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1.
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
2.
J Integr Neurosci ; 18(3): 245-251, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31601072

RESUMO

The cognitive impairment associated with schizophrenia is highly prevalent and affects the overall functioning of subjects. The stimulation of the serotonin 1A receptor is a primary characteristic of some atypical antipsychotic drugs. We measured the levels of cognitive impairment using the Morris water maze test and protein kinase A activity in hippocampal neurons on presynaptic and postsynaptic serotonin 1A receptors to investigate the effect of dizocilpine-induced cognitive impairment associated with atypical antipsychotic drugs in rats treated by quetiapine alone or combined with WAY100635/tandospirone. The results of the Morris water maze test presented evidence that quetiapine alone alleviated the cognitive impairment associated with atypical antipsychotic drugs induced by dizocilpine. However, quetiapine plus WAY100635 induced no improvement of cognitive impairment associated with atypical antipsychotic drugs. The results of protein kinase A assay suggested that neither quetiapine alone nor in combination with tandospirone, but not quetiapine plus WAY100635, raised protein kinase A activity in hippocampus neurons. The present study demonstrated the key role of presynaptic serotonin 1A receptors on the therapeutic effect of quetiapine on cognitive impairment associated with atypical antipsychotic drugs. Moreover, that protein kinase A activity in hippocampal cells is involved in the mechanism of quetiapine's effect on cognitive impairment associated with atypical antipsychotic drugs.


Assuntos
Antipsicóticos/farmacologia , Disfunção Cognitiva , Fumarato de Quetiapina/farmacologia , Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Esquizofrenia , Animais , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Pré-Sinápticos/efeitos dos fármacos , Esquizofrenia/complicações , Esquizofrenia/metabolismo
3.
Endocr Regul ; 53(3): 165-177, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31517634

RESUMO

OBJECTIVE: The aim of the present study was to demonstrate the spatial relationship between the c-Fos immunoreactive cells elicited by an acute treatment with neuroleptics including amisulpride (AMI), olanzapine (OLA), quetiapine (QUE), and aripiprazole (ARI) and enkephalinergic (ENK), substance P (SP), and tyrosine hydroxylase (TH) innervation fields in the rat septum. METHODS: Male Sprague Dawley rats received a single injection of OLA (5 mg), ARI (10 mg), AMI (20 mg), QUE (15 mg/kg/b.w.). Ninety min after antipsychotics administration, the animals were transcardially perfused with a fixative and the brains cryocut into serial coronal sections of 35 µm thickness. The sections were processed for c-Fos staining using an avidin-biotin-peroxidase complex and visualized by nickel intensified diaminobenzidine to reach black endproduct. Afterwards, the sections were exposed to ENK, SP, and TH antibodies and the reaction product visualized by biotin-labeled fluorescent AlexaFluor 564 dye. The data were evaluated from the sections either simultaneously illuminated with fluorescent and transmission microscope beams or after merging the separately illuminated sections in the Adobe Photoshop 7.0 software. RESULTS: ENK, SP, and TH displayed characteristic spatial images formed by a dense accumulation of immunoreactive fibers and terminals on the both sides of the septum. A dense plexus of axons formed by ENK and SP immunopositive terminals were situated predominantly in the lateral, while TH ones more medial portion of the septum. QUE and AMI activated distinct amount of c-Fos expression in cells located within the SP-immunoreactive principal innervation field. The OLA effect on the c-Fos expression was very pronounced in the ventral TH-labeled principal innervation field including the space between the ENK field ventral portion and the dorsal margin of the accumbens nucleus shell. Generally, the occurrence of c-Fos cells in the ENK-immunoreactive principal innervation field, in comparison with the surrounding septal area, was less abundant after all of the four antipsychotics treatments. CONCLUSION: The data of the present study indicate that ENK, SP, and TH innervation fields may influence separate populations of septal cells activated by AMI, OLA, QUE, and ARI and that each of these region-differently innervated cells may be associated with the functional heterogeneity of the individual lateral septal nuclei.


Assuntos
Antipsicóticos/farmacologia , Encefalinas/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Septo do Cérebro/efeitos dos fármacos , Substância P/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo , Amissulprida/farmacologia , Animais , Aripiprazol/farmacologia , Imuno-Histoquímica , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Olanzapina/farmacologia , Proteínas Proto-Oncogênicas c-fos/efeitos dos fármacos , Fumarato de Quetiapina/farmacologia , Ratos , Ratos Sprague-Dawley , Septo do Cérebro/metabolismo , Distribuição Tecidual/efeitos dos fármacos
4.
PLoS One ; 14(9): e0221747, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31490950

