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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]

It is widely hoped that statistical models can improve decision-making related to medical treatments. Because of the cost and scarcity of medical outcomes data, this hope is typically based on investigators observing a modelÕs success in one or two datasets or clinical contexts. We scrutinized this optimism by examining how well a machine learning model performed across several independent clinical trials of antipsychotic medication for schizophrenia. Models predicted patient outcomes with high accuracy within the trial in which the model was developed but performed no better than chance when applied out-of-sample. Pooling data across trials to predict outcomes in the trial left out did not improve predictions. These results suggest that models predicting treatment outcomes in schizophrenia are highly context-dependent and may have limited generalizability. [ABSTRACT FROM AUTHOR]

Aims: To characterise the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single ascending doses of oxathridine, a first‐in‐class histamine‐3 receptor partialagonist, in healthy male volunteers. Methods: A randomised, double‐blind, placebo‐controlled study including the NeuroCart, consisting of a battery of drug sensitive neurophysiological tests, was performed. Oxathridine was administered orally as an aqueous solution. After dosing, safety and NeuroCart tests (adaptive tracking [AT], body sway [BS], saccadic peak velocity [SPV], smooth pursuit [SP] eye movements, VAS according to Bond and Lader, VAS according to Bowdle [VAS B&L, Bowdle], pharmaco‐electroencephalogram [pEEG], Sustained Attention to Response Task [SART]) were performed at set times. Results: Forty volunteers completed the study. Given doses were: 0.5, 2.5, 5, 0.25 and 1.5 mg. At 5 mg, unacceptable and unanticipated adverse events (AEs) of (orthostatic) hypotension and pseudo‐hallucinations were reported. Statistically significant effects ([CI]; p‐value) of 2.5 mg and 5 mg oxathridine were observed on AT ([−8.28, −1.60]; p = 0.0048), ([−8.10, −1.51]; p = 0.00530), BS ([0.6, 80.2]; p = 0.0455), ([5.9, 93.1]; p = 0.0205) and SPV ([−59.0, −15.9]; p = 0.0011), ([−43.9, −1.09]; p = 0.0399), respectively. Oxathridine 5 mg significantly increased all three VAS Bowdle subscale scores; VAS external ([0.183, 0.476]; p = <.0001), VAS internal ([0.127, 0.370]; p = 0.0001) and VAS feeling high ([0.263, 0.887]; p = 0.0006). Conclusion: NeuroCart tests indicated central nervous system (CNS) depressant effects. Oxathridine also unexpectedly caused pseudohallucinations. Although this led to the decision to stop further development of oxathridine, these observations suggest that the H3R system could be an interesting new target for the development of novel antipsychotics. [ABSTRACT FROM AUTHOR]

The glutamatergic hypothesis of schizophrenia suggests a correlation between NMDA receptor hypofunction and negative psychotic symptoms. It has been observed that the expression of the proline transporter (PROT) in the central nervous system (CNS) is associated with glutamatergic neurotransmission, as l-proline has the capacity to activate and modulate AMPA and NMDA receptors. In this study, we aimed to investigate whether inhibition of proline transporters could enhance glutamatergic neurotransmission and potentially exhibit antipsychotic effects in an experimental schizophrenia model. Using molecular dynamics analysis in silico, we validated an innovative PROT inhibitor, LQFM215. We quantified the cytotoxicity of LQFM215 in the Lund human mesencephalic cell line (LUHMES). Subsequently, we employed the ketamine-induced psychosis model to evaluate the antipsychotic potential of the inhibitor, employing behavioral tests including open-field, three-chamber interaction, and prepulse inhibition (PPI). Our results demonstrate that LQFM215, at pharmacologically active concentrations, exhibited negligible neurotoxicity when astrocytes were co-cultured with neurons. In the ketamine-induced psychosis model, LQFM215 effectively reduced hyperlocomotion and enhanced social interaction in a three-chamber social approach task across all administered doses. Moreover, the compound successfully prevented the ketamine-induced disruption of sensorimotor gating in the PPI test at all tested doses. Overall, these findings suggest that PROT inhibition could serve as a potential therapeutic target for managing symptoms of schizophrenia model. [ABSTRACT FROM AUTHOR]

Therapeutic drug monitoring improves the benefit–risk balance of antipsychotic therapy. Ultra-high-performance liquid chromatography–tandem mass spectrometry (UHPLC-MS/MS) is considered the gold-standard method for measuring plasma drug concentrations; however, the Alinity C system has emerged as a promising alternative. This is the first study aimed at comparing UHPLC-MS/MS versus Alinity C in measuring plasma concentrations of aripiprazole and dehydroaripiprazole. A total of 86 plasma samples were analyzed. The active moiety of aripiprazole was measured in 60 samples using both systems and 26 samples were analyzed twice using Alinity C with an intermediate period of 6 months to assess its reproducibility. Spearman's correlation revealed a good association between the two assays (rs = 0.96) and no significance differences were found by McNemar's test when classifying samples between infra-, supra- and therapeutic ranges. Passing–Bablock regression showed a good correlation among methods (rs = 0.93) and a slope of 1.12 indicating a slight tendency of Alinity C to measure higher values than UHPLC-MS/MS. In addition, a good intra-method correlation across the two sequential analyses with Alinity C was obtained (rs = 0.99). Nonetheless, clinical decisions could be different in 15% of the cases depending on the chosen method. No differences were found in active moiety determination by Alinity C depending on the concentration of aripiprazole and dehydroaripiprazole of the samples. [ABSTRACT FROM AUTHOR]

Long-acting injectable (LAI) neuroleptics constitute an effective therapeutical alternative for individuals suffering from persistent mental illness. These injectable pharmaceuticals help patients manage their condition better and improve long-term outcomes by preventing relapses and improving compliance. This review aims to analyse the current formulation aspects of LAI neuroleptics, with particular emphasis on analysis of drug release profiles as a critical test to guarantee drug quality and relevant therapeutical activity. While there is no officially approved procedure for depot parenteral drug formulations, various dissolution tests which were developed by LAI manufacturers are described. In vitro dissolution tests also possess a critical function in the estimation of the in vivo performance of a drug formulation. For that reason, thorough inspection of the in vitro–in vivo correlation (IVIVC) is also discussed. [ABSTRACT FROM AUTHOR]

As the prevalence of old-age individuals with schizophrenia (OAS) increases in a society undergoing demographic aging, the exploration of medication choices becomes increasingly crucial. Due to the current scarcity of literature on OAS, this study seeks to examine how the utilization and cumulative dosages of psychotropic medications influence both overall and cause-specific mortality risks within this population. A national cohort of 6433 individuals diagnosed with OAS was followed up for 5 years. This study involved comparing the mortality rates associated with low, moderate, and high dosages of antipsychotics, antidepressants, mood stabilizers, and sedative/hypnotic drugs against the 'no exposure' category, based on individual dosages. Cox regression was employed for survival analyses to compare overall mortality and specific-cause mortality across various dosage groups. The exposure variable examined was the dosage of a specific psychotropic medication. Covariates were adjusted accordingly. The analysis revealed that patients on low/moderate antipsychotic doses had improved survival compared to non-exposed individuals. Moderate antipsychotic use corresponded to reduced cardiovascular disease mortality risk. Similarly, those exposed to antidepressants had enhanced survival in low and moderate doses. Sedative-hypnotic exposure was linked to decreased mortality risk in low doses. This study observed that low/moderate antipsychotic doses in older adults with schizophrenia were associated with decreased all-cause mortality, emphasizing the significance of precise medication selection and dosing. It underscores the need for vigilant polypharmacy management and tailored medication strategies in addressing the complexities of treating OAS. [ABSTRACT FROM AUTHOR]

