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1.
Acta Psychiatr Scand ; 142(3): 242-248, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32677065

RESUMO

OBJECTIVE: Synthetic glucocorticoids cause various psychiatric symptoms. Prescription of psychotropic drugs could be considered to be a proxy for manifestation of psychiatric symptoms. The aim of this study was to investigate the prescriptions of psychotropics in outpatients receiving synthetic glucocorticoids. METHODS: We used the claims sampling data during January 2015 from the National Database of Health Insurance Claims and Specific Health Checkups of Japan made by the Ministry of Health, Labor, and Welfare in Japan. We compared the prescription rates of psychotropics between outpatients receiving oral synthetic glucocorticoids and age- and sex-matched controls and the prescription rates of psychotropics among the eight dosage groups of synthetic glucocorticoids by chi-squared test, and chlorpromazine/imipramine/diazepam equivalent doses (or daily defined doses) of respective psychotropics among these groups using Welch's t-test. RESULTS: Synthetic glucocorticoids were prescribed to 3.1% (n = 18 122) of 581 990 patients. The prescription rates of psychotropics were significantly higher among the synthetic glucocorticoid recipients than among the non-recipients: antipsychotics, 1.8% (n = 321) vs. 1.1% (n = 201) (P = 1.4 × 10-7 ); antidepressants, 4.0% (n = 724) vs. 2.0% (n = 359) (P = 8.7 × 10-30 ); anxiolytics/hypnotics, 16.7% (n = 3029) vs. 10.2% (n = 1841) (P = 2.7 × 10-75 ); and mood stabilizers, 1.3% (n = 238) vs. 0.7% (n = 120) (P = 3.6 × 10-10 ) respectively. There was no significant difference in the prescription rates of any psychotropic drugs, other than anxiolytics/hypnotics, among the eight synthetic glucocorticoid dosage groups. CONCLUSION: Prescriptions of oral synthetic glucocorticoids were found to be associated with the use of any of the types of psychotropic drugs, other than anxiolytics/hypnotics, although a causal relationship could not be confirmed due to the retrospective and cross-sectional nature of this study.


Assuntos
Glucocorticoides , Psicotrópicos , Estudos Transversais , Prescrições de Medicamentos , Glucocorticoides/efeitos adversos , Humanos , Prescrições , Psicotrópicos/efeitos adversos , Estudos Retrospectivos
2.
Acta Psychiatr Scand ; 139(2): 108-116, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30198163

RESUMO

OBJECTIVE: To examine characteristics of placebo responders and seek optimal criteria of early improvement with placebo for predicting subsequent placebo response in patients with schizophrenia. METHOD: Data of 672 patients with schizophrenia randomized to placebo in nine double-blind antipsychotic trials were analyzed. Multiple logistic regression analyses were conducted to examine associations between placebo response at week 6 (i.e., a ≥ 25% reduction in the Positive and Negative Syndrome Scale [PANSS] score) and gender, age, study locations, baseline PANSS total or Marder 5-Factor scores, and per cent PANSS score reduction at week 1. Predictive power of improvement at week 1 for subsequent response was investigated; sensitivity and specificity of incremental 5% cutoff points between 5% and 25% reduction in the PANSS total score at week 1 were calculated. RESULTS: Per cent PANSS total score reduction at week 1 and lower PANSS Marder disorganized thought scores at baseline were significantly associated with subsequent placebo response. A 10% reduction in a per-protocol analysis or a 15% reduction in last-observation-carried-forward analysis in the PANSS total score at week 1 showed the highest predictive power. CONCLUSION: These findings are informative to identify potential placebo responders at the earliest opportunity for optimal trial design for schizophrenia.


Assuntos
Antipsicóticos/farmacologia , Placebos/farmacologia , Esquizofrenia/tratamento farmacológico , Adolescente , Adulto , Idoso , Antipsicóticos/uso terapêutico , Criança , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Efeito Placebo , Placebos/administração & dosagem , Valor Preditivo dos Testes , Escalas de Graduação Psiquiátrica , Esquizofrenia/epidemiologia , Sensibilidade e Especificidade , Adulto Jovem
3.
Acta Psychiatr Scand ; 137(4): 316-327, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29141100