RESUMO

Multiple sclerosis (MS) is characterized by demyelinated lesions in the central nervous system. Destruction of myelin and secondary damage to axons and neurons leads to significant disability, particularly in people with progressive MS. Accumulating evidence suggests that the potential for myelin repair exists in MS, although for unclear reasons this process fails. The cells responsible for producing myelin, the oligodendrocytes, and their progenitors, oligodendrocyte precursor cells (OPCs), have been identified at the site of lesions, even in adults. Their presence suggests the possibility that endogenous remyelination without transplantation of donor stem cells may be a mechanism for myelin repair in MS. Strategies to develop novel therapies have focused on induction of signaling pathways that stimulate OPCs to mature into myelin-producing oligodendrocytes that could then possibly remyelinate lesions. We have been investigating pharmacological approaches to enhance OPC differentiation, and have identified that the combination of two agents, triiodothyronine (T3) and quetiapine, leads to an additive effect on OPC differentiation and consequent myelin production via both overlapping and distinct signaling pathways. While the ultimate production of myelin requires cholesterol biosynthesis, we identified that quetiapine enhances gene expression in this pathway more potently than T3. Two blockers of cholesterol production, betulin and simvastatin, reduced OPC differentiation into myelin producing oligodendrocytes. Elucidating the nature of agents that lead to complementary and additive effects on oligodendrocyte differentiation and myelin production may pave the way for more efficient induction of remyelination in people with MS.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Colesterol/biossíntese , Células Precursoras de Oligodendrócitos/citologia , Células Precursoras de Oligodendrócitos/efeitos dos fármacos , Fumarato de Quetiapina/farmacologia , Tri-Iodotironina/farmacologia , Animais , Sinergismo Farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Proteína Básica da Mielina/metabolismo , Células Precursoras de Oligodendrócitos/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Sinvastatina/farmacologia , Triterpenos/farmacologia
6.
Psychiatr Q ; 90(2): 431-445, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31054021

RESUMO

To evaluate the outcomes of the antiarousal medications valproate, risperidone, and quetiapine on completion of treatment of cognitive processing therapy (CPT) for PTSD. A case series of fifty treatment-seeking adult (≥18 years) veterans with mild traumatic brain injury and combat-related PTSD who had unsuccessful trials of 2 or more first-line agents and previously declined treatment with trauma-focused therapy, seen at the psychiatric outpatient services of the local Polytrauma Rehabilitation Center from January 1, 2014, through December 31, 2017. Patients were prescribed valproate (n = 8), risperidone (n = 17), or quetiapine (n = 25) and were referred for individual weekly treatment with CPT. Outcome measurements of interest were measures of engagement and completion rate of CPT, PTSD Checklist total score (range, 0-80; higher scores indicate greater PTSD severity) and arousal subscale score (range, 0-24; higher scores indicate greater arousal severity), and clinical observations of sleep variables. Of the 50 patients included in the study, 48 (96%) were men; mean (SD) age was 36 (8) years. Eighteen (86%) patients initially receiving quetiapine and none taking valproate or risperidone became adequately engaged in and completed CPT. Among patients who completed CPT, the mean decrease in the PTSD Checklist score was 25 [95% CI, 30 to 20] and 9 (50%) patients no longer met criteria for PTSD. These preliminary findings support quetiapine as an adjunctive medication to facilitate CPT. A pragmatic trial is needed to evaluate the efficacy, safety, and feasibility of quetiapine to improve engagement in and completion rate of CPT.


Assuntos
Antipsicóticos/farmacologia , Concussão Encefálica/terapia , Terapia Cognitivo-Comportamental , Distúrbios de Guerra/terapia , Avaliação de Resultados em Cuidados de Saúde , Fumarato de Quetiapina/farmacologia , Transtornos de Estresse Pós-Traumáticos/terapia , Cooperação e Adesão ao Tratamento , Veteranos , Adulto , Concussão Encefálica/tratamento farmacológico , Distúrbios de Guerra/tratamento farmacológico , Terapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico
7.
J Neuroimmune Pharmacol ; 14(3): 383-390, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31119596

RESUMO

Quetiapine, an atypical antipsychotic medication has lacked pre-clinical validation for its purported benefits in the treatment of delirium. This laboratory investigation examined the effects of quetiapine on the attentional set shifting task (ASST), a measure of cognitive flexibility and executive functioning, in a rodent model of lipopolysaccharide (LPS) mediated neuroinflammation. 19 Sprague Dawley female rats were randomly selected to receive intraperitoneal placebo (N = 5), LPS and placebo (N = 7) or LPS and quetiapine (n = 7) and performed the ASST. We measured trials to criterion, errors, non-locomotion episodes and latency to criterion, serum cortisol and tumor necrosis factor alpha (TNF-α) levels. TNF-α levels were not different between groups at 24 h. Cortisol levels in the LPS + Quetiapine group were reduced compared to LPS + Placebo (P < 0.001) and did not differ from the placebo group (P = 0.15). Analysis between LPS + Quetiapine and LPS + Placebo treated rats demonstrated improvement in the compound discrimination reversal (CD Rev1) (P = 0.016) and the intra-dimensional reversal (ID Rev2) (P = 0.007) discriminations on trials to criterion. LPS + Quetiapine treated rats had fewer errors than LPS + Placebo treated animals in the compound discrimination (CD) (P = 0.007), CD Rev1 (P = 0.005), ID Rev2 (P < 0.001) discriminations. There was no difference in non-locomotion frequency or latency to criterion between the three groups in all discriminations (P > 0.0167). We demonstrated preserved reversal learning, no effect on attentional set shifting and normalized cortisol levels in quetiapine-treated rats in this neuroinflammatory model of delirium. This suggests that quetiapine's beneficial effects in delirium may be related to the preservation of reversal learning and potential downstream effects related to reduction in cortisol production. Graphical Abstract.


