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1.
Ann Neurol ; 80(1): 35-45, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27129611

RESUMO

OBJECTIVE: Aberrant glutamate and γ-aminobutyric acid (GABA) neurotransmission contribute to seizure generation and the epileptic state. However, whether levels of these neurochemicals are abnormal in epileptic patients is unknown. Here, we report on interictal levels of glutamate, glutamine, and GABA in epilepsy patients at seizure onset and nonepileptic sites, cortical lesions, and from patients with poorly localized neocortical epilepsies. METHODS: Subjects (n = 79) were medically refractory epilepsy patients undergoing intracranial electroencephalogram evaluation. Microdialysis probes (n = 125) coupled to depth electrodes were implanted within suspected seizure onset sites and microdialysis samples were obtained during interictal periods. Glutamate, glutamine, and GABA were measured using high-performance liquid chromatography. Probe locations were subsequently classified by consensus of expert epileptologists. RESULTS: Glutamate levels were elevated in epileptogenic (p = 0.03; n = 7), nonlocalized (p < 0.001), and lesional cortical sites (p < 0.001) when compared to nonepileptogenic cortex. Glutamate was also elevated in epileptogenic (p < 0.001) compared to nonepileptogenic hippocampus. There were no statistical differences in GABA or glutamine, although GABA levels showed high variability across patients and groups. INTERPRETATION: Our findings indicate that chronically elevated extracellular glutamate is a common pathological feature among epilepsies with different etiology. Contrary to our predictions, GABA and glutamine levels were not decreased in any of the measured areas. Whereas variability in GABA levels may in part be attributed to the use of GABAergic antiepileptic drugs, the stability in glutamine across patient groups indicate that extracellular glutamine levels are under tighter metabolic regulation than previously thought. Ann Neurol 2016;80:35-45.


Assuntos
Córtex Cerebral/metabolismo , Epilepsia Resistente a Medicamentos/metabolismo , Ácido Glutâmico/metabolismo , Glutamina/metabolismo , Hipocampo/metabolismo , Microdiálise , Ácido gama-Aminobutírico/metabolismo , Adolescente , Adulto , Criança , Eletrodos Implantados , Eletroencefalografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
2.
Epilepsia ; 57(2): 288-97, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26749134

RESUMO

OBJECTIVE: The effect of electrical stimulation on brain glutamate release in humans is unknown. Glutamate is elevated at baseline in the epileptogenic hippocampus of patients with refractory epilepsy, and increases during spontaneous seizures. We examined the effect of 50 Hz stimulation on glutamate release and its relationship to interictal levels in the hippocampus of patients with epilepsy. In addition, we measured basal and stimulated glutamate levels in a subset of these patients where stimulation elicited a seizure. METHODS: Subjects (n = 10) were patients with medically refractory epilepsy who were undergoing intracranial electroencephalography (EEG) evaluation in an epilepsy monitoring unit. Electrical stimulation (50 Hz) was delivered through implanted hippocampal electrodes (n = 11), and microdialysate samples were collected every 2 min. Basal glutamate, changes in glutamate efflux with stimulation, and the relationships between peak stimulation-associated glutamate concentrations, basal zero-flow levels, and stimulated seizures were examined. RESULTS: Stimulation of epileptic hippocampi in patients with refractory epilepsy caused increases in glutamate efflux (p = 0.005, n = 10), and 4 of ten patients experienced brief stimulated seizures. Stimulation-induced increases in glutamate were not observed during the evoked seizures, but rather were related to the elevation in interictal basal glutamate (R(2) = 0.81, p = 0.001). The evoked-seizure group had lower basal glutamate levels than the no-seizure group (p = 0.04), with no stimulation-induced change in glutamate efflux (p = 0.47, n = 4). Conversely, increased glutamate was observed following stimulation in the no-seizure group (p = 0.005, n = 7). Subjects with an atrophic hippocampus had higher basal glutamate levels (p = 0.03, n = 7) and higher stimulation-induced glutamate efflux. SIGNIFICANCE: Electrical stimulation of the epileptic hippocampus either increased extracellular glutamate efflux or induced seizures. The magnitude of stimulated glutamate increase was related to elevation in basal interictal glutamate, suggesting a common mechanism, possibly impaired glutamate metabolism. Divergent mechanisms may exist for seizure induction and increased glutamate in patients with epilepsy. These data highlight the potential risk of 50 Hz stimulation in patients with epilepsy.


Assuntos
Epilepsia Resistente a Medicamentos/metabolismo , Estimulação Elétrica , Ácido Glutâmico/metabolismo , Hipocampo/metabolismo , Convulsões/metabolismo , Adolescente , Adulto , Atrofia , Epilepsia Resistente a Medicamentos/fisiopatologia , Eletrocorticografia , Eletrodos Implantados , Eletroencefalografia , Espaço Extracelular/metabolismo , Feminino , Hipocampo/patologia , Hipocampo/fisiopatologia , Humanos , Masculino , Microdiálise , Pessoa de Meia-Idade , Convulsões/fisiopatologia , Adulto Jovem
3.
J Cogn Neurosci ; 23(10): 2892-904, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20946054

