RESUMEN
BACKGROUND: The 'off-label' effect of alprazolam on depression has not been systematically evaluated. OBJECTIVES: To determine the antidepressant effect, including tolerability and acceptability, of alprazolam as monotherapy for major depression, when compared to placebo and conventional antidepressants in outpatients and patients in primary care. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials and the Cochrane Depression, Anxiety and Neurosis Group Register, which includes relevant randomised controlled trials from the following bibliographic databases: The Cochrane Library (all years to February 2012); EMBASE (1970 to February 2012); MEDLINE (1950 to February 2012) and PsycINFO (1960 to February 2012). Two review authors identified relevant trials by assessing the abstracts of all possible studies. We applied no language restrictions. SELECTION CRITERIA: We selected randomised controlled trials (RCTs) of alprazolam versus placebo or conventional antidepressants for depression in adults, excluding studies with inpatients only. DATA COLLECTION AND ANALYSIS: Two review authors performed the data extraction and 'Risk of bias' assessment independently with disagreements resolved through discussion with a third review author. Primary outcomes included the mean difference (MD) in reduction of depression on a continuous measure of depression symptoms, and the risk ratio (RR) of the clinical response based on a dichotomous measure, with 95% confidence intervals (CI). MAIN RESULTS: We identified 21 alprazolam studies (22 reports) with a total of 2693 participants. Seven studies used a placebo (n = 771) and 20 used cyclic antidepressants (n = 1765). The typical duration of the studies was four to six weeks. We considered six studies to have a high risk of bias.When alprazolam was compared with placebo for reduction in symptoms all estimates indicated a positive effect for alprazolam. Pooled estimates of efficacy data showed a moderately large continuous mean difference (MD) at the end of trial (-5.34, 95% CI -7.48 to -3.20; I(2) = 68%). The risk difference (RD) for the dichotomous measure of clinical response (50% improvement) was 0.32 in favour of alprazolam (95% CI 0.22 to 0.42; I(2) = 0%), with a number needed to treat to benefit (NNTB) of 3 (95% CI 2 to 5). The RD of all-cause withdrawals did not differ between alprazolam and placebo.When depression severity was measured as a continuum the effect of alprazolam did not differ statistically or clinically from the effects of any of the conventional antidepressants combined (MD 0.25, 95% CI -0.93 to 1.43; I(2) = 55%). However, for dichotomised depression severity, alprazolam had less effect than antidepressants (RR 0.86, 95% CI 0.75 to 0.99; I(2) = 37%; RD -0.11, 95% CI -0.24 to 0.01; I(2) = 58%; NNTB 9, 95% CI 4 to 100). The RD of all-cause withdrawals was -0.04 (95% CI -0.07 to 0.00; I(2) = 35%), in favour of alprazolam. AUTHORS' CONCLUSIONS: Alprazolam appears to reduce depressive symptoms more effectively than placebo and as effectively as tricyclic antidepressants. However, the studies included in the review were heterogeneous, of poor quality and only addressed short-term effects, thus limiting our confidence in the findings. Whilst the rate of all-cause withdrawals did not appear to differ between alprazolam and placebo, and withdrawals were less frequent in the alprazolam group than in any of the conventional antidepressants combined group, these findings should be interpreted with caution, given the dependency properties of benzodiazepines.
Asunto(s)
Alprazolam/uso terapéutico , Antidepresivos/uso terapéutico , Depresión/tratamiento farmacológico , Adulto , Anciano , Humanos , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
CONTEXT: Elevated plasma free fatty acids, excess reactive oxygen species, inflammation, and gluco-counterregulatory hormones induce insulin resistance (IR) through activation of Jun NH(2)-terminal kinase and nuclear factor-kappaB inhibitor kappaB kinase, which leads to hyperphosphorylation of the insulin receptor substrate type 1. Aspirin blocks nuclear factor-kappaB inhibitor kappaB kinase and improves IR in type 2 diabetes mellitus. OBJECTIVE: We hypothesized that high-dose aspirin would also attenuate fasting-induced IR in healthy lean subjects. DESIGN: Glucose and glutathione (GHS) metabolism was studied after 12 and 60 h of fasting on two occasions: with and without aspirin (6 g/d). SETTING: The study took place at the Academic Medical Center, Metabolic Research Unit. PARTICIPANTS: Six healthy lean men participated. INTERVENTION: Intervention included 60 h of fasting with or without aspirin ( approximately 6 g/d). MAIN OUTCOME MEASURE: Main outcome measures included glucose and GSH metabolism. RESULTS: Fasting decreased insulin-mediated peripheral glucose uptake by 46% after 60 h (P = 0.03). Aspirin did not alter this effect of 60 h of fasting on insulin sensitivity (P = 0.03). GSH concentration decreased during fasting, but the fractional synthetic rate of GSH was unaffected either with or without aspirin. Fasting did not affect inflammatory parameters, although aspirin increased soluble TNF receptors I and II. CONCLUSION: Prolonged fasting induces profound peripheral IR. In contrast to type 2 diabetes mellitus, high-dose salicylate does not affect fasting-induced peripheral IR.