RESUMO

OBJECTIVE: The impact of religious/spiritual activities on clinical outcomes in patients with serious mental illnesses remains controversial, which was addressed in this international cross-sectional study. METHOD: Three-hundred sixty-nine subjects were recruited from Austria (n = 189) and Japan (n = 180), consisting of 112 outpatients with paranoid schizophrenia, 120 with bipolar I disorder (DSM-IV), and 137 healthy controls. Religiosity was assessed in terms of attendance and importance of religious/spiritual activities, while resilience was assessed using the 25-item Resilience Scale. General linear models were used to test whether higher religiosity will be associated with higher resilience, higher social functioning, and lower psychopathology. The association between levels of spiritual well-being and resilience was also examined. RESULTS: Attendance of religious services (F[4,365] = 0.827, P = 0.509) and importance of religion/spirituality (F[3,365] = 1.513, P = 0.211) did not show significant associations with resilience. Regarding clinical measures, a modest association between higher importance of religion/spirituality and residual manic symptoms was observed in bipolar patients (F[3,118] = 3.120, P = 0.029). In contrast to the findings regarding religiosity, spiritual well-being showed a strong positive correlation with resilience (r = 0.584, P < 0.001). CONCLUSION: The protective effect of religiosity in terms of resilience, social functioning, and psychopathology was not evident in our sample. Spiritual well-being appears more relevant to resilience than religiosity.


Assuntos
Transtorno Bipolar/psicologia , Religião , Resiliência Psicológica , Esquizofrenia Paranoide/psicologia , Espiritualidade , Adulto , Áustria , Estudos Transversais , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade
4.
Bull Math Biol ; 80(9): 2452-2480, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30097919

RESUMO

The Neolithic transition began the spread of early agriculture throughout Europe through interactions between farmers and hunter-gatherers about 10,000 years ago. Archeological evidence produced by radiocarbon dating indicates that the expanding velocity of farming is roughly constant all over Europe. Theoretical understanding of such evidence has been performed from mathematical modeling viewpoint. However, the expanding velocity determined by existing modeling approaches is faster than the observed velocity. For understanding this difference, we propose a three-component reaction-diffusion system which consists of two different types of farmers (sedentary and migratory) and hunter-gatherers from the viewpoint of the influence of farming technology. Our purpose is to study the relation between the expanding velocity of farmers and the farming technology parameter (say, [Formula: see text]). In this paper, we mainly focus on the one-dimensional traveling wave solution with minimal velocity and show that the minimal velocity decreases, as [Formula: see text] increases. This can be compatible with the observed velocity when farming technology is developed. Our results suggest that the reason for the slowdown of the Neolithic transition might be related to the increase in the development of farming technology.


Assuntos
Agricultura/história , Fazendeiros/história , Migração Humana/história , Agricultura/estatística & dados numéricos , Animais , Arqueologia/estatística & dados numéricos , Dieta Paleolítica/história , Domesticação , Europa (Continente) , Fazendeiros/estatística & dados numéricos , História Antiga , Humanos , Conceitos Matemáticos , Modelos Teóricos
5.
Acta Psychiatr Scand ; 136(3): 259-268, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28547796

RESUMO

OBJECTIVE: To investigate the association between serum total cholesterol (TC) and suicide using a large general population cohort with long follow-up times. METHOD: Analyses included 16 341 men and 28 905 women aged 40-69 from the Japan Public Health Center-based Prospective Study followed from 1990 to 2012. TC levels were defined per clinical guidelines: low (<4.66 mmol/l [180 mg/dl]), normal (4.66-5.70 mmol/l [180-220 mg/dl]), and high (≥5.70 mmol/l [220 mg/dl]). Cox proportional hazards regression models were used to determine hazard ratios (HR) and confidence intervals (CI) for suicide according to TC level. Mean follow-up time was 19 years for men and 20 years for women. RESULTS: There were 185 suicides (men: 107; women: 78) during follow-up. Compared to women with normal TC, women with high TC had a significantly increased risk of suicide (HR = 1.90, 95% CI, 1.13-3.19). Incremental increases (0.26 mmol/l [10 mg/dl]) of low-density lipoprotein (HR = 1.11, 95% CI, 1.02-1.21) and non-high-density lipoprotein cholesterol (HR = 1.09, 95% CI, 1.01-1.18) were also associated with increased risk of suicide in women. There was no association between TC levels, or lipid fractions, and suicide in men. CONCLUSION: High TC levels may be associated with an increased risk of suicide in women.


