Asunto(s)
Antiinflamatorios/farmacología , Disfunción Cognitiva , Trastorno Depresivo , Fitosteroles/farmacología , Adulto , Animales , Disfunción Cognitiva/dietoterapia , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/metabolismo , Trastorno Depresivo/dietoterapia , Trastorno Depresivo/tratamiento farmacológico , Trastorno Depresivo/metabolismo , Humanos , RatasAsunto(s)
Antidepresivos/efectos adversos , Dieta , Cardiopatías/inducido químicamente , Enfermedades Renales/inducido químicamente , Litio/efectos adversos , Nitratos/administración & dosificación , Anciano , Antidepresivos/uso terapéutico , Dieta/estadística & datos numéricos , Cardiopatías/prevención & control , Humanos , Enfermedades Renales/prevención & control , Litio/uso terapéutico , Persona de Mediana EdadRESUMEN
PURPOSE: Rosenblat and McIntyre (Acta Psychiatr Scand. 2015;132: 180-191) propose that immune disorders are important mediators between bipolar disorders and medical comorbidities. Rosenblat et al (Bipolar Disord. 2016;18:89-101) present a meta-analysis showing that adjunctive anti-inflammatory agents could evoke moderate antidepressant responses in bipolar disorders. We propose using the anti-inflammatory drug colchicine to improve the long-term safety and efficacy of lithium treatment for bipolar disorders. METHODS: This report is based on searches of the PubMed and Web of Science databases. RESULTS: Bipolar disorders are associated with significant medical comorbidities such as hypertension, overweight/obesity, diabetes mellitus, metabolic syndrome, and arteriosclerosis, accompanied by enhanced release of pro-inflammatory markers during changes in mood state. During lithium therapy, granulocyte-colony stimulating factor, CD34+ hematopoietic stem/progenitor cells, and neutrophil elastase enter the circulation with activated neutrophils to promote the extravascular migration of activated neutrophils and enhance tissue inflammation. Concurrent treatment with lithium and low-dose colchicine could facilitate the responsiveness of bipolar patients to lithium by reducing leukocyte tissue emigration, the release of neutrophil elastase, and the release of leukocyte pro-inflammatory cytokines such as IL-1ß that are regulated by the NLRP3 inflammasome assembly complex. CONCLUSIONS: Concurrent therapy with lithium and low-dose colchicine could reduce complications involving leukocyte-mediated inflammatory states in bipolar patients and promote patient acceptance and responsiveness to lithium therapy.
Asunto(s)
Colchicina/administración & dosificación , Inflamación/prevención & control , Compuestos de Litio/efectos adversos , Antiinflamatorios/administración & dosificación , Antiinflamatorios/farmacología , Trastorno Bipolar/complicaciones , Trastorno Bipolar/tratamiento farmacológico , Colchicina/farmacología , Citocinas , Relación Dosis-Respuesta a Droga , Humanos , Inflamación/inducido químicamente , Compuestos de Litio/administración & dosificación , Aceptación de la Atención de Salud , Resultado del TratamientoRESUMEN
The stimulatory guanine nucleotide binding protein Gs couples many cellular receptors to adenylate cyclase, and the Gsα subunit activates all 9 isoforms of the adenylate cyclase catalytic unit to produce the enzyme product cyclicAMP or cAMP. In prefrontal cortex and cerebellum of unipolar depressive suicides, Rasenick and colleagues have found increased concentrations of Gsα in membrane lipid microdomains (Donati et al., 2008), where the ensconced Gsα is less likely to activate adenylate cyclase by receptor and postreceptor pathways (Allen et al., 2005, 2009). We report that a group of 7 depressed patients (DP-1) had (1) reduced activation of platelet receptor-stimulated adenylate cyclase by both prostaglandins E2 and D2 compared to controls, and (2) reduced postreceptor stimulation of adenylate cyclase by aluminum fluoride ion in both platelets and mononuclear leukocytes when compared to both another group of depressed patients (DP-2, n = 17) and to controls (n = 21). Our observations in the blood cells of the group DP-1 support the findings of Donati et al. (2008), and they reflect the importance of this interaction between the activated Gsα subunit and membrane lipid microdomains in the pathophysiology and treatment of some major depressive disorders.
