quetiapine-fumarate and Memory-Disorders

Quetiapine, an atypical antipsychotic drug, may have beneficial effects in Alzheimer's disease (AD), and the effect of quetiapine on object recognition memory in AD has never been measured. The aim of the present study was to evaluate the effects of quetiapine on object recognition memory and on oxidative stress that could be involved in the AD pathogenesis in an amyloid precursor protein/presenilin-1 double transgenic mouse model of AD. Nontransgenic and transgenic mice were treated with quetiapine (0 or 5 mg/kg/day) in drinking water from the age of 2 months. After 10 months of continuous quetiapine administration, object recognition memory impairment and the increased hippocampal protein expression of nitrotyrosine, a protein marker of oxidative stress, were attenuated in the AD mice. These results suggest that quetiapine can attenuate object recognition memory impairment and brain oxidative stress in an amyloid precursor protein/presenilin-1 transgenic mouse model of AD and indicate that the antioxidative effect of early quetiapine intervention may be associated with the beneficial effect of quetiapine on memory in AD.

Topics: Alzheimer Disease; Animals; Antipsychotic Agents; Behavior, Animal; Dibenzothiazepines; Disease Models, Animal; Female; Hippocampus; Memory Disorders; Mice; Mice, Transgenic; Oxidative Stress; Quetiapine Fumarate; Recognition, Psychology

Our previous study has shown the preventive effects of quetiapine, an atypical antipsychotic drug, on memory impairment and brain pathological changes in a mouse model of Alzheimer's disease (AD). The aim of the present study was to evaluate the therapeutic effects of quetiapine on memory deficit and neuropathology in an amyloid precursor protein (APP)/presenilin-1 (PS1) double transgenic mouse model of AD. The APP/PS1 mice started to have detectable brain β-amyloid (Aβ) at 3 months of age. Non-transgenic and transgenic mice were treated with quetiapine (0, 2.5, or 5 mg/(kg day)) in drinking water from the age of 4 months. After 8 months of continuous quetiapine administration, memory deficit was reversed and brain Aβ plaque pathology was attenuated in the AD mice. Quetiapine also decreased the soluble Aβ peptide levels in brain and cerebrospinal fluid (CSF), and attenuated the decreased synaptic protein levels in the AD mice. Furthermore, quetiapine normalized the abnormal activity of glycogen synthase kinase-3β (GSK-3β), an AD-involved kinase, in the AD mice. These results suggest that quetiapine can treat and alleviate the neuropathology in an APP/PS1 transgenic mouse model of AD, and indicate that quetiapine may have therapeutic effects in the treatment of AD.

Topics: Alzheimer Disease; Animals; Blotting, Western; Brain; Dibenzothiazepines; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Humans; Maze Learning; Memory; Memory Disorders; Mice; Mice, Transgenic; Neuroprotective Agents; Plaque, Amyloid; Quetiapine Fumarate

Since working memory deficits in schizophrenia have been linked to negative symptoms, we tested whether features of the one could predict the treatment outcome in the other. Specifically, we hypothesized that working memory-related functional connectivity at pre-treatment can predict improvement of negative symptoms in antipsychotic-treated patients. Fourteen antipsychotic-naive patients with first-episode schizophrenia were clinically assessed before and after 7 months of quetiapine monotherapy. At baseline, patients underwent functional magnetic resonance imaging while performing a verbal n-back task. Spatial independent component analysis identified task-modulated brain networks. A linear support vector machine was trained with these components to discriminate six patients who showed improvement in negative symptoms from eight non-improvers. Classification accuracy and significance was estimated by leave-one-out cross-validation and permutation tests, respectively. Two frontoparietal and one default mode network components predicted negative symptom improvement with a classification accuracy of 79% (p = 0.003). Discriminating features were found in the frontoparietal networks but not the default mode network. These preliminary data suggest that functional patterns at baseline can predict negative symptom treatment-response in schizophrenia. This information may be used to stratify patients into subgroups thereby facilitating personalized treatment.

