RESUMO

INTRODUCTION: Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in children. ADHD leads to significant impairment in overall functioning of the child. There is limited information concerning the clinical scenario of ADHD within Nepal. The study aims to determine the clinico-demographic profile and pattern of medication use in the treatment of ADHD. METHODS: This study retrospectively examines the records of children diagnosed with ADHD at the Child and Adolescent Psychiatry (CAP) Unit, Kanti Children's Hospital (KCH), Nepal. Approval for the study was granted by KCH's Institutional Review Board. The analysis focused on data extracted from hospital records of ADHD patients spanning from 1 January 2021 to 30 June 2023 encompassing two and a half years. RESULTS: A total of 585 children were diagnosed with ADHD, with a mean age 7±3.04 years. The majority 501 (85.64%) were male, and 377 (64.44%) were from the school going age group (6 to 11 years). The prevalent psychiatric comorbidities included Autism Spectrum Disorder (ASD) at 102 (17.43%), Intellectual Disability (ID) at 93(15.89%), and Oppositional Defiant Disorder (ODD) at 36 (6.15%). The commonly used medication was Clonidine 165 (28.20%) followed by Atomoxetine 154 (26.32%) and Risperidone 65 (11.11%). CONCLUSIONS: The study indicates that ADHD is highly prevalent in Nepal. Comorbidities like ASD and ID are frequently seen which further necessitates the need for structured assessments and multidisciplinary approaches to address ADHD. In our context with limited treatment options, the management of ADHD is extremely challenging.

Assuntos

Transtorno do Deficit de Atenção com Hiperatividade , Transtorno do Espectro Autista , Centros de Atenção Terciária , Humanos , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Criança , Masculino , Feminino , Nepal/epidemiologia , Estudos Transversais , Adolescente , Estudos Retrospectivos , Transtorno do Espectro Autista/epidemiologia , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/epidemiologia , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/tratamento farmacológico , Deficiência Intelectual/epidemiologia , Comorbidade , Cloridrato de Atomoxetina/uso terapêutico , Risperidona/uso terapêutico , Pré-Escolar , Clonidina/uso terapêutico , Estimulantes do Sistema Nervoso Central/uso terapêutico

RESUMO

The complexity of brain activity reflects its ability to process information, adapt to environmental changes, and transition between states. However, it remains unclear how schizophrenia (SZ) affects brain activity complexity, particularly its dynamic changes. This study aimed to investigate the abnormal patterns of brain activity complexity in SZ, their relationship with cognitive deficits, and the impact of antipsychotic medication. Forty-four drug-naive first-episode (DNFE) SZ patients and thirty demographically matched healthy controls (HC) were included. Functional MRI-based sliding window analysis was utilized for the first time to calculate weighted permutation entropy to characterize complex patterns of brain activity in SZ patients before and after 12 weeks of risperidone treatment. Results revealed reduced complexity in the caudate, putamen, and pallidum at baseline in SZ patients compared to HC, with reduced complexity in the left caudate positively correlated with Continuous Performance Test (CPT) and Category Fluency Test scores. After treatment, the complexity of the left caudate increased. Regions with abnormal complexity showed decreased functional connectivity, with complexity positively correlated with connectivity strength. We observed that the dynamic complexity of the brain exhibited the characteristic of spontaneous, recurring "complexity drop", potentially reflecting transient state transitions in the resting brain. Compared to HC, patients exhibited reduced scope, intensity, and duration of complexity drop, all of which improved after treatment. Reduced duration was negatively correlated with CPT scores and positively with clinical symptoms. The results suggest that abnormalities in brain activity complexity and its dynamic changes may underlie cognitive deficits and clinical symptoms in SZ patients. Antipsychotic treatment partially restores these abnormalities, highlighting their potential as indicators of treatment efficacy and biomarkers for personalized therapy.

Assuntos

Antipsicóticos , Encéfalo , Imageamento por Ressonância Magnética , Risperidona , Esquizofrenia , Humanos , Esquizofrenia/tratamento farmacológico , Esquizofrenia/fisiopatologia , Esquizofrenia/diagnóstico por imagem , Masculino , Feminino , Adulto , Antipsicóticos/uso terapêutico , Antipsicóticos/farmacologia , Risperidona/uso terapêutico , Risperidona/farmacologia , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Adulto Jovem , Estudos de Casos e Controles , Neuroimagem , Núcleo Caudado/diagnóstico por imagem , Núcleo Caudado/fisiopatologia , Putamen/diagnóstico por imagem , Putamen/fisiopatologia

RESUMO

Monodisperse biodegradable polymer microspheres show broad applications in drug delivery and other fields. In this study, we developed an effective method that combines microfluidics with interfacial instability to prepare monodispersed poly(lactic-co-glycolic acid)-b-polyethylene glycol (PLGA-PEG)/poly(lactic-co-glycolic acid) (PLGA) microspheres with tailored surface morphology. By adjusting the mass ratio of PLGA-PEG to PLGA, the concentration of stabilizers and the type of PLGA, we generated microspheres with various unique folded morphologies, such as "fishtail-like", "lace-like" and "sponge-like" porous structures. Additionally, we demonstrated that risperidone-loaded PLGA-PEG/PLGA microspheres with these folded morphologies significantly enhanced drug release, particularly in the initial stage, by exhibiting a logarithmic release profile. This feature could potentially address the issue of delayed release commonly observed in sustained-release formulations. This study presents a straightforward yet effective approach to construct precisely engineered microspheres offering enhanced control over drug release dynamics.