Patients with schizophrenia have a high mortality risk, and the role of antipsychotic medications remains inconclusive. In an aging society, older patients with schizophrenia warrant increased attention. This study investigated the association of antipsychotic medication dosages with mortality in patients with schizophrenia by using data from Taiwan's National Health Insurance Research Database from 2010 to 2014. This study included 102,964 patients with schizophrenia and a subgroup of 6433 older patients in addition to an age- and sex-matched control group. The findings revealed that among patients with schizophrenia, the no antipsychotic exposure group had the highest mortality risk (3.61- and 3.37-fold higher risk for overall and cardiovascular mortality, respectively) in the age- and sex-adjusted model, followed by the high, low, and moderate exposure groups. A similar pattern was observed in the older patients with schizophrenia. High exposure to antipsychotics was associated with the highest risks of overall and cardiovascular mortality (3.01- and 2.95-fold higher risk, respectively). In conclusion, the use of antipsychotics can be beneficial for patients with schizophrenia with recommended exposure levels being low to moderate. In older patients, high antipsychotic exposure was associated with the highest mortality risk, indicating that clinicians should be cautious when administering antipsychotic medications to such patients. [ABSTRACT FROM AUTHOR]

Propose: The propose is to investigate the reasons for the insolubility of Form III in water and to explore the mechanism of the hydration process of Form III. Methods: The conformational and cohesive energies of Form III and Form H1 were calculated using Gaussian 16 and Crystal Explorer 17. Gaussian 16 and Multiwfn 3.8 was used to calculate the molecular surface electrostatic potential of Form III and Form H1 and to calculate the energies of the stronger intermolecular interactions in the crystal structure. The behaviors of Form III in water were simulated using Gromacs 2020.6. Finally, the hydration process from Form III to Form H1 was monitored in situ using Raman spectroscopy. Results: The conformational energies of Form III and H1 are almost the same. The cohesion energy of Form H1 is much larger than that of Form III because both number of hydrogen bonds and van der Waals interactions are higher in the Form H1. During the simulation, the supercell of APZ form a supramolecular cluster. Several molecules manually dismantled from the cluster spontaneously combine to form new molecular clusters. Both increases in temperature and external energy input accelerate the hydration process. Conclusions: More hydrogen bonds and strong van der Waals interactions in Form H1 lead to a greater stability. The overall decrease in polarity and the strong binding effect on APZ molecule clusters due to intermolecular interactions lead to the water insolubility of Form III. The hydration process from Form III to Form H1 follows a novel, dandelion sowing-like hydration mechanism. [ABSTRACT FROM AUTHOR]

To explore the effect of escitalopram combined with aripiprazole on cognitive function in patients with major depressive disorder (MDD), and to evaluate the clinical efficacy of the combination therapy. A total of 70 patients with first-episode MDD were randomly divided into the study group or the control group, receiving escitalopram combined with aripiprazole (5 mg/day) or escitalopram monotherapy respectively for 8 weeks. The severity of illness was assessed by using the Hamilton Rating Scale for Depression (HAMD) at baseline, at the end of 4th and 8th week, and cognitive function was assessed by using the THINC integrated tool (THINC-it), the Wisconsin Card Sorting Test (WCST), and the Continuous Performance Test (CPT). Rating Scale for Extrapyramidal Side Effects (RSESE) was applied to assess adverse reactions. The average HAMD-17 and HAMA scores decreased over time in both the control and the study groups, but the reductions were not statistically different between two groups with the passage of time. In WCST, total number of response (TR) of the study group decreased relative to the baseline at the end of the eighth week, but the control group did not significantly change during whole eight weeks. Perseverative errors (PE) in the control group eventually decreased at the end of Week 8 compared to that at Week 4, but in the study group, it was a continuous trend of decrease. In CPT, the decrease of leakage responses (LR) in the study group was higher than that of the control group in 2-digit number, and LR of the control group was higher than that of the study group at the end of Week 8 in 4-digit number. The downtrend of LR in 4-digit number kept for the whole period in study group, while in the control group, the LR did not decrease significantly until the end of Week 8 compared to that at baseline. Escitalopram combined with a low-dose of aripiprazole, and escitalopram monotherapy could both enhance cognitive function of MDD patients, while the improvements of combination therapy might happen relatively earlier. The combined use of escitalopram and aripiprazole might be more beneficial to the domains of executive function (EF) and continuous attention compared to escitalopram monotherapy. There was no significant differences between two treatment options in alleviating depressive and anxiety symptoms. • This is a study based on cognitive function improvement and drug efficacy in patients with first-episode depression. • Compared to escitalopram monotherapy, combining aripiprazole could be more beneficial to some areas of cognitive function. • Both two options could alleviate depressive and anxiety symptoms, but there seemed no significant differences between them. [ABSTRACT FROM AUTHOR]

Non-compliance includes various behaviors and attitudes, ranging from total refusal of drug therapy to incorrect use or premature discontinuation, with a potential impact on the severity of symptoms. In the psychiatric setting, patients' reluctance to adhere to medications may result from a lack of insight, fostering unfavorable opinions about pharmacotherapy. This study explores the connections between antidepressant medication adherence, insight, and attitudes towards medications. The participant pool included both inpatients and outpatients, including individuals with established psychiatric diagnoses and excluding those with intellectual disabilities, major neurocognitive disorders, or acute psychotic relapses. Adherence was assessed using the Visual Analog Scale (VAS) item of the Brief Adherence Rating Scale (BARS), attitude towards drugs was measured with the Drug Attitude Inventory (DAI), and insight with the Insight Orientation Scale (IOS). The analysis revealed a significant direct correlation between adherence and attitude towards the drug (ρ = .76; p < .001). Adherence showed a significant direct correlation with both DAI subscales, assessing subjective responses to antipsychotics (ρ = .65; p < .001) and subjective attitude towards treatment (ρ = .72; p < .001). Although the IOS scale did not have a significant correlation with the BARS total score and DAI global score, it did show a significant correlation with the DAI factor II (ρ = .35; p < .01). These findings highlight the central role of patients' attitude towards medications in influencing medication adherence. [ABSTRACT FROM AUTHOR]

Schizophrenia is a highly heritable neuropsychiatric disorder characterized by cognitive and social dysfunction. Genetic, epigenetic, and environmental factors are together implicated in the pathogenesis and development of schizophrenia. DNA methylation, 5-methycytosine (5mC) and 5-hydroxylcytosine (5hmC) have been recognized as key epigenetic elements in neurodevelopment, ageing, and neurodegenerative diseases. Recently, distinctive 5mC and 5hmC pattern and expression changes of related genes have been discovered in schizophrenia. Antipsychotic drugs that affect 5mC status can alleviate symptoms in patients with schizophrenia, suggesting a critical role for DNA methylation in the pathogenesis of schizophrenia. Further exploring the signatures of 5mC and 5hmC in schizophrenia and developing precision-targeted epigenetic drugs based on this will provide new insights into the diagnosis and treatment of schizophrenia. [ABSTRACT FROM AUTHOR]