Topics: Adolescent; Adult; Antipsychotic Agents; Artificial Intelligence; Brain; Brain Mapping; Dibenzothiazepines; Female; Humans; Image Processing, Computer-Assisted; Male; Memory Disorders; Memory, Short-Term; Middle Aged; Nerve Net; Oxygen; Prospective Studies; Psychiatric Status Rating Scales; Quetiapine Fumarate; Schizophrenia; Young Adult

Cognitive dysfunctions in patients suffering from schizophrenia (SZ) are also found in their unaffected parents though to a lesser degree. According to several researchers, short-term memory (STM) deficits are a potential marker of vulnerability to SZ. However, the cognitive processes underlying the observed STM deficits remain underspecified in SZ (Lee & Park, 2005). In the present study, our goal was to pinpoint those processes at play in the manifestation of STM deficits by using the paradigm of the sandwich effect (e.g., Hitch, 1975) to manipulate information load (5 vs. 7 to-be-remembered items) and distraction (control vs. sandwich) in the verbal domain. Our study comprises four groups: patients with SZ (n = 25), their unaffected parents (n = 25), and their respective healthy controls. The pattern of results indicates a generalized dysfunction of STM in patients with SZ characterized by saturation and an increased susceptibility to distraction. The impact of saturation and distraction was also observed in unaffected parents of patients with SZ to a lesser degree. The methodological strategy adopted here allowed us to show that the dysfunction of STM is genuine, can be aggravated by deficits in selective attention, and is a good candidate for further research on genetic epidemiology.

Topics: Age of Onset; Antipsychotic Agents; Attention; Clozapine; Dibenzothiazepines; Female; Humans; Male; Memory Disorders; Memory, Short-Term; Neuropsychological Tests; Parents; Quetiapine Fumarate; Risperidone; Schizophrenia; Severity of Illness Index; Young Adult

Previous studies have suggested that quetiapine, an atypical antipsychotic drug, may have beneficial effects on cognitive impairment, and be a neuroprotectant in treating neurodegenerative diseases. In the present study, we investigated the effects of quetiapine on memory impairment and pathological changes in an amyloid precursor protein (APP)/presenilin-1 (PS-1) double transgenic mouse model of Alzheimer's disease (AD). Non-transgenic and transgenic mice were treated with quetiapine (0, 2.5, or 5mg/(kg day)) for 1, 4, and 7 months in drinking water from the age of 2 months. After 4 and 7 months of continuous quetiapine administration, memory impairment was prevented, and the number of beta-amyloid (Abeta) plaques decreased in the cortex and hippocampus of the transgenic mice. Quetiapine also decreased brain Abeta peptides, beta-secretase activity and expression, and the level of C99 (an APP C-terminal fragment following cleavage by beta-secretase) in the transgenic mice. Furthermore, quetiapine attenuated anxiety-like behavior, up-regulated cerebral Bcl-2 protein, and decreased cerebral nitrotyrosine in the transgenic mice. These findings suggest that quetiapine can alleviate cognitive impairment and pathological changes in an APP/PS1 double transgenic mouse model of AD, and further indicate that quetiapine may have preventive effects in the treatment of AD.

Topics: Aging; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Antipsychotic Agents; Anxiety; Brain; Dibenzothiazepines; Disease Models, Animal; Female; Male; Memory Disorders; Mice; Mice, Transgenic; Plaque, Amyloid; Presenilin-1; Protease Nexins; Proto-Oncogene Proteins c-bcl-2; Quetiapine Fumarate; Receptors, Cell Surface; Tyrosine

Quetiapine, a new atypical antipsychotic drug, has beneficial effects on cognitive impairment and neuropathological changes in treating chronic neurodegenerative diseases. Our previous studies have demonstrated that quetiapine may have neuroprotective properties. In the present study, we investigated the effects of a 2-week pre-administration of quetiapine (10 mg/kg/day, i.p.) on spatial memory impairment and hippocampal neurodegeneration induced by 60-minute bilateral common carotid artery occlusion (CCAO). Following a 7-day recovery phase from CCAO, the spatial memory of the mice was tested using a modified water maze test. After the behavioural test, the mice were sacrificed and brain sections were stained with NeuN (a neuron-specific soluble nuclear antigen), cresyl violet (Nissl), and Fluoro-Jade B. CCAO significantly induced spatial memory impairment and caused neurodegeneration in the hilus of hippocampus, while quetiapine significantly attenuated these changes. This is the first study showing that quetiapine significantly attenuates CCAO-induced spatial memory impairment and this improvement parallels the alleviative effects of quetiapine on CCAO-induced neurodegeneration in the hilus of hippocampus. The results suggest that quetiapine may have defending effects on the impairments induced by cerebral ischemia, which enhances our understanding about the mechanisms of quetiapine.

