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1.
Int J Mol Sci ; 22(8)2021 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-33920193

RESUMO

Atypical or second-generation antipsychotics are used in the treatment of psychosis and behavioral problems in older persons with dementia. However, these pharmaceutical drugs are associated with an increased risk of stroke in such patients. In this study, we evaluated the effects of risperidone treatment on phospholipid and sphingolipid composition and lipid raft function in peripheral blood mononuclear cells (PBMCs) of older patients (mean age >88 years). The results showed that the levels of dihydroceramides, very-long-chain ceramides, and lysophosphatidylcholines decreased in PBMCs of the risperidone-treated group compared with untreated controls. These findings were confirmed by in vitro assays using human THP-1 monocytes. The reduction in the levels of very-long-chain ceramides and dihydroceramides could be due to the decrease in the expression of fatty acid elongase 3, as observed in THP-1 monocytes. Moreover, risperidone disrupted lipid raft domains in the plasma membrane of PBMCs. These results indicated that risperidone alters phospholipid and sphingolipid composition and lipid raft domains in PBMCs of older patients, potentially affecting multiple signaling pathways associated with these membrane domains.


Assuntos
Ceramidas/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Transtornos Psicóticos/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Antipsicóticos/farmacologia , Membrana Celular/genética , Membrana Celular/metabolismo , Feminino , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Metabolismo dos Lipídeos/genética , Lisofosfolipídeos/genética , Masculino , Olanzapina/farmacologia , Transtornos Psicóticos/sangue , Transtornos Psicóticos/patologia , Risperidona/farmacologia , Esfingolipídeos/genética
2.
Int J Mol Sci ; 22(9)2021 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-33922377

RESUMO

Microglial cells are resident macrophages in the brain that have been implicated in the pathophysiology of schizophrenia. There is a lack of studies covering the effects of antipsychotics on microglial cells. The current literature points to a possible anti-inflammatory action without clear mechanisms of action. The aim of this study is to characterize the effects of haloperidol, risperidone and aripiprazole on BV-2 microglial cells in in vitro conditions. We have used immunofluorescence and flow cytometry to analyze the classical pro and anti-inflammatory markers, while a real-time metabolic assay (Seahorse) was used to assess metabolic function. We analyzed the expression of p70S6K to evaluate the mTOR pathway activity with Western blot. In this study, we demonstrate the varying effects of haloperidol, risperidone and aripiprazole administration in BV-2 microglial cells. All three tested antipsychotics were successful in reducing the pro-inflammatory action of microglial cells, although only aripiprazole increased the expression of anti-inflammatory markers. Most significant differences in the possible mechanisms of action were seen in the real-time metabolic assays and in the mTORC1 signaling pathway activity, with aripiprazole being the only antipsychotic to reduce the mTORC1 activity. Our results shed some new light on the effects of haloperidol, risperidone and aripiprazole action in microglial cells, and reveal a novel possible mechanism of action for aripiprazole.


Assuntos
Aripiprazol/farmacologia , Haloperidol/farmacologia , Mediadores da Inflamação/metabolismo , Microglia/efeitos dos fármacos , Risperidona/farmacologia , Antipsicóticos/farmacologia , Sobrevivência Celular , Células Cultivadas , Humanos , Microglia/imunologia , Microglia/metabolismo
3.
Int J Mol Sci ; 22(1)2021 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-33401717

RESUMO

Risperidone, a second-generation antipsychotic drug used for schizophrenia treatment with less-severe side effects, has recently been applied in major depressive disorder treatment. The mechanism underlying risperidone-associated metabolic disturbances and liver and renal adverse effects warrants further exploration. This research explores how risperidone influences weight, glucose homeostasis, fatty liver scores, liver damage, and renal impairment in high-fat diet (HFD)-administered C57BL6/J mice. Compared with HFD control mice, risperidone-treated obese mice exhibited increases in body, liver, kidney, and retroperitoneal and epididymal fat pad weights, daily food efficiency, serum triglyceride, blood urea nitrogen, creatinine, hepatic triglyceride, and aspartate aminotransferase, and alanine aminotransferase levels, and hepatic fatty acid regulation marker expression. They also exhibited increased insulin resistance and glucose intolerance but decreased serum insulin levels, Akt phosphorylation, and glucose transporter 4 expression. Moreover, their fatty liver score and liver damage demonstrated considerable increases, corresponding to increases in sterol regulatory element-binding protein 1 mRNA, fatty acid-binding protein 4 mRNA, and patatin-like phospholipid domain containing protein 3 expression. Finally, these mice demonstrated renal impairment, associated with decreases in glutathione peroxidase, superoxide dismutase, and catalase levels. In conclusion, long-term administration of risperidone may exacerbate diabetes syndrome, nonalcoholic fatty liver disease, and kidney injury.