Assuntos

Liberação Controlada de Fármacos , Microesferas , Polietilenoglicóis , Polietilenoglicóis/química , Técnicas Analíticas Microfluídicas/instrumentação , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Portadores de Fármacos/química , Risperidona/química , Porosidade , Tamanho da Partícula , Poliglactina 910

RESUMO

BACKGROUND: Treatment resistant schizophrenia (TRS) is broadly defined as inadequate response to adequate treatment and is associated with a substantial increase in disease burden. Clozapine is the only approved treatment for TRS, showing superior clinical effect on overall symptomatology compared to other drugs, and is the prototype of atypical antipsychotics. Risperidone, another atypical antipsychotic with a more distinctive dopamine 2 antagonism, is commonly used in treatment of schizophrenia. Here, we conducted a genome-wide association study on patients treated with clozapine (TRS) vs. risperidone (non-TRS) and investigated whether single variants and/or polygenic risk score for schizophrenia are associated with TRS status. We hypothesized that patients who are treated with clozapine and risperidone might exhibit distinct neurobiological phenotypes that match pharmacological profiles of these drugs and can be explained by genetic differences. The study population (n = 1286) was recruited from a routine therapeutic drug monitoring (TDM) service between 2005 and 2022. History of a detectable serum concentration of clozapine and risperidone (without TDM history of clozapine) defined the TRS (n = 478) and non-TRS (n = 808) group, respectively. RESULTS: We identified a suggestive association between TRS and a common variant within the LINC00523 gene with a significance just below the genome-wide threshold (rs79229764 C > T, OR = 4.89; p = 1.8 × 10-7). Polygenic risk score for schizophrenia was significantly associated with TRS (OR = 1.4, p = 2.1 × 10-6). In a large post-mortem brain sample from schizophrenia donors (n = 214; CommonMind Consortium), gene expression analysis indicated that the rs79229764 variant allele might be involved in the regulation of GPR88 and PUDP, which plays a role in striatal neurotransmission and intellectual disability, respectively. CONCLUSIONS: We report a suggestive genetic association at the rs79229764 locus with TRS and show that genetic liability for schizophrenia is positively associated with TRS. These results suggest a candidate locus for future follow-up studies to elucidate the molecular underpinnings of TRS. Our findings further demonstrate the value of both single variant and polygenic association analyses for TRS prediction.

Assuntos

Antipsicóticos , Clozapina , Estudo de Associação Genômica Ampla , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Risperidona , Esquizofrenia Resistente ao Tratamento , Humanos , Clozapina/uso terapêutico , Herança Multifatorial/genética , Risperidona/uso terapêutico , Masculino , Feminino , Antipsicóticos/uso terapêutico , Adulto , Polimorfismo de Nucleotídeo Único/genética , Pessoa de Meia-Idade , Esquizofrenia Resistente ao Tratamento/genética , Esquizofrenia Resistente ao Tratamento/tratamento farmacológico , Esquizofrenia Resistente ao Tratamento/patologia , Predisposição Genética para Doença , Esquizofrenia/genética , Esquizofrenia/tratamento farmacológico , Esquizofrenia/patologia

RESUMO

BACKGROUND: Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that is significantly increasing, resulting in severe distress. The approved treatment for ASD only partially improves the sympoms, but it does not entirely reverse the symptoms. Developing novel disease-modifying drugs is essential for the continuous improvement of ASD. Because of its pleiotropic effect, atorvastatin has been garnered attention for treating neuronal degeneration. The present study aimed to investigate the therapeutic effects of atorvastatin in autism and compare it with an approved autism drug (risperidone) through the impact of these drugs on TLR4/NF-κB/NOX-2 and the apoptotic pathway in a valproic acid (VPA) induced rat model of autism. METHODS: On gestational day 12.5, pregnant rats received a single IP injection of VPA (500 mg/kg), for VPA induced autism, risperidone and atorvastatin groups, or saline for control normal group. At postnatal day 21, male offsprings were randomly divided into four groups (n = 6): control, VPA induced autism, risperidone, and atorvastatin. Risperidone and atorvastatin were administered from postnatal day 21 to day 51. The study evaluated autism-like behaviors using the three-chamber test, the dark light test, and the open field test at the end of the study. Biochemical analysis of TLR4, NF-κB, NOX-2, and ROS using ELISA, RT-PCR, WB, histological examination with hematoxylin and eosin and immunohistochemical study of CAS-3 were performed. RESULTS: Male offspring of prenatal VPA-exposed female rats exhibited significant autism-like behaviors and elevated TLR4, NF-κB, NOX-2, ROS, and caspase-3 expression. Histological analysis revealed structural alterations. Both risperidone and atorvastatin effectively mitigated the behavioral, biochemical, and structural changes associated with VPA-induced rat model of autism. Notably, atorvastatin group showed a more significant improvement than risperidone group. CONCLUSIONS: The research results unequivocally demonstrated that atorvastatin can modulate VPA-induced autism by suppressing inflammation, oxidative stress, and apoptosis through TLR4/NF-κB/NOX-2 signaling pathway. Atorvastatin could be a potential treatment for ASD.

