A Randomized, placebo-controlled, crossover pilot trial of the oral selective NR2B antagonist MK-0657 in patients with treatment-resistant major depressive disorder.

Converging lines of evidence suggest that the glutamatergic system may play an increasingly important role in the development of novel therapeutics for major depressive disorder (MDD), particularly agents associated with rapid antidepressant effects. Diverse glutamatergic modulators targeting N-methyl-D-aspartate receptors have shown efficacy in MDD, but their associated psychotomimetic effects presently preclude their use in larger samples. This small, randomized, double-blind, placebo-controlled, crossover pilot study evaluated the potential antidepressant efficacy and tolerability of an oral formulation of the selective N-methyl-D-aspartate NR2B antagonist MK-0657 in patients with treatment-resistant MDD (TRD). The TRD subjects underwent a 1-week drug-free period and were subsequently randomized to receive either MK-0657 monotherapy (4-8 mg/d) or placebo for 12 days. Because of recruitment challenges and the discontinuation of the compound's development by the manufacturer, only 5 of the planned 21 patients completed both periods of the crossover administration of MK-0657 and placebo. Significant antidepressant effects were observed as early as day 5 in patients receiving MK-0657 compared with those receiving placebo, as assessed by the Hamilton Depression Rating Scale and Beck Depression Inventory; however, no improvement was noted when symptoms were assessed with the Montgomery-Asberg Depression Rating Scale, the primary efficacy measure. No serious or dissociative adverse effects were observed in patients receiving this oral formulation of MK-0657. Despite the small sample size, this pilot study suggests that an oral formulation of the NR2B antagonist MK-0657 may have antidepressant properties in TRD patients. Further studies with larger sample sizes are necessary to confirm these preliminary findings.

Targeting glutamatergic signaling for the development of novel therapeutics for mood disorders.

There have been no recent advances in drug development for mood disorders in terms of identifying drug targets that are mechanistically distinct from existing ones. As a result, existing antidepressants are based on decades-old notions of which targets are relevant to the mechanisms of antidepressant action. Low rates of remission, a delay of onset of therapeutic effects, continual residual depressive symptoms, relapses, and poor quality of life are unfortunately common in patients with mood disorders. Offering alternative options is requisite in order to reduce the individual and societal burden of these diseases. The glutamatergic system is a promising area of research in mood disorders, and likely to offer new possibilities in therapeutics. There is increasing evidence that mood disorders are associated with impairments in neuroplasticity and cellular resilience, and alterations of the glutamatergic system are known to play a major role in cellular plasticity and resilience. Existing antidepressants and mood stabilizers have prominent effects on the glutamate system, and modulating glutamatergic ionotropic or metabotropic receptors results in antidepressant-like properties in animal models. Several glutamatergic modulators targeting various glutamate components are currently being studied in the treatment of mood disorders, including release inhibitors of glutamate, N-methyl-D-aspartate (NMDA) antagonists, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) throughput enhancers, and glutamate transporter enhancers. This paper reviews the currently available knowledge regarding the role of the glutamatergic system in the etiopathogenesis of mood disorders and putative glutamate modulators.

Prevalencia de depresión y factores asociados con ella en la población colombiana / The prevalence of and factors associated with depression in Colombia

OBJETIVOS: Analizar la prevalencia del síndrome depresivo y los factores asociados con la depresión en Colombia entre los años 2000 y 2001. MÉTODOS: Para este estudio descriptivo de corte transversal se aplicó una encuesta entre noviembre de 2000 y enero de 2001 a 1 116 adultos de 18 años de edad o más de uno u otro sexo que residían en viviendas particulares seleccionadas mediante un muestreo representativo nacional polietápico, estratificado según el grado de urbanización del área incluida en el muestreo. La depresión se clasificó en breve, subclínica o clínica (leve, moderada o grave) en los 30 días y los 12 meses previos a la entrevista. Se calcularon las frecuencias simples y estratificadas por la edad y el sexo, y los intervalos de confianza de 95 por ciento (IC95 por ciento) de más de 500 variables. La asociación de las variables seleccionadas con episodios depresivos se evaluó mediante un modelo de regresión logística con múltiples variables. RESULTADOS: De las personas estudiadas, 10,0 por ciento (IC95 por ciento: 9,2 a 10,7) presentaron algún episodio depresivo en los 12 meses previos a la encuesta y 8,5 por ciento (IC95 por ciento: 7,8 a 9,2) sufrieron alguno durante el último mes. Hubo una mayor proporción de mujeres con depresión en ambos períodos. Más de 50 por ciento de los episodios fueron moderados, tanto en hombres como en mujeres, y las mayores prevalencias se encontraron en las personas mayores de 45 años. Los factores asociados con la depresión en el último mes fueron ser mujer, considerar el estado de salud propio como regular o malo, sufrir de dolores o molestias, tener dificultades en las relaciones interpersonales, consumir marihuana o sustancias adictivas, medicamentos estimulantes o calmantes, tener dependencia del alcohol, o estar desempleado con discapacidad. CONCLUSION: La depresión es una afección frecuente en Colombia. Se deben poner en marcha medidas dirigidas a reducir el riesgo de depresión, especialmente en mujeres y en personas mayores de 45 años de edad.