Assuntos
Intolerância à Glucose/metabolismo , Insulina/sangue , Hepatopatia Gordurosa não Alcoólica/enzimologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Risperidona/farmacologia , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Adiponectina/metabolismo , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Peso Corporal/efeitos dos fármacos , Catalase/metabolismo , Proteínas de Ligação a DNA/metabolismo , Ácido Graxo Sintases/sangue , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Glutationa Peroxidase/metabolismo , Resistência à Insulina , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Fosfolipases A2 Independentes de Cálcio/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Superóxido Dismutase-1/metabolismo , Fatores de Transcrição/metabolismo , Triglicerídeos/sangue
4.
J Clin Psychiatry ; 81(2)2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32220153

RESUMO

OBJECTIVE: Patients with schizophrenia and comorbid alcohol use disorder remain understudied. This post hoc analysis evaluated data from Phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness in Schizophrenia study (January 2001-December 2004). METHODS: Patients without substance abuse (except marijuana use) in the month before study entry were categorized into those with a history of alcohol use disorder (SZ + AUD) within 5 years before study entry and those without alcohol use disorder (SZ-only) per DSM-IV criteria. Time to first and recurrent exacerbations and hospitalizations were compared between disease states and between olanzapine and perphenazine, quetiapine, risperidone, and ziprasidone. RESULTS: A total of 1,338 patients (SZ + AUD = 22.6%; SZ-only = 77.4%) were included. Time to first exacerbation of SZ was significantly shorter in the SZ + AUD versus SZ-only population (median = 5.4 vs 6.4 months; hazard ratio [HR] = 1.20 [95% CI, 1.01-1.42]; P = .039). Similar findings were observed for first hospitalization (HR = 1.63 [95% CI, 1.20-2.22]; P = .002) and recurrent hospitalizations (HR = 1.60 [95% CI, 1.18-2.15]; P = .002). The most common reasons leading to exacerbation in both groups were an increase in symptom severity and lack of efficacy. In patients with SZ + AUD related or unrelated to marijuana, perphenazine, quetiapine, risperidone, and ziprasidone were associated with significantly shorter time to first exacerbation versus olanzapine. CONCLUSIONS: This post hoc analysis confirmed that patients with SZ + AUD had a worse illness course than patients with SZ-only and suggests that olanzapine may be associated with a longer time to first and recurrent exacerbations versus other antipsychotics in this difficult-to-treat population. Further research is needed to identify effective treatments for this important yet understudied patient population. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00014001.


Assuntos
Alcoolismo , Antipsicóticos/farmacologia , Hospitalização , Olanzapina/farmacologia , Avaliação de Resultados em Cuidados de Saúde , Transtornos Psicóticos/tratamento farmacológico , Esquizofrenia/tratamento farmacológico , Exacerbação dos Sintomas , Adulto , Alcoolismo/epidemiologia , Comorbidade , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Perfenazina/farmacologia , Piperazinas/farmacologia , Transtornos Psicóticos/epidemiologia , Fumarato de Quetiapina/farmacologia , Risperidona/farmacologia , Esquizofrenia/epidemiologia , Índice de Gravidade de Doença , Tiazóis/farmacologia , Fatores de Tempo
5.
Eur J Pharmacol ; 874: 173027, 2020 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-32084421

RESUMO

We evaluated the inhibitory effects of the atypical antipsychotic drug risperidone on voltage-dependent K+ (Kv) channels in rabbit coronary arterial smooth muscle cells. Risperidone suppressed Kv currents in reversible and concentration-dependent manners with an apparent half-maximal effective concentration (IC50 value) of 5.54 ± 0.66 µM and a slope factor of 1.22 ± 0.07. The inactivation of Kv currents was significantly accelerated by risperidone. The rate constants of association and dissociation for risperidone were 0.25 ± 0.01 µM-1s-1 and 1.36 ± 0.14 s-1, respectively. Application of risperidone shifted the steady-state activation curve in the positive direction and the inactivation curve in the negative direction, suggesting that the risperidone-induced inhibition of Kv channels was mediated by effects on the voltage sensors of the channels. Application of train pulses at 1 and 2 Hz led to a progressive increase in the blockage of Kv currents by risperidone. In addition, the recovery time constants from inactivation were extended in the presence of risperidone, indicating that risperidone inhibited Kv channels in a use (state)-dependent manner. Pretreatment with the Kv1.5 subtype inhibitor reduced the inhibitory effects of risperidone on Kv channels. However, pretreatment with a Kv2.1 or Kv7.X subtype inhibitor did not affect the inhibitory effects of risperidone. Risperidone induced vasoconstriction and membrane depolarization. Based on these results, we conclude that risperidone inhibits Kv channels in a concentration-, time-, and state-dependent manners. Our results should be taken into consideration when using risperidone to study the kinetics of K+ channels in vascular smooth muscle.


Assuntos
Antipsicóticos/farmacologia , Miócitos de Músculo Liso/efeitos dos fármacos , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/antagonistas & inibidores , Risperidona/farmacologia , Animais , Vasos Coronários/citologia , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/fisiologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/fisiologia , Coelhos
6.
Nat Commun ; 11(1): 1074, 2020 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-32103023

RESUMO

The D2 dopamine receptor (DRD2) is one of the most well-established therapeutic targets for neuropsychiatric and endocrine disorders. Most clinically approved and investigational drugs that target this receptor are known to be subfamily-selective for all three D2-like receptors, rather than subtype-selective for only DRD2. Here, we report the crystal structure of DRD2 bound to the most commonly used antipsychotic drug, haloperidol. The structures suggest an extended binding pocket for DRD2 that distinguishes it from other D2-like subtypes. A detailed analysis of the structures illuminates key structural determinants essential for DRD2 activation and subtype selectivity. A structure-based and mechanism-driven screening combined with a lead optimization approach yield DRD2 highly selective agonists, which could be used as chemical probes for studying the physiological and pathological functions of DRD2 as well as promising therapeutic leads devoid of promiscuity.