Clozapine is an effective atypical antipsychotic indicated for treatment-resistant schizophrenia, but is under-prescribed due to the risk of severe adverse drug reactions such as myocarditis. A mechanistic understanding of clozapine cardiotoxicity remains elusive. This study aimed to investigate the contribution of selected CYP isoforms to cycling between clozapine and its major circulating metabolites, N-desmethylclozapine and clozapine-N-oxide, with the potential for reactive species production. CYP supersome™-based in vitro techniques were utilised to quantify specific enzyme activity associated with clozapine, clozapine-N-oxide and N-desmethylclozapine metabolism. The formation of reactive species within each incubation were quantified, and known intermediates detected. CYP3A4 predominately catalysed clozapine-N-oxide formation from clozapine and was associated with concentration-dependent reactive species production, whereas isoforms favouring the N-desmethylclozapine pathway (CYP2C19 and CYP1A2) did not produce reactive species. Extrahepatic isoforms CYP2J2 and CYP1B1 were also associated with the formation of clozapine-N-oxide and N-desmethylclozapine but did not favour one metabolic pathway over another. Unique to this investigation is that various CYP isoforms catalyse clozapine-N-oxide reduction to clozapine. This process was associated with the concentration-dependent formation of reactive species with CYP3A4, CYP1B1 and CYP1A1 that did not correlate with known reactive intermediates, implicating metabolite cycling and reactive oxygen species in the mechanism of clozapine-induced toxicity. [ABSTRACT FROM AUTHOR]

Background: Schizophrenia is a life-shortening disease. The standardized mortality ratio has been higher than that of the general population, and it has doubled what it was 3-4 decades ago. This rise is mostly attributed to the increased cardiovascular risk associated with high second-generation antipsychotic (SGA) use. Evidence from the first-generation antipsychotic (FGA) era shows a lower prevalence of hypertension (HTN) but data regarding SGAs is scarce. Purpose: The purpose of the study was to assess the prevalence of HTN and related factors using standardized methodology in patients with schizophrenia on treatment with SGAs. Methods: A cross-sectional study through convenient sampling was done. Blood pressure, anthropometry, physical activity, and health-related lifestyle factors were assessed using the standard World Health Organization (WHO) methodology of cardiovascular survey methods and the Global Physical Activity Questionnaire (GPAQ) version 2. The prevalence of HTN, obesity, inadequate physical activity, and other demographic and clinical correlates like antipsychotic use, duration of illness, and family history of non-communicable diseases (NCDs) were studied. Results: The prevalence of HTN is 20.50%, and it increases with age. SGAs with the use of a single agent are the most common. In total, 45.50% of persons with schizophrenia have a positive family history of a NCD; 22.00% and 07.50% are current tobacco and alcohol users, respectively; and 70% have abdominal obesity, and 54% have generalized obesity. Waist circumference, obesity, and family history of NCDs are significant correlates of HTN. A family history of NCDs is the most significant predictor. Conclusion: The prevalence of HTN is lower than that of the general population despite the high prevalence of SGA use, obesity, and inadequate physical activity. [ABSTRACT FROM AUTHOR]

Understanding the patient perspective is a significant part of the deprescribing process. This study aimed to explore the attitudes of older patients with psychiatric disorders towards deprescribing. A total of 72 of psychiatric outpatients (68% women; median age 76 years) completed the validated Danish version of the revised Patients' Attitudes Towards Deprescribing (rPATD) questionnaire. Patients used a median of eight medications (interquartile range 6–12), with 88%, 49% and 24% using antidepressants, antipsychotics and anxiolytics, respectively. Fifty‐one percent of patients reported an intrinsic desire to stop one of their medications, while 92% would be willing to stop one on their physician's advice. Seventy‐five percent of patients would be worried about missing out on future benefits following deprescribing and 37% had previous bad deprescribing experiences. Use of ≥8 regular medications was associated with more concerns about stopping medication and greater perceived burden of using medication, while use of antipsychotics was not associated with any differences in rPATD factor scores. It is crucial for health care professionals to be aware of patients' specific concerns and past experiences to promote a patient‐centred deprescribing approach that takes into account the needs and preferences of older patients with psychiatric disorders. [ABSTRACT FROM AUTHOR]

Most patients with schizophrenia need life-long treatment. There is therefore a continued need for effective and tolerable treatment options. A 2-monthly LAI formulation of aripiprazole, Aripiprazole 2-Month Ready-to-Use 960 mg (Ari 2MRTU 960) has recently been approved in the US. Here, the possible role in therapy for this new treatment option is discussed in a narrative review. PubMed was searched for literature on long-acting injectables with a focus on patient-reported outcomes and real-world evidence on extended injection intervals (2–3 months). Dopamine D2 partial agonists, one of which is aripiprazole, exhibit favorable tolerability and safety properties. Additionally, there are many advantages in using long-acting injectable formulations such as enhanced treatment persistence and stability of patients as well as reduced rates of relapses, hospitalizations, and death. Some of these advantages become more pronounced with longer injection intervals. Additional advantages of longer injection intervals are more room for non-medication-related communication between healthcare professionals and patients, patient and physician preferences, reduced caregiver burden, and easier transitioning from inpatient to outpatient treatment. Taken together, since aripiprazole may be a good treatment choice for many patients based on its favorable safety and tolerability profile, and given the advantages of LAI treatment over oral treatment and the advantages of reduced dosing frequency, Ari 2MRTU 960 may become an important treatment option for many clinically stable patients with schizophrenia. [ABSTRACT FROM AUTHOR]

Aripiprazole (ARI), an antipsychotic having low solubility and stability. To overcome this, formation of binary and ternary using inclusion complexes of Methyl-β-cyclodextrin (MβCD) /Hydroxy propyl beta cyclodextrin (HPβCD) and L-Arginine (ARG)/ Lysine (LYS) are analyzed by dissolution testing and phase stability study along with their complexation efficacy and solubility constants made by physical mixing. Inclusion complexes with ARG were better than LYS and prepared by solvent evaporation and lyophilization method as well. They are characterized by Attenuated Total Reflection Fourier Transform Infrared Spectroscopy (AT-FTIR), X-ray powder diffractometry (XRD), Differential Scanning Calorimetry (DSC), Scanning electron microscopy (SEM) and Thermal gravimetric analysis (TGA). The bond shifting in AT-FTIR confirmed the molecular interactions between host and guest molecules. The SEM images also confirmed a complete change of drug morphology in case of ternary inclusion complexes prepared by lyophilization method for both the polymers. ARI: MβCD: ARG when used in the specific molar ratio of 1:1:0.27 by prepared by lyophilization method has 18 times best solubility while ARI:HPβCD:ARG was 7 times best solubility than pure drug making MβCD a better choice than HPβCD. Change in the molar ratio will cause loss of stability or solubility. Solvent evaporation gave significant level of solubility but less stability [ABSTRACT FROM AUTHOR]