[The prevalence of and factors associated with depression in Colombia]. / Prevalencia de depresión y factores asociados con ella en la población colombiana.

OBJECTIVES: To analyze the prevalence of depression and the factors associated with it in Colombia in 2000 and 2001. METHODS: For this descriptive cross-sectional study a survey was conducted between November 2000 and January 2001 with 1,116 men and women 18 years of age or older who were living in private homes that were selected through a multistage national representative sampling, stratified according to the degree of urbanization of the area included in the sampling. Depression was classified as brief recurrent depression, subclinical depression, or mild, moderate, or serious clinical depressive episodes in the 30 days and in the 12 months prior to the interview. Simple and stratified frequencies of over 500 variables, along with their 95% confidence intervals (95% CIs), were calculated by age and gender. The association that the selected variables had with depressive episodes was evaluated through a multivariate logistic regression model. RESULTS: Of the persons studied, 10.0% of them (95% CI: 9.2% to 10.7%) had had a depressive episode in the 12 months prior to the survey, and 8.5% (95% CI: 7.8% to 9.2%) had suffered a depressive episode in the preceding month. There was a higher proportion of women with depression in both of the periods. More than 50% of the episodes were moderate, in both men and women. There were higher prevalences of depression in persons older than 45 years. The factors associated with depression in the preceding month were: female gender; considering one's health to be moderate or bad; suffering from pain or discomfort; having difficulties in interpersonal relations; consuming marijuana, addictive substances, stimulants, or tranquilizers; being dependent on alcohol; and being unemployed and unable to work. CONCLUSIONS: Depression is a frequent disorder in Colombia. Measures directed at reducing the risk of depression should be implemented, especially among women and in persons over 45 years old.

Suicidio y lesiones autoinflingidas Colombia, 1973-1996 / Suicide and selfinjuries Colombia 1973-1996

Objetivos: (1) describir la mortalidad por suicidio y lesiones autoinfligidas desde 1973 hasta 1996, basándonos en los datos emanados del certificado de defunción del DAÑE. (2) Establecer los factores asociados al suicidio en la población colombiana, utilizando modelos de regresión logística. Diseño: análisis secundario de los registros de defunción del DAÑE (1973- 1996). Resultados: entre las variables sociodemográfícas estudiadas para el lapso 1973-1996 encontramos que la mayor proporción de muertes causadas por suicidio se presentó dentro del grupo de 15 a 24 años, para las mujeres, y mayores de 60 años, para los hombres. La tasa de suicidio fue de 2-4/100.000 para ambos géneros y para todos los grupos de edad durante estos años, y osciló entre 4-6/100.000 para hombres y de 1-3/100.000 para mujeres. Las cifras aumentan a 4-5/100.000 para personas mayores de 15 años. Se presentan los modelos de asociación para 3 años (1985, 1993 y 1996), en los cuales se observó durante 1996 un OR = 54,4 (IC 95 por ciento: 38,4-77,1, p> 0,05) para el grupo de 15 a 24 años, y de 8,7 (6,1-12,3) para aquellos de 25 a 59 años. Para los hombres se calculó un OR = 3,1(2,7-3,6), así como un OR = 0,4 (0,3-0,5) para la zona urbana. Igualmente, se describen otras proporciones y asociaciones de importancia