Assuntos
Antipsicóticos/uso terapêutico , Atenção/efeitos dos fármacos , Delírio/tratamento farmacológico , Modelos Animais de Doenças , Hidrocortisona/metabolismo , Inflamação/tratamento farmacológico , Fumarato de Quetiapina/uso terapêutico , Reversão de Aprendizagem/efeitos dos fármacos , Enquadramento Psicológico , Animais , Antipsicóticos/farmacologia , Comportamento Apetitivo/efeitos dos fármacos , Delírio/fisiopatologia , Avaliação Pré-Clínica de Medicamentos , Função Executiva/efeitos dos fármacos , Feminino , Lobo Frontal/fisiopatologia , Inflamação/induzido quimicamente , Inflamação/psicologia , Lipopolissacarídeos/toxicidade , Fumarato de Quetiapina/farmacologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Recompensa , Fator de Necrose Tumoral alfa/metabolismo
8.
J Cancer Res Clin Oncol ; 145(6): 1495-1507, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31028540

RESUMO

PURPOSE: Constructed from a theoretical framework, the coordinated undermining of survival paths in glioblastoma (GBM) is a combination of nine drugs approved for non-oncological indications (CUSP9; aprepitant, auranofin, captopril, celecoxib, disulfiram, itraconazole, minocycline, quetiapine, and sertraline) combined with temozolomide (TMZ). The availability of these drugs outside of specialized treatment centers has led patients to embark on combination treatments without systematic follow-up. However, no experimental data on efficacy using the CUSP9 strategy in GBM have been reported. METHODS: Using patient-derived glioblastoma stem cell (GSC) cultures from 15 GBM patients, we described stem cell properties of individual cultures, determined the dose-response relationships of the drugs in the CUSP9, and assessed the efficacy the CUSP9 combination with TMZ in concentrations clinically achievable. The efficacy was evaluated by cell viability, cytotoxicity, and sphere-forming assays in both primary and recurrent GSC cultures. RESULTS: We found that CUSP9 with TMZ induced a combination effect compared to the drugs individually (p < 0.0001). Evaluated by cell viability and cytotoxicity, 50% of the GSC cultures displayed a high sensitivity to the drug combination. In clinical plasma concentrations, the effect of the CUSP9 with TMZ was superior to TMZ monotherapy (p < 0.001). The Wnt-signaling pathway has been shown important in GSC, and CUSP9 significantly reduces Wnt-activity. CONCLUSIONS: Adding experimental data to the theoretical rationale of CUSP9, our results demonstrate that the CUSP9 treatment strategy can induce a combination effect in both treatment-naïve and pretreated GSC cultures; however, predicting response in individual cultures will require further profiling of GSCs.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Animais , Aprepitanto/administração & dosagem , Aprepitanto/farmacologia , Auranofina/administração & dosagem , Auranofina/farmacologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Captopril/administração & dosagem , Captopril/farmacologia , Celecoxib/administração & dosagem , Celecoxib/farmacologia , Dissulfiram/administração & dosagem , Dissulfiram/farmacologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Itraconazol/administração & dosagem , Itraconazol/farmacologia , Camundongos , Camundongos SCID , Minociclina/administração & dosagem , Minociclina/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Fumarato de Quetiapina/administração & dosagem , Fumarato de Quetiapina/farmacologia , Reprodutibilidade dos Testes , Sertralina/administração & dosagem , Sertralina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Temozolomida/administração & dosagem , Temozolomida/farmacologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
9.
J Psychiatr Res ; 109: 18-26, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30463035

RESUMO

Previous studies suggest immunological alterations in patients with first-episode psychosis (FEP). Some studies show that antipsychotic compounds may cause immunomodulatory effects. To evaluate the immunological changes and the possible immunomodulatory effects in FEP, we recruited patients with FEP (n = 67) and matched controls (n = 38), aged 18-40 years, from the catchment area of the Helsinki University Hospital and the City of Helsinki, Finland. Fasting peripheral blood samples were collected between 8 and 10 a.m. in 10 ml PAXgene tubes. We applied the NanoString nCounter in-solution hybridization technology to determine gene expression levels of 147 candidate genes reflecting activation of the immune system. Cases had higher gene expression levels of BDKRB1 and SPP1/osteopontin compared with controls. Of the individual medications used as monotherapy, risperidone was associated with a statistically significant upregulation of 11 immune system genes, including cytokines and cytokine receptors (SPP1, IL1R1, IL1R2), pattern recognition molecules (TLR1, TLR2 and TLR6, dectin-1/CLEC7A), molecules involved in apoptosis (FAS), and some other molecules with functions in immune activation (BDKRB1, IGF1R, CR1). In conclusion, risperidone possessed strong immunomodulatory properties affecting mainly innate immune response in FEP patients, whereas the observed effects of quetiapine and olanzapine were only marginal. Our results further emphasize the importance of understanding the immunomodulatory mechanisms of antipsychotic treatment, especially in terms of specific compounds, doses and duration of medication in patients with severe mental illness. Future studies should evaluate the response pre- and post-treatment, and the possible role of this inflammatory activation for the progression of psychiatric and metabolic symptoms.


