Implicación del polimorfismo genético del transportador de serotonina (5-htt) en la susceptibilidad a la depresión mayor

Introducción. La depresión mayor es una enfermedad frecuente y compleja de origen poligénico. Dada su importancia en la fisiopatología y terapéutica de la enfermedad, se ha demostrado que el gen que codifica para el transportador de serotonina (5-HTT) está asociado con el desarrollo de la enfermedad. Se realizó un estudio para evaluar la asociación entre polimorfismos del gen 5-HTT y trastorno depresivo mayor. Métodos. Estudio de casos y controles pareados 1:1. Los participantes se clasificaron a partir de la entrevista estructurada del DSM-IV-TR. Los resultados fueron analizados con OR de McNemar y ji-cuadrado y pruebas exactas pareadas. Se utilizó la regresión logística condicional. Se evaluó la presencia de Equilibrio de Hardy-Weinberg con ji-cuadrado de Pearson. Resultados. Se evaluaron 69 casos y 69 controles, cuyas características socio-demográficas y clínicas fueron similares a lo reportado previamente en la literatura. La muestra se encontraba en equilibrio de Hardy-Weinberg. No se encontró asociación estadísticamente significativa entre trastorno depresivo mayor y polimorfismos del gen 5-HTT en general, aunque se encontró la asociación en sujetos de 37 años y menos. Conclusión. Los resultados son similares a lo previamente reportado por otros estudios en pacientes colombianos con trastorno bipolar, lo cual sugiere que en esta población no hay asociación entre trastornos afectivos y polimorfismos del gen 5-HTT. Se necesitan más estudios en el área.

New Generation Antidepressants in Painful Diabetic Neuropathy

The incidence of diabetic neuropathy increases with the duration of diabetes and the degree of hyperglycaemia. Pain is one of the most common and incapacitating symptoms of diabetic neuropathy and its pharmacological control is complex. The effectiveness of antidepressive agents has been described in different types of neuropathic pain, but their effectiveness, when used as analgesics in painful diabetic neuropathy, still remains controversial. Objective: To review the possible role of new-generation antidepressive agents in the treatment of pain in diabetic peripheral neuropathy. This work has thus consisted of a meta-analysis for determining which antidepressive agent had the best analgesic potential in managing pain in patients suffering from painful diabetic neuropathy. Methods: This search covered the Cochrane, MEDLINE, EMBASE and LILACS databases, between January 2000 and August 2007. The following information was obtained from each article: criteria for diagnosing diabetic neuropathy, patients' age average, antidepressant drug received and dose, sample size, duration of the disease and treatment follow-up, outcome measurement, evaluation of pain and rescue medication. Results: A combined RR: 1.67 (95% CI 1.38 - 2.02) was obtained; this result indicated that the antidepressive agent duloxetine, was effective for controlling pain in diabetic neuropathy. The corresponding NNT for Duloxetine was established, according to our interests; NNT = 6 (95% CI 5- 8) for achieving greater than 50% analgesia in patients suffering from painful diabetic neuropathy. Discussion: Antidepressive agents are frequently employed in the specific case of diabetic neuropathy; their analgesic benefit has been demonstrated.

Evidencia actual sobre características demográficas en mastitis granulomatosa idiopática

Introducción: La mastitis granulomatosa idiopática es una enfermedad crónica benigna, rara y de etiología desconocida; tiende a confundirse con otras enfermedades debido a síntomas similares. Este estudio pretende identificar y cuantificar las características demográficas, los antecedentes ginecoobstétricos relevantes y las manifestaciones clínicas prediagnósticas de esta enfermedad Metodología: Se realizó una revisión sistemática con análisis agrupado de datos tipo meta análisis. Se utilizó una estrategia de búsqueda en PubMed. Todos los estudios relacionados con la definición, manifestaciones clínicas, diagnóstico, tratamiento y pronóstico de la mastitis granulomatosa idiopática fueron elegibles. Las variables de interés fueron edad, país, antecedente de contracepción hormonal, tiempo de evolución, tiempo desde el último embarazo, diagnóstico inicial, y manifestaciones clínicas previas a la consulta. No hubo restricción en fechas de publicación. Resultados: Fueron incluidas 641 mujeres con diagnóstico de MGI reportadas en 68 publicaciones que cumplieron los criterios de selección. La edad media fue 35.9 años, 14.1% de ellas estaba embarazada o lactando, el antecedente de consumo de anticonceptivos hormonales fue 21% y el tiempo promedio desde el último parto fue de 3.9 años. La afectación ocurre principalmente en mama izquierda y en cuadrante superoexterno. El cáncer de mama y el absceso mamario son diagnósticos diferenciales en la consulta. Discusión: El diagnóstico de MGI es un reto para el ginecólogo desde la consulta inicial. Debido a que sus manifestaciones clínicas no son específicas, su diagnóstico parece apuntar a la necesidad de un proceso de descarte de otras patologías más frecuentes e incluso de peor pronóstico. Palabras clave mastitis granulomatosa idiopática

