Atypical Antipsychotic Drugs Research Articles

Therapeutic drug monitoring of clozapine in human serum by high-throughput paper spray mass spectrometry

IntroductionMonitoring the atypical antipsychotic drug clozapine is crucial to ensure patient safety. This article showcases a high-throughput analytical method for measuring clozapine and its primary metabolite norclozapine (N-desmethylclozapine) in serum using paper spray mass spectrometry (PS-MS). ObjectivesThis study aimed to assess the viability of a PS-MS method for the rapid measurement of clozapine and norclozapine in human serum samples as an alternative to liquid chromatography mass spectrometry (LC-MS). MethodsSerum samples were processed by protein precipitation followed by deposition of the supernatant containing labelled internal standards onto paper spray substrates mounted in cartridges. Analytes were then analyzed using a triple quadrupole mass spectrometer equipped with a commercial paper spray ionization source. The results obtained from the patient samples were compared to those from a validated LC-MS assay. ResultsPS-MS calibrations for clozapine and norclozapine were linear (R2 > 0.99) over five days. Between-run precision was below 8 %, and within-run precision did not exceed 10 %. When compared to a validated LC-MS method, the mean bias for 39 patient samples was −9% for clozapine and −1% for norclozapine, with no outliers. Mass spectrometry ion ratio comparisons indicated no interference for patient samples above the lower limit of quantification. There was less than 7 % change in the measured concentrations of both analytes over five days for samples dried on paper substrates. Notably, virtually no maintenance of the MS source was required during this study. ConclusionThis study illustrates the potential of PS-MS for serum drug monitoring in the clinical laboratory.

Inhibition of HCN1 by norquetiapine—an active metabolite of the atypical anti-psychotic drug quetiapine

Inhibition of HCN1 by norquetiapine—an active metabolite of the atypical anti-psychotic drug quetiapine

Modulatory effect of olanzapine on neuronal nitric oxide synthase (nNOS) expression in the rat striatum.

Nitric oxide (NO) has been thought to be a novel factor involved in the mechanisms of mental disorders pathogenesis for quite some time. However, little is known about potential crosstalk between neuronal NO signaling and neuroleptics action. The present work was, therefore, focused on gene expression of neuronal NO synthase (nNOS) in the brains of rats chronically treated with olanzapine, an atypical antipsychotic drug. Studies were carried out on adult, male Sprague-Dawley rats that were divided into 2 groups: control and experimental animals treated with olanzapine (28-day-long intraperitoneal injection, at dose 5mg/kg daily). All individuals were killed under anesthesia and the whole brains excised. Immunohistochemical procedure was used for histological assessment of the whole brain, and for both descriptive and quantitative analysis of nNOS protein distribution in selected brain structures. Long-term treatment with olanzapine is reflected in different changes in the number of enzyme-expressing cells in the rat brain. Olanzapine decreased the number of nNOS-expressing cells and possibly reduced NO synthesis in the rat striatum. Olanzapine can be taken into account as a potential inhibitor of NO synthesis in the rat striatum.

Comparison of oral olanzapine versus oral ondansetron for prevention of postoperative nausea and vomiting in female patients undergoing laparoscopic cholecystectomy under general anaesthesia

Introduction: Postoperative nausea and vomiting is one of the significant problem in anaesthesia practice The incidence is even high following laparoscopic surgeries. 5HT3 receptor antagonists are routinely used to prevent postoperative nausea and vomiting (PONV). Olanzapine, an atypical antipsychotic drug with its activity on multiple receptor sites particularly at D2 and 5HT3 receptors, has potential antiemetic properties. This study aimed to compare the efficacy of ondansetron with olanzapine in prevention of PONV following laparoscopic cholesystectomy under general anaesthesia. Materials and methods: This randomized double blind controlled study was done by recruiting 120 female patients belonging to ASA I/II posted for laparoscopic cholecystectomy under general anaesthesia. Patients were assigned to one of the two groups. Group A received tablet Olanzapine 5mg, 4 hrs before surgery and Group B received tablet ondansetron 16mg 1hr before surgery. Postoperatively nausea, retching, vomiting complete response and sedation were assessed for 24hrs at the interval of 0-4hrs, 4-8hrs, 8-12hrs and 12-24hrs. Results: There was no statistical difference in the incidence of postoperative nausea, retching and vomiting between the groups at 0-4hrs, 4-8hrs. Statistical difference between the groups were seen at 8-12hr interval (nausea p=0.048, retching=0.042, vomiting p=0.042) and at 12-24 hr (nausea p=0.028, retching p=0.001, vomiting p=0.006). There was a significant difference in the use of rescue drug at 8-12hrs (6.7% patients required rescue drug in Group B whereas none required in Group B). Conclusion: Olanzapine 5 mg can be used safely and effectively for prophylaxis against PONV and is more effective in preventing PONV during the late postoperative period compared to ondansetron.