Assuntos
Antipsicóticos/farmacologia , Citocinas/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Imunidade Inata/genética , Fatores Imunológicos/farmacologia , Olanzapina/farmacologia , Transtornos Psicóticos/tratamento farmacológico , Fumarato de Quetiapina/farmacologia , Receptores de Citocinas/genética , Risperidona/farmacologia , Adolescente , Adulto , Feminino , Humanos , Masculino , Regulação para Cima , Adulto Jovem
10.
Acta Psychiatr Scand ; 138(5): 420-431, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30168131

RESUMO

OBJECTIVE: To test the validity and sensitivity of the six-item version (PANSS-6) of the 30-item Positive and Negative Syndrome Scale (PANSS-30) in treatment-resistant schizophrenia (TRS). METHOD: Using data from the clozapine phase (2E) of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, we investigated the following: (i) The scalability of PANSS-6 and PANSS-30; (ii) The correlation between PANSS-6 and PANSS-30 total scores; (iii) Whether PANSS-6 could identify cross-sectional symptom remission; and (iv) The efficacy of clozapine, olanzapine, risperidone and quetiapine in TRS using the 'speed of change' on PANSS-6 and PANSS-30 (change in total score per week) as outcome measures. RESULTS: We found that (i) only PANSS-6 and not PANSS-30 was scalable; (ii) The correlation between PANSS-6 and PANSS-30 total scores was high (Spearman coefficient: 0.85), (iii) PANSS-6 accurately identified cross-sectional symptom remission as defined by the Andreasen et al. criteria; and (iv) The only antipsychotic that caused improvement (speed of change significantly lower than 0 during the first three months of treatment) was clozapine, both when using PANSS-6 (speed of change: -0.50 points/week; 95%CI: -0.84, -0.17) and PANSS-30 (speed of change: -1.41 points/week; 95%CI: -2.80, -0.02) as outcome measures. CONCLUSION: PANSS-6 validly measures severity, remission and antipsychotic efficacy in TRS.


Assuntos
Antipsicóticos/farmacologia , Clozapina/farmacologia , Avaliação de Resultados em Cuidados de Saúde/normas , Escalas de Graduação Psiquiátrica/normas , Estudos Transversais , Humanos , Olanzapina/farmacologia , Fumarato de Quetiapina/farmacologia , Reprodutibilidade dos Testes , Risperidona/farmacologia , Esquizofrenia , Sensibilidade e Especificidade
11.
Int J Neuropsychopharmacol ; 21(12): 1090-1101, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30215723

RESUMO

Background: Different effectiveness profiles among second-generation antipsychotics may be a key point to optimize treatment in patients suffering a first episode of psychosis to affect long-term outcome. The aim of this study was to compare the clinical effectiveness of aripiprazole, ziprasidone, and quetiapine in the treatment of first episode of psychosis at 3-year follow-up. Method: From October 2005 to January 2011, a prospective, randomized, open-label study was undertaken. Two hundred-two first-episode, drug-naïve patients were randomly assigned to aripiprazole (n=78), ziprasidone (n =62), or quetiapine (n=62) and followed-up for 3 years. The primary effectiveness measure was all cause of treatment discontinuation. In addition, an analysis based on the intention-to-treat principle was conducted in the analysis for clinical efficacy. Results: The overall dropout rate at 3 years reached 19.3%. Treatment discontinuation rates were significantly different among treatment groups (aripiprazole=73.08%, ziprasidone=79.03%, and quetiapine=95.16%) (χ2=11.680; P=.001). Statistically significant differences in terms of nonefficacy, nonadherence, and side effects were observed among treatment groups along the 3-year follow-up determining significant differences in time to all-cause discontinuation (log-rank=32.260; P=.001). Significant differences between treatments were found in the categories of sleepiness/sedation (χ2=9.617; P=.008) and increased sleep duration (χ2=6.192; P=.004). No significant differences were found in the profile of extrapyramidal symptoms. Patients on aripiprazole were more likely to be prescribed benzodiazepines. Conclusions: First-episode psychosis patients on quetiapine were more likely to discontinue treatment due to nonefficacy. Identifying different discontinuation patterns may contribute to optimize treatment selection after first episode of psychosis.