Eficacia de la estimulación magnética transcraneal en la disminución de severidad en el trastorno depresivo mayor en monoterapia y coadyuvante comparado con tratamientos farmacológicos. Revisión sistemática y meta-análisis

Resumen Introducción Una posible opción de tratamiento para el manejo del trastorno depresivo mayor (TDM) es la estimulación magnética transcraneal (EMT) que ha mostrado propiedades antidepresivas superiores al placebo con un buen perfil de seguridad. El objetivo del presente trabajo es determinar la reducción en la severidad del TDM y la proporción de eventos adversos (EA) en pacientes con TDM refractario y no refractario, posterior al uso de EMT administrada en monoterapia o tratamiento coadyuvante comparado con terapia farmacológica. Metodología Se planteó una pregunta PICOT de la cual se realizó una búsqueda sistemática de estudios clínicos en las bases de datos Medline, EMBASE y Cochrane. Dos investigadores en forma independiente realizaron la selección de artículos, evaluación de calidad con la herramienta de la colaboración Cochrane y extracción de datos. Se extrajeron datos de eficacia como tasa de respuesta, porcentaje de remisión, calidad de vida, diminución sintomática del trastorno depresivo mayor en la escala de Hamilton y capacidad funcional. Igualmente, proporción de pacientes con EA. Se realizó un meta-análisis de estas variables teniendo en cuenta la heterogeneidad. Resultados La presente revisión sistemática incluyó 26 estudios clínicos aleatorizados de baja calidad metodológica mostrando que la EMT presentó una eficacia superior cuando es usada como coadyuvante a las terapias con que venían siendo tratados los pacientes con TDM refractario y no refractario en los desenlaces de tasa de respuesta y porcentaje de remisión. En el caso de intervenciones farmacológicas específicas, la EMT presento eficacia similar, tanto en terapia coadyuvante como en monoterapia comparado con las intervenciones farmacológicas. En cuanto a seguridad, la EMT presenta un buen perfil de seguridad debido a que en todos los escenarios estudiados los EA fueron no serios y baja frecuencia Conclusiones La evidencia disponible sugiere que la EMT mostró ser efectivo y seguro para el manejo del TDM refractario y no refractario. Sin embargo, la evidencia es débil por lo tanto se necesita mayor investigación clínica que soporte su uso.

A pilot randomised, open, uncontrolled, clinical study of two dosages of St John's wort (Hypericum perforatum) herb extract (LI-160) as an aid to motivational/behavioural support in smoking cessation

There is an association between smoking and depression, yet the herbal antidepressant St John's wort (Hypericum perforatum L.: SJW) herb extract has not previously been investigated as an aid in smoking cessation. In this open, uncontrolled, pilot study, 28 smokers of 10 or more cigarettes per day for at least one year were randomised to receive SJW herb extract (LI-160) 300mg once or twice daily taken for one week before and continued for 3 months after a target quit date. In addition, all participants received motivational/behavioural support from a trained pharmacist. At 3 months, the point prevalence and continuous abstinence rates were both 18%, and at 12 months were 0%. Fifteen participants (54%) reported 23 adverse events up to the end of the 3-month follow-up period. There was no statistically significant difference in the frequency of adverse events for participants taking SJW once or twice daily (p > 0.05). Most adverse events were mild, transient and non-serious. This preliminary study has not provided convincing evidence that a SJW herb extract plus individual motivational/behavioural support is likely to be effective as an aid in smoking cessation. However, it may be premature to rule out a possible effect on the basis of a single, uncontrolled pilot study, and other approaches involving SJW extract may warrant investigation.