Assuntos
Antipsicóticos/farmacologia , Haloperidol/farmacologia , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D2/ultraestrutura , Cristalografia por Raios X , Humanos , Conformação Proteica/efeitos dos fármacos , Receptores de Dopamina D2/agonistas , Risperidona/metabolismo , Risperidona/farmacologia
7.
J Pharmacol Exp Ther ; 373(1): 24-33, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31907305

RESUMO

Neurodevelopmental disorder with involuntary movements (Online Mendelian Inheritance in Man: 617493) is a severe, early onset neurologic condition characterized by a delay in psychomotor development, hypotonia, and hyperkinetic involuntary movements. Heterozygous de novo mutations in the GNAO1 gene cause neurodevelopmental disorder with involuntary movements. Gα o, the gene product of GNAO1, is the alpha subunit of Go, a member of the heterotrimeric Gi/o family of G proteins. Go is found abundantly throughout the brain, but the pathophysiological mechanisms linking Gα o functions to clinical manifestations of GNAO1-related disorders are still poorly understood. One of the most common mutant alleles among the GNAO1 encephalopathies is the c.626G>A or p.Arg209His (R209H) mutation. We developed heterozygous knock-in Gnao1 +/R209H mutant mice using CRISPR/Cas9 methodology to assess whether a mouse model could replicate aspects of the neurodevelopmental disorder with involuntary movements clinical pattern. Mice carrying the R209H mutation exhibited increased locomotor activity and a modest gait abnormality at 8-12 weeks. In contrast to mice carrying other mutations in Gnao1, the Gnao1 +/R209H mice did not show enhanced seizure susceptibility. Levels of protein expression in multiple brain regions were unchanged from wild-type (WT) mice, but the nucleotide exchange rate of mutant R209H Gα o was 6.2× faster than WT. The atypical neuroleptic risperidone has shown efficacy in a patient with the R209H mutation. It also alleviated the hyperlocomotion phenotype observed in our mouse model but suppressed locomotion in WT mice as well. In this study, we show that Gnao1 +/R209H mice mirror elements of the patient phenotype and respond to an approved pharmacological agent. SIGNIFICANCE STATEMENT: Children with de novo mutations in the GNAO1 gene may present with movement disorders with limited effective therapeutic options. The most common mutant variant seen in children with GNAO1-associated movement disorder is R209H. Here we show, using a novel Gnao1 +/R209H mouse, that there is a clear behavioral phenotype that is suppressed by risperidone. However, risperidone also affects wild-type mouse activity, so its effects are not selective for the GNAO1-associated movement disorder.


Assuntos
Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/genética , Variação Genética/genética , Transtornos dos Movimentos/tratamento farmacológico , Transtornos dos Movimentos/genética , Risperidona/uso terapêutico , Animais , Sequência de Bases , Antagonistas de Dopamina/farmacologia , Antagonistas de Dopamina/uso terapêutico , Feminino , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Risperidona/farmacologia
8.
Acta Bioeng Biomech ; 21(3): 39-47, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31798027

RESUMO

PURPOSE: Poly(L-lactide-co-glycolide-co-trimethylene carbonate) rods with risperidone and 17-ß-estradiol were sterilized by electron beam irradiation. The aim of the study was to assess electron beam irradiation impact on terpolymer composition, chain microstructure, glass transition temperature, molecular weight and the morphological features of rods. METHODS: Hot melt extrusion in the formulation of rods was applied. Sterilization of the rods was performed by electron beam in an electron beam accelerator (10 MeV, 360 mA, 25 kGy). The following methods in the development of rods were applied: nuclear magnetic resonance, differential scanning calorimetry, gel permeation chromatography and scanning electron microscopy. RESULTS: Sterilization influenced only glass transition temperature in blind rods and rods with risperidone. As for the other parameters, no significant changes were observed as far as a sterilization effect is concerned. However, some changes were noted after introducing drug substances and after extrusion. CONCLUSIONS: Electron beam irradiation of rods with risperidone and rods with 17-ß-estradiol is an adequate method for sterilizing implantable drug delivery systems.