Assuntos
Antipsicóticos/farmacologia , Aripiprazol/farmacologia , Avaliação de Resultados em Cuidados de Saúde , Piperazinas/farmacologia , Transtornos Psicóticos/tratamento farmacológico , Fumarato de Quetiapina/farmacologia , Esquizofrenia/tratamento farmacológico , Tiazóis/farmacologia , Adulto , Antipsicóticos/administração & dosagem , Aripiprazol/administração & dosagem , Feminino , Seguimentos , Humanos , Masculino , Piperazinas/administração & dosagem , Fumarato de Quetiapina/administração & dosagem , Tiazóis/administração & dosagem , Adulto Jovem
12.
Inflamm Res ; 67(10): 847-861, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30109356

RESUMO

OBJECTIVE AND DESIGN: To investigate the amelioration effects of quetiapine on rheumatoid arthritis with RAW 264.7 macrophage and collagen-induced arthritis (CIA) DBA/1J mouse model. SUBJECTS: RAW 264.7 macrophage and DBA/1J mice. TREATMENT: Lipopolysaccharide and collagen. METHODS: RAW 264.7 macrophages stimulated by lipopolysaccharide (LPS) followed by quetiapine treatments were investigated. Activations of CD80 and CD86 were analyzed by flow cytometry. Pro-inflammatory cytokines such as IL-6, TNF-α and IL-1ß were analyzed by ELISA. Proteins involved in signaling pathways related to the formation of rheumatoid arthritis were assayed by Western blotting. Therapeutic efficacy of quetiapine in CIA mouse model was also assayed. 18F-FDG/micro-PET was used to monitor the inflammation status in the joints, and the severity of bone erosion was evaluated with micro-CT and H&E staining. RESULTS: The inhibition of pro-inflammatory cytokines by quetiapine was found through the ERK and AKT phosphorylation and subsequent NF-κB and CREB signaling pathways. Pro-inflammatory cytokines such as IL-17, IL-6 and IL-1ß were decreased, while immunosuppressive factors such as TGF-ß and IL-10 were increased in CIA mice treated with quetiapine. Notably, no uptake of 18F-FDG and bone erosion was found with micro-PET images on days 32 and 43 in the quetiapine-treated and normal control groups. However, significant uptake of 18F-FDG could be observed in the CIA group during the same time course. Similar results were further verified with ex vivo autoradiography. CONCLUSION: Taken together, these results suggest that quetiapine is a potential anti-inflammatory drug, and may be used as an adjuvant for the treatment of rheumatoid arthritis.


Assuntos
Anti-Inflamatórios/uso terapêutico , Artrite Experimental/tratamento farmacológico , Fumarato de Quetiapina/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Artrite Experimental/metabolismo , Lipopolissacarídeos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos DBA , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fumarato de Quetiapina/farmacologia , Células RAW 264.7
13.
BMC Psychiatry ; 18(1): 231, 2018 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-30016952

RESUMO

BACKGROUND: There are interindividual differences in the adverse effects of atypical antipsychotics, which include autonomic nervous system (ANS) dysfunction. Accordingly, to clarify the interindividual differences in the adverse effects of specific atypical antipsychotics in schizophrenia, we investigated the association between ANS dysfunction and ATP-binding cassette transport sub-family B member 1 (ABCB1) gene polymorphisms in patients with schizophrenia. METHODS: In total, 233 Japanese patients with schizophrenia participated in this study. All of the participants received an atypical antipsychotic as monotherapy: 89 participants received risperidone, 69 olanzapine, 48 aripiprazole, and 27 quetiapine. ANS activity was assessed by means of a power spectral analysis of heart rate variability. Four single nucleotide polymorphisms (SNPs) in ABCB1 (rs1045642, rs1128503, rs2032582, and rs2235048) were genotyped using the TaqMan method. RESULTS: For aripiprazole, sympathetic and total autonomic nervous activities were significantly lower in the rs1045642 T allele carrier-rs2235048 C allele carrier group than in the rs1045642 non-T allele carrier-rs2235048 non-C allele carrier group. In addition, in the aripiprazole group, the T-C-T-A haplotype (rs1045642-rs2235048-rs1128503-rs2032582) was associated with decreased ANS activity. However, there were no significant associations between ANS activity and ABCB1 gene polymorphisms in the risperidone, olanzapine, and quetiapine groups. Multiple regression analysis revealed that sympathetic and total nervous activities were significantly associated with the ABCB1 rs1045642-rs2235048 genotype and the T-C-T-A haplotype (rs1045642-rs2235048-rs1128503-rs2032582). CONCLUSION: We suggest that ABCB1 genetic polymorphisms affect aripiprazole-related ANS dysfunction but do not affect risperidone-, olanzapine-, or quetiapine-related ANS dysfunction.


Assuntos
Antipsicóticos/uso terapêutico , Frequência Cardíaca/fisiologia , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Adulto , Idoso , Antipsicóticos/efeitos adversos , Antipsicóticos/farmacologia , Aripiprazol/efeitos adversos , Aripiprazol/farmacologia , Aripiprazol/uso terapêutico , Sistema Nervoso Autônomo/efeitos dos fármacos , Sistema Nervoso Autônomo/fisiologia , Sistema Nervoso Autônomo/fisiopatologia , Estudos Transversais , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Olanzapina/farmacologia , Olanzapina/uso terapêutico , Fumarato de Quetiapina/efeitos adversos , Fumarato de Quetiapina/farmacologia , Fumarato de Quetiapina/uso terapêutico , Risperidona/efeitos adversos , Risperidona/farmacologia , Risperidona/uso terapêutico , Esquizofrenia/fisiopatologia
14.
J Trauma Acute Care Surg ; 85(5): 968-976, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29985239