Perceptions of psychological content in the GP consultation - the role of practice, personal and prescribing attributes

Objective: The aim of the present study was to determine the relationship between the characteristics of general practices and the perceptions of the psychological content of consultations by GPs in those practices. Methods: A cross-sectional survey was conducted of all GPs (22 GPs based in nine practices) serving a discrete inner city community of 41 000 residents. GPs were asked to complete a log-diary over a period of five working days, rating their perception of the psychological content of each consultation on a 4-point Likert scale, ranging from 0 (no psychological content) to 3 (entirely psychological in content). The influence of GP and practice characteristics on psychological content scores was examined. Results: Data were available for every surgery-based consultation (n = 2206) conducted by all 22 participating GPs over the study period. The mean psychological content score was 0.58 (SD 0.33). Sixty-four percent of consultations were recorded as being without any psychological content; 6% were entirely psychological in content. Higher psychological content scores were significantly associated with younger GPs, training practices (n = 3), group practices (n = 4), the presence of on-site mental health workers (n = 5), higher antidepressant prescribing volumes and the achievement of vaccine and smear targets. Training status had the greatest predictive power, explaining 51% of the variation in psychological content. Neither practice consultation rates, GP list size, annual psychiatric referral rates nor volumes of benzodiazepine prescribing were related to psychological content scores. Conclusion: Increased awareness by GPs of the psychological dimension within a consultation may be a feature of the educational environment of training practices.

Increases in prefrontal cortex activity when regulating negative emotion predicts symptom severity trajectory over six months in depression

Context: Emotion regulation is critically disrupted in depression and use of paradigms tapping these processes may uncover essential changes in neurobiology during treatment. In addition, as neuroimaging outcome studies of depression commonly utilize solely baseline and endpoint data – which is more prone to week-to week noise in symptomatology – we sought to use all data points over the course of a six month trial. Objective: To examine changes in neurobiology resulting from successful treatment. Design: Double-blind trial examining changes in the neural circuits involved in emotion regulation resulting from one of two antidepressant treatments over a six month trial. Participants were scanned pretreatment, at 2 months and 6 months posttreatment. Setting: University functional magnetic resonance imaging facility. Participants: 21 patients with Major Depressive Disorder and without other Axis I or Axis II diagnoses and 14 healthy controls. Interventions: Venlafaxine XR (doses up to 300mg) or Fluoxetine (doses up to 80mg). Main Outcome Measure: Neural activity, as measured using functional magnetic resonance imaging during performance of an emotion regulation paradigm as well as regular assessments of symptom severity by the Hamilton Rating Scale for Depression. To utilize all data points, slope trajectories were calculated for rate of change in depression severity as well as rate of change of neural engagement. Results: Those depressed individuals showing the steepest decrease in depression severity over the six months were those individuals showing the most rapid increases in BA10 and right DLPFC activity when regulating negative affect over the same time frame. This relationship was more robust than when using solely the baseline and endpoint data. Conclusions: Changes in PFC engagement when regulating negative affect correlate with changes in depression severity over six months. These results are buttressed by calculating these statistics which are more reliable and robust to week-to-week variation than difference scores.

SSRI administration reduces resting state functional connectivity in dorso-medial prefrontal cortex

Recent evidence suggests that an area in the dorsal medial prefrontal cortex (dorsal nexus) shows dramatic increases in connectivity across a network of brain regions in depressed patients during the resting state;1 this increase in connectivity is suggested to represent hotwiring of areas involved in disparate cognitive and emotional functions.1, 2, 3 Sheline et al.1 concluded that antidepressant action may involve normalisation of the elevated resting state functional connectivity seen in depressed patients. However, the effects of conventional pharmacotherapy for depression on this resting state functional connectivity is not known and the effects of antidepressant treatment in depressed patients may be confounded by change in symptoms following treatment.

The D2 antagonist sulpiride modulates the neural processing of both rewarding and aversive stimuli in healthy volunteers.