Asunto(s)
Aspirina/farmacología , Inhibidores Enzimáticos/farmacología , Ayuno/metabolismo , Resistencia a la Insulina/fisiología , Adulto , Glucosa/metabolismo , Técnica de Clampeo de la Glucosa , Glutatión/metabolismo , Humanos , Insulina/sangre , Masculino , Pérdida de Peso/efectos de los fármacos , Pérdida de Peso/fisiologíaRESUMEN
OBJECTIVE: Our objective was to measure insulin sensitivity and body composition in antipsychotic-naive patients with DSM IV schizophrenia and/or schizoaffective disorder compared with matched controls. DESIGN: Seven antipsychotic medication-naive patients fulfilling the DSM IV A criteria for schizophrenia/schizoaffective disorder were matched for body mass index, age, and sex with seven control subjects. We measured endogenous glucose production and peripheral glucose disposal using a hyperinsulinemic euglycemic clamp (plasma insulin concentration approximately 200 pmol/liter) in combination with stable isotopes. Fat content and fat distribution were determined with a standardized single-slice computed tomography scan and whole body dual-energy x-ray absorptiometry. RESULTS: Endogenous glucose production during the clamp was 6.7 micromol/kg x min (sd 2.7) in patients vs. 4.1 micromol/kg x min (sd 1.6) in controls (P = 0.02) (95% confidence interval -5.2 to 0.006). Insulin-mediated peripheral glucose uptake was not different between patients and controls. The amount of sc abdominal fat in patients was 104.6 +/- 28.6 cm(3) and 63.7 +/- 28.0 cm(3) in controls (P = 0.04) (95% confidence interval 4.4-77.2). Intraabdominal fat and total fat mass were not significantly different. CONCLUSIONS: Antipsychotic medication-naive patients with schizophrenia or schizoaffective disorder display hepatic insulin resistance compared with matched controls. This finding cannot be attributed to differences in intraabdominal fat mass or other known factors associated with hepatic insulin resistance and suggests a direct link between schizophrenia and hepatic insulin resistance.
Asunto(s)
Glucemia/metabolismo , Resistencia a la Insulina/fisiología , Insulina/metabolismo , Hígado/metabolismo , Esquizofrenia/metabolismo , Absorciometría de Fotón , Adulto , Composición Corporal/fisiología , Calorimetría Indirecta , Estudios de Casos y Controles , Epinefrina/sangre , Ácidos Grasos no Esterificados/sangre , Glucagón/sangre , Técnica de Clampeo de la Glucosa , Humanos , Hidrocortisona/sangre , Insulina/sangre , Masculino , Norepinefrina/sangre , Consumo de Oxígeno/fisiología , Estadísticas no ParamétricasRESUMEN
CONTEXT: Thiazolidinediones increase peripheral insulin sensitivity and decrease plasma free fatty acids (FFA). However, their exact mechanism of action has not been fully elucidated. OBJECTIVE: We studied the protective effect of pioglitazone on FFA-induced insulin resistance and the effects on intramyocellular glycosphingolipids. DESIGN: We studied glucose metabolism in the basal state and during a hyperinsulinemic euglycemic clamp by using stable isotopes. Studies were performed at baseline and after 4 months of treatment with pioglitazone. Patients were then studied on a third occasion during infusion of a lipid emulsion to increase