RESUMO

BACKGROUND: The integrity of the blood-brain barrier (BBB) is paramount in limiting vasogenic edema following traumatic brain injury (TBI). The purpose of this study was to ascertain if quetiapine, an atypical antipsychotic commonly used in trauma/critical care for delirium, protects the BBB and attenuates hyperpermeability in TBI. METHODS: The effect of quetiapine on hyperpermeability was examined through molecular modeling, cellular models in vitro and small animal models in vivo. Molecular docking was performed with AutoDock Vina to matrix metalloproteinase-9. Rat brain microvascular endothelial cells (BMECs) were pretreated with quetiapine (20 µM; 1 hour) followed by an inflammatory activator (20 µg/mL chitosan; 2 hours) and compared to controls. Immunofluorescence localization for tight junction proteins zonula occludens-1 and adherens junction protein ß-catenin was performed. Human BMECs were grown as a monolayer and pretreated with quetiapine (20 µM; 1 hour) followed by chitosan (20 µg/mL; 2 hours), and transendothelial electrical resistance was measured. C57BL/6 mice (n = 5/group) underwent mild to moderate TBI (controlled cortical impactor) or sham craniotomy. The treatment group was given 10 mg/kg quetiapine intravenously 10 minutes after TBI. The difference in fluorescence intensity between intravascular and interstitium (ΔI) represented BBB hyperpermeability. A matrix metalloproteinase-9 activity assay was performed in brain tissue from animals in the experimental groups ex vivo. RESULTS: In silico studies showed quetiapine thermodynamically favorable binding to MMP-9. Junctional localization of zonula occludens-1 and ß-catenin showed retained integrity in quetiapine-treated cells as compared with the chitosan group in rat BMECs. Quetiapine attenuated monolayer permeability compared with chitosan group (p < 0.05) in human BMECs. In the animal studies, there was a significant decrease in BBB hyperpermeability and MMP-9 activity when compared between the TBI and TBI plus quetiapine groups (p < 0.05). CONCLUSION: Quetiapine treatment may have novel anti-inflammatory properties to provide protection to the BBB by preserving tight junction integrity. LEVEL OF EVIDENCE: level IV.


Assuntos
Antipsicóticos/farmacologia , Barreira Hematoencefálica/metabolismo , Lesões Encefálicas Traumáticas/fisiopatologia , Células Endoteliais/fisiologia , Fumarato de Quetiapina/farmacologia , Junções Íntimas/metabolismo , Animais , Encéfalo/irrigação sanguínea , Células Cultivadas , Quitosana/farmacologia , Simulação por Computador , Modelos Animais de Doenças , Impedância Elétrica , Humanos , Microscopia Intravital , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Microvasos/diagnóstico por imagem , Modelos Moleculares , Permeabilidade/efeitos dos fármacos , Ratos , Junções Íntimas/efeitos dos fármacos , Proteína da Zônula de Oclusão-1/metabolismo , beta Catenina/metabolismo
15.
Neuropsychopharmacology ; 43(11): 2256-2263, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29946107

RESUMO

The need for treatment response predictive biomarkers is being increasingly recognized in children and adolescents with psychiatric disorders. Structural gray matter abnormalities as a predictor of treatment outcome in pediatric bipolar disorder have not been systematically investigated, especially early in the illness course. With a prospective longitudinal study design, the present study enrolled 52 bipolar adolescents with no history of treatment with mood stabilizers or a therapeutic dose of antipsychotic drugs and 31 healthy controls. Patients were randomly assigned to treatment with quetiapine or lithium after pretreatment data collection. A hierarchical cluster analysis was performed using pretreatment cortical thickness data that identified two discrete patient subgroups. Compared to healthy subjects, patients in subgroup 1 (n = 16) showed widespread greater cortical thickness mainly across heteromodal cortex but also involving some regions of unimodal cortex, while those in subgroup 2 (n = 36) showed regional cortical thinning mainly in superior temporal and superior parietal regions. Patients within subgroup 1 showed a significantly higher response rate to quetiapine than those in subgroup 2 (100% vs 53%). No statistically significant difference was found in lithium response rate between the patient subgroups (63% vs 53%). Pretreatment clinical ratings and neuropsychological data did not differ across subgroups. Our findings suggest the existence of distinct and clinically relevant subgroups of pediatric bipolar patients, as defined by pattern of cortical thickness. These groups appear to differentially respond to antipsychotic treatment-notably with greater cortical thickness relative to controls predicting better treatment response.