Rationale: Animal studies indicate that dopamine pathways in the ventral striatum code for the motivational salience of both rewarding and aversive stimuli, but evidence for this mechanism in humans is less established. We have developed a functional magnetic resonance imaging (fMRI) model which permits examination of the neural processing of both rewarding and aversive stimuli. Objectives: The aim of the study was to determine the effect of the dopamine receptor antagonist, sulpiride, on the neural processing of rewarding and aversive stimuli in healthy volunteers. Methods: We studied 30 healthy participants who were randomly allocated to receive a single dose of sulpiride (400 mg) or placebo, in a double-blind, parallel-group design. We used fMRI to measure the neural response to rewarding (taste or sight of chocolate) and aversive stimuli (sight of mouldy strawberries or unpleasant strawberry taste) 4 h after drug treatment. Results: Relative to placebo, sulpiride reduced blood oxygenation level-dependent responses to chocolate stimuli in the striatum (ventral striatum) and anterior cingulate cortex. Sulpiride also reduced lateral orbitofrontal cortex and insula activations to the taste and sight of the aversive condition. Conclusions: These results suggest that acute dopamine receptor blockade modulates mesolimbic and mesocortical neural activations in response to both rewarding and aversive stimuli in healthy volunteers. This effect may be relevant to the effects of dopamine receptor antagonists in the treatment of psychosis and may also have implications for the possible antidepressant properties of sulpiride.

6-Sulfatoxymelatonin as a predictor of clinical outcome in depressive patients

Objectives This study established the value of the 6-sulfatoxymelatonin (aMT6s) urine concentration as a predictor of the therapeutic response to noradrenaline reuptake inhibitors in depressive patients. Methods Twenty-two women aged 18-60 years were selected. Depressive symptoms were assessed by using the Hamilton Depression Scale. Urine samples were collected at 0600-1200 h, 1200-1800 h, 1800-2400 h, and 2400-0600 h intervals, 1 day before and 1 day after starting on the nortriptyline treatment. Urine aMT6s concentration was analyzed by a one-way analysis of variance/Bonferroni test. Spearman`s rank correlation coefficient was used to analyze the correlation between depressive symptoms after 2 weeks of antidepressant treatment and the increase in aMT6s urine concentration. Results Higher and lower size effect groups were compared by independent Student`s t-tests. At baseline, the 2400- to 0600-h interval differed from all other intervals presenting a significantly higher aMT6s urine concentration. A significant difference in aMT6s urine concentrations was found 1 day after treatment in all four intervals. Higher size effect group had lower levels of depressive symptoms 2 weeks after the treatment. A positive correlation between depressive symptoms and the delta of aMT6s in the 2400-0600h interval was observed. Conclusion Our results reinforce the hypothesis that aMT6s excretion is a predictor of clinical outcome in depression, especially in regard to noradrenaline reuptake inhibitors. Copyright (C) 2011 John Wiley & Sons, Ltd.

Effect of antidepressants on melatonin metabolite in depressed patients

Antidepressants increase melatonin levels, but it is still unclear whether this effect is related to the improvement of depressive symptoms or to unrelated pharmacological action of antidepressants. To answer this question, the effect of antidepressants on 6-sulphatoxymelatonin (aMT6s), the main melatonin urinary metabolite, was examined in drug-free depressed patients - most of them antidepressant-naive. aMT6s was evaluated in 34 depressed patients, before and after 8 weeks of placebo (n = 12) or antidepressant (n = 22; fluoxetine, duloxetine or Hypericum perforatum). Both groups showed an improvement of depressive symptoms after treatment compared to baseline (Hamilton Depression scores): 17.0 +/- 1.4 vs. 9.0 +/- 2.8, P = 0.007 for placebo, and 18.6 +/- 1.1 vs. 11.8 +/- 1.6, P < 0.001 for antidepressants). After treatment, aMT6s levels increased after antidepressants (P < 0.01), but not after placebo (P > 0.05). As depressive symptoms improved both in patients taking antidepressant and in those taking placebo, but an effect of antidepressants could only be seen in those taking antidepressants, we suggest that melatonin changes after antidepressants are more likely due to a pharmacological action of these drugs on melatonin secretion.

Two-dimensional QSAR studies on arylpiperazines as high-affinity 5-HT(1A) receptor ligands

5-HT(1A) receptor plays an important role in the delayed onset of antidepressant action of a class of selective serotonin reuptake inhibitors. Moreover, 5-HT(1A) receptor levels have been shown to be altered in patients suffering from major depression. In this work, hologram quantitative structure-activity relationship (HQSAR) studies were performed on a series of arylpiperazine compounds presenting affinity to the 5-HT(1A) receptor. The models were constructed with a training set of 70 compounds. The most significant HQSAR model (q(2) = 0.81, r(2) = 0.96) was generated using atoms, bonds, connections, chirality, and donor and acceptor as fragment distinction, with fragment size of 6-9. Predictions for an external test set containing 20 compounds are in good agreement with experimental results showing the robustness of the model. Additionally, useful information can be obtained from the 2D contribution maps.