Background: Clinical practice guidelines support efforts to improve functioning in patients with schizophrenia. Discrepancies in the perception of cognitive status between clinicians, patients with schizophrenia, and their caregivers have been associated with impaired functional abilities in patients; medication side effects might worsen both cognition and daily functioning. We assessed daily/social functioning and cognition in stable patients with schizophrenia who switched to the long-acting injectable (LAI) antipsychotic aripiprazole lauroxil (AL). Methods: Clinically stable adults with residual symptoms of schizophrenia or intolerance following three or more doses of paliperidone palmitate or risperidone LAI were switched to flexibly dosed open-label AL treatment (441mg, 662mg, or 882mg every 4 weeks or 882mg every 6 weeks) for six months (ClinicalTrials.gov identifier: NCT02634320). Daily/social functioning was assessed using the Personal and Social Performance Scale (PSP); total and subscale scores were summarized using descriptive statistics. The cognitive status of patients was assessed using the New York Assessment of Adverse Cognitive Effects of Neuropsychiatric Treatment (NY-AACENT) at baseline and Month 6 or early termination, providing patient, caregiver, and clinician perspectives. A post hoc analysis assessed level of agreement in ratings of cognitive status among respondents, evaluated at baseline and last assessment, using weighted kappa coefficients (0.01-0.20, slight agreement; 0.21-0.40, fair agreement; 0.41-0.60, moderate agreement; 0.61-0.80, substantial agreement.). Results: All 51 enrolled patients received one or more AL doses; 35 completed the study, and 45 contributed data at last assessment. Mean age was 40.6 years; 72.5 percent of patients were male. Based on PSP total score, functioning was maintained from baseline (mean [standard deviation (SD)]: 55.1 [10.5]) through six months of AL treatment (mean [SD]: 57.7 [13.2]). Proportions of patients rating personal and social functioning issues as "not present" or "mild" remained stable between baseline and Month 6 for each PSP subscale. At baseline (n=50), cognitive difficulties were most commonly rated "not present" or "mild" in all NY-AACENT domains by patients (58-86% across domains), clinicians (62-94%), and caregivers (50-92%), and these rates were maintained or increased at last assessment for all reporters. Weighted kappa coefficients indicated fair-to-substantial agreement between patients and clinicians across domains at last assessment (0.32-0.64; baseline: 0.14-0.55); patient--caregiver agreement ranged from 0.07 to 0.50 at last assessment (baseline: 0.25-0.60). Conclusion: In clinically stable patients with schizophrenia who initiated AL, self-reported functioning was maintained over six months of treatment. Clinician-, caregiver-, and patient-reported cognitive function was stable at baseline and maintained in all NY-AACENT domains; patient--clinician agreement on level of cognitive impairment increased over six months of treatment with AL. [ABSTRACT FROM AUTHOR]

A vigorously debated issue in the psychiatric literature is whether long-acting injectable antipsychotics (LAIs) show clinical benefit over antipsychotics taken orally. In addressing this question, it is critical that systematic reviews incorporate risk of bias assessments of trial data in a robust way and are free of undue industry influence. In this paper, we present a case analysis in which we identify some of the design problems in a recent systematic review on LAIs vs oral formulations. This case illustrates how evidence syntheses that are shaped by commercial interests may undermine patient-centered models of recovery and care. We offer recommendations that address both the bioethical and research design issues that arise in the systematic review process when researchers have financial conflicts of interest. [ABSTRACT FROM AUTHOR]

Herein, we aimed to formulate a novel oral disintegrating tablet (ODT) of aripiprazole (ARP) capable of rapid disintegration using a direct compression technique. Different ODTs were fabricated with directly compressible excipients, and their disintegration time, wettability (water absorption ratio and wetting time), and mechanical properties (hardness and friability) were evaluated. The optimized ODT comprised F-Melt® type C, Prosolv® SMCC HD90, and Na croscarmellose (10 mg of ARP in a 130 mg tablet). The ODT with 3.1–5.2 kp hardness exhibited rapid disintegration (14.1–17.2 sec), along with appropriate mechanical strength (friability < 0.24%). In a bioequivalent study in Korean healthy subjects (randomized, single-dose, two-period crossover design, n = 37), the novel ODT offered the equivalent pharmacokinetic profile to that of a conventional immediate release tablet (Otsuka, Abilify®, Japan), despite different disintegration and dissolution profiles. The 90% confidence intervals of the geometric mean test to reference ratios considering the area-under-the-curve and maximum plasma drug concentrations were 1.0306–11051 and 0.9448–1.1063, respectively, satisfying FDA regulatory criteria for bioequivalence. The novel ART ODT was physicochemically stable under the accelerated storage condition (40 °C, RH75%) for 24 weeks. Therefore, the novel ARP-loaded ODT is expected to be an alternative to oral ARP therapy, providing improved patient adherence. [ABSTRACT FROM AUTHOR]

This research studies the dose–plasma level (PL) relationship of second-generation antipsychotics, together with the treatment outcomes achieved, in seriously ill people with schizophrenia. An observational, prospective, one-year follow-up study was carried out with patients (N = 68) with severe schizophrenia treated with paliperidone three-month (PP3M) or aripiprazole one-month (ARIM). Participants were divided into standard-dose or high-dose groups. PLs were divided into "standard PL" and "high PL" (above the therapeutic reference range, TRR) groups. The dose/PL relationship, and severity, hospitalizations, tolerability, compliance, and their relationship with doses and PLs were evaluated. There was no clear linear relationship between ARIM or PP3M doses and the PLs achieved. In half of the subjects, standard doses reached PLs above the TRR. The improvements in clinical outcomes (decrease in clinical severity and relapses) were related to high PLs, without worse treatment tolerability or adherence. All participants remained in the study, regardless of dose or PL. Clinical severity and hospitalizations decreased significantly more in those patients with high PLs. Considering the non-linear dose–PL relationship of ARIM and PP3M in people with severe schizophrenia, PLs above the TRR are linked to better treatment outcomes, without worse tolerability. The need in a notable number of cases for high doses to reach those effective PLs is highlighted. [ABSTRACT FROM AUTHOR]

Developing novel antipsychotic mechanisms of action and repurposing established compounds for the treatment of schizophrenia is of utmost importance to improve relevant symptom domains and to improve the risk/benefit ratio of antipsychotic compounds. Novel trial design concepts, pathophysiology-based targeted treatment approaches, or even the return to old values may improve schizophrenia outcomes in the future. In this review of the clinical trial landscape in schizophrenia, we present an overview of the challenges and gaps in current clinical trials and elaborate on potential solutions to improve the outcomes of people with schizophrenia. The classic parallel group design may limit substantial advantages in drug approval or repurposing. Collaborative approaches between regulatory authorities, industry, academia, and funding agencies are needed to overcome barriers in clinical schizophrenia research to allow for meaningful outcome improvements for the patients. [ABSTRACT FROM AUTHOR]