Assuntos
Antidepressivos/uso terapêutico , Transtorno Bipolar/diagnóstico por imagem , Transtorno Bipolar/tratamento farmacológico , Córtex Cerebral/diagnóstico por imagem , Carbonato de Lítio/uso terapêutico , Fumarato de Quetiapina/uso terapêutico , Adolescente , Antidepressivos/farmacologia , Córtex Cerebral/efeitos dos fármacos , Criança , Feminino , Humanos , Carbonato de Lítio/farmacologia , Imagem por Ressonância Magnética/métodos , Masculino , Tamanho do Órgão , Valor Preditivo dos Testes , Fumarato de Quetiapina/farmacologia , Resultado do Tratamento
16.
Psychopharmacol Bull ; 48(2): 8-17, 2018 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-29713096

RESUMO

Objectives: A previous randomized placebo-controlled trial in military veterans posttraumatic stress disorder (PTSD) found that quetiapine improved global PTSD symptoms severity, depression and anxiety as well as the re-experiencing and hypearousal clusters. However, it is not known if individual symptoms had a preferential response to this medication. The goal of this study was to analyze the individual symptom response in this group of patients. Methods: Data from a previous trial was re-analyzed. Each of the of the scale items was analyzed individually using Repeated Measures Analysis of Variance. Results: Compared to placebo, there was a significant decline in the Clinician-Administered PTSD Scale intrusive memories and insomnia questions. In the Davidson Trauma Scale, greater improvements were observed on irritability, difficulty concentrating, hyperstartle and a trend was observed on avoiding thoughts or feelings about the event. Greater improvements compared with placebo were noted on the Hamilton Depression (HAM-D) middle and late insomnia items. On the Hamilton Anxiety scale (HAM-A), the insomnia item was significantly improved. Conclusions: Quetiapine demonstrated greater effect than placebo on several symptoms. The strongest response was seen on insomnia, which the highest significance level on the CAPS. The insomnia items of both the HAM-D and HAM-A also demonstrated improvement with quetiapine. These finding indicate quetiapine improved sleep measure. Insomnia can be a difficult problem to treat in PTSD patients, therefore quetiapine should be considered in difficult cases.


Assuntos
Antipsicóticos/farmacologia , Distúrbios de Guerra/tratamento farmacológico , Distúrbios de Guerra/fisiopatologia , Avaliação de Resultados em Cuidados de Saúde , Fumarato de Quetiapina/farmacologia , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Adulto , Antipsicóticos/administração & dosagem , Humanos , Masculino , Escalas de Graduação Psiquiátrica , Fumarato de Quetiapina/administração & dosagem , Veteranos
17.
Neurochem Int ; 118: 242-251, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29627379

RESUMO

Recent studies have revealed that oligodendrocyte differentiation deficits and de-myelination occur in the brains of schizophrenic patients. Cell cycle proteins play a critical role in modulating oligodendrocyte proliferation and differentiation. In our previous studies, we found that cuprizone, a copper chelant, induces oligodendrocyte loss and demyelination, and this effect can be alleviated by using the atypical antipsychotic drug quetiapine. To explore the mechanisms of quetiapine in oligodendrocyte development, we examined the effects of quetiapine on cell cycle progression. Quetiapine promoted cell cycle exit and blocked the mitogenic effect of PDGF in cultured rat cortical oligodendrocyte progenitor cells (OPCs). Quetiapine accelerated OPC differentiation in vitro. Moreover, the systemic administration of quetiapine up-regulated p21 mRNA expression, a cyclin-dependent kinase inhibitor, in mice. Knocking down p21 expression by RNA interference enhanced proliferation and delayed differentiation. Our results suggest that cell cycle regulation may contribute to the differentiation-promoting effect of quetiapine.


Assuntos
Antipsicóticos/farmacologia , Ciclo Celular/fisiologia , Diferenciação Celular/fisiologia , Oligodendroglia/fisiologia , Fumarato de Quetiapina/farmacologia , Animais , Animais Recém-Nascidos , Ciclo Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Masculino , Camundongos , Oligodendroglia/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
18.
Transl Psychiatry ; 8(1): 59, 2018 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-29507281

RESUMO

Mood disturbances seen in first-episode mania (FEM) are linked to disturbed functional connectivity of the striatum. Lithium and quetiapine are effective treatments for mania but their neurobiological effects remain largely unknown. We conducted a single-blinded randomized controlled maintenance trial in 61 FEM patients and 30 healthy controls. Patients were stabilized for a minimum of 2 weeks on lithium plus quetiapine then randomly assigned to either lithium (serum level 0.6 mmol/L) or quetiapine (dosed up to 800 mg/day) treatment for 12 months. Resting-state fMRI was acquired at baseline, 3 months (patient only) and 12 months. The effects of treatment group, time and their interaction, on striatal functional connectivity were assessed using voxel-wise general linear modelling. At baseline, FEM patients showed reduced connectivity in the dorsal (p = 0.05) and caudal (p = 0.008) cortico-striatal systems when compared to healthy controls at baseline. FEM patients also showed increased connectivity in a circuit linking the ventral striatum with the medial orbitofrontal cortex, cerebellum and thalamus (p = 0.02). Longitudinally, we found a significant interaction between time and treatment group, such that lithium was more rapid, compared to quetiapine, in normalizing abnormally increased functional connectivity, as assessed at 3-month and 12-month follow-ups. The results suggest that FEM is associated with reduced connectivity in dorsal and caudal corticostriatal systems, as well as increased functional connectivity of ventral striatal systems. Lithium appears to act more rapidly than quetiapine in normalizing hyperconnectivity of the ventral striatum with the cerebellum. The study was registered on the Australian and New Zealand Clinical Trials Registry (ACTRN12607000639426). http://www.anzctr.org.au.