Formulation and statistical optimization of clozapine solid self emulsification system for improving the dissolution properties

Clozapine is an atypical antipsychotic drug that exhibits low bioavailability (>27%) due to poor solubility and higher hepatic metabolism. The present investigation was aimed to prepare a solid self-emulsifying drug delivery system (S-SEDDS) of clozapine to improve its dissolution properties. Various long-chained natural dietary oils, surfactants, and cosurfactants were screened to evaluate their drug solubilization ability and emulsification efficiency which was measured in terms of % transmittance of the formed system. A ternary phase diagram was generated to identify compositions that were able to form emulsions with the required globule size. The simplex lattice design was used to understand the effect of change in the composition of excipients on important product characteristics. The regression analysis suggested a significant effect of the change in the proportion of composition on selected response variables. The Liquid-SEDDS (L-SEDDS) were mixed with solid carriers (aerosil-200 and MCC) to form S-SEDDS. The results of Differential Scanning Calorimetry (DSC) and Powder X-Ray Diffraction (PXRD) studies indicated the complete transformation of the crystalline drug into the amorphous or molecular level dispersed state for the S-SEDDS prepared using aerosil-200 as a carrier. The results of in-vitro dissolution studies proved significant improvement in the dissolution of the drug from the S-SEDDS compared to the pure drug.

Cognitive effects of brief and intensive neurofeedback treatment in schizophrenia: a single center pilot study.

Schizophrenia is characterized by significant cognitive impairments and affects up to 98% of patients. Neurofeedback (NF) offers a means to modulate neural network function through cognitive processes such as learning and memorization, with documented structural changes in the brain, most notably an increase in grey matter volume in targeted regions. The present 2-week, open-label, preliminary study aims to evaluate the efficacy on cognition of an adjunctive short and intensive (8 daily sessions lasting 30 minutes) alpha/theta NF training in a sample of subjects affected by schizophrenia on stabilized treatment with atypical antipsychotic drugs. The efficacy was measured at baseline and at the end of the study by the Brief Neuropsychological Examination 2 (ENB 2), the Mini Mental State Examination (MMSE), and the Stroop color-word interference test; the clinical symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS). A final sample of nine patients completed the study. Regarding the cognitive performance, at the final assessment (week 2), the NF treatment significantly improved the performance in the "Story Recall Immediate" (p = 0.024), "Story Recall Delayed" (p = 0.007), "Interference Memory 30 s" (p = 0.024), "Clock Test" (p = 0.014) sub-tests, and the ENB2 Total Score (p = 0.007). Concerning the clinical symptoms, no significant changes were observed in the PANSS subscales and the PANSS Total score. NF could represent an adjunctive treatment strategy in the therapeutic toolbox for schizophrenia cognitive symptoms.

Therapeutic Drug Monitoring to Optimize Risperidone Treatment in Children with Autism Spectrum Disorder.

Risperidone is an atypical antipsychotic drug used to treat irritability and aggression in children and adolescents with autism spectrum disorder. In an earlier study, the sum trough concentration of risperidone and its metabolite (9-hydroxyrisperidone) was positively correlated with weight gain and effectiveness. The aim of this study was to determine the therapeutic window for risperidone sum trough concentrations that balances weight gain with treatment effectiveness in this population. In addition, the effect of therapeutic drug monitoring (TDM) on treatment optimization was simulated. In a retrospective cohort (n = 24 children), the target window for risperidone leading to the least increase in body mass index z-scores while retaining effectiveness as measured by the irritability subscale of the Aberrant Behavior Checklist was determined using receiver operating curve analysis. This target range was used to simulate the effect of TDM using a population PK model implemented in the software platform InsightRX. Dosing advice was based on plasma trough concentrations and the dose administered at 12 weeks to simulate whether more children would be on target at 24 weeks after the start of treatment. A risperidone sum trough target range of 3.5-7.0 mcg/L would minimize increase in body mass index z-score and optimize effectiveness. Dosing advice using TDM and a population PK model would lead to a larger proportion of children achieving the target concentration range (62.5% versus 16.7%). TDM may be a useful tool for optimizing risperidone treatment in children and adolescents with autism spectrum disorder.