Assuntos
Causas de Morte , Colesterol/sangue , Suicídio/estatística & dados numéricos , Adulto , Idoso , LDL-Colesterol/sangue , Feminino , Seguimentos , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Fatores Sexuais
6.
Mol Psychiatry ; 20(10): 1151-60, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26077694

RESUMO

Hypofunction of N-methyl-d-aspartate (NMDA) receptors has been proposed to have an important role in the cognitive impairments observed in schizophrenia. Although glutamate modulators may be effective in reversing such difficult-to-treat conditions, the results of individual studies thus far have been inconsistent. We conducted a systematic review and meta-analysis to examine whether glutamate positive modulators have beneficial effects on cognitive functions in patients with schizophrenia. A literature search was conducted to identify double-blind randomized placebo-controlled trials in schizophrenia or related disorders, using Embase, Medline, and PsycINFO (last search: February 2015). The effects of glutamate positive modulators on cognitive deficits were evaluated for overall cognitive function and eight cognitive domains by calculating standardized mean differences (SMDs) between active drugs and placebo added to antipsychotics. Seventeen studies (N=1391) were included. Glutamate positive modulators were not superior to placebo in terms of overall cognitive function (SMD=0.08, 95% confidence interval=-0.06 to 0.23) (11 studies, n=858) nor each of eight cognitive domains (SMDs=-0.03 to 0.11) (n=367-940) in this population. Subgroup analyses by diagnosis (schizophrenia only studies), concomitant antipsychotics, or pathway of drugs to enhance the glutamatergic neurotransmission (glycine allosteric site of NMDA receptors or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors) suggested no procognitive effect of glutamate positive modulators. Further, no effect was found in individual compounds on cognition. In conclusion, glutamate positive modulators may not be effective in reversing overall cognitive impairments in patients with schizophrenia as adjunctive therapies.


Assuntos
Transtornos Cognitivos/tratamento farmacológico , Fármacos Atuantes sobre Aminoácidos Excitatórios/uso terapêutico , Esquizofrenia/tratamento farmacológico , Transtornos Cognitivos/metabolismo , Transtornos Cognitivos/psicologia , Método Duplo-Cego , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores de N-Metil-D-Aspartato/metabolismo , Esquizofrenia/metabolismo , Psicologia do Esquizofrênico , Transmissão Sináptica/efeitos dos fármacos
7.
Eur J Gynaecol Oncol ; 37(4): 451-454, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-29894065

RESUMO

AIM: The outcomes of treatment for women with recurrent or advanced epithelial ovarian carcinoma previously treated with pacli- taxel plus platinum-based chemotherapy were analyzed. MATERIALS AND METHODS: Retrospective analysis was performed in a total of 65 series of treatments provided for 35 patients with a history of paclitaxel plus platinum-based chemotherapy. The chemotherapy regimens used were classified into the following four types for analysis: conventional paclitaxel plus carboplatin therapy (TC arm), pegylated liposomal doxorubicin-containing regimens (PLD arm), CPT-11-containing regimens (CPT-11 arm), and others. Disease-control rates (DCRs) were compared and subjected to univariate analysis. Progression-free survival (PFS) was determined from the date of the first cycle of each chemotherapy with the Kaplan-Meier method, and comparisons were performed using the log-rank test. RESULTS: DCR was 80%, 71%, and 26% for the TC, PLD, and CPT-l arms, respectively. The median PFS was 286, 372, and 76 days for the TC, PLD, and CPT-11 arms, respectively. There was no discernible difference in PFS between the TC and the PLD arm. In contrast, PFS of the CPT- 11 arm was significantly shorter than that of the TC and PLD arms. In addition, three of seven (42.9%) treatments in the PLD arm maintained a progression-free period for longer than one year, while only one of 25 (4%) treatments in the TC arm maintained a progression-free period for more than one year. CONCLUSIONS: The PFS of PLD is similar to that of TC. PLD-containing regimens might have a potential benefit with a higher PFS over one year than the TC regimen.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Carboplatina/administração & dosagem , Carcinoma Epitelial do Ovário , Intervalo Livre de Doença , Humanos , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Platina/administração & dosagem , Estudos Retrospectivos
8.
Pharmacopsychiatry ; 48(7): 286-91, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26506574