plasma FFA to pretreatment levels. All studies were combined with muscle biopsies to measure intramyocellular ceramide and glycosphingolipids. PATIENTS: Patients were obese with poorly controlled type 2 diabetes mellitus. INTERVENTION: Patients were treated with 30 mg pioglitazone once daily. MAIN OUTCOME MEASURE: The change in peripheral insulin sensitivity after treatment with pioglitazone and during the infusion of the lipid emulsion was the main outcome measure. RESULTS: Peripheral glucose uptake (Rd) increased significantly, but returned to baseline levels after increasing plasma FFA to pretreatment levels. Insulin-mediated suppression of FFA was increased significantly. Intramyocellular ceramide concentrations were higher during the hyperinsulinemic clamp after treatment with pioglitazone, but not in the basal state. The intramyocellular content of glycosphingolipids and plasma concentrations of ceramide and glycosphingolipids did not change. CONCLUSIONS: Pioglitazone increases Rd and insulin-mediated suppression of plasma FFA, but does not protect patients with type 2 diabetes mellitus from FFA-induced insulin resistance. This effect of pioglitazone is not attained via a decrease in intramyocellular concentrations of ceramide or glycosphingolipids.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Ácidos Grasos no Esterificados/fisiología , Hipoglucemiantes/uso terapéutico , Resistencia a la Insulina , Obesidad/complicaciones , Tiazolidinedionas/uso terapéutico , Adiponectina/sangre , Ceramidas/sangre , Diabetes Mellitus Tipo 2/sangre , Femenino , Glucosa/metabolismo , Glucosilceramidas/sangre , Humanos , Masculino , Pioglitazona , Análisis de RegresiónRESUMEN
The aim of this study was to examine the mechanisms by which dietary carbohydrate and fat modulate fasting glycemia. We compared the effects of an eucaloric high-carbohydrate (89% carbohydrate) and high-fat (89% fat) diet on fasting glucose metabolism and insulin sensitivity in seven obese patients with type 2 diabetes using stable isotopes and euglycemic hyperinsulinemic clamps. At basal insulin levels glucose concentrations were 148 +/- 11 and 123 +/- 11 mg/dl (8.2 +/- 0.6 and 6.8 +/- 0.6 mmol/liter) on the high-carbohydrate and high-fat diet, respectively (P < 0.001), with insulin concentrations of 12 +/- 2 and 10 +/- 1 microIU/ml (82 +/- 11 and 66 +/- 10 pmol/liter) (P = 0.08). Glucose production was higher on the high-carbohydrate diet (1.88 +/- 0.06 vs. 1.55 +/- 0.05 mg/kg.min (10.44 +/- 0.33 vs. 8.61 +/- 0.28 micromol/kg.min) (P < 0.001) because of higher glycogenolysis. Gluconeogenic rates were not different between the diets. During the use of hyperinsulinemic euglycemic clamps, insulin-mediated suppression of glucose production and stimulation of glucose disposal were not different between the diets. Free fatty concentrations were suppressed by 89 and 62% (P < 0.0001) on the high-carbohydrate and high-fat diet, respectively. We conclude that short-term variations in dietary carbohydrate to fat ratios affect basal glucose metabolism in people with type 2 diabetes merely through modulation of the rate of glycogenolysis, without affecting insulin sensitivity of glucose metabolism.