Metergoline Shares Properties with Atypical Antipsychotic Drugs Identified by Gene Expression Signature Screen

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.

Association of smoking cigarettes, age, and sex with serum concentrations of olanzapine in patients with schizophrenia.

Olanzapine is an atypical antipsychotic drug which is effective in the treatment of schizophrenia. Cigarette smoking, age, and sex could be related to the pharmacokinetics and serum concentrations of olanzapine in patients with schizophrenia. The aim of the study was to examine whether there was a significant difference in the serum olanzapine concentrations with regard to the mentioned factors. A total of 58 outpatients with schizophrenia (37 smokers, 42 men, 35 older than 40 years) participated in the study. Blood was sampled in serum tubes just before taking the next dose of olanzapine. Olanzapine was extracted by liquid-liquid extraction and was measured by an in-house high-performance liquid chromatography method on Shimadzu Prominence HPLC System with diode array detector SPD-M20A (Shimadzu, Kyoto, Japan). The results were expressed as the ratio of concentration to the daily dose of olanzapine (C/D). Non-parametric statistical tests were used to analyse differences between variables. The median C/D of olanzapine (interquartile range) in smokers was 6.0 (3.4-10.2) nmol/L/mg and in non-smokers 10.1 (5.9-17.6) nmol/L/mg; P = 0.007. The median C/D of olanzapine in patients younger than 40 years was 5.6 (4.5-10.2) nmol/L/mg and in patients older than 40 years 8.4 (5.6-13.0) nmol/L/mg; P = 0.105. The median C/D of olanzapine in male patients was 6.6 (4.6-10.4) nmol/L/mg and in female patients 9.0 (5.9-15.3) nmol/L/mg; P = 0.064. The serum olanzapine concentration was significantly lower in smoking than in non-smoking patients with schizophrenia. No significant difference was demonstrated with regard to age and sex.

Clozapine suppresses NADPH oxidase activation, counteracts cytosolic H2O2, and triggers early onset mitochondrial dysfunction during adipogenesis of human liposarcoma SW872 cells

Long-term treatment of schizophrenia with clozapine (CLZ), an atypical antipsychotic drug, is associated with an increased incidence of metabolic disorders mediated by poorly understood mechanisms. We herein report that CLZ, while slowing down the morphological changes and lipid accumulation occurring during SW872 cell adipogenesis, also causes an early (day 3) inhibition of the expression/nuclear translocation of CAAT/enhancer-binding protein β and peroxisome proliferator-activated receptor γ. Under the same conditions, CLZ blunts NADPH oxidase-derived reactive oxygen species (ROS) by a dual mechanism involving enzyme inhibition and ROS scavenging. These effects were accompanied by hampered activation of the nuclear factor (erythroid-derived2)-like 2 (Nrf2)-dependent antioxidant responses compared to controls, and by an aggravated formation of mitochondrial superoxide. CLZ failed to exert ROS scavenging activities in the mitochondrial compartment but appeared to actively scavenge cytosolic H2O2 derived from mitochondrial superoxide. The early formation of mitochondrial ROS promoted by CLZ was also associated with signs of mitochondrial dysfunction. Some of the above findings were recapitulated using mouse embryonic fibroblasts.We conclude that the NADPH oxidase inhibitory and cytosolic ROS scavenging activities of CLZ slow down SW872 cell adipogenesis and suppress their Nrf2 activation, an event apparently connected with increased mitochondrial ROS formation, which is associated with insulin resistance and metabolic syndrome. Thus, the cellular events characterised herein may help to shed light on the more detailed molecular mechanisms explaining some of the adverse metabolic effects of CLZ.