Background and Objectives: Aripiprazole (APZ), an atypical antipsychotic, is mainly prescribed for conditions such as schizophrenia and bipolar disorder, while ongoing research indicates promising neuroprotective qualities. APZ's mechanism of action, involving the regulation of neurotransmitter levels, appears to contribute to its potential to shield neural tissues from specific forms of harm and degeneration. Materials and Methods: To investigate its neuroprotective mechanisms, groups of rats were orally administered APZ at 1 or 2 mg/kg once daily for a 30-day period. In addition, neuronal toxicity was induced through intraperitoneal injection of four doses of lipopolysaccharide (LPS) at a concentration of 1 mg/kg. To evaluate cognitive function, particularly, short-term recognition memory, the procedure implemented the novel object recognition (NOR) task. Subsequently, brain tissues were gathered to examine markers linked with neuroinflammation, oxidative stress, and apoptosis. Results: The administration of LPS led to a decline in memory performance during the NOR tasks. Simultaneously, this LPS treatment raised inflammatory markers like cyclooxygenase (COX)-2, tumor necrosis factor (TNF)-α, and nuclear factor kappa B (NF-κB), increased oxidative markers such as malondialdehyde (MDA), and triggered apoptosis markers like Caspase-3 and Bcl2 associated X protein (Bax) within the brain. Furthermore, it decreased levels of antioxidants like reduced glutathione (GSH) and catalase, as well as the anti-apoptotic marker B-cell lymphoma (Bcl)-2 in brain tissue. The use of APZ resulted in enhanced recognition memory performance, as indicated by improved exploration and discrimination abilities of the objects in the NOR task. Moreover, APZ lowered the markers associated with neuronal vulnerability, such as COX-2, NF-κB, MDA, Caspase-3, and Bax. Additionally, it increased the levels of protective markers, including GSH, catalase, and Bcl-2 in LPS-challenged brains. Conclusions: In summary, the findings suggest that APZ exhibits protective properties against neuronal inflammation, oxidative stress, and apoptosis markers in the context of inflammatory-related neurodegeneration. Additional in-depth investigations are needed to further explore potential applications. [ABSTRACT FROM AUTHOR]

Many children with autism spectrum disorder (ASD) also have attention-deficit/hyperactivity disorder (ADHD). ADHD in children is associated with increased risk of negative outcomes, and early intervention is critical. Current guidelines recommend psychosocial interventions such as behavioral training as the first line of therapy in managing ADHD symptoms in children with or without ASD. Where symptoms are refractory to these interventions, medications such as stimulants, α2-adrenergic agonist inhibitors, selective norepinephrine reuptake inhibitors, and second-generation antipsychotics are recommended. However, these pharmacotherapies do not have regulatory approval for use in children of preschool age, and evidence on their safety and efficacy in this population has historically been very limited. Since publication of the current guidelines in 2020, several new randomized controlled trials and real-world studies have been published that have investigated the efficacy and tolerability of these medications in preschool children with ADHD, with or without comorbid ASD. Here, we provide a review of the key findings of these studies, which suggest that there is growing evidence to support the use of pharmacological interventions in the management of ADHD in preschool children with comorbid ASD.

BackgroundThe present study aimed to investigate the drug–drug interaction and initial dosage optimization of aripiprazole in patients with schizophrenia based on population pharmacokinetics.Research design and methodsA total of 119 patients with schizophrenia treated with aripiprazole were included to build an aripiprazole population pharmacokinetic model using nonlinear mixed effects.ResultsThe weight and concomitant medication of fluoxetine influenced aripiprazole clearance. Under the same weight, the aripiprazole clearance rates were 0.714:1 in patients with or without fluoxetine, respectively. In addition, without fluoxetine, for the once-daily aripiprazole regimen, dosages of 0.3 and 0.2 mg kg−1 day−1 were recommended for patients with schizophrenia weighing 40–95 and 95–120 kg, respectively, while for the twice-daily aripiprazole regimen, 0.3 mg kg−1 day−1 was recommended for those weighing 40–120 kg. With fluoxetine, for the once-daily aripiprazole regimen, a dosage of 0.2 mg kg−1 day−1 was recommended for patients with schizophrenia weighing 40–120 kg, while for the twice-daily aripiprazole regimen, 0.3 and 0.2 mg kg−1 day−1 were recommended for those weighing 40–60 and 60–120 kg, respectively.ConclusionThis is the first investigation of the effects of fluoxetine on aripiprazole via drug–drug interaction. The optimal aripiprazole initial dosage is recommended in patients with schizophrenia.

The incidence of major depressive disorder (MDD) after heart transplantation is high; however, there are no reports on treatment options when antidepressant therapy fails to improve the condition. We herein report on the case of a woman with MDD after heart transplantation who partially improved with antidepressant treatment but continued to have a loss of appetite. Augmentation treatment with aripiprazole improved her appetite, and her MDD went into remission. When antidepressant treatment is not sufficiently effective for MDD after heart transplantation, augmentation treatment with antipsychotics, such as aripiprazole, should be considered. [ABSTRACT FROM AUTHOR]

Introduction Clozapine, a second-generation antipsychotic (SGA), is considered the gold standard medication to treat patients with treatment-resistant schizophrenia (TRS). Despite its efficacy, clozapine is associated with adverse effects, notably neutropenia and agranulocytosis. Other hematological adverse effects are less common. Severe anemia is a rare adverse effect seldom reported in the literature and is typically associated with pure red cell aplasia (PRCA). Nevertheless, the benefits of clozapine in managing TRS make rechallenge a reasonable option. Case Report We present the case of a 35-year-old man with TRS, resistant to previous antipsychotics, who experienced severe anemia during clozapine treatment. An investigation for clozapine-induced anemia revealed PRCA on myelogram. After discontinuing clozapine, the patient's hemoglobin levels recovered. Subsequent treatments with olanzapine, zuclopenthixol, and aripiprazole proved ineffective, leading us to consider a clozapine rechallenge. The rechallenge, monitored for 58 days, resulted in improved psychiatric symptoms and stable hemoglobin levels. The patient remained stable during 6 months of follow-up, with no hematological changes. Discussion PRCA is a very rare adverse effect of clozapine. The cause of drug-induced PRCA is still unknown; for clozapine, there are no studies. Rechallenge after a severe and rare adverse effect is a complex decision. This case is the first to report a successful clozapine rechallenge following severe anemia without other blood dyscrasias, emphasizing the imperative need for close monitoring during the rechallenge process. Further study is warranted to understand the predictive factors for a successful outcome in clozapine rechallenges. [ABSTRACT FROM AUTHOR]

Objective: Unusual clinical course Background: We report the case of a 28-year-old man with comorbidity of OCD, PTSD, and DID responding to aripiprazole augmentation of clomipramine combined with psychoeducation and exposure and response prevention (ERP). Case Report: A 28-year-old, well-educated man presented with depression, obsessive thoughts, behavioral impulsivity, and suicidal thoughts/behavior. He was known to be stubborn and sensitive to criticism since childhood. The obsessive thoughts and compulsive behaviors also started at an early age. He had 4 past psychiatric hospitalizations, mostly for dissociative episodes and bizarre behaviors, complicated with significant anxiety and distress from traumatic experiences during doctoral study. He had no-to-minimal responses to various psychotropics and traditional Chinese medicine. A thorough assessment showed he met the diagnostic criteria for OCD, PTSD, and DID. He was then treated with clomipramine in combination with aripiprazole, plus psychoeducation and exposure and response prevention (ERP). His anxiety and irritability significantly improved within 2 months and his obsessive thoughts faded away. At 6-month follow-up, the patient achieved clinical remission. One year later, he remained stable and reported having a normal life. Conclusions: The case illustrates both how impairing the comorbidity of OCD, PTSD, and DID can be and how concurrent use of tricyclic antidepressant (TCA) clomipramine and partial dopamine agonist aripiprazole, together with psychoeducation and ERP, can improve outcomes when other treatment choices fail to be effective. [ABSTRACT FROM AUTHOR]