Topics: Animals; Carotid Arteries; Carotid Artery Diseases; Dibenzothiazepines; Hippocampus; Male; Maze Learning; Memory Disorders; Mice; Mice, Inbred ICR; Neurodegenerative Diseases; Quetiapine Fumarate; Staining and Labeling

Quetiapine, a new atypical antipsychotic drug, effectively alleviates positive and negative symptoms, as well as cognitive impairment that may be caused by neurodegeneration, in schizophrenia patients. Earlier in vivo and in vitro studies have demonstrated that quetiapine may be a neuroprotectant. The present study was designed to examine the beneficial effects of quetiapine on the possible cognitive impairment and changes of brain apoptotic regulation proteins induced by phencyclidine (PCP) in rats. Rats were treated with quetiapine (10 mg/kg/day; intraperitoneal (i.p.)) or vehicle for 16 days. On day 14, 1 h after the administration of quetiapine, the rats were given PCP (50 mg/kg; subcutaneous (s.c.)) or vehicle. Then quetiapine was administrated for an additional 2 days. One day after the last quetiapine injection (3 days after the PCP injection), the rats were trained on a spatial memory task in a radial arm maze. After the behavioural test, the rats were decapitated for Western blot analysis. PCP induced reference memory impairment, and a decrease of the ratio of an anti-apoptotic Bcl-2 family member (Bcl-XL) to a pro-apoptotic analogue (Bax) in the posterior cingulate cortex. Chronic administration of quetiapine counteracted the PCP-induced reference memory impairment and decrease of Bcl-XL/Bax ratio in the posterior cingulate cortex. These results suggest that quetiapine may have ameliorating effects on the cognitive impairment and brain apoptotic processes induced by PCP.

Topics: Analysis of Variance; Animals; Antipsychotic Agents; bcl-2-Associated X Protein; bcl-X Protein; Behavior, Animal; Blotting, Western; Dibenzothiazepines; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Female; Gene Expression Regulation; Gyrus Cinguli; Memory Disorders; Phencyclidine; Quetiapine Fumarate; Rats; Rats, Sprague-Dawley; Time Factors

Previous studies have suggested that quetiapine, a new atypical antipsychotic drug, may have beneficial effects on cognitive impairment and be a neuroprotectant in treating neurodegenerative diseases. In the present study, we investigated the therapeutic effects of chronic administration of quetiapine on methamphetamine (METH)-induced recognition memory impairment and dopaminergic terminal neurotoxicity in rats. Rats were pretreated with METH (5 mg/kg; s.c.) four times at 2-h intervals while their body temperature was monitored. Fifteen minutes after the last METH injection, rats were administered quetiapine (10 mg/kg/day; i.p.) for 28 days. One day after the last quetiapine injection, rats were trained and tested on an object recognition task on days 29 and 30. Finally, on day 31, rats were sacrificed for immunohistochemistry, 1 day after the object recognition task. METH induced hyperthermia, recognition memory impairment and a decrease of tyrosine hydroxylase immunoreactivity in the caudate putamen (CPu) of striatum. Quetiapine attenuated the METH-induced hyperthermia. Furthermore, chronic post-treatment of quetiapine reversed the METH-induced memory impairment and dopaminergic terminal deficit. These findings suggest that quetiapine may have therapeutic effects in the treatment of cognitive impairment and neurodegeneration induced by METH.

Topics: Animals; Antipsychotic Agents; Biomarkers; Body Temperature; Central Nervous System Stimulants; Dibenzothiazepines; Dopamine; Exploratory Behavior; Immunohistochemistry; Male; Memory; Memory Disorders; Methamphetamine; Presynaptic Terminals; Quetiapine Fumarate; Rats; Rats, Sprague-Dawley; Recognition, Psychology; Tyrosine 3-Monooxygenase

Previous studies have demonstrated that adult rats with excitotoxic lesions of the hippocampus display deficits in memory-related behaviors similar to the memory deficits associated with schizophrenia. In this study, we assessed the sub-chronic effects of quetiapine, risperidone and haloperidol on performance deficits after intracerebroventricular administration of the excitotoxin, kainic acid, using paradigms for contextual and cued fear conditioning and spatial reversal learning in rats. The effects of three doses of quetiapine (5, 10 and 20 mg/kg) and single doses of risperidone (0.5 mg/kg) and haloperidol (0.15 mg/kg) were compared. Quetiapine administration at the lowest dose (5 mg/kg) reversed deficits in contextual and cued fear conditioning, but not deficits in spatial reversal learning, in kainic acid-treated animals. However, the two higher doses of quetiapine, and the single doses of risperidone and haloperidol, did not reverse any of the kainic acid-induced behavioral deficits. These results may be relevant to the effects of quetiapine and other antipsychotic drugs on memory deficits in patients with schizophrenia.

Topics: Animals; Antipsychotic Agents; Conditioning, Operant; Cranial Nerve Diseases; Cues; Dibenzothiazepines; Electroshock; Excitatory Amino Acid Agonists; Fear; Hippocampus; Injections, Intraventricular; Kainic Acid; Male; Memory Disorders; Motor Activity; Neurotoxins; Quetiapine Fumarate; Rats; Rats, Sprague-Dawley; Reversal Learning