Assuntos

Atorvastatina , Modelos Animais de Doenças , NADPH Oxidase 2 , NF-kappa B , Risperidona , Receptor 4 Toll-Like , Ácido Valproico , Animais , Risperidona/farmacologia , Atorvastatina/farmacologia , Ácido Valproico/farmacologia , Receptor 4 Toll-Like/metabolismo , NF-kappa B/metabolismo , Ratos , Feminino , NADPH Oxidase 2/metabolismo , Masculino , Gravidez , Transtorno Autístico/induzido quimicamente , Transtorno Autístico/tratamento farmacológico , Ratos Sprague-Dawley , Transtorno do Espectro Autista/induzido quimicamente , Transtorno do Espectro Autista/tratamento farmacológico , Transtorno do Espectro Autista/metabolismo , Transdução de Sinais/efeitos dos fármacos , Apoptose/efeitos dos fármacos

RESUMO

BACKGROUND: We need to better understand the risk factors and predictors of medication-related weight gain to improve metabolic health of individuals with schizophrenia. This study explores how trajectories of antipsychotic medication (AP) use impact body weight early in the course of schizophrenia. METHODS: We recruited 92 participants with first-episode psychosis (FEP, n = 92) during their first psychiatric hospitalization. We prospectively collected weight, body mass index (BMI), metabolic markers, and exact daily medication exposure during 6-week hospitalization. We quantified the trajectory of AP medication changes and AP polypharmacy using a novel approach based on meta-analytical ranking of medications and tested it as a predictor of weight gain together with traditional risk factors. RESULTS: Most people started treatment with risperidone (n = 57), followed by olanzapine (n = 29). Then, 48% of individuals remained on their first prescribed medication, while 33% of people remained on monotherapy. Almost half of the individuals (39/92) experienced escalation of medications, mostly switch to AP polypharmacy (90%). Only baseline BMI was a predictor of BMI change. Individuals in the top tercile of weight gain, compared to those in the bottom tercile, showed lower follow-up symptoms, a trend for longer prehospitalization antipsychotic treatment, and greater exposure to metabolically problematic medications. CONCLUSIONS: Early in the course of illness, during inpatient treatment, baseline BMI is the strongest and earliest predictor of weight gain on APs and is a better predictor than type of medication, polypharmacy, or medication switches. Baseline BMI predicted weight change over a period of weeks, when other traditional predictors demonstrated a much smaller effect.

Assuntos

Antipsicóticos , Índice de Massa Corporal , Hospitalização , Transtornos Psicóticos , Esquizofrenia , Aumento de Peso , Humanos , Antipsicóticos/uso terapêutico , Antipsicóticos/efeitos adversos , Aumento de Peso/efeitos dos fármacos , Feminino , Masculino , Transtornos Psicóticos/tratamento farmacológico , Adulto , Hospitalização/estatística & dados numéricos , Esquizofrenia/tratamento farmacológico , Adulto Jovem , Risperidona/uso terapêutico , Risperidona/efeitos adversos , Olanzapina/uso terapêutico , Polimedicação , Estudos Prospectivos , Fatores de Risco

RESUMO

Caffeine, a methylxanthine alkaloid, works as a nonselective adenosine receptor antagonist. It is the most widely used psychostimulant drug worldwide. However, caffeine overdose can lead to acute intoxication, posing a clinical problem. Hyperthermia and hyperactivity are associated issues with acute caffeine intoxication; however, no definitive treatment exists. This study aimed to assess the ability of risperidone to attenuate caffeine-induced hyperthermia and hyperactivity while elucidating the unknown mechanisms of caffeine intoxication. The rats received intraperitoneal injections of saline, risperidone (0.25 mg/kg, 0.5 mg/kg), WAY-100635, ketanserin, haloperidol, sulpiride, or SCH 23390, 5 min after the administration of caffeine (25 mg/kg). Subcutaneous temperature and activity counts were measured using nano tag ® for up to 90 min. In vivo microdialysis was used to determine the effect of risperidone on caffeine-induced elevation of dopamine (DA), serotonin (5-HT), and noradrenaline (NA) concentrations in the anterior hypothalamus. Rats were injected with caffeine (25 mg/kg), followed by saline or risperidone (0.5 mg/kg) 5 min later. The levels of DA, 5-HT, and noradrenaline were measured every 15 min for up to 90 min after caffeine administration. Risperidone and 5-HT2A receptor antagonist ketanserin attenuated caffeine-induced hyperthermia and hyperactivity. Haloperidol and dopamine D1 antagonist SCH-23390 exacerbated hyperthermia without any effect on the hyperactivity. In the microdialysis study, risperidone treatment further attenuated caffeine-induced 5-HT elevation, but not DA and NA. Our results indicate that risperidone attenuates caffeine-induced hyperthermia and hyperactivity by blocking 5-HT2A receptor activity and may be potentially useful for treating caffeine intoxication.

Assuntos

Cafeína , Hipertermia , Risperidona , Serotonina , Animais , Cafeína/farmacologia , Risperidona/farmacologia , Masculino , Hipertermia/induzido quimicamente , Serotonina/metabolismo , Ratos Sprague-Dawley , Dopamina/metabolismo , Ratos , Hipercinese/induzido quimicamente , Hipercinese/prevenção & controle , Estimulantes do Sistema Nervoso Central/farmacologia , Estimulantes do Sistema Nervoso Central/toxicidade , Norepinefrina/metabolismo

