Microarray analysis of rat brain following chronic treatment with antipsychotic drugs or mood stabilizers
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE66277 | GEO | 2015/03/16
SECONDARY ACCESSION(S): PRJNA276307
REPOSITORIES: GEO
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Project description:BackgroundThe relative benefits and risks of long-term maintenance treatment with antipsychotics have not been well studied in patients with bipolar disorder and major depressive disorder. For example, while antipsychotic dose reduction has been recommended in the management of serious side effects associated with antipsychotics, there is limited evidence on the impact of lowering doses on the course of underlying mood disorders.MethodsThis retrospective cohort study analyzed the impact of antipsychotic dose reduction in patients with bipolar disorder or major depressive disorder. Medical claims from six US states over a 6-year period were analyzed for patients with ≥10% or ≥ 30% reductions in antipsychotic dose (cases) and compared using survival analyses with matched controls receiving a stable dosage. Outcomes included hospitalizations for disease-specific mood disorders, other psychiatric disorders and all-cause emergency room visits, and claims for tardive dyskinesia.ResultsA total of 23,992 patients with bipolar disorder and 17,766 with major depressive disorder had a ≥ 10% dose reduction, while 19,308 and 14,728, respectively, had a ≥ 30% dose reduction. In multivariate analyses, cases with a ≥ 10% dose reduction had a significantly increased risk of disease-specific admission (bipolar disorder: hazard ratio [95% confidence interval], 1.22 [1.15-1.31]; major depressive disorder: 1.22 [1.11-1.34]), other psychiatric admission (bipolar disorder: 1.19 [1.13-1.24]; major depressive disorder: 1.17 [1.11-1.23]), all-cause admission (bipolar disorder: 1.17 [1.12-1.23]; major depressive disorder: 1.11 [1.05-1.16]), and all-cause emergency room visits (bipolar disorder: 1.09 [1.05-1.13]; major depressive disorder: 1.07 [1.02-1.11]) (all P < 0.01). Similar results were observed following an ≥30% dose reduction. Dose reduction was not associated with decreased claims for tardive dyskinesia.ConclusionsPatients with mood disorders who had antipsychotic dose reductions showed small but statistically significant increases in all-cause and mental health-related hospitalizations, which may lead to increased healthcare costs. These results highlight the need for additional long-term studies of the necessity and safety of maintenance antipsychotic treatment in mood disorders.
| S-EPMC7353680 | biostudies-literature
Project description:Here, we examined mouse brain trancriptional changes 1 hour after the 10th daily i.p. treament with one of the four following treaments: i) vehicle control (45% saline, 45% PEG-400 and 10% DMSO administered at 7.5mL/kg), ii) Cpd-60, 45mg/kg , administered at 7.5mL/kg or iii) SAHA, 25mg/kg, administered at 5mL/kg) or iv) CI-994, 10mg/kg, administered at 5mL/kg. Cpd-60 is a benzamide HDAC inhibitor with selectivity for class I HDAC subtypes HDAC1 and HDAC2; CI-994 is a benzamide inhibitor with selectivity for HDACs1,2 and 3; SAHA is a hydroxamic acid HDAC inhibitor with selectivity for class I HDAC subtypes 1,2, and 3 and the class II HDAC subtype HDAC 6. We examined transcript differences using the Illumnia WG-6 2.0 whole genome expression array and profiled 3 specific brain regions (prefrontal cortex, nucleus accumbens, hippocampus) from each of 36 mice (n=6 mice / treatment group) . For application to array chips, we pooled two biological replicates from like treatment and brain region-groups such that 36 samples were applied in total: 4 treatment groups x 3 brain regions per treament group x 3 pools of two samples each for each treatment/brain region.
2013-05-29 | GSE47452 | GEO
Project description:Antipsychotic drugs (APs) are of great benefit in several psychiatric disorders, but they can be associated with various adverse effects, including seizures. To investigate the effects of chronic antipsychotic treatment on seizure susceptibility in genetically epilepsy-prone rats, some APs were administered for 7 weeks, and seizure susceptibility (audiogenic seizures) was evaluated once a week during treatment and for 5 weeks after drug withdrawal. Furthermore, acute and subchronic (5-day treatment) effects were also measured. Rats received haloperidol (0.2-1.0 mg/kg), clozapine (1-5 mg/kg), risperidone (0.03-0.50 mg/kg), quetiapine (2-10 mg/kg), aripriprazole (0.2-1.0 mg/kg), and olanzapine (0.13-0.66 mg/kg), and tested according to treatment duration. Acute administration of APs had no effect on seizures, whereas, after regular treatment, aripiprazole reduced seizure severity; haloperidol had no effects and all other APs increased seizure severity. In chronically treated rats, clozapine showed the most marked proconvulsant effects, followed by risperidone and olanzapine. Quetiapine and haloperidol had only modest effects, and aripiprazole was anticonvulsant. Finally, the proconvulsant effects lasted at least 2-3 weeks after treatment suspension; for aripiprazole, a proconvulsant rebound effect was observed. Taken together, these results indicate and confirm that APs might have the potential to increase the severity of audiogenic seizures but that aripiprazole may exert anticonvulsant effects. The use of APs in patients, particularly in patients with epilepsy, should be monitored for seizure occurrence, including during the time after cessation of therapy. Further studies will determine whether aripiprazole really has a potential as an anticonvulsant drug and might also be clinically relevant for epileptic patients with psychiatric comorbidities.
