RESUMEN
MOTIVATION: The number of significantly associated regions reported in genome-wide association studies (GWAS) for polygenic traits typically increases with sample size. A traditional tool for quality control and identification of significant regions has been a visual inspection of how significant and correlated genetic variants cluster within a region. However, while inspecting hundreds of regions, this subjective method can misattribute significance to some loci or neglect others that are significant. RESULTS: The GWAS quality score (GQS) identifies suspicious regions and prevents erroneous interpretations with an objective, quantitative and automated method. The GQS assesses all measured single nucleotide polymorphisms (SNPs) that are linked by inheritance to each other [linkage disequilibrium (LD)] and compares the significance of trait association of each SNP to its LD value for the reported index SNP. A GQS value of 1.0 ascribes a high level of confidence to the entire region and its underlying gene(s), while GQS values <1.0 indicate the need to closely inspect the outliers. We applied the GQS to published and non-published genome-wide summary statistics and report suspicious regions requiring secondary inspection while supporting the majority of reported regions from large-scale published meta-analyses. AVAILABILITY AND IMPLEMENTATION: The GQS code/scripts can be cloned from GitHub (https://github.com/Xswapnil/GQS/). The analyst can use whole-genome summary statistics to estimate GQS for each defined region. We also provide an online tool (http://35.227.18.38/) that gives access to the GQS. The quantitative measure of quality attributes by GQS and its visualization is an objective method that enhances the confidence of each genomic hit. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Estudio de Asociación del Genoma Completo , Genómica , Estudio de Asociación del Genoma Completo/métodos , Fenotipo , Desequilibrio de Ligamiento , Genómica/métodos , Bases de Datos Genéticas , Polimorfismo de Nucleótido SimpleRESUMEN
The pharmacological treatment of depression consists of stages of trial and error, with less than 40% of patients achieving remission during first medication trial. However, in a large, randomized-controlled trial (RCT) in the U.S. ("GUIDED"), significant improvements in response and remission rates were observed in patients who received treatment guided by combinatorial pharmacogenomic testing, compared to treatment-as-usual (TAU). Here we present results from the Canadian "GAPP-MDD" RCT. This 52-week, 3-arm, multi-center, participant- and rater-blinded RCT evaluated clinical outcomes among patients with depression whose treatment was guided by combinatorial pharmacogenomic testing compared to TAU. The primary outcome was symptom improvement (change in 17-item Hamilton Depression Rating Scale, HAM-D17) at week 8. Secondary outcomes included response (≥50% decrease in HAM-D17) and remission (HAM-D17 ≤ 7) at week 8. Numerically, patients in the guided-care arm had greater symptom improvement (27.6% versus 22.7%), response (30.3% versus 22.7%), and remission rates (15.7% versus 8.3%) compared to TAU, although these differences were not statistically significant. Given that the GAPP-MDD trial was ultimately underpowered to detect statistically significant differences in patient outcomes, it was assessed in parallel with the larger GUIDED RCT. We observed that relative improvements in response and remission rates were consistent between the GAPP-MDD (33.0% response, 89.0% remission) and GUIDED (31.0% response, 51.0% remission) trials. Together with GUIDED, the results from the GAPP-MDD trial indicate that combinatorial pharmacogenomic testing can be an effective tool to help guide depression treatment in the context of the Canadian healthcare setting (ClinicalTrials.gov NCT02466477).
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Trastorno Depresivo Mayor , Pruebas de Farmacogenómica , Antidepresivos/uso terapéutico , Canadá , Depresión , Trastorno Depresivo Mayor/inducido químicamente , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/genética , Humanos , Resultado del TratamientoRESUMEN
As knowledge of Alzheimer's disease (AD) progression improves, the field has recognized the need to diversify the pipeline, broaden strategies and approaches to therapies, as well as delivery mechanisms. A better understanding of the earliest biological processes of AD/dementia would help inform drug target selection. Currently there are a number of programs exploring these alternate avenues. This meeting will allow experts in the field (academia, industry, government) to provide perspectives and experiences that can help elucidate what the pipeline looks like today and what avenues hold promise in developing new therapies across the stages of AD. The focus here is on Active Immunotherapies and Alternative Therapeutic Modalities. This topic includes active vaccines, antisense oligomers, and cell-based therapy among others, and highlights new clinical developments that utilize these modalities.