Asunto(s)
Adenilil Ciclasas/metabolismo , Células Sanguíneas/metabolismo , Trastorno Depresivo Mayor/sangre , Subunidades alfa de la Proteína de Unión al GTP Gs/metabolismo , Microdominios de Membrana/metabolismo , Prostaglandinas/metabolismo , Adulto , Compuestos de Aluminio/metabolismo , Plaquetas/metabolismo , Dinoprostona/metabolismo , Femenino , Fluoruros/metabolismo , Humanos , Linfocitos/metabolismo , Masculino , Persona de Mediana Edad , Prostaglandina D2/metabolismoRESUMEN
To study the delay (2-6 weeks) between initial administration of norepinephrine reuptake inhibitor antidepressants and onset of clinical antidepressant action, we examined the effects of desipramine treatment on urinary and plasma catecholamines and their metabolites during the initial 6 weeks of treatment in depressed patients. Catecholamines and metabolites in 24-h urine collections and 8:00 a.m. plasma samples were measured at baseline and after 1, 4, and 6 weeks of desipramine treatment. Desipramine treatment produced significant increases in urinary norepinephrine (NE) and normetanephrine (NMN) and plasma NE at Weeks 4 and 6, but not at Week 1. The ratio of urinary NE/NMN was increased at Weeks 4 and 6, suggesting a reduction in the metabolism of NE to NMN at extraneuronal sites by Weeks 4 and 6. The increases in urinary NE and NMN and plasma NE at Weeks 4 and 6 of desipramine treatment were associated with a reduction in the conversion of NE to NMN. This would be compatible with a blockade of the extraneuronal monoamine transporter (organic cation transporter 3; SLC22A3) by NMN. Inhibition of the extraneuronal monoamine transporter may be an important component in the clinical pharmacology of the norepinephrine reuptake inhibitor antidepressant drugs, such as desipramine.
Asunto(s)
Inhibidores de Captación Adrenérgica/farmacología , Inhibidores de Captación Adrenérgica/uso terapéutico , Trastorno Depresivo/tratamiento farmacológico , Desipramina/farmacología , Desipramina/uso terapéutico , Norepinefrina/biosíntesis , Proteínas de Transporte de Catión Orgánico/efectos de los fármacos , Proteínas de Transporte de Catión Orgánico/metabolismo , Inhibidores de Captación Adrenérgica/metabolismo , Adulto , Catecolaminas/sangre , Catecolaminas/metabolismo , Catecolaminas/orina , Trastorno Depresivo/sangre , Trastorno Depresivo/orina , Desipramina/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Monoaminooxidasa/metabolismo , Norepinefrina/sangre , Norepinefrina/orina , Normetanefrina/biosíntesis , Normetanefrina/sangre , Normetanefrina/orina , Receptores Adrenérgicos alfa 2/efectos de los fármacos , Receptores Adrenérgicos alfa 2/metabolismoRESUMEN
OBJECTIVE: The authors considered the possible role of the extraneuronal monoamine transporter (uptake 2) in accounting for the delay in clinical action of norepinephrine reuptake inhibitor antidepressant drugs. METHOD: Literature searches were performed by means of the MEDLINE and Current Contents databases with search terms such as "extraneuronal uptake," "uptake 2," "extraneuronal monoamine transporter," and "organic cation transporter type-3." RESULTS: The findings in this literature indicate that inhibition of glial uptake 2 by normetanephrine or other inhibitors of uptake 2 would enhance the accumulation of norepinephrine in the synapse. CONCLUSIONS: The authors propose the hypothesis that drugs or other agents that increase levels of normetanephrine or otherwise inhibit the extraneuronal monoamine transporter, uptake 2, in the brain will speed up the clinical effects of norepinephrine reuptake inhibitor antidepressant drugs.