Drug therapy combined with PBL on depression of college students

BackgroundThe treatment of depression is mainly to eliminate and improve the symptoms of patients. At present, there are a variety of clinical antidepressants for the treatment of depression, however, there are still some patients with no significant therapeutic effect. When the effect of antidepressants alone is not satisfactory for patients with refractory depression, synergistic therapy can be considered, which is atypical antipsychotics being used as synergists in combination with antidepressants. Based on this background, this project conducted relevant research on patients with depression as research samples.Subjects and MethodsThe control group was given paroxetine tablets at a dose of 20 mg/d as prescribed by the doctor, and the dose was increased to 30 mg/d after 1 week. On the basis of the control group, the study group was given atypical antipsychotic olanzapine tablets at a dose of 5 mg/d as prescribed by the doctor. The score of depression degree was represented by the Hamilton Rating Scale for Depression (HAMD) score. The score of life quality was referred to the brief form of Health survey (SF-36 scale). SPSS20.0 software was used for statistical processing of various indicators of the 2 groups.ResultsAfter treatment, HAMD scores decreased and SF-36 scores increased in the study group and control group, and HAMD scores and SF-36 scores in the study group were significantly better than those in the control group after treatment (P < 0.05).ConclusionsAntidepressant drugs (paroxetine tablets) combined with atypical antipsychotic drugs (olanzapine tablets) are effective in the treatment of depression, and can effectively improve the quality of life of patients.Acknowledgement2019 Teaching Reform Research Project of Chongqing Municipal Education Commission (No. 193144); Chongqing Educational Science Planning Project (No. 2019-GX-352).

Factors Influencing Blood Prolactin Levels in Patients with Schizophrenia under Risperidone Treatment

Abstract Objectives: Risperidone, a dopamine and serotonin antagonist or a second-generation (atypical) antipsychotic drug, is commonly prescribed for various psychiatric disorders, including schizophrenia, bipolar disorder, and autism spectrum disorders. While effective, risperidone often leads to hyperprolactinemia, impacting about 40%–80% of patients. In this study, we intended to examine the prevalence of hyperprolactinemia in Taiwanese patients with schizophrenia who received risperidone medication and to analyze potential links between prolactin blood levels and clinical variables. Methods: Patients with schizophrenia receiving risperidone monotherapy were included in this cross-sectional study. Blood levels of prolactin and metabolic parameters were measured. Results: A total of 176 participants diagnosed with schizophrenia, including 87 women and 89 men, were enrolled in our study. The prevalence of hyperprolactinemia and metabolic syndrome was 75.6% and 31.8%, respectively. Patients with hyperprolactinemia showed significantly higher insulin blood levels (p < 0.05) and significantly higher homeostasis model assessment for insulin resistance (HOMA-IR) indexes (p < 0.05) than those without hyperprolactinemia. The results of multivariate linear regression analysis showed that female sex (p = 0.001), HOMA-IR index (p < 0.01), and risperidone daily dosage (p < 0.05) were significantly associated with prolactin blood level. Conclusion: This study adds to the existing knowledge concerning risperidone-induced hyperprolactinemia in Taiwanese patients with schizophrenia. Hyperprolactinemia and metabolic syndrome are prevalent in patients with schizophrenia treated with risperidone. Clinicians are advised to be aware of these problems and monitor them regularly with their patients who receive treatment with risperidone.

Effect of Atypical Antipsychotic Usage at Therapeutic Doses on Daytime Sleepiness

The aim of this study is to determine the effect of using atypical antipsychotic drug usage at therapeutic doses on daytime sleepiness. One hundred twenty volunteers who met the inclusion-exclusion criteria were divided into two equal groups. Group 1: patient group (60 patients volunteers used atypical antipsychotic in therapeutic doses and hospitalized in the psychiatry clinic of Tekirdağ Namık Kemal University Hospital and Group 2: control group (60 control volunteers). Socio-demographic and Clinical Information Form consist of 14 questions was administration all volunteers. Also, Epworth Sleepiness Scale which is a survey that determines the degree of sleepiness in eight different situations during the day was administered to all volunteers. Atypical antipsychotic drug usage at therapeutic doses significantly increased patients’ daytime sleepiness compared to the control group. Among the atypical antipsychotic drugs usage in therapeutic dose, the drug that caused the most daytime sleepiness was clozapine. Also, using of atypical antipsychotic drugs in therapeutic doses markedly decreased patients’ life quality compared to the control group. Atypical antipsychotic drug usage at therapeutic doses could cause daytime sleepiness and reduce patients’ quality of life.