RESUMO

Background and Objectives: Vertical rhythmic dyskinetic movements that are primarily drug-induced and affect solely the jaw, mouth, and lips without involving the tongue have been historically described as "rabbit" syndrome (RS). Evidence on the unique features and implications of this disorder remains limited. This literature review aims to evaluate the clinical-epidemiological profile, pathological mechanisms, and management of this movement disorder. Materials and Methods: Two reviewers identified and assessed relevant reports in six databases without language restriction published between 1972 and 2024. Results: A total of 85 articles containing 146 cases of RS were found. The mean frequency of RS among adults in psychiatric hospitals was 1.2% (range 0-4.4%). The mean age of affected patients was 49.2 (SD: 17.5), and 63.6% were females. Schizophrenia was the most frequent comorbidity found in 47.6%, followed by bipolar disorder (17.8%), major depressive disorder (10.3%), and obsessive-compulsive disorder (3.7%). Five cases were idiopathic. The most common medications associated with RS were haloperidol (17%), risperidone (14%), aripiprazole (7%), trifluoperazine (5%), and sulpiride (5%). The mean duration of pharmacotherapy before RS was 21.4 weeks (SD: 20.6). RS occurred in association with drug-induced parkinsonism (DIP) in 27.4% and with tardive dyskinesia (TD) in 8.2% of cases. Antipsychotic modification and/or anticholinergic drugs resulted in full or partial recovery in nearly all reported cases in which they were prescribed. Conclusions: RS occurs as a distinct drug-induced syndrome associated primarily but not exclusively with antipsychotics. Distinguishing RS from TD is important because the treatment options for the two disorders are quite different. By contrast, RS may be part of a spectrum of symptoms of DIP with similar course, treatment outcomes, and pathophysiology.

Assuntos

Antipsicóticos , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antipsicóticos/efeitos adversos , Discinesia Induzida por Medicamentos/diagnóstico , Discinesia Induzida por Medicamentos/epidemiologia , Discinesia Induzida por Medicamentos/etiologia , Discinesia Induzida por Medicamentos/terapia , Haloperidol/efeitos adversos , Boca/fisiopatologia , Risperidona/efeitos adversos , Síndrome , Idoso

RESUMO

INTRODUCTION: Many articles suggest that clozapine was strongly associated with a higher incidence of new-onset diabetes mellitus, and the issue has remained unsettled. Many articles have compared clozapine with FGAs, but few have compared clozapine with SGAs. We aimed to compare the risk of new-onset diabetes mellitus in adults with schizophrenia treated with clozapine and other SGAs. METHODS: We conducted a comprehensive search of databases from their inception up until August 26, 2023. The specific databases include PubMed, Embase and others. We included non-randomized controlled trials involving the use of SGAs such as clozapine, olanzapine, risperidone, quetiapine, amisulpride, and zotepine, with a focus on new-onset diabetes mellitus as an outcome. We utilized odds ratio with 95 % credible intervals (95 % CI) as our effect size measures. The study protocol is registered with PROSPERO, number CRD42024511280. RESULTS: We included 7 studies with sufficient data to include in the meta-analysis. A total of eight studies with 641,48 participants met the eligibility criteria. The OR of the incidence rates of new-onset diabetes between clozapine and olanzapine was 0.95 (95 % CI:[0.82-1.09]), between clozapine and risperidone was 1.25 (95 % CI: [1.09-1.44]), between clozapine and quetiapine was 1.44 (95 % CI: [0.92-2.25]). CONCLUSION: In patients with schizophrenia, clozapine has been found to have a higher rate of new-onset diabetes mellitus compared to risperidone. However, there was no significant difference in incidence rate between clozapine versus olanzapine and quetiapine. These findings can assist clinicians in balancing the risks and benefits of those drugs.

Assuntos

Antipsicóticos , Clozapina , Diabetes Mellitus , Olanzapina , Fumarato de Quetiapina , Risperidona , Esquizofrenia , Adulto , Humanos , Antipsicóticos/administração & dosagem , Antipsicóticos/efeitos adversos , Clozapina/administração & dosagem , Clozapina/efeitos adversos , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/induzido quimicamente , Olanzapina/administração & dosagem , Olanzapina/efeitos adversos , Fumarato de Quetiapina/administração & dosagem , Fumarato de Quetiapina/efeitos adversos , Risperidona/administração & dosagem , Risperidona/efeitos adversos , Esquizofrenia/tratamento farmacológico , Esquizofrenia/epidemiologia

RESUMO

PURPOSE: The removal of the residual solvent dichloromethane from biodegradable poly(D,L-lactic-co-glycolic acid) (PLGA) microparticles was investigated by aqueous or alcoholic wet extraction or vacuum-drying. METHODS: Microparticles were prepared by the O/W solvent extraction/evaporation method. The solidified microparticles were separated by filtration and the effect of subsequent drying and wet extraction methods were investigated. The residual solvent content was analysed with gas chromatography (organic solvents) and Karl Fischer titration (water). The effect of extraction conditions on microparticle aggregation, surface morphology and encapsulation of the drugs dexamethasone and risperidone was investigated. RESULTS: Residual dichloromethane was reduced to 2.43% (w/w) (20 °C) or 0.03% (w/w) (35 °C) by aqueous wet extraction. With vacuum-drying, residual dichloromethane only decreased from about 5% (w/w) to 4.34% (w/w) (20 °C) or 3.20% (w/w) (35 °C) due to the lack of the plasticizing effect of water. Redispersion of filtered, wet microparticles in alcoholic media significantly improved the extraction due to an increased PLGA plasticization. The potential of different extractants was explained with the Gordon-Taylor equation and Hansen solubility parameters. Extraction in methanol: or ethanol:water mixtures reduced residual dichloromethane from 4 - 7% (w/w) to 0.5 - 2.3% (w/w) within 1 h and 0.08 - 0.18% (w/w) within 6 h. Higher alcohol contents and higher temperature resulted in aggregation of microparticles and lower drug loadings. CONCLUSION: The final removal of residual dichloromethane was more efficient with alcoholic wet extraction followed by aqueous wet extraction at elevated temperature and vacuum drying of the microparticles.

