Navegando por Palavras-chave "Clozapine"
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- ItemSomente MetadadadosAlterações comportamentais após retirada abruptado tratamento prolongado com clozapina em ratos(Universidade Federal de São Paulo (UNIFESP), 2017-10-26) Silva, Neide Derci Da [UNIFESP]; Abílio, Vanessa Costhek [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)Background: Treatment of schizophrenia is performed with typical and atypical antipsychotic drugs for long periods of duration, and induces numerous side effects. Clozapine, the gold standard of atypical antipsychotic drugs, is indicated for patients with schizophrenia resistant to other treatments. Nonetheless, clozapine may induce severe side effects, such as agranulocytosis, and in some cases, it is necessary to discontinue treatment. Several reports show that abrupt interruption of antipsychotic treatment produces withdrawal psychosis. However, other effects promoted by withdrawal of an antipsychotic drug – apart from psychosis – are poorly studied in both patients and animal models. Aim: To evaluate the behavioral abnormalities after abrupt withdrawal from a longterm treatment with clozapine, considering dose and duration of deprivation. The acute effects of typical and atypical antipsychotic drugs on these abnormalities were also evaluated. Methods: Male adult Wistar rats (three months old) were treated for 30 days with clozapine (5.0; 10 or 15 mg/kg – i.p.). Seventy-two hours after the last injection, they were submitted to the following behavioral evaluations: 1) social interaction and locomotor activity in the open field arena, 2) pre-pulse inhibition of startle (PPI) and 3) contextual fear conditioning (CFC). In a second series of experiments, rats were treated for 30 days with 10 mg/kg of clozapine and the same behavioral analysis were performed 48, 72 or 96 hours after treatment interruption. In a third series of experiments, we evaluated the acute effects of haloperidol and clozapine on the behavioral changes seen in the two previous experimental situations. Results: 1) 72-hours deprivation of clozapine treatment (10 and 15 mg/kg) increased social interaction, 2) After treatment with clozapine 10 mg/kg, 48 hours of deprivation promoted contextual fear conditioning deficit, and 72 hours of deprivation increased social interaction; 3) Acute administration of haloperidol and clozapine reversed the contextual fear conditioning deficit. Conclusion: Abrupt withdrawal of clozapine induces behavioral abnormalities that depend on the dose and the duration of the withdrawal. The acute effects of antipsychotic drugs on these behavioral alterations vary.
- ItemSomente MetadadadosAtypical antipsychotic clozapine reversed deficit on prepulse inhibition of the acoustic startle reflex produced by microinjection of DOI into the inferior colliculus in rats(Elsevier Science Bv, 2017) Oliveira, Rodolpho Pereira de [UNIFESP]; Nagaishi, Karen Yuriko [UNIFESP]; Silva, Regina Cláudia Barbosa da [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)Dysfunctions of the serotonergic system have been suggested to be important in the neurobiology of schizophrenia. Patients with schizophrenia exhibit deficits in an operational measure of sensorimotor gating: prepulse inhibition (PPI) of startle. PPI is the normal reduction in the startle response caused by a low intensity non-startling stimulus (prepulse) which is presented shortly before the startle stimulus (pulse). Tile hallucinogen 2,5-dimethoxy-4-iodoamphetamine (DOI), a 5-hydroxytryptamine(HT)2 receptor agonist disrupted PPI in rats. The inferior colliculus (IC) is a critical nucleus of the auditory pathway mediating acoustic PPI. The activation of the IC by the acoustic prepulse reduces startle magnitude. The present study investigated the role of serotonergic transmission in the IC on the expression of acoustic PPI. For that we investigated whether 5-HT2A receptor activation or blockade would affect this response. Unilateral microinjection of DOI (10 mu g,/0.3 mu L ) into the IC disrupted PPI, while microinjection of the 5-HT2A receptor antagonist ritanserin (4 p,mu g/0.3 mu l), into this structure did not alter PPI. We also examined the ability of the atypical antipsychotic clozapine (5.0 mg/kg I.P.) to reverse the disruption of PPI produced by unilateral microinjections of DOI into the IC of rats. Pretreatment with clozapine blocked DOI-induced disruption of PPI. Altogether, these results suggest that serotonin-mediated mechanisms of the IC are involved in the expression of PPI in rodents and that this response is sensitive to atypical antipsychotic clozapine.