RESUMO

How do animals distinguish between sensations coming from external sources and those resulting from their own actions? A corollary discharge system has evolved that involves the transmission of a copy of motor commands to sensory cortex, where the expected sensation is generated. Through this mechanism, sensations are tagged as coming from self, and responsiveness to them is minimized. The present study investigated whether neural phase synchrony between motor command and auditory cortical areas is related to the suppression of the auditory cortical response. We recorded electrocorticograms from the human brain during a vocalizing/listening task. Neural phase synchrony between Broca's area and auditory cortex in the gamma band (35 to ∼50 Hz) in the 50-msec time window preceding speech onset was greater during vocalizing than during listening to a playback of the same spoken sounds. Because prespeech neural synchrony was correlated (r = -.83, p = .006), with the subsequent suppression of the auditory cortical response to the spoken sound, we hypothesize that phase synchrony in the gamma band between Broca's area and auditory cortex is the neural instantiation of the transmission of a copy of motor commands. We suggest that neural phase synchrony of gamma frequencies may contribute to transmission of corollary discharges in humans.


Assuntos
Córtex Auditivo/fisiopatologia , Mapeamento Encefálico , Sincronização de Fases em Eletroencefalografia/fisiologia , Epilepsia/patologia , Potenciais Evocados Auditivos/fisiologia , Adulto , Análise de Variância , Eletroencefalografia , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Vias Neurais/fisiologia , Tempo de Reação
4.
Front Psychiatry ; 11: 590567, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33391054

RESUMO

Long-term potentiation (LTP) is a form of experience-dependent synaptic plasticity mediated by glutamatergic transmission at N-methyl-D-aspartate receptors (NMDARs). Impaired neuroplasticity has been implicated in the pathophysiology of schizophrenia, possibly due to underlying NMDAR hypofunction. Analogous to the high frequency electrical stimulation used to induce LTP in vitro and in vivo in animal models, repeated high frequency presentation of a visual stimulus in humans in vivo has been shown to induce enduring LTP-like neuroplastic changes in electroencephalography (EEG)-based visual evoked potentials (VEPs) elicited by the stimulus. Using this LTP-like visual plasticity paradigm, we previously showed that visual high-frequency stimulation (VHFS) induced sustained changes in VEP amplitudes in healthy controls, but not in patients with schizophrenia. Here, we extend this prior work by re-analyzing the EEG data underlying the VEPs, focusing on neuroplastic changes in stimulus-evoked EEG oscillatory activity following VHFS. EEG data were recorded from 19 patients with schizophrenia and 21 healthy controls during the visual plasticity paradigm. Event-related EEG oscillations (total power, intertrial phase coherence; ITC) elicited by a standard black and white checkerboard stimulus (~0.83 Hz, several 2-min blocks) were assessed before and after exposure to VHFS with the same stimulus (~8.9 Hz, 2 min). A cluster-based permutation testing approach was applied to time-frequency data to examine LTP-like plasticity effects following VHFS. VHFS enhanced theta band total power and ITC in healthy controls but not in patients with schizophrenia. The magnitude and phase synchrony of theta oscillations in response to a visual stimulus were enhanced for at least 22 min following VHFS, a frequency domain manifestation of LTP-like visual cortical plasticity. These theta oscillation changes are deficient in patients with schizophrenia, consistent with hypothesized NMDA receptor dysfunction.

5.
Epilepsia ; 49(8): 1358-66, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18410365

RESUMO

PURPOSE: Temporal lobe epilepsy (TLE) is associated with smaller hippocampal volume and with elevated extracellular (EC) glutamate levels. We investigated the relationship between the hippocampal volume and glutamate in refractory TLE patients. METHODS: We used quantitative MRI volumetrics to measure the hippocampal volume and zero-flow microdialysis to measure the interictal glutamate, glutamine, and GABA levels in the epileptogenic hippocampus of 17 patients with medication-resistant epilepsy undergoing intracranial EEG evaluation. The relationships between hippocampal volume, neurochemical levels, and relevant clinical factors were examined. RESULTS: Increased EC glutamate in the epileptogenic hippocampus was significantly related to smaller ipsilateral (R(2)= 0.75, p < 0.0001), but not contralateral hippocampal volume when controlled for glutamine and GABA levels, and for clinical factors known to influence hippocampal volume. Glutamate in the atrophic hippocampus was significantly higher (p = 0.008, n = 9), with the threshold for hippocampal atrophy estimated as 5 microM. GABA and glutamine levels in the atrophic and nonatrophic hippocampus were comparable. Decreased hippocampal volume was related to higher seizure frequency (p = 0.008), but not to disease duration or febrile seizure history. None of these clinical factors were related to the neurochemical levels. CONCLUSIONS: We provide evidence for a significant association between increased EC glutamate and decreased ipsilateral epileptogenic hippocampal volume in TLE. Future work will be needed to determine whether the increase in glutamate has a causal relationship with hippocampal atrophy, or whether another, yet unknown factor results in both. This work has implications for the understanding and treatment of epilepsy as well as other neurodegenerative disorders associated with hippocampal atrophy.