Preclinical and clinical studies have shown that the antipsychotic drug aripiprazole and the antioxidant N‐acetylcysteine have unique biological properties. The aim of the study was to investigate, in a rat model of schizophrenia, the effects of chronic administration of these drugs on schizophrenia‐like behaviors and anaerobic cysteine metabolism in the hippocampus (HIP). The schizophrenia‐type changes were induced in Sprague–Dawley rats by repeated administration of the glutathione synthesis inhibitor l‐butionine‐(S,R)‐sulfoximine in combination with the dopamine reuptake inhibitor GBR 12909 in the early postnatal period. Adult model rats were chronically treated with aripiprazole (0.3 mg·kg−1, i.p.) or N‐acetylcysteine (30 mg·kg−1, orally), and their effects on schizophrenia‐like behaviors were assessed using the social interaction test and novel object recognition test. In the HIP, the level of anaerobic cysteine metabolites, H2S, and bound sulfane sulfur were determined by a fluorescence method, while the expression of H2S‐synthetizing enzymes: cystathionine β‐synthase (CBS) and mercaptopyruvate sulfurtransferase (MST) by western blot. Long‐term treatment with aripiprazole or N‐acetylcysteine reversed social and cognitive deficits and reduced the exploratory behaviors. In the HIP of 16‐day‐old model pups, H2S levels and MST protein expression were significantly decreased. In adult model rats, H2S levels remained unchanged, bound sulfane sulfur significantly increased, and the expression of CBS and MST slightly decreased. The studied drugs significantly reduced the level of bound sulfane sulfur and the expression of tested enzymes. The reduction in bound sulfane sulfur level coincided with the attenuation of exploratory behavior, suggesting that modulation of anaerobic cysteine metabolism in the HIP may have therapeutic potential in schizophrenia. [ABSTRACT FROM AUTHOR]

Huntington’s disease (HD) is a rare neurodegenerative autosomal dominant disorder of the central nervous system. It is characterised by involuntary choreiform movements with behavioural, psychiatric and cognitive disturbances progressing to dementia. This case study describes a 49-year-old female patient with acute psychosis, choreiform movements and a history of depression and anxiety symptoms lasting two years, who was hospitalised at the psychiatry clinic. The treatment included oral risperidone and intramuscular diazepam, resulting in the quick disappearance of choreiform movements. The absence of neurological changes during examination complicated the diagnosis. Laboratory tests showed no abnormalities, but a brain computed tomography (CT) scan revealed a small hypodense lesion in the right nucleus lentiform area. Further investigation using magnetic resonance imaging (MRI) indicated a frontal horn to cranial caudate ratio (FH)/CC) of approximately 1,95, suggestive of Huntington’s disease. Additionally, dilatation of ventricles, brain sulci, and basal cisterns was observed. Genetic testing confirmed the diagnosis of HD with 45 CAG repeats in the HTT gene. This case underscores the challenges in diagnosing a rare neurodegenerative disease that initially presented with psychiatric symptoms and was complicated by antipsychotic treatment. [ABSTRACT FROM AUTHOR]

Bruxism is a movement disorder of uncertain aetiology. Beside local peripheral and central psychological factors, drugs were suspected. Using the World Health Organization (WHO) global pharmacovigilance database, Vigibase®, we investigated through disproportionality analyses potential associations between exposure to drugs and bruxism reports. All reports of bruxism in adults between 01/01/2000 and 31/12/2022 were included. Results are expressed as reporting odds ratio (ROR). Among the 564 reports of bruxism, an association was found with eight antidepressants (first sertraline followed by escitalopram, venlafaxine, vortioxetine, citalopram, paroxetine, fluoxetine, duloxetine) and four antipsychotics (first ziprasidone followed by aripiprazole, olanzapine, risperidone). A signal was also described for oxybate sodium and metoclopramide. For antidepressants, a negative association was found between ROR values and NET (norepinephrine transporter) but not SERT (serotonin transporter) pKi values, suggesting this ADR is more closely linked to norepinephrine than serotonin reuptake inhibition. [ABSTRACT FROM AUTHOR]

Aripiprazole is an atypical antipsychotic medication, and its use in treating borderline personality disorder (BPD) is debatable because it is not FDA-approved for treating BPD. This study aimed to investigate the efficacy and safety of aripiprazole in patients with BPD. On July 2, 2021, the protocol (CRD42021256647) was registered in PROSPERO. PubMed, Scopus, Web of Science, Ovid-Medline, Embase, PsycINFO, and Cochrane (CENTRAL) were searched without regard for language or publication date. We also searched trial registries on ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform. Randomized clinical trials with adult patients diagnosed with BPD met the inclusion criteria. The Cochrane risk of bias for randomized trials (RoB-2) method was used to assess the quality of the included studies. We included two previously published randomized clinical trials. There were 76 patients with BPD, with 38, 12, and 26 assigned to the aripiprazole, olanzapine, and placebo groups, respectively. Most patients (88.16%) were females, with ages ranging from 22.1 to 28.14 yr. Aripiprazole has been proven to reduce anxiety, depression, anger, hostility, clinical severity, and obsessive–compulsive behavior, insecurity, melancholy, anxiety, aggressiveness/hostility, phobic anxiety, paranoid thinking, psychoticism, and somatization. The adverse effects were headache, insomnia, restlessness, tremor, and akathisia. The risk of bias was considerable in both trials, which is somewhat problematic considering that prejudice can lead to incorrect outcomes and conclusions. Aripiprazole has demonstrated encouraging outcomes in the treatment of patients with BPD. More randomized controlled studies are needed. [ABSTRACT FROM AUTHOR]

Introduction: The screening of multicomponent crystal system (MCC) is a key method for improving physicochemical properties of active pharmaceutical ingredients (APIs). The challenges associated with experimental salt screening include a large number of potential counterions and solvent systems and tendency to undergo disproportionation to produce free form during crystallization. These challenges may be mitigated by a combination of experimental and computational approaches to salt screening. The goal of this study is to evaluate performance of the counterion screening methods and propose and validate novel approaches to virtual solvent screening for MCC crystallization. Methods: The actual performance of the ΔpKa > 3 rule for counterion selection was validated using multiple screenings reports. Novel computational models for virtual solvent screening to avoid MCC incongruent crystallization were proposed. Using the ΔpKa rule, 10 acid counterions were selected for experimental aripiprazole (APZ) salt screening using 10 organic solvents. The experimental results were used to validate the proposed novel virtual solvent screen models. Results: Experimental APZ salt screening resulted in a total of eight MCCs which included glucuronate, mesylate, oxalate, tartrate, salicylate and mandelate. The new model to virtually screen solvents provided a general agreement with APZ experimental findings in terms of selecting the optimal solvent for MCC crystallization. Conclusion: The rational selection of counterions and organic solvents for MCC crystallization was presented using combined novel computational model as well as experimental studies. The current virtual solvent screen model was successfully implemented and validated which can be easily applied to newly discovered APIs. [ABSTRACT FROM AUTHOR]