RESUMEN
OBJECTIVES: The objective of this project was to determine pharmacy cost savings and improvement in adherence based on a combinatorial pharmacogenomic test (CPGx ) in patients who had switched or added a new psychiatric medication after having failed monotherapy for their psychiatric disorder. RESEARCH DESIGN AND METHODS: The prospective project compared 1 year pharmacy claims between a GeneSight CPGx guided cohort and a propensity-matched control group. Patients were project eligible if they augmented or switched to a different antidepressant or antipsychotic medication within the previous 90 days. Following the medication switch or augmentation, pharmacogenomic (PGx) testing was offered to each patient's treating clinician. Pharmacy claims were extracted from the Medco pharmacy claims database for each patient (n = 2168) for 1 year following testing and compared to a 5-to-1 propensity-matched treatment as usual (TAU), standard of care control group (n = 10,880). MAIN OUTCOME MEASURES: Total pharmacy spend per member per year; adherence. RESULTS: Patients who received PGx testing saved $1035.60 in total medication costs (both CNS and non-CNS medications) over 1 year compared to the non-tested standard of care cohort (p = 0.007). PGx testing improved adherence compared to standard of care (ΔPDCCPGx = 0.11 vs ΔPDCTAU = -0.01; p < 0.0001). Pharmacy cost savings averaged $2774.53 for patients who were changed to a CPGx congruent medication regimen, compared to those who were not (p < 0.0001). CONCLUSIONS: PGx testing provides significant 'real world' cost savings, while simultaneously improving adherence in a difficult to treat psychiatric population. Limitations of this study include the lack of therapeutic efficacy follow-up data and possible confounding due to matching only on demographic and psychiatric variables.
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Antidepresivos , Antipsicóticos , Pruebas Genéticas/economía , Farmacogenética , Adulto , Anciano , Antidepresivos/economía , Antidepresivos/uso terapéutico , Antipsicóticos/economía , Antipsicóticos/uso terapéutico , Ahorro de Costo/estadística & datos numéricos , Costos de los Medicamentos/estadística & datos numéricos , Honorarios Farmacéuticos/estadística & datos numéricos , Femenino , Pruebas Genéticas/métodos , Humanos , Masculino , Cumplimiento de la Medicación/psicología , Cumplimiento de la Medicación/estadística & datos numéricos , Trastornos Mentales/tratamiento farmacológico , Trastornos Mentales/psicología , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Farmacogenética/economía , Farmacogenética/métodos , Estudios Prospectivos , Estados UnidosRESUMEN
DNA of 258 patients with treatment-resistant depression was collected in three 8-10 week, two-arm, prospective clinical trials. Forty-four allelic variations were measured in genes for the cytochrome P450 (CYP) enzymes CYP2D6, CYPC19, and CYP1A2, the serotonin transporter (SLC6A4), and the 5-HT2A receptor (HTR2A). The combinatorial pharmacogenomic (CPGx™) GeneSight test results were provided to clinicians to support medication changes from baseline (guided arm), or they were provided at the end of each study to clinicians of unguided patients who were treated as usual (TAU). TAU subjects who at baseline were prescribed medications genetically discordant for them showed only a 12% symptom improvement, far less than the 32.5% or 28.5% improvements of the TAU subjects on yellow-category ('use with caution'; p = 0.002) or green-category medications ('use as recommended'; p = 0.02), respectively. The odds of a clinical response were increased 2.3-fold among all GeneSight-guided compared to all TAU subjects (p = 0.004), and overall, the guided group had a 53% greater improvement in depressive symptoms (p = 0.0002), a 1.7-fold relative improvement in response (p = 0.01), and a number needed to treat for one clinical response above that seen in the TAU group of 6.07.
RESUMEN
OBJECTIVE: This literature review assessed the burden of treatment-resistant depression in the United States by compiling published data about the clinical, societal, and economic outcomes associated with failure to respond to one or more adequate trials of drug therapy. METHODS: PubMed and the Tufts Cost-Effectiveness Analyses Registry were searched for English-language articles published between January 1996 and August 2013 that collected primary data about treatment-resistant depression. Two researchers independently assessed study quality and extracted data. RESULTS: Sixty-two articles were included (N=59,462 patients). Patients with treatment-resistant depression had 3.8±2.1 prior depressive episodes and illness duration of 4.4±3.3 years and had completed 4.7±2.7 unsuccessful drug trials involving 2.1±.3 drug classes. Response rates for treatment-resistant depression were 36%±1%. A total of 17%±6% of patients had prior suicide attempts (1.1±.2 attempts per patient). Quality-of-life scores (scale of 0-1, with 0 indicating death and 1 indicating perfect health) for patients with treatment-resistant depression were .41±.8 and .26±.8 points lower, respectively, than for patients who experienced remission or response. Annual costs for health care and lost productivity were $5,481 and $4,048 higher, respectively, for patients with treatment-resistant versus treatment-responsive depression. CONCLUSIONS: Treatment-resistant depression exacts a substantial toll on patients' quality of life. At current rates of 12%-20% among all depressed patients, treatment-resistant depression may present an annual added societal cost of $29-$48 billion, pushing up the total societal costs of major depression by as much as $106-$118 billion. These findings underscore the need for research on the mechanisms of depression, new therapeutic targets, existing and new treatment combinations, and tests to improve the efficacy of and adherence to treatments for treatment-resistant depression.