Assuntos
Elétrons , Estradiol/farmacologia , Próteses e Implantes , Risperidona/farmacologia , Esterilização , Varredura Diferencial de Calorimetria , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Sistemas de Liberação de Medicamentos , Peso Molecular , Polímeros/química , Espectroscopia de Prótons por Ressonância Magnética , Temperatura
9.
J Clin Psychopharmacol ; 39(6): 575-582, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31688451

RESUMO

BACKGROUND: Current treatments for psychotic symptoms associated with schizophrenia often provide inadequate efficacy with unacceptable adverse effects. Improved therapeutics have long been a goal of research. Preclinical testing suggests that phosphodiesterase 10A (PDE10A) inhibitors may provide a novel approach to treating psychosis associated with schizophrenia. METHODS: The efficacy and safety of a highly selective PDE10A inhibitor, PF-02545920, was evaluated in a phase 2 multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Eligible patients (18-65 years) with an acute exacerbation of schizophrenia were randomized 2:2:1:2 to PF-02545920 (5 or 15 mg every 12 hours [Q12H] titrated), risperidone (3 mg Q12H), or placebo for 28 days (n = 74:74:37:74). The primary objectives were to evaluate the efficacy of PF-02545920 using the Positive and Negative Syndrome Scale (PANNS) and safety/tolerability. RESULTS: At day 28, PF-02545920 (either dose) was not significantly different from placebo for mean change from baseline in the PANNS total score (primary end point) or most other end points. Pharmacokinetics exposures seemed adequate for binding/inhibiting PDE10A enzyme. Risperidone was statistically different from placebo for the PANNS total score, demonstrating study sensitivity. Incidence rates for adverse events were similar among the groups. Both doses of PF-02545920 were generally well tolerated. Dystonia occurred in 1, 6, 0, and 3 patients in the PF-02545920 5 mg Q12H, PF-02545920 15 mg Q12H, risperidone, and placebo groups, respectively. CONCLUSIONS: Neither dose of PF-02545920 was superior to placebo for the primary and most secondary end points. This indicates that PDE10A inhibition does not produce an antipsychotic effect in patients with acute exacerbation of schizophrenia.


Assuntos
Antipsicóticos/farmacologia , Distonia/induzido quimicamente , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/efeitos dos fármacos , Pirazóis/farmacologia , Quinolinas/farmacologia , Risperidona/farmacologia , Esquizofrenia/tratamento farmacológico , Resultado do Tratamento , Doença Aguda , Adulto , Antipsicóticos/administração & dosagem , Antipsicóticos/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores de Fosfodiesterase/administração & dosagem , Inibidores de Fosfodiesterase/efeitos adversos , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Quinolinas/administração & dosagem , Quinolinas/efeitos adversos , Risperidona/administração & dosagem , Risperidona/efeitos adversos , Índice de Gravidade de Doença
10.
Eur J Pharmacol ; 865: 172764, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31678081

RESUMO

The extended amygdala has been proposed to play an essential role in cognitive and affective processes and in neuropsychiatric disorders. In the present study, we examined the induction of Fos-like nuclei in the central amygdaloid nucleus (CeA), sublenticular extended amygdala (SLEA), interstitial nucleus of the posterior limb of the anterior commissure (IPAC), and bed nucleus of the stria terminalis (BSTL) of rodents to improve the knowledge regarding the pharmacological profile, therapeutic efficacy, and side-effects of olanzapine, an atypical antipsychotic drug and risperidone, a mixed atypical/typical antipsychotic drug in the rat brain. In addition, we evaluated the induction of Fos-like-nuclei in areas connected with these structures such as prefrontal cortex (PFCx), and nucleus accumbens shell, and in other important areas including the lateral septum and caudate-putamen that are involved in the therapeutic efficacy or side-effects of antipsychotic drugs. Fos-like-immunoreactivity induced by olanzapine and risperidone was compared with that by the atypical antipsychotic clozapine and typical antipsychotic haloperidol. Regarding the extended amygdala, and similarly to clozapine, olanzapine (5-10 mg/kg) and, with a lower efficacy, risperidone (1-3 mg/kg), induced Fos-like-nuclei in CeA, IPAC, SLEA, and BSTL. Both these drugs increased the induction of Fos-like-nuclei in PFCx, nucleus accumbens shell, lateral septum, and caudate-putamen. On the contrary, the increase of Fos-like-nuclei in the extended amygdala by haloperidol was restricted to IPAC only. These findings, consistent with the important role of extended amygdala in neuropsychiatric disorders characterized by affective disturbances, showed that olanzapine and risperidone, contrary to haloperidol, preferentially activated Fos-expression in these brain areas.


Assuntos
Antipsicóticos/farmacologia , Encéfalo/efeitos dos fármacos , Olanzapina/farmacologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Risperidona/farmacologia , Animais , Encéfalo/metabolismo , Masculino , Ratos Sprague-Dawley
11.
J Pharmacol Sci ; 140(3): 263-272, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31474557

