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Clozapine working memory

Deanna L Kelly, Kelli M Sullivan, Joseph P McEvoy, Robert P McMahon, Heidi J Wehring, James M Gold, Fang Liu, Dale Warfel, Gopal Vyas, Charles M Richardson, Bernard A Fischer, William R Keller, Maju Mathew Koola, Stephanie M Feldman, Jessica C Russ, Richard S E Keefe, Jennifer Osing, Leeka Hubzin, Sharon August, Trina M Walker, Robert W Buchanan
OBJECTIVE: Clozapine is the most effective antipsychotic for treatment refractory people with schizophrenia, yet many patients only partially respond. Accumulating preclinical and clinical data suggest benefits with minocycline. We tested adjunct minocycline to clozapine in a 10-week, double-blind, placebo-controlled trial. Primary outcomes tested were positive, and cognitive symptoms, while avolition, anxiety/depression, and negative symptoms were secondary outcomes. METHODS: Schizophrenia and schizoaffective participants (n = 52) with persistent positive symptoms were randomized to receive adjunct minocycline (100 mg oral capsule twice daily; n = 29) or placebo (n = 23)...
August 2015: Journal of Clinical Psychopharmacology
Herbert Y Meltzer
No abstract text is available yet for this article.
June 2015: American Journal of Psychiatry
Germana Silva Vasconcelos, Naiara Coelho Ximenes, Caren Nádia Soares de Sousa, Tatiana de Queiroz Oliveira, Laio Ladislau Lopes Lima, David Freitas de Lucena, Clarissa Severino Gama, Danielle Macêdo, Silvânia Maria Mendes Vasconcelos
Oxidative stress has important implications in schizophrenia. Alpha-lipoic acid (ALA) is a natural antioxidant synthesized in human tissues with clinical uses. We studied the effect of ALA or clozapine (CLZ) alone or in combination in the reversal of schizophrenia-like alterations induced by ketamine (KET). Adult male mice received saline or KET for 14 days. From 8th to 14th days mice were additionally administered saline, ALA (100 mg/kg), CLZ 2.5 or 5 mg/kg or the combinations ALA+CLZ2.5 or ALA+CLZ5. Schizophrenia-like symptoms were evaluated by prepulse inhibition of the startle (PPI) and locomotor activity (positive-like), social preference (negative-like) and Y maze (cognitive-like)...
July 2015: Schizophrenia Research
Tarek K Rajji, Benoit H Mulsant, Simon Davies, Sawsan M Kalache, Christopher Tsoutsoulas, Bruce G Pollock, Gary Remington
OBJECTIVE: Clozapine's potent antagonism of muscarinic M1 receptors is thought to worsen working memory deficits associated with schizophrenia. In contrast, its major metabolite, N-desmethylclozapine (NDMC), is thought to enhance working memory via its M1 receptor agonist activity. The authors hypothesized that the ratio of serum clozapine and NDMC concentrations would be inversely associated with working memory performance in schizophrenia. METHOD: Thirty patients with schizophrenia or schizoaffective disorder who were receiving clozapine monotherapy at bedtime completed the MATRICS Consensus Cognitive Battery (MCCB) on the day their blood was collected to assess concentrations of clozapine and NDMC as well as serum anticholinergic activity...
June 2015: American Journal of Psychiatry
Ashley M Fortress, Eric D Hamlett, Elena M Vazey, Gary Aston-Jones, Wayne A Cass, Heather A Boger, Ann-Charlotte E Granholm
Designer receptors exclusively activated by designer drugs (DREADDs) are novel and powerful tools to investigate discrete neuronal populations in the brain. We have used DREADDs to stimulate degenerating neurons in a Down syndrome (DS) model, Ts65Dn mice. Individuals with DS develop Alzheimer's disease (AD) neuropathology and have elevated risk for dementia starting in their 30s and 40s. Individuals with DS often exhibit working memory deficits coupled with degeneration of the locus coeruleus (LC) norepinephrine (NE) neurons...
January 28, 2015: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
R E Nielsen, S Levander, G Kjaersdam Telléus, S O W Jensen, T Østergaard Christensen, S Leucht
OBJECTIVE: To investigate the effect of second-generation antipsychotics on cognitive function in patients diagnosed with schizophrenia or schizoaffective disorder. METHOD: Multiple-treatments meta-analysis model. RESULTS: On cognitive composite score, sertindole was superior to clozapine, effect size (ES) 0.87; 95% CI: 0.12-1.63, quetiapine, ES 0.75; 95% CI: 0.00-1.49, and first-generation antipsychotics (FGAs), ES 0.89; 95% CI: 0.14-1.64...