| S-EPMC4322085 | biostudies-other
Project description:Bipolar disorder is a devastating illness that is marked by recurrent episodes of mania and depression. There is growing evidence that the disease is correlated with disruptions in synaptic plasticity cascades involved in cognition and mood regulation. Alleviating the symptoms of bipolar disorder involves chronic treatment with mood stabilizers like lithium or valproate. These two structurally dissimilar drugs are known to alter prominent signaling cascades in the hippocampus, but their effects on the post-synaptic density complex remain undefined. In this work, we utilized mass spectrometry for quantitative profiling of the rat hippocampal post-synaptic proteome to investigate the effects of chronic mood stabilizer treatment. Our data show that in response to chronic treatment of mood stabilizers there were not gross qualitative changes but rather subtle quantitative perturbations in post-synaptic density proteome linked to several key signaling pathways. Our data specifically support the changes in actin dynamics on valproate treatment. Using label-free quantification methods, we report that lithium and valproate significantly altered the abundance of 21 and 43 proteins, respectively. Seven proteins were affected similarly by both lithium and valproate: Ank3, glutamate receptor 3, dynein heavy chain 1, and four isoforms of the 14-3-3 family. Immunoblotting the same samples confirmed the changes in Ank3 and glutamate receptor 3 abundance. Our findings support the hypotheses that BPD is a synaptic disorder and that mood stabilizers modulate the protein signaling complex in the hippocampal post-synaptic density.
| S-EPMC3192943 | biostudies-literature
Project description:Here, we examined mouse brain trancriptional changes 1 hour after the 10th daily i.p. treament with one of the four following treaments: i) vehicle control (45% saline, 45% PEG-400 and 10% DMSO administered at 7.5mL/kg), ii) Cpd-60, 45mg/kg , administered at 7.5mL/kg or iii) SAHA, 25mg/kg, administered at 5mL/kg) or iv) CI-994, 10mg/kg, administered at 5mL/kg. Cpd-60 is a benzamide HDAC inhibitor with selectivity for class I HDAC subtypes HDAC1 and HDAC2; CI-994 is a benzamide inhibitor with selectivity for HDACs1,2 and 3; SAHA is a hydroxamic acid HDAC inhibitor with selectivity for class I HDAC subtypes 1,2, and 3 and the class II HDAC subtype HDAC 6. We examined transcript differences using the Illumnia WG-6 2.0 whole genome expression array and profiled 3 specific brain regions (prefrontal cortex, nucleus accumbens, hippocampus) from each of 36 mice (n=6 mice / treatment group) . For application to array chips, we pooled two biological replicates from like treatment and brain region-groups such that 36 samples were applied in total: 4 treatment groups x 3 brain regions per treament group x 3 pools of two samples each for each treatment/brain region. Treatment groups: All adult male, C57BL/6 mice (n=6mice/treatment group) were sacrificed by rapid cervical dislocation and decapitation 1 hour after the tenth daily i.p. injection with one of the four following treaments: i) vehicle control (45% saline, 45% PEG-400 and 10% DMSO administered at 7.5mL/kg), ii) Cpd-60, 45mg/kg , administered at 7.5mL/kg or iii) SAHA, 25mg/kg, administered at 5mL/kg) or iv) CI-994, 10mg/kg, administered at 5mL/kg. Brains were removed, frozen immediately on dry ice and stored at -80°C until use. Frozen mouse brains (n = 6/ treatment group) were rapidly dissected at 4°C, isolating medial prefrontal cortex, nucleus accumbens and hippocampus. RNA was isolated using the Qiagen RNeasy Lipid Tissue mini kit, RNA concentration was determined using a NanoDrop spectrophotometer and quality was assessed using Agilent Bioanalyzer PICO chips, with the RNA Integrity Number (RIN) determined at 7.0-8.8 for all samples assayed, indicative of good RNA quality. For microarray experiments on Illumina MouseWG-6 BeadChips, RNA samples were pooled from two biological replicates such that the total number of samples was 36 (3 treatment groups x 3 brain regions x 3 RNA pools representing two mice per pool). All microarray analysis and gene set analysis (GSA) was performed using GeneSpring software (v.11.5.1) with raw signals adjusted using quantile normalization and baseline transformation with the median signal in all samples set to zero. Data were included in subsequent analyses if the normalized signal, thresholded at 0.8, was ‘present’ for 3 of 3 replicates for like treatment and tissue groups.