Clozapine is an effective antipsychotic medication used for treatment‐resistant schizophrenia. However, it is underutilized due to rigorous hematologic monitoring requirements and many adverse drug reactions. Publications have highlighted the occurrence of inflammatory reactions, some life‐threatening, particularly during the early stages of clozapine treatment. Although guidelines have suggested monitoring for inflammatory processes during clozapine initiation, screening in clinical practice is not universal. This systematic review aimed to investigate the relationship between clozapine and inflammation and assess the importance of monitoring for inflammatory reactions. A comprehensive literature search yielded 6915 unique publication records after removal of duplicates. After a rigorous screening process, 75 publications were included in the review, which focused on three main aspects: (i) the impact of clozapine on inflammatory markers, (ii) monitoring cardiac and other organ function during clozapine‐associated inflammatory processes, and (iii) monitoring non‐specific signs and symptoms of inflammation. Elevated levels of C‐reactive protein (CRP) and several proinflammatory cytokines have been observed in association with clozapine treatment. However, the practicality of measuring specific markers in clinical practice remains uncertain. Current evidence supports monitoring CRP levels during the first 4–8 weeks of treatment, especially to facilitate myocarditis screening. Further research is needed to establish clinically relevant CRP thresholds for intervention. The implementation of monitoring protocols during the early phase of clozapine treatment may mitigate adverse reactions and allow for continued use of clozapine. Future studies should also explore the association between clozapine‐associated inflammation and pneumonia, as well as investigate the impact of inflammation on clozapine metabolism to predict the need for dose adjustment. These endeavors may facilitate the development and implementation of evidence‐based guidelines for the monitoring of clozapine‐associated inflammation. [ABSTRACT FROM AUTHOR]

Objective: The efficacy and safety of long-acting injectable (LAI) antipsychotics in the pediatric population is not well established due to limited evidence. This case series aims to describe off-label use of aripiprazole lauroxil (AL) LAI in adolescent inpatients, including findings on safety and readmission trends. Methods: This was a retrospective chart review of patients who were initiated on AL LAI while admitted at a county-based adolescent psychiatric unit between March 2021 and March 2023. Data comprised sociodemographic and clinical characteristics, such as psychiatric diagnoses, prior antipsychotic trials, and history of nonadherence. Other observations of interest included tolerability of AL LAI and time to readmission. Results: This analysis identified 12 adolescents who received AL LAI within a 2-year period. The mean age was 16 ± 1 years, and seven (58%) patients were female. There were varying primary psychiatric diagnoses, with the most common being bipolar disorder (25%), schizophrenia (17%), major depressive disorder with psychotic features (17%), and unspecified mood disorder (17%). Eleven (92%) patients had previously trialed at least one antipsychotic, with seven (58%) having exposure to oral aripiprazole before admission. Nonadherence was the driving factor for LAI consideration in all but one patient. AL LAI was well tolerated short term; one patient reported experiencing injection site pain, and one patient discontinued the LAI after discharge due to anxiety. Time to readmission ranged from 15 to 658 days for seven patients who were hospitalized again; two of the readmissions occurred within 1 month. Conclusion: This is the first case series to describe initiation of AL LAI at an inpatient adolescent psychiatric unit. Our study illustrates that AL LAI may hold potential as an acceptably tolerated treatment in adolescents with varying psychiatric diagnoses. Further studies are needed to evaluate long-term safety and effectiveness of AL LAI in youth. [ABSTRACT FROM AUTHOR]

Lurasidone is a novel atypical antipsychotic drug acting on dopaminergic, serotonergic and noradrenergic receptors; it is applied for the long-term treatment of schizophrenia and depression in patients with bipolar disorders. We aimed at performing a comparative study on the influence of chronic treatment with lurasidone on the expression of cytochrome P450 enzymes in the liver and in peripheral blood lymphocytes, and to evaluate the relationship between changes in the expression of CYP enzymes in the two experimental models. The obtained results show a fairly similar expression pattern of the main CYP enzymes in the rat livers and lymphocytes, and they indicate that in the liver, lurasidone exerts an inhibitory effect on the activity, protein and mRNA levels of CYP2B1/2 (not CYP2B2 mRNA), CYP2C11 and CYP2E1, while in the case of CYP3A1 and CYP3A2, it causes enzyme induction. At the same time, lurasidone decreases the expression of CYP2B, CYP2C11 (CYP2C11 protein only) and CYP2E1 but increases that of CYP3A2 (not CYP3A1) in lymphocyte cells. In conclusion, chronic treatment with lurasidone simultaneously and in the same way influences the expression and activity of CYP2B, CYP2C11, CYP2E1 and CYP3A2 in the liver and peripheral blood lymphocytes of rats. Thus, the lymphocyte cytochrome P450 profile may be utilized as an indicator of the hepatic cytochrome P450 profile in further clinical studies with lurasidone, and lymphocytes may serve as easily available surrogates for examining the impact of new drugs and chronic in vivo treatments on CYP enzyme expression, as well as to estimate drug–drug interactions and toxicity risk. [ABSTRACT FROM AUTHOR]

Rationale: Inadequate responses to current schizophrenia treatments have accelerated research into novel therapeutic approaches. Objectives: This study investigated the efficacy and tolerability of adjunctive L-theanine, an ingredient with neuroimmunomodulatory and neuroprotective properties, for chronic schizophrenia. Methods: Eighty chronic schizophrenia inpatients were equally assigned to receive risperidone (6 mg/day) plus either L-theanine (400 mg/day) or matched placebo in this 8-week, randomized, parallel-group, double-blind, placebo-controlled trial. The participants were assessed using the Positive and Negative Syndrome Scale (PANSS) by recording the results of subscales at baseline and weeks 4 and 8 to measure treatment efficacy. Additionally, the participants were assessed for the Hamilton Depression Rating Scale (HDRS) and adverse events, including the Extrapyramidal Symptom Rating Scale (ESRS). Results: Sixty patients, 30 in each group, were included in the analyses. All baseline demographic and clinical characteristics were comparable between the groups (p-values > 0.05). The reduction rates from baseline to endpoint in negative, general psychopathology, and total scores of PANSS were greater in the L-theanine group (p-values = 0.03, 0.01, and 0.04, respectively). Regarding general psychopathology scores, the reduction in the L-theanine group was also greater until week 4 (p-value < 0.01). The time × treatment interaction effect was significant on negative (p-value = 0.03), general psychopathology (p-value < 0.01), and total (p-value = 0.04) scores of PANSS, indicating additional improvements in the L-theanine group. The HDRS and side effects were comparable between the groups (p-values > 0.05). Conclusions: L-Theanine adjunct to risperidone safely and tolerably outperformed adjunctive placebo for schizophrenia, and promising evidence indicated its effects on primary negative symptoms, which need to be scrutinized in further studies. Trial registration: The study protocol was registered and published prospectively in the Iranian Registry of Clinical Trials (http://www.irct.ir; registration number: IRCT20090117001556N133) on 2020–12-12. [ABSTRACT FROM AUTHOR]

Coagulation fractionation techniques have also been developed for transdermal proniosome arrays using various nonionic surfactants. Span-60 proniosome has lower HLB value, longer alkyl chain and higher phase transition temperature, resulting in higher resistance (94.13 ± 4.76). The addition of LDL cholesterol and lecithin also increases the strength of the bilayer.With the Twain method, the vesicle size decreases and increases with delay and recall. Low polydispersity index and high zeta potential were found in the Pronisome preparation. TEM studies confirmed perfectly round vesicles. IR studies have confirmed that there are no drug interactions in the body and that no drug is blocked. The release kinetics of Pronisome was confirmed to be slower than control. Aripiprazole in 30% PEG. Additionally, Span's emission rate is lower than Tween's, which may be due to the lipophilicity of Span and aripiprazole. Release data favor the Higuchi version, which shows that drug release is controlled by diffusion. The transdermal flow of aripiprazole is highest as it passes through the pores and skin of closed excised rats with the Span 60 system. [ABSTRACT FROM AUTHOR]