Assuntos
Epilepsia do Lobo Temporal/metabolismo , Espaço Extracelular/metabolismo , Ácido Glutâmico/metabolismo , Hipocampo/anatomia & histologia , Imageamento por Ressonância Magnética , Adolescente , Adulto , Atrofia/patologia , Cromatografia Líquida de Alta Pressão , Eletroencefalografia , Epilepsia do Lobo Temporal/patologia , Epilepsia do Lobo Temporal/fisiopatologia , Feminino , Lateralidade Funcional/fisiologia , Hipocampo/patologia , Hipocampo/fisiopatologia , Humanos , Masculino , Microdiálise , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Ácido gama-Aminobutírico/metabolismo
6.
Epilepsy Behav ; 13(1): 12-24, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18346939

RESUMO

Despite our understanding of hormonal influences on central nervous system (CNS) function, there is still much to learn about the pathogenesis of menstrual cycle-linked disorders. A growing literature suggests that the influence of sex steroids on neurological and psychiatric disorders is in part mediated by an aberrant CNS response to neuroactive steroids. Although sex steroids such as estradiol, progesterone, and the progesterone derivative allopregnanolone (ALLO) influence numerous neurotransmitter systems, it is their potent effect on the brain's primary inhibitory and excitatory neurotransmitters gamma-aminobutyric acid (GABA) and glutamate that links the study of premenstrual dysphoric disorder (PMDD) and catamenial epilepsy (CE). After providing an overview of these menstrual cycle-linked disorders, this article focuses on the preclinical and clinical research investigating the role of estradiol and progesterone (via ALLO) in the etiology of PMDD and CE. Through exploration of the phenomenological and neurobiological overlap between CE and PMDD, we aim to highlight areas for future research and development of treatments for menstrual cycle-linked neuropsychiatric disorders.


Assuntos
Epilepsia/metabolismo , Estradiol/metabolismo , Síndrome Pré-Menstrual/metabolismo , Progesterona/metabolismo , Epilepsia/diagnóstico , Epilepsia/terapia , Feminino , Humanos , Síndrome Pré-Menstrual/diagnóstico , Síndrome Pré-Menstrual/terapia
7.
Pharmacol Biochem Behav ; 84(4): 635-43, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16860856

RESUMO

A growing literature suggests that hormonal fluctuations occurring across the menstrual cycle, during and after pregnancy, and during the menopausal transition are associated with onset of affective disorders or exacerbation of existing disorders. This influence of the neuroendocrine system on psychiatric disorders is thought to be mediated by an abnormality in central nervous system response to neuroactive steroids such as estradiol, progesterone, and the progesterone derivative allopregnanolone (ALLO). This interplay is considerably complex as neuroactive steroids modulate the function of multiple neurotransmitter systems throughout various stages of development. While one could choose to study any number of steroid-neurotransmitter interactions, our group in addition to others has focused our investigative efforts on unraveling the contribution of neuroactive steroids to psychiatric syndromes and disorders via their modulation of gamma aminobutyric acid (GABA), the brain's major inhibitory neurotransmitter. The goal of this article is two-fold: to synthesize the clinical and preclinical research focusing on the interplay between neuroactive steroids and GABA as they relate to neuropsychiatric and substance use disorders in women and to integrate data from our laboratory using proton magnetic resonance spectroscopy into this context.


Assuntos
Transtornos Mentais/fisiopatologia , Neurotransmissores/fisiologia , Esteroides/fisiologia , Ácido gama-Aminobutírico/fisiologia , Afeto/fisiologia , Depressão Pós-Parto/fisiopatologia , Feminino , Humanos , Menstruação/psicologia , Gravidez , Complicações na Gravidez/fisiopatologia , Complicações na Gravidez/psicologia , Síndrome Pré-Menstrual/fisiopatologia , Abandono do Hábito de Fumar , Transtornos Relacionados ao Uso de Substâncias/fisiopatologia
8.
Biol Psychiatry ; 54(1): 59-69, 2003 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-12842309

RESUMO

BACKGROUND: Estradiol affects neuronal plasticity, mood, and cognition. We examined the effects of the estrous cycle, acute and chronic estradiol treatments on BDNF mRNA expression in the hippocampus and cortex of female rats. The roles of 5-HT2A receptors and of stress on the BDNF mRNA regulation were also explored. METHODS: BDNF mRNA levels were measured using in situ hybridization at proestrus and estrus, and following acute and chronic estradiol treatment of acutely and chronically ovariectomized (OVX) female rats. Some rats were pretreated with 5-HT2A agonist and antagonist, and another group was subjected to two-hour immobilization stress. RESULTS: BDNF mRNA levels in the dentate gyrus and the medial prefrontal cortex were decreased during estrus, when estradiol levels are highest. Acute estradiol treatment decreased hippocampal BDNF mRNA in acutely OVX rats, but neither acute nor chronic estradiol had effect in chronically OVX rats. Estradiol pretreatment reduced the 5-HT2A receptor-mediated cortical upregulation in BDNF mRNA and did not effect the stress-induced down-regulation of BDNF mRNA in the dentate gyrus. CONCLUSIONS: The duration of the estradiol treatment and the duration of the ovarian hormone deprivation are important factors in the regulation of BDNF synthesis and possibly in the functional outcome of estrogen treatment.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Córtex Cerebral/efeitos dos fármacos , Estradiol/metabolismo , Hipocampo/efeitos dos fármacos , Receptores de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/farmacologia , Estresse Psicológico/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/efeitos dos fármacos , Córtex Cerebral/metabolismo , Estradiol/administração & dosagem , Ciclo Estral/metabolismo , Feminino , Hipocampo/metabolismo , Imobilização , Hibridização In Situ , Ovariectomia , Ratos , Ratos Sprague-Dawley , Receptor 5-HT2A de Serotonina
9.
Am J Psychiatry ; 159(7): 1093-102, 2002 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12091184