2013-05-29 | E-GEOD-47452 | biostudies-arrayexpress
Project description:Microarray analysis was performed to look at the mRNA and miRNA profiles of several antidepressant drugs in the rat hippocampus after Traumatic Brain Injury to test the hypothesis that antidepressant drugs ameliorate gene and miRNA dysregulation after TBI.
2019-05-01 | GSE115614 | GEO
Project description:ObjectiveThis study aims to investigate whether orexigenic antipsychotic drugs may induce dyslipidemia and glucose disturbances in female rats through direct perturbation of metabolically active peripheral tissues, independent of prior weight gain.MethodsIn the current study, we examined whether a single intraperitoneal injection of clozapine or olanzapine induced metabolic disturbances in adult female outbred Sprague-Dawley rats. Serum glucose and lipid parameters were measured during time-course experiments up to 48 h. Real-time quantitative PCR was used to measure specific transcriptional alterations in lipid and carbohydrate metabolism in adipose tissue depots or in the liver.ResultsOur results demonstrated that acute administration of clozapine or olanzapine induced a rapid, robust elevation of free fatty acids and glucose in serum, followed by hepatic accumulation of lipids evident after 12-24 h. These metabolic disturbances were associated with biphasic patterns of gluconeogenic and lipid-related gene expression in the liver and in white adipose tissue depots.ConclusionOur results support that clozapine and olanzapine are associated with primary effects on carbohydrate and lipid metabolism associated with transcriptional changes in metabolically active peripheral tissues prior to the development of drug-induced weight gain.
| S-EPMC3259403 | biostudies-literature
Project description:Mood disorders are common and debilitating, resulting in a significant public health burden. Current treatments are only partly effective and patients who have failed to respond to trials of existing antidepressant agents (eg, those who suffer from treatment-resistant depression [TRD]) require innovative therapeutics with novel mechanisms of action. Although neuroscience research has elucidated important aspects of the basic mechanisms of antidepressant action, most antidepressant drugs target monoaminergic mechanisms identified decades ago. Glutamate, the major excitatory neurotransmitter in the central nervous system, and glutamatergic dysfunction has been implicated in mood disorders. These data provide a rationale for the pursuit of glutamatergic agents as novel therapeutic agents. Here, we review preclinical and clinical investigations of glutamatergic agents in mood disorders with a focus on depression. We begin with discussion of evidence for the rapid antidepressant effects of ketamine, followed by studies of the antidepressant efficacy of the currently marketed drugs riluzole and lamotrigine. Promising novel agents currently in development, including N-methyl-D-aspartate (NMDA) receptor modulators, 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propanoic acid (AMPA) receptor modulators, and drugs with activity at the metabotropic glutamate (mGlu) receptors are then reviewed. Taken together, both preclinical and clinical evidence exists to support the pursuit of small molecule modulators of the glutamate system as novel therapeutic agents in mood disorders. It is hoped that by targeting neural systems outside of the monoamine system, more effective and perhaps faster acting therapeutics can be developed for patients suffering from these disabling disorders.
| S-EPMC3747027 | biostudies-literature
Project description: Not available
| S-EPMC6464566 | biostudies-literature
Project description:BACKGROUND: Fluoxetine, a selective serotonin reuptake inhibitor, is approved for treatment of childhood depression. In rats, fluoxetine influences neuronal development, but it is unclear whether it also influences glia development. S100B is a glia-derived calcium-binding protein, which may influence the development of serotonergic fibers and, vice versa, serotonin may influence the expression of S100B. OBJECTIVES: The purpose of this study was to investigate whether fluoxetine treatment influences the expression of S100B during postnatal development, and whether potential changes are regionally dependent upon the time frame of drug administration. METHODS: S100B gene expression and S100B protein expression in three different brain regions (frontal cortex, hippocampus, and striatum) were studied by real-time polymerase chain reaction (PCR) and immunohistochemistry, respectively. First, a short-term effect, 24 hours after a 14 day fluoxetine treatment (5 mg/kg/bw s.c.) of rats either from postnatal day (PD) 1 to 15, 21 to 35, or 50 to 64, was investigated. Then, the same treatment was used to analyze S100B gene and protein levels at PD 90 (long-term effect). RESULTS: At PD 90, a significant increase of gene and protein expression was observed in all regions if rats were treated during PDs 21-35, whereas treatment during other periods had no long-term effects. A short-term effect 24 hours after fluoxetine treatment was found for almost all development stages and regions, demonstrated by a significant increase of S100B. CONCLUSIONS: These results support recent research indicating a highly drug-sensitive period (i.e., periadolescence) of rat brain development. Therefore, further clinical studies should be performed to clarify whether such a sensitive period also exists in children.
| S-EPMC3779020 | biostudies-literature