RESUMO

Atypical antipsychotics improve positive and negative symptoms but are not effective for treating cognitive impairments in patients with schizophrenia. We previously reported that cognitive impairments in neonatal ventral hippocampus (NVH)-lesioned rats show resistance to atypical antipsychotics risperidone and are associated with reduced calcium/calmodulin-dependent protein kinase II (CaMKII) and protein kinase C (PKC) signaling in memory-related regions. The cognitive enhancer ST101 (spiro[imi-dazo[1,2-a]pyridine-3,2-indan]-2(3H)-one) stimulates CaMKII activity in the hippocampus and medial prefrontal cortex (mPFC). We thus tested ST101 on cognitive impairments in NVH-lesioned rats. Chronic ST101 administration (0.1 and/or 0.5 mg/kg, p.o.) significantly improved deficits in prepulse inhibition (PPI), social interaction, and cognitive function in NVH-lesioned rats. ST101 administration (0.5 mg/kg, p.o.) significantly restored the decreased CaMKII autophosphorylation (Thr-286) in the mPFC and hippocampal CA1 regions of NVH-lesioned rats when assessed by immunohistochemistry. Chronic ST101 administration (0.1 mg/kg, p.o.) improved the decline in phosphorylation levels of CaMKII (Thr-286), PKCα (Ser-657), α-amino-3-hydroxy-5-methyl-4-isoxazol- propionic acid (AMPA)-type glutamate receptor subunit 1 (GluA1: Ser-831), and N-methyl-d-aspartate (NMDA) receptor subunit 1 (GluN1: Ser-896) in the mPFC and hippocampal CA1 regions. Taken together, these results suggest that ST101 improves schizophrenia-like behaviors and cognitive impairment by enhancing CaMKII/PKCα signaling in the mPFC and hippocampus in NVH-lesioned rats.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Transtornos Cognitivos/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Indanos/farmacologia , Proteína Quinase C-alfa/metabolismo , Esquizofrenia/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Compostos de Espiro/farmacologia , Animais , Animais Recém-Nascidos , Antipsicóticos/farmacologia , Cognição/efeitos dos fármacos , Transtornos Cognitivos/metabolismo , Feminino , Hipocampo/metabolismo , Masculino , Memória/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo , Risperidona/farmacologia , Esquizofrenia/metabolismo
12.
J Psychopharmacol ; 33(10): 1227-1236, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31487208

RESUMO

PURPOSE: This study aimed to investigate the efficacy and tolerability of aripiprazole, olanzapine and risperidone in first-episode schizophrenia (FES). METHODS: The eight-week, open, randomised study was conducted in six Chinese medical centres. Altogether, 498 FES subjects were randomised to aripiprazole (n = 165), olanzapine (n = 168) or risperidone (n = 165). Efficacy was measured with the Positive and Negative Syndrome Scale (PANSS), tolerability with the Udvalg for Kliniske Undersogelser Side Effect Rating Scale (UKU) and functioning with the Personal and Social Performance Scale (PSP). RESULTS: All three antipsychotics significantly improved the baseline to end-point PANSS total and each of the sub-scale scores (p < 0.001). Risperidone was superior to olanzapine and aripiprazole regarding PANSS total end-point scores (p < 0.05). Cumulative response (PANSS total score reduction ⩾30%) was similar between risperidone, olanzapine and aripiprazole (74.8%, 73.5% and 70.1%; p = 0.707), but risperidone was superior to aripiprazole regarding PANSS total score reduction ⩾50% (37.8% vs. 26.6%; p < 0.05). Olanzapine was associated with the largest weight gain at week 4 and 8 (p < 0.01), weight gain ⩾7% (olanzapine = 49.0% vs. risperidone = 32.5% vs. aripiprazole = 17.0%; p < 0.01), more psychic side effects at week 8 (p < 0.01 each) and more 'other' side effects at week 4 (p < 0.001) and week 8 (p < 0.05) but fewer neurological side effects at week 4 (p < 0.05) and week 8 (p < 0.01). PSP improved more with risperidone than with aripiprazole at week 4 and 8 (p < 0.05). CONCLUSIONS: For FES, risperidone might be a better choice than aripiprazole due to improved efficacy and functional improvement, without inferior tolerability. Aripiprazole is a better choice to avoid relevant short-term weight gain. Olanzapine could be chosen to avoid neurological adverse effects.


Assuntos
Antipsicóticos/farmacologia , Aripiprazol/farmacologia , Olanzapina/farmacologia , Avaliação de Resultados em Cuidados de Saúde , Risperidona/farmacologia , Esquizofrenia/tratamento farmacológico , Adolescente , Adulto , Feminino , Humanos , Masculino , Adulto Jovem
13.
J Psychiatr Res ; 118: 66-72, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31494376

RESUMO

BACKGROUND: Schizophrenia (SZ) is associated with cognitive impairment that contributes to disability, but the cognitive dysfunction is relatively refractory to pharmacologic intervention. Though Valproate augmentation is reported to improve psychopathology among patients with SZ, its effects on cognitive functions have not been investigated systematically. METHODS: Using a randomized double blind placebo controlled design, the effects of Valproate or placebo as adjuncts to risperidone (RISP) treatment were evaluated among patients with early course SZ (N = 109). Domains of cognitive function, estimated using the Arabic version of the Penn Computerized Neurocognitive Battery, were the prime outcomes. Clinical severity and social function were secondary outcomes. We also explored the effects of valproate treatment on serological responses to Toxoplama Gondii (TOXO), a putative risk factor for cognitive dysfunction in SZ. RESULTS: There were no significant differences between Valproate and placebo (PLA) treated groups with respect to changes in cognitive functions, positive or negative symptom scores or daily function scores at the beginning and end of the study. No significant Valproate/PLA differences were noted on TOXO serostatus or TOXO-related cognitive dysfunction. CONCLUSION: Valproate treatment may not be beneficial for cognitive dysfunction in SZ or for TOXO infection.


