conditions, including insulin resistance and type 2 diabetes (T2D). It is well established that T2D and its precursors (i.e., insulin resistance) are more prevalent in patients with schizophrenia who are treated with antipsychotics, as well as in antipsychotic-naïve patients experiencing their first episode of psychosis, compared with the general population. However, the mechanism(s) underlying the increased susceptibility, shared genetics, and possible cause–effect relationship between schizophrenia and T2D remain largely unknown. The objective of this narrative review was to synthesize important studies, including Mendelian randomization (MR) analyses that have integrated genome-wide association studies (GWAS), as well as results from in vitro models, in vivo models, and observational studies of patients with schizophrenia. Both GWAS and MR studies have found that schizophrenia and T2D/insulin resistance share genetic risk factors, and this may mediate a connection between peripheral or brain insulin resistance and T2D with cognition impairment and an increased risk of developing prediabetes and T2D in schizophrenia. Moreover, accumulating evidence supports a causal role for insulin resistance in schizophrenia and emphasizes the importance of a genetic basis for susceptibility to T2D in patients with schizophrenia before they receive psychotic treatment. The present findings and observations may have clinical implications for the development of better strategies to treat patients with schizophrenia, with both pharmacological (i.e., samidorphan, empagliflozin) and/or nonpharmacological (i.e., lifestyle changes) approaches. Additionally, this review may benefit the design of future studies by physicians and clinical investigators. [ABSTRACT FROM AUTHOR]