March 2015: Acta Psychiatrica Scandinavica
Paul C Baier, Magdalena M Brzózka, Ali Shahmoradi, Lisa Reinecke, Christina Kroos, Sven P Wichert, Henrik Oster, Michael C Wehr, Reshma Taneja, Johannes Hirrlinger, Moritz J Rossner
Increasing evidence suggests that clock genes may be implicated in a spectrum of psychiatric diseases, including sleep and mood related disorders as well as schizophrenia. The bHLH transcription factors SHARP1/DEC2/BHLHE41 and SHARP2/DEC1/BHLHE40 are modulators of the circadian system and SHARP1/DEC2/BHLHE40 has been shown to regulate homeostatic sleep drive in humans. In this study, we characterized Sharp1 and Sharp2 double mutant mice (S1/2-/-) using online EEG recordings in living animals, behavioral assays and global gene expression profiling...
2014: PloS One
Frederike Schirmbeck, Daniela Mier, Christine Esslinger, Franziska Rausch, Susanne Englisch, Sarah Eifler, Andreas Meyer-Lindenberg, Peter Kirsch, Mathias Zink
BACKGROUND: Patients with schizophrenia have an approximately 10-fold higher risk for obsessive-compulsive symptoms (OCS) than the general population. A large subgroup seems to experience OCS as a consequence of second-generation antipsychotic agents (SGA), such as clozapine. So far little is known about underlying neural mechanisms. METHODS: To investigate the role of SGA treatment on neural processing related to OCS in patients with schizophrenia, we stratified patients according to their monotherapy into 2 groups (group I: clozapine or olanzapine; group II: amisulpride or aripiprazole)...
March 2015: Journal of Psychiatry & Neuroscience: JPN
Vicente Molina, Diana Taboada, María Aragüés, Juan A Hernández, Javier Sanz-Fuentenebro
Cortical thickness may be useful as a treatment response predictor in first-episode (FE) patients with schizophrenia, although this possibility has been scarcely assessed. In this study we assessed the possible relation between cortical thickness in regions of interest selected because of previously reported structural alterations in schizophrenia and clinical and cognitive changes after two years of treatment with risperidone or clozapine in 31 neuroleptic-naïve FE patients with schizophrenia (16 of them treated with clozapine and 15 with risperidone)...
September 2014: Schizophrenia Research
Mar Carceller-Sindreu, Maria J Portella, Cristina Carmona, Giuseppina Rametti, Dolors Puigdemont, María Figueras, Aina Fernández-Vidal, Laia Villalta, Enric Alvarez
INTRODUCTION: Clozapine is a second-generation antipsychotic drug that is mainly prescribed for treatment-resistant psychotic disorder. It is known to have several undesirable side effects, including cognitive functional complaints, such as memory or attention. The aim of this work is to study if reduction of the dosage within the therapeutic margins could improve cognitive performance of Clozapine treated patients. To do so, a study was made of the relationship between Clozapine plasma levels and neuropsychological performance in patients undergoing Clozapine monotherapy...
March 2014: Actas Españolas de Psiquiatría
Rudy Schreiber, Adrian Newman-Tancredi
Atypical antipsychotics fail to substantially improve cognitive impairment associated with schizophrenia (CIAS) and one strategy to improve it is to stimulate adult neurogenesis in hippocampus, because this structure is part of an altered circuitry that underlies aspects of CIAS. Deficits in hippocampal adult neurogenesis may disrupt cognitive processes that are dependent on newborn neurons, such as pattern separation (the formation of distinct representations of similar inputs). Mechanisms by which hippocampal adult neurogenesis can be increased are therefore of therapeutic interest and a promising molecular target is the activation of serotonin 5-HT(1A) receptors because agonists at this site increase adult neuronal proliferation in the dentate gyrus...
April 2014: Neurobiology of Learning and Memory
Bruna Mara Machado Ribeiro, Marta Regina Santos do Carmo, Rosemayre Souza Freire, Nayrton Flávio Moura Rocha, Vládia Célia Moreira Borella, Antonio Teles de Menezes, Aline Santos Monte, Patrícia Xavier Lima Gomes, Francisca Cléa Florenço de Sousa, Mariana Lima Vale, David Freitas de Lucena, Clarissa Severino Gama, Danielle Macêdo
Schizophrenia was proposed as a progressive neurodevelopmental disorder. In this regard herein we attempted to determine progressive inflammatory and oxidative alterations induced by a neonatal immune challenge and its possible reversal by clozapine administration. For this end, Wistar rats at postnatal day (PN) 5-7 were administered the viral mimetic polyriboinosinic-polyribocytidilic acid (polyI:C) or saline. A distinct group of animals additionally received the antipsychotic drug clozapine (25mg/kg) from PN60 to 74...
December 2013: Schizophrenia Research
Robert Freedman
α7-Nicotinic acetylcholine receptors have emerged as a potential therapeutic target for the treatment of neurocognitive dysfunctions in schizophrenia that are often resistant to existing antipsychotic drugs. Molecular evidence for involvement in schizophrenia of CHRNA7, the gene for the receptor subunit, in the neurobiology of deficits in attention is a critical rationale for the clinical study of α7-nicotinic receptor agonists to improve neurocognition. Initial clinical trials show enhancement of inhibitory neuron function related to sensory gating and increased attention and working memory, as well as improvement in negative symptoms such as anhedonia and alogia...