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Costo de Enfermedad , Trastorno Depresivo Mayor , Trastorno Depresivo Resistente al Tratamiento , Calidad de Vida , Trastorno Depresivo Mayor/economía , Trastorno Depresivo Mayor/epidemiología , Trastorno Depresivo Mayor/psicología , Trastorno Depresivo Resistente al Tratamiento/economía , Trastorno Depresivo Resistente al Tratamiento/epidemiología , Trastorno Depresivo Resistente al Tratamiento/psicología , HumanosRESUMEN
Patients with schizophrenia often fail to respond to an initial course of therapy. This study systematically reviewed the societal and economic burden of treatment-resistant schizophrenia (TRS). Studies that described patients with TRS published 1996-2012 were included if they collected primary data on clinical, social, or economic outcomes. All studies were independently reviewed and extracted by at least two investigators. Sixty-five studies were identified. Almost 60% (SD 18%) of patients failed to achieve response after 23 weeks on antipsychotic drug therapy. Patients with TRS had high rates of smoking (56%), alcohol abuse (51%), substance abuse (51%), and suicide ideation (44%). The incidence of severe adverse events to treatment was 4% (SD 7%). Mean quality of life for patients who were unresponsive or intolerant to treatment was â¼20% lower than that of patients in remission. Annual costs for patients with schizophrenia are $15 500-$22 300 and are 3-11-fold higher for patients with TRS. TRS remains common and costly, despite availability of many treatment options, and contributes to a significant loss in patient quality of life. Although estimates in the literature vary greatly, TRS conservatively adds more than $34 billion in annual direct medical costs in the USA.
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Esquizofrenia/economía , Antipsicóticos/efectos adversos , Antipsicóticos/uso terapéutico , Comorbilidad , Costo de Enfermedad , Costos y Análisis de Costo , Resistencia a Medicamentos , Humanos , Escalas de Valoración Psiquiátrica , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto , Esquizofrenia/complicaciones , Esquizofrenia/epidemiología , Esquizofrenia/terapia , Psicología del EsquizofrénicoRESUMEN
OBJECTIVE: A prospective double-blind randomized control trial (RCT) to evaluate the benefit of a combinatorial, five gene pharmacogenomic test and interpretive report (GeneSight) for the management of psychotropic medications used in the treatment of major depression in an outpatient psychiatric practice. METHODS: Depressed adult outpatients were randomized to a treatment as usual (TAU, n=25) arm or a pharmacogenomic-informed GeneSight (n=26) arm. Subjects were blinded to their treatment group and depression severity was assessed by blinded study raters. Within two days of enrollment, clinicians of subjects in the guided group received the GeneSight report that categorized each of 26 psychotropic medications within a green, yellow, or red "bin" based on the relationship of each medication to a subject's pharmacokinetic and pharmacodynamic combinatorial gene variant profile. Antidepressant medication changes began within 2 weeks after baseline assessments. Depression severity was assessed by blinded study raters using the HAMD-17, PHQ-9, QIDS-SR, and QIDS-CR administered 4, 6, and 10 weeks after baseline assessment. RESULTS: Between-group trends were observed with greater than double the likelihood of response and remission in the GeneSight group measured by HAMD-17 at week 10. Mean percent improvement in depressive symptoms on HAMD-17 was higher for the GeneSight group over TAU (30.8% vs 20.7%; p=0.28). TAU subjects who had been prescribed medications at baseline that were contraindicated based on the individual subject's genotype (i.e., red bin) had almost no improvement (0.8%) in depressive symptoms measured by HAMD-17 at week 10, which was far less than the 33.1% improvement (p=0.06) in the pharmacogenomic guided subjects who started on a red bin medication and the 26.4% improvement in GeneSight subjects overall (p=0.08). CONCLUSIONS: Pharmaco-genomic-guided treatment with GeneSight doubles the likelihood of response in all patients with treatment resistant depression and identifies 30% of patients with severe gene-drug interactions who have the greatest improvement in depressive symptoms when switched to genetically suitable medication regimens.