Assuntos
Antimaníacos/farmacologia , Antipsicóticos/farmacologia , Disfunção Cognitiva/tratamento farmacológico , Risperidona/farmacologia , Esquizofrenia/tratamento farmacológico , Toxoplasmose/tratamento farmacológico , Ácido Valproico/farmacologia , Adolescente , Adulto , Antimaníacos/administração & dosagem , Antipsicóticos/administração & dosagem , Disfunção Cognitiva/etiologia , Método Duplo-Cego , Sinergismo Farmacológico , Quimioterapia Combinada , Humanos , Pessoa de Meia-Idade , Risperidona/administração & dosagem , Esquizofrenia/complicações , Resultado do Tratamento , Ácido Valproico/administração & dosagem , Adulto Jovem
14.
Eur Neuropsychopharmacol ; 29(11): 1282-1287, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31537475

RESUMO

Recently, a single injection of the nitric oxide donor sodium nitroprusside (SNP) was found to induce a rapid and sustained antipsychotic effect in treatment-resistant schizophrenia (TRS). Moreover, a single i.p. injection of SNP in rats was found to generate both rapid and persisting changes in brain synaptic plasticity, including enhanced excitatory postsynaptic current responses and spine morphology in layer V pyramidal cells in the medial prefrontal cortex (mPFC) brain slices. Here we used the conditioned avoidance response (CAR) test in rats to investigate the antipsychotic-like efficacy of SNP in combination with low-dose risperidone. In addition, we performed microdialysis experiments in freely moving rats to measure neurotransmitter efflux in the mPFC and the nucleus accumbens (NAc). Risperidone caused only 20% suppression of CAR, which is far below the degree of CAR suppression required to predict a significant clinical antipsychotic effect. Addition of a low dose of SNP to risperidone dramatically enhanced the antipsychotic-like effect to a clinically relevant level. SNP significantly enhanced the risperidone-induced dopamine output in the mPFC but not in the NAc. The increased prefrontal dopamine release induced by the drug combination may also improve cognition as indicated by previous preclinical and clinical studies and, furthermore, via enhanced synaptic spine function and morphology in mPFC generate a both rapid and prolonged antipsychotic and pro-cognitive effect. Our results delineate SNP as a promising new treatment option for schizophrenia, including TRS, when added to currently available antipsychotic medication in order to improve efficacy at maintained or even reduced dosage.


Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Nitroprussiato/farmacologia , Risperidona/farmacologia , Animais , Dopamina/metabolismo , Sinergismo Farmacológico , Masculino , Microdiálise , Núcleo Accumbens/metabolismo , Córtex Pré-Frontal/metabolismo , Ratos
15.
J Neurosci ; 39(43): 8584-8599, 2019 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-31519825

RESUMO

Reduction of the dendritic arbor length and the lack of dendritic spines in the pyramidal cells of the prefrontal cortex (PFC) are prevalent pathological features in schizophrenia (SZ). Neonatal ventral hippocampus lesion (NVHL) in male rats reproduces these neuronal characteristics and here we describe how this is a consequence of BDNF/TrkB pathway disruption. Moreover, COX-2 proinflammatory state, as well as Nrf-2 antioxidant impairment, triggers oxidative/nitrosative stress, which also contributes to dendritic spine impairments in the PFC. Interestingly, oxidative/nitrosative stress was also detected in the periphery of NVHL animals. Furthermore, risperidone treatment had a neurotrophic effect on the PFC and antioxidant effects on the brain and periphery of NVHL animals; these cellular effects were related to behavioral improvement. Our data highlight the link between brain development and immune response, as well as several other factors to understand mechanisms related to the pathophysiology of SZ.SIGNIFICANCE STATEMENT Prefrontal cortex dysfunction in schizophrenia can be a consequence of morphological abnormalities and oxidative/nitrosative stress, among others. Here, we detailed how impaired plasticity-related pathways and oxidative/nitrosative stress are part of the dendritic spine pathology and their modulation by atypical antipsychotic risperidone treatment in rats with neonatal ventral hippocampus lesion. Moreover, we found that animals with neonatal ventral hippocampus lesion had oxidative/nitrosative stress in the brain as well as in the peripheral blood, an important issue for the translational approaches of this model. Then, risperidone restored plasticity and reduced oxidative/nitrosative stress of prefrontal cortex pyramidal cells, and ultimately improved the behavior of lesioned animals. Moreover, risperidone had differential effects than the brain on peripheral blood oxidative/nitrosative stress.


Assuntos
Antipsicóticos/uso terapêutico , Atrofia/tratamento farmacológico , Hipocampo/patologia , Estresse Nitrosativo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Córtex Pré-Frontal/patologia , Risperidona/uso terapêutico , Animais , Antipsicóticos/farmacologia , Atrofia/metabolismo , Atrofia/patologia , Espinhas Dendríticas/metabolismo , Hipocampo/metabolismo , Masculino , Córtex Pré-Frontal/metabolismo , Ratos , Risperidona/farmacologia
16.
J Autism Dev Disord ; 49(11): 4595-4602, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31468273

RESUMO

Using a dataset involving 415 individuals with irritability, aggression, agitation and self-injury (IAAS) behaviors from the fragile X syndrome (FXS) FORWARD database, we describe the psychopharmacologic management of IAAS and features of the population of persons with FXS treated with drug therapy for IAAS. Among those with FXS exhibiting IAAS, individuals with FXS receiving drug treatment of IAAS were older, more predominantly male, have more significant intellectual disability, more like to have comorbid autism, hyperarousal, and social impairments. The most commonly utilized medications for IAAS in FXS are antipsychotic medications, specifically aripiprazole and risperidone (37% and 27%, respectively). The majority of subjects (63%) experienced no side effects noted from the use of their psychopharmacologic medications.