- ItemSomente MetadadadosDesorganização como preditor de resistência ao tratamento e desfechos desfavoráveis na esquizofrenia(Universidade Federal de São Paulo (UNIFESP), 2019-10-25) Ortiz, Bruno Bertolucci [UNIFESP]; Araripe Neto, Ary Gadelha De Alencar [UNIFESP]; http://lattes.cnpq.br/8107200180236710; http://lattes.cnpq.br/3379099368507304; Universidade Federal de São Paulo (UNIFESP)The heterogeneous outcomes and symptoms in schizophrenia hinder the development of more effective diagnostic methods and treatments. Patients with greater severity of disorganized symptoms appear to be a distinct group, with poor response to conventional antipsychotics and poor outcome. Disorganized syndrome then applies to be a valid marker to identify a more homogeneous subgroup of disease. General objective: To validate disorganization as a predictor of unfavorable outcomes. The following outcomes were investigated in 5 studies: treatment resistance, global severity, functional impairment and symptom progression. Methods: Three samples were included in the analyzes: 1- Longitudinal sample (n = 203), with patients evaluated at admission and discharged during hospitalization in the psychiatry ward of Hospital Luzia de Pinho Melo - included in the five studies. 2- Cross-sectional sample (n = 207) of patients with multiple episodes from the schizophrenia outpatient clinic (Schizophrenia Program- Proesq, UNIFESP) - included in three studies. 3- A cohort (N = 55) of first-episode from Santa Casa de Misericórdia of São Paulo - included in one study. In all samples, the diagnosis of schizophrenia was confirmed by the SCID-I and symptom intensity was assessed using the Positive and Negative Symptoms Syndrome Scale (PANSS), Calgary Depression Scale for Schizophrenia (Calgary), Clinical Global Impression (CGI) and the Global Assessment of Functioning Scale (GAF). Results: Study 1: Eighty-five patients classified 13 according to traditional subtypes were compared for symptom severity and prevalence of treatment resistant schizophrenia (TRS). Patients with disorganized schizophrenia had a higher prevalence of ERT (60%) than paranoid schizophrenia (20%) (Chi-square = X value, p = 0.001). Study 2: The positive, disorganized and negative PANSS dimensions were compared for overall severity with CGI in the acute and stable phase in patients from 3 different centers (n = 298). The disorganized dimension presented the highest correlation with the CGI (0.86). Study 3: In patients from 2 different centers (n = 247), the dimensions of PANSS were compared with functioning in the acute, stable and remission phase. Increased disorganization at baseline predicted non-remission after treatment (p = 0.007; OR = 1.18). It was the dimension that most impaired functioning of patients in the acute phase (p <0.001). Study 4: Patients from 2 different centers (n = 203) were separated into 3 groups (first episode, with up to 5 years of disease and with more than 5 years of disease) and the intensity of each dimension were compared. The disorganized dimension presented the largest progressive increase in intensity among the first episode groups, up to 5 years of disease and more than 5 years of disease. Study 5: In a discovery sample (n = 164), a predictive model of TRS was built based on PANSS items, which were tested in a replication sample (n = 207). The accuracy of the model was tested on a ROC curve in the exploration and replication samples. The sensitivity and specificity of the exploration sample and the replication sample were, respectively, 77.8% and 83.3%, 72.3% and 74.4%. Conclusion: Integrating dimensional and categorical aspects into the psychopathology of schizophrenia has the potential to generate empirical validated data for both clinical practice and research. Dimensions and categories are still the most accessible diagnostic tools for the clinician. New syndrome models associated with clinical outcomes will be instrumental in progressively progressing to precision medicine in psychiatry.