RESUMO

INTRODUCTION: Due to high inter-individual variability in peripheral pharmacokinetic parameters, dosing of antipsychotics currently relies on clinical trial-and-error, and predicting antipsychotic plasma concentrations before changing a dose has been a challenge. METHODS: Patients with schizophrenia receiving a stable dose of olanzapine were included. 2 plasma samples were collected at 2 given time points for the measurement of plasma olanzapine concentrations. At least 7 days after a dosage change of olanzapine, a third sample was collected. The plasma concentration of the third sample was predicted in a blinded fashion using a mixed-effects model with NONMEM(®), using the following information: the 2 baseline plasma concentrations, the interval between the last dose and blood draw, and clinical and demographic information. RESULTS: 31 subjects (mean±SD age=56.0±11.6; 19 men) were enrolled. The mean prediction (95% confidence interval) errors were 1.6 (-2.8 to 6.0) ng/mL. A highly significant correlation was observed between the observed and predicted concentrations of the third sample (r=0.91, p<0.001). DISCUSSION: Plasma olanzapine concentrations following an actual dosage change can be predicted in advance with a high degree of certainty.


Assuntos
Antipsicóticos/farmacocinética , Benzodiazepinas/farmacocinética , Esquizofrenia/tratamento farmacológico , Adulto , Idoso , Antipsicóticos/administração & dosagem , Antipsicóticos/sangue , Benzodiazepinas/administração & dosagem , Benzodiazepinas/sangue , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Olanzapina , Esquizofrenia/sangue
9.
Pharmacopsychiatry ; 47(7): 259-62, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25181576

RESUMO

INTRODUCTION: The objective of this study was to examine the evolution of antidepressant switch and adjunctive therapy. METHODS: This chart review was conducted at 6 primary psychiatric clinics or hospitals, in Tokyo, Japan. A chart review of longitudinal prescriptions was conducted regarding 633 outpatients with major depressive disorder for up to 2 years after their first visit. Patients who had already received antidepressants prior to the visit were excluded. RESULTS: 22.6% (N=143) of the patients completed or continued the outpatient treatment over the 2 years while 27 (4.3%), 23 (3.6%), and 439 (69.4%) patients discontinued it due to hospitalization, referral to another clinic, and loss to follow-up, respectively. A total of 597 episodes of antidepressant treatment were identified. Among them, 482 episodes (80.7%) were associated with the suggested dose ranges while antidepressant drugs were under-dosed in 19.3% (N=115) of the episodes. 50 patients (7.9%) received adjunctive therapy; it was employed after a median of only one antidepressant had been tried. CONCLUSION: Psychiatrists may be hasty in prescribing an adjunctive therapy in the treatment of depression.


Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Adulto , Antidepressivos/administração & dosagem , Fármacos do Sistema Nervoso Central/uso terapêutico , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Hospitais Psiquiátricos , Humanos , Japão , Masculino , Pessoa de Meia-Idade
10.
Anaesthesia ; 69(7): 752-6, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24800903

RESUMO

We hypothesised that an in-vivo adjustment method and/or a newer sensor would increase the accuracy of non-invasive and continuous haemoglobin monitoring (SpHb) measurements. Two sensors, the R1-25 and R2-25a (the newer version), were used with laboratory total haemoglobin concentration (tHb) values simultaneously recorded. In-vivo adjusted SpHb (AdHb) was calculated by a simple formula: AdHb = SpHb - (1(st) SpHb - 1(st) tHb). The correlation coefficients between SpHb (or AdHb) and tHb were compared: SpHb in both sensors correlated strongly with tHb (p < 0.0001). In-vivo adjustment improved the correlation coefficient between SpHb and tHb from 0.86 to 0.95 for the R1-25 and from 0.83 to 0.93 for the R2-25a. There was no difference between the R1-25 and R2-25a sensors. The in vivo adjustment method improved the accuracy of SpHb measurements in both sensors.