Assuntos

Dexametasona , Cloreto de Metileno , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Solventes , Solventes/química , Cloreto de Metileno/química , Dexametasona/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Tamanho da Partícula , Risperidona/química , Ácido Láctico/química , Ácido Poliglicólico/química , Composição de Medicamentos/métodos , Microesferas

RESUMO

An escalating trend of antipsychotic drug use in children with ADHD, disruptive behavior disorder, or mood disorders has raised concerns about the impact of these drugs on brain development. Since antipsychotics chiefly target dopamine receptors, it is important to assay the function of these receptors after early-life antipsychotic administration. Using rats as a model, we examined the effects of early-life risperidone, the most prescribed antipsychotic drug in children, on locomotor responses to the dopamine D1/D2 receptor agonist, apomorphine, and the D2/D3 receptor agonist, quinpirole. Female and male Long-Evans rats received daily subcutaneous injections of risperidone (1.0 and 3.0 mg/kg) or vehicle from postnatal day 14-42. Locomotor responses to one of three doses (0.03, 0.1, and 0.3 mg/kg) of apomorphine or quinpirole were tested once a week for four weeks beginning on postnatal day 76 and 147 for each respective drug. The locomotor activity elicited by the two lower doses of apomorphine was significantly greater in adult rats, especially females, administered risperidone early in life. Adult rats administered risperidone early in life also showed more locomotor activity after the low dose of quinpirole. Overall, female rats were more sensitive to the locomotor effects of each agonist. In a separate group of rats administered risperidone early in life, autoradiography of forebrain D2 receptors at postnatal day 62 revealed a modest increase in D2 receptor density in the medial caudate. These results provide evidence that early-life risperidone administration can produce long-lasting changes in dopamine receptor function and density.

Assuntos

Antipsicóticos , Apomorfina , Agonistas de Dopamina , Atividade Motora , Quimpirol , Ratos Long-Evans , Risperidona , Animais , Apomorfina/farmacologia , Apomorfina/administração & dosagem , Risperidona/farmacologia , Risperidona/administração & dosagem , Quimpirol/farmacologia , Ratos , Agonistas de Dopamina/farmacologia , Agonistas de Dopamina/administração & dosagem , Feminino , Masculino , Atividade Motora/efeitos dos fármacos , Antipsicóticos/farmacologia , Antipsicóticos/administração & dosagem , Relação Dose-Resposta a Droga , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D2/efeitos dos fármacos , Animais Recém-Nascidos , Fatores Etários , Fatores Sexuais

RESUMO

Schizophrenia is a complex neuropsychiatric disorder with positive, negative, and cognitive symptoms. In rats, sub-chronic administration of ketamine is used for the induction of schizophrenia model. Increased locomotor activity is one of the most important features of psychotic-like symptoms in rodents. On the other hand, risperidone is a potent antipsychotic medication that is approved for the treatment of schizophrenia and bipolar disorder. In the present research, we aimed to investigate the effect of sub-chronic treatment of ketamine on cognitive and behavioral functions, and brain-derived neurotrophic factor (BDNF) expression level in the prefrontal cortex. Also, we assessed the efficacy of risperidone on cognitive and behavioral impairments induced by ketamine. Possible sex differences were also measured. Ketamine was intraperitoneally injected at the dose of 30 mg/kg for five consecutive days. Risperidone was also intraperitoneally injected at the dose of 2 mg/kg. Novel object recognition memory, pain threshold, locomotor activity, rearing behavior, and BDNF level were evaluated. The results showed that ketamine injection for five consecutive days impaired the acquisition of long-term recognition memory and decreased BDNF level in the prefrontal cortex in both sexes. Also, it decreased pain threshold in females, increased rearing behavior in males, and induced hyperlocomotion with greater effect in females. On the other hand, risperidone restored or attenuated the effect of ketamine on all the behavioral effects and BDNF level. In conclusion, we suggested that there were sex differences in the effects of ketamine on pain perception, locomotion, and rearing behavior in a rat model of schizophrenia.

Assuntos

Fator Neurotrófico Derivado do Encéfalo , Modelos Animais de Doenças , Ketamina , Córtex Pré-Frontal , Risperidona , Esquizofrenia , Caracteres Sexuais , Animais , Ketamina/farmacologia , Ketamina/administração & dosagem , Esquizofrenia/tratamento farmacológico , Esquizofrenia/induzido quimicamente , Esquizofrenia/fisiopatologia , Masculino , Feminino , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Risperidona/farmacologia , Risperidona/administração & dosagem , Ratos , Antipsicóticos/farmacologia , Antipsicóticos/administração & dosagem , Reconhecimento Psicológico/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Ratos Wistar , Comportamento Animal/efeitos dos fármacos , Limiar da Dor/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos

RESUMO

BACKGROUND: Second-generation antipsychotics (SGAs) are commonly used to treat schizophrenia (SCZ), but SGAs may differ in the severity of side effects. Long-term studies are lacking, and previous observational studies have limitations, such as failure to account for confounding factors and short follow-up durations. AIMS: To compare the long-term anthropometric and metabolic side effects of seven SGAs in a Chinese population, using a within-subject approach to reduce the risk of confounding. METHOD: We collected longitudinal data of SGA prescriptions, concomitant medications, fasting blood glucose (BG), lipid profiles, and BMI in a cohort of 767 patients with SCZ, with follow-up lasting up to 18.7 years (median ∼6.2 years). A total of 192,152 prescription records were retrieved, with 27,723 metabolic measures analysed. Linear mixed models were used to estimate the effects of SGA on BG, lipid profiles and BMI. Besides studying the effects of SGA medications (as binary predictors), we also investigated the effects of SGA dosage on metabolic profiles. RESULTS: Considering SGA medications as binary predictors, clozapine and olanzapine were associated with the most substantial worsening of lipid profiles and BMI. A significant increase in BG was observed with clozapine only. Amisulpride, paliperidone and quetiapine were associated with worsened lipid profiles and increased BMI. Conversely, aripiprazole was associated with significant improvement in lipid profiles but a small increase in BMI. When SGA dosage was considered, the model showed consistent results overall. At the minimum effective dose, clozapine was associated with the most severe metabolic side effects, followed by olanzapine. Risperidone and aripiprazole showed the least metabolic side effects, with aripiprazole being significantly associated with lower lipids. CONCLUSIONS: This study clarified the long-term and dose-dependent effects of different SGAs on anthropometric and metabolic parameters in Chinese SCZ patients. Our findings may inform clinicians and SCZ patients of SGA choices.

Assuntos

Antipsicóticos , Olanzapina , Esquizofrenia , Humanos , Antipsicóticos/efeitos adversos , Antipsicóticos/administração & dosagem , Esquizofrenia/tratamento farmacológico , Feminino , Masculino , Adulto , China , Olanzapina/efeitos adversos , Olanzapina/administração & dosagem , Pessoa de Meia-Idade , Índice de Massa Corporal , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Estudos Longitudinais , Clozapina/efeitos adversos , Clozapina/administração & dosagem , Fumarato de Quetiapina/efeitos adversos , Fumarato de Quetiapina/administração & dosagem , Risperidona/efeitos adversos , Risperidona/administração & dosagem , Seguimentos , Adulto Jovem , Relação Dose-Resposta a Droga , Aripiprazol/administração & dosagem , Aripiprazol/efeitos adversos , Aripiprazol/farmacologia , Lipídeos/sangue , População do Leste Asiático

RESUMO

PURPOSE: This study aimed to create and validate robust machine-learning-based prediction models for antipsychotic drug (risperidone) continuation in children and teenagers suffering from mania over one year and to discover potential variables for clinical treatment. METHOD: The study population was collected from the national claims database in China. A total of 4,532 patients aged 4-18 who began risperidone therapy for mania between September 2013 and October 2019 were identified. The data were randomly divided into two datasets: training (80%) and testing (20%). Five regularly used machine learning methods were employed, in addition to the SuperLearner (SL) algorithm, to develop prediction models for the continuation of atypical antipsychotic therapy. The area under the receiver operating characteristic curve (AUC) with a 95% confidence interval (CI) was utilized. RESULTS: In terms of discrimination and robustness in predicting risperidone treatment continuation, the generalized linear model (GLM) performed the best (AUC: 0.823, 95% CI: 0.792-0.854, intercept near 0, slope close to 1.0). The SL model (AUC: 0.823, 95% CI: 0.791-0.853, intercept near 0, slope close to 1.0) also exhibited significant performance. Furthermore, the present findings emphasize the significance of several unique clinical and socioeconomic variables, such as the frequency of emergency room visits for nonmental health disorders. CONCLUSIONS: The GLM and SL models provided accurate predictions regarding risperidone treatment continuation in children and adolescents with episodes of mania and hypomania. Consequently, applying prediction models in atypical antipsychotic medicine may aid in evidence-based decision-making.

Assuntos

Antipsicóticos , Aprendizado de Máquina , Mania , Risperidona , Humanos , Adolescente , Antipsicóticos/uso terapêutico , Feminino , Risperidona/uso terapêutico , Masculino , Criança , Mania/tratamento farmacológico , Pré-Escolar , China , Transtorno Bipolar/tratamento farmacológico , Resultado do Tratamento

RESUMO

Risperidone is a second-generation antipsychotic for treating schizophrenia and bipolar disorder. It can potently inhibit IKr, but is classified into conditional risk for torsade de pointes (TdP) by CredibleMeds®. Our previous studies using chronic atrioventricular block dogs showed that risperidone alone did not induce TdP, and that dl-sotalol (ß-adrenoceptor blockade plus IKr inhibition) induced TdP three times more frequently than d-sotalol (IKr inhibition alone). Since risperidone can block α1-adrenoceptor and decrease blood pressure, the resulting reflex-mediated increase of sympathetic tone on ß-adrenoceptor might protect the heart from its IKr inhibition-associated TdP. To validate this hypothesis, risperidone was administered to chronic atrioventricular block dogs after ß-adrenoceptor blocker atenolol infusion with monitoring J-Tpeak and Tpeak-Tend, which are proarrhythmic surrogate markers of "substrate" and "trigger" toward TdP, respectively. Atenolol alone induced TdP in 1 out of 5 dogs; moreover, an additional infusion of risperidone induced TdP in 3 out of 4 dogs. Risperidone prolonged QT interval, J-Tpeak and Tpeak-Tend in animals that induced TdP. These findings indicate that ß-adrenoceptor blockade can diminish repolarization reserve to augment risperidone's torsadogenic potential, thus advising caution when using ß-adrenoceptor blockers in patients with IKr inhibition-linked labile repolarization.