Assuntos
Agressão/efeitos dos fármacos , Antipsicóticos/uso terapêutico , Síndrome do Cromossomo X Frágil/tratamento farmacológico , Humor Irritável/efeitos dos fármacos , Agitação Psicomotora/tratamento farmacológico , Comportamento Autodestrutivo/tratamento farmacológico , Adolescente , Adulto , Agressão/fisiologia , Agressão/psicologia , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Antipsicóticos/farmacologia , Criança , Comorbidade , Estudos Transversais , Feminino , Síndrome do Cromossomo X Frágil/epidemiologia , Síndrome do Cromossomo X Frágil/psicologia , Humanos , Humor Irritável/fisiologia , Masculino , Pessoa de Meia-Idade , Agitação Psicomotora/epidemiologia , Agitação Psicomotora/psicologia , Risperidona/farmacologia , Risperidona/uso terapêutico , Comportamento Autodestrutivo/epidemiologia , Comportamento Autodestrutivo/psicologia , Adulto Jovem
17.
Pharmacol Biochem Behav ; 185: 172763, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31445955

RESUMO

Pharmacotherapy and cognitive behavioral therapy, both fail to treat post-traumatic stress disorder (PTSD) in a considerable number of populations. The persistence of traumatic memories and deficit in extinction contributes to the failure of exposure therapy in PTSD. With the objective to enhance the outcomes of exposure therapy by targeting the extinction window using pharmacological agents in PTSD, the present study was aimed to explore the effect of piracetam, risperidone and their combinations in experimentally-induced PTSD-like phenotype in rats. Male SD rats were exposed to single prolonged stress model (SPS) for induction of PTSD-like behavioral changes. Piracetam, risperidone and their combination were used as therapeutic interventions while sertraline was used as a standard treatment for 14 days along with extinction training. Induction of PTSD-like behaviors were assessed in behavioral tests such as fear conditioning, elevated plus maze, social interaction test, and the marble burying test. Neurotransmitters (dopamine and serotonin and their metabolites), BDNF, proinflammatory cytokines (TNF-α, IL-6), caspase-3, and markers for oxidative stress were assessed in the hippocampus and cortex while corticosterone and nitrite levels were estimated in plasma. Our result indicated that the SPS paradigm efficiently induced PTSD-like phenotype in rats. Risperidone and piracetam were found to be effective alone, while their high dose combination, produced potentiating effect in reversing the extinction deficit, behavioral alterations, altered cortical and hippocampal BDNF, IL-6, TNF-α, caspase-3, oxidative stress markers, and neurotransmitter levels. Plasma corticosterone and nitrite levels were also found to be reversed in the combination treated groups. Our preliminary study suggests that piracetam, risperidone and their combination restored the physiological cascades in cortex and hippocampus along with successful suppression of fear memory and a symptom cluster of PTSD-like phenotype in rats. Hence they could be used as an effective adjunct to enhance the outcome of exposure therapy for the management of PTSD.


Assuntos
Antipsicóticos/farmacologia , Hipocampo/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Piracetam/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Risperidona/farmacologia , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Animais , Antipsicóticos/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Corticosterona/sangue , Modelos Animais de Doenças , Sinergismo Farmacológico , Quimioterapia Combinada , Extinção Psicológica/efeitos dos fármacos , Medo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Piracetam/administração & dosagem , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Sprague-Dawley , Risperidona/administração & dosagem , Estresse Psicológico/tratamento farmacológico
18.
Neuropharmacology ; 158: 107743, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31430459

RESUMO

Atypical antipsychotic drugs (APDs) used to treat positive and negative symptoms in schizophrenia block serotonin receptors 5-HT2AR and dopamine receptors D2R and stimulate 5-HT1AR directly or indirectly. However, the exact cellular mechanisms mediating their therapeutic actions remain unresolved. We recorded neural activity in the prefrontal cortex (PFC) and hippocampus (HPC) of freely-moving mice before and after acute administration of 5-HT1AR, 5-HT2AR and D2R selective agonists and antagonists and atypical APD risperidone. We then investigated the contribution of the three receptors to the actions of risperidone on brain activity via statistical modeling and pharmacological reversal (risperidone + 5-HT1AR antagonist WAY-100635, risperidone + 5-HT2A/2CR agonist DOI, risperidone + D2R agonist quinpirole). Risperidone, 5-HT1AR agonism with 8-OH-DPAT, 5-HT2AR antagonism with M100907, and D2R antagonism with haloperidol reduced locomotor activity of mice that correlated with a suppression of neural spiking, power of theta and gamma oscillations in PFC and HPC, and reduction of PFC-HPC theta phase synchronization. By contrast, activation of 5-HT2AR with DOI enhanced high-gamma oscillations in PFC and PFC-HPC high gamma functional connectivity, likely related to its hallucinogenic effects. Together, power changes, regression modeling and pharmacological reversals suggest an important role of 5-HT1AR agonism and 5-HT2AR antagonism in risperidone-induced alterations of delta, beta and gamma oscillations, while D2R antagonism may contribute to risperidone-mediated changes in delta oscillations. This study provides novel insight into the neural mechanisms for widely prescribed psychiatric medication targeting the serotonin and dopamine systems in two regions involved in the pathophysiology of schizophrenia.