Assuntos
Hemoglobinometria/instrumentação , Hemoglobinometria/métodos , Monitorização Intraoperatória/instrumentação , Monitorização Intraoperatória/métodos , Desenho de Equipamento , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oximetria/instrumentação , Oximetria/métodos , Reprodutibilidade dos Testes
11.
Pharmacopsychiatry ; 45(4): 133-7, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22174025

RESUMO

INTRODUCTION: While patients with schizophrenia are often treated with psychotropic polypharmacy, how and when polypharmacy begins is not well documented. METHODS: A systematic chart review of 300 patients, 100 of whom were psychotropic-free prior to their first visit, was conducted to examine 2-year longitudinal prescription patterns of concomitant psychotropics, in addition to a primary antipsychotic. RESULTS: Overall polypharmacy occurred in 79% patients, with 2-year rates of the use of hypnotics, benzodiazepine derivative anxiolytics, anticholinergic drugs, antidepressants, and mood stabilizers were 56.7, 49.7, 38.3, 21.3, and 14.0%, respectively. Once polypharmacy had started, it was continued until their final visit in >70% of the patients. In a subgroup of 100 psychotropic-free patients, mood stabilizers, antidepressants, anticholinergic antiparkinsonian drugs, anxiolytics, and hypnotics were initiated after 2.3, 2.3, 2.1, 1.6, and 1.5 antipsychotics had been prescribed, respectively (mean duration before the introduction of a concomitant drug in days: 17.7, 121.6, 86.4, 32.1, and, 57.7, respectively). CONCLUSION: Routine practice deviates significantly from algorithms--with polypharmacy often being initiated early, often a without trial of other options, and once started commonly stays.


Assuntos
Antipsicóticos/uso terapêutico , Polimedicação , Esquizofrenia/tratamento farmacológico , Adulto , Ansiolíticos/uso terapêutico , Antidepressivos/uso terapêutico , Feminino , Humanos , Hipnóticos e Sedativos/uso terapêutico , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
12.
J Evol Biol ; 23(2): 249-58, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20021549

RESUMO

High-dispersal rates in heterogeneous environments and historical rapid range expansion can hamper local adaptation; however, we often see clinal variation in high-dispersal tree species. To understand the mechanisms of the species' distribution, we investigated local adaptation and adaptive plasticity in a range-wide context in Sitka spruce, a wind-pollinated tree species that has recently expanded its range after glaciations. Phenotypic traits were observed using growth chamber experiments that mimicked temperature and photoperiodic regimes from the limits of the species realized niche. Bud phenology exhibited parallel reaction norms among populations; however, putatively adaptive plasticity and strong divergent selection were seen in bud burst and bud set timing respectively. Natural selection appears to have favoured genotypes that maximize growth rate during available frost-free periods in each environment. We conclude that Sitka spruce has developed local adaptation and adaptive plasticity throughout its range in response to current climatic conditions despite generally high pollen flow and recent range expansion.


Assuntos
Adaptação Biológica , Clima , Fenótipo , Picea/genética , Fluxo Gênico , Fotoperíodo , Plântula/crescimento & desenvolvimento , Temperatura
13.
eNeurologicalSci ; 10: 19-21, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29430525

RESUMO

Thalamic chronotaraxis is an isolated disorientation of time caused by the damage of thalamus, especially the mediodorsal nucleus. We performed interval timing trials on a patient with this phenomenon. Based on the results of those trials and compared to the previous reports, thalamic chronotaraxis of our case might be due to the disfunction of the dorsolateral prefrontal cortex caused by the right thalamic infarction.

14.
Transl Psychiatry ; 7(9): e1242, 2017 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-28949340

RESUMO

Systematic review of observational studies has revealed that fish consumption and levels of n-3 polyunsaturated fatty acids (PUFAs) such as eicosapentaenoic acid (EPA) and docosahexaenoic acid are associated with a reduced risk of depression. A reverse J-shaped effect of n-3 PUFAs was suggested. However, there is limited evidence from populations with high fish consumption and no studies have used a standard psychiatrist-based diagnosis of major depressive disorder (MDD). Therefore, this population-based, prospective study investigated the association of dietary fish, n-3 PUFA, and n-6 PUFA consumption with risk of psychiatrist-diagnosed MDD in Japan. A total of 12 219 subjects were enrolled from the Saku area in 1990. Of these, we extracted 1181 participants aged 63-82 years who completed food frequency questionnaires in both 1995 and 2000 and also underwent a mental health examination in 2014-2015. Odds ratios (ORs) and 95% confidence intervals (CIs) for MDD according to fish intake and PUFA quartiles were calculated. Current MDD was diagnosed in 95 patients. We found a reduced risk of MDD in the third quartile for fish intake (111.1 g per day, OR=0.44, 95% CI=0.23-0.84), second quartile for EPA (307.7 mg per day, OR=0.54, 95% CI=0.30-0.99) and third quartile for docosapentaenoic acid (DPA) (123.1 mg per day, OR=0.42, 95% CI=0.22-0.85). ORs adjusted for cancer, stroke, myocardial infarction and diabetes remained significant for fish and DPA intake. Our results suggest that moderate fish intake could be recommended for the prevention of MDD in aged Japanese individuals.


