Therapeutic Modalities for Treatment Resistant Depression: Focus on Vagal Nerve Stimulation and Ketamine

Treatment resistant depression (TRD) is a global health concern affecting a large proportion of depressed patients who then require novel therapeutic options. One such treatment option that has received some attention in the past several years is vagal nerve stimulation (VNS). The present review briefly describes the relevance of this treatment in the light of other existing pharmacological and non-pharmacological options. It then summarizes clinical findings with respect to the efficacy of VNS. The anatomical rationale for its efficacy and other potential mechanisms of its antidepressant effects as compared to those employed by classical antidepressant drugs are discussed. VNS has been approved in some countries and has been used for patients with TRD for quite some time. A newer, fast-acting, non-invasive pharmacological option called ketamine is currently in the limelight with reference to TRD. This drug is currently in the investigational phase but shows promise. The clinical and preclinical findings related to ketamine have also been summarized and compared with those for VNS. The role of neurotrophin factors, specifically brain derived neurotrophic factor and its receptor, in the beneficial effects of both VNS and ketamine have been highlighted. It can be concluded that both these therapeutic modalities, while effective, need further research that can reveal specific targets for intervention by novel drugs and address concerns related to side-effects, especially those seen with ketamine.

Interação da atividade autonômica e resposta imunomoduladora na fase aguda do infarto do miocárdio experimental / Interaction of autonomic activity and immunomodulatory response in acute experimental myocardial infarction

INTRODUÇÃO: A atuação do sistema nervoso parassimpático em células imunes é conhecida como "Via Anti-inflamatória Colinérgica". Trabalhos prévios demonstraram que a estimulação vagal reduz a inflamação e melhora a sobrevida em modelos experimentais com sepse. Neste estudo avaliamos se o uso do anticolinesterásico piridostigmina: altera o número de linfócitos T (CD4+ e CD8+) convencionais (CD25+Foxp3-) e reguladores (CD25+Foxp3+) no sangue periférico, no baço e no miocárdio; modifica a concentração de citocinas (interleucina 1, interleucina 6, TNFalfa) no miocárdio; e influencia a função ventricular após infarto agudo do miocárdio experimental (IAM) em ratos. MÉTODOS: Utilizamos ratos machos adultos da linhagem Wistar, com peso variando entre 200 e 250 g, divididos em 3 grupos de 20 animais cada: grupo controle (GC), grupo infartado sem tratamento (IC) e grupo infartado tratado com piridostigmina (IP). O infarto agudo do miocárdio (IAM) foi obtido com a técnica da ligadura da artéria coronária esquerda, e o grupo IP recebeu piridostigmina na dose de 40mg/kg/dia na água de beber, iniciada 4 dias antes do IAM. Todos os animais foram submetidos à canulação da artéria femoral no dia seguinte ao IAM para registro das curvas de pressão arterial, e posterior análise dos componentes da variabilidade da freqüência cardíaca (VFC), domínio do tempo (SDNN e RMSSD) e da freqüência (componentes LF e HF); o estudo ecocardiográfico foi realizado no segundo dia pós IAM. No terceiro dia pós IAM, os ratos foram divididos em subgrupos de 10 animais, e sacrificados de forma específica para coleta de materiais: 500 ul de sangue periférico e baço fresco para realização da técnica de citometria de fluxo; ventrículo esquerdo para dosagem de citocinas pela técnica de ELISA; e ventrículo esquerdo para realização de imunohistoquímica. Foram usadas as técnicas padronizadas e de uso corrente nos laboratórios...