Augmentation therapy with serotonin1A receptor partial agonists on neurocognitive function in schizophrenia: A systematic review and meta-analysis

BackgroundIn a previous meta-analysis, the use of serotonin1A(5-HT1A) receptor partial agonists of the azapirone class as an add-on therapy was associated with beneficial effects on positive symptoms and attention/processing speed in schizophrenia patients. This meta-analysis builds on that study by examining the effects of adjunctive treatment with 5-HT1A partial agonists in improving other domains of neurocognitive function in schizophrenia patients. MethodsA literature search was performed from 1987 to May 2023 to identify randomized controlled trials. The standardized mean difference (SMD) with 95 % confidence intervals (CI) was calculated when there were two or more studies. Four studies, involving 313 patients, met the inclusion criteria and were used in the analysis. Results5-HT1A partial agonists (buspirone or tandospirone) did not have a significant effect on verbal learning (SMD = 0.08, 95 % CI = −0.31 to 0.47) or working memory (SMD = 0.15, 95 % CI = −0.09 to 0.39). Regarding executive functions (Wisconsin Card Sorting Test), positive but non-significant results were seen with the category number (SMD = 0.26, 95 % CI = −0.81 to 1.32), while non-significant effects were noted for percent preservation errors (SMD = −0.10, 95 % CI = −0.53 to 0.33). ConclusionsThe absence of any significant benefits in the cognitive domains studied here may have been due to the variance in the concomitant medication (typical vs atypical antipsychotic drugs), the level of cognition at baseline, or other factors. Further studies with various types of 5-HT1A agonists are warranted to examine the potential cognitive efficacy of stimulating these receptors.

Effect of taxifolin on clozapine-induced experimental oxidative and inflammatory heart damage in rats

AimClozapine is an atypical antipsychotic (AAP) drug used in treatment-resistant schizophrenia patients. The adverse effects of clozapine on the heart may result in death and require drug discontinuation. Inflammatory mechanisms are thought to be responsible for the negative effect of clozapine on the heart. This suggests that using an agent with anti-inflammatory and antioxidant properties, which may be specific to clozapine-induced heart damage, may prevent possible damage. The aim of our study is to evaluate the effect of taxifolin (3,5,7,3’,4’-pentahydroxy flavanone), an agent with known antioxidant and anti-inflammatory effects, on myocardial damage caused by clozapine with biochemical and histopathological data. Material and methodThe rats were divided into three equal groups: healthy control group (HC), clozapine-treated group (CLN), and taxifolin+clozapine-treated group (TCL). To perform this experiment, taxifolin was administered to TCL (n-6) rats at a dose of 50mg/kg orally by gavage into the stomach. In the HC (n-6) and CLN (n-6) groups, the same volume of distilled water was administered orally as a solvent. One hour after the administration of taxifolin and distilled water, clozapine was administered orally at a dose of 20mg/kg to the TCL and CLN groups once a day for 28 days. At the end of the period, troponin I (TP I) and creatine kinase MB (CK-MB) levels were measured in the venous blood of each group. Malondialdehyde (MDA), total glutathione (tGSH), TNF-α, NF-▪B, and IL-1β levels were measured in samples taken from heart tissues. Additionally, heart tissues were evaluated histopathologically. ResultsTroponin I, CK-MB, MDA, TNF-α, NF-▪B, and IL-1β levels, myocardial degeneration, myofiber irregularity, and congestion scores were significantly higher and tGSH levels were lower in the clozapine group than in the healthy control and taxifolin+clozapine groups (P<0.05). Compared with the healthy control group, troponin I, tGSH, and NF-KB levels were similar (P>0.05), CK-MB, MDA, TNF-α, and IL-1β levels were higher in the taxifolin+clozapine group, while they were significantly lower than the clozapine group (P<0.05). Histopathologically evaluated myocardial degeneration, myofiber irregularity, and congestion score were significantly lower in the taxifolin+clozapine group than in the clozapine group. In the clozapine group (CLN group), myofibers were found to have irregular patterns and were observed as irregular. In the taxifolin+clozapine group (TLC group), myofibrils generally showed a regular morphology. ConclusionWe found that taxifolin can ameliorate damage to myocardial tissue by regulating oxidant-antioxidant and proinflammatory cytokine levels. The data of our study suggest that taxifolin may be useful in the treatment of clozapine-induced myocardial injury.