Assuntos
Transtorno Depressivo Maior/epidemiologia , Dieta , Ácidos Graxos Ômega-3 , Alimentos Marinhos , Idoso , Idoso de 80 Anos ou mais , Transtorno Depressivo Maior/prevenção & controle , Ácidos Graxos Ômega-6 , Feminino , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco
15.
Eur Psychiatry ; 46: 42-47, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28992535

RESUMO

BACKGROUND: Health-related quality of life (HRQOL) is significantly affected in individuals with schizophrenia or bipolar I disorder (BD-I). The current study investigated whether symptomatic remission and resilience might differently impact HRQOL in these patients. METHODS: Fifty-two patients with schizophrenia and 60 patients suffering from BD-I from outpatient mental health services as well as 77 healthy control subjects from the general community were included into a cross-sectional study. HRQOL and resilience were assessed using the WHOQOL-BREF and the Resilience Scale. In patients, psychopathology was quantified by the Positive and Negative Syndrome Scale or the Montgomery Asberg Depression Rating Scale and the Young Mania Rating Scale, respectively. RESULTS: Notably, both patient groups showed lower HRQOL and resilience compared to control subjects, non-remitted patients indicated lower HRQOL than remitted ones. The effect of remission on HRQOL was significantly larger in patients with BD-I than in those with schizophrenia but did not explain the difference in HRQOL between groups. Resilience predicted HRQOL in all three groups. When accounting for the effect of resilience among remitted patients, only the difference in HRQOL between schizophrenia patients and control subjects was significant. CONCLUSION: These findings demonstrate the impact of symptomatic remission and resilience on HRQOL of both patients suffering from schizophrenia and BD-I and indicate that these factors are especially relevant for HRQOL of patients with BD-I.


Assuntos
Transtorno Bipolar/psicologia , Qualidade de Vida , Psicologia do Esquizofrênico , Adulto , Estudos Transversais , Feminino , Humanos , Masculino , Remissão Espontânea , Resiliência Psicológica
16.
Neuroscience ; 295: 80-9, 2015 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-25818554

RESUMO

Working memory (WM) impairment has received attention as a behavioral characteristic of schizophrenia. Neurobiological studies have led to the hypothesis that a deficit in dopamine transmission through D1 receptors in the prefrontal cortex (PFC) is associated with WM impairment in schizophrenia. However, empirical approaches that aim to clarify the nature of the impairment and its underlying mechanism are difficult to enact, especially in unmedicated patients. By contrast, computational approaches using biologically plausible models have formed a powerful theoretical framework for the study of WM impairment in schizophrenia. This article attempts to directly connect neurobiological findings to the neuropsychological behaviors present in patients with schizophrenia. Using a biologically plausible prefrontal cortical circuit model, we simulated sustained activity during a simultaneous, multi-target WM task. We subsequently analyzed how dopaminergic modulation via D1 receptor activation alters the capacity and precision of WM and investigated the underlying mechanism. Hypodopaminergic modulation resulted in imprecision and a reduced capacity in WM primarily due to decreased N-methyl-d-aspartate (NMDA) conductance. Increasing NMDA conductance ameliorated both impairments. These results account for the mechanism that underlies WM impairments in schizophrenia and provide a theoretical basis for combination therapy with antipsychotic drugs and drugs that enhance NMDA receptor function, which is expected to be effective for the treatment of WM impairments in these patients.


Assuntos
Simulação por Computador , Dopamina/metabolismo , Memória de Curto Prazo/fisiologia , Modelos Neurológicos , Rede Nervosa/fisiologia , Neurônios/fisiologia , Dopaminérgicos/farmacologia , Humanos , Memória de Curto Prazo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Esquizofrenia/patologia , Esquizofrenia/fisiopatologia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia
17.
J Med Chem ; 44(24): 4082-91, 2001 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-11708912