A chemometric study of the 5-HT1A receptor affinities presented by arylpiperazine compounds

Arylpiperazine compounds are promising 5-HT1A receptor ligands that can contribute for accelerating the onset of therapeutic effect of selective serotonin reuptake inhibitors. In the present work, the chemometric methods HCA, PCA, KNN, SIMCA and PLS were employed in order to obtain SAR and QSAR models relating the structures of arylpiperazine compounds to their 5-HT1A receptor affinities. A training set of 52 compounds was used to construct the models and the best ones were obtained with nine topological descriptors. The classification and regression models were externally validated by means of predictions for a test set of 14 compounds and have presented good quality, as verified by the correctness of classifications, in the case of pattern recognition studies, and b, the high correlation coefficients (q(2) = 0.76, r(2) = 0.83) and small prediction errors for the PLS regression. Since the results are in good agreement with previous SAR studies, we can suggest that these findings can help in the search for 5-HT1A receptor ligands that are able to improve antidepressant treatment. (c) 2007 Elsevier Masson SAS. All rights reserved.

Applicatiion of Almost ideal demand system for a pharmaceutical

This thesis is an application of the Almost Ideal Demand System approach of Deaton and Muellbauer,1980, for a particular pharmaceutical, Citalopram, in which GORMAN´s (1971) multi-stage budgeting approach is applied basically since it is one of the most useful approach in estimating demand for differentiated products. Citalopram is an antidepressant drug that is used in the treatment of major depression. As for most other pharmaceuticals whose the patent has expired, there exist branded and generic versions of Citalopram. This paper is aimed to define its demand system with two stage models for the branded version and five generic versions, and to show whether generic versions are able to compete with the branded version. I calculated the own price elasticities, and it made me possible to compare and make a conclusion about the consumers’ choices over the brand and generic drugs. Even though the models need for being developed with some additional variables, estimation results of models and uncompensated price elasticities indicated that the branded version has still power in the market, and generics are able to compete with lower prices. One important point that has to be taken into consideration is that the Swedish pharmaceutical market faced a reform on October 1, 2002, that aims to make consumer better informed about the price and decrease the overall expenditures for pharmaceuticals. Since there were not significantly enough generic sales to take into calculation before the reform, my paper covers sales after the reform.

Investigating the Effects of Mifepristone (RU486) in the Behavioral, Hormonal and Central Responses to Acute Stress

Depression is associated with glucocorticoid hypersecretion, due to dysfunction of the hypothalamo-pituitary-adrenocorticol axis (HPA-axis). Because excess glucocorticoids are associated with depressive-like features in humans, glucocorticoid receptor antagonists are currently being tested for antidepressant efficacy in clinical trials. In the current study the hypothesis that mifepristone (RU486), a glucocorticoid receptor antagonist, would decrease the neuroendocrine and central HPA-axis responses to an acute stressor and attentuate depressive like behavior in an animal model of behavioral helplessness (forced swim test) was tested. Adult male rats were treated with 10 mglkg RU486 (subcutaneous) for five days and then exposed to a IO-minute forced swim test (FST), conducted in Plexiglas cylinders. FST sessions were videotaped for later analysis of behavioral immobility. Plasma ACTH and corticosterone CORT were measured at 15min and 90min after FST cessation. Animals were perfused and brains were collected for immunocytochemical assessment of c-Fos expression in the medial prefrontal cortex (mPFC), a brain region implicated in both depression and central control of the HPA axis. RU486 significantly decreased peak ACTH and CORT concentrations following FST exposure. In addition, glucocorticoid negative feedback was at1enuated in RU486-treated animals exposed to the FST. Exposure to FST alone induced c-FOS expression in the mPFC, as measured by the number of c-Fos positive neurons. Treatment with RU486 significantly increased the number of rnPFC c-Fos positive cell following FST exposure. The behavioral data obtained from FST paradigm, demonstrated that RU486 decreased immobility in the FST illustrating the potential efficacy of this drug as an antidepressant. Collectively these data suggest that RU486 dampens HPA-axis responses to stress, possibly by enhancing the excitability of stress-inhibitory neurons in the mPFC. This is particularly exciting, given the fact that this neural region is associated with decreased neural activity during depression in humans.