Asunto(s)
Diabetes Mellitus Tipo 2/dietoterapia , Diabetes Mellitus Tipo 2/metabolismo , Carbohidratos de la Dieta/administración & dosificación , Grasas de la Dieta/administración & dosificación , Glucosa/metabolismo , Glucógeno/metabolismo , Periodo Posprandial , Diabetes Mellitus Tipo 2/sangre , Relación Dosis-Respuesta a Droga , Femenino , Técnica de Clampeo de la Glucosa , Humanos , Insulina/sangre , Masculino , Persona de Mediana Edad , Concentración OsmolarRESUMEN
Treatment for HIV-1 infection is often complicated by a lipodystrophy syndrome associated with insulin resistance and an elevated rate of lipolysis. In eight HIV-1 infected men with lipodystrophy syndrome, we studied the effects of replacement of protease inhibitor (PI) by abacavir on insulin sensitivity and lipolysis by hyperinsulinemic euglycemic clamp and on fat distribution assessed by dual-energy x-ray absorptiometry and computed tomography scan. Glucose metabolism and lipolysis were assessed by tracer dilution employing [6,6-(2)H(2)]glucose and [(2)H(5)]glycerol, respectively. Data are expressed as mean +/- sd or 95% confidence interval (CI), as appropriate. There were no significant changes in fat distribution assessed by dual-energy x-ray absorptiometry and computed tomography scan at wk 36 and wk 96. The fasting total glucose production decreased from 16.1 +/- 2.5 at study entry by 1.1 (range, -2.1 to -0.1) to 15.0 +/- 1.5 micromol/kg.min after PI withdrawal at wk 36 (n = 8). In an analysis restricted to the patients on treatment at wk 96 (n = 6), the decrease was 0.9 (range, -2.1 to 0.3) micromol/kg.min. During insulin infusion, glucose oxidation (as percent of total glucose disposal) increased from 36.8 +/- 12.7% by 11.0% (range, 1.3-20.8) to 47.9 +/- 13.9% in the wk 36 analysis. In the analysis restricted to the patients on treatment at wk 96 (n = 6) the increase was 7.7 (-4.0 to 19.4)%. Fasting lipolysis decreased from 2.7 +/- 0.6 micromol/kg.min by 0.9 (-1.6 to -0.2) to 1.8 +/- 0.3 micromol/kg.min in the wk-96 analysis (n = 6). The replacement of the studied PIs by abacavir in severe lipodystrophic HIV-1-infected patients results in a marked reduction of lipolysis. In contrast, fasting glucose production and insulin-stimulated glucose oxidation improve moderately, whereas insulin-stimulated glucose disposal and fat distribution do not change.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Didesoxinucleósidos/uso terapéutico , Glucosa/metabolismo , Síndrome de Lipodistrofia Asociada a VIH/metabolismo , Lipólisis/efectos de los fármacos , Inhibidores de Proteasas/administración & dosificación , Absorciometría de Fotón , Tejido Adiposo/diagnóstico por imagen , Adulto , Composición Corporal/efectos de los fármacos , Esquema de Medicación , Técnica de Clampeo de la Glucosa , Glicerol/metabolismo , Síndrome de Lipodistrofia Asociada a VIH/diagnóstico por imagen , Síndrome de Lipodistrofia Asociada a VIH/fisiopatología , Humanos , Resistencia a la Insulina , Masculino , Persona de Mediana Edad , Retratamiento , Índice de Severidad de la Enfermedad , Tomografía Computarizada por Rayos XRESUMEN
Fasting gluconeogenesis (GNG) is often quantified using the 2H2O technique, which is based on plasma 2H2O enrichment and ensuing enrichment of plasma glucose at the C5 and C2 positions. Fractional (fr)GNG can be calculated using the ratio of C5 to C2 enrichment or the ratio of C5 to plasma 2H2O enrichment. For the latter, equilibration of 2H2O and C2 is required. The optimal equilibration period of 2H2O and C2 remains to be elucidated. In six healthy male subjects fasted for 18 h, we studied the effects of 3-, 5-, and 15-h 2H2O incubation periods on 1) the equilibration of plasma 2H2O and C2 glucose enrichment, 2) the measurement of frGNG, and 3) C5 labeling of hepatic glycogen after 1 mg of glucagon administration. After 3-h 2H2O incubation, plasma 2H2O and C2 were not equilibrated, frGNG C5/2H2O and C5/C2 were also different as was gluconeogenesis calculated with C5/2H2O and C5/C2. After 5- and 15-h 2H2O incubation, plasma 2H2O and C2 were equilibrated, and frGNG C5/2H2O and C5/C2 were similar, as was GNG calculated with C5/2H2O and C5/C2. After glucagon administration, no difference of C5 enrichment was found between 3, 5, and 15 h of 2H2O incubation. In conclusion, for reliable measurement of GNG in healthy subjects with C5/2H2O incubation periods longer than 3 h are required. After 5- and 15-h 2H2O incubation, GNG can be reliably measured with C5/2H2O. Gluconeogenetic labeling of glycogen did not affect the results after 3, 5, or 15 h of 2H2O incubation.