NU-1223, a simplified analog of alstonine, with 5-HT2cR agonist-like activity, rescues memory deficit and positive and negative symptoms in subchronic phencyclidine mouse model of schizophrenia

The serotonin (5-HT)2 C receptor(R) is a widely distributed G-protein-coupled receptor, expressed abundantly in the central nervous system. Alstonine is a natural product that has significant properties of atypical antipsychotic drugs (AAPDs), in part attributed to 5-HT2 CR agonism. Based on alstonine, we developed NU-1223, a simplified β carboline analog of alstonine, which shows efficacies comparable to alstonine and to other 5-HT2 CR agonists, Ro-60–0175 and lorcaserin. The 5-HT2 CR antagonism of some APDs, including olanzapine, contributes to weight gain, a major side effect which limits its tolerability, while the 5-HT2 CR agonists and/or modulators, may minimize weight gain. We used the well-established rodent subchronic phencyclidine (PCP) model to test the efficacy of NU-1223 on episodic memory, using novel object recognition (NOR) task, positive (locomotor activity), and negative symptoms (social interaction) of schizophrenia (SCH). We found that NU-1223 produced both transient and prolonged rescue of the subchronic PCP-induced deficits in NOR and SI. Further, NU-1223, but not Ro-60–0175, blocked PCP and amphetamine (AMPH)-induced increase in LMA in subchronic PCP mice. These transient efficacies in LMA were blocked by the 5-HT2 CR antagonist, SB242084. Sub-chronic NU-1223 treatment rescued NOR and SI deficits in subchronic PCP mice for at least 39 days after 3 days injection. Chronic treatment with NU-1223, ip, twice a day for 21 days, did not increase average body weight vs olanzapine. These findings clearly indicate NU-1223 as a class of small molecules with a possible 5-HT2 CR-agonist-like mechanism of action, attributing to its efficacy. Additional in-depth receptor mechanistic studies are warranted, as this small molecule, both transiently and chronically rescued PCP-induced deficits. Furthermore, NU-1223 did not induce weight gain post long-term administrations vs AAPDs such as olanzapine, making NU-1223 a putative therapeutic compound for SCH.

Near-Infrared Fluorescent Probe for the In Situ Visualization of Oxidative Stress in the Brains of Neuroinflammatory and Schizophrenic Mice.

Schizophrenia is a common mental disorder with unclear mechanisms. Oxidative stress and neuroinflammation play important roles in the pathological process of schizophrenia. Superoxide anion (O2•-) is an important oxidative stress biomarker in vivo. However, due to the existence of the blood-brain barrier (BBB), few near-infrared (NIR) fluorescent probes have been used for the sensing and detection of O2•- in the brain. With this research, we developed the first near-infrared fluorescent probe (named CT-CF3) for noninvasive detection of endogenous O2•- in the brain of mice. Enabling fluorescence monitoring of the dynamic changes in O2•- flux due to the prolonged activation of microglia in neuroinflamed and schizophrenic (SZ) mice brains, thereby providing direct evidence for the relationship between oxidative stress, neuroinflammation, and schizophrenia. Furthermore, we confirmed the O2•- burst in the brains of first-episode schizophrenic mice and assessed the effect of two atypical antipsychotic drugs (risperidone and olanzapine) on redox homeostasis.

Posterior Reversible Encephalopathy after Quetiapine Overdose

Quetiapine is an atypical antipsychotic drug that can cause sinus tachycardia, hypotension, coma, etc. with overdose, and rarely convulsions, rhabdomyolysis and neuroleptic malignant syndrome. Posterior reversible encephalopathy syndrome usually occurs in association with hypertension, but can occur rarely in rhabdomyolysis accompanied by acute kidney injury and arginine vasopressin axis hyperstimulation. We report the experience of a patient hospitalized with a quetiapine overdose who developed drug-induced rhabdomyolysis and reversible encephalopathy without hypertension after acute renal injury.