Assuntos

Antagonistas Adrenérgicos beta , Antipsicóticos , Atenolol , Risperidona , Torsades de Pointes , Risperidona/farmacologia , Animais , Cães , Atenolol/farmacologia , Antipsicóticos/farmacologia , Antipsicóticos/efeitos adversos , Antagonistas Adrenérgicos beta/farmacologia , Torsades de Pointes/induzido quimicamente , Bloqueio Atrioventricular/induzido quimicamente , Masculino

RESUMO

PURPOSE: The CYP2D6 gene exhibits significant polymorphism, contributing to variability in responses to drugs metabolized by CYP2D6. While CYP2D6*2 and CYP2D6*35 are presently designated as alleles encoding normal metabolism, this classification is based on moderate level evidence. Additionally, the role of the formerly called "enhancer" single nucleotide polymorphism (SNP) rs5758550 is unclear. In this study, the impacts of CYP2D6*2, CYP2D6*35 and rs5758550 on CYP2D6 activity were investigated using risperidone clearance as CYP2D6 activity marker. METHODS: A joint parent-metabolite population pharmacokinetic model was used to describe 1,565 serum concentration measurements of risperidone and 9-hydroxyrisperidone in 512 subjects. Risperidone population clearance was modeled as the sum of a CYP2D6-independent clearance term and the partial clearances contributed from each individually expressed CYP2D6 allele or haplotype. In addition to the well-characterized CYP2D6 alleles (*3-*6, *9, *10 and *41), *2, *35 and two haplotypes assigned as CYP2D6*2-rs5758550G and CYP2D6*2-rs5758550A were evaluated. RESULTS: Each evaluated CYP2D6 allele was associated with significantly lower risperidone clearance than the reference normal function allele CYP2D6*1 (p < 0.001). Further, rs5758550 differentiated the effect of CYP2D6*2 (p = 0.005). The haplotype-specific clearances for CYP2D6*2-rs5758550A, CYP2D6*2-rs5758550G and CYP2D6*35 were estimated to 30%, 66% and 57%, respectively, relative to the clearance for CYP2D6*1. Notably, rs5758550 is in high linkage disequilibrium (R2 > 0.85) with at least 24 other SNPs and cannot be assigned as a functional SNP. CONCLUSION: CYP2D6*2 and CYP2D6*35 encode reduced risperidone clearance, and the extent of reduction for CYP2D6*2 is differentiated by rs5758550. Genotyping of these haplotypes might improve the precision of genotype-guided prediction of CYP2D6-mediated clearance.

Assuntos

Antipsicóticos , Citocromo P-450 CYP2D6 , Haplótipos , Palmitato de Paliperidona , Polimorfismo de Nucleotídeo Único , Risperidona , Risperidona/farmacocinética , Risperidona/sangue , Humanos , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Masculino , Feminino , Adulto , Antipsicóticos/farmacocinética , Antipsicóticos/sangue , Palmitato de Paliperidona/farmacocinética , Palmitato de Paliperidona/sangue , Pessoa de Meia-Idade , Taxa de Depuração Metabólica , Alelos , Adulto Jovem , Genótipo , Modelos Biológicos

RESUMO

Experimental evidence indicates that the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists ketamine and MK-801 induce schizophrenia-like symptoms in rodents, including cognitive deficits. Crocins are among the active components of the plant Crocus sativus L. and were found to be effective in different models of psychiatric disorders comprising schizophrenia. The present study was designed to evaluate the efficacy of the joint administration of sub-effective doses of crocins with those of the atypical antipsychotics clozapine and risperidone in alleviating nonspatial recognition and emotional memory deficits induced either by ketamine (3 mg/kg) or MK-801 (0.1 mg/kg) in the rat. To this end, the object recognition and the step-through passive avoidance tests were used. Co-administration of sub-effective doses of crocins (5 mg/kg) with those of clozapine (0.1 mg/kg) or risperidone (0.03 mg/kg) counteracted nonspatial recognition and emotional memory deficits induced by NMDA receptor antagonists. The current findings suggest that this combinatorial treatment was efficacious in attenuating cognitive impairments related to the blockade of the NMDA receptor. In addition, the present results support the potential of crocins as an adjunctive drug for the therapy of schizophrenia.

Assuntos

Antipsicóticos , Carotenoides , Clozapina , Crocus , Maleato de Dizocilpina , Transtornos da Memória , Ratos Wistar , Receptores de N-Metil-D-Aspartato , Risperidona , Animais , Crocus/química , Carotenoides/farmacologia , Antipsicóticos/farmacologia , Risperidona/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Ratos , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Masculino , Clozapina/farmacologia , Maleato de Dizocilpina/farmacologia , Ketamina/farmacologia , Esquizofrenia/tratamento farmacológico , Extratos Vegetais/farmacologia