RESUMO

OBJECTIVE: Many clinical syndromes in neuropsychiatry suggest focal brain activation. Repetitive transcranial magnetic stimulation (rTMS) has been proposed as a method for selectively altering neural activity. METHOD: Studies assessing effects of "slow" rTMS, administered up to once per second, in normal people and in those with pathological conditions are reviewed. The findings are compared with those of animal studies examining long-term depression and long-term depotentiation through direct electrical stimulation of cortical tissue. RESULTS: Data suggest that slow rTMS reduces cortical excitability, both locally and in functionally linked cortical regions. Preliminary studies of patients with focal dystonia, epileptic seizures, and auditory hallucinations indicate symptom reductions following slow rTMS. Long-term depotentiation exhibits many features congruent with those of slow rTMS, including frequency dependence, spread to functionally linked cortical regions, additive efficacy, and extended duration of effects. CONCLUSIONS: Slow rTMS offers a new method for probing and possibly treating brain hyperexcitability syndromes. Further studies linking slow rTMS to animal models of neuroplasticity are indicated.


Assuntos
Encéfalo/fisiologia , Transtorno Depressivo/terapia , Distúrbios Distônicos/terapia , Epilepsias Parciais/terapia , Alucinações/terapia , Potenciação de Longa Duração/fisiologia , Estimulação Magnética Transcraniana/uso terapêutico , Animais , Encéfalo/fisiopatologia , Córtex Cerebral/fisiologia , Córtex Cerebral/fisiopatologia , Transtorno Depressivo/fisiopatologia , Distúrbios Distônicos/fisiopatologia , Estimulação Elétrica , Epilepsias Parciais/fisiopatologia , Alucinações/fisiopatologia , Humanos , Modelos Neurológicos , Plasticidade Neuronal/fisiologia , Ratos
10.
Neuro Oncol ; 6(1): 65-74, 2004 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-14769143

RESUMO

In individuals with brain tumors, pharmacodynamic and pharmacokinetic studies of therapeutic agents have historically used analyses of drug concentrations in serum or cerebrospinal fluid, which unfortunately do not necessarily reflect concentrations within the tumor and adjacent brain. This review article introduces to neurological and medical oncologists, as well as pharmacologists, the application of microdialysis in monitoring drug metabolism and delivery within the fluid of the interstitial space of brain tumor and its surroundings. Microdialysis samples soluble molecules from the extracellular fluid via a semipermeable membrane at the tip of a probe. In the past decade, it has been used predominantly in neurointensive care in the setting of brain trauma, vasospasm, epilepsy,and intracerebral hemorrhage. At the first Carolyn Frye-Halloran Symposium held at Massachusetts General Hospital in March 2002, the concept of microdialysis was extended to specifically address its possible use in treating brain tumor patients. In doing so we provide a rationale for the use of this technology by a National Cancer Institute consortium, New Approaches to Brain Tumor Therapy, to measure levels of drugs in brain tissue as part of phase 1 trials.


Assuntos
Antineoplásicos/metabolismo , Neoplasias Encefálicas/metabolismo , Microdiálise/métodos , Microdiálise/normas , Animais , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Ensaios Clínicos Fase I como Assunto/instrumentação , Ensaios Clínicos Fase I como Assunto/métodos , Ensaios Clínicos Fase I como Assunto/normas , Avaliação Pré-Clínica de Medicamentos/instrumentação , Avaliação Pré-Clínica de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos/normas , Humanos , Microdiálise/instrumentação
11.
J Child Adolesc Psychopharmacol ; 23(8): 545-57, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24111980