Short-term treatment with risperidone ameliorated 1,2-diacetylbenzene-induced liver dysfunction

1,2-Diacetylbenze (C10H10O2, DAB) is a potential inducer or activator of toxic mechanisms. DAB exerts high absorption by the gastrointestinal tract and high blood–brain barrier penetration. However, only the effects of DAB on the central nervous system were reported, with a dearth of evidence of DAB’s effects on the liver, which is more susceptible to toxic substances. Risperidone, an atypical antipsychotic drug, has been shown to protect against DAB-induced cognitive impairment in an animal model. Risperidone was found to have little or no effect on the liver after short-term administration. The question of whether risperidone can protect against DAB-induced liver dysfunction, particularly after short-term administration, is unknown. Thus, this study aimed to assess the hepatoprotective effects of risperidone on DAB-induced liver dysfunction in male C57BL/6 mice treated with DAB 5 mg/kg for 1 week and risperidone 0.125–0.25 mg/kg for 2 weeks. After exposure to DAB 5 mg/kg for 1 week, we found that DAB induced liver damage by increasing liver function biomarkers (GGT, ALT, and AST), reactive oxygen species, nitric oxide, and proinflammatory cytokines (IL-1α, IL-1β, IL-6, IL-12, and TNF- α), activating apoptosis (elevated Caspase-3 and Bax levels and reduced Bcl2 level), TLR4/JNK/NF-κB, Jak2/Stat5 pathways, and suppressing Jak2/Stat3 and IRS1/PI3K/AKT/MDM2 pathways. After a 2-week course of treatment, risperidone was able to lessen these effects; the higher dose (0.25 mg/kg) appeared to be more effective than the lower dose (0.125 mg/kg). To strengthen findings from in vivo analysis, in silico analysis also found three targets (Stat3, Caspase-3, AKT, IL-1β), two miRNAs (miR-26b-5p and miR-34a-5p), two transcription factors (NFKB1 and NFKB2), and numerous pathways (“AGE-RAGE signaling pathway in diabetic complications”, “hepatitis B”, “alcoholic liver disease”, “apoptosis”, and “liver cirrhosis”) as the key molecular processes involved in the pathogenesis of DAB-induced liver damage and targeted by risperidone. The physicochemical characteristics and pharmacokinetics of DAB and risperidone also support the toxic effects of DAB and the beneficial properties of risperidone in the liver. In conclusion, these findings reflect the therapeutic effects of risperidone on DAB-induced liver dysfunction after 1 week and 2 weeks exposure to DAB and risperidone, respectively.

DRD2, DRD3, and HTR2A Single-Nucleotide Polymorphisms Involvement in High Treatment Resistance to Atypical Antipsychotic Drugs.

The objective of this study was to investigate the DRD2 rs1800497, rs1799732, rs1801028, DRD3 rs6280, and HTR2A rs6314, rs7997012, and rs6311 single-nucleotide polymorphism (SNP) correlations with resistance to second-generation antipsychotics (SGAs) in a real-world sample of patients with treatment-resistant mental disorders. We divided 129 participants into a high treatment resistance (HTR) group (current treatment with two SGAs, or clozapine, or classic neuroleptics for a failure of previous SGAs trials) and a low treatment resistance (LTR) group (current treatment with one atypical antipsychotic). We used Next-Generation Sequencing on DNA isolated from peripheral blood samples to analyze the polymorphisms. We performed logistic regression to search for predictors of HTR membership. A diagnosis of schizophrenia significantly predicted the HTR membership compared to other diagnoses. Other predictors were the DRD3 rs6280 C|T (OR = 22.195) and T|T (OR = 18.47) vs. C|C, HTR2A rs7997012 A|G vs. A|A (OR = 6.859) and vs. G|G (OR = 2.879), and DRD2 rs1799732 I|I vs. D|I (OR = 12.079) genotypes. A diagnosis of schizophrenia and the DRD2 rs1799732, DRD3 rs6280, and HTR2A rs7997012 genotypes can predict high treatment resistance to SGAs.