2014: Annual Review of Medicine
H Geerts, P Roberts, A Spiros
Although the positive symptoms of schizophrenia are reasonably well-controlled by current antipsychotics, cognitive impairment remains largely unaddressed. The Matrics initiative lays out a regulatory path forward and a number of targets have been tested in the clinic, so far without much success. To address this translational disconnect, we have developed a mechanism-based humanized computer model of a relevant key cortical brain network with schizophrenia pathology involved with the maintenance aspect of working memory (WM)...
2013: CPT: Pharmacometrics & Systems Pharmacology
Karen E Stevens, Lijun Zheng, Daniel J Abrams
Deficient sensory inhibition, the failure to inhibit responses to repeated stimuli, is a hallmark of schizophrenia, and is thought to be related to difficulties with attention and working memory. Sensory inhibition is assessed by comparing the auditory-evoked EEG responses to 2 closely-spaced identical stimuli. Normal individuals show suppressed response to the second stimulus while schizophrenia patients have responses of similar magnitude to both stimuli. This deficit has been linked to polymorphisms in the promoter for the α7 nicotinic receptor gene, resulting in reduced numbers of receptors on hippocampal interneurons...
September 2013: Schizophrenia Research
Ulrike Stadlbauer, Wolfgang Langhans, Urs Meyer
Functional changes in neuropeptide Y (NPY) signaling at the Y2 receptor subtype have been widely implicated in stress-related neuropsychiatric illnesses such as depression and anxiety disorders. Altered Y2 receptor signaling may also play a role in the precipitation of behavioral and cognitive symptoms associated with schizophrenia. To seek preclinical evidence for this possibility, we explored the functional consequences of treatment with the selective Y2 receptor agonist PYY(3-36) using translational tests for the assessment of schizophrenia-relevant behavioral and cognitive deficits in mice...
November 2013: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
Mira Jakovcevski, Rahul Bharadwaj, Juerg Straubhaar, Guangping Gao, David P Gavin, Igor Jakovcevski, Amanda C Mitchell, Schahram Akbarian
BACKGROUND: Postmortem brain studies have shown that HDAC1-a lysine deacetylase with broad activity against histones and nonhistone proteins-is frequently expressed at increased levels in prefrontal cortex (PFC) of subjects diagnosed with schizophrenia and related disease. However, it remains unclear whether upregulated expression of Hdac1 in the PFC could affect cognition and behavior. METHODS: Using adeno-associated virus, an Hdac1 transgene was expressed in young adult mouse PFC, followed by behavioral assays for working and long-term memory, repetitive activity, and response to novelty...
November 1, 2013: Biological Psychiatry
Handan Gunduz-Bruce, Stephen Oliver, Ralitza Gueorguieva, Kimberlee Forselius-Bielen, Deepak C D'Souza, Zoran Zimolo, Cenk Tek, Styliani Kaliora, Susan Ray, Georgios Petrides
INTRODUCTION: A substantial number of patients with treatment-resistant schizophrenia respond only partially to clozapine. Therefore, it has been common practice to use augmentation strategies to maximize clozapine's effect. But the efficacy of this strategy remains poorly established. We have conducted a randomized double-blind placebo controlled clinical trial in patients with schizophrenia currently receiving clozapine with partial response, and tested the efficacy of pimozide augmentation on positive and negative symptoms and also on neurocognitive measures...
February 2013: Schizophrenia Research
Ann Olincy, Robert Freedman
Nicotine is heavily abused by persons with schizophrenia. Nicotine better enables people with schizophrenia to filter out extraneous auditory stimuli. Nicotine also improves prepulse inhibition when compared to placebo. Nicotine similarly increases the amplitude of patients' duration mismatch negativity. The 15q13-14 region of the genome coding for the α7 nicotinic receptor is linked to schizophrenia. Multiple single nucleotide polymorphisms have been identified in this 15q13-14 gene promoter region that are more frequently present in people with schizophrenia than in normal controls...
2012: Handbook of Experimental Pharmacology
Ana P Herrmann, Paula Lunardi, Luísa Klaus Pilz, Ana C Tramontina, Viviane M Linck, Christopher O Okunji, Carlos A Gonçalves, Elaine Elisabetsky
A dysfunctional glutamatergic system is thought to be central to the negative symptoms and cognitive deficits recognized as determinant to the poor quality of life of people with schizophrenia. Modulating glutamate uptake has, thus, been suggested as a novel target for antipsychotics. Alstonine is an indole alkaloid sharing with atypical antipsychotics the profile in animal models relevant to schizophrenia, though divergent in its mechanism of action. The aim of this study was to evaluate the effects of alstonine on glutamate uptake...
December 2012: Neurochemistry International
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