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Antidepresivos/uso terapéutico , Trastorno Depresivo Mayor/tratamiento farmacológico , Adulto , Trastorno Depresivo Mayor/genética , Método Doble Ciego , Esquema de Medicación , Genotipo , Humanos , Resultado del TratamientoRESUMEN
Adverse events, response failures and medication non-compliance are common in patients receiving medications for the treatment of mental illnesses. A systematic literature review assessed whether pharmacokinetic (PK) or pharmacodynamic (PD) responses to 26 commonly prescribed antipsychotic and antidepressant medications, including efficacy or side effects, are associated with nucleotide polymorphisms in eight commonly studied genes in psychiatric pharmacotherapy: CYP2D6, CYP2C19, CYP2C9, CYP1A2, CYP3A4, HTR2C, HTR2A, and SLC6A4. Of the 294 publications included in this review, 168 (57%) showed significant associations between gene variants and PK or PD outcomes. Other studies that showed no association often had insufficient control for confounding variables, such as co-medication use, or analysis of medications not substrates of the target gene. The strongest gene-outcome associations were for the PK profiles of CYP2C19 and CYP2D6 (93% and 90%, respectively), for the PD associations between HTR2C and weight gain (57%), and for SLC6A4 and clinical response (54%), with stronger SLC6A4 response associations for specific drug classes (60-83%). The preponderance of evidence supports the validity of analyzing nucleotide polymorphisms in CYP and pharmacodynamic genes to predict the metabolism, safety, or therapeutic efficacy of psychotropic medications commonly used for the treatment of depression, schizophrenia, and bipolar illness.
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Antidepresivos , Antipsicóticos , Sistema Enzimático del Citocromo P-450/genética , Polimorfismo Genético/genética , Receptores de Serotonina/genética , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Antidepresivos/farmacocinética , Antidepresivos/farmacología , Antipsicóticos/farmacocinética , Antipsicóticos/farmacología , Sistema Enzimático del Citocromo P-450/metabolismo , HumanosRESUMEN
Antidepressants are among the most widely prescribed medications, yet only 35-45% of patients achieve remission following an initial antidepressant trial. The financial burden of treatment failures in direct treatment costs, disability claims, decreased productivity, and missed work may, in part, derive from a mismatch between optimal and actual prescribed medications. The present 1 year blinded and retrospective study evaluated eight direct or indirect health care utilization measures for 96 patients with a DSM-IV-TR diagnosis of depressive or anxiety disorder. The eight measures were evaluated in relation to an interpretive pharmacogenomic test and reporting system, designed to predict antidepressant responses based on DNA variations in cytochrome P450 genes (CYP2D6, CYP2C19, CYP2C9 and CYP1A2), the serotonin transporter gene (SLC6A4) and the serotonin 2A receptor gene (5HTR2A). All subjects had been prescribed at least one of 26 commonly prescribed antidepressant or antipsychotic medications. Subjects whose medication regimen included a medication identified by the gene-based interpretive report as most problematic for that patient and are in the 'red bin' (medication status of 'use with caution and frequent monitoring'), had 69% more total health care visits, 67% more general medical visits, greater than three-fold more medical absence days, and greater than four-fold more disability claims than subjects taking drugs categorized by the report as in the green bin ('use as directed') or yellow bin ('use with caution'). There were no correlations between the number of medications taken and any of the eight healthcare utilization measures. These results demonstrate that retrospective psychiatric pharmacogenomic testing can identify past inappropriate medication selection, which led to increased healthcare utilization and cost.
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Antidepresivos/economía , Trastornos de Ansiedad/economía , Trastorno Depresivo/economía , Recursos en Salud/estadística & datos numéricos , Farmacogenética/economía , Adulto , Análisis de Varianza , Antidepresivos/uso terapéutico , Trastornos de Ansiedad/tratamiento farmacológico , Sistema Enzimático del Citocromo P-450/genética , Trastorno Depresivo/tratamiento farmacológico , Recursos en Salud/economía , Humanos , Prescripción Inadecuada/economía , Persona de Mediana Edad , Receptor de Serotonina 5-HT2A/genética , Estudios Retrospectivos , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genéticaRESUMEN
Dimebon (dimebolin) treatment enhances cognition in patients with Alzheimer's disease (AD) or Huntington's disease. Although Dimebon was originally thought to improve cognition and memory through inhibition of acetylcholinesterase (AChE) and the N-methyl-d-aspartate (NMDA) receptor, the low in vitro affinity for these targets suggests that these mechanisms may not contribute to its clinical effects. To test this hypothesis, we assessed whether Dimebon enhances cognition in rats and if such an action is related to either mechanism or additional candidate mechanisms. Acute oral administration of Dimebon to rats (0.05, 0.5, and 5 mg/kg) enhanced cognition in a novel object recognition task and produced Dimebon brain concentrations of 1.7 +/- 0.43, 14 +/- 5.1, and 172 +/- 94 nM, respectively. At these concentrations, Dimebon did not alter the activity of recombinant human or rat brain AChE. Unlike the AChE inhibitors donepezil and galantamine, Dimebon did not change acetylcholine levels in the hippocampus or prefrontal cortex of freely moving rats. Dimebon displays affinity for the NMDA receptor (K(i) = 105 +/- 18 microM) that is considerably higher than brain concentrations associated with cognition enhancement in the novel object recognition task and 200-fold weaker than that of memantine (K(i) = 0.54 +/- 0.05 microM). Dimebon did not block NMDA-induced calcium influx in primary neuronal cells (IC(50) > 50 microM), consistent with a lack of significant effect on this pathway. The cognition-enhancing effects of Dimebon are unlikely to be mediated by AChE inhibition or NMDA receptor antagonism, and its mechanism of action appears to be distinct from currently approved medications for AD.