Assuntos
Antipsicóticos/farmacologia , Hipocampo/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Receptor 5-HT2A de Serotonina/efeitos dos fármacos , Receptores de Dopamina D2/efeitos dos fármacos , Risperidona/farmacologia , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Anfetaminas/farmacologia , Animais , Ondas Encefálicas/efeitos dos fármacos , Sincronização Cortical/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Eletroencefalografia , Fluorbenzenos/farmacologia , Ritmo Gama/efeitos dos fármacos , Haloperidol/farmacologia , Hipocampo/metabolismo , Camundongos , Vias Neurais/efeitos dos fármacos , Piperazinas/farmacologia , Piperidinas/farmacologia , Córtex Pré-Frontal/metabolismo , Piridinas/farmacologia , Quimpirol/farmacologia , Receptor 5-HT1A de Serotonina/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Receptores de Dopamina D2/metabolismo , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia
19.
Mol Inform ; 38(11-12): e1900044, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31433121

RESUMO

Dopamine receptors constitute a unique class of G-protein coupled receptors that mediate the activities of dopamine, a neurotransmitter implicated in diverse neurological diseases when dysregulated. Over the years, antipsychotic drugs have been primarily directed towards D2 dopamine receptor (DRD2) while associable adverse effects have been centred on non-selective targeting. The recent crystal structure of DRD2 in complex with atypical antipsychotic could further aid the structure-based design of highly DRD2-selective antipsychotics. Therefore, in this study, we comprehensively investigate the molecular recognition and differential binding landscapes of class-I and II DRD2 atypical antipsychotics, using membrane-bilayer molecular dynamics simulation and binding free energy techniques. Findings revealed that selected class-I antipsychotics exhibited binding dynamics and poses dissimilar to the class-II types with different interactive mechanisms at the binding cavity of DRD2. More interestingly, the class-II drugs established a highly coordinated binding at the DRD2 active site with a pertinent and recurrent involvement of Asp114 via strong hydrogen interactions. Furthermore, while these compounds exert distinct effects on DRD2 structure, findings revealed that the class-II types favourably engaged the deep hydrophobic pocket of DRD2 compared to the class-I drugs. We speculate that these findings will be fundamental to the discovery of highly selective DRD2 antipsychotics.


Assuntos
Antipsicóticos/farmacologia , Receptores de Dopamina D2/metabolismo , Risperidona/farmacologia , Antipsicóticos/química , Descoberta de Drogas , Humanos , Modelos Moleculares , Estrutura Molecular , Receptores de Dopamina D2/química , Risperidona/química
20.
Eur Neuropsychopharmacol ; 29(7): 880-896, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31229322

RESUMO

Inflammation and oxidative stress (IOS) are considered key pathophysiological elements in the development of mental disorders. Recent studies demonstrated that the antipsychotic risperidone elicits an antiinflammatory effect in the brain. We administered risperidone for 2-weeks at adolescence to assess its role in preventing brain-related IOS changes in the maternal immune stimulation (MIS) model at adulthood. We also investigated the development of volumetric and neurotrophic abnormalities in areas related to the HPA-axis. Poly I:C (MIS) or saline (Sal) were injected into pregnant Wistar rats on GD15. Male offspring received risperidone or vehicle daily from PND35-PND49. We studied 4 groups (8-15 animals/group): Sal-vehicle, MIS-vehicle, Sal-risperidone and MIS-risperidone. [18F]FDG-PET and MRI studies were performed at adulthood and analyzed using SPM12 software. IOS and neurotrophic markers were measured using WB and ELISA assays in brain tissue. Risperidone elicited a protective function of schizophrenia-related IOS deficits. In particular, risperidone elicited the following effects: reduced volume in the ventricles and the pituitary gland; reduced glucose metabolism in the cerebellum, periaqueductal gray matter, and parietal cortex; higher FDG uptake in the cingulate cortex, hippocampus, thalamus, and brainstem; reduced NFκB activity and iNOS expression; and increased enzymatic activity of CAT and SOD in some brain areas. Our study suggests that some schizophrenia-related IOS changes can be prevented in the MIS model. It also stresses the need to search for novel strategies based on anti-inflammatory compounds in risk populations at early stages in order to alter the course of the disease.


Assuntos
Antipsicóticos/farmacologia , Encéfalo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Risperidona/farmacologia , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Modelos Animais de Doenças , Imagem por Ressonância Magnética , Masculino , NF-kappa B/metabolismo , Poli I-C , Tomografia por Emissão de Pósitrons , Ratos , Ratos Wistar
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