RESUMO

OBJECTIVE: The purpose of this study was to evaluate the short- and long-term efficacy and safety of ziprasidone in children and adolescents with bipolar I disorder. METHODS: Subjects 10-17 years of age with a manic or mixed episode associated with bipolar I disorder participated in a 4 week, randomized, double-blind, placebo-controlled multicenter trial (RCT) followed by a 26 week open-label extension study (OLE). Subjects were randomized 2:1 to initially receive flexible-dose ziprasidone (40-160 mg/day, based on weight) or placebo. Primary outcome was the change in Young Mania Rating Scale (YMRS) scores from baseline. Safety assessments included weight and body mass index (BMI), adverse events (AEs), vital signs, laboratory measures, electrocardiograms, and movement disorder ratings. RESULTS: In the RCT, 237 subjects were treated with ziprasidone (n=149; mean age, 13.6 years) or placebo (n=88; mean age, 13.7 years). The estimated least squares mean changes in YMRS total (intent-to-treat population) were -13.83 (ziprasidone) and -8.61 (placebo; p=0.0005) at RCT endpoint. The most common AEs in the ziprasidone group were sedation (32.9%), somnolence (24.8%), headache (22.1%), fatigue (15.4%), and nausea (14.1%). In the OLE, 162 subjects were enrolled, and the median duration of treatment was 98 days. The mean change in YMRS score from the end of the RCT to the end of the OLE (last observation carried forward) was -3.3 (95% confidence interval, -5.0 to -1.6). The most common AEs were sedation (26.5%), somnolence (23.5%), headache (22.2%), and insomnia (13.6%). For both the RCT and the OLE, no clinically significant mean changes in movement disorder scales, BMI z-scores, liver enzymes, or fasting lipids and glucose were observed. One subject on ziprasidone in the RCT and none during the OLE had Fridericia-corrected QT interval (QTcF) ≥ 460 ms. CONCLUSION: These results demonstrate that ziprasidone is efficacious for treating children and adolescents with bipolar disorder. Ziprasidone was generally well tolerated with a neutral metabolic profile. CLINICAL TRIALS REGISTRY: NCT00257166 and NCT00265330 at ClinicalTrials.gov.


Assuntos
Antipsicóticos/efeitos adversos , Antipsicóticos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Piperazinas/efeitos adversos , Piperazinas/uso terapêutico , Tiazóis/efeitos adversos , Tiazóis/uso terapêutico , Adolescente , Criança , Método Duplo-Cego , Feminino , Humanos , Masculino , Resultado do Tratamento
12.
J Child Adolesc Psychopharmacol ; 23(8): 531-44, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24111983

RESUMO

OBJECTIVE: The purpose of this study was to evaluate the short- and long-term efficacy, safety, and tolerability of ziprasidone in adolescents with schizophrenia. METHODS: Subjects ages 13-17 years with schizophrenia (American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. [DSM-IV]) were enrolled in a 6 week, randomized, double-blind, placebo-controlled multicenter trial (RCT) followed by a 26 week open-label extension study (OLE). Subjects were randomized in a 2:1 ratio to flexible-dose oral ziprasidone (40-160 mg/day, based on weight) or placebo. Primary end-point was change from baseline in Brief Psychiatric Rating Scale-Anchored (BPRS-A) total score. Safety assessments included adverse events, vital signs, laboratory measures, electrocardiograms, weight and body mass index, and movement disorder ratings. RESULTS: Planned interim analysis for the primary end-point in the RCT resulted in early termination of both studies because of futility. In the RCT, 283 subjects received ziprasidone (n=193) or placebo (n=90). In the intent-to-treat analysis population, the least squares mean (SE) BPRS-A score decrease from baseline at week 6 was not significantly different (p=0.15; -14.16 [0.78] for ziprasidone and -12.35 [1.05] for placebo). Per-protocol analysis was significant (p=0.02). In the OLE, 221 subjects entered the OLE and received ziprasidone for a median of 99 days. The mean (SD) change in BPRS-A score from end of RCT to end of OLE (last observation carried forward) was -6.9 (8.9). The most common treatment-emergent adverse events (≥ 10%) for all causalities during the RCT were somnolence and extrapyramidal disorders, and during OLE was somnolence only. No subjects had Fridericia's corrected QT (QTcF) ≥ 500 ms in the RCT or OLE phases. One completed suicide occurred during the OLE phase. For RCT and OLE, no clinically significant changes were reported in metabolic indices and laboratory measures. CONCLUSIONS: Ziprasidone failed to separate from placebo in treatment of schizophrenia in adolescents. Ziprasidone was generally well tolerated with an overall neutral weight and metabolic profile. CLINICAL TRIALS REGISTRY: NCT00257192 and NCT00265382 at ClinicalTrials.gov .


Assuntos
Antipsicóticos/efeitos adversos , Antipsicóticos/uso terapêutico , Piperazinas/efeitos adversos , Piperazinas/uso terapêutico , Esquizofrenia/tratamento farmacológico , Tiazóis/efeitos adversos , Tiazóis/uso terapêutico , Adolescente , Método Duplo-Cego , Término Precoce de Ensaios Clínicos , Feminino , Humanos , Masculino , Placebos , Resultado do Tratamento
14.
J Clin Psychiatry ; 73(11): 1412-9, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23218157

RESUMO

OBJECTIVE: To assess the efficacy and safety of adjunctive ziprasidone in subjects with acute mania treated with lithium or divalproex, with an inadequate response to the mood stabilizer. METHOD: The study enrolled subjects aged 18-65 years who had a primary DSM-IV diagnosis of bipolar I disorder, with the most recent episode manic or mixed, with or without rapid cycling, and a Young Mania Rating Scale (YMRS) score ≥ 18. Subjects were randomized under double-blind conditions to receive ziprasidone, 20 to 40 mg (n = 226) or 60 to 80 mg (n = 232), or placebo (n = 222) twice a day for 3 weeks in addition to their mood stabilizer. The primary efficacy variable was change in YMRS scores from baseline to 3 weeks. Secondary efficacy measures included the Montgomery-Asberg Depression Rating Scale, Positive and Negative Syndrome Scale, Clinical Global Impressions-Severity of Illness and -Improvement scales, and Global Assessment of Functioning. Computer-administered YMRS was included for quality control and to evaluate study performance. The study was conducted between April 2006 and December 2008. RESULTS: Least-squares mean ± standard error changes in YMRS scores from baseline to week 3 were -10.2 ± 0.80 in the mood stabilizer + ziprasidone 60- to 80-mg group, -11.0 ± 0.80 in the mood stabilizer + ziprasidone 20- to 40-mg group, and -9.5 ± 0.80 in the mood stabilizer + placebo group. Mean treatment differences between adjunctive ziprasidone groups and placebo were not statistically significant on primary or secondary efficacy measures. Ziprasidone was well tolerated. CONCLUSIONS: Adjunctive ziprasidone treatment failed to separate from mood stabilizer (lithium or divalproex) treatment on primary and secondary end points. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00312494.