RESUMO

In the joint experimental and computational efforts reported here to obtain novel chemical entities as growth hormone secretagogues (GHSs), a small database of peptides and non-peptides known to have GHS activity was used to generate and assess a 3D pharmacophore for this activity. This pharmacophore was obtained using a systematic and efficient procedure, "DistComp", developed in our laboratory. The 3D pharmacophore identified was then used to search 3D databases to explore chemical structures that could be novel GHSs. A number of these were chosen for synthesis and assessment of their ability to release growth hormone (GH) from rat pituitary cells. Among the compounds tested, those with a benzothiazepin scaffold were discovered with micromolar activity. To facilitate lead optimization, a second program, a site-dependent fragment QSAR procedure was developed. This program calculates a library of chemical and physical properties of "fragments" or chemical components in a known pharmacophore and determines which, if any, of these properties are important for the observed activity. The combined use of the 3D pharmacophore and the results of the site-dependent fragment QSAR analysis led to the discovery and synthesis of a novel series of potent GHSs, a number of which had nanomolar in vitro activity.


Assuntos
Hormônio do Crescimento/metabolismo , Tiazepinas/síntese química , Animais , Bases de Dados Factuais , Desenho de Fármacos , Hormônio do Crescimento/agonistas , Hormônio do Crescimento/química , Técnicas In Vitro , Modelos Moleculares , Mimetismo Molecular , Adeno-Hipófise/citologia , Adeno-Hipófise/metabolismo , Relação Quantitativa Estrutura-Atividade , Ratos , Tiazepinas/química , Tiazepinas/farmacologia
18.
Biochem Pharmacol ; 48(7): 1524-7, 1994 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-7945454

RESUMO

Differences in the catalytic roles of rat and human cytochrome P450 2A enzymes in testosterone 7 alpha- and coumarin 7-hydroxylase activities were examined. Liver microsomes from 18 human samples catalyzed coumarin 7-hydroxylation at a mean rate of about 60 pmol/min/nmol P450, but did not show any measurable activity for testosterone 7 alpha-hydroxylation. In rats, both activities were found to be developmentally regulated; 3-week-old rats had the highest activities for these two reactions. Anti-P450 2A1 antibodies and methoxsalen, a potent inhibitor of P450 2A-dependent monooxygenase activities in several animal species, inhibited almost completely both testosterone 7 alpha- and coumarin 7-hydroxylations catalyzed by liver microsomes prepared from 3-week-old male rats. Interestingly, although Km values for coumarin 7-hydroxylation activities in liver microsomes from 3-week-old rats were not different from those of adult humans, the Vmax value in rats was only 1/30 of that obtained in 18 human samples. Thus, the present results support the view that marked differences exist in the catalytic roles of rat and human P450 2A enzymes, which, in turn, may sometimes cause species-related differences in susceptibilities toward drug actions and toxicities.


Assuntos
Hidrocarboneto de Aril Hidroxilases , Sistema Enzimático do Citocromo P-450/metabolismo , Microssomos Hepáticos/enzimologia , Oxigenases de Função Mista/metabolismo , Esteroide Hidroxilases/metabolismo , Envelhecimento , Animais , Citocromo P-450 CYP2A6 , Feminino , Humanos , Hidroxitestosteronas/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Especificidade da Espécie
19.
Biochem Pharmacol ; 47(11): 1957-63, 1994 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-7912070

RESUMO

Bufuralol hydroxylation activities of liver microsomal cytochrome P450 (P450) enzymes were studied in the rat; the reaction has been used widely in determining levels of liver microsomal P450 2D6, which shows debrisoquine-type genetic polymorphism in humans. Liver microsomes catalyzed the conversion of bufuralol to 1'-hydroxybufuralol and a structurally unidentified metabolite (termed here as M-1) in the presence of an NADPH-generating system and molecular oxygen. Bufuralol 1'-hydroxylation activities catalyzed by the liver microsomes were not increased in rats treated with several P450 inducers, whereas beta-naphthoflavone treatment (and to a lesser extent that of isosafrole) caused a significant induction of M-1 formation. The major role of P450 1A1/2 in M-1 formation was confirmed by catalytic inhibition with anti-P450 antibodies and alpha-naphthoflavone in liver microsomes of beta-naphthoflavone-treated rats, and by reconstitution experiments containing P450 1A1 and 1A2. Among nine forms of purified rat P450 enzymes studied in the reconstituted system, P450 2C11 displayed the highest activities for bufuralol 1'-hydroxylation, followed by P450 1A1 and P450 2D1. A female-specific form of P450 2C12 did not catalyze bufuralol 1'-hydroxylation. In liver microsomes of male rats, however, P450 2D1 was the dominant enzyme because only anti-P450 2D1 antibodies, and not anti-P450 2C11 and anti-P450 1A1, inhibited the bufuralol hydroxylation activities, and a specific P450 2D1 inhibitor, quinine, caused a dramatic decrease in the hydroxylation activities. The major contribution of P450 2D1 in the bufuralol 1'-hydroxylation activities was also supported by a kinetic analysis of the reconstituted system; P450 2D1 enzyme had a very low Km value (8.4 microM) as compared with those of P450 2C11 (Km = 83 microM) and P450 1A1 (Km = 230 microM). Thus, the present results suggested that different P450 enzymes are involved in the hydroxylation of bufuralol in rat liver microsomes, and the kinetic analysis, as well as immunoinhibition and chemical inhibition experiments, may be of great importance for determining the major roles of P450 enzymes in drug hydroxylation reactions.