INTRODUTION: The role of the parasympathetic nervous system in immune cells is known as "Cholinergic anti-inflammatory pathway". In previous work has demonstrated that vagal stimulation reduces inflammation and improves survival in experimental sepsis models. The aim of the present study evalued the use of anticholinesterase pyridostigmine: change the number of T lymphocytes (CD4+ and CD8+) conventional (CD25+Foxp3-) and regulatory (CD25+Foxp3+) in peripheral blood, spleen, and myocardium: modifies the concentration of cytokines (interleukin-1, interleukin-6, TNFalfa) in the myocardium, and influences ventricular function after experimental myocardial infarction (MI) in rats. METHODS: Adult male rats of Wistar strain, weighing between 200 and 250 g were divided into 3 groups of 20 animals each: control group (GC); untreated group without treatment (IC) and infarcted group treated with pyridostigmine (IP). Acute myocardial infarction (AMI) was obtained with the technique of ligation of the left coronary artery, and the IP group received pyridostigmine dose of 40 mg/Kg/day in drinking water starting 4 days before the AMI. All animals underwent cannulation of the femoral artery on the day following AMI to record the blood pressure curves, and subsequent analysis of the components of heart rate variability (HRV), the time domain (SDNN and RMSSD) and frequency (components LF and HF), the echocardiografic study was performed on the second day after AMI. On the third day post-MI, mice were divided into subgroups of 10 animals, and were sacrificed in order to collet specific materials: 500 ul of fresh peripheral blood and spleen technique for performing flow cytometry left ventricle for measurement of cytokine ELISA, and the left ventricle to perform immunohistochemistry. Techniques used were standardized and commonly used in laboraties. The results were evaluated by analysis of variance (ANOVA) multifactorial, using the GraphPad Prism with Tukey post hoc test...

Estimulación crónica intermitente del nervio vago en el tratamiento de epilepsia refractaria: experiencia en México con 35 casos / Chronic intermittent vagal nerve stimulation in the treatment of refractory epilepsy: experience in Mexico with 35 cases

Introducción: El papel de la estimulación crónica intermitente del nervio vago (ECINV) en el tratamiento de la epilepsia refractaria está evolucionando y requiere precisarse mediante la descripción de resultados, efectos adversos y complicaciones en poblaciones específicas. Material y métodos: Se seleccionaron los pacientes con epilepsia refractaria sometidos a ECINV con mínimo 12 meses de seguimiento, utilizando estadística descriptiva e inferencial para valorar el efecto sobre la frecuencia e intensidad de las crisis, memoria, ánimo, estado de alerta, recuperación postictal y calidad de vida (escala subjetiva, cuestionario QoLIE-31), y los factores (sexo, edad, tiempo de evolución, número/tipo crisis, parámetros de estimulación) asociados a la respuesta clínica. Se describen los parámetros de estimulación usados, empleo del magneto, complicaciones y efectos adversos. Resultados: Se seleccionaron 35 pacientes, edad de cinco a 48 años, 18 con epilepsia parcial, 17 con generalizada. No hubo complicaciones, infección o alteración de la cicatrización en los procedimientos quirúrgicos. La reducción promedio en crisis fue de 55.65 % (p < 0.001). En epilepsias generalizadas hubo 58.8 % de respondedores y 88.9 % en parciales. Cuatro sujetos presentaron mejoría > 90 %, con control total; en dos pacientes aumentó la frecuencia de las crisis. La respuesta al tratamiento fue buena subjetivamente en 33 pacientes. La calificación global de QoLIE-31 aumentó 12.6 puntos (p = 0.020). Solo el tipo de crisis se asoció con la respuesta clínica. Los efectos adversos fueron transitorios y respondieron al cambio de parámetros de estimulación. Conclusiones: la ECINV es segura, bien tolerada y eficaz para el tratamiento paliativo en casos seleccionados de crisis parciales y generalizadas multifocales refractarias.

BACKGROUND: The role of vagal nerve stimulation (VNS) in the treatment of refractory epilepsy is still evolving and requires precision through extensive description of acute and chronic results, adverse effects and complications in specific populations. METHODS: We selected patients with refractory epilepsy subjected to VNS who had completed at least a 12-month followup. Descriptive and inferential statistics were used to review and assess the effects of VNS on seizure frequency/intensity, memory, alertness, mood, postictal recovery, and quality of life (subjective scale, QoL IE-31 inventory) as well as factors (gender, age, age of onset, time of surgery, stimulation parameters, seizure frequency and type) associated with clinical response. We describe stimulation parameters, complications and adverse effects compared to other series. RESULTS: We selected 35 patients with an age range of 5-48 years; 18 patients presented partial epilepsy and 17 generalized epilepsy. All procedures and wound healing were uneventful, and no infections were reported. Median reduction in seizure frequency was 55.65% (p <0.001). Four patients showed improvement of >90%. Two patients became seizure free, whereas seizure frequency increased in two patients. The subjectively qualified response to treatment was good in 33 patients. The mean global increase in the QoLIE-31 Scale was 12.6 (p = 0.020). Improvements in memory, mood, alertness and postictal recovery period were documented. Only seizure type showed statistically significant association with clinical response. Adverse effects were transitory and responded to changes in stimulation parameters. CONCLUSIONS: VNS is a safe, feasible, well-tolerated and effective palliative treatment in appropriately selected cases of refractory partial and multifocal generalized seizures.