Assuntos
Antimaníacos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Carbonato de Lítio/uso terapêutico , Piperazinas/uso terapêutico , Tiazóis/uso terapêutico , Ácido Valproico/uso terapêutico , Administração Oral , Adolescente , Adulto , Antimaníacos/efeitos adversos , Doenças dos Gânglios da Base/induzido quimicamente , Doenças dos Gânglios da Base/diagnóstico , Transtorno Bipolar/diagnóstico , Transtorno Bipolar/psicologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Carbonato de Lítio/efeitos adversos , Masculino , Pessoa de Meia-Idade , Piperazinas/efeitos adversos , Escalas de Graduação Psiquiátrica , Tiazóis/efeitos adversos , Resultado do Tratamento , Ácido Valproico/efeitos adversos , Adulto Jovem
15.
J Clin Psychiatry ; 73(11): 1420-5, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23218158

RESUMO

OBJECTIVES: High failure rates of randomized controlled trials (RCTs) are well recognized but poorly understood. We report exploratory analyses from an adjunctive ziprasidone double-blind RCT in adults with bipolar I disorder (reported in part 1 of this article). Data collected by computer interviews and by site-based raters were analyzed to examine the impact of eligibility criteria on signal detection. METHOD: Clinical assessments and a remote monitoring system, including a computer-administered Young Mania Rating Scale (YMRS(Comp)) were used to categorize subjects as eligible or ineligible on 3 key protocol-specified eligibility criteria. Data analyses compared treatment efficacy for eligible versus ineligible subgroups. All statistical analyses reported here are exploratory. Criteria were considered "impactful" if the difference between eligible and ineligible subjects on the YMRS change scores was ≥ 1 point. RESULTS: 504 subjects had baseline and ≥ 1 post-randomization computer-administered assessments but only 180 (35.7%) met all 3 eligibility criteria based on computer assessments. There were no statistically significant differences between treatment groups in change from baseline YMRS score on the basis of site-based rater or computer assessments. All criteria tested improved signal detection except the entry criteria excluding subjects with ≥ 25% improvement from screen to baseline. CONCLUSIONS: On the basis of computer assessments, nearly two-thirds of randomized subjects did not meet at least 1 protocol-specified eligibility criterion. These results suggest enrollment of ineligible subjects is likely to contribute to failure of acute efficacy studies. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00312494.


Assuntos
Antimaníacos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Carbonato de Lítio/uso terapêutico , Seleção de Pacientes , Piperazinas/uso terapêutico , Detecção de Sinal Psicológico/efeitos dos fármacos , Tiazóis/uso terapêutico , Ácido Valproico/uso terapêutico , Administração Oral , Adolescente , Adulto , Antimaníacos/efeitos adversos , Transtorno Bipolar/diagnóstico , Transtorno Bipolar/psicologia , Diagnóstico por Computador , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Humanos , Entrevista Psicológica , Carbonato de Lítio/efeitos adversos , Masculino , Pessoa de Meia-Idade , Piperazinas/efeitos adversos , Escalas de Graduação Psiquiátrica/estatística & dados numéricos , Psicometria , Projetos de Pesquisa , Tiazóis/efeitos adversos , Resultado do Tratamento , Ácido Valproico/efeitos adversos , Adulto Jovem
16.
Biol Psychiatry ; 71(6): 512-20, 2012 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-22364738

RESUMO

BACKGROUND: Impaired cortical plasticity may be part of the core pathophysiology of schizophrenia (SZ). Long-term potentiation is a form of neuroplasticity that has been recently demonstrated in humans by showing that repetitive visual stimulation produces lasting enhancement of visual evoked potentials (VEP). Using this paradigm, we examined whether visual cortical plasticity is impaired in SZ. METHODS: Electroencephalographic data were recorded from 19 SZ and 22 healthy control (HC) subjects during a visual long-term potentiation paradigm. Visual evoked potentials were elicited by standard visual stimuli (∼.83 Hz, 2-minute blocks) at baseline and at 2, 4, and 20 minutes following exposure to visual high-frequency stimulation (HFS) (∼8.8 Hz, 2 minutes) designed to induce VEP potentiation. To ensure attentiveness during VEP assessments, subjects responded with a button press to infrequent (10%) target stimuli. Visual evoked potentials were subjected to principal components analysis. Two negative-voltage components prominent over occipital-parietal electrode sites were evident at 92 msec (C1) and at 146 msec (N1b). Changes in C1 and N1b component scores from baseline to the post-HFS assessments were compared between groups. RESULTS: High-frequency stimulation produced sustained potentiation of visual C1 and N1b in HCs but not in SZs. The HCs and SZs had comparable HFS-driven electroencephalographic visual steady state responses. However, greater visual steady state responses to the HFS predicted greater N1b potentiation in HCs but not in SZs. Schizophrenia patients with greater N1b potentiation decreased their reaction times to target stimuli. CONCLUSIONS: Visual cortical plasticity is impaired in schizophrenia, consistent with hypothesized deficits in N-methyl-D-aspartate receptor function.