Assuntos
Antagonistas Adrenérgicos beta/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Etanolaminas/metabolismo , Isoenzimas/metabolismo , Microssomos Hepáticos/enzimologia , Animais , Anticorpos/farmacologia , Benzoflavonas/farmacologia , Citocromo P-450 CYP1A2 , Inibidores das Enzimas do Citocromo P-450 , Sistema Enzimático do Citocromo P-450/imunologia , Feminino , Hidroxilação , Isoenzimas/antagonistas & inibidores , Isoenzimas/imunologia , Masculino , Oxirredutases/metabolismo , Ratos , Ratos Sprague-Dawley
20.
Biochem Pharmacol ; 51(3): 313-9, 1996 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-8573198

RESUMO

7-Ethoxycoumarin O-deethylation has been used widely as a marker activity for assessing substrate specificities of cytochromes P450 (P450) in liver microsomes of mammals, and extensive studies have shown that in rats and mice the major catalysts are P450 1A1, 1A2, and 2B enzymes. In contrast to findings in experimental animal models, P450 2E1 has been reported to be a principal enzyme involved in 7-ethoxy-coumarin O-deethylation in human livers. In this study, we further examined the roles of individual forms of human P450 involved in 7-ethoxycoumarin O-deethylation using microsomes from different human liver samples and from human lymphoblastoid cells expressing human P450 enzymes and purified P450 enzymes isolated from the membrane of Escherichia coli expressing modified P450 proteins. Kinetic analysis showed that there were at least two different enzymes involved in 7-ethoxycoumarin O-deethylation in different human samples. Samples that contained high amounts of P450 2E1 in liver microsomes showed biphasic curves for O-deethylation with relatively high turnover numbers, whereas P450 1A2-rich samples tended to have low Km values with low Vmax values. Anti-human P450 2E1 antibodies inhibited markedly (P < 0.05) the 7-ethoxycoumarin O-deethylation activities catalyzed by human liver microsomes particularly when examined at a high substrate concentration (200 microM). However, we also found that anti-P450 1A2 antibodies suppressed O-deethylation activities only at a low substrate concentration (10 microM). Recombinant human P450 1A2 was found to have a low Km value for 7-ethoxycoumarin O-deethylation, whereas P450 2E1 showed a high Km value. Of the P450 enzymes examined, P450 1A1 gave the highest O-deethylation activities with a low Km value, although this enzyme is reported to be expressed extrahepatically in humans. Other human P450 enzymes, including P450 2A6, 2C10, 2D6, 3A4, and 3A5, did not show significant O-deethylation activities except that P450 2B6, a minor P450 component in human livers, was found to have a Vmax value similar to that of P450 1A2 and a Km value similar to that of P450 2E1. These results suggest that P450 1A2 is a low Km enzyme for 7-ethoxycoumarin O-deethylation in human liver microsome, although it has a low Vmax value than P450 2E1.


Assuntos
O-Dealquilase 7-Alcoxicumarina/metabolismo , Cumarínicos/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Microssomos Hepáticos/enzimologia , Oxirredutases N-Desmetilantes/metabolismo , Oxirredutases/metabolismo , Citocromo P-450 CYP1A2 , Citocromo P-450 CYP2E1 , Sistema Enzimático do Citocromo P-450/isolamento & purificação , Escherichia coli , Humanos , Cinética , Oxirredutases/isolamento & purificação , Oxirredutases N-Desmetilantes/isolamento & purificação , Proteínas Recombinantes/metabolismo
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