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Goldberg X.,University of Barcelona | Goldberg X.,Institute Salud Carlos III | Fatjo-Vilas M.,University of Barcelona | Fatjo-Vilas M.,Institute Salud Carlos III | And 7 more authors.
Journal of Psychiatric Research | Year: 2013

The functional variant Val158Met in the coding sequence of COMT gene is involved in the modulation of dopamine availability in the prefrontal cortex in both clinical and general population samples. It has been suggested that the interplay between this genotype and early environmental factors could be used to predict the observed variation in cognitive flexibility. However, other genetic variants and environmental factors may confound the association and produce the inconsistent results commonly found in the literature. In the present study we aimed at testing putative interaction mechanisms between childhood maltreatment and COMT genotypic variability that might explain a proportion of the observed variability of cognitive flexibility in the population. Our design was based on a sample of adult monozygotic twins, which allowed us to test these effects free from potential genetic and shared-environmental confounding factors. Results showed that unique environmental effects of childhood maltreatment significantly impacted cognitive performance among Met/Met subjects. Interestingly, the direction of the association indicated that exposure to early stressful experiences was associated with enhanced cognitive flexibility in this genotype group. These results suggest that COMT may operate as a plasticity gene that provides differential cognitive capacity to respond to environmental stressors. © 2013 Elsevier Ltd.

Sugranyes G.,Institute Of Neurociencies | Thompson J.L.,Columbia University | Corcoran C.M.,Columbia University
Journal of Psychiatric Research | Year: 2012

Aim: Increased basal cortisol secretion has been associated with heightened clinical risk for psychosis, and among at-risk individuals, has been variably related to positive and mood symptoms, as well as clinical outcome. Methods: Basal salivary cortisol secretion was assessed in 33 patients at clinical high risk (CHR) for psychosis (21 medication-free and 12 taking a serotonin reuptake inhibitor and/or atypical antipsychotic), and 13 healthy controls. Among the CHR patients, we also examined associations of basal salivary cortisol with symptoms (positive, negative, mood, stress sensitivity) and clinical outcome. Results: Basal salivary cortisol secretion was significantly higher in CHR patients who were medication-free compared to CHR patients taking medications and to healthy controls. In this small cohort, basal salivary cortisol secretion was associated at trend level with stress sensitivity, and was not significantly related to other symptoms. Conclusions: Our finding of elevated basal cortisol secretion in CHR patients supports the premise that excess activation of the HPA axis and/or neuroendocrine abnormalities characterize the psychosis risk state for at least a subset of patients. Our findings further suggest that psychotropic medications may have a normalizing effect on HPA-axis dysfunction in CHR patients, which could potentially inform intervention strategies for the prodrome. © 2012 Elsevier Ltd.

Pintor L.,Neuroscience Institute | Valldeoriola F.,Institute Of Neurociencies | Fernandez-Egea E.,Neuroscience Institute | Sanchez R.,Institute Of Neuropsiquiatria I Addiccions | And 5 more authors.
Journal of ECT | Year: 2012

INTRODUCTION: Mental dysfunction and especially gait disorders, such as freezing and postural instability in "on phase," are partially unresponsive to dopaminergic therapy late in the course of Parkinson disease (PD). Some of them have been related to decreased sensitivity of postsynaptic dopaminergic receptors, and it is known that electroconvulsive therapy (ECT) enhances the sensitivity of these receptors. The aim of this study was to determine the efficacy and safety of ECT in patients with advanced Parkinson disease with symptoms partially unresponsive to L-dopa. METHODS: Neurologic (Parkinson's Disease Questionnaire, Unified Parkinson's Disease Rating Scale, Tinetti Scale, and the Sit-to-Stand test), psychiatric (structured interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and Hamilton Depression Rating Scale) and neuropsychological (Mini Mental State Examination, executive functions, declarative and procedural memory, visual processing, and reaction time) evaluation was performed on 9 patients with a diagnosis of L-dopa-resistant PD by the Movement Disorders Working Group. This evaluation was done before and after 8 sessions of bitemporal ECT. Six patients completed the study. RESULTS: Statistically significant differences were found in the number of steps and freezing episodes in the on phase when they were compared before and after the ECT administration. However, no statistically significant differences were found in the "off" phenomena, motor fluctuations, or dyskinesias before and after ECT administration. No patient showed psychiatric symptoms before, during, or after the ECT. No statistically significant differences were observed in the neuropsychological results between the pretreatment and posttreatment evaluations. All patients showed transient amnesia after the ECT administration, which lasted for 48 hours. CONCLUSIONS: Electroconvulsive therapy could be a safe and effective therapeutic option in L-dopa-resistant patients with PD with predominantly axial "on" phenomena; nevertheless, it needs to be confirmed in later studies. Copyright © 2012 by Lippincott Williams & Wilkins.

Bolea I.,Institute Of Neurociencies | Juarez-Jimenez J.,Institute Of Biomedicina Ibub | De Los Rios C.,Laboratorio Of Radicales Libres Y Quimica Computacional | Chioua M.,Hospital Universitario Of La Princesa | And 5 more authors.
Journal of Medicinal Chemistry | Year: 2011

A new family of multitarget molecules able to interact with acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as with monoamino oxidase (MAO) A and B, has been synthesized. Novel compounds (3-9) have been designed using a conjunctive approach that combines the benzylpiperidine moiety of the AChE inhibitor donepezil (1) and the indolyl propargylamino moiety of the MAO inhibitor N-[(5-benzyloxy-1-methyl-1H-indol-2- yl)methyl]-N-methylprop-2-yn-1-amine (2), connected through an oligomethylene linker. The most promising hybrid (5) is a potent inhibitor of both MAO-A (IC 50 = 5.2 ± 1.1 nM) and MAO-B (IC 50 = 43 ± 8.0 nM) and is a moderately potent inhibitor of AChE (IC 50 = 0.35 ± 0.01 μM) and BuChE (IC 50 = 0.46 ± 0.06 μM). Moreover, molecular modeling and kinetic studies support the dual binding site to AChE, which explains the inhibitory effect exerted on Aβ aggregation. Overall, the results suggest that the new compounds are promising multitarget drug candidates with potential impact for Alzheimer's disease therapy. (Figure presented) © 2011 American Chemical Society.

Modol L.,Autonomous University of Barcelona | Casas C.,Institute Of Neurociencies | Llido A.,Autonomous University of Barcelona | Navarro X.,Institute Of Neurociencies | And 2 more authors.
Journal of Steroid Biochemistry and Molecular Biology | Year: 2014

The maintenance of levels of endogenous neurosteroids (NS) across early postnatal development of the brain, particularly to the hippocampus, is crucial for their maturation. Allopregnanolone (Allop) is a NS that exerts its effect mainly through the modulation of the GABAA receptor (GABAAR). During early development, GABA, acting through GABAAR, that predominantly produces depolarization shifts to hyperpolarization in mature neurons, around the second postnatal week in rats. Several factors contribute to this change including the progressive increase of the neuron-specific K+/Cl- co-transporter 2 (KCC2) (a chloride exporter) levels. Thus, we aimed to analyze whether a different profile of NS levels during development is critical and can alter this natural progression of KCC2 stages. We administrated sustained Allop (20 mg/kg) or Finasteride (5α-reductase inhibitor, 50 mg/kg) from the 5th postnatal day (PD5) to PD9 and assessed changes in the hippocampal expression of KCC2 at transcript and protein levels as well as its active phosphorylated state in male rats. Taken together data indicated that manipulation of NS levels during early development influence KCC2 levels and point out the importance of neonatal NS levels for the hippocampal development. © 2014 Elsevier Ltd.

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