Assuntos
Potenciais Evocados Visuais , Plasticidade Neuronal , Esquizofrenia/fisiopatologia , Córtex Visual/fisiopatologia , Adulto , Eletroencefalografia , Feminino , Humanos , Masculino , Estimulação Luminosa , Tempo de Reação , Fatores de Tempo
17.
J Psychiatr Pract ; 17(2): 100-9, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21430488

RESUMO

OBJECTIVE: The objectives of this study were to evaluate the effects of switching from quetiapine to ziprasidone on weight, safety, and effectiveness METHODS: In this study, 241 subjects with schizophrenia or schizo affective disorder who had been treated with quetiapine (≥300 mg/day) for ≥3 months with either suboptimal efficacy or poor tolerability were enrolled in a 16-week, open-label, flexible-dose trial, with a 16-week follow-up (total 32 weeks). Quetiapine was tapered and discontinued over the course of 2 weeks, while ziprasidone was titrated up and dosed at 40-80 mg b.i.d. The primary endpoint was weight change (kg) from baseline at 16 weeks. Secondary endpoints were change in waist/hip circumference, lipid profile, fasting glucose, and glycosylated hemoglobin (HbA1c). Additional secondary endpoints included changes in scores on the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impressions Improvement and Severity Scales (CGI-I and CGI-S), the Calgary Depression Scale for Schizophrenia (CDSS), the Schizophrenia Cognition Rating Scale (ScoRS), and the Global Assessment of Functioning (GAF). Safety measures included adverse event (AE) reporting and administration of the Abnormal Involuntary Movement Scale (AIMS). RESULTS: At week 16, there was a small but statistically significant decrease in weight, with a mean change from baseline of -0.73 kg (1-sided 95% upper confidence bound=-0.33) using the last observation carried forward [LOCF] approach. There were small mean decreases in levels of total cholesterol, low density lipoprotein (LDL), and triglycerides at week 16, but no change in fasting glucose or HbA1c. At week 16, there were also significant changes indicating improvement in the secondary clinical assessments, including the PANSS scores, CGI-S, CDSS, SCoRS and GAF. There was no change in the AIMS. AEs included insomnia (12.4%), somnolence (13.7%), and nausea (9.1%). CONCLUSION: Subjects switching from quetiapine to ziprasidone showed a small but significant decrease in weight as well as improved lipid profiles, regardless of their metabolic status and disease severity at baseline. Subjects also showed improvement in clinical symptoms and in cognitive functioning. Ziprasidone, with a comparatively neutral metabolic profile relative to other antipsychotics, may be an effective treatment alternative for patients experiencing weight gain or lack of tolerability with quetiapine.


Assuntos
Antipsicóticos/efeitos adversos , Dibenzotiazepinas/efeitos adversos , Piperazinas/efeitos adversos , Transtornos Psicóticos/tratamento farmacológico , Esquizofrenia/tratamento farmacológico , Tiazóis/efeitos adversos , Adolescente , Adulto , Antipsicóticos/administração & dosagem , Glicemia , Peso Corporal/efeitos dos fármacos , Colesterol/sangue , Cognição/efeitos dos fármacos , Dibenzotiazepinas/administração & dosagem , Esquema de Medicação , Feminino , Hemoglobinas Glicadas , Humanos , Masculino , Pessoa de Meia-Idade , Pacientes Ambulatoriais , Piperazinas/administração & dosagem , Escalas de Graduação Psiquiátrica , Fumarato de Quetiapina , Tiazóis/administração & dosagem , Resultado do Tratamento , Triglicerídeos/sangue , Adulto Jovem
18.
Wiley Interdiscip Rev Cogn Sci ; 1(5): 766-773, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26271660

RESUMO

Long-term potentiation (LTP) is the principal candidate synaptic mechanism underlying learning and memory, and has been studied extensively at the cellular and molecular level in laboratory animals. Inquiry into the functional significance of LTP has been hindered by the absence of a human model as, until recently, LTP has only been directly demonstrated in humans in isolated cortical tissue obtained from patients undergoing surgery, where it displays properties identical to those seen in non-human preparations. In this brief review, we describe the results of paradigms recently developed in our laboratory for inducing LTP-like changes in visual-, and auditory-evoked potentials. We describe how rapid, repetitive presentation of sensory stimuli leads to a persistent enhancement of components of sensory-evoked potential in normal humans. Experiments to date, investigating the locus, stimulus specificity, and NMDA receptor dependence of these LTP-like changes suggest that they have the essential characteristics of LTP seen in experimental animals. The ability to elicit LTP from non-surgical patients will provide a human model system allowing the detailed examination of synaptic plasticity in normal subjects and may have future clinical applications in the assessment of cognitive disorders. Copyright © 2010 John Wiley & Sons, Ltd. For further resources related to this article, please visit the WIREs website.