Assuntos
Antimaníacos/farmacologia , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/fisiopatologia , Conectoma/métodos , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/fisiopatologia , Compostos de Lítio/farmacologia , Fumarato de Quetiapina/farmacologia , Adolescente , Adulto , Antimaníacos/administração & dosagem , Transtorno Bipolar/diagnóstico por imagem , Cerebelo/diagnóstico por imagem , Cerebelo/efeitos dos fármacos , Cerebelo/fisiopatologia , Corpo Estriado/diagnóstico por imagem , Feminino , Seguimentos , Humanos , Compostos de Lítio/administração & dosagem , Imagem por Ressonância Magnética , Masculino , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiopatologia , Fumarato de Quetiapina/administração & dosagem , Método Simples-Cego , Tálamo/diagnóstico por imagem , Tálamo/efeitos dos fármacos , Tálamo/fisiopatologia , Adulto Jovem
19.
Int J Mol Sci ; 19(4)2018 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-29570608

RESUMO

Quetiapine is a new type of antipsychotic drug, with effective protection of pheochromocytoma PC12 cells from oxidative stress-induced apoptosis. Ultraviolet-B radiation can increase reactive oxygen species (ROS) production, resulting in significant inflammatory responses in damaged skin. Thus, the purpose of this study is to explore whether quetiapine protects the skin from intermediate-wave ultraviolet (UVB)-induced damage through antioxidant stress. In vivo, we found quetiapine treatment was able to significantly decrease skin thickness, erythema, and edema, as well as inflammation compared to control group. Moreover, quetiapine treatment increased the activities of antioxidant enzymes, including superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). In addition, it reduced the production of malondialdehyde (MDA), a kind of oxidized lipid. In vitro, we found that quetiapine blocked UVB-induced intracellular ROS generation and maintained the cell activity at a normal level. Furthermore, we tested the phosphorylation of p38 both in vivo and in vitro, and we found that quetiapine could inhibit phosphorylation of p38, which is caused by UVB irradiation. We concluded that quetiapine was able to relieve UVB-induced skin damage through its antioxidative properties. These effects might be associated with p38 MAPK signaling pathway.


Assuntos
Antioxidantes/farmacologia , Fumarato de Quetiapina/farmacologia , Pele/efeitos dos fármacos , Pele/efeitos da radiação , Raios Ultravioleta , Linhagem Celular Tumoral , Glutationa Peroxidase/metabolismo , Humanos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/efeitos da radiação , Fosforilação/efeitos da radiação , Espécies Reativas de Oxigênio/metabolismo , Pele/metabolismo , Superóxido Dismutase/metabolismo
20.
Depress Anxiety ; 35(5): 402-410, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29329498

RESUMO

BACKGROUND: The impact of psychosis on the treatment of bipolar depression is remarkably understudied. The primary aim of this study was to compare treatment outcomes of bipolar depressed individuals with and without psychosis. The secondary aim was to compare the effect of lithium and quetiapine, each with adjunctive personalized treatments (APTs), in the psychotic subgroup. METHODS: We assessed participants with DSM-IV bipolar depression included in a comparative effectiveness study of lithium and quetiapine with APTs (the Bipolar CHOICE study). Severity was assessed by the Bipolar Inventory of Symptoms Scale (BISS) and by the Clinical Global Impression Scale-Severity-Bipolar Version (CGI-S-BP). Mixed models were used to assess the course of symptom change, and Cox regression survival analysis was used to assess the time to remission. RESULTS: Psychotic features were present in 10.6% (n = 32) of the depressed participants (n = 303). Those with psychotic features had higher scores on the BISS before (75.2 ± 17.6 vs. 54.9 ± 16.3; P < .001) and after (37.2 ± 19.7 vs. 26.3 ± 18.0; P = .003) 6-month treatment. The CGI-S-BP yielded similar results. Participants with and without psychosis had similar course of symptom improvement and similar time to remission. There was no significant difference in the treatment outcomes of lithium (n = 11) and quetiapine (n = 21) among the psychotic subgroup. CONCLUSION: Bipolar depressive episodes with psychotic features are more severe, and compared to nonpsychotic depressions, present a similar course of improvement. Given the small number of participants presenting psychosis, the lack of statistically significant difference between lithium- and quetiapine-based treatment of psychotic bipolar depressive episodes needs replication in a larger sample.


Assuntos
Antimaníacos/farmacologia , Antipsicóticos/farmacologia , Transtorno Bipolar , Compostos de Lítio/farmacologia , Transtornos Psicóticos , Fumarato de Quetiapina/farmacologia , Resultado do Tratamento , Adulto , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/epidemiologia , Transtorno Bipolar/fisiopatologia , Comorbidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Psicóticos/tratamento farmacológico , Transtornos Psicóticos/epidemiologia , Transtornos Psicóticos/fisiopatologia , Adulto Jovem
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