RESUMO

INTRODUCTION: Rare genetic functional variants can contribute to 30-40% of functional variability in genes relevant to drug action. Therefore, we investigated the role of rare functional variants in antidepressant response. METHOD: Mexican-American individuals meeting the Diagnostic and Statistical Manual-IV criteria for major depressive disorder (MDD) participated in a prospective randomized, double-blind study with desipramine or fluoxetine. The rare variant analysis was performed using whole-exome genotyping data. Network and pathway analyses were carried out with the list of significant genes. RESULTS: The Kernel-Based Adaptive Cluster method identified functional rare variants in 35 genes significantly associated with treatment remission (False discovery rate, FDR <0.01). Pathway analysis of these genes supports the involvement of the following gene ontology processes: olfactory/sensory transduction, regulation of response to cytokine stimulus, and meiotic cell cycleprocess. LIMITATIONS: Our study did not have a placebo arm. We were not able to use antidepressant blood level as a covariate. Our study is based on a small sample size of only 65 Mexican-American individuals. Further studies using larger cohorts are warranted. CONCLUSION: Our data identified several rare functional variants in antidepressant drug response in MDD patients. These have the potential to serve as genetic markers for predicting drug response. TRIAL REGISTRATION: ClinicalTrials.gov NCT00265291.

Assuntos

Transtorno Depressivo Maior , Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Método Duplo-Cego , Humanos , Americanos Mexicanos/genética , Farmacogenética , Estudos Prospectivos , Resultado do Tratamento

RESUMO

Coronavirus disease 2019 (Covid-19) has affected millions of people and may disproportionately affect those with hypertension and diabetes. Because of inadequate methods in published systematic reviews, the prevalence of diabetes and hypertension and associated risks of poor outcomes in Covid-19 patients are unknown. We searched databases from December 1, 2019, to April 6, 2020, and selected observational peer-reviewed studies in English of patients with Covid-19. Independent reviewers extracted data on study participants, interventions, and outcomes and assessed risk of bias, and the certainty of evidence. We included 65 (15 794 participants) observational studies at moderate to high risk of bias. Overall prevalence of diabetes and hypertension was 12% (95% confidence interval [CI], 10-15; n = 12 870; I 2: 89%), and 17% (95% CI, 13-22; n = 12 709; I 2: 95%), respectively. In severe Covid-19, the prevalence of diabetes and hypertension were 18% (95% CI, 16-20; n = 1099; I 2: 0%) and 32% (95% CI, 16-54; n = 1078; I 2: 63%), respectively. Unadjusted relative risk for intensive care unit admission and mortality were 1.96 (95% CI, 1.19-3.22; n = 8890; I 2: 80%; P = .008) and 2.78 (95% CI, 1.39-5.58; n = 2058; I 2: 75%; P = .0004) for diabetics; and 2.95 (95% CI, 2.18-3.99; n = 1737; I 2: 0%; P < .001) and 2.39 (95% CI, 1.54-3.73; n = 3107; I 2: 66%; P < .001) for hypertensives. Neither diabetes (1.50; 95% CI, 0.90-2.50; n = 1991; I 2: 74%; P = .119) nor hypertension (1.48; 95% CI, 0.99-2.23; n = 2023; I 2: 69%; P = .058) was associated with severe Covid-19. In conclusion, the risk of intensive care unit admission and mortality for patients with diabetes or hypertension who developed Covid-19 is increased compared with those without these comorbidities. PROSPERO REGISTRATION NUMBER: CRD42020176582.