RESUMO

BACKGROUND AND OBJECTIVES: The increasing amount of open-access medical data provides new opportunities to gain clinically relevant information without recruiting new patients. We developed an open-source computational pipeline, that utilizes the publicly available electroencephalographic (EEG) data of the Temple University Hospital to identify EEG profiles associated with the usage of neuroactive medications. It facilitates access to the data and ensures consistency in data processing and analysis, thus reducing the risk of errors and creating comparable and reproducible results. Using this pipeline, we analyze the influence of common neuroactive medications on brain activity. METHODS: The pipeline is constructed using easily controlled modules. The user defines the medications of interest and comparison groups. The data is downloaded and preprocessed, spectral features are extracted, and statistical group comparison with visualization through a topographic EEG map is performed. The pipeline is adjustable to answer a variety of research questions. Here, the effects of carbamazepine and risperidone were statistically compared with control data and with other medications from the same classes (anticonvulsants and antipsychotics). RESULTS: The comparison between carbamazepine and the control group showed an increase in absolute and relative power for delta and theta, and a decrease in relative power for alpha, beta, and gamma. Compared to antiseizure medications, carbamazepine showed an increase in alpha and theta for absolute powers, and for relative powers an increase in alpha and theta, and a decrease in gamma and delta. Risperidone compared with the control group showed a decrease in absolute and relative power for alpha and beta and an increase in theta for relative power. Compared to antipsychotic medications, risperidone showed a decrease in delta for absolute powers. These results show good agreement with state-of-the-art research. The database allows to create large groups for many different medications. Additionally, it provides a collection of records labeled as "normal" after expert assessment, which is convenient for the creation of control groups. CONCLUSIONS: The pipeline allows fast testing of different hypotheses regarding links between medications and EEG spectrum through ecological usage of readily available data. It can be utilized to make informed decisions about the design of new clinical studies.

Assuntos

Mineração de Dados , Eletroencefalografia , Humanos , Eletroencefalografia/métodos , Mineração de Dados/métodos , Carbamazepina/uso terapêutico , Carbamazepina/farmacologia , Risperidona , Antipsicóticos/farmacologia , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Encéfalo/efeitos dos fármacos

RESUMO

Hydrogel-forming microneedle array patches (HFMAPs) are microneedles that create microconduits upon insertion and swelling in the skin, potentially allowing prolonged drug delivery without generating sharps waste. Delivering hydrophobic drugs using HFMAPs poses challenges, which can be addressed using solubility enhancers such as cyclodextrins (CDs). This study aimed to deliver risperidone (RIS) transdermally using HFMAPs. To enhance the aqueous solubility of RIS hydroxypropyl-beta-cyclodextrin (HP-ß-CD) and hydroxypropyl-gamma-cyclodextrin (HP-γ-CD) were utilised and their performance was tested using phase solubility studies. The aqueous solubility of RIS was enhanced by 4.75-fold and 2-fold using HP-ß-CD and HP-γ-CD, respectively. RIS-HP-ß-CD complex (CX) and physical mixture (PM) directly compressed tablets were prepared and combined with HFMAPs. Among the tested formulations, RIS-HP-ß-CD PM reservoirs with 11 x 11 PVA/PVP HFMAPs exhibited the best performance in ex vivo studies and were further evaluated in in vivo experiments using female Sprague Dawley rats. The extended wear time of the MAPs resulted in the sustained release of RIS and its active metabolite 9-hydroxyrisperidone (9-OH-RIS) in plasma samples, lasting from 3 to 5 days with a 1-day application and up to 10 days with a 5-day application. For a 1-day application, HFMAPs showed greater systemic exposure to RIS compared to intramuscular control (AUC0-t: 13330.05 ± 2759.95 ng/mL/hour versus 2706 ± 1472 ng/mL/hour). Moreover, RIS exposure was extended to 5 days (AUC0-t: 12292.37 ± 1801.94 ng/mL/hour). In conclusion, HFMAPs could serve as an alternative for delivering RIS in a sustained manner, potentially improving the treatment of schizophrenia.

Assuntos

2-Hidroxipropil-beta-Ciclodextrina , Administração Cutânea , Sistemas de Liberação de Medicamentos , Hidrogéis , Risperidona , Solubilidade , Risperidona/administração & dosagem , Risperidona/farmacocinética , Risperidona/química , Animais , Hidrogéis/química , Sistemas de Liberação de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/instrumentação , 2-Hidroxipropil-beta-Ciclodextrina/química , Ratos , Agulhas , Ratos Sprague-Dawley , Absorção Cutânea , Ciclodextrinas/química , Antipsicóticos/administração & dosagem , Antipsicóticos/farmacocinética , Feminino , Pele/metabolismo

RESUMO

Pharmacogenetic markers are current targets for the personalized treatment of psychosis. Limited data exist on COMT and NRG1 polymorphisms in relation to risperidone treatment. This study focuses on the impact of COMT rs4680 and NRG1 (rs35753505, rs3924999) polymorphisms on risperidone treatment in schizophrenia spectrum disorders (SSDs). This study included 103 subjects with SSD treated with risperidone monotherapy. COMT rs4680, NRG1 rs35753505, and rs3924999 were analyzed by RT-PCR. Participants were evaluated via the Positive and Negative Syndrome Scale (PANSS) after six weeks. Socio-demographic and clinical characteristics were collected. COMT rs4680 genotypes significantly differed in PANSS N scores at admission: AG>AA genotypes (p = 0.03). After six weeks of risperidone, PANSS G improvement was AA>GG (p = 0.05). The PANSS total score was as follows: AA>AG (p = 0.04), AA>GG (p = 0.02). NRG1 rs35753504 genotypes significantly differed across educational levels, with CC>CT (p = 0.02), and regarding the number of episodes, TT>CC, CT>CC (p = 0.01). The PANSS total score after six weeks of treatment showed a better improvement for TT

Assuntos

Antipsicóticos , Catecol O-Metiltransferase , Neuregulina-1 , Polimorfismo de Nucleotídeo Único , Risperidona , Esquizofrenia , Humanos , Neuregulina-1/genética , Catecol O-Metiltransferase/genética , Risperidona/uso terapêutico , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Masculino , Feminino , Adulto , Antipsicóticos/uso terapêutico , Pessoa de Meia-Idade , Medicina de Precisão/métodos , Genótipo