- ItemSomente MetadadadosParticipação da neurotransmissão serotoninérgica do colículo inferior na modulação da resposta de inibição por pré- pulso do reflexo de sobressalto acústico e interação social em ratos wistar(Universidade Federal de São Paulo (UNIFESP), 2017-03-23) Oliveira, Rodolpho Pereira de [UNIFESP]; Silva, Regina Cláudia Barbosa da [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)Schizophrenia is a devastating psychiatric disorder that affects approximately 1% of the population over a lifetime, and generally affects individuals in the prime of their productive potential. The relationship between serotonergic dysfunction and schizophrenia began with the discovery of the effects of lysergic acid diethylamide (LSD) that shows high affinity for the 5-HT2A receptor, and that generated delusions and hallucinations which are positive symptoms of schizophrenia. Another substance, 2,5-dimethoxy-4-iodoanfetamine (DOI), also displays hallucinogenic properties and 5- HT2A antagonism as LSD. An animal model widely used, based on attentional processes, is the model of pre-pulse inhibition (PPI) of the startle reflex. The primary neuronal pathway, mediating PPI response is in the brainstem, and the inferior colliculus (IC) is a key structure in this circuitry. One of the main negative symptoms of schizophrenia is the social withdrawal that leads to important losses in the personal and professional sphere of the individual. In this sense, the objective of this study was to investigate the role of serotonergic neurotransmission of the IC in the modulation of PPI response and social interaction. To this end, we microinjected an agonist and an antagonist of 5-HT2A receptors, DOI (10.0 ug/0.3uL ), and ritanserin (4 ug/0.3uL ), respectively in the IC of these animals. In an attempt to establish a parallel with the clinic, we verified whether pre-treatment with clozapine (5 mg/kg) prior to intracollicular microinjection of DOI could reverse the deficits of PPI and social interaction. The results showed that the microinjection of DOI into de IC produced deficits in PPI and social interaction that were reversed by pretreatment with clozapine. The microinjection of ritanserin in this structure did not produce any effect on PPI and social interaction responses. Together, our results point to the involvement of the serotonergic system of the IC as a critical neural substrate in mediating these responses.
- ItemAcesso aberto (Open Access)Participação dos receptores CB1 do colículo inferior na modulação da resposta de inibição por pré-pulso do reflexo de sobressalto acústico em ratos Wistar(Universidade Federal de São Paulo, 2021-04-16) Barbosa, Ana Carolina Ferreira de Lima [UNIFESP]; Silva, Regina Cláudia Barbosa da [UNIFESP]; http://lattes.cnpq.br/7507421915981968; http://lattes.cnpq.br/0255442854256284; Universidade Federal de São Paulo (UNIFESP)Evidências apontam para um possível envolvimento do sistema endocanabinoide (SEC) na fisiopatologia da esquizofrenia devido a observações de ocorrência de sintomas psicóticos transitórios, em indivíduos após o consumo de Cannabis sativa. Foram detectadas concentrações elevadas de anandamida (AEA), um endocanabinoide agonista não seletivo de receptor canabinoide do tipo 1 (CB1), no líquido cefalorraquidiano e plasma de pacientes com esquizofrenia e concentrações reduzidas em algumas estruturas do tecido cerebral post mortem. Assim, tem sido investigado se a modulação do SEC, via bloqueio do receptor CB1, pode induzir efeitos antipsicóticos. Um modelo animal de esquizofrenia baseado em processos atencionais é o de inibição por pré-pulso (IPP) do reflexo de sobressalto acústico. Déficits de IPP se manifestam como distúrbios de atenção seletiva e refletem também déficits na integração do processamento de informação sensorial, tendo sido observados em pacientes com esquizofrenia. A via neural primária que medeia a resposta de IPP do reflexo de sobressalto acústico encontra-se no tronco encefálico, sendo o colículo inferior (CI) uma estrutura chave nesta circuitaria. O objetivo deste estudo foi avaliar os efeitos da administração intracolicular de AEA (50 pmol/0.2μl) na expressão da resposta de IPP do reflexo de sobressalto acústico em ratos. Verificou-se também se o pré-tratamento com o antipsicótico atípico clozapina (5 mg/kg; i.p.), largamente utilizado na clínica, seria capaz de reverter possíveis déficits de IPP induzidos pela microinjeção intracolicular da AEA. Os resultados mostraram que os ratos tratados com AEA apresentaram déficits de IPP em comparação ao grupo controle, corroborando dados da literatura onde o agonismo de receptores CB1 pode induzir déficits nesse modelo. O pré-tratamento com a clozapina atenuou os déficits de maneira não significativa.