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Inhibidores de la Colinesterasa , Cognición/efectos de los fármacos , Indoles/farmacología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Reconocimiento en Psicología/efectos de los fármacos , Acetilcolina/metabolismo , Acetilcolinesterasa/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Química Encefálica/efectos de los fármacos , Donepezilo , Relación Dosis-Respuesta a Droga , Antagonistas de Aminoácidos Excitadores/farmacología , Indanos/farmacología , Indoles/sangre , Masculino , Memantina/farmacología , Microdiálisis , Piperidinas/farmacología , Desempeño Psicomotor/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Receptores Histamínicos H1/efectos de los fármacos , Receptores Histamínicos H1/metabolismo , Receptores de N-Metil-D-Aspartato/agonistasRESUMEN
Gene expression changes in neuropsychiatric and neurodegenerative disorders, and gene responses to therapeutic drugs, provide new ways to identify central nervous system (CNS) targets for drug discovery. This review summarizes gene and pathway targets replicated in expression profiling of human postmortem brain, animal models, and cell culture studies. Analysis of isolated human neurons implicates targets for Alzheimer's disease and the cognitive decline associated with normal aging and mild cognitive impairment. In addition to tau, amyloid-beta precursor protein, and amyloid-beta peptides (Abeta), these targets include all three high-affinity neurotrophin receptors and the fibroblast growth factor (FGF) system, synapse markers, glutamate receptors (GluRs) and transporters, and dopamine (DA) receptors, particularly the D2 subtype. Gene-based candidates for Parkinson's disease (PD) include the ubiquitin-proteosome system, scavengers of reactive oxygen species, brain-derived neurotrophic factor (BDNF), its receptor, TrkB, and downstream target early growth response 1, Nurr-1, and signaling through protein kinase C and RAS pathways. Increasing variability and decreases in brain mRNA production from middle age to old age suggest that cognitive impairments during normal aging may be addressed by drugs that restore antioxidant, DNA repair, and synaptic functions including those of DA to levels of younger adults. Studies in schizophrenia identify robust decreases in genes for GABA function, including glutamic acid decarboxylase, HINT1, glutamate transport and GluRs, BDNF and TrkB, numerous 14-3-3 protein family members, and decreases in genes for CNS synaptic and metabolic functions, particularly glycolysis and ATP generation. Many of these metabolic genes are increased by insulin and muscarinic agonism, both of which are therapeutic in psychosis. Differential genomic signals are relatively sparse in bipolar disorder, but include deficiencies in the expression of 14-3-3 protein members, implicating these chaperone proteins and the neurotransmitter pathways they support as possible drug targets. Brains from persons with major depressive disorder reveal decreased expression for genes in glutamate transport and metabolism, neurotrophic signaling (eg, FGF, BDNF and VGF), and MAP kinase pathways. Increases in these pathways in the brains of animals exposed to electroconvulsive shock and antidepressant treatments identify neurotrophic and angiogenic growth factors and second messenger stimulation as therapeutic approaches for the treatment of depression.
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Biomarcadores/análisis , Enfermedades del Sistema Nervioso Central/tratamiento farmacológico , Enfermedades del Sistema Nervioso Central/genética , Sistemas de Liberación de Medicamentos , Descubrimiento de Drogas/métodos , Perfilación de la Expresión Génica , Animales , Encéfalo/metabolismo , Encéfalo/fisiopatología , Línea Celular , Estudios de Evaluación como Asunto , Humanos , Trastornos Mentales/genética , Enfermedades Neurodegenerativas/genéticaRESUMEN
BACKGROUND: Genes associated with energy metabolism are decreased in schizophrenia brain and human and rodent diabetic skeletal muscle. These and other similarities between diabetes and schizophrenia suggest that an insulin signaling deficit may underlie schizophrenia. We determined with human SH-SY5Y neuroblastoma and astrocyte cell lines whether insulin or other molecules could modulate genes opposite to their change reported in schizophrenia brain. METHODS: Both cell lines were treated with insulin, insulin-like growth factor (IGF)-1, IGF-2, or brain-derived neurotrophic factor (BDNF). Genes whose expression was found with microarrays to be changed by insulin in a reciprocal manner to their change in schizophrenia were used in a 16-gene miniarray to identify small molecules that might mimic insulin. RESULTS: Insulin phosphorylated its receptor in the neuroblastoma cells but not in astrocytes and, like IGF-1, increased ERK1/2 and Akt phosphorylation. Insulin and IGF-1 increased the expression of genes decreased in schizophrenia, including those involved in mitochondrial functions, glucose and energy metabolism, hydrogen ion transport, and synaptic function. These gene effects were confirmed and shown to be dose related with the 16-gene miniarrays. Most of 1940 pharmacologically unique compounds failed to alter gene expression, with the exception of muscarinic agonists, which mimicked insulin and IGF-1, and which were blocked by the muscarinic antagonists atropine and telenzepine. CONCLUSIONS: Stimulation of muscarinic and insulin/IGF-1 receptors alter genes associated with metabolic and synaptic functions in a manner reciprocal to their changes in schizophrenia. Pharmacologic activation of these receptors may normalize genomic alterations in schizophrenia and better address root causes of this disease.