RESUMO

OBJECTIVE: The authors compared the effectiveness of fluoxetine and desipramine treatment in a prospective double-blind pharmacogenetics study in first-generation Mexican Americans and examined the role of whole-exome functional gene variations in the patients' antidepressant response. METHOD: A total of 232 Mexican Americans who met DSM-IV criteria for major depressive disorder were randomly assigned to receive 8 weeks of double-blind treatment with desipramine (50-200 mg/day) or fluoxetine (10-40 mg/day) after a 1-week placebo lead-in period. Outcome measures included the Hamilton Depression Rating Scale (HAM-D), the Hamilton Anxiety Rating Scale, and the Beck Depression Inventory. At week 8, whole-exome genotyping data were obtained for 36 participants who remitted and 29 who did not respond to treatment. RESULTS: Compared with desipramine treatment, fluoxetine treatment was associated with a greater reduction in HAM-D score, higher response and remission rates, shorter time to response and remission, and lower incidences of anticholinergic and cardiovascular side effects. Pharmacogenetics analysis showed that exm-rs1321744 achieved exome-wide significance for treatment remission. This variant is located in a brain methylated DNA immunoprecipitation sequencing site, which suggests that it may be involved in epigenetic regulation of neuronal gene expression. This and two other common gene variants provided a highly accurate cross-validated predictive model for treatment remission of major depression (receiver operating characteristic integral=0.95). CONCLUSIONS: Compared with desipramine, fluoxetine treatment showed a more rapid reduction of HAM-D score and a lower incidence of side effects in a population comprising primarily first-generation Mexican Americans with major depression. This study's pharmacogenetics approach strongly implicates the role of functional variants in antidepressant treatment response.

Assuntos

Antidepressivos/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/genética , Transtorno Depressivo Maior/tratamento farmacológico , Desipramina/uso terapêutico , Fluoxetina/uso terapêutico , Americanos Mexicanos , Polimorfismo de Nucleotídeo Único , Inibidores da Captação Adrenérgica/uso terapêutico , Adulto , Idoso , Antidepressivos/administração & dosagem , Antidepressivos/efeitos adversos , Antidepressivos de Segunda Geração/uso terapêutico , Antidepressivos Tricíclicos/uso terapêutico , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/psicologia , Desipramina/administração & dosagem , Desipramina/efeitos adversos , Método Duplo-Cego , Esquema de Medicação , Epigênese Genética , Feminino , Fluoxetina/administração & dosagem , Fluoxetina/efeitos adversos , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Farmacogenética , Valor Preditivo dos Testes , Estudos Prospectivos , Escalas de Graduação Psiquiátrica , Projetos de Pesquisa , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Resultado do Tratamento

RESUMO

During marijuana and alcohol consumption as well as during inflammation the reproductive axis is inhibited, mainly through the inhibition of luteinizing hormone-releasing hormone release. In male rats, this inhibitory effect is mediated, at least in part, by the activation of hypothalamic cannabinoid type 1 receptors (CB1). During inflammation, this activation of the endocannabinoid system seems to be mediated by an increase in TNF-alpha production followed by anandamide augmentations, similarly the effect of intragastric administration of ethanol (3 g/kg) seems to be due to an increase in anandamide. On the other hand, a number of different actions mediated by the endocannabinoid system in various organs and tissues have been described. Both cannabinoid receptors, CB1 and CB2, are localized in the submandibular gland where they mediate the inhibitory effect of intrasubmandibular injections of the endocannabinoid anandamide (6 x 10(-5)M) on salivary secretion. Lipopolysaccharide (5 mg/kg/3 h) injected intraperitoneally and ethanol (3 g/kg/1 h) injected intragastrically inhibited the salivary secretion induced by the sialogogue metacholine; this inhibitory effect was blocked by CB1 and/or CB2 receptor antagonists. Similar to the hypothalamus, these effects seem to be mediated by increased anandamide. In summary, similar mechanisms mediate the inhibitory actions of endocannabinoids and cannabinoids in both hypothalamus and submandibular gland during drug consumption and inflammation.

Assuntos

Moduladores de Receptores de Canabinoides/fisiologia , Endocanabinoides , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Inflamação/tratamento farmacológico , Glândulas Salivares/efeitos dos fármacos , Fator de Necrose Tumoral alfa/fisiologia , Animais , Ácidos Araquidônicos/metabolismo , Canabinoides/farmacologia , Etanol/farmacologia , Humanos , Sistema Hipotálamo-Hipofisário/imunologia , Sistema Hipotálamo-Hipofisário/metabolismo , Inflamação/imunologia , Alcamidas Poli-Insaturadas/metabolismo , Receptores de Canabinoides/efeitos dos fármacos , Receptores de Canabinoides/imunologia , Glândulas Salivares/imunologia , Glândulas Salivares/metabolismo