19.
Epilepsia ; 49 Suppl 3: 31-41, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18304254

RESUMO

PURPOSE: Because of the large and continuous energetic requirements of brain function, neurometabolic dysfunction is a key pathophysiologic aspect of the epileptic brain. Additionally, neurometabolic dysfunction has many self-propagating features that are typical of epileptogenic processes, that is, where each occurrence makes the likelihood of further mitochondrial and energetic injury more probable. Thus abnormal neurometabolism may be not only a chronic accompaniment of the epileptic brain, but also a direct contributor to epileptogenesis. METHODS: We examine the evidence for neurometabolic dysfunction in epilepsy, integrating human studies of metabolic imaging, electrophysiology, microdialysis, as well as intracranial EEG and neuropathology. RESULTS: As an approach of noninvasive functional imaging, quantitative magnetic resonance spectroscopic imaging (MRSI) measured abnormalities of mitochondrial and energetic dysfunction (via 1H or 31P spectroscopy) are related to several pathophysiologic indices of epileptic dysfunction. With patients undergoing hippocampal resection, intraoperative 13C-glucose turnover studies show a profound decrease in neurotransmitter (glutamate-glutamine) cycling relative to oxidation in the sclerotic hippocampus. Increased extracellular glutamate (which has long been associated with increased seizure likelihood) is significantly linked with declining energetics as measured by 31P MR, as well as with increased EEG measures of Teager energy, further arguing for a direct role of glutamate with hyperexcitability. DISCUSSION: Given the important contribution that metabolic performance makes toward excitability in brain, it is not surprising that numerous aspects of mitochondrial and energetic state link significantly with electrophysiologic and microdialysis measures in human epilepsy. This may be of particular relevance with the self-propagating nature of mitochondrial injury, but may also help define the conditions for which interventions may be developed.


Assuntos
Encefalopatias/metabolismo , Mapeamento Encefálico/métodos , Epilepsia/metabolismo , Doenças Metabólicas/metabolismo , Doenças Mitocondriais/metabolismo , Animais , Encefalopatias/diagnóstico , Encefalopatias/diagnóstico por imagem , Isótopos de Carbono/metabolismo , Dominância Cerebral/fisiologia , Eletrodos Implantados , Eletroencefalografia/métodos , Eletroencefalografia/estatística & dados numéricos , Epilepsia/diagnóstico , Epilepsia/diagnóstico por imagem , Glucose/metabolismo , Hipocampo/diagnóstico por imagem , Hipocampo/metabolismo , Humanos , Sistema Límbico/diagnóstico por imagem , Sistema Límbico/metabolismo , Espectroscopia de Ressonância Magnética/estatística & dados numéricos , Doenças Metabólicas/diagnóstico , Microdiálise/estatística & dados numéricos , Doenças Mitocondriais/diagnóstico , Vias Neurais/diagnóstico por imagem , Vias Neurais/metabolismo , Neurônios/metabolismo , Tomografia por Emissão de Pósitrons/estatística & dados numéricos , Ratos , Transmissão Sináptica/fisiologia , Ácido gama-Aminobutírico/metabolismo , Ácido gama-Aminobutírico/fisiologia
20.
Ann Neurol ; 57(2): 226-35, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15668975

RESUMO

Interictal brain energy metabolism and glutamate-glutamine cycling are impaired in epilepsy and may contribute to seizure generation. We used the zero-flow microdialysis method to measure the extracellular levels of glutamate, glutamine, and the major energy substrates glucose and lactate in the epileptogenic and the nonepileptogenic cortex and hippocampus of 38 awake epileptic patients during the interictal period. Depth electrodes attached to microdialysis probes were used to identify the epileptogenic and the nonepileptogenic sites. The epileptogenic hippocampus had surprisingly high basal glutamate levels, low glutamine/glutamate ratio, high lactate levels, and indication for poor glucose utilization. The epileptogenic cortex had only marginally increased glutamate levels. We propose that interictal energetic deficiency in the epileptogenic hippocampus could contribute to impaired glutamate reuptake and glutamate-glutamine cycling, resulting in persistently increased extracellular glutamate, glial and neuronal toxicity, increased lactate production together with poor lactate and glucose utilization, and ultimately worsening energy metabolism. Our data suggest that a different neurometabolic process underlies the neocortical epilepsies.


Assuntos
Córtex Cerebral/metabolismo , Epilepsia do Lobo Temporal/metabolismo , Líquido Extracelular/química , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Adolescente , Adulto , Cromatografia Líquida de Alta Pressão , Eletroencefalografia , Feminino , Glucose/análise , Glucose/metabolismo , Ácido Glutâmico/análise , Ácido Glutâmico/metabolismo , Glutamina/análise , Glutamina/metabolismo , Humanos , Ácido Láctico/análise , Ácido Láctico/metabolismo , Masculino , Microdiálise , Pessoa de Meia-Idade
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