Niosomes were prepared using thin-film hydration and sonication techniques. For the film hydration method, surfactant, cholesterol, stearylamine (65.0:30.0:5.0 mM), and aripiprazole (2 mg) were dissolved in a mixture of chloroform:ethanol (3:1).The solvent was evaporated in vacuo on a field evaporator to form a thin film. Then hydrate the film with 10 ml of phosphate buffer (pH 7.4) using a stirrer. Surfactant, cholesterol, and stearylamine for sonication method (65.0:30.0:5.0 mM) and aripiprazole (2 mg) were placed in a beaker and 10 mL of phosphate buffer (pH 7.4) was added. I let it sit for 5 hours. A free dispersion (niosome) is synthesized 7 minutes before sonication is required.In the ether injection process, the solution containing the mixture of ether and surfactant slowly enters the aqueous solution (preheated to 60 °C) to evaporate the ether and synthesize the milky pest. Various parameters of the product such as percent encapsulation efficiency, vesicle size, polydispersity index and zeta potential were analyzed and selected as the best method for liposome production according to specification #1. [ABSTRACT FROM AUTHOR]

Novel approaches are required to find new treatments for schizophrenia and other neuropsychiatric disorders. This study utilised a combination of in vitro transcriptomics and in silico analysis with the BROAD Institute's Connectivity Map to identify drugs that can be repurposed to treat psychiatric disorders. Human neuronal (NT2-N) cells were treated with a combination of atypical antipsychotic drugs commonly used to treat psychiatric disorders (such as schizophrenia, bipolar disorder, and major depressive disorder), and differential gene expression was analysed. Biological pathways with an increased gene expression included circadian rhythm and vascular endothelial growth factor signalling, while the adherens junction and cell cycle pathways were transcriptionally downregulated. The Connectivity Map (CMap) analysis screen highlighted drugs that affect global gene expression in a similar manner to these psychiatric disorder treatments, including several other antipsychotic drugs, confirming the utility of this approach. The CMap screen specifically identified metergoline, an ergot alkaloid currently used to treat seasonal affective disorder, as a drug of interest. In mice, metergoline dose-dependently reduced MK-801- or methamphetamine-induced locomotor hyperactivity confirming the potential of metergoline to treat positive symptoms of schizophrenia in an animal model. Metergoline had no effects on prepulse inhibition deficits induced by MK-801 or methamphetamine. Taken together, metergoline appears a promising drug for further studies to be repurposed as a treatment for schizophrenia and possibly other psychiatric disorders. [ABSTRACT FROM AUTHOR]

Although switching to antipsychotic monotherapy improves patient outcomes in schizophrenia, antipsychotic deprescribing is rarely performed, and its use varies between countries, as do psychotropic prescribing patterns. This study aimed to determine factors associated with antipsychotic deprescribing at discharge after a psychiatric hospitalization and to compare psychotropic prescribing patterns between Belgium and Québec, Canada. Data on adult inpatients with schizophrenia were collected retrospectively in seven hospitals. At discharge, the number of antipsychotics had decreased in 22.2% of the 63 Canadian patients and 9.9% of the 516 Belgian patients. A number of factors increased the likelihood of antipsychotic deprescribing: a hospitalization in the Canadian hospital (aOR = 4.13, 95% CI 1.48–11.5), living in a residential facility (aOR = 2.51, 95% CI 1.05–4.39), ≥2 previous antipsychotic trials (aOR = 15.38, 95% CI 3.62–65.36), having an antipsychotic side effect (aOR = 1.86, 95% CI 1.01–3.44) and being in a general hospital (aOR = 2.28, 95% CI 1.09–4.75). Patients on a long‐acting injectable antipsychotic (aOR = 0.51, 95% CI 0.26–0.98), with prior clozapine use (aOR = 0.36, 95% CI 0.13–0.95), greater antipsychotic exposure (aOR = 0.35, 95% CI 0.2–0.61) and more hypno‐sedatives (aOR = 0.65, 95% CI 0.43–0.98), were less likely to be deprescribed. Specific deprescribing interventions could target patients who are less likely to be deprescribed. [ABSTRACT FROM AUTHOR]

Objective: While several drugs have been linked to acute pancreatitis (AP), the APrelated risk of most drugs remains unclear. This study investigated the risk factors for drug-induced AP by analyzing a large dataset from the FDA Adverse Event Reporting System (FAERS). Methods: The reporting odds ratios (ROR) were used to assess the reports of druginduced AP from the first quarter of 2004 to the second quarter of 2022. Singlefactor, LASSO, and multi-factor regression analysis were performed to explore drug-related AP-related risk factors. Bonferroni correction was applied for the multiple comparisons performed. Results: A total of 264 drugs associated with AP, including antineoplastic drugs (35/264), antidiabetic drugs (28/264), antibacterial drugs (24/264), immunomodulatory drugs (11/264), antipsychotic drugs (6/264), and other drugs (160/264) were retrieved. Multi-factor analysis showed that males, age 41-54 years old, and 36 drugs, including Tigecycline, were risk factors for drugrelated AP. The median time to drug-related AP onset was 31 days (interquartile range [IQR] 7-102 days) and about 75% of adverse events occurred within 100 days. Conclusion: These findings may help clinicians to identify drug-related AP at the early stage and can be used to inform future studies of drug-related AP pathogenesis. [ABSTRACT FROM AUTHOR]

This systematic review compared the efficacy and tolerance of oral antipsychotics (APDs) used in the treatment of schizophrenia following the PRISMA-P© statement (n = 21). The primary outcomes of interest were clinical response measured with symptoms' improvement, tolerance to side effects and discontinuation reasons. There was better individual patients' response to aripiprazole vs. ziprasidone and quetiapine ((CDSS p = 0.04), BPRS p = 0.02, YMRS p = 0.001) and ziprasidone vs. quetiapine (CGI p = 0.02, CDSS p = 0.02). Aripiprazole was more tolerated than risperidone, ziprasidone and quetiapine (p < 0.05). Quetiapine was more tolerated than aripiprazole, ziprasidone and risperidone (p < 0.05). Ziprasidone was more tolerated than quetiapine haloperidol and olanzapine (p < 0.05). Risperidone was more tolerated than olanzapine (p = 0.03) and haloperidol was more tolerated than olanzapine and quetiapine (p < 0.05). Olanzapine caused less discontinuation than quetiapine; quetiapine caused less discontinuation than ziprasidone, aripiprazole and haloperidol; ziprasidone caused less discontinuation than quetiapine, aripiprazole and haloperidol; aripiprazole caused less discontinuation than quetiapine, ziprasidone and olanzapine and olanzapine caused less discontinuation than ziprasidone and haloperidol (p < 0.05). It was concluded that individual patient clinical response, tolerance to side effects and life-threatening side effects remain the most reliable basis for selecting and continuing the use of APD. [ABSTRACT FROM AUTHOR]