Lateral Third Infraclavicular Implantation of the Vagal Nerve Stimulation Generator Through Axillary Incision

OBJECTIVE: This report describes the clinical study of the surgical method of lateral third infraclavicular implantation of vagal nerve stimulation (VNS) generator through the axillary wrinkle incision. METHODS: In a retrospective study, the data for 20 patients with medically intractable epilepsy treated by this approach were examined. The mean age was 31.4 years (range : 14-50), and the mean follow-up period was 12.15 months (range : 4-21 months). The male to female ratio was 2.3 : 1. The subcutaneous pocket for the generator was located in the lateral third infraclavicular area through the axillary wrinkle. Our method was a modification of the standard VNS generator implantation in the mid-infraclavicular pocket through anterior axillary incision. RESULTS: There were the excellent or good cosmetic satisfaction in 95% of the cases and fair in 5%. The generator was located outside the lung field in 15%, periphery of the lung field in 45%, and crossed over the lung field in 40%. Discomfort from shoulder motion occurred transiently in 35% of cases. Other complications were minimal. CONCLUSION: These results demonstrate that the lateral third infraclavicular apporach will offers cosmetic benefits and reduction of obscuration of the lung field without serious complications. Thus, this technique provides an attractive alternative among the surgical techniques for the vagal nerve stimulation.

Estimulación del sistema nervioso para el control de la epilepsia refractaria / Stimulating the nervous system to control refractory epilepsy

Vagal nerve stimulation (VNS), an indirect stimulation of the brain, proved effective in animal models of epilepsy, and then in open, as well as double-blinded trials, in over 450 patients. The benefit, seizure reduction, improved for at least 1 1/2 years with almost 50% of treated patients achieving about a 50% reduction in seizure frequency. Other benefits are: seizure termination and improved mood. Benefits have been shown in children and adults with partial and generalized epilepsies, and in specific epilepsy syndromes. Implantation is easy. The method of action is largely unknown, although VNS appears to alter metabolic activity in specific brain nuclei. The improvement in mood has led to its approved use in patients with severe depression. Deep brain stimulation (DBS) is under investigation as an alternate method for controlling medically refractory seizures. It is based on the observation that thalamic stimulation can influence the EEG over a wide area. Several thalamic nuclei, as well as the amygdalahippocampus complex, caudate nucleus, and substantia nigra, have been the object of stimulation, all holding promise in the treatment of medically refractory epilepsy. Intraoperative brain imaging is essential and the procedure is done under local anesthesia. Experience with DBS is limited, but growing

La estimulación del nervio vago (ENV), una estimulación indirecta del cerebro, demostró ser efectiva en modelos de epilepsia con animales y, posteriormente, en un estudio de tipo abierto y en ensayos a doble ciego con más de 450 pacientes. El beneficio, valorado por la disminución en el número de episodios convulsivos, se mantuvo por al menos un año y medio; aproximadamente el 50% de los pacientes tratados logró una reducción de casi el 50% en la frecuencia de las convulsiones. Otros beneficios fueron: la terminación de las convulsiones y la mejoría en el estado de ánimo. Los beneficios se demostraron en niños y adultos con epilepsias generalizadas y parciales y en síndromes epilépticos específicos. El procedimiento de implante es sencillo. El mecanismo de acción es desconocido, aunque la ENV parece alterar la actividad metabólica en núcleos cerebrales específicos. La mejoría en el estado de ánimo llevó a que su uso fuese aprobado en pacientes con depresión grave. La estimulación cerebral profunda (ECP) está en investigación como método alternativo para el control de las convulsiones refractarias a la medicación. Se basa en que la estimulación talámica puede influir sobre el EEG en un área extensa. Diversos núcleos talámicos, así como el complejo amígdala-hipocampo, el núcleo caudado y la sustancia negra fueron objeto de la estimulación, con resultados promisorios en el tratamiento de la epilepsia refractaria al tratamiento médico. El procedimiento se realiza bajo anestesia local y es esencial la obtención de imágenes cerebrales intraoperatorias. La experiencia con la ECP es limitada, pero creciente