RESUMO

It is known that Delta(9)-tetrahydrocannabinol (THC), the major active ingredient of marijuana, can suppress reproductive function. Also, we reported previously that the endocannabinoid, anandamide (AEA), inhibited gonadotropin-releasing hormone (LHRH) release from medial basal hypothalamus (MBH) of male rats incubated in vitro as well as reduced plasma LH levels after i.c.v. AEA injections into the cerebral lateral ventricle. On the other hand, it is known that during endotoxemia the hypothalamic gonadotropin axis is inhibited. Therefore, the aim of the present study was to determine whether the effect of TNF-alpha, a proinflammatory cytokine induced by lipopolysaccharide (LPS) that inhibits LHRH release, is mediated by the activation of the endocannabinoid system. The intraperitoneal injection of LPS (5 mg/kg) as well as the i.c.v. injection of tumor necrosis factor-alpha (TNF-alpha) (100 ng/rat) increased significantly the AEA synthesis measured ex vivo in MBHs removed 3 h after the treatments. To examine the possibility that TNF-alpha also acted by increasing the synthesis of AEA that was released and activated the CB1-r followed by inhibition of LHRH release, we measured the effect of TNF-alpha on the AEA synthase activity in MBHs incubated in vitro. As expected, we found that TNF-alpha (2.9 x 10(-9) M) increased the AEA synthesis. Second, we showed that TNF-alpha reduced significantly the forskolin-stimulated LHRH release and that the CB1-r antagonist AM251 (10(-5) M) blocked that inhibition, supporting the hypothesis that TNF-alpha inhibits LHRH release, acting at least in part by activating the endocannabinoid system. Therefore, our data demonstrate a key role for the endocannabinoid system in the response of the reproductive system to inflammatory signals.

Assuntos

Moduladores de Receptores de Canabinoides/metabolismo , Endocanabinoides , Hormônio Liberador de Gonadotropina/metabolismo , Hipotálamo/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Amidoidrolases/metabolismo , Animais , Colforsina/farmacologia , AMP Cíclico/metabolismo , Ativação Enzimática/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Hipotálamo/imunologia , Injeções Intraperitoneais , Injeções Intraventriculares , Lipopolissacarídeos/farmacologia , Masculino , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/metabolismo , Fator de Necrose Tumoral alfa/metabolismo

RESUMO

The adrenal cortex is a major stress organ in mammals that reacts rapidly to a multitude of external and internal stressors. Adrenocorticotropin (ACTH) is the main stimulator of the adrenal cortex, activating corticosteroid synthesis and secretion. We evaluated the mechanism of action of ACTH on adrenals of male rats, preserving the architecture of the gland in vitro. We demonstrated that both sodium nitroprusside (NP), a nitric oxide (NO) donor, and ACTH stimulate corticosterone release. NO mediated the acute response to ACTH because Nomega-nitro-l-arginine methyl ester, a NO synthase inhibitor, and hemoglobin, a NO scavenger, blocked the stimulation of corticosterone release induced by ACTH. NP stimulated prostaglandin E release, which in turn stimulated corticosterone release from the adrenal. Additionally, indomethacin, which inhibits cyclooxygenase, and thereby, prostaglandin release, prevented corticosterone release from the adrenal induced by both NP and ACTH, demonstrating that prostaglandins mediate acute corticosterone release. Corticosterone content in adrenals after incubation with ACTH or NP was lower than in control glands, indicating that any de novo synthesis of corticosterone during this period was not sufficient to keep up with the release of the stored hormone. The release induced by ACTH or NP depleted the corticosterone content in the adrenal by approximately 40% compared with the content of glands incubated in buffer. The mechanism of rapid release is as follows: NO produced by NO synthase activation by ACTH activates cyclooxygenase, which generates PGE(2), which in turn releases corticosterone stored in microvesicles and other organelles.

Assuntos

Córtex Suprarrenal/metabolismo , Hormônio Adrenocorticotrópico/fisiologia , Corticosterona/metabolismo , Dinoprostona/farmacologia , Óxido Nítrico/fisiologia , Córtex Suprarrenal/efeitos dos fármacos , Hormônio Adrenocorticotrópico/metabolismo , Animais , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Nitroprussiato/farmacologia , Ratos , Ratos Wistar