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Expresión Génica/efectos de los fármacos , Factor I del Crecimiento Similar a la Insulina/farmacología , Insulina/farmacología , Agonistas Muscarínicos/farmacología , Esquizofrenia/genética , Adulto , Trastorno Bipolar/patología , Encéfalo , Estudios de Casos y Controles , Línea Celular Tumoral , Corteza Cerebral , Femenino , Perfilación de la Expresión Génica/métodos , Humanos , Concentración de Iones de Hidrógeno , Masculino , Persona de Mediana Edad , Neuroblastoma , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Esquizofrenia/patologíaRESUMEN
BACKGROUND: Aripiprazole (Abilify) is an atypical antipsychotic drug primarily characterized by partial agonist activity at dopamine (DA) D2 receptors and low side effects. Based on pharmacologic properties that include a stabilization of mesocorticolimbic DA activity, a pathway implicated in addiction, aripiprazole was tested for its ability to prevent relapse to cocaine seeking in rats. METHODS: We assessed the dose-dependent effects of aripiprazole on conditioned cue-induced and cocaine-primed reinstatement of drug-seeking behavior following chronic intravenous cocaine self-administration in an animal model of relapse. RESULTS: Aripiprazole potently and dose-dependently attenuated responding on the previously cocaine-paired lever during both reinstatement conditions, with slightly greater efficacy at reducing conditioned-cued reinstatement. Aripiprazole was effective at doses that failed to alter cocaine self-administration, food self-administration, reinstatement of food-seeking behavior, or basal locomotor activity, suggesting selective effects of aripiprazole on motivated drug-seeking behavior. CONCLUSIONS: These results in a relapse model show that aripiprazole can block cocaine seeking without affecting other behaviors. The D2 partial agonist properties of aripiprazole likely account for the blockade of reinstatement of cocaine-seeking behavior. Given its established efficacy and tolerability as a treatment for psychosis, aripiprazole may be an excellent therapeutic choice for reducing craving and preventing relapse in people with cocaine dependency.
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Antipsicóticos/uso terapéutico , Conducta Adictiva/prevención & control , Trastornos Relacionados con Cocaína/psicología , Piperazinas/uso terapéutico , Quinolonas/uso terapéutico , Animales , Aripiprazol , Conducta Adictiva/etiología , Conducta Animal/efectos de los fármacos , Cocaína/administración & dosificación , Trastornos Relacionados con Cocaína/complicaciones , Condicionamiento Operante/efectos de los fármacos , Modelos Animales de Enfermedad , Inhibidores de Captación de Dopamina/administración & dosificación , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Extinción Psicológica/efectos de los fármacos , Masculino , Actividad Motora/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Prevención Secundaria , Autoadministración/métodosRESUMEN
Hemizygous deletion of a 3 Mb region of 22q11.2 is found in 1/4000 humans and produces 22q11 deletion syndrome (22q11DS). Up to 35% of 22q11DS patients develop schizophrenia, making it the second highest risk factor for schizophrenia. A mouse model for 22q11DS, the Df1/+ mouse, carries a hemizygous deletion in a region syntenic with the human deletion. Df1/+ mice are mostly viable but display deficits in prepulse inhibition and learning and memory, two common traits of schizophrenia thought to result, at least in part, from defects in hippocampal neurons. We used oligonucleotide microarrays and QRT-PCR to evaluate gene expression changes in hippocampal dentate granule neurons of Df1/+ mice versus wild-type littermates (n=12/group). The expression of only 287 genes changed with p value significance below 0.05 by microarray, yet 12 of the 21 Df1 region genes represented on the array showed highly significantly reduced expression compared to wild-type controls (33% on average, p values from 10(-3) to 10(-7)). Variants in two of these genes, COMT and PRODH, have been linked with schizophrenia. Overlap of the 287 genes with the reportedly reduced expression of mitochondrial, ubiquitin/proteasome, and synaptic plasticity genes in schizophrenia dentate granule neurons, was not significant. However, modest increases in expression of mitochondrial electron transport genes were observed in the Df1/+ mice. This perhaps indicates a compensation for mitochondrial dysfunction caused by the strongly reduced expression of the Df1 region-encoded mitochondrial enzymes proline dehydrogenase (Prodh) and thioredoxin reductase 2 (Txnrd2).
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Deleción Cromosómica , Cromosomas Humanos Par 22/genética , Giro Dentado/metabolismo , Giro Dentado/fisiopatología , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Hipocampo/fisiopatología , Neuronas/metabolismo , Animales , Catecol O-Metiltransferasa/genética , Catecol O-Metiltransferasa/metabolismo , Síndrome de DiGeorge/genética , Síndrome de DiGeorge/metabolismo , Síndrome de DiGeorge/fisiopatología , Biblioteca de Genes , Humanos , Ratones , Mutación Puntual/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Esquizofrenia/genética , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatologíaRESUMEN
BACKGROUND: Hippocampal dentate granule neurons are altered in schizophrenia, but it is unknown if their gene expressions change in schizophrenia or other psychiatric diseases. METHODS: Laser-captured dentate granule neurons from two groups of schizophrenia and control cases and from major depression and bipolar disease cases were examined for alterations in gene expression using complementary DNA (cDNA) microarrays and reverse transcription polymerase chain reaction (RT-PCR). RESULTS: Compared with 24 control cases, the 22 schizophrenia patients in both groups revealed decreases in clusters of genes that encode for protein turnover (proteasome subunits and ubiquitin), mitochondrial oxidative energy metabolism (isocitrate, lactate, malate, nicotinamide adenine dinucleotide [NADH], and succinate dehydrogenases; cytochrome C oxidase; adenosine triphosphate [ATP] synthase), and genes associated with neurite outgrowth, cytoskeletal proteins, and synapse plasticity. These changes were not obtained in 9 bipolar cases or 10 major depression cases and were not associated with age, sex, brain weight, body weight, postmortem interval, or drug history. Brain pH contributed to the variance of some genes but was mostly independent of the disease effect. CONCLUSIONS: Decreases in hippocampal neuron gene expression are consistent with brain imaging and microarray studies of the frontal cortex in schizophrenia. A mitochondrial and ubiquitin-proteasome hypofunctioning of dentate granule neurons may contribute to the deficits of schizophrenia.
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Giro Dentado/metabolismo , Metabolismo Energético/genética , Neuronas/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Esquizofrenia/metabolismo , Ubiquitina/metabolismo , Análisis de Varianza , Trastorno Bipolar/genética , Trastorno Bipolar/metabolismo , Estudios de Casos y Controles , ADN Mitocondrial/análisis , Giro Dentado/patología , Trastorno Depresivo Mayor/genética , Trastorno Depresivo Mayor/metabolismo , Proteínas del Complejo de Cadena de Transporte de Electrón/genética , Proteínas del Complejo de Cadena de Transporte de Electrón/metabolismo , Perfilación de la Expresión Génica , Humanos , Concentración de Iones de Hidrógeno , Neuronas/patología , Análisis de Secuencia por Matrices de Oligonucleótidos , Complejo de la Endopetidasa Proteasomal/genética , Esquizofrenia/genética , Índice de Severidad de la Enfermedad , Ubiquitina/genéticaRESUMEN
Repeated maternal separation of rat pups during the early postnatal period may affect brain-derived neurotrophic factor (BDNF) or neurons in brain areas that are compromised by chronic stress. In the present study, a highly significant increase in hippocampal BDNF protein concentration was found in adult rats that as neonates had been subjected to 180 min of daily separation compared with handled rats separated for 15 min daily. BDNF protein was unchanged in the frontal cortex and hypothalamus/paraventricular nucleus. Expression of BDNF mRNA in the CA1, CA3, or dentate gyrus of the hippocampus or in the paraventricular hypothalamic nucleus was not affected by maternal separation. All animals displayed similar behavioral patterns in a forced-swim paradigm, which did not affect BDNF protein concentration in the hippocampus or hypothalamus. Repeated administration of bromodeoxyuridine revealed equal numbers of surviving, newly generated granule cells in the dentate gyrus of adult rats from the 15 min or 180 min groups. The age-dependent decline in neurogenesis from 3 months to 7 months of age did not differ between the groups. Insofar as BDNF can stimulate neurogenesis and repair, we propose that the elevated hippocampal protein concentration found in maternally deprived rats might be a compensatory reaction to separation during the neonatal period, maintaining adult neurogenesis at levels equal to those of the handled rats.
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Factor Neurotrófico Derivado del Encéfalo/metabolismo , Hipocampo/metabolismo , Privación Materna , Neuronas/fisiología , Factores de Edad , Animales , Animales Recién Nacidos , Conducta Animal , Factor Neurotrófico Derivado del Encéfalo/genética , Bromodesoxiuridina/metabolismo , Recuento de Células , Ensayo de Inmunoadsorción Enzimática/métodos , Femenino , Regulación de la Expresión Génica/fisiología , Hipocampo/citología , Inmunohistoquímica/métodos , Hibridación in Situ/métodos , Masculino , Embarazo , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Células Madre/citología , Células Madre/metabolismo , Estrés Fisiológico/metabolismo , NataciónRESUMEN
Valproate, an anticonvulsant drug used to treat bipolar disorder, was studied for its ability to promote neurogenesis from embryonic rat cortical or striatal primordial stem cells. Six days of valproate exposure increased by up to fivefold the number and percentage of tubulin beta III-immunopositive neurons, increased neurite outgrowth, and decreased by fivefold the number of astrocytes without changing the number of cells. Valproate also promoted neuronal differentiation in human fetal forebrain stem cell cultures. The neurogenic effects of valproate on rat stem cells exceeded those obtained with the neurotrophins brain-derived growth factor (BDNF) or NT-3, and slightly exceeded the effects obtained with another mood stabilizer, lithium. No effect was observed with carbamazepine. Most of the newly formed neurons were GABAergic, as shown by 10-fold increases in neurons that immunostained for GABA and the GABA-synthesizing enzyme GAD65/67. Double immunostaining for bromodeoxyuridine and tubulin beta III showed that valproate increased by four- to fivefold the proliferation of neuronal progenitors derived from rat stem cells and increased cyclin D2 expression. Valproate also regulated the expression of survival genes, Bad and Bcl-2, at different times of treatment. The expression of prostaglandin E synthase, analyzed by quantitative RT-PCR, was increased by ninefold as early as 6 h into treatment by valproate. The enhancement of GABAergic neuron numbers, neurite outgrowth, and phenotypic expression via increases in the neuronal differentiation of neural stem cell may contribute to the therapeutic effects of valproate in the treatment of bipolar disorder.
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Neuronas/efectos de los fármacos , Prosencéfalo/citología , Células Madre/efectos de los fármacos , Ácido Valproico/farmacología , Ácido gamma-Aminobutírico/metabolismo , Animales , Astrocitos/efectos de los fármacos , Astrocitos/fisiología , Western Blotting/métodos , Bromodesoxiuridina/metabolismo , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Recuento de Células/métodos , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Ciclina D2 , Ciclinas/metabolismo , Relación Dosis-Respuesta a Droga , Embrión de Mamíferos , Inhibidores Enzimáticos/farmacología , Proteína Ácida Fibrilar de la Glía/metabolismo , Glutamato Descarboxilasa/metabolismo , Histonas/metabolismo , Humanos , Ácidos Hidroxámicos/farmacología , Inmunohistoquímica/métodos , Interleucina-6/farmacología , Factor Inhibidor de Leucemia , Cloruro de Litio/farmacología , Neuronas/fisiología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , ARN Mensajero/biosíntesis , Ratas , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Células Madre/fisiología , Factores de Tiempo , Transactivadores/genética , Transactivadores/metabolismo , Tretinoina/farmacología , Tubulina (Proteína)/metabolismo , Proteína Letal Asociada a bclRESUMEN
The antipsychotic efficacy of aripiprazole is not generally associated with extrapyramidal symptoms, cardiovascular effects, sedation or elevations in serum prolactin that characterize typical or atypical antipsychotics. The aim of this study was to clarify the mechanism of action of aripiprazole that underlies its favourable clinical profiles. The preclinical efficacy and side-effect profiles of aripiprazole were evaluated using several pharmaco-behavioural test systems in mice and rats, both in vivo and ex vivo, and compared with those of other conventional and atypical antipsychotics. Each of the antipsychotics induced catalepsy and inhibited apomorphine-induced stereotypy. The catalepsy liability ratios for these drugs were 6.5 for aripiprazole, 4.7 for both olanzapine and risperidone. The ptosis liability ratios for aripiprazole, olanzapine and risperidone were 14, 7.2 and 3.3, respectively. Aripiprazole slightly increased DOPA accumulation in the forebrain of reserpinised mice, reduced 5-HTP accumulation at the highest dose and exhibited a weaker inhibition of 5-methoxy-N,N-dimethyl-tryptamine-induced head twitches. Aripiprazole did not inhibit physostigmine- or norepinephrine-induced lethality in rats. In conclusion, aripiprazole shows a favourable preclinical efficacy and side-effect profile compared to a typical antipsychotics. This profile may result from its high affinity partial agonist activity at D2 and 5-HT1A receptors